Clinical trial NCT01972217
Conditions: Metastatic Castration-resistant Prostate Cancer
Keywords: Olaparib castration-resistant, metastatic prostate cancer Prior Docetaxel Chemotherapy
Sponsor: AstraZeneca
Start date: 2014-04-01; Completion date: 2023-08-24
Enrollment: 158 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 2-part study in patients with metastatic CRPC. Part A is an open-label safety run-in study to assess the safety, tolerability and pharmacokinetics (PK) of olaparib when given in addition to abiraterone 1000 mg once daily. Part B is a randomised, double-blind, placebo controlled comparison of the efficacy, safety and tolerability of the dose of olaparib selected from Part A when given in addition to abiraterone, versus placebo given in addition to abiraterone. Abiraterone is indicated in combination with prednisone or prednisolone for the treatment of patients with metastatic CRPC. Prednisone or prednisolone 5 mg twice daily (bid) will be administered with the abiraterone in this study.

Detailed description:
This is a 2-part study in patients with metastatic CRPC. Part A is an open-label safety run-in study to assess the safety, tolerability and PK of olaparib when given in addition to abiraterone 1000 mg once daily. Part B is a randomised, double-blind, placebo-controlled comparison of the efficacy, safety and tolerability of the dose of olaparib selected from Part A when given in addition to abiraterone, versus placebo in addition to abiraterone.

Abiraterone is indicated in combination with prednisone or prednisolone for the treatment of patients with metastatic CRPC. Prednisone or prednisolone 5 mg bid will be administered with the abiraterone in this study, but throughout this protocol the treatment will be referred to simply as abiraterone.

For Part A of the study, 15 to 18 evaluable patients (Cohorts 1 and 2) are planned to be enrolled from approximately 4 sites in approximately 1 or 2 countries, and a further 12 patients may be recruited into a 3rd cohort if necessary.

For Part B of the study, approximately 140 patients who have received prior chemotherapy containing docetaxel will be randomised from approximately 40 sites in North America and Europe. Patients who have been dosed in Part A of the study may not participate in Part B.

Arms: arm 1: 200 mg or 300 mg bid arm 2: placebo to match olaparib bid
Interventions: intervention 1: Olaparib intervention 2: Placebo intervention 3: Abiraterone intervention 4: Prednisone or prednisolone
Intervention descriptions: intervention 1: Olaparib bid intervention 2: Placebo bid intervention 3: Abiraterone 1000 mg intervention 4: Prednisone or prednisolone 5 mg bid will be co-administered with the abiraterone in this study.

Protocol documents:
Prot_000.pdf: 


 
2(134) 
PROTOCOL SYNOPSIS 
 
A Randomised, Double-Blind, Placebo-Controlled, Multicentre Phase II 
Study to Compare the Efficacy, Safety and Tolerability of Olaparib Versus 
Placebo When Given in Addition to Abiraterone Treatment in Patients 
With Metastatic Castrate-Resistant Prostate Cancer Who Have Received 
Prior Chemotherapy Containing Docetaxel 
 
 
International Co-ordinating Investigator 
Noel Clarke ChM FRCS(Urol) 
Study centre(s) and number of patients planned 
For Part A of the study, 15 to 18 evaluable patients (Cohorts 1 and 2) are planned to be 
enrolled from approximately 4 sites in 1 or 2 countries; a further 12 patients may be recruited 
into a 3rd cohort if necessary. 
For Part B of the study, approximately 140 patients will be randomised from approximately 
40 sites in North America and Europe. 
Study period 
 
Phase of development 
Estimated date of first patient enrolled 
Q4 2013 
II 
Estimated date of last patient enrolled 
Q2 2015 
 
Estimated date of data cut-off for primary 
analysis of progression-free survival 
Q2 2016 
 
Estimated date of last patient last visit (data 
cut-off for survival analysis) 
Q1 2018 
 
 
Objectives 
Primary 
Part A, Safety run-in 
To assess the safety and tolerability of olaparib when given in addition to abiraterone and to 
recommend, by assessment of dose-limiting toxicities and other safety and tolerability data, a 
dose of olaparib for further study when given in addition to abiraterone. 


Revised Clinical Study Protocol Synopsis 
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
3(134) 
Part B 
To compare the efficacy of olaparib when given in addition to abiraterone, with placebo given 
in addition to abiraterone, by assessment of radiologic progression-free survival (rPFS) using 
Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) and Prostate Cancer 
Working Group 2 (PCWG-2) criteria. 
Secondary 
Part A, Safety run-in 
To evaluate the presence of any drug interaction between olaparib and abiraterone by 
determination of steady state exposure to olaparib in the presence and absence of abiraterone, 
and determination of steady state exposure to abiraterone in the presence and absence of 
olaparib. 
Part B: 
To compare the safety and tolerability of olaparib when given in addition to abiraterone, with 
placebo given in addition to abiraterone. 
To assess the anti-tumour activity of olaparib when given in addition to abiraterone, compared 
with placebo given in addition to abiraterone, by measurement of changes in circulating 
prostate specific antigen (PSA) and circulating tumour cells (CTCs), calculation of overall 
radiological objective response rate (ORR) (by RECIST 1.1 and PCWG-2 bone scan criteria) 
and malignant soft tissue ORR (by RECIST 1.1), time to first subsequent therapy (TFST) for 
prostate cancer, and time to second subsequent therapy (TSST) for prostate cancer. 
To assess the efficacy of olaparib when given in addition to abiraterone, compared with 
placebo given in addition to abiraterone, by assessment of overall survival (OS). 
To assess the efficacy of olaparib when given in addition to abiraterone, compared with 
placebo given in addition to abiraterone, by assessment of time from randomisation to second 
progression (PFS2). 
To investigate BRCA and ATM mutations as candidate predictors of response to olaparib.  
Note: This objective is dependent upon the number of evaluable samples obtained from the 
study. 
Exploratory 
Exploratory objectives include, in brief: to explore of the effects of olaparib compared to 
placebo, when given in addition to abiraterone, on pain and pain interference with daily life, 
bone pain, prostate cancer related symptoms, Health-Related Quality of Life (HRQL), and 
health utilities and resource use; to investigate the impact of treatment and disease progression 
on metastatic castrate-resistant prostate cancer (CRPC) management resource use; possible 
future exploratory research into factors that may influence development of cancer and/or 


Revised Clinical Study Protocol Synopsis 
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
4(134) 
response to treatment, using tumour, CTC, blood and urine samples; to explore whether 
resistance mechanisms to olaparib can be identified through analysis of tumour, CTC, blood 
and urine samples; to collect and store optional DNA samples for future exploratory research 
into genes/genetic variation that may influence response to study treatments and/or 
susceptibility to disease. 
Study design 
This is a 2-part study in patients with metastatic CRPC.  Part A is an open-label safety run-in 
study to assess the safety, tolerability and pharmacokinetics (PK) of olaparib when given in 
addition to abiraterone 1000 mg once daily.  Part B is a randomised, double-blind, placebo-
controlled comparison of the efficacy, safety and tolerability of the dose of olaparib selected 
from Part A when given in addition to abiraterone, versus placebo given in addition to 
abiraterone. 
Abiraterone is indicated in combination with prednisone or prednisolone for the treatment of 
patients with metastatic CRPC.  Prednisone or prednisolone 5 mg twice daily (bid) will be 
administered with the abiraterone in this study, but throughout this protocol the treatment will 
be referred to simply as abiraterone. 
All patients will attend a screening visit within 28 days before starting study treatment. 
Part A: Safety run-in/dose escalation 
Patients will attend the clinic on the first day of study treatment, at 1 and 2 weeks, then every 
4 weeks up to Week 52, and every 12 weeks thereafter. 
Cohort 1 (up to 6 patients) 
At least 3 and up to 6 evaluable patients will be enrolled in Cohort 1.  Patients will receive 
olaparib 200 mg bid and abiraterone 1000 mg once daily.  Dose-limiting toxicities (DLTs) 
will be assessed by a Safety Review Committee (SRC) after a minimum of 14 days’ treatment. 
Cohort 2 (12 patients) 
If the combination of olaparib 200 mg bid and abiraterone 1000 mg once daily is tolerated, a 
cohort of 12 patients (split into 2 groups of 6 patients) will be treated with olaparib 300 mg 
bid given in addition to abiraterone 1000 mg once daily. 
Dose-limiting toxicities will be assessed by the SRC after a minimum of 14 days’ treatment 
with both olaparib and abiraterone. 
Group 1: 
Patients will receive olaparib alone (300 mg bid) for between 3 and 7 days.  Blood samples 
will then be collected to determine the steady state PK profile for olaparib.  Patients will then 
receive abiraterone (1000 mg once daily) starting from the day after the olaparib PK profile 


Revised Clinical Study Protocol Synopsis 
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
5(134) 
has been collected.  Olaparib and abiraterone will continue to be dosed in combination for at 
least 5 days, then blood samples will be collected again to determine both olaparib and 
abiraterone PK profiles. 
Group 2: 
Patients will receive abiraterone alone (1000 mg once daily) for between 5 and 7 days.  Blood 
samples will then be collected to determine the steady state PK profile for abiraterone.  
Patients will receive olaparib (300 mg bid) starting immediately after the 24-hour abiraterone 
PK sample has been collected.  Olaparib and abiraterone will continue to be dosed in 
combination for at least 3 days, then blood samples will be collected again to determine both 
olaparib and abiraterone PK profiles. 
Cohort 3 (12 patients) 
If 4 or more DLTs occur in Cohort 2, a further 12-patient cohort may be recruited and treated 
with olaparib 200 mg bid given in addition to abiraterone 1000 mg once daily and evaluated 
for safety, tolerability and PK as above.  If 4 DLTs occur in this cohort, the study will be 
stopped. 
Part B: Randomised part 
Patients who have been dosed in Part A of the study may not participate in Part B. 
Patients will receive olaparib or placebo (randomisation ratio 1:1), at the dose determined by 
Part A of the study, and abiraterone 1000 mg once daily.  They will attend the clinic on the 
first day of study treatment, then every 4 weeks up to Week 52, and every 12 weeks thereafter. 
Tumour evaluation using RECIST 1.1 and PCWG-2 criteria will be conducted at screening 
and then every 12 weeks from the date of randomisation until objective disease progression 
(every 24 weeks after Week 72).  Patients will be evaluated until disease progression 
regardless of whether study treatment is discontinued, and will then be followed for PFS2 and 
survival. 
An archival tumour sample will be collected, where available, to measure BRCA and ATM 
mutation status; other biomarkers such as ERG expression/fusion status, homologous 
recombination related gene mutations, androgen receptor (AR) and phosphatase and tensin 
homolog (PTEN) may also be measured. 
Blood samples will be collected for measurement of the following: 
• 
PSA 
• 
Biomarkers: where assays are available for measuring markers as a surrogate for 
tumour tissue (urine also may be tested) 


Revised Clinical Study Protocol Synopsis 
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
6(134) 
• 
CTCs: enumeration and characterisation where assays are available for measuring 
markers as a surrogate for tumour tissue. 
Patient reported outcomes (PROs) will be measured using the Brief Pain Inventory – Short 
Form (BPI-SF), an individual item on bone pain and the FACT-P (Functional Assessment of 
Cancer Therapy – Prostate Cancer) questionnaires. 
Both Parts A and B 
Optional blood samples for pharmacogenetic research will be obtained from consenting 
patients and stored for long-term exploratory purposes. 
A follow-up visit will be conducted 30 days (±7 days) after the last dose of study treatment 
(olaparib/placebo or abiraterone). 
Target patient population 
Patients must have a histologically or cytologically proven diagnosis of prostate cancer, and 
be a candidate for abiraterone therapy with documented evidence of metastatic CRPC 
(metastatic status is defined as at least one documented metastatic lesion on either bone scan 
or CT/MRI scan; CRPC is defined as rising PSA or other signs of disease progression despite 
treatment with androgen deprivation therapy and the presence of a castrate level of 
testosterone [50 ng/dL]).  Patients must have an Eastern Cooperative Oncology Group 
(ECOG) performance status of 0 to 2 with no deterioration during the previous 2 weeks.  For 
the randomised phase, patients must have received chemotherapy in the form of docetaxel 
treatment for metastatic CRPC. 
Investigational product and additional study drugs, dosage and mode of administration 
The investigational product (olaparib) and additional study drugs (abiraterone and 
prednisone/prednisolone) should be taken orally with water.  Patients should aim to take their 
doses at similar times each day, with the twice daily doses approximately 12 hours apart.  
Patients must fast (except water) from at least 2 hours before until 1 hour after each dose 
(morning and evening). 
Part A, Cohort 1: 
200 mg olaparib (2 x 100 mg tablets) bid. 
1000 mg abiraterone (4 x 250 mg tablets) once daily in the morning and prednisone or 
prednisolone 5 mg (1 x 5 mg tablet) bid. 
Part A, Cohort 2, Group 1: 
300 mg olaparib (2 x 150 mg tablets) bid, starting on Day 1. 
1000 mg abiraterone (4 x 250 mg tablets) once daily, in the morning, and prednisone or 
prednisolone 5 mg bid, starting the day after completion of the olaparib PK profiling. 
Part A, Cohort 2, Group 2: 
1000 mg abiraterone (4 x 250 mg tablets) once daily, in the morning, and prednisone or 


Revised Clinical Study Protocol Synopsis 
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
7(134) 
prednisolone 5 mg bid, starting on Day 1. 
300 mg olaparib (2 x 150 mg tablets) bid, starting after completion of the abiraterone PK 
profiling (after the 24-hour sample). 
Part A, Cohort 3, Groups 1 and 2 (if required): 
200 mg olaparib (2 x 100 mg tablets) bid, as described for Cohort 2, Groups 1 and 2. 
1000 mg abiraterone (4 x 250 mg tablets) once daily, in the morning, and prednisone or 
prednisolone 5 mg bid, as described for Cohort 2, Groups 1 and 2. 
Part B: 
300 mg olaparib or placebo (2 x 150 mg tablets) bid (or 200 mg olaparib/placebo bid, if 
3 cohorts are dosed in Part A). 
1000 mg abiraterone (4 x 250 mg tablets) once daily, in the morning, and prednisone or 
prednisolone 5 mg (1 x 5 mg tablet) bid. 
Duration of treatment 
Patients will continue to receive study treatment until disease progression, or until a time 
when the Investigator considers that they are no longer deriving clinical benefit, or they stop 
taking treatment for any other reason including having met any of the criteria for treatment 
discontinuation. 
Outcome variable(s): 
Primary outcome variables – Part A: 
• 
Safety and tolerability 
− 
Assessment of adverse events (AEs) graded by Common Terminology Criteria 
for Adverse Events (CTCAE) v4.0, vital signs (including blood pressure, 
pulse), and evaluation of laboratory parameters (clinical chemistry and 
haematology). 
− 
Incidence of dose-limiting toxicities (DLTs) 
Primary outcome variables – Part B: 
• 
Efficacy 
− 
rPFS, defined as the time from randomisation to disease progression according 
to RECIST 1.1 (for soft tissue disease) and/or PCWG-2 criteria (for bone 
disease), or death. 


Revised Clinical Study Protocol Synopsis 
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
8(134) 
Secondary outcome variables – Part A: 
• 
Pharmacokinetics 
− 
Olaparib and abiraterone PK parameters (where the data allow): maximum 
plasma concentration at steady state (Cmax ss), time to reach maximum plasma 
concentration at steady state (tmax ss), area under the plasma concentration-time 
curve at steady state (AUCss), minimum plasma concentration at steady state 
(Cmin ss) 
Secondary outcome variables – Part B: 
• 
Efficacy 
− 
Overall survival (OS) 
− 
Time to second progression (PFS2) 
− 
Tumour response in terms of ORR (malignant soft tissue response and overall 
radiological response [malignant soft tissue response by RECIST 1.1 and 
overall radiological response by RECIST 1.1 and PCWG-2]) 
− 
TFST for prostate cancer and TSST for prostate cancer 
• 
Safety and tolerability 
− 
Assessment of AEs graded by CTCAE v4.0, vital signs (including blood 
pressure, pulse), and evaluation of laboratory parameters (clinical chemistry 
and haematology). 
• 
Biomarkers 
− 
Percentage change from baseline in PSA levels and PSA response 
− 
Change in CTC numbers 
− 
BRCA and ATM mutation status; if the number of events in these groups is 
sufficient then the primary analysis of rPFS will be repeated in all BRCA and 
ATM mutation positive patients. 
Exploratory outcome variables: 
Exploratory outcome variables (Part B) will include, in brief: PROs including BPI-SF pain 
scores, worst bone pain item and FACT-P scores; pharmacogenetic correlates for the response 
to olaparib; changes in health utilities (as measured by EuroQuol-5 Dimensions, five level 
[EQ-5D-5L]); health economics outcomes; PTEN and AR status, and their correlation with 
response to olaparib. 


Revised Clinical Study Protocol Synopsis 
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
9(134) 
Statistical methods 
There is no formal sample size calculation for Part A of the study; an empirically based 
approach, customary to Phase I studies, was used.  The primary endpoint of Part A is to assess 
the safety profile of olaparib, including DLTs, and to identify the recommended dose for 
Part B. 
The primary endpoint of Part B is rPFS.  The sample size of 140 patients will have 80% power 
to detect a significant difference at the 1-sided 10% level after 100 events have occurred in the 
full analysis set, if the assumed true treatment effect was hazard ratio (HR) 0.65.  This 
translates to a 3.75 month benefit in median rPFS on olaparib given with abiraterone 
compared to placebo given with abiraterone.  A log-rank test and Kaplan-Meier summaries 
will be undertaken for the primary and sensitivity analyses of rPFS, and all other secondary 
and exploratory time-to endpoints. 
The secondary endpoint in Part A is the estimation of PK parameters to evaluate the presence 
of any drug-drug interaction (DDI) between olaparib and abiraterone.  For inclusion in the 
evaluation of a DDI, patients must have provided steady state PK profiles both for 
olaparib/abiraterone alone and in combination, and had no protocol violations affecting the PK 
endpoint. 
In Part B, OS will be analysed after approximately 60% deaths have occurred in the full 
analysis set. 
Other secondary endpoints are safety (AEs, laboratory safety assessments, vital signs; these 
will be summarised using the safety analysis set), tumour response (PSA, CTC; descriptive 
statistics will be presented using the full analysis set), and efficacy endpoints (PFS2, ORR, 
TFST, TSST; these will use the full analysis set for time-to analyses and logistic regression of 
ORR). 
In Part B only, if sufficient evaluable samples are obtained, analyses of rPFS will be 
undertaken for patients with positive ERG expression/fusion status and BRCA mutations.  
Other markers including PTEN, AR, disease related biomarkers, demographic and disease 
characteristics may be looked at in exploratory analyses.  Other exploratory endpoints include 
PRO endpoints, which will be summarised using the full analysis set. 
 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
10(134) 
TABLE OF CONTENTS 
PAGE
 
TITLE PAGE ............................................................................................................................ 1 
PROTOCOL SYNOPSIS ......................................................................................................... 2 
TABLE OF CONTENTS ....................................................................................................... 10 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................... 18 
1. 
INTRODUCTION ................................................................................................. 23 
1.1 
Background ............................................................................................................ 23 
1.1.1 
Prostate cancer ....................................................................................................... 23 
1.1.2 
Olaparib and PARP inhibition ............................................................................... 23 
1.1.3 
Rationale for olaparib in prostate cancer ............................................................... 23 
1.1.4 
Pre-clinical experience ........................................................................................... 24 
1.1.5 
Toxicology and safety pharmacology summary .................................................... 24 
1.1.6 
Clinical experience ................................................................................................. 25 
1.1.6.1 
Patient experience .................................................................................................. 25 
1.1.6.2 
Clinical pharmacokinetics ...................................................................................... 25 
1.2 
Research hypothesis ............................................................................................... 25 
1.3 
Rationale for conducting this study ....................................................................... 26 
1.4 
Benefit/risk and ethical assessment ....................................................................... 27 
2. 
STUDY OBJECTIVES .......................................................................................... 27 
2.1 
Primary objectives ................................................................................................. 27 
2.2 
Secondary objectives ............................................................................................. 28 
2.3 
Exploratory objectives ........................................................................................... 30 
3. 
STUDY PLAN AND PROCEDURES .................................................................. 31 
3.1 
Overall study design and flow chart ...................................................................... 31 
3.1.1 
Part A: Safety run-in/dose escalation ..................................................................... 32 
3.1.1.1 
Cohort 1 (up to 6 patients) ..................................................................................... 32 
3.1.1.2 
Cohort 2 (12 patients) ............................................................................................ 33 
3.1.1.3 
Cohort 3 (12 patients) ............................................................................................ 34 
3.1.1.4 
Definition of dose-limiting toxicity ....................................................................... 34 
3.1.2 
Part B: Randomised part ........................................................................................ 34 
3.1.3 
Discontinuation ...................................................................................................... 35 
3.1.4 
30-Day follow-up ................................................................................................... 36 
3.1.5 
Survival follow-up (Part B only) ........................................................................... 36 
3.1.6 
Safety Review Committee (SRC) .......................................................................... 37 
3.2 
Rationale for study design, doses and control groups ............................................ 55 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
11(134) 
3.2.1 
Patient population .................................................................................................. 55 
3.2.2 
Dose ....................................................................................................................... 55 
3.2.3 
Part A ..................................................................................................................... 55 
3.2.4 
Part B ..................................................................................................................... 56 
3.2.4.1 
Randomisation and blinding .................................................................................. 56 
3.2.4.2 
Choice of endpoints ............................................................................................... 56 
3.2.4.3 
Use of placebo and abiraterone .............................................................................. 56 
3.2.4.4 
Rationale for patient reported outcomes (PROs) ................................................... 57 
3.2.4.5 
Rationale for health economics: utilities and resource use .................................... 57 
3.2.4.6 
Rationale for biomarkers ........................................................................................ 58 
3.2.4.7 
Rationale for pharmacogenetic samples ................................................................ 58 
4. 
PATIENT SELECTION CRITERIA ..................................................................... 58 
4.1 
Inclusion criteria .................................................................................................... 58 
4.2 
Exclusion criteria ................................................................................................... 59 
5. 
STUDY CONDUCT .............................................................................................. 62 
5.1 
Restrictions during the study ................................................................................. 62 
5.2 
Patient enrolment and randomisation and initiation of investigational 
product ................................................................................................................... 62 
5.2.1 
Procedures for enrolment ....................................................................................... 62 
5.2.1.1 
Part A ..................................................................................................................... 62 
5.2.1.2 
Part B ..................................................................................................................... 63 
5.2.2 
Procedures for randomisation (Part B only) .......................................................... 63 
5.3 
Procedures for handling patients incorrectly enrolled or randomised or 
initiated on investigational product ........................................................................ 64 
5.4 
Blinding and procedures for unblinding the study ................................................. 64 
5.4.1 
Methods for ensuring blinding ............................................................................... 64 
5.4.2 
Methods for unblinding the study .......................................................................... 64 
5.5 
Treatments .............................................................................................................. 65 
5.5.1 
Identity of investigational product(s) ..................................................................... 65 
5.5.2 
Doses and treatment regimens – overview ............................................................ 65 
5.5.3 
Doses and treatment regimens – olaparib/placebo ................................................. 66 
5.5.3.1 
Part A ..................................................................................................................... 66 
5.5.3.2 
Part B ..................................................................................................................... 67 
5.5.4 
Additional study drug – abiraterone and prednisone/prednisolone ....................... 67 
5.5.4.1 
Part A ..................................................................................................................... 68 
5.5.4.2 
Part B ..................................................................................................................... 68 
5.5.5 
Labelling ................................................................................................................ 68 
5.5.6 
Storage ................................................................................................................... 69 
5.6 
Concomitant and post-study treatment(s) .............................................................. 69 
5.6.1 
Olaparib and drug-drug interactions ...................................................................... 69 
5.6.2 
Other concomitant medications ............................................................................. 70 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
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5.6.3 
Palliative radiotherapy ........................................................................................... 71 
5.6.4 
Administration of other anti-cancer agents ............................................................ 71 
5.6.5 
Live virus and bacterial vaccines ........................................................................... 71 
5.6.6 
Abiraterone, prednisone and prednisolone interactions ......................................... 72 
5.7 
Treatment compliance ............................................................................................ 72 
5.7.1 
Accountability ........................................................................................................ 72 
5.8 
Discontinuation of investigational product ............................................................ 73 
5.8.1 
Procedures for discontinuation of a patient from investigational product ............. 73 
5.8.1.1 
Discontinuation of olaparib/placebo only .............................................................. 74 
5.8.1.2 
Discontinuation of abiraterone only ....................................................................... 74 
5.9 
Withdrawal from study .......................................................................................... 74 
5.10 
Guidance for Investigators ..................................................................................... 75 
5.10.1 
Dose reduction and toxicity management strategy ................................................ 75 
5.10.1.1 Management of toxicity of study treatment ........................................................... 76 
5.10.1.2 Management of anaemia ........................................................................................ 76 
5.10.1.3 Management of neutropenia and leukopenia ......................................................... 77 
5.10.1.4 Management of thrombocytopenia ........................................................................ 77 
5.10.1.5 Management of prolonged haematological toxicities while on study 
treatment ................................................................................................................ 77 
5.10.1.6 Management of new or worsening pulmonary symptoms ..................................... 78 
5.10.1.7 Management of nausea and vomiting .................................................................... 78 
5.10.1.8 Interruptions for intercurrent non-toxicity related events ...................................... 78 
5.10.1.9 Dose management of abiraterone and prednisone/prednisolone............................ 79 
6. 
COLLECTION OF STUDY VARIABLES ........................................................... 79 
6.1 
Recording of data ................................................................................................... 79 
6.2 
Data collection at enrolment and follow-up ........................................................... 80 
6.2.1 
Post-treatment ........................................................................................................ 80 
6.3 
Efficacy .................................................................................................................. 80 
6.3.1 
Measures of tumour progression and response ...................................................... 80 
6.3.1.1 
RECIST 1.1 assessment of soft tissue malignant disease ...................................... 80 
6.3.1.2 
PCWG-2 bone scan ................................................................................................ 82 
6.3.1.3 
Second progression ................................................................................................ 83 
6.3.2 
Overall survival (OS) ............................................................................................. 83 
6.3.3 
Time to subsequent therapies for prostate cancer .................................................. 83 
6.3.4 
Patient management post-primary analysis ........................................................... 83 
6.3.5 
Patient management post-final analysis ................................................................. 84 
6.4 
Safety ..................................................................................................................... 84 
6.4.1 
Definition of adverse events .................................................................................. 84 
6.4.2 
Definitions of serious adverse event ...................................................................... 85 
6.4.3 
Recording of adverse events .................................................................................. 85 
6.4.4 
Reporting of serious adverse events....................................................................... 89 
6.4.5 
Laboratory safety assessment ................................................................................ 90 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
13(134) 
6.4.5.1 
Full haematology assessments for safety ............................................................... 90 
6.4.5.2 
Clinical chemistry assessments for safety .............................................................. 91 
6.4.5.3 
Bone marrow or blood cytogenetic samples .......................................................... 91 
6.4.6 
Physical examination ............................................................................................. 92 
6.4.7 
Resting 12-lead ECG ............................................................................................. 92 
6.4.8 
Vital signs .............................................................................................................. 92 
6.4.8.1 
Pulse and blood pressure ........................................................................................ 92 
6.4.8.2 
Body temperature ................................................................................................... 92 
6.4.9 
Safety guidance for the use of abiraterone ............................................................. 92 
6.5 
Patient reported outcomes (PRO) .......................................................................... 93 
6.5.1 
Brief Pain Inventory – Short Form (BPI-SF) ......................................................... 94 
6.5.2 
Bone pain item ....................................................................................................... 94 
6.5.3 
Investigator administration of BPI-SF and bone pain item over the 
telephone ................................................................................................................ 94 
6.5.4 
FACT-P .................................................................................................................. 95 
6.6 
Pharmacokinetics ................................................................................................... 96 
6.6.1 
Collection of samples ............................................................................................. 96 
6.6.2 
Determination of drug concentration ..................................................................... 96 
6.7 
Biomarkers ............................................................................................................. 96 
6.7.1 
Collection of biomarker samples ........................................................................... 96 
6.7.1.1 
Prostate specific antigen (PSA) ............................................................................. 97 
6.7.1.2 
Circulating tumour cells ......................................................................................... 97 
6.7.1.3 
Archival tumour samples for biomarker analysis .................................................. 97 
6.7.1.4 
Blood samples for biomarker analysis ................................................................... 97 
6.7.1.5 
Urine samples for biomarker analysis .................................................................... 98 
6.8 
Pharmacogenetics (optional) .................................................................................. 98 
6.8.1 
Collection of pharmacogenetic samples ................................................................ 98 
6.9 
Health economics ................................................................................................... 98 
6.9.1 
Utilities: EQ-5D-5L ............................................................................................... 98 
6.9.2 
Resource use .......................................................................................................... 98 
7. 
BIOLOGICAL SAMPLING PROCEDURES ....................................................... 99 
7.1 
Volume of blood .................................................................................................... 99 
7.2 
Handling, storage and destruction of biological samples .................................... 101 
7.2.1 
Pharmacokinetic samples ..................................................................................... 101 
7.2.2 
Pharmacogenetic samples (optional) ................................................................... 101 
7.3 
Labelling and shipment of biohazard samples ..................................................... 101 
7.4 
Chain of custody of biological samples ............................................................... 102 
7.5 
Withdrawal of informed consent for donated biological samples ....................... 102 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 103 
8.1 
Ethical conduct of the study ................................................................................. 103 


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8.2 
Patient data protection .......................................................................................... 103 
8.3 
Ethics and regulatory review ............................................................................... 103 
8.4 
Informed consent ................................................................................................. 104 
8.5 
Changes to the protocol and informed consent form ........................................... 104 
8.6 
Audits and inspections ......................................................................................... 105 
9. 
STUDY MANAGEMENT BY ASTRAZENECA .............................................. 105 
9.1 
Pre-study activities ............................................................................................... 105 
9.2 
Training of study site personnel ........................................................................... 106 
9.3 
Monitoring of the study ....................................................................................... 106 
9.3.1 
Source data ........................................................................................................... 107 
9.4 
Study agreements ................................................................................................. 107 
9.4.1 
Archiving of study documents ............................................................................. 107 
9.5 
Study timetable and end of study ......................................................................... 107 
10. 
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE .................... 108 
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA OR DELEGATE .................................................................... 109 
11.1 
Calculation or derivation of efficacy variable(s) ................................................. 109 
11.1.1 
Tumour response rate: malignant soft tissue response (RECIST v1.1) ............... 109 
11.1.2 
Metastatic bone disease status ............................................................................. 110 
11.1.3 
Radiologic progression-free survival (rPFS) ....................................................... 110 
11.1.3.1 Time to second progression (PFS2) ..................................................................... 111 
11.1.4 
Overall survival (OS) ........................................................................................... 111 
11.1.5 
Objective response rate and associated variables ................................................ 111 
11.1.6 
Time to subsequent therapies ............................................................................... 112 
11.2 
Calculation or derivation of safety variable(s) ..................................................... 112 
11.2.1 
Adverse events ..................................................................................................... 112 
11.2.2 
Other significant adverse events .......................................................................... 112 
11.2.3 
Dose-limiting toxicities (DLT) ............................................................................ 112 
11.2.4 
Concomitant medications ..................................................................................... 113 
11.2.5 
Compliance and exposure .................................................................................... 113 
11.3 
Calculation or derivation of patient reported outcome variables ......................... 113 
11.3.1 
Brief Pain Inventory – Short Form (BPI-SF) ....................................................... 113 
11.3.2 
Worst bone pain item ........................................................................................... 114 
11.3.3 
FACT-P ................................................................................................................ 114 
11.4 
Calculation or derivation of pharmacokinetic variables ...................................... 116 
11.5 
Calculation or derivation of biomarker variable(s) .............................................. 117 
11.5.1 
Prostate specific antigen ...................................................................................... 117 
11.5.1.1 PSA response ....................................................................................................... 117 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
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11.5.1.2 PSA changes on continuous scale ........................................................................ 117 
11.5.2 
Circulating tumour cell counts ............................................................................. 117 
11.5.3 
ATM mutation ..................................................................................................... 117 
11.5.4 
BRCA mutation ................................................................................................... 117 
11.5.5 
Further biomarker research analysis .................................................................... 118 
11.6 
Calculation or derivation of pharmacogenetic variables ...................................... 118 
11.7 
Calculation or derivation of health economic variables ....................................... 118 
11.7.1 
Utilities: EQ-5D-5L ............................................................................................. 118 
11.7.2 
Resource use ........................................................................................................ 118 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
BY ASTRAZENECA OR DELEGATE .............................................................. 119 
12.1 
Description of analysis sets .................................................................................. 119 
12.1.1 
Full analysis set .................................................................................................... 119 
12.1.2 
PK analysis set ..................................................................................................... 119 
12.1.3 
Safety analysis sets .............................................................................................. 119 
12.2 
Methods of statistical analyses ............................................................................. 120 
12.2.1 
Efficacy data ........................................................................................................ 120 
12.2.1.1 Radiological progression-free survival ................................................................ 121 
12.2.1.2 Time to second progression (PFS2) ..................................................................... 122 
12.2.1.3 Overall survival (OS) ........................................................................................... 122 
12.2.1.4 Objective response rate ........................................................................................ 123 
12.2.1.5 Time to subsequent therapies ............................................................................... 123 
12.2.2 
Biomarker data (PSA and CTCs) ......................................................................... 123 
12.2.3 
Patient reported outcomes (PRO) ........................................................................ 124 
12.2.4 
Safety data ............................................................................................................ 124 
12.2.4.1 Adverse events ..................................................................................................... 125 
12.2.4.2 Dose-limiting toxicities ........................................................................................ 125 
12.2.4.3 Laboratory data .................................................................................................... 125 
12.2.4.4 Concomitant medications ..................................................................................... 125 
12.2.4.5 Vital signs ............................................................................................................ 126 
12.2.4.6 Other safety variables .......................................................................................... 126 
12.2.4.7 Exposure and compliance .................................................................................... 126 
12.2.5 
PK data (Part A only) ........................................................................................... 126 
12.2.6 
Health economics data ......................................................................................... 127 
12.2.6.1 Utilities: EQ-5D-5L ............................................................................................. 127 
12.2.6.2 Resource use ........................................................................................................ 128 
12.2.7 
Interim analyses (Not applicable) ........................................................................ 128 
12.3 
Determination of sample size ............................................................................... 128 
12.3.1 
Part A ................................................................................................................... 128 
12.3.2 
Part B ................................................................................................................... 128 
12.4 
Data monitoring committee (Not applicable) ...................................................... 129 


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13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ................................................................................................ 129 
13.1 
Medical emergencies and AstraZeneca contacts ................................................. 129 
13.2 
Overdose .............................................................................................................. 129 
13.3 
Pregnancy ............................................................................................................. 130 
13.3.1 
Maternal exposure ................................................................................................ 130 
13.3.2 
Paternal exposure ................................................................................................. 130 
14. 
LIST OF REFERENCES ..................................................................................... 130 
 
LIST OF TABLES 
Table 1 
Primary objectives .................................................................................... 2 
Table 2 
Secondary objectives ................................................................................ 28 
Table 3 
Exploratory objectives .............................................................................. 30 
Table 4 
Study Plan – Part A, Cohort 1 (Olaparib 200 mg bid + 
Abiraterone) .............................................................................................. 43 
Table 5 
Study Plan – Part A, Cohort 2 (Olaparib 300 mg bid + 
Abiraterone) .............................................................................................. 45 
Table 6 
Dosing and PK sampling options for Cohort 2, Group 1 ......................... 48 
Table 7 
Dosing and PK sampling options for Cohort 2, Group 2 ......................... 48 
Table 8 
Study Plan – Part B, Randomised Part ..................................................... 49 
Table 9 
Study plan – Randomised part (follow-up post discontinuation of 
study treatment) ........................................................................................ 53 
Table 10 
Identity of investigational product (Olaparib) .......................................... 65 
Table 11 
Identity of additional study drugs ............................................................. 67 
Table 12 
Management of anaemia  .......................................................................... 76 
Table 13 
Dose reductions for olaparib..................................................................... 79 
Table 14 
Overall PCWG-2 response for bone lesions ............................................. 83 
Table 15 
Volume of blood to be drawn from each patient in Cohort 1,  
Part A ........................................................................................................ 99 
Table 16 
Volume of blood to be drawn from each patient in Cohort 2,  
Part A ...................................................................................................... 100 
Table 17 
Volume of blood to be drawn from each patient in Part B ..................... 100 
Table 18 
Definition of visit response for FACT-P, FAPSI-8, TOI, PCS and 
FWB ....................................................................................................... 115 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
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Table 19 
Overall score response for FACT-P, FAPSI-8, TOI, PCS, FWB ........... 116 
LIST OF FIGURES 
Figure 1 
Study design flow chart ............................................................................ 38 
Figure 2 
Flow chart for Part A, Cohort 1 ................................................................ 39 
Figure 3 
Flow chart for Part A, Cohort 2, Group 1 ................................................. 40 
Figure 4 
Flow chart for Part A, Cohort 2, Group 2 ................................................. 41 
Figure 5 
Flow chart for Part B ................................................................................ 42 
 
LIST OF APPENDICES 
Appendix A 
Signatures (Not Applicable) 
Appendix B 
Additional Safety Information  
Appendix C 
International Airline Transportation Association (IATA) 6.2 Guidance 
Document 
Appendix D 
Pharmacogenetics research 
Appendix E 
Actions required in cases of combined increase of aminotransferase and 
total bilirubin – Hy’s Law 
Appendix F 
Guidelines for Tumour Assessment: RECIST soft tissue and PCWG-2 bone 
lesions 
Appendix G 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Appendix H 
Brief Pain Inventory (Short Form) 
Appendix I 
Bone Pain Item 
Appendix J 
FACT-P 
Appendix K 
EQ-5D-5L Health Questionnaire 
Appendix L 
Acceptable Birth Control Methods 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event (see definition in Section 6.4.1) 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AR 
Androgen receptor 
AST 
Aspartate aminotransferase 
ATM 
Ataxia telangiectasia mutated gene 
AUC 
Area under plasma concentration-time curve from zero to infinity 
AUCss 
Area under the plasma concentration-time curve at steady state 
bid 
Twice daily (Latin: bis die) 
BP 
Blood pressure 
BPI-SF 
Brief Pain Inventory – Short Form 
BRCA 
Breast cancer gene, ie, BRCA1 and BRCA2 
BRCP 
Breast cancer resistance protein 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
Cmax ss 
Maximum plasma concentration at steady state 
Cmin ss 
Minimum plasma concentration at steady state 
CR 
Complete response 
CRF 
Case Report Form 
CRPC 
Castrate-resistant prostate cancer 
CSA 
Clinical Study Agreement 
CSF 
Colony-stimulating factor 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTC 
Circulating tumour cell 
CTCAE 
Common Terminology Criteria for Adverse Event 
%CV 
Coefficient of variation  


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
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Abbreviation or 
special term 
Explanation 
CYP 
Cytochrome P450 
DAE 
Discontinuation of Investigational Product due to Adverse Event 
DCO 
Data cut-off 
DDI 
Drug-drug interaction 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
DSBs 
Double strand breaks 
E-code 
Enrolment code 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EQ-5D-5L 
EuroQuol-5 Dimensions, five level 
ERG 
Erythroblast transformation-specific (ETS) related gene 
ETS 
Erythroblast transformation-specific 
EU 
European Union 
EWB 
Emotional well-being 
FACT-P 
Functional Assessment of Cancer Therapy – Prostate Cancer 
FAPSI-8 
Functional Assessment of Prostate Cancer Symptoms Index 8 
FISH 
Fluorescence in situ hybridisation 
FPI 
First patient in 
FWB 
Functional well-being 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
%GCV 
Geometric %CV 
GMP 
Good Manufacturing Practice 
Hb 
Haemoglobin 
Hct 
Haematocrit 
HR 
Hazard ratio 
HRQL 
Health-Related Quality of Life 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
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Abbreviation or 
special term 
Explanation 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
ICU 
Intensive care unit 
INR 
International normalised ratio 
International 
Co-ordinating 
Investigator 
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally.  
IP 
Investigational Product  
IRB 
Institutional Review Board 
ITT 
Intention to treat 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LHRH 
Luteinising hormone releasing hormone 
LOQ 
Limit of quantification 
LVEF 
Left ventricular ejection fraction 
MATE 
Multidrug and toxin extrusion protein 
mCRPC 
Metastatic Castration Resistant Prostate Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDR1 
Multidrug resistance protein 1 
MRI 
Magnetic resonance imaging 
MUGA 
Multi gated acquisition scan 
NC 
Not calculable 
NCI 
National Cancer Institute 
NE 
Non evaluable 
NED 
No evidence of disease 
NL 
New lesion 
NQ 
Non-quantifiable 
NRS 
Numerical rating scale 
NTL 
Non-target lesion 
OAE 
Other Significant Adverse Event (see definition in Section 11.2.2) 
OAT 
Organic anion transporter 
OATP1B1 
Organic anion transporter protein B1 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
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Abbreviation or 
special term 
Explanation 
OCT1 
Organic cation transporter 1 
ORR 
Objective response rate 
OS 
Overall survival 
PARP 
Polyadenosine 5’-diphosphoribose polymerase 
PCS 
Prostate cancer symptoms 
PCWG-2 
Prostate Cancer Working Group 2 
PD 
Progression of disease 
PFS 
Progression-free survival 
PFS2 
Second progression 
Pgp 
P-glycoprotein 
PGx 
Pharmacogenetic research / pharmacogenetics 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PR 
Partial response 
PRO 
Patient Reported Outcome 
PSA 
Prostate specific antigen 
PTEN 
Phosphatase and tensin homolog 
PWB 
Physical well-being 
QTc 
Corrected QT interval 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumours version 1.1 
rPFS 
Radiologic progression-free survival 
SAE 
Serious adverse event (see definition in Section 6.4.2). 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SD 
Standard deviation 
SRC 
Safety Review Committee 
SSBs 
Single strand breaks 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
SWB 
Social well-being 
TFST 
Time to first subsequent therapy 
TL 
Target lesion 
tmax ss 
Time to reach maximum plasma concentration at steady state 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
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Abbreviation or 
special term 
Explanation 
TMPRSS2 
Transmembrane protease serine 2 
TMPRSS2-ERG 
TMPRSS2 erythroblast transformation-specific (ETS) related gene 
TOI 
Trial outcome index 
TSST 
Time to second subsequent therapy 
UGT 
UDP-glucuronosyltransferase 
ULN 
Upper limit of normal 
WBC 
White blood cells 
WBDC 
Web Based Data Capture 
 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
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1. 
INTRODUCTION 
1.1 
Background 
Investigators should be familiar with the current olaparib Investigator Brochure (IB). 
1.1.1 
Prostate cancer 
Prostate cancer is the most prevalent form of cancer in men in the Western world.  One in 
6 men will be diagnosed with cancer of the prostate during their lifetime and it is the second 
most common cause of male cancer death.  The National Cancer Institute (NCI) have 
estimated that 238,590 men will be diagnosed and 29,720 men will die of cancer of the 
prostate in the United States in 2013.  According to Cancer Research UK, 40,975 men were 
diagnosed with prostate cancer in the UK in 2010, with 10,721 deaths from the disease. 
Castrate-resistant prostate cancer (CRPC) is associated with a broad array of symptoms but is 
predominately characterised by bone pain, fatigue and urinary dysfunction (including 
incontinence, dysuria and increased urinary frequency/urgency) (Gater et al 2011,  
Lindqvist et al 2008).  These symptoms can have a profound impact on men’s daily lives  
and contribute to diminished levels of health-related quality of life (HRQL) observed in this 
population (Eton and Lepore 2002). 
1.1.2 
Olaparib and PARP inhibition 
Olaparib (AZD2281, KU-0059436) is a potent polyadenosine 5’diphosphoribose [poly ADP 
ribose] polymerase (PARP) inhibitor (PARP-1, -2 and -3) that is being developed as an oral 
therapy, both as a monotherapy (including maintenance) and for combination with 
chemotherapy and other anti-cancer agents. 
PARP inhibition is a novel approach to targeting tumours with deficiencies in 
deoxyribonucleic acid (DNA) repair mechanisms.  PARP enzymes are essential for repairing 
DNA single strand breaks (SSBs).  Inhibiting PARPs leads to the persistence of SSBs, which 
are then converted to the more significant DNA double strand breaks (DSBs) during the 
process of DNA replication.  During the process of cell division, DSBs can be efficiently 
repaired in normal cells by homologous recombination repair. 
1.1.3 
Rationale for olaparib in prostate cancer 
Prostate cancer is a heterogeneous disease and androgen deprivation therapy with luteinising 
hormone releasing hormone (LHRH) analogs or orchidectomy is usually initially effective at 
controlling metastatic disease, but patients inevitably progress from an androgen-sensitive to a 
castration-resistant phenotype.  Until recently, effective treatment at this stage has been 
largely limited to docetaxel chemotherapy after studies showed it could improve overall 
survival in this population.  Cabazitaxel, enzalutamide, abiraterone acetate (hereafter referred 
to as abiraterone) and radium-223 (Parker et al 2013) have now been shown to give further 
improvements in time to progression and overall survival when used after docetaxel therapy.  
The optimum strategy for managing patients after docetaxel has not been established, but in 
many countries all 4 of these agents are licensed for use in the post-docetaxel phase of 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
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metastatic CRPC, with enzalutamide and abiraterone, which both target the androgen receptor 
(AR) pathway, being preferred because of their good tolerability profiles and absence of 
chemotherapy-associated side effects.  In Part A of this study, metastatic CRPC patients will 
be recruited irrespective of whether they have already had chemotherapy in order to facilitate 
recruitment to this part of the study. 
Recent pre-clinical data demonstrate a role for PARP-1, distinct from its role in DNA repair, 
in AR-dependent transcriptional signalling.  Specifically relevant to this study is the 
observation that PARP-1 inhibition co-operates with androgen depletion to suppress cell 
proliferation (Schiewer et al 2012).  Furthermore, chromosomal rearrangements placing 
coding region on erythroblast transformation-specific (ETS) genes (eg, ETS-related gene 
[ERG]) occur with high frequency in prostate cancer and result in AR-dependent expression 
of pro-tumourigenic ETS genes.  ERG has been shown to physically interact with PARP-1, 
and PARP-1 inhibition preferentially sensitises ETS over-expressing xenografts to PARP 
inhibition (Brenner et al 2011).  In addition, over-expression of ERG leads to accelerated 
carcinogenesis in mouse prostates with phosphatase and tensin homolog (PTEN) deletion, and 
PTEN loss itself has been suggested to sensitise cells to PARP inhibitors  
(Mendes-Pereira 2009).  Hence, there is a rationale for combination of olaparib with 
abiraterone in prostate cancer and a possibility that this combination may be preferentially 
active based on measures of ETS fusions (eg, ERG expression), AR status and PTEN.  There 
may also be a small number of patients who may benefit due to the presence of a BRCA 
mutation in their tumour.  Although only a small number of patients have germline mutations 
(Castro et al 2013), the number with somatic mutations may be significantly higher  
(Beltran et al 2013).  Recent clinical data suggest that PTEN and TMPRSS2-ERG are not key 
determinants of PARP inhibitor sensitivity in mCRPC but do strongly suggest that mutations 
in DNA repair genes, in particular BRCA2 and ATM, are associated with response to, and 
duration of therapy on, olaparib (Mateo et al 2015). 
This study will evaluate the investigational drug olaparib when given on a background of the 
approved drug abiraterone in patients with metastatic CRPC.  Part A of this study will provide 
an initial assessment of safety/tolerability and potential for pharmacokinetic (PK) interaction 
between the drugs.  For the randomised phase of this study, only post-chemotherapy CRPC 
patients will be studied.  This therefore facilitates a robust assessment of the primary endpoint 
of radiologic progression-free survival (radiologic PFS, rPFS) within a reasonable timeframe 
for a Phase II study. 
1.1.4 
Pre-clinical experience 
The pre-clinical experience is fully described in the current version of the olaparib IB. 
1.1.5 
Toxicology and safety pharmacology summary 
Olaparib has been tested in a standard range of safety pharmacology studies, eg, dog 
cardiovascular and respiratory function tests, and the rat Irwin test.  There were no noticeable 
effects on the cardiovascular or respiratory parameters in the anaesthetised dog or any 
behavioural, autonomic, or motor effects in the rat at the doses studied. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
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Rodent and dog toxicology studies have indicated that the primary target organ of toxicity is 
the bone marrow with recovery seen following withdrawal of olaparib.  Ex vivo studies have 
confirmed that olaparib is cytotoxic to human bone marrow cells. 
Olaparib was not mutagenic in the Ames test but was clastogenic in the Chinese hamster 
ovary (CHO) chromosome aberration test in vitro.  When dosed orally, olaparib also induced 
micronuclei in the bone marrow of rats.  This profile is consistent with the potential for 
genotoxicity in man. 
Reproductive toxicology data indicate that olaparib can have adverse effects on embryofoetal 
survival and development at dose levels that do not induce significant maternal toxicity.  
Further information can be found in the current version of the olaparib IB. 
1.1.6 
Clinical experience 
The clinical experience with olaparib is fully described in the current version of the olaparib 
IB. 
1.1.6.1 
Patient experience 
As of 20 May 2013, an estimated 2034 patients with ovarian, breast, pancreatic, gastric and a 
variety of other solid tumours are estimated to have received treatment with either olaparib 
tablets or capsules across the dose range 10 mg once daily to 600 mg twice daily (bid).  
Olaparib has been given as either monotherapy or combination therapy. 
1.1.6.2 
Clinical pharmacokinetics 
Following administration of single oral doses of the tablet formulation at doses of 25, 50 and 
250 mg (n=6 per cohort), absorption was rapid and slightly more rapid than seen following the 
capsule dose.  The maximum plasma concentration (Cmax) was typically achieved between 
0.5 hours and 2 hours after dosing.  Following the peak, plasma concentrations declined 
biphasically with a terminal half-life (t½) across all 3 dose levels, of between 5 and 9 hours 
(average = 6.97 hours ±1.03 standard deviation [SD]).  Both geometric mean Cmax and area 
under the plasma concentration-time curve from zero to infinity (AUC) increased 
approximately proportionally with dose (8- and 12-fold, respectively, for a 10-fold increase in 
dose).  The mean volume of distribution (Vz/F) of olaparib was 54.9 L ±30.2 SD and the mean 
apparent plasma clearance following oral administration (CL/F) was 5.42 L/h ±2.62 SD. 
Further information on the PK and metabolism of olaparib is provided in the current version 
of the IB. 
1.2 
Research hypothesis 
Administration of olaparib when given in addition to abiraterone will result in greater 
efficacy, as determined by rPFS, in patients with metastatic CRPC than treatment with 
abiraterone alone. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
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1.3 
Rationale for conducting this study 
The primary objective for Part A of this study is to perform an initial evaluation of the safety 
and tolerability of olaparib when given in addition to abiraterone and to establish a 
recommended Phase II combination dose of olaparib with abiraterone.  Secondary objectives 
for Part A include establishing whether there is a drug interaction between olaparib and 
abiraterone. 
Pre-clinical data provide evidence for the role of PARP-1 in mediating AR-dependent gene 
expression.  AstraZeneca therefore believe that olaparib may be used to enhance prostate 
cancer sensitivity to AR-directed therapeutics such as abiraterone, with the potential for 
olaparib therapy on a background of abiraterone being more effective than abiraterone alone.  
The primary objective of the randomised part of this study, Part B, is therefore to assess the 
efficacy of olaparib when given in addition to abiraterone compared with abiraterone alone, as 
measured by rPFS. 
Supportive secondary objectives for the study include the additional assessment of efficacy as 
defined by overall survival (OS) and objective response rate (ORR), the assessment of 
efficacy as defined by time from randomisation to second progression (PFS2), times to first 
and second subsequent therapies for prostate cancer, and the determination of safety and 
tolerability. 
It is important to assess how a patient functions and feels due to their disease and its 
treatment.  This study will also explore patients’ experience of treatment with olaparib when 
given in addition to abiraterone, compared to placebo with abiraterone, by assessment of 
patient-reported symptoms and HRQL using patient reported outcome instruments. 
As part of the clinical drug development program for olaparib, AstraZeneca plans to include 
investigations into variations in pharmacodynamic and exploratory biomarker profiles and 
their relationship to drug effect.  These biomarkers may be derived from DNA, ribonucleic 
acids (RNA), proteins and/or metabolites.  There are many potential benefits of this 
exploratory research, including the possibility to identify patients most likely to benefit from 
treatment, explain outliers or non-responders, or explain adverse reactions related to drug 
exposure.  This research may result in an understanding of the impact of variation between 
individuals and how it can be utilised to bring better drugs to the clinic.  The ability to acquire 
appropriate consent to collect biological samples is of utmost importance in order to establish 
an archive and allow future meta-analysis of data derived from a number of studies with 
olaparib. 
AstraZeneca intends to perform pharmacogenetic research in the olaparib clinical 
development programme to explore how genetic variations may affect the clinical parameters 
associated with olaparib.  Collection of DNA samples from populations with well described 
clinical characteristics may lead to improvements in the design and interpretation of clinical 
studies and possibly, to genetically guided treatment strategies. 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
27(134) 
1.4 
Benefit/risk and ethical assessment 
Once patients with prostate cancer have progressed from an androgen-sensitive to a castration-
resistant phenotype, docetaxel is an accepted first-line treatment, with cabazitaxel, 
enzalutamide and abiraterone indicated in the post-docetaxel phase.  There is a clear clinical 
need to enhance the care of patients who have suffered disease progression during or 
following docetaxel therapy.  Because of abiraterone’s effectiveness in this setting and the 
promise of PARP inhibition enhancing its effects, a randomised trial comparing olaparib plus 
abiraterone to placebo plus abiraterone is appropriate. 
In view of the potential for olaparib, given in addition to abiraterone, to have anti-tumour 
activity in metastatic CRPC population, the current study is designed to allow for patients to 
continue on olaparib/abiraterone therapy until progression of disease.  However, patients may 
stop treatment at any time if they choose to do so or if the Investigator believes it is in the best 
interest of the patient.  Additionally, in the event of unmanageable toxicity, directions for 
reducing or stopping olaparib are provided.  The assessment of HRQL will provide 
information on patients’ experience of the treatment and will be part of the benefit-risk 
assessment. 
The molecular targeting of olaparib to specific subsets of tumours may provide an opportunity 
for more effective and potentially less toxic cancer treatments in the advanced disease setting 
compared with currently available regimens.  Based on the available data on efficacy and 
safety (see the olaparib IB), AstraZeneca believes that olaparib continues to demonstrate an 
overall positive benefit-risk balance to support its further clinical development.  The benefit-
risk assessment, therefore, strongly favours the current and proposed olaparib study in patients 
with advanced prostate cancer. 
Full details of the benefits and risks of olaparib are provided in the current olaparib IB.  The 
Investigator should refer to the abiraterone prescribing information for details on the risks of 
abiraterone. 
2. 
STUDY OBJECTIVES 
2.1 
Primary objectives 
Table 1 
Primary objectives 
Primary objective 
Primary outcome variable 
Part A, Safety run-in: 
To assess the safety and tolerability of 
olaparib when given in addition to abiraterone 
and to recommend, by assessment of dose-
limiting toxicities and other safety and 
tolerability data, a dose of olaparib for further 
study when given in addition to abiraterone. 
 
Assessment of AEs graded by CTCAE v4.0, 
vital signs (including BP, pulse), and 
evaluation of laboratory parameters (clinical 
chemistry and haematology. 
Incidence of dose-limiting toxicities during 
the initial evaluation period. 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
28(134) 
Table 1 
Primary objectives 
Primary objective 
Primary outcome variable 
Part B: 
To compare the efficacy of olaparib when 
given in addition to abiraterone, with placebo 
given in addition to abiraterone, by 
assessment of rPFS using RECIST 1.1 and 
PCWG-2 criteria. 
 
rPFS, defined as the time from randomisation 
to disease progression according to RECIST 
1.1 (for soft tissue disease) and/or PCWG-2 
criteria (for bone disease), or death. 
AE  adverse event;  BP  blood pressure;  CTCAE  Common Terminology Criteria for Adverse Event; 
PCWG-2  Prostate Cancer Working Group 2; 
RECIST 1.1  Response Evaluation Criteria in Solid Tumours version 1.1; 
rPFS  Radiologic progression-free survival. 
 
2.2 
Secondary objectives 
Table 2 
Secondary objectives 
Secondary objective 
Secondary outcome variables 
Part A, Safety run-in: 
To evaluate the presence of any drug 
interaction between olaparib and abiraterone 
by determination of steady state exposure to 
olaparib in the presence and absence of 
abiraterone, and determination of steady state 
exposure to abiraterone in the presence and 
absence of olaparib. 
 
Olaparib and abiraterone PK parameters 
(where the data allow): Cmax ss, tmax ss, Cmin ss, 
AUCss. 
Part B: 
To compare the safety and tolerability of 
olaparib when given in addition to 
abiraterone, with placebo given in addition to 
abiraterone. 
 
Assessment of AEs graded by CTCAE v4.0, 
vital signs (including BP, pulse), and 
evaluation of laboratory parameters (clinical 
chemistry and haematology). 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
29(134) 
Table 2 
Secondary objectives 
Secondary objective 
Secondary outcome variables 
To assess the anti-tumour activity of olaparib 
when given in addition to abiraterone, 
compared with placebo given in addition to 
abiraterone, by measurement of changes in 
circulating prostate specific antigen (PSA) 
and circulating tumour cells (CTCs), 
calculation of overall radiological objective 
response rate (ORR) (by RECIST 1.1 and 
PCWG-2 bone scan criteria) and malignant 
soft tissue ORR (by RECIST 1.1), time to 
first subsequent therapy (TFST) for prostate 
cancer, and time to second subsequent 
therapy (TSST) for prostate cancer. 
Percentage change from baseline in PSA 
levels and PSA response. 
Change in CTC numbers. 
Tumour response in terms of ORR (malignant 
soft tissue response and overall radiological 
response [malignant soft tissue response by 
RECIST 1.1 and overall radiological response 
by RECIST 1.1 and PCWG-2]). 
TFST and TSST. 
To assess the efficacy of olaparib when given 
in addition to abiraterone, compared with 
placebo given in addition to abiraterone, by 
assessment of OS. 
OS, defined as time from randomisation to 
the date of death from any cause. 
To assess the efficacy of olaparib when given 
in addition to abiraterone, compared with 
placebo given in addition to abiraterone, by 
assessment of time from randomisation to 
PFS2. 
PFS2.  Progression defined by local standard 
clinical practice.  May involve any of: 
objective radiological progression, 
symptomatic progression, rises in PSA or 
death. 
To investigate BRCA and ATM mutations as 
candidate predictors of response to olaparib.  
Note: This objective is dependent upon the 
number of evaluable samples obtained from 
the study. 
BRCA and ATM mutation status; if the 
number of events in these groups is sufficient 
then the primary analysis of rPFS will be 
repeated in all patients with  BRCA and ATM 
mutations. 
AE  adverse event;  AUCss  area under the plasma concentration-time curve at steady state;  BP  blood pressure 
BRCA Breast cancer gene;  Cmax ss  maximum plasma concentration at steady state; 
Cmin ss  minimum plasma concentration at steady state;  CTCs  circulating tumour cells;   
DoR  duration of response;  ERG  Erythroblast transformation-specific related gene; 
ORR  objective response rate;  OS  overall survival;  PFS2  second progression;  PSA  prostate specific antigen; 
tmax ss  time to reach maximum plasma concentration at steady state; 
TFST  time to first subsequent therapy; TSST  time to second subsequent therapy 
 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
30(134) 
2.3 
Exploratory objectives 
Table 3 
Exploratory objectives 
Exploratory objectives 
Exploratory outcome variables 
To explore the effects of olaparib on pain 
and other prostate cancer-related symptoms 
compared to placebo. 
Change from baseline in worst pain, general 
pain and pain interference in daily activities 
scales of the BPI-SF and the worst bone pain 
item. 
Change from baseline in the FAPSI-8, as 
derived from 8 items within the FACT-P, 
and the PCS, as derived from the 12 items in 
the prostate-specific module of the FACT-P. 
To explore the effects of olaparib on HRQL 
compared to placebo. 
Change from baseline, as measured by the 
FACT-P scales: FWB, PWB, EWB, SWB, 
the Total FACT-P score, and the TOI score 
(the sum of the PWB, FWB and PCS 
scores). 
To assess the time to deterioration in pain. 
Time to deterioration in the BPI-SF worst 
pain item and time to deterioration in the 
worst bone pain item. 
To assess time to deterioration in HRQL. 
 
Time to deterioration in HRQL, as measured 
by FACT-P TOI score. 
To explore the impact of treatment and 
disease state on health state utility. 
EQ-5D-5L health state utility index. 
To investigate the impact of treatment and 
disease progression on metastatic CRPC 
management resource use. 
Resource use will be captured, focussing on 
in-patient and ICU admissions, length of 
stay, palliative interventions and reason for 
admission into hospital and interventions. 
Future exploratory research into factors that 
may influence development of cancer 
(including PTEN, AR status) and/or 
response to treatment (where response is 
defined broadly to include efficacy, 
tolerability or safety) may be performed on 
the collected and stored archival tumour 
samples (where available), blood samples 
(mandatory), urine samples (mandatory), 
and CTC samples (mandatory). 
PTEN and AR status in archival tumour 
tissue (where available), CTCs, blood and 
urine samples – the primary analysis of rPFS 
may be repeated by patient PTEN and AR 
status. 




Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
32(134) 
Abiraterone is indicated in combination with prednisone or prednisolone for the treatment of 
patients with metastatic CRPC.  Prednisone or prednisolone 5 mg bid will be administered 
with the abiraterone in this study, but throughout this protocol the treatment will be referred to 
simply as abiraterone. 
For Part A of the study, 15 to 18 evaluable patients (Cohorts 1 and 2) are planned to be 
enrolled from approximately 4 sites in approximately 1 or 2 countries, and a further 
12 patients may be recruited into a 3rd cohort if necessary. 
For Part B of the study, approximately 140 patients who have received prior chemotherapy 
containing docetaxel will be randomised from approximately 40 sites in North America and 
Europe.  Patients who have been dosed in Part A of the study may not participate in Part B. 
A flow chart of Part A of the study and dose decisions is illustrated in Figure 1. 
3.1.1 
Part A: Safety run-in/dose escalation 
Patients will attend the clinic for assessments on the first day of study treatment, at 1 and 
2 weeks, then every 4 weeks up to Week 52, and every 12 weeks thereafter.  They will also 
attend for study treatment supplies at 16 weeks and every 4 weeks thereafter.  
3.1.1.1 
Cohort 1 (up to 6 patients) 
At least 3 and up to 6 evaluable patients with metastatic CRPC will be enrolled in Cohort 1 
using a rolling 6 design (Skolnik et al 2008).  Patients will receive olaparib 200 mg bid and 
abiraterone 1000 mg once daily.  Patients will attend the clinic for safety assessments as 
shown in the flow chart (Figure 2) and study plan (Table 4). 
Dose-limiting toxicities (DLTs) from all patients will be assessed by a Safety Review 
Committee (SRC; see Section 3.1.6) after a minimum of 3 patients have received a minimum 
of 14 days’ treatment.  Dose escalation will follow the scheme below, according to the 
following logic: 
• 
Dose increases will be permitted after review of data from a minimum of 
3 evaluable patients has been performed.  Evaluable patients will be those that have 
completed at least 14 days of dosing with olaparib and abiraterone.  If no DLT is 
observed (for definition see Section 3.1.1.4) in the initial cohort of 3 to 6 evaluable 
patients, then dose escalation may occur. 
• 
If 1 patient experiences a DLT in the initial cohort of 3 or more evaluable patients 
then the cohort will be expanded to include a total of 6 evaluable patients.  If only 
1 DLT is observed in the complete cohort of 6 evaluable patients then dose 
escalation may occur. 
• 
If 2 or more patients experience a DLT in Cohort 1, irrespective of the number of 
patients enrolled, the dose will be considered not tolerated and recruitment to the 
cohort and dose escalation will cease.  The study may be terminated at this stage or 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
33(134) 
amended to allow doses below 200 mg bid of olaparib to be studied following 
review of safety data. 
3.1.1.2 
Cohort 2 (12 patients) 
If the combination of olaparib 200 mg bid and abiraterone 1000 mg once daily is tolerated, a 
cohort of 12 patients (split into 2 groups of 6 patients) will be treated with olaparib 300 mg 
bid given in addition to abiraterone 1000 mg once daily, and will be evaluated for safety, 
tolerability and PK. 
Group 1: 
Patients will receive olaparib alone (300 mg bid) for between 3 and 7 days.  Blood samples 
will be collected to determine the steady state PK profile for olaparib; this may be done on any 
day between Days 3 and 7, starting after the morning dose. 
Patients will then receive abiraterone (1000 mg once daily) starting from the day after the 
olaparib PK profile has been collected.  Olaparib and abiraterone will continue to be dosed in 
combination for at least 5 days, then blood samples will be collected again to determine both 
olaparib and abiraterone PK profiles. 
A flow chart of the study visits is shown in Figure 3.  Visits and assessments will be 
conducted as shown in Table 5.  The timings for starting the olaparib and abiraterone doses, 
and the corresponding options for PK sampling days, are provided in Table 6. 
Group 2: 
Patients will receive abiraterone alone (1000 mg once daily) for between 5 and 7 days.  Blood 
samples will be collected to determine the steady state PK profile for abiraterone (any day 
between Days 5 and 7). 
Patients will receive olaparib (300 mg bid) starting immediately after the 24-hour abiraterone 
PK sample has been collected.  Olaparib and abiraterone will continue to be dosed in 
combination for at least 3 days, then blood samples will be collected again to determine both 
olaparib and abiraterone PK profiles. 
A flow chart of the study visits is shown in Figure 4.  Visits and assessments will be 
conducted as shown in Table 5.  The timings for starting the olaparib and abiraterone doses, 
and the corresponding options for PK sampling days, are provided in Table 7. 
Dose-limiting toxicities will be assessed by the SRC after a minimum of 14 days’ treatment 
with both olaparib and abiraterone.  If <2 DLTs occur in the first 9 patients that have 
completed at least 14 days’ dosing with both olaparib and abiraterone, then the randomised 
part of the study, Part B, may commence with this dose combination and the remaining 
3 patients to be dosed in Part A may be recruited in parallel with Part B.  If 2 or more DLTs 
occur then all 12 patients must be dosed before a decision is made to progress to Part B.  If 
<4 DLTs occur in this cohort of 12 patients (Groups 1 and 2), then the randomised part of the 
study, Part B, will commence with this dose combination. 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
34(134) 
3.1.1.3 
Cohort 3 (12 patients) 
If 4 or more DLTs occur in Cohort 2, a further 12-patient cohort may be recruited and treated 
with olaparib 200 mg bid in combination with abiraterone 1000 mg once daily and evaluated 
for safety, tolerability and PK as described for Cohort 2 (see Section 3.1.1.2). 
If Cohort 3 is dosed and there are <4 DLTs, then Part B may proceed using a 200 mg bid dose 
of olaparib.  If 4 or more DLTs are observed, then the study will be terminated. 
3.1.1.4 
Definition of dose-limiting toxicity 
A DLT is defined as any toxicity which is not a recognised adverse effect of abiraterone or 
prednisolone, and not attributable to the disease or disease-related processes under 
investigation, which occurs during a minimum of 14 days’ treatment and which includes: 
1. 
Haematological toxicity  CTCAE Grade 4 present for more than 4 days 
− 
Except anaemia 
2. 
Non-haematological toxicity  CTCAE Grade 3 including: 
− 
Infection including febrile neutropenia 
− 
Corrected QT interval (QTc) prolongation (> 500 msec) 
3. 
Any other toxicity that is greater than that at baseline, is clinically significant and/or 
unacceptable, does not respond to supportive care, results in a disruption of dosing 
schedule of 7 days or more, or is judged to be a DLT by the SRC 
A DLT excludes:  
1. 
Alopecia of any grade 
2. 
Isolated laboratory changes of any grade without clinical sequelae or clinical 
significance 
3.1.2 
Part B: Randomised part 
Progression to Part B will be based on a review of all available safety, tolerability and PK data 
from Part A of the study.  This will be performed when sufficient evaluable patients in both of 
the patient groups in Part A Cohort 2 (or Cohort 3 if necessary) have completed a minimum of 
14 days’ treatment.  The selection of the dose for Part B will be taken by the SRC and 
AstraZeneca (see Section 3.1.6).  This review may be conducted on pre-database lock data 
that have not been formally analysed. 
Patients will receive olaparib/placebo 300 mg bid (or 200 mg bid, if 200 mg bid is the 
maximum tolerated dose in Part A) and abiraterone 1000 mg once daily.  They will attend the 
clinic for assessments on the first day of study treatment, then every 4 weeks up to Week 52, 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
35(134) 
and every 12 weeks thereafter.  They will also attend for study treatment supplies at 16 weeks 
and every 4 weeks thereafter. 
Tumours will be evaluated using RECIST 1.1 and PCWG-2 criteria (see Appendix F).  
Baseline assessments should be performed no more than 28 days before the date of 
randomisation and ideally should be performed as close as possible to the date of 
randomisation.  Follow-up assessments will be performed every 12 weeks (±1 week) from the 
date of randomisation (every 24 weeks after Week 72).  Malignant soft tissue RECIST v1.1 
assessments will be performed using computed tomography (CT) or magnetic resonance 
imaging (MRI) scans of chest, abdomen and pelvis.  Bone lesion PCWG-2 assessments will 
be performed using bone scan (preferably whole body). 
An archival tumour sample will be collected, where available, to measure ERG 
expression/fusion status and BRCA mutation; other biomarkers such as AR and PTEN may 
also be measured. 
Blood samples will be collected for measurement of the following: 
• 
PSA 
• 
Biomarkers: where assays are available for measuring markers as a surrogate for 
tumour tissue (urine also may be tested) 
• 
CTCs: enumeration and characterisation where assays are available for measuring 
markers as a surrogate for tumour tissue. 
Patient reported outcomes (PROs) will be measured using the BPI-SF, an individual item on 
bone pain and the FACT-P questionnaires. 
A flow chart of the study visits is shown in Figure 5.  Visits and assessments will be 
conducted as shown in Table 8. 
Patients will be evaluated until disease progression regardless of whether study treatment is 
discontinued.  The collection of RECIST 1.1/PCWG-2 data will then stop and patients will be 
followed for PFS2 and survival. 
The primary analysis will be performed once approximately 100 progression events have 
occurred (see Section 9.5). 
3.1.3 
Discontinuation 
Patients will continue to receive study treatment until disease progression, or until a time 
when the Investigator considers that they are no longer deriving clinical benefit, or they stop 
taking treatment for any other reason including having met any of the criteria for treatment 
discontinuation. 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
36(134) 
Once patients on olaparib/placebo have been discontinued from treatment, other treatment 
options will be at the discretion of the Investigator.  All subsequent therapies should continue 
to be recorded on the appropriate eCRF. 
For further details on discontinuation, see Sections 5.8 and 5.9. 
3.1.4 
30-Day follow-up 
A follow-up visit should be conducted 30 days (±7 days) after the last dose of study treatment 
(olaparib/placebo or abiraterone).  Any serious and/or non-serious AEs ongoing at the time of 
the treatment discontinuation visit or which have occurred during the defined 30-day 
follow-up period must be followed-up (in accordance with Sections 6.4.3 and 6.4.4).  
Appropriate safety evaluations should be repeated and/or additional tests performed at any 
time when clinically indicated, or at the discretion of the Investigator, until resolution, unless, 
in the Investigator’s opinion, the condition is unlikely to resolve due to the patient’s 
underlying disease.  If the patient is lost to follow-up, then this should be noted in the 
electronic Case Report Form (eCRF).  The assessments to be carried out at the 30-day 
follow-up visit are detailed in the study plan (Table 8). 
3.1.5 
Survival follow-up (Part B only) 
Assessments for PFS2 and survival should be made every 12 weeks following objective 
disease progression.  Information may be obtained via telephone contact with the patient, 
patient’s family or by contact with the patient’s current physician.  If the contact is with the 
patient directly, the BPI-SF worst pain item and the worst bone pain item will also be 
administered over the telephone (see Section 6.5.3).  The details of first and subsequent 
therapies for cancer, after discontinuation of treatment, will be collected.  Survival and PFS2 
data will be collected up to the time of the final OS analysis. 
In addition, patients should be contacted in the 2 weeks following the data cut-off (DCO) and 
survival status and latest date known to be alive recorded for the final survival analyses to 
provide complete survival data. 
All patients will be followed for PFS2 and survival data until approximately 60% of patients 
have died at which point the final analysis will occur and the database will be closed (see 
Section 9.5).  Patients are, however, permitted to continue to receive study treatment beyond 
the closure of the database if, in the opinion of the Investigator, they are continuing to receive 
benefit from treatment with olaparib/placebo and abiraterone. 
Survival status for withdrawn consent and lost to follow up patients 
At the time of OS analyses, all patients’ survival status should be re-checked; this includes 
those patients that withdrew consent or are classified as ‘lost to follow up’. 
• 
Lost to Follow up – site personnel should check hospital records, the patients’ 
current physician and a publicly available death registry (if available) to obtain a 
current survival status in the 2 weeks following DCO 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
37(134) 
• 
In the event that the patient has actively withdrawn consent to the processing of 
their personal data, the survival status of the patient can be obtained by site 
personnel from publicly available resources where it is possible to do so under 
applicable local laws. 
For US-based patients, the FDA provides guidance to this point in ‘Guidance for Sponsors, 
Clinical Investigators, and IRBs.  Data Retention When Subjects Withdraw from FDA-
Regulated Clinical Trials’. 
http://www.fda.gov/downloads/regulatoryinforamtion/guidances/ucm126489.pdf 
• 
Patients who have withdrawn consent – site personnel should check a publicly 
available death registry (if available) in the 2 weeks following DCO. 
For further information on patient withdrawal, see Section 5.9. 
3.1.6 
Safety Review Committee (SRC) 
The SRC will consist of: 
• 
AstraZeneca Study Physician, or delegate, who will chair the committee 
• 
Quintiles Study Team Physician, or delegate 
• 
Principal Investigator (PI), or delegate, from each investigational site. 
Other physicians and representatives from AstraZeneca and Quintiles, such as the Global 
Safety Physician, will also be invited, as appropriate. 
Further internal or external experts may be consulted by the SRC, as necessary.  Any PI can 
request an ad hoc SRC meeting at any time in order to facilitate the immediate communication 
of any emerging safety issues during the course of the study. 
The SRC will evaluate available safety, tolerability, PK and anti-tumour data, and in 
agreement with AstraZeneca, will define the recommended dose for Part B. 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
38(134) 
Figure 1 
Study design flow chart 
Part A – Dose selection 
 
Part B – Efficacy 
 
Cohort 2 
Group 1 
Group 2 
6 patients 
6 patients 
 
 
          Part B 
            140 patients 
 
Olaparib 300 mg 
bid alone, then with 
abiraterone 
1000 mg once daily 
Abiraterone 
1000 mg once daily 
alone, then with 
olaparib 300 mg bid 
<2 DLTs in first 9 patientsa, or 
<4 DLTs in all 12 patients, proceed to Part B 
with 300 mg bid dose of olaparib 
 
4 DLTs 
 
Olaparib/placebo 300 mg bid 
(200 mg bid, if 200 mg is max 
tolerated dose in Part A) 
with abiraterone 
1000 mg once daily 
Cohort 1 
3-6 patients 
 
 
1 DLT 
 
 
Cohort 3 
Group 1 
Group 2 
6 patients 
6 patients 
 
 
Olaparib 200 mg bid 
with abiraterone 
1000 mg once daily 
 
 
 
Olaparib 200 mg bid 
alone, then with 
abiraterone 1000 mg 
once daily 
Abiraterone 
1000 mg once daily 
alone, then with 
olaparib 200 mg bid 
 
<4 DLT, proceed to Part B with 
200 mg bid dose of 
olaparib/placebo 
 
 
 
 
 
 
2 DLTs 
 
4 DLTs 
 
 
 
 
Stop study 
   (or consider doses 
below 200 mg olaparib) 
 
 
         Stop study 
 
 
 
a 
<2 DLTs in the first 9 patients that have completed at least 14 days’ dosing with both olaparib and abiraterone; the remaining 3 patients in the cohort 
may then be recruited in parallel with Part B 
 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
39(134) 
Figure 2 
Flow chart for Part A, Cohort 1 
 
 
a 
Unless patients discontinue study treatment, they will remain in the study and be assessed every 12 weeks. 
Laboratory assessments will be performed every 4 weeks up to Week 52 while the patient is on treatment, 
whichever comes first, and then every 12 weeks for as long as the patient is on treatment. 
  1 week
  2 weeks
  4 weeks
  12 weeks
Discontinuation                    
of study treatments
30-Day follow-up                   
30 ±7 days after last dose of study 
treatment
Visits 5 to 7                       
Weeks 4, 8 and 12                  
Patients visit every 4 weeks
Visit 2                            
Day 1, Week 0                     
Eligibility confirmed                 
Start treatment with olaparib 200 mg bid 
and abiraterone 1000 mg once daily
Visit 1            
Screening         
Day -28 to -1
Visits 3 and 4                      
Weeks 1 and 2                      
Patients visit weekly
Visit 9 onwards
a                                
Week 24 onwards                   
Patients visit every 12 weeks  
Visit 8 onwards
a                                
Week 16 onwards                   
Patients visit every 4 weeks (for study 
treatment supply, laboratory assessments 
and AE review only)


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
40(134) 
Figure 3 
Flow chart for Part A, Cohort 2, Group 1 
 
 
a 
Laboratory assessments will be performed every 4 weeks up to Week 52 while the patient is on 
treatment, whichever comes first, and then every 12 weeks for as long as the patient is on treatment. 
  
Olaparib 300 mg bid only
Olaparib 300 mg bd with abiraterone 1000 mg once daily
Visit 8 onwardsa                                        
Week 16 onwards                       
Patients visit every 4 weeks (for study 
treatment supply, laboratory assessments and 
AE review only)
Visit 1                
Screening             
Day -28 to -1
Visits 5 to 7                           
Weeks 4, 8 and 12                       
Patients visit every 4 weeks
Visit 9 onwards                        
Week 24 onwards                       
Patients visit every 12 weeks  
Discontinuation                        
of study treatments
30-Day follow-up                       
30 ±7 days after last dose of study treatment
Visit 3                                                
Week 1                                                
Olaparib PK profiling any day between Days 3 and 7            
Abiraterone 1000 mg once daily to start the day after olaparib PK
Visit 2                                                
Day 1, Week 0                                          
Eligibility confirmed                                     
Start treatment with olaparib 300 mg bid
Visit 4                                                
Week 2                                                
Olaparib and abiraterone PK profiling                       
after dosing olaparib and abiraterone together for at least 5 days


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
41(134) 
Figure 4 
Flow chart for Part A, Cohort 2, Group 2 
 
 
a 
Laboratory assessments will be performed every 4 weeks up to Week 52 while the patient is on 
treatment, whichever comes first, and then every 12 weeks for as long as the patient is on treatment. 
  
Visit 8 onwardsa                                       
Week 16 onwards                       
Patients visit every 4 weeks (for study 
treatment supply, laboratory assessments and 
AE review only)
Discontinuation                        
of study treatments
30-Day follow-up                       
30 ±7 days after last dose of study treatment
Visit 1               
Screening             
Day -28 to -1
Abiraterone 1000 mg once daily only
Visit 2                                                
Day 1, Week 0                                          
Eligibility confirmed                                     
Start treatment with abiraterone 1000 mg once daily
Visit 3                                                
Week 1                                               
Abiraterone PK profiling any day between Days 5 and 7         
Olaparib 300 mg bd to start after abiraterone 24 h PK sample
Olaparib 300 mg bd with abiraterone 1000 mg once daily
Visit 4                                                
Week 2                                               
Olaparib and abiraterone PK profiling                       
after dosing olaparib and abiraterone together for at least 3 days
Visits 5 to 7                           
Weeks 4, 8 and 12                      
Patients visit every 4 weeks
Visit 9 onwards                        
Week 24 onwards                       
Patients visit every 12 weeks  


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
42(134) 
Figure 5 
Flow chart for Part B 
 
 
a 
Laboratory assessments will be performed every 4 weeks up to Week 52 while the patient is on 
treatment, whichever comes first, and then every 12 weeks for as long as the patient is on treatment. 
  4 weeks
  4 weeks
  4 weeks
  12 weeks
  Disease progression or other reason
Visit 1                            
Screening                         
Day -28 to -1                      
CT/MRI scan and Bone scan
Visit 7 onwards                                     
Week 24 onwards                                   
Patients visit every 12 weeks up to and including Week 72, 
then every 24 weeks, until progression                   
CT/MRI scan and Bone scan 
Survival and PFS2 
follow-up         
Calls to patient 
every 12 weeks
Visit 2                                            
Day 1, Week 0                                      
Randomisation to olaparib with abiraterone               
or placebo with abiraterone
Visits 3 and 4                      
Weeks 4 and 8                     
Patients visit every 4 weeks
Discontinuation                    
of study treatments
Visit 6 onwards
a                                 
Week 16 onwards                   
Patients visit every 4 weeks (for study 
treatment supply, laboratory assessments 
and AE review only)
30-Day follow-up                   
30 ±7 days after last dose of study 
treatment
Visit 5                            
Week 12                          
CT/MRI scan and Bone scan
If treatment 
discontinued due 
to disease 
progression
If treatment discontinued for 
reason other than disease 
progression
Patient followed 
up until confirmed 
disease progression




Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
44(134) 
Table 4 
Study Plan – Part A, Cohort 1 (Olaparib 200 mg bid + Abiraterone) 
Visit 
1 
Screening
2 
3 
4 
5 
6 
7 
8+ 
9+j 
Discontin-
uation of IP
30-day 
follow-upk 
Visit window (days) 
–28 to -1
±0 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
 
 
Week 
 
0 
1 
2 
4 
8 
12 
16+ (every 
4 weeks) 
24+ (every 
12 weeks)
 
 
Day 
- 
1 
8 
15 
29 
57 
85 
113+ 
169+ 
- 
- 
Treatment 
dispensed/returned 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE  adverse event;  BRCA  Breast cancer gene;  ECOG  Eastern Cooperative Oncology Group;  ECG  electrocardiogram;  IP  investigational product; 
PSA prostate specific antigen;  PGx  pharmacogenetics;  SAE  serious adverse event 
a 
Demographics include date of birth (if allowed by local regulations), race, and ethnic group. 
b 
Height and weight will be recorded at the first examination only. 
c 
Collect any locally available PSA data for the 12 months prior to study entry, and any locally available BRCA mutation data. 
d 
At screening, a 12-lead ECG will be performed to ensure a QTc value of 470 ms for eligibility.  If the QTc value is >470, the screening ECG may be 
repeated up to 2 times (at least 24 hours apart).  The average of these screening ECGs (up to 3 ECGs) must be 470 ms to confirm patient eligibility. If 
the screening ECG is obtained within 3 days before Day 1 (Visit 2), then the screening ECG will be considered the baseline, and an ECG will not be 
necessary on Day 1.  Failing to meet this time frame, a baseline ECG must be performed on Day 1 (Visit 2).  After baseline, ECGs are only required if 
clinically indicated. 
e 
Including blood pressure (BP), pulse and temperature.  Measurements at Visit 2 must take place before first dose of study drug. 
f 
Concomitant medication should include all medications taken by the patient before and during the study. 
g 
When an AE of nausea or vomiting occurs, there is an additional eCRF for completion. 
h 
The Visit 2 (Day 1) laboratory assessments need only be taken if the screening assessments were collected more than 7 days before Day 1 (Visit 2).  
From Visit 8 (Week 16) onwards, laboratory assessments will be performed every 4 weeks up to Week 52, while the patient is on treatment, whichever 
comes first, and then every 12 weeks for as long as the patient is on treatment. See Section 6.4.5 for a complete list of haematology and chemistry 
assessments. 
i 
Sample will only be collected if separate PGx informed consent has been signed. 
j 
Assessments apply to Visit 9 and subsequent visits occurring every 12 weeks thereafter. 
k 
30-day follow-up visit for post-study drug assessment of AEs and concomitant medications as required.  All ongoing AEs/SAEs and any new AEs/SAEs 
identified during the 30-day follow up period must be followed to resolution. 






Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
47(134) 
h 
The Visit 2 (Day 1) laboratory assessments need only be taken if the screening assessments were collected more than 7 days before Day 1 (Visit 2).  
From Visit 8 (Week 16) onwards, laboratory assessments will be performed every 4 weeks up to Week 52, while the patient is on treatment, whichever 
comes first, and then every 12 weeks for as long as the patient is on treatment. See Section 6.4.5 for a complete list of haematology and chemistry 
assessments. 
i 
Sample will only be collected if separate PGx informed consent has been signed. 
j 
Assessments apply to Visit 9 and subsequent visits occurring every 12 weeks thereafter. 
k 
30-day follow-up visit for post-study drug assessment of AEs and concomitant medications as required.  All ongoing AEs/SAEs and any new AEs/SAEs 
identified during the 30-day follow up period must be followed to resolution. 
l 
Group 1: Olaparib (300 mg bid) dosing starts Day 1.  Olaparib steady state PK profile collected any day between Days 3 and 7 after morning dose. 
Abiraterone (1000 mg) dosing to start the day after the olaparib PK profile has been collected. 
Continue dosing both drugs together for at least 5 days then collect both olaparib and abiraterone PK profiles.  See Table 6. 
Group 2: Abiraterone (1000 mg) dosing starts Day 1.  Abiraterone steady state PK profile collected any day between Days 5 and 7 after morning dose. 
Olaparib dosing (300 mg bid) to start after the abiraterone PK profile has been collected (immediately after the 24-hour sample). 
Continue dosing both drugs together for at least 3 days then collect both olaparib and abiraterone PK profiles.  See Table 7. 
m 
Blood samples for determination of olaparib to be collected pre-dose and at 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after morning dose on each sampling day. 
n 
Blood samples for determination of abiraterone to be collected pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after morning dose on each sampling 
day. 
o 
Patients will be asked to complete a questionnaire to assess their study treatment compliance from Day 1 until after the PK profiling has been completed. 
 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
48(134) 
Table 6 
Dosing and PK sampling options for Cohort 2, Group 1 
Day olaparib 
dosing starts 
Day of PK 
sampling for 
olaparib 
Day abiraterone 
dosing starts 
(olaparib ongoing) 
Day of PK sampling 
for olaparib and 
abirateronea 
1 
3 
4 
9 – 14 
1 
4 
5 
10 – 14 
1 
5 
6 
11 – 14 
1 
6 
7 
12 – 14 
1 
7 
8 
13 – 14 
a 
Samples for PK profiling may be collected on any one of the listed days. 
 
Table 7 
Dosing and PK sampling options for Cohort 2, Group 2 
Day abiraterone 
dosing starts 
Day of PK 
sampling for 
abiraterone 
Day olaparib 
dosing starts 
(abiraterone ongoing) 
Day of PK sampling 
for olaparib and 
abirateronea 
1 
5 
6 
9 – 14 
1 
6 
7 
10 – 14 
1 
7 
8 
11 – 14 
a 
Samples for PK profiling may be collected on any one of the listed days. 
 
 








Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
52(134) 
d 
Bone scan required to confirm progression due to new bone lesions, preferably at the next scheduled visit for a bone scan and at least 6 weeks later. 
e 
Collect any locally available PSA data for the 12 months prior to study entry, and any locally available BRCA mutation data. 
f 
At screening, a 12-lead ECG will be performed to ensure a QTc value of 470 ms for eligibility.  If the QTc value is >470, the screening ECG may be 
repeated up to 2 times (at least 24 hours apart).  The average of these screening ECGs (up to 3 ECGs) must be 470 ms to confirm patient eligibility.  If 
the screening ECG is obtained within 3 days before Day 1 (Visit 2), then the screening ECG will be considered the baseline, and an ECG will not be 
necessary on Day 1.  Failing to meet this time frame, a baseline ECG must be performed on Day 1 (Visit 2).  After baseline, ECGs are only required if 
clinically indicated. 
g 
Including blood pressure (BP), pulse and temperature.  Measurements at Visit 2 must take place before first dose of study drug. 
h 
Concomitant medication should include all medications taken by the patient before and during the study. 
i 
When an AE of nausea or vomiting occurs, there is an additional eCRF for completion. 
j 
The Visit 2 (Day 1) laboratory assessments need only be taken if the screening assessments were collected more than 7 days before Day 1 (Visit 2).  
From Visit 6 (Week 16) onwards, laboratory assessments will be performed every 4 weeks up to Week 52, while the patient is on treatment, whichever 
comes first, and then every 12 weeks for as long as the patient is on treatment. See Section 6.4.5 for a complete list of haematology, chemistry 
assessments. 
k 
Visit 2 (Day 1) sample to be collected pre-dose.   
l 
Sample will only be collected if separate PGx informed consent has been signed. 
m 
The patient should complete the PRO questionnaires in a quiet place before any investigations have been carried out.  Site personnel should not 
influence the patient’s answers to the questions.  Please refer to Section 6.5. 
n 
If the patient discontinues study treatment for reasons other than RECIST or PCWG-2 progression, the ‘Oncology Hospital Admission’ form, FACT-P 
and EQ-5D-5L should continue to be administered until progression has been confirmed.  After progression, see Table 9. 
o 
With the exception of laboratory assessments (see Footnote j for details), assessments apply to Visit 7 and subsequent visits occurring every 12 weeks up 
to and including Week 72, and every 24 weeks thereafter. 
p 
30-day follow-up visit for post-study drug assessment of AEs and concomitant medications as required.  All ongoing AEs/SAEs and any new AEs/SAEs 
identified during the 30-day follow up period must be followed to resolution. 
 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
53(134) 
Table 9 
Study plan – Randomised part (follow-up post discontinuation of study treatment) 
Visit 
Off treatment follow-up for: 
Patients who have discontinued 
study treatment due to 
reasons other than disease 
progression 
 
Visits every 12 weeks 
Follow up for 1st progression 
Time to second progression (PFS2) and survival for: 
Patients who have discontinued study treatment due to 
disease progression 
Patients who have progressed off treatment 
Patients followed up by telephone every 12 weeks 
post discontinuation of study treatment 
Visit window 
±7 days 
±7 days 
ECOG Performance Status 
X 
X 
CT or MRI scan of the chest, 
abdomen and pelvis (RECIST 1.1)a 
X 
 
Bone scan (PCWG-2)a 
X 
 
BPI-SF and bone pain item 
X 
 
BPI-SF worst pain item and worst 
bone pain itemb 
 
X 
PSA blood sample (local)c 
X 
 
Subsequent cancer therapy following 
discontinuation of study treatmentd 
X 
X 
EQ-5D-5L questionnaire 
X 
 
FACT-P 
X 
 
Oncology resource usee 
X 
Xb 
Time to second progression 
 
X 
Survivalf,g 
X 
X 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
54(134) 
BPI-SF  Brief Pain Inventory – Short Form;  CT  CT  Computed tomography;  MRI  magnetic resonance imaging;   
PCWG-2  Prostate Cancer Working Group 2;  PFS2  second progression;  PSA prostate specific antigen 
a 
Patients will continue to be assessed by objective tumour assessments every 12 weeks (±1 week) relative to date of randomisation up to and including 
Week 72, then every 24 weeks until progression, via RECIST 1.1 and PCWG-2.   
b 
Administered by the Investigator over the telephone. 
c 
Scheduled PSA samples will not be collected during the PFS2 and OS follow-up, but a standard of care local PSA value should be collected at the time 
of PFS2 and included on the database. 
d 
All anti-cancer treatments (including, but not limited to, chemotherapy and targeted agents), and the Investigator’s opinion of response to them, plus the 
date of progression post discontinuation of study treatment, need to be recorded. 
e 
The full ‘Oncology Hospital Admission’ form will be completed until rPFS; thereafter, an abridged version will be completed. 
f 
The status of ongoing, withdrawn (from the study) and ‘lost to follow-up’ patients at the time of an OS analysis should be obtained by the site personnel 
by checking the patients notes, hospital records, contacting the patient’s general practitioner and checking publicly available death registries.  In the 
event that the patient has actively withdrawn consent to the processing of their personal data the vital status of the patient can be obtained by site 
personnel from publicly available resources where it is possible to do so under applicable local laws (see Section 3.1.5). 
g 
In addition to their regular 12 weekly contact, patients will be contacted in the 7 days following a specified date (data cut off date) for each survival 
analysis.  


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
55(134) 
3.2 
Rationale for study design, doses and control groups 
3.2.1 
Patient population 
In Part A, metastatic CRPC patients may be recruited regardless of whether they have already 
had chemotherapy or not to facilitate recruitment of suitable patients.  For the randomised 
phase of this study, only post-chemotherapy CRPC patients will be studied, as this is a patient 
population for whom abiraterone is an approved therapy with proven benefit but there is still a 
relatively short time to disease progression and patients could benefit from additional agents. 
3.2.2 
Dose 
Part A of the study, the safety run-in, will use an initial dose of 200 mg bid olaparib, to 
minimise the risk of unexpected AEs when olaparib is given for the first time on a background 
of abiraterone.  If there is 1 DLT, then 300 mg bid olaparib will be administered with 
abiraterone to the next cohort of patients.  If this is well tolerated (<4 DLTs in 12 patients), 
then the 300 mg bid dose will be used in Part B of the study.  The 300 mg bid dose of olaparib 
will deliver exposure that has been previously demonstrated to be tolerated in cancer patients 
(see olaparib IB), and is the dose to be used in the monotherapy maintenance setting in the 
ovarian cancer Phase III programme. 
3.2.3 
Part A 
The design of the Part A safety run-in allows an escalation of dose with intensive safety 
monitoring to ensure the safety of the patients. 
The cohort size of at least 3 and up to 6 patients (‘rolling six design’) has been employed to 
improve the rate of accrual of patients to cohorts nearer the presumed therapeutic dose by 
reducing the need for late replacement of patients who become non-evaluable during the 
minimum 14-day treatment period, whilst not compromising collection of safety data  
(Skolnik et al 2008). 
To date, no in vivo drug-drug interaction (DDI) studies have been performed for olaparib.  In 
in vitro experiments, olaparib produced little or no competitive inhibition of CYPs 1A2, 2A6, 
2B6, 2C8, 2C9, 2C19, 2D6 or 2E1 but produced modest inhibition of CYP3A4 at the highest 
concentration tested (100 ȝM).  Olaparib was not a time-dependent inhibitor or an inducer of 
CYPs.  The compound is itself a substrate for CYP3A4 and is cleared predominantly via 
metabolic clearance.  It has also been shown to be a substrate for multidrug resistance 
protein 1 (MDR1) and an inhibitor of organic anion transporter protein B1 (OATP1B1) and 
organic cation transporter 1 (OCT1).  Thus there is the potential for it to be a victim of DDIs 
through CYP3A or MDR1 inhibition/induction and for it to be a perpetrator of DDIs with 
substrates of OATP1B1 and OCT1. 
Abiraterone is reported, in vitro, to be an inhibitor of CYPs 1A2, 2C8, 2C9, 2C19 and 3A4/5.  
In vivo it has been shown to be an inhibitor of CYP2D6.  It has also been shown, in vitro, to 
be an inhibitor but not a substrate of MDR1; no studies have been conducted with other 
transporter proteins.  Its 2 main circulating metabolites are produced via CYP3A4 and 
SULT2A1.  Thus there is the potential for it to be a victim of DDIs through CYP3A 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
56(134) 
inhibition/induction and for it to be a perpetrator of DDIs with substrates of CYP2D6 and 
MDR1. 
Based on this information, the potential for a DDI between olaparib and abiraterone does exist 
but the likelihood is considered to be low.  However, it was considered prudent to take the 
opportunity to conduct PK sampling to evaluate the presence of any DDI within Part A of the 
study as this is examining the safety and tolerability of olaparib in combination with 
abiraterone in a small number of patients prior to the larger randomised part. 
3.2.4 
Part B 
3.2.4.1 
Randomisation and blinding 
The study design is randomised and double-blinded in order to minimise bias when assessing 
whether olaparib given with abiraterone shows better efficacy than placebo given with 
abiraterone. 
3.2.4.2 
Choice of endpoints 
Radiological progression-free survival is considered to be the most appropriate primary 
endpoint for this Phase II study because it is a widely used and accepted measure that can be 
measured robustly.  The primary assessment of rPFS will be based on objective radiological 
findings as per the RECIST 1.1 guidelines (for malignant soft tissue disease) and/or PCWG-2 
recommendations (for bone lesions) to determine progression, or death.  It is believed that the 
use of a rPFS primary endpoint in this study will provide a good predictor for survival results 
in a future Phase III trial.  Progression-free survival can be assessed in less time than OS to 
allow a quicker decision to progress to Phase III.  Although a formal link between a PFS 
outcome in clinical trials and OS outcomes has not been established, a positive correlation 
between PFS and OS outcomes has been reported in a CRPC population (Ryan et al 2013). 
The secondary endpoints of the study include other measures of clinical benefit including OS, 
ORR, PSA and CTC measurements, PFS2, TFST, TSST and the exploratory PRO endpoints 
of symptoms and HRQL, to provide supportive data on the benefit of olaparib. 
Safety and tolerability are also secondary endpoints of the study.  These data will add to the 
safety database for patients with advanced solid malignancies treated with oral olaparib.  
3.2.4.3 
Use of placebo and abiraterone 
The use of a placebo control in Part B of this study provides for a robust assessment of the 
benefit of olaparib when given in addition to abiraterone, and is considered appropriate in this 
patient population because abiraterone is approved for use as a 2nd line treatment of patients 
with prostate cancer.  Abiraterone, in combination with prednisone/prednisolone, is one of the 
most commonly prescribed drugs for treatment of metastatic CRPC in the post-docetaxel 
phase, at a dose of 1000 mg once daily, and remains a recognised standard of care in this 
setting.  As such, all patients, including those randomised to the placebo/olaparib arm, will be 
receiving an approved post-docetaxel therapy for metastatic CRPC. 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
57(134) 
3.2.4.4 
Rationale for patient reported outcomes (PROs) 
In addition to assessing survival in oncology clinical trials it is important to understand how 
patients feel and function.  This will be addressed by symptom assessment as well as HRQL 
assessment throughout the study.  As many patients will be asymptomatic or mildly 
symptomatic as they enter the study, assessment of their cancer symptoms in future studies 
will support the efficacy evaluation.  The results from this study will guide selection of future 
PRO instruments and endpoints. 
The main purpose of the HRQL assessment is to show the overall influence of the benefits and 
toxicity of the treatment from a patient perspective, and to aid understanding of the risk-
benefit evaluation.  The PRO instruments were selected because they include the most 
relevant symptoms and domains of prostate cancer impact.  Both the BPI-SF and FACT-P are 
well-established instruments that have been previously included in prostate cancer clinical 
trials, including abiraterone.  The instruments were developed specifically for use in cancer 
and prostate cancer studies and both the BPI-SF (Gater et al 2011, Cleeland 2008,  
Cleeland et al 2005, Di Lorenzo et al 2007a, Di Lorenzo et al 2007b, Hong et al 2007) and the 
FACT-P (LoRusso et al 2003, Tester et al 2006, Esper et al 1997, Rosenfeld et al 2004,  
Yount et al 2003, Cella et al 2009) have been shown to be valid, reliable and responsive to 
changes in underlying prostate cancer.  The FACT-P includes scales assessing domains of 
HRQL, and also supports the calculation of a symptom score, the FAPSI-8, which is 
calculated from 8 symptom items within the FACT-P.  Thus the FACT-P supports the 
assessment of both symptoms and relevant domains of HRQL. 
Bone pain is of primary interest in advanced prostate cancer and has emerged in literature 
review and patient interviews as being important to patients.  As bone pain is not included in 
either of the 2 selected instruments, a ‘worst bone pain’ item similar to the ‘worst pain item’ 
in the BPI-SF was developed for this study.  The item differs from the wording of the BPI-SF 
pain item only by the addition of ‘bone’ in front of ‘pain’ in the item.  Based upon patient 
interviews, Gater et al 2011 reported that patients can distinguish between bone pain and other 
types of pain, based not only on the pain’s location, but also on its intensity and temporal 
features, including onset, frequency and duration.  Patients will rate their bone pain severity at 
its worst on a 0 to 10 point numeric rating scale (NRS).  This bone pain item will appear after 
the BPI SF paper-based instrument and will be administered at the same time as the BPI SF, at 
the clinic visits. 
3.2.4.5 
Rationale for health economics: utilities and resource use 
The EuroQuol-5 Dimensions five-level (EQ-5D-5L) questionnaire will be used to explore the 
impact of treatment and disease state on health state utility.  This exploratory analysis will be 
primarily used to support future economic evaluations of olaparib. 
The assessment of interventions (resource use) will increase the understanding of the 
relationship between treatment impact on tumour and related cancer symptoms and resource 
use, such as the need for palliative procedures, including transurethral resection of the prostate 
(TURP), colostomy or nephrostomy. 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
58(134) 
3.2.4.6 
Rationale for biomarkers 
The objective of the tumour, blood and urine biomarker research is to collect and store 
samples for future exploratory research to identify possible resistance mechanisms to olaparib, 
and to identify biomarkers that may allow selection of sub-populations that can benefit from 
olaparib treatment. 
Molecular profiling of late stage prostate cancers has defined a number of key genes that may 
identify sub-groups of patients with different risk factors.  Androgen receptor amplification 
and splice variants, PTEN loss, and transmembrane protease serine 2-ERG (TMPRSS2-ERG) 
fusion, have been implicated in regulating disease progression.  The presence of BRCA 
mutations may predict for worse prostate cancer prognosis (Castro et al 2013). 
Phosphatase and tensin homolog (PTEN) loss, occurring in approximately 70% of late stage 
prostate cancers, has been suggested to sensitise cells to PARP inhibitors.  Fusion of 
TMPRSS2 and ERG, found in approximately 50% of late stage prostate cancers, leads to the 
aberrant expression of ERG (an ETS family transcription factor), in response to androgen 
activation of the TMPRSS2 promoter, and consequent activation of genes implicated in 
tumour progression.  Furthermore, ERG has been shown to physically interact with PARP-1, 
and PARP-1 inhibition has been shown to preferentially sensitise ERG over-expressing 
xenograft tumours to PARP inhibition.  Finally, AR splice variants have been associated with 
continued AR signalling and resistance to AR-directed treatments such as abiraterone, and as 
a consequence activation of AR-regulated gene expression such as TMPRSS2-ERG.  Hence, 
there is a rationale for combination of olaparib with abiraterone in prostate cancer, and a 
possibility that this combination may be preferentially active based on measures of 
TMPRSS2-ERG fusion/ERG expression, BRCA mutation, AR and PTEN. 
3.2.4.7 
Rationale for pharmacogenetic samples 
Please refer to Appendix D. 
4. 
PATIENT SELECTION CRITERIA 
Investigator(s) should keep a record, the patient screening log, of patients who entered 
pre-study screening. 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. 
4.1 
Inclusion criteria 
For inclusion in the study, patients should fulfil the following criteria: 
1. 
Provision of signed and dated written informed consent prior to any study specific 
procedures. 
2. 
Male aged 18 years and older. 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
59(134) 
3. 
Histologically or cytologically proven diagnosis of prostate cancer. 
4. 
Candidate for abiraterone therapy with documented evidence of metastatic 
castration-resistant prostate cancer.  Metastatic status is defined as at least one 
documented metastatic lesion on either bone scan or CT/MRI scan.  Castration-
resistant prostate cancer is defined as rising PSA or other signs of disease 
progression despite treatment with androgen deprivation therapy and the presence 
of a castrate level of testosterone (50 ng/dL). 
5. 
Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 with no 
deterioration over the previous 2 weeks. 
6. 
Patients must have a life expectancy 12 weeks. 
7. 
Patients are willing and able to comply with the protocol for the duration of the 
study including undergoing treatment and scheduled visits and examinations, and 
completing PRO instruments. 
8. 
Patients must be on a stable concomitant medication regimen, defined as no 
changes in medication or in dose within 2 weeks prior to start of olaparib dosing, 
except for bisphosphonates, denosumab and corticosteroids, which should be stable 
for at least 4 weeks prior to start of olaparib dosing. 
9. 
For the randomised phase only, patients must have received chemotherapy in the 
form of docetaxel treatment for metastatic castration-resistant prostate cancer.  
Note: patients who discontinued docetaxel for toxicity reasons and without 
completing the full course will still be eligible to enter this study provided they 
received at least 2 cycles of chemotherapy. 
Please refer to Section 3.1 of Appendix D (‘Pharmacogenetics Research’) for inclusion criteria 
for the optional pharmacogenetics research. 
4.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff, its agents and/or staff at the study site). 
2. 
Previous treatment in the present study. 
3. 
Treatment with any of the following: 
− 
Previous exposure to any 2nd generation anti-hormonal including abiraterone 
and enzalutamide 
− 
More than 2 prior courses of chemotherapy for metastatic prostate cancer 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
60(134) 
− 
Previous use of immunotherapy or radium-223 for the treatment of metastatic 
prostate cancer 
− 
Any investigational agents or study drugs from a previous clinical study within 
30 days of the first dose of study treatment 
− 
Any previous exposure to a CYP17 (17Į-hydroxylase/C17,20-lyase) inhibitor 
− 
Substrates of CYP2D6 with a narrow therapeutic index (eg, thioridazine) 
− 
Potent inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of 
study treatment (3 weeks for St John’s Wort) 
− 
Any previous treatment with a PARP inhibitor, including olaparib. 
4. 
With the exception of alopecia or toxicities related to the use of gonadotropin-
releasing hormone agonists, any unresolved toxicities from prior therapy greater 
than CTCAE Grade 2 at the time of starting study treatment. 
5. 
Spinal cord compression or brain metastases unless asymptomatic, treated and 
stable and not requiring steroids for at least 4 weeks prior to start of study treatment. 
6. 
As judged by the Investigator, any evidence of severe or uncontrolled systemic 
diseases, including uncontrolled hypertension, active bleeding diatheses, or active 
infection including hepatitis B, hepatitis C and human immunodeficiency virus 
(HIV).  Screening for chronic conditions is not required. 
7. 
Any of the following cardiac criteria: 
− 
Mean resting QTc >470 msec obtained from 3 ECGs 
− 
Any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECG eg, complete left bundle branch block, third degree heart block 
− 
Any factors that increase the risk of QTc prolongation or risk of arrhythmic 
events such as heart failure, hypokalaemia, congenital long QT syndrome, 
family history of long QT syndrome or unexplained sudden death under 
40 years of age or any concomitant medication known to prolong the QT 
interval. 
8. 
Other malignancy within the last 5 years except: adequately treated non-melanoma 
skin cancer or other solid tumours including lymphomas (without bone marrow 
involvement) curatively treated with no evidence of disease for 5 years. 
9. 
Inadequate bone marrow reserve or organ function as demonstrated by any of the 
following laboratory values: 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
61(134) 
− 
Absolute neutrophil count (ANC) <1.5 x 109/L 
− 
Platelet count <100 x 109/L 
− 
Haemoglobin (Hb) <100 g/L 
− 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>2.5 x upper limit of normal (ULN) if no demonstrable liver metastases or 
>5 x ULN in the presence of liver metastases 
− 
Total bilirubin >1.5 x ULN if no liver metastases or >3 x ULN in the presence 
of liver metastases (except in the case of Gilbert’s disease) 
− 
Creatinine >1.5 x ULN concurrent with creatinine clearance <50 mL/min 
(measured or calculated by Cockcroft and Gault equation); confirmation of 
creatinine clearance is only required when creatinine is >1.5 x ULN 
− 
If bone metastases are present and liver function is otherwise considered 
adequate by the Investigator then elevated alkaline phosphatase (ALP) will not 
exclude the patient. 
10. 
Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to 
swallow the formulated product or previous significant bowel resection that would 
preclude adequate absorption of olaparib or abiraterone. 
11. 
History of hypersensitivity to active or inactive excipients of olaparib or abiraterone 
or drugs with a similar chemical structure or class to olaparib or abiraterone. 
12. 
Patients with myelodysplastic syndrome/acute myeloid leukaemia. 
13. 
Current disease or condition known to interfere with absorption, distribution, 
metabolism, or excretion of drugs, at the Investigator’s discretion. 
14. 
Major surgery within 2 weeks of starting study treatment and patients must have 
recovered from any effects of any major surgery. 
15. 
Judgment by the Investigator that the patient should not participate in the study if 
the patient is unlikely to comply with study procedures, restrictions and 
requirements. 
Please refer to Section 3.1 of Appendix D (‘Pharmacogenetics Research’) for exclusion 
criteria for the optional pharmacogenetics research. 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
62(134) 
5. 
STUDY CONDUCT 
5.1 
Restrictions during the study 
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after: 
Contraception 
Patients and their partners, who are sexually active and of childbearing potential, must agree 
to the use of two highly effective forms of contraception in combination, throughout the 
period of taking study treatment and for 3 months after last dose of study drugs due to the 
unknown effects of the study drugs on the sperm, or they must totally/truly abstain from any 
form of sexual intercourse when this is in line with their preferred and usual lifestyle.  Male 
patients should not donate sperm throughout the period of taking study treatment and for 3 
months following the last dose of study drugs. 
If patients wish to father children they should be advised to arrange for freezing of sperm 
samples prior to the start of study treatment. 
See Appendix L for details of acceptable birth control methods to be used within the study. 
Concomitant medications 
For restrictions regarding concomitant medications, please see Section 5.6. 
Other restrictions 
Patients will be required to fast from at least 2 hours before until 1 hour after each dose of 
olaparib or abiraterone, due to a potential effect of food on absorption.  Water can be allowed 
as desired. 
5.2 
Patient enrolment and randomisation and initiation of 
investigational product 
5.2.1 
Procedures for enrolment 
5.2.1.1 
Part A 
The PI will: 
1. 
Determine patient eligibility.  See Sections 4.1 and 4.2. 
2. 
Obtain signed informed consent from the potential patient before any study-specific 
procedures are performed. 
3. 
Assign each potential patient a unique enrolment code (E-code) beginning with ‘E#’ 
after written informed consent has been obtained, using the centralised Interactive 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
63(134) 
Voice/Web Response System (IVRS/IWRS).  The E-code (EXXXXYYY) will 
consist of a 4-digit centre number (XXXX) and a 3-digit serial number (YYY) 
issued in order of informed consent taken. 
Patient codes will be assigned strictly sequentially as patients are eligible for dosing. 
If a patient withdraws from participation in the study, then his/her enrolment code cannot be 
reused.  If patients discontinue their participation in the study, then they cannot re-enter the 
study. 
5.2.1.2 
Part B 
Informed consent and enrolment using the centralised IVRS/IWRS must occur no more than 
28 days before randomisation (ie, Day -28). 
The PI or delegate will contact the IVRS/IWRS, by telephone or using the web, to register the 
patient when they are entered into the study, and will record a unique E-code assigned to the 
patient by IVRS/IWRS in the patient medical records.  The E-code (EXXXXYYY) will 
consist of a 4-digit centre number (XXXX) and a 3-digit serial number (YYY).  This number 
is the patient’s unique identifier and is used to identify the patient on the eCRF.  The E code 
numbers used in Part A will not be used in Part B. 
All enrolled patients are assigned an E-code and will be listed on the patient enrolment and 
identification log irrespective of whether or not they are subsequently randomised.  If the 
patient is not randomised, the IVRS/IWRS should be contacted to allow the termination of the 
patient in the system.  If a patient withdraws from participation in the study, the patient 
E-code will not be reused. 
If a patient discontinues their participation in the study, they cannot re-enter the study. 
5.2.2 
Procedures for randomisation (Part B only) 
At Visit 2, eligible patients will be randomised centrally using IVRS/IWRS, according to the 
randomisation scheme generated by the Biostatistics Group, AstraZeneca or delegate.  The 
randomisation scheme will be produced by a computer software program called GRand (AZ 
Global Randomisation system) that incorporates a standard procedure for generating random 
numbers.  Patients will be randomised in a 1:1 ratio to either olaparib in combination with 
abiraterone or matching placebo in combination with abiraterone.  The randomisation scheme 
will not be stratified for any factors and will not be stratified by centre or country. 
Once the eligibility of a patient has been confirmed, the Investigator (or nominated assistant) 
should contact the centralised IVRS/IWRS, by telephone or using the web, for allocation of 
randomised therapy.  Patients will be identified to the centralised IVRS/IWRS using patient 
E-code and date of birth (where local regulations allow collection of full date of birth).  The 
IVRS/IWRS will inform the Investigator of the Kit ID number to be allocated to the patient at 
the randomisation visit. 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
64(134) 
5.3 
Procedures for handling patients incorrectly enrolled or 
randomised or initiated on investigational product 
Patients who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be enrolled or receive study medication.  There can be no exceptions to this 
rule. 
Where patients that do not meet the inclusion and/or exclusion criteria, are enrolled in error, or 
incorrectly started on treatment, or where patients subsequently fail to meet the study criteria 
post initiation, a discussion should occur between the AstraZeneca Physician or his/her 
representative and the Investigator regarding whether to continue or discontinue the patient 
from treatment.  Once a decision is made, investigators need to ensure they comply with all 
applicable requirements for human patient protection and ethical review. 
The AstraZeneca Physician or his/her representative is to ensure all such decisions are 
appropriately documented.  In situations where an agreement cannot be reached in terms of 
how best to manage the patient going forward, the patient should have their study therapy 
stopped and a discontinuation visit should be arranged. 
5.4 
Blinding and procedures for unblinding the study 
5.4.1 
Methods for ensuring blinding 
Part A of the study, the safety run-in, is open-label. 
In Part B of the study, olaparib and placebo-matched olaparib treatment will be blinded. 
For Part B of the study, the study medication will be labelled using a unique Kit ID number, 
which is linked to the randomisation scheme.  The active and placebo tablets will be identical 
and presented in the same packaging to ensure blinding of the study medication. 
5.4.2 
Methods for unblinding the study 
Part A of the study, the safety run-in, is open-label. 
For Part B of the study, individual treatment codes, indicating the treatment randomisation for 
each randomised patient, will be available to the Investigator(s) from the IVRS/IWRS.  
Routines for this will be described in the IVRS/IWRS user manual that will be provided to 
each centre. 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation.  The 
Investigator documents and reports the action to AstraZeneca or its representative, without 
revealing the treatment given to the patient to the AstraZeneca staff. 
AstraZeneca or its representative retains the right to break the code for SAEs that are 
unexpected and are suspected to be causally related to an IP and that potentially require 
expedited reporting to regulatory authorities.  Treatment codes will not be broken for the 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
65(134) 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented. 
The study will be centrally unblinded at the time of the primary analysis, but patients and 
Investigators will remain blinded until after the database is verified and closed, and 60% of 
patients have died (the trigger for the OS analysis). 
5.5 
Treatments 
5.5.1 
Identity of investigational product(s) 
The AstraZeneca Pharmaceutical Development R&D Supply Chain will supply the olaparib 
and matching placebo to the Investigator as green film-coated tablets.  Details of the IPs are 
shown in Table 10. 
Table 10 
Identity of investigational product (Olaparib) 
Investigational product 
Dosage form and strength 
Olaparib 
100 mg tablet 
Olaparib 
150 mg tablet 
Placebo to olaparib 100 mg 
Placebo to match olaparib 100 mg tablet 
Placebo to olaparib 150 mg 
Placebo to match olaparib 150 mg tablet 
Full descriptive information for olaparib can be found in the IB. 
For all centres, olaparib and matching placebo will be packed in high density polyethylene 
(HDPE) bottles with child resistant closures.  Each dosing container will contain sufficient 
medication for at least each treatment period plus overage.  Multiple bottles of study treatment 
may be required for dispensing in order to make up the desired dose. 
5.5.2 
Doses and treatment regimens – overview 
In Part A, all patients will take olaparib.  In Part B, patients will be randomised to receive 
either olaparib or placebo.  The olaparib/placebo will be taken bid, in the morning and 
evening.  The doses administered are described in Section 5.5.3. 
All patients will take abiraterone, 1000 mg once daily, at the same time as the 
olaparib/placebo morning dose.  They will also take prednisone or prednisolone 5 mg bid (at 
the same times as the olaparib doses); this medication is indicated in combination with 
abiraterone for the treatment of patients with metastatic CRPC. 
Patients will be required to fast (except water) from at least 2 hours before until 1 hour after 
each dose.  The fasting is a requirement for abiraterone dosing, but will be applied to all study 
treatment doses, for simplicity. 
Patients in Part A, Cohort 2 (and Cohort 3, if required), will receive olaparib alone (Group 1) 
or abiraterone alone (Group 2) for a few days before starting the other treatment in 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
66(134) 
combination, so that steady state olaparib/abiraterone PK can be determined in the absence of 
the other treatment.  The schedules are described in Section 5.5.3, and in Table 6 and Table 7. 
Patients will continue to receive study treatment (ie, olaparib/placebo given in addition to 
abiraterone and prednisone/prednisolone) until disease progression, or until a time when the 
Investigator considers that they are no longer deriving clinical benefit, or they stop taking 
treatment for any other reason including having met any of the criteria for treatment 
discontinuation. 
5.5.3 
Doses and treatment regimens – olaparib/placebo 
5.5.3.1 
Part A 
The olaparib tablets will be administered orally with approximately 240 mL water.  The 
patient will administer their study medication themselves on Day 1, under the supervision of 
the Investigator or his/her delegate, after the required assessments have been completed.  
Thereafter, patients should aim to take their doses at similar times each day, approximately 
12 hours apart.  The tablets should be swallowed whole and not chewed, crushed, dissolved or 
divided. 
Cohort 1 
Each patient will receive 200 mg olaparib (administered as 2 x 100 mg tablets), bid. 
Cohort 2, Group 1 
Each patient will receive 300 mg olaparib (administered as 2 x 150 mg tablets) bid, as 
described for Cohort 1, starting on Day 1. 
Cohort 2, Group 2 
Each patient will receive 300 mg olaparib (administered as 2 x 150 mg tablets) bid, as 
described for Cohort 1, starting after completion of the abiraterone PK profiling (after the 
24-hour sample; see Table 7). 
Cohort 3 
If a 3rd cohort is required, patients will receive 200 mg olaparib (administered as 2 x 100 mg 
tablets) bid, as described for Cohort 2. 
All cohorts 
On clinic days on which PK samples are scheduled to be taken, dosing should be delayed until 
arrival at the clinic and until the pre-dose PK sample has been taken and any other pre-dose 
assessments have been performed.  Patients should not take their dose until instructed to do so 
by the Investigator/Study Nurse.  If a patient takes their dose study medication before arrival 
at the clinic, he or she should return to the clinic the next day (or another suitable day) to have 
the dose and PK samples taken as instructed. 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
67(134) 
Wherever possible, doses should not be missed.  If a patient misses taking a scheduled dose, 
window ±2 hours, they should take the next dose at the next scheduled time and the missed 
dose will not be made up. 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted.  Should any patient enrolled on the 
study miss a scheduled dose for whatever reason (eg, as a result of forgetting to take the 
tablets or vomiting), the patient will be allowed to take the scheduled dose up to a maximum 
of 2 hours after that scheduled dose time.  If greater than 2 hours after the scheduled dose 
time, the missed dose is not to be taken and the patient should take their allotted dose at the 
next scheduled time. 
Any deviations from dosing schedule, dose interruptions, dose reductions and dose 
adjustments should be recorded in the eCRF.  This includes details of vomiting after taking 
study medication (only required for Cohorts 2 and 3), eg, date and time of vomiting in relation 
to dosing. 
5.5.3.2 
Part B 
For Part B of the study, each patient will receive 300 mg olaparib/placebo (administered as 2 x 
150 mg tablets) bid (or 200 mg bid, if 200 mg bid is the maximum tolerated dose in Part A) or 
placebo.  The olaparib/placebo will be administered orally with approximately 240 mL water.  
The patient will administer their study medication themselves on Day 1, under the supervision 
of the Investigator or his/her delegate, after the required assessments have been completed.  
Thereafter, patients should aim to take their doses at similar times each day, approximately 
12 hours apart.  The tablets should be swallowed whole and not chewed, crushed, dissolved or 
divided.  In the event of vomiting, the procedures should be followed as described in 
Section 5.5.3. 
The initial dose of olaparib/placebo can be reduced/adjusted under circumstances described in 
Section 5.10. 
5.5.4 
Additional study drug – abiraterone and prednisone/prednisolone 
Details of the additional study drugs are shown in Table 11.  Abiraterone and prednisolone or 
prednisolone will be sourced locally as commercially available materials. 
Table 11 
Identity of additional study drugs 
Additional study drugs 
Dosage form and strength 
Abiraterone acetate 
250 mg tablet 
Prednisone 
5 mg tablet 
Prednisolone 
5 mg tablet 
 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
68(134) 
Dose interruptions and reductions will not be permitted for abiraterone, prednisone or 
prednisolone only during part A. Dose modifications strategies of abiraterone and prednisone 
or prednisolone during part B are detailed in Section 5.10.1.9. 
5.5.4.1 
Part A 
Cohort 1 
Patients will receive 1000 mg abiraterone once daily in the morning and prednisone or 
prednisolone 5 mg bid.  The tablets should be swallowed whole with water and not crushed or 
chewed.  The patient will administer their study medication themselves on Day 1, under the 
supervision of the Investigator or his/her delegate, after the required assessments have been 
completed.  Patients should aim to take their doses at similar times each day, with the 
prednisone/prednisolone doses approximately 12 hours apart. 
Cohort 2, Group 1 
Patients will receive 1000 mg abiraterone once daily in the morning and prednisone or 
prednisolone 5 mg bid, as described for Cohort 1, starting the day after completion of the 
olaparib PK profiling (any day of Day 4, 5, 6 or 7). 
Cohort 2, Group 2 
Patients will receive 1000 mg abiraterone once daily in the morning and prednisone or 
prednisolone 5 mg bid, as described for Cohort 1, starting on Day 1. 
Cohort 3 
If a 3rd cohort is required, patients will receive abiraterone and prednisone/prednisolone as 
described for Cohort 2, Groups 1 and 2. 
5.5.4.2 
Part B 
Patients will receive 1000 mg abiraterone once daily in the morning and prednisone or 
prednisolone 5 mg bid.  The patient will administer their study medication themselves on 
Day 1, under the supervision of the Investigator or his/her delegate, after the required 
assessments have been completed.  The abiraterone tablets should be swallowed whole with 
water and not crushed or chewed.  Patients should aim to take their doses at similar times each 
day, with the prednisone/prednisolone doses approximately 12 hours apart. 
5.5.5 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language. 
Specific dosing instructions will not be included on the label; the site must complete the 
‘Patient Dispensing Card’ with the details of the dosing instructions at the time of dispensing. 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
69(134) 
The patient emergency contact details will not be on the label, but can be found in the 
informed consent and the ‘Patient Dispensing Card’.  For emergency purposes, the patient 
must be in possession of the emergency contact details at all times. 
Abiraterone, prednisone and prednisolone will be supplied and labelled locally in accordance 
with local procedures if applicable. 
5.5.6 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The IP 
label on the bottle specifies the appropriate storage. 
5.6 
Concomitant and post-study treatment(s) 
5.6.1 
Olaparib and drug-drug interactions 
The use of any natural/herbal products or other traditional remedies should be discouraged, 
but use of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the eCRF. 
Effect of Other Drugs on Olaparib 
CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of 
olaparib. Clinical studies to evaluate the impact of known CYP3A inhibitors and 
inducers  have shown that co-administration of a potent CYP3A inhibitor increased olaparib 
Cmax 1.42-fold (90% CI: 1.33-1.52) and increased mean AUC 2.70-fold (90% CI: 2.44-2.97) 
and that co-administration of a potent CYP inducer decreased Cmax by 71% (Treatment ratio: 
0.29; 90% CI: 0.24-0.33) and mean AUC by 87% (Treatment ratio: 0.13; 90% CI: 0.11-0.16). 
It is therefore recommended that known strong inhibitors or inducers of these isozymes should 
be avoided with olaparib. 
While this is not an exhaustive list, it covers the known potent CYP3A4/5 inhibitors, which 
have most often previously been reported to be associated with clinically significant drug 
interactions: 
• 
ketoconazole, itraconazole, boosted protease inhibitors (ritonavir, indinavir, 
saquinavir, telithromycin, nelfinavir, boceprevir, telaprevir)  and clarithromycin 
For patients taking any of the above, the required washout period prior to starting olaparib is 
1 week. 
In addition, to avoid potential reductions in exposure due to drug interactions, the following 
CYP3A4/5 inducers should be avoided: 
• 
phenytoin, rifampicin, rifapentin, rifabutin, carbamazepine, phenobarbital, 
nevirapine, modafinil, and St. John’s Wort 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
70(134) 
For patients taking any of the above CYP3A4/5 inducers, the required washout periods prior 
to starting olaparib in Part A are: 
• 
phenobarbital, 5 weeks 
• 
for any of the others, 3 weeks. 
If the use of any potent inducers or inhibitors of CYP3A4/5are considered necessary for the 
patient’s safety and welfare during Part B, the Investigator must contact the AstraZeneca 
Physician or their designated Medical Monitor.  A decision to allow the patient to continue in 
the study will be made on a case-by-case basis. 
Long term use of potent inducers and inhibitors of CYP3A4/5should be avoided.  If a decision 
is made to allow patients to use a potent inducer or inhibitor then they must be monitored 
carefully for any change in efficacy or safety of olaparib. 
In vitro olaparib is a substrate for the efflux transporter Pgp. Clinical studies to evaluate the 
impact of known Pgp inhibitors and inducers have not been conducted. 
Effect of Olaparib on Other Drugs 
Olaparib can inhibit CYP3A4 and UGT1A1 in vitro. These findings suggest that olaparib has 
the potential to cause clinically significant interactions with other CYP3A4 substrates or 
UGT1A1 substrates in the liver or gastrointestinal tract. Therefore, caution should be 
exercised when substrates of CYP3A4 are combined with olaparib, in particular those with a 
narrow therapeutic margin (eg, simvastatin, cisapride, cyclosporine, ergot alkaloids, fentanyl, 
pimozide, sirolimus, tacrolimus and quetiapine). Substrates of UGT1A1 should also be given 
with caution in combination with olaparib (eg, irinotecan, nintedanib, ezetimibe, raltegravir or 
buprenorphine). 
Induction of CYP1A2, 2B6 and 3A4 has been shown in vitro with CYP3A4 being most likely 
to be induced to a clinically relevant extent. The potential for olaparib to induce CYP2C9, 
CYP2C19 and Pgp is unknown.  It cannot be excluded that olaparib upon co administration 
may reduce the exposure to substrates of these metabolic enzymes and transport protein. The 
efficacy of hormonal contraceptives may be reduced if co administered with olaparib. 
In vitro olaparib has been shown to be an inhibitor of Pgp, OATP1B1, OCT1, OCT2, OAT3, 
MATE1 and MATE2K and is a weak inhibitor of BRCP. It cannot be excluded that olaparib 
may increase the exposure to substrates of Pgp (eg. statins, digoxin, dabigatran, colchicine), 
OATP1B1 (eg, bosentan, glibenclamide, repaglinide, statins, and valsartan), OCT1 (eg, 
metformin), OCT2 (eg, serum creatinine), OAT3, MATE1 and MATE2K. In particular, 
caution should be exercised if olaparib is administered in combination with any statin. 
5.6.2 
Other concomitant medications 
Any medications, with the exceptions noted in Section 5.6.4 below, which are considered 
necessary for the patient’s welfare, and which are believed will not interfere with the IP, may 


Revised Clinical Study Protocol  
Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
71(134) 
be given at the discretion of the Investigator, providing the medications, the doses, dates, and 
reasons for administration are recorded in the eCRF. 
In addition, any unplanned diagnostic, therapeutic, or surgical procedure performed during the 
study period must be recorded in the comments section of the corresponding AE report. 
Anticoagulant therapy: Patients who are taking warfarin may participate in this study; 
however, it is recommended that prothrombin time (international normalised ratio [INR] and 
activated partial thromboplastin time [aPTT]) be monitored carefully at least once per week 
for the first month, then monthly if the INR is stable.  Subcutaneous heparin is permitted. 
Anti-emetics/anti-diarrhoeals: Prophylactic anti-emetics and/or anti-diarrhoeals will not be 
routinely given.  Should a patient develop nausea, vomiting, and/or diarrhoea, which, in the 
Investigator’s opinion, is considered related to the IP, then appropriate treatment may be 
given. 
Leukopenia and/or anaemia treatment:  The use of colony-stimulating factors (CSFs) (eg, 
granulocyte-CSF [G-CSF], or granulocyte-macrophage CSF [GM-CSF]) should be managed 
as deemed appropriate by the Investigator for the treatment of haematological AEs during 
Part B of the study (see Section 5.10). 
The reason(s) for use, doses, and dates of treatment should be recorded in the patient’s 
medical records and appropriate section of the eCRF. 
All medications (prescriptions or over-the-counter medications) present at the start of the 
study or started during the study or until 30 days from the end of the last protocol treatment 
and different from the IP must be documented in the eCRF. 
5.6.3 
Palliative radiotherapy 
Palliative radiotherapy may be used for the treatment of pain at the site of bony metastases 
that were present at baseline, provided they cannot be managed with local or systemic 
analgesics and that the Investigator does not feel that these are indicative of clinical disease 
progression during the study. 
5.6.4 
Administration of other anti-cancer agents 
Patients must not receive any other concurrent anti-cancer therapy (chemotherapy, 
immunotherapy, biological therapy or other novel agent), including investigational agents, 
while on IP.  Patients may continue the use of bisphosphonates or denosumab for bone 
disease, and corticosteroids, provided the dose is stable before and during the study and they 
were started at least 4 weeks prior to beginning IP (see Section 4.1 and Section 4.2).  The use 
of LHRH-analogues is permitted. 
5.6.5 
Live virus and bacterial vaccines 
Live virus and bacterial vaccines should not be administered whilst the patient is receiving IP 
and during the 30-day follow-up period.  An increased risk of infection by the administration 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
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of live virus and bacterial vaccines has been observed with conventional chemotherapy drugs 
and the effects with olaparib are unknown. 
5.6.6 
Abiraterone, prednisone and prednisolone interactions 
The Investigator should refer to the respective prescribing information for restrictions and 
cautions required when administering concomitant medications with abiraterone, prednisone 
or prednisolone. 
5.7 
Treatment compliance 
The administration of all study drugs (including IPs) should be recorded in the appropriate 
sections of the eCRF. 
Patients should be given clear instructions on how and when to take their study treatment.  
Patients will self-administer olaparib or matching placebo, abiraterone and 
prednisone/prednisolone.  Compliance of the first dose and any doses taken on the day of any 
study visit (except for study treatment supply visits) will be assured by supervised 
administration by the Investigator or delegate.  Study site pharmacy staff will make tablet 
counts at regular intervals during treatment.  Compliance will be assessed by the tablet count 
and the information will be recorded in the appropriate section of the eCRF.  After the tablet 
count has been performed, the remaining tablets will not be returned to the patient but will be 
retained by the Investigative site until reconciliation is completed by the study monitor.  All 
patients must return their bottles of study medication at the appropriate scheduled visit, when 
new bottles will be dispensed.  Patients will be instructed to notify study site personnel of 
missed doses.  Dates of missed or held doses will be recorded on the eCRF. 
Patients in Cohort 2 (and Cohort 3, if conducted), ie, the PK part of the study, will be asked to 
complete a questionnaire to assess their study treatment compliance. 
5.7.1 
Accountability 
The study medications provided for this study are for use only as directed in the study 
protocol.  It is the Investigator/institution’s responsibility to establish a system for handling 
study treatments, including IPs, so as to ensure that: 
• 
Deliveries of such products from AstraZeneca or its representative are correctly 
received by a responsible person 
• 
Such deliveries are recorded 
• 
Study treatments are handled and stored safely and properly as stated on the label 
• 
Study treatments are only dispensed to study patients in accordance with the 
protocol. 
The study personnel will account for all study drugs dispensed to and returned from the 
patient. 


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At the end of the study, it must be possible to reconcile delivery records with records of usage 
and destroyed/returned stock.  Records of usage should include the identification of the person 
to whom the study treatment was dispensed, the quantity and date of dispensing and unused 
study treatment returned to the Investigator.  This record is in addition to any drug 
accountability information recorded on the eCRF.  Any discrepancies must be accounted for 
on the appropriate forms.  Certificates of delivery and return must be signed, preferably by the 
Investigator or a pharmacist, and copies retained in the Investigator site file. 
Study site personnel will account for additional study drugs (ie, abiraterone and prednisolone/ 
prednisone) locally procured at the site, and for appropriate destruction. 
Dispensing and accountability records will continue to be collected for as long as patients 
continue to receive study treatment, although they will not be entered on the database after the 
database has closed. 
5.8 
Discontinuation of investigational product 
Patients may be discontinued from IP in the following situations: 
• 
Patient decision.  The patient is free to discontinue treatment at any time, without 
prejudice to further treatment 
• 
Adverse event 
• 
Severe non-compliance to study protocol 
• 
Objective progression according to RECIST 1.1/PCWG-2 criteria 
• 
The Investigator believes they are no longer deriving clinical benefit. 
In Part B of the study, if patients are discontinued from randomised study treatment for 
reasons other than objective disease progression, they should continue to be followed for 
confirmed progressive disease (RECIST1.1/PCWG-2).  All patients should be followed for 
PFS2 and survival according to the study schedule, unless consent is withdrawn. 
Withdrawal of consent for pharmacogenetic and biological sampling is included in 
Section 7.5. 
5.8.1 
Procedures for discontinuation of a patient from investigational product 
A patient that decides to discontinue IP will always be asked about the reason(s) for 
discontinuation and the presence of any AEs.  If possible, they will be seen and assessed by an 
investigator(s) who will perform the best possible observation(s), test(s), and evaluation(s), as 
well as give appropriate medication and all possible measures for the safety of the patient  
(see Table 4, Table 5 and Table 8 for assessments conducted upon discontinuation).  In 
addition, the Investigator will record on the eCRF the date of discontinuation, the reasons, 
manifestation, and treatment at the time of discontinuation.  The patient should return all IP. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
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Any patient discontinuing IP should also be seen at 30 days (±7 days) after their last dose for 
the evaluations outlined in the study schedule.  All ongoing AEs/SAEs and any new 
AEs/SAEs identified during the 30-day follow up period must be followed to resolution. 
After discontinuation of the IP at any point in the study, all ongoing AEs or SAEs must be 
followed until resolution or stabilisation, in the Investigator’s opinion, the condition is 
unlikely to resolve due to the patient’s underlying disease, or the patient is lost to follow up 
(see Sections 6.4.3 and 6.4.4).  All new AEs and SAEs occurring during the 30 calendar days 
after the last dose of IP must be reported (if SAEs, they must be reported to AstraZeneca or its 
representative within 24 hours as described in Section 6.4.4) and followed to resolution as 
above. 
Patients in Part B should continue to be followed for disease progression (radiologic and 
PFS2) unless they withdraw consent from these assessments and/or the study  
(see Section 5.9). 
If patients discontinue IP, the AstraZeneca monitor or its representative must be informed 
immediately. 
If a patient is withdrawn from study, see Section 5.9. 
5.8.1.1 
Discontinuation of olaparib/placebo only 
If a patient discontinues olaparib/placebo but remains on abiraterone, procedures should be 
followed for the discontinuation and follow-up visits. For randomised part B see Table 9. 
5.8.1.2 
Discontinuation of abiraterone only 
Patients who discontinue abiraterone and remain on olaparib/placebo should continue to be 
seen and have assessments performed as outlined in the study plans (see Table 4, Table 5 and 
Table 8). Once olaparib/placebo treatment is permanently discontinued, procedures should be 
followed for the discontinuation and follow-up visits. For randomised part B see Table 9. 
The date and reasons for discontinuation of abiraterone should be captured in the eCRF. 
5.9 
Withdrawal from study 
Patients are free to withdraw from the study (IP and assessments) at any time, without 
prejudice to further treatment (withdrawal of consent).  Such patients will always be asked 
about the reason(s) and the presence of any AEs.  If possible, they will be seen and assessed 
by an investigator (see Table 4, Table 5 and Table 8 for assessments conducted upon 
discontinuation).  Adverse events will be followed up (see Sections 6.4.3 and 6.4.4).  All study 
drugs should be returned by the patient. 
In Part A of the study, the safety run-in, non-evaluable patients can be replaced to ensure a 
minimum of 3 evaluable patients. 
Withdrawn patients will not be replaced in Part B of the study. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
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Reasons for withdrawal from the study may include: 
• 
Voluntary withdrawal by the patient who is at any time free to discontinue their 
participation in the study, without prejudice to further treatment 
• 
Severe non-compliance to protocol as judged by the Investigator and/or 
AstraZeneca or its representative 
• 
Incorrectly enrolled patients, ie, the patient does not meet the required 
inclusion/exclusion criteria for the study 
• 
Patient lost to follow-up (defined by the inability to reach the patient after 
3 documented phone calls, faxes or emails, and lack of response by the patient to 
one letter by registered/certified mail; all attempts at contact should be documented 
in the patient’s medical records). 
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent 
to: 
• 
further participation in the study including any further follow up (eg, survival calls) 
• 
the use of any samples (see Section 7.5). 
If a patient wishes to withdraw their consent to further participation in the study, including 
survival follow-up, this should be clearly documented in the patient notes and in the clinical 
study database. 
The status of ongoing, withdrawn (from the study) and ‘lost to follow-up’ patients at the time 
of an OS analysis should be obtained by the site personnel by checking the patients notes, 
hospital records, contacting the patients general practitioner and checking publicly available 
death registries.  In the event that the patient has actively withdrawn consent to the processing 
of their personal data, the survival status of the patient can be obtained by site personnel from 
publicly available resources where it is possible to do so under applicable local laws. 
After withdrawal from the study, patients will continue to receive standard treatment 
according to their own doctor’s discretion. 
See Appendix D for details of withdrawal from optional pharmacogenetic research. 
5.10 
Guidance for Investigators 
5.10.1 
Dose reduction and toxicity management strategy 
Dose interruptions are not permitted in Part A of the study until after all PK assessments are 
complete. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
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If a patient’s dose is reduced or interrupted at the time of a scheduled study visit, they should 
still attend the clinic for the scheduled assessments. 
For olaparib/placebo, once dose is reduced escalation is not permitted.  
5.10.1.1 Management of toxicity of study treatment 
Any toxicity observed during the course of the study may be managed by interruption of the 
dose of study treatment if deemed appropriate by the Investigator.  Repeat dose interruptions 
are allowed as required, for a maximum of 14 days on each occasion.  If the interruption is 
any longer than this the AstraZeneca study team must be informed.  Study treatment must be 
interrupted until the patient recovers completely or the toxicity reverts to CTCAE Grade 1 or 
less. 
Where toxicity reoccurs following re-challenge with study treatment, and where further dose 
interruptions are considered inadequate for management of toxicity, then the patient should be 
considered for dose reduction or must permanently discontinue study treatment.  Treatment 
must be interrupted if any CTCAE Grade 3 or 4 AE occurs which the Investigator considers to 
be related to administration of study treatment. 
5.10.1.2 Management of anaemia 
Adverse events of anaemia CTCAE Grade 1 or 2 (Hb 8 g/dL) should be investigated and 
managed as deemed appropriate by the Investigator with or without interruption of study drug 
or change in dose, taking into account previous history of anaemia. For reference see Table 
12. 
Table 12 
Management of anaemia  
Haemoglobin 
Action to be taken 
Hb < 10 but  8 g/dl 
(CTCAE Grade 2) 
Give appropriate supportive treatment and investigate causality.  
Investigator judgement to continue olaparib with supportive treatment  
(eg transfusion) or interrupt dose for a maximum of 4 weeks.  
If repeat Hb< 10 but  8 g/dl, dose interrupt (for max of 4 weeks) until 
Hb  10 g/dl and upon recovery dose reduction to 250 mg twice daily as 
a first step and to 200 mg twice daily as a second step may be considered.
Hb < 8 g/dl 
Give appropriate supportive treatment (e.g. transfusion) and investigate 
causality.  
Interrupt olaparib for a maximum of 4 weeks until improved to  
Hb  10 g/dl. 
Upon recovery dose reduce to 250 mg twice daily as a first step and to 
200 mg twice daily as a second step in the case of repeat Hb decrease. 
 
Common treatable causes of anaemia (eg, iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  In some cases, 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
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management of anaemia may require blood transfusions.  For cases where patients develop 
prolonged haematological toxicity (2 week interruption/delay in study treatment due to 
CTCAE Grade 3 [Hb <8 g/dL] or worse anaemia and/or development of blood transfusion 
dependence), refer to Section 5.10.1.5 for the management of this. 
5.10.1.3 Management of neutropenia and leukopenia 
Adverse events of neutropenia and leukopenia should be managed as deemed appropriate by 
the Investigator with close follow-up and interruption of study drug if CTCAE Grade 3 or 
worse neutropenia occurs.  Primary prophylaxis with G-CSF is not recommended; however, if 
the patient develops febrile neutropenia, study treatment should be stopped and appropriate 
management including G-CSF should be given according to local hospital guidelines.  Please 
note that G-CSF should not be used within at least 24 hours of the last dose of study treatment. 
Study treatment can be restarted at the same dose if an AE of neutropenia or leucopenia have 
been recovered up to CTCAE Grade >1 (ANC >1.5 x 109/L).  Growth factor support should 
be stopped at least 24 hours before restarting study drug (7 days for pegylated G-CSF).  Any 
subsequent interruptions will require study treatment dose reductions to 250 mg bid as a first 
step and to 200 mg bid as a second step. 
5.10.1.4 Management of thrombocytopenia 
An AE of thrombocytopenia should be managed as deemed appropriate by the Investigator.  If 
a patient develops thrombocytopenia CTCAE Grade 3 or worse study treatment should be 
interrupted for a maximum of 4 weeks.  In some cases, management of thrombocytopenia may 
require platelet transfusions.  Platelet transfusions should be done according to local hospital 
guidelines. 
5.10.1.5 Management of prolonged haematological toxicities while on study treatment 
If the patient develops prolonged haematological toxicity such as: 
• 
2 week interruption/delay in study treatment due to CTCAE Grade 3 or worse 
anaemia and/or development of blood transfusion dependence 
• 
2 week interruption/delay in study treatment due to CTCAE Grade 3 or worse 
neutropenia (ANC <1 x 109/L) 
• 
2 week interruption/delay in study treatment due to CTCAE Grade 3 or worse 
thrombocytopenia (platelets <50 x 109/L) 
Weekly differential blood counts including reticulocytes (calculate reticulocyte index, RI1) 
and peripheral blood smear should be performed.  If blood parameters remain clinically 
abnormal after 4 weeks of dose interruption or if more than one blood cell line is affected, the 
                                                 
1 RI = reticulocyte count x haematocrit (Hct)/normal Hct.  A value of 45 is usually used for normal Hct. 


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Edition Number 2 
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patient should be referred to a haematologist for further investigations.  Bone marrow analysis 
or blood cytogenetic analysis should be considered at this stage; see Section 6.4.5.3. 
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should 
be reported as a SAE and full reports must be provided by the Investigator to AstraZeneca 
Patient Safety.  Study treatment should be discontinued if diagnosis of myelodysplastic 
syndrome is confirmed. 
5.10.1.6 Management of new or worsening pulmonary symptoms 
If new or worsening pulmonary symptoms (eg, dyspnoea) or radiological abnormality occurs, 
an interruption in study treatment dosing is recommended and a diagnostic workup (including 
a high resolution CT scan) should be performed, to exclude pneumonitis.  Following 
investigation, if no evidence of abnormality is observed on CT imaging and symptoms 
resolve, then study treatment can be restarted, if deemed appropriate by the Investigator.  If 
significant pulmonary abnormalities are identified, these need to be discussed with the 
AstraZeneca Study Physician or representative. 
5.10.1.7 Management of nausea and vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment.  In study 
D0810C00019, nausea was reported in 71% of the olaparib treated patients and 36% in the 
placebo treated patients, and vomiting was reported in 34% of the olaparib treated patients and 
14% in the placebo treated patients.  They are generally mild to moderate (CTCAE Grade 1 or 
2) severity, intermittent and manageable on continued treatment.  The first onset generally 
occurs in the first month of treatment with the incidence of nausea and vomiting not showing 
an increase over the treatment cycles. 
No routine prophylactic anti-emetic treatment is required at the start of study treatment; 
however, patients should receive appropriate anti-emetic treatment at the first onset of nausea 
or vomiting and as required thereafter in accordance with local treatment practice guidelines. 
5.10.1.8 Interruptions for intercurrent non-toxicity related events 
Study treatment dose interruption for conditions other than toxicity resolution should be kept 
as short as possible.  If a patient cannot restart study treatment within 4 weeks for resolution 
of intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with the AstraZeneca Study Physician or representative. 
If a patient discontinues treatment for intercurrent condition and progresses while off 
treatment, they can restart study treatment if the Investigator feels the patient is receiving 
clinical benefit.  Please note that evidence of objective radiological disease progression is 
required. 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
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If a patient discontinues study treatment whilst having a dose interruption, the discontinuation 
should be recorded using the date at which the decision to discontinue was made and not the 
last dose of study treatment. 
Study treatment should be stopped at least 3 days prior to planned surgery.  After surgery, 
study treatment can be restarted when the wound has healed.  No stoppage of study treatment 
is required for any biopsy procedure. 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
therapeutic palliative radiation treatment.  Study treatment should be restarted within 4 weeks 
as long as any bone marrow toxicity has recovered. 
The dose reduction schedule is shown in Table 13. 
Table 13 
Dose reductions for olaparib 
Reduction 
Dose level (tablets) 
Initial dose level 
300 mg bid (2 x 150 mg tablets) 
1st dose reduction due to CTCAE Grade 3 or 
4 treatment-related SAE/AEs 
250 mg bid 
(1 x 150 mg tablet and 1 x 100 mg tablet) 
2nd dose reduction due to CTCAE Grade 3 or 
4 treatment related SAE/AEs 
200 mg bid 
(2 x 100 mg tablets) 
 
5.10.1.9 Dose management of abiraterone and prednisone/prednisolone 
Please refer to the respective, locally applicable prescribing information for further details and 
for any additional restrictions or cautions required due to the administration of abiraterone or 
prednisone/prednisolone. 
6. 
COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
The InForm Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The Investigator will ensure that data are recorded on the eCRFs as specified 
in the study protocol and in accordance with the instructions provided. 
The Investigator ensures the accuracy, completeness and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA).  
The Investigator will sign the completed eCRF.  A copy of the completed eCRFs will be 
archived at the study site. 


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Edition Number 2 
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6.2 
Data collection at enrolment and follow-up 
See Table 4, Table 5 and Table 8 and refer to Section 3.1 for details on procedures/ 
assessments required at all time points throughout the study. 
It is important that PK sampling occurs as close as possible to the scheduled time.  In order to 
achieve this, other assessments scheduled at the same time may be initiated prior to the time 
point.  The sequence to be followed at a particular post-dose time point is: 
1. 
Vital signs 
2. 
PK blood sample (at scheduled time) 
3. 
Any other assessments. 
6.2.1 
Post-treatment 
For patients who discontinue study treatment in Part A, there will be no further follow-up or 
data collection after their 30-day follow-up visit. 
Patients who discontinue study treatment in Part B will be followed up until disease 
progression.  Thereafter, they will be followed up for PFS2 and survival in accordance with 
the study plan (see Table 8). 
Dispensing and accountability records will continue to be collected after follow-up for as long 
as patients continue to receive IP. 
6.3 
Efficacy 
The primary and all secondary endpoints will be analysed using the full analysis set unless 
otherwise stated. 
6.3.1 
Measures of tumour progression and response 
Disease progression will be deemed to have occurred if one or more of the following criteria 
is met: 
• 
Soft tissue disease progression as defined by RECIST 1.1  
• 
Bone lesion progression as defined by PCWG-2 bone scan 
• 
Death. 
6.3.1.1 
RECIST 1.1 assessment of soft tissue malignant disease 
RECIST v1.1 guidelines for the assessment of target lesions (TLs), non-target lesions (NTLs), 
new lesions (NLs), and malignant soft tissue tumour response are presented in Appendix F. 


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Edition Number 2 
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In this study, bone lesions will not be included in the RECIST assessment as NTLs.  For 
bone lesion assessments, see Section 6.3.1.2. 
Baseline tumour assessments (CT/MRI scans of the chest, abdomen and pelvis) may include 
additional areas that may be involved, based on signs and symptoms of individual patients. 
Baseline assessments should be performed no more than 4 weeks (28 days) before 
randomisation and should be performed as close as possible to the start of study treatment. 
The methods of assessment used at baseline should be used at each subsequent follow-up 
assessment.  Assessments should be repeated every 12 weeks (±1 week) from start of olaparib 
treatment until disease progression, death, or withdrawal of consent (every 24 weeks after 
Week 72).  Any other sites at which new disease is suspected should be managed 
appropriately.  If an unscheduled assessment is performed and there is no evidence of disease 
progression, every attempt should be made to perform subsequent assessments at the 
scheduled visits. 
Categorisation of objective tumour response assessment of soft tissue lesions will be based on 
the RECIST v1.1 guidelines for response: complete response (CR), partial response (PR), 
stable disease (SD), progression of disease (PD), no evidence of disease (NED) and not 
evaluable (NE).  Target lesion progression will be calculated by comparing the tumour burden 
at progression with the smallest burden (ie, the smallest sum of diameters) observed at any 
prior assessment during the study.  In the absence of progression, tumour response (CR, PR, 
SD) will be calculated in comparison to the baseline tumour measurements obtained before 
starting treatment. 
Patients with no disease at baseline will be assessed according to RECIST 1.1 criteria for new 
lesions, with responses of NED or progression of disease. 
For patients who only have non-measurable disease at baseline, categorisation of objective 
tumour response assessment will be based on the modified RECIST v1.1 guidelines for 
response for NTLs: CR, PD and Non CR/Non PD. 
If the Investigator is in doubt as to whether progression has occurred, particularly with regard 
to NTLs or the appearance of a new lesion, it is advisable to continue treatment and reassess 
the tumour burden at the next scheduled assessment or sooner if clinically indicated. 
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more NTLs is usually 
not sufficient to qualify for unequivocal disease progression status. 
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
study plan in Table 8, and to Appendix F. 


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Study Code D081DC00008 
Edition Number 2 
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6.3.1.2 
PCWG-2 bone scan 
Bone lesions will be assessed by bone scintigraphy (bone scans).  Guidelines for the 
assessment of bone lesions are presented in Appendix F.  A baseline bone scan should be 
performed no more than 28 days before randomisation, and ideally should be performed as 
close as possible to the start of study treatment.  Subsequent assessments will be performed 
every 12 weeks (±1 week) from the start of treatment until disease progression, death, or 
withdrawal of consent (every 24 weeks after Week 72). 
Bone lesions will be assessed by bone scan and will not be part of the RECIST v1.1 malignant 
soft tissue assessment.  Positive hot spots on the bone scan should be considered significant 
and unequivocal sites of malignant disease to be recorded as metastatic bone lesions. 
If an unscheduled assessment, eg, confirmation of progression scan, is performed and there is 
no evidence of disease progression, every attempt should be made to perform the subsequent 
assessments at their scheduled visits while the patient remains on study treatment. 
Progression on a bone scan is assessed as: 
• 
At the 12 week scan: 
If 2 or more new metastatic bone lesions are observed on the first 12-week scan, the 
confirmatory scan performed, preferably at the next scheduled visit for a bone scan 
(ie, Week 24) and at least 6 weeks later, must show 2 or more additional new 
metastatic bone lesions (for a total of 4 or more new metastatic bone lesions since 
the baseline assessment) for progression to be documented. 
• 
After the 12 week scan: 
If 2 or more new metastatic bone lesions are observed on scans obtained after the 
first 12-week assessment, confirmatory scan performed preferably at the next 
scheduled visit for a bone scan (eg, Week 36) and at least 6 weeks later needs to 
show the persistence of or an increase in the number of metastatic bone lesions 
compared to the prior scan. 
The date of progression is the date of the first scan that shows the change. 
If the Investigator is in doubt as to whether progression has occurred, it is advisable to 
continue study treatment and reassess the bone lesion status at the next scheduled assessment, 
or sooner if clinically indicated. 
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
study plan in Table 8, and to Appendix F. 
Table 14 provides the definitions of the criteria to determine tumour visit response for bone 
lesions. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
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Date 20 October 2015 
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Table 14 
Overall PCWG-2 response for bone lesions 
Non–progressive disease (non-PD) 
Persistence of one or more bone lesions or disappearance of all 
bone lesions 
Progressive disease (PD) 
Bone lesions fulfilling the requirements for new lesions and 
confirmation of progression 
Non evaluable (NE) 
Only relevant if a bone scan is not performed at that visit 
 
For full details of the bone lesions assessments, please see Appendix F. 
6.3.1.3 
Second progression 
Following the progression event used for the primary variable rPFS (the first progression), 
patients will be assessed every 12 weeks for PFS2 (using the patient’s status at first 
progression as the reference for assessment of PFS2).  A patient’s PFS2 status is defined 
according to local standard clinical practice and may involve any of: objective radiological 
progression, symptomatic progression, PSA or death (see Section 11.1.3.1).  RECIST 1.1 and 
PCWG-2 assessments will not be collected for assessment of PFS2.  The date of PFS2 
assessment and investigator opinion of progression status (progressed or non-progressed) at 
each assessment will be recorded in the eCRF. 
Standard of care local PSA values should be collected at the time of PFS2 and included on the 
database. 
6.3.2 
Overall survival (OS) 
Assessments for survival will be conducted every 12 weeks following objective disease 
progression or treatment discontinuation.  Survival information may be obtained via telephone 
contact with the patient, patient’s family, by contact with the patient’s current physician, or 
local death registries as described in Section 3.1.5.  The details of first and subsequent 
therapies for cancer, after discontinuation of treatment, will be collected. 
6.3.3 
Time to subsequent therapies for prostate cancer 
Following the discontinuation of olaparib, the time from randomisation to first and second 
subsequent therapies for prostate cancer (TFST and TSST) will be measured. 
6.3.4 
Patient management post-primary analysis 
The data cut-off date for the statistical analysis for the primary objective of the study will be 
established when ~100 confirmed progression events are expected to have occurred. 
The study will be centrally unblinded at this time, but patients and Investigators will remain 
blinded.  After the primary rPFS analysis, patients will continue to be assessed by RECIST 
1.1/PCWG-2 until disease progression; assessments will be conducted every 12 weeks up to 
and including Week 72, and every 24 weeks thereafter.  Patients on study treatment at the time 


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of the data cut-off will continue to receive study treatment until they meet any discontinuation 
criteria as described in Section 5.8. 
6.3.5 
Patient management post-final analysis 
The data cut off date for the final statistical analysis of the study will be established when 
~60% deaths have occurred. 
At this time point, the clinical study database will close to new data and all patients will be 
unblinded.  Patients who are still receiving olaparib can either choose to discontinue from the 
study or, where the Investigator believes patients are gaining clinical benefit, patients may 
continue to receive olaparib.  All patients will receive follow-up care in accordance with 
standard local clinical practice.  Patients that are on placebo will not be offered olaparib as a 
study treatment. 
Serious adverse events will continue to be reported to AstraZeneca Patient Safety Department, 
for any patients who continue on olaparib until 30 days after study treatment is discontinued, 
in accordance with Section 6.4.4.  Additionally, as stated, any SAE or non-serious AE that is 
ongoing at the end of the study must be followed up to resolution unless the event is 
considered by the Investigator to be unlikely to resolve, or the patient is lost to follow-up.  If 
an Investigator learns of any SAEs, including death, at any time after a patient has completed 
the study, and he/she considers there is a reasonable possibility that the event is causally 
related to the investigational product, the Investigator should notify AstraZeneca, Patient 
Safety. 
Drug accountability should continue to be performed until the patient stops study treatment 
completely. 
6.4 
Safety 
The PI is responsible for ensuring that all staff involved in the study is familiar with the 
content of this section. 
6.4.1 
Definition of adverse events 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, ECG).  In clinical studies, an AE 
can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
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6.4.2 
Definitions of serious adverse event 
A SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-up), 
that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalisation or prolongation of existing hospitalisation  
• 
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above. 
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol. 
6.4.3 
Recording of adverse events 
Time period for collection of adverse events 
Adverse events will be collected from the time of signature of informed consent, throughout 
the treatment periods, and up to and including the 30-day (±7 days) follow-up visit after 
discontinuation of study treatment, until the time of the final analysis (rPFS).   
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the patient’s last AE assessment in the study (ie, 30-day 
follow-up visit) are followed up by the Investigator for as long as medically indicated, but 
without further recording in the eCRF.  AstraZeneca or its representative retains the right to 
request additional information for any patient with ongoing AE(s)/SAE(s) at the end of the 
study, if judged necessary. 
Post follow-up adverse events 
After study treatment completion (ie, after any scheduled post-treatment follow-up period has 
ended) there is no obligation to actively report information on new AEs or SAEs occurring in 
former study patients.  However, if an investigator learns of any SAEs, including death, at any 
time after a patient has completed the study and he/she considers there is a reasonable 
possibility that the event is related to olaparib, the Investigator should notify AstraZeneca, 
Patient Safety department or its representative. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
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Variables 
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
The maximum CTCAE grade attained 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against olaparib/placebo (yes or no) 
• 
Action taken with regard to olaparib/placebo 
• 
Causality assessment in relation to abiraterone, prednisone or prednisolone 
• 
AE caused patient’s withdrawal from study (yes or no) 
• 
Outcome. 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date Investigator became aware of SAE 
• 
AE is serious due to [reason] 
• 
Date of hospitalisation 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Description of AE. 
Severity of AE 
The grading scales found in the revised National Cancer Institute CTCAE (NCI-CTCAE) 
version 4.0 will be utilised for all events with an assigned CTCAE grading  


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Drug Substance Olaparib (AZD2281, KU-0059436)  
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(CTCAE v4.03 2010).  For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate and severe events into 
CTCAE grades should be used. 
A copy of the CTCAE version can be downloaded from the United States Department of 
Health and Human Services, National Institutes of Health, National Cancer Institute website 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf) . 
For each episode, the highest severity grade attained should be reported. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.4.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE. 
Causality collection 
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?’ 
Causal relationship will also be assessed for additional study drug (AEs and SAEs) and study 
procedures (SAEs only).  Note that for SAEs that could be associated with any study 
procedure the causal relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol. 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit?’, or 
revealed by observation will be collected and recorded in the eCRF.  When collecting AEs, 
the recording of diagnoses is preferred (when possible) to recording a list of signs and 
symptoms.  However, if a diagnosis is known and there are other signs or symptoms that are 
not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately. 
Adverse events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report (CSR).  Deterioration as compared to baseline in protocol-mandated 
laboratory values, vital signs and other safety variables should therefore only be reported as 
AEs if they fulfil any of the SAE criteria or are the reason for discontinuation of treatment 
with the IP. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
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If deterioration in a laboratory value/vital sign/ECG is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result/vital sign/ECG will be considered as additional information.  Wherever possible the 
reporting investigator uses the clinical, rather than the laboratory term (eg, anaemia versus low 
Hb value).  In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
NB. Cases where a patient shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT 3xULN together with total bilirubin 2xULN 
may need to be reported as SAEs.  Please refer to Appendix E ‘Actions required in cases of 
combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’for further 
instructions on cases of increases in liver biochemistry and evaluation of Hy’s Law. 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease.  Expected progression of 
the patient’s cancer and/or expected progression of signs and symptoms of the cancer, unless 
more severe in intensity or more frequent than expected for the patient’s condition, should be 
considered as disease progression and not as an AE.  Any events that are unequivocally due to 
disease progression should not be reported as an AE during the study. 
New cancers 
The development of a new primary cancer (including skin cancers) should be regarded as an 
AE and will generally meet at least one of the serious criteria (see Section 6.4.2).  New 
primary cancers are those that are not the primary reason for the administration of the IP and 
have developed after the inclusion of the patient into the study. They do not include 
metastases of the original cancer. Symptoms of metastasis or the metastasis itself should not 
be reported as an AE/SAE, as they are considered to be disease progression. 
Lack of efficacy 
When there is deterioration in the condition for which the IP(s) is being used (prostate cancer), 
there may be uncertainty as to whether this is lack of efficacy or an AE.  In such cases, unless 
the Sponsor or the reporting physician considers that the IP contributed to the deterioration of 
the condition, or local regulations state to the contrary, the deterioration should be considered 
to be a lack of efficacy and not an AE. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
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Deaths 
All deaths that occur during the study, or within the protocol-defined 30-day post-study 
follow-up period after the administration of the last dose of IP, must be reported as follows: 
• 
Death that is clearly the result of disease progression should be reported to the study 
monitor at the next monitoring visit and should be documented in the eCRF but 
should not be reported as a SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to the study monitor as a SAE 
within 24 hours (see Section 6.4.2 for further details).  The report should contain a 
comment regarding the co-involvement of progression of disease, if appropriate, 
and should assign main and contributory causes of death.  This information can be 
captured in the ‘death CRF’. 
• 
Deaths with an unknown cause should always be reported as a SAE.  A post 
mortem may be helpful in the assessment of the cause of death, and if performed a 
copy of the post-mortem results should be forwarded to AstraZeneca or its 
representative within the usual timeframes. 
6.4.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
appropriate AstraZeneca representatives immediately, or no later than 24 hours of when he 
or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within one 
calendar day of initial receipt for fatal and life threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
Once the investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative. 
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone. 


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The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed. 
The reference document for definition of expectedness/listedness is the IB for olaparib and the 
European Union (EU) Summary of Product Characteristics (SPC) for the abiraterone, 
prednisone and prednisolone. 
6.4.5 
Laboratory safety assessment 
Blood samples for determination of clinical chemistry and haematology will be taken at the 
times indicated in the Study Plans (see Table 4, Table 5 and Table 8). 
These tests will be performed by the hospital’s local laboratory.  Additional analyses may be 
performed if clinically indicated.  Routine urinalysis should be performed if clinically 
indicated. 
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF. 
For blood volume see Section 7.1. 
The following laboratory variables will be measured: 
6.4.5.1 
Full haematology assessments for safety 
• 
Haemoglobin  
• 
Red blood cells [RBC] 
• 
Platelets 
• 
Mean cell volume [MCV] 
• 
Mean cell haemoglobin concentration [MCHC]  
• 
Mean cell haemoglobin [MCH] 
• 
White blood cells [WBC] 
• 
Absolute differential white cell count (neutrophils, lymphocytes, monocytes, 
eosinophils and basophils) and absolute neutrophil count (ANC) or segmented 
neutrophil count and band forms should be performed at each visit and when 
clinically indicated; if absolute differentials not available please provide 
% differentials 
• 
Activated partial thromboblastin time (APTT) and international normalised ratio 
(INR) will be performed if clinically indicated.  For patients taking warfarin, INR 


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and APTT should be measured at baseline, and periodic monitoring during the 
study is recommended as described in Section 5.6.2. 
6.4.5.2 
Clinical chemistry assessments for safety 
• 
Sodium 
• 
Potassium 
• 
Calcium  
• 
Creatinine 
• 
Total bilirubin 
• 
ALP 
• 
AST 
• 
ALT 
• 
Urea or blood urea nitrogen [BUN] 
• 
Total protein 
• 
Albumin 
• 
Lactic dehydrogenase [LDH]. 
NB. In case a patient shows an AST or ALT 3xULN together with total bilirubin 2xULN 
please refer to Appendix E ‘Actions required in cases of combined increase of 
Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions. 
If a patient has an AST or ALT 5xULN or total bilirubin 3xULN, then abiraterone 
treatment should be interrupted and liver function tests closely monitored. 
6.4.5.3 
Bone marrow or blood cytogenetic samples 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
haematological toxicities as defined in Section 5.10.1.5.  
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity.  If it is not 
possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to carry out the tests on a blood sample.  Full reports must be 
provided by the investigator for documentation on the Patient Safety database. 


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6.4.6 
Physical examination 
For timing of individual measurements, please refer to the study plans (see Table 4, Table 5 
and Table 8). 
Full physical examinations will be performed, including height and weight (screening only), 
BP, pulse and temperature. 
Performance status will be assessed using the ECOG scale (see Appendix G) at baseline and 
as outlined in the study schedule. 
6.4.7 
Resting 12-lead ECG 
Twelve-lead ECGs will be conducted at screening and when clinically indicated. 
The ECGs will be obtained after the patient has been rested in a supine position for at least 
5 minutes in each case.  All 12-lead ECGs should be recorded while the patient is in the 
supine position.  The Investigator or designated physician will review the paper copies of each 
12-lead ECG. 
All ECGs should be assessed by the Investigator as to whether they are clinically significantly 
abnormal or not clinically significantly abnormal.  If there is a clinically significant abnormal 
finding, the Investigator will record it as an AE on the eCRF.  A copy of the ECG indicating 
the study number, without patient identifiers, will be included in the patient’s study file for 
monitoring by the study monitor. 
6.4.8 
Vital signs 
Vital signs (including body temperature, where indicated) will be measured at the times 
specified in the study plans (see Table 4, Table 5 and Table 8).  However, the Investigator 
reserves the right to add extra assessments if there are any abnormal findings or for any other 
reason the Investigator feels meets this requirement. 
6.4.8.1 
Pulse and blood pressure 
Supine BP and pulse will be measured using a semi-automatic BP recording device with an 
appropriate cuff size after the patient has been resting in bed for 10 minutes. 
Deterioration as compared with baseline in protocol-mandated vital signs should only be 
reported as AEs if they fulfil any of the SAE criteria or are the reason for discontinuation of 
treatment with the IP, or the Investigator insists the abnormality should be reported as an AE. 
6.4.8.2 
Body temperature 
Body temperature will be measured in degrees Celsius. 
6.4.9 
Safety guidance for the use of abiraterone 
The prescribing information for abiraterone suggests the following assessments.  These 
additional data do not need to be recorded on the study database. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
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• 
Serum transaminases should be measured every 2 weeks for the first 3 months of 
treatment and monthly thereafter 
• 
Blood pressure, serum potassium and fluid retention should be monitored monthly 
• 
To mitigate the risk of hypokalaemia and also QTc prolongation, the patient’s 
potassium level should be maintained at 4.0 mM at inclusion and during the study. 
6.5 
Patient reported outcomes (PRO) 
Each centre must allocate responsibility for monitoring compliance with completion of the 
PRO questionnaires described in this section to a specific individual (eg, a Research Nurse).  
The Clinical Team will arrange for relevant training in administration of the questionnaires.  
The PRO questionnaires should be administered and completed at the clinic in accordance 
with the study plans (see Table 8 and Table 9).  Patients must complete the BPI-SF, the worst 
bone pain item, then the FACT-P questionnaire.  These instruments should be completed prior 
to the EQ-5D-5L. 
It is also important that the significance and relevance of the data are explained carefully to 
participating patients so that they are motivated to comply with data collection. 
The date of completion of each PRO questionnaire should be recorded. 
The instructions for completion of each PRO are as follows: 
1. 
It must be completed in private by the patient in their own time 
2. 
It must be completed by the patient before any investigations or discussions about 
their disease with the clinic staff 
3. 
On completion of the questionnaire it should be handed back to the PRO designated 
person who should check for completeness 
4. 
Only 1 answer should be recorded for each question 
5. 
The patient should not receive help from relatives, friends or clinic staff to answer 
the questionnaire.  However, if the patient is unable to read the questionnaire (eg, is 
blind or illiterate) the questionnaire may be read out and responses recorded; this 
should be documented, along with the reason why, on the cover page. 
Once a patient has left the clinic, they cannot be queried (for example, if they missed an item).  
The clinical nurse should quickly make sure that no items have been skipped as soon as the 
patient turns in the form.  If he/she notices an item is missing, the patient can be asked if they 
would mind completing the one item.  If the patient replies that they do not wish to complete 
the item, then it should be left blank and it should be noted by the clinical nurse that this was 
checked. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
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Health-related quality of life data should be monitored on a site by site basis.  If it is noted that 
a site has a lot of missing HRQL forms or a lot of missing data within forms, the clinical trials 
monitor should contact the site and assess what is causing the difficulty and take measures to 
improve the situation.  AstraZeneca may be involved in this. 
6.5.1 
Brief Pain Inventory – Short Form (BPI-SF) 
Worst pain, general pain and pain’s interference with daily life will be assessed during Part B 
of the study using the BPI-SF (see Appendix H) at the times outlined in the study plan 
(Table 8).  The BPI-SF comprises a total of 15 items measuring 2 domains: pain severity and 
pain interference.  Items measuring pain severity (including ‘worst pain’) are rated on an 
11-point NRS ranging from 0=No pain to 10=Pain as bad as you can imagine.  All BPI-SF 
items are measured using a 24-hour recall period. 
6.5.2 
Bone pain item 
Patients will also be asked to rate their worst bone pain severity on a 0 to 10 point NRS at the 
same times as the BPI-SF, as outlined in the study plan (Table 8).  The worst bone pain item 
will be developed specifically for this study, following the same format as the BPI-SF worst 
pain item, again with a 24-hour recall period (see Appendix I). 
6.5.3 
Investigator administration of BPI-SF and bone pain item over the telephone 
The BPI-SF ‘worst pain’ item and the newly developed ‘worst bone pain’ item will be 
administered over the telephone to patients being followed up for PFS2 and survival  
(see Table 9).  The instructions, questions and response options for these items will all be read 
out to the patient, and the patients will provide responses to each question over the telephone.  
The individual responsible for administering the questions must accurately record the patient’s 
responses onto the paper questionnaire.  Following completion of the questionnaire items with 
the patient over the telephone, the site staff can either enter the information into the electronic 
database system or arrange to have the paper questionnaire items sent to the Data 
Management centre for database entry. 
Each centre must allocate the responsibility for the administration of the questionnaire items 
to a specific individual (eg, a research nurse, study co-ordinator) and if possible assign a back-
up person to cover if that individual is absent.  The AstraZeneca Study Team (or delegate) will 
provide relevant training in administration of the questionnaires.  The significance and 
relevance of the data need to be explained carefully to participating patients so that they are 
motivated to comply with data collection.  Additionally, as the questionnaire items are to be 
administered over the telephone, individuals administering the questionnaires to patients must 
adhere to all instruction for completion, which are as follows: 
• 
The items must be completed prior to any discussion of disease progress to avoid 
biasing the patient’s responses to the questions. 
• 
All instructions, questions and available response options for each item should be 
read aloud by the administrator word for word, with absolutely no paraphrasing. 


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• 
All instructions, questions and response options should be read slowly to the 
patient. 
− 
If a patient misheard any aspect of the instructions, items or response options, 
all information should be repeated to the patient, slowly. 
• 
The patient should be given sufficient time to provide a response to each question at 
their own pace. 
• 
The patient should not receive help from relatives, friends or clinic staff to answer 
the questions.  If a patient asks for help, s/he should be instructed to answer on their 
own. 
• 
One answer should be recorded for each question. 
− 
If a patient has difficulty choosing between 2 response options, s/he should be 
instructed to choose the worse or more severe option. 
− 
If a patient wishes to change a response, the individual administering the 
questionnaire items should put a line through the incorrect response, circle the 
correct response, and initial the change. 
• 
Repeat each selected response back to the patient to confirm it is has been 
accurately recorded. 
• 
Upon completion of the questionnaire items, the individual administrating them 
should check for completeness.  If any questions are missing it should be pointed 
out to the patient and s/he should be encouraged to answer. 
− 
If the patient is unable to provide responses to the item, the reason for this 
should be recorded by the individual responsible for administering the items. 
• 
It is highly important that missing PRO data is minimised; if there are high levels of 
missing data, PRO results become meaningless. 
6.5.4 
FACT-P 
The FACT-P was developed to measure HRQL in men with prostate cancer (Esper et al 1997, 
Cella et al 1993).  It consists of 4 subscales (physical, emotional, functional and social/family 
well-being) plus a 12-item prostate-specific module, the Prostate Cancer Symptoms (PCS) 
subscale, which highlights concerns specific to patients with prostate cancer (see Appendix J).  
In addition, the FACT-P also supports the calculation of a TOI score (the sum of the PWB, 
FWB and PCS scores), and the FAPSI-8, a symptom score made up of 8 items from within the 
FACT-P (pain [n=3], fatigue [n=1], weight loss [n=1], urinary conditions [n=2], and concerns 
about the condition getting worse [n=1]).  Changes in all of these scores are included as 


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exploratory endpoints, in addition to time to deterioration in the TOI score.  The FACT-P will 
be measured at the times outlined in the study plans (Table 8 and Table 9). 
6.6 
Pharmacokinetics 
6.6.1 
Collection of samples 
Part A 
Blood samples for determination of olaparib (2 mL) and abiraterone (2 mL) in plasma will be 
taken at the times presented in the Cohort 2 study plan (see Table 5) and in Table 6 and 
Table 7. 
On PK sampling days, the morning dose of study medications should not occur until the 
pre-dose PK samples have been taken.  The second dose of olaparib should be taken after the 
last PK samples have been taken on that day and approximately 12 hours after the first dose. 
Although every attempt should be made to collect all samples as per protocol, it is accepted 
that this will not always be possible and therefore it is essential that the actual time and date of 
collection of each blood sample (whether collected as per protocol or not) is recorded in the 
eCRF. 
For blood volume see Section 7.1. 
Samples will be collected, labelled, stored and shipped as detailed in Laboratory Manual. 
6.6.2 
Determination of drug concentration 
Samples for determination of olaparib and abiraterone concentrations in plasma will be 
analysed by Covance on behalf of the Clinical Bioanalysis Alliance, AstraZeneca R&D, using 
appropriate bioanalytical methods.  Full details of the bioanalytical methods used will be 
described in a separate bioanalytical report. 
Results will only be reported for plasma samples shipped within a timeframe for which the 
stability of olaparib and abiraterone in the samples has been validated and shown to be 
acceptable. 
Additional analyses may be conducted on the olaparib PK plasma samples to further 
investigate the presence and/or identity of drug metabolites and/or to investigate 
reproducibility of incurred samples.  Any results from these exploratory analyses will not be 
reported in the CSR but will be reported separately in a metabolism or a bioanalytical report. 
6.7 
Biomarkers 
6.7.1 
Collection of biomarker samples 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
For blood volumes see Section 7.1. 


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6.7.1.1 
Prostate specific antigen (PSA) 
Blood samples (approximately 5 mL, depending on local laboratory requirements) will be 
taken for PSA assessment at the times indicated in the study plans (Table 4, Table 5 and 
Table 8).  PSA will continue to be collected after discontinuation of study treatment and after 
primary disease progression until PFS2.  The samples will be analysed at the local laboratory. 
6.7.1.2 
Circulating tumour cells 
In Part B of the study, CTC analysis will support secondary (CTC enumeration) and 
exploratory (biomarker) research objectives. 
Whole blood samples (10 mL) will be taken for analysis of CTCs using the Veridex assay (for 
CTC enumeration) and the EPIC assay (for CTC enumeration and biomarker measurement) at 
the times shown in the study plan (see Table 8). 
Samples will be shipped under ambient conditions on the day of acquisition so as to be 
received by the AstraZeneca approved laboratory within 48 hours of blood sampling. 
The biomarker samples will be assessed for the expression of ERG fusion and ERG protein, 
and possibly for other exploratory biomarkers, eg, PTEN and AR status. 
6.7.1.3 
Archival tumour samples for biomarker analysis 
An archival tumour sample will be collected from all patients, where available. 
The tumour samples will preferably be in the form of a formalin fixed paraffin embedded 
block (tissue derived from the primary tumour or a metastatic site).  If this is not possible, 10 
to 20 slides of freshly prepared unstained 5 micron sections from the archival tumour block 
may be provided.  If an archival sample is not available, a fresh biopsy (formalin fixed and 
paraffin embedded) may be taken if the investigator deems this to be appropriate. 
Tumour samples (where available) will be assessed for BRCA and ATM mutations, and 
possibly other exploratory biomarkers such as AR and PTEN.  Where validated assays are 
available, other study samples may be used as surrogates of tumour to increase the numbers of 
patients within molecularly defined subgroups. 
6.7.1.4 
Blood samples for biomarker analysis 
The following blood samples will be taken at Visit 2 and discontinuation of study treatment: 
• 
1 x 2.5 mL whole blood 
• 
1 x 8.5 mL whole blood to provide plasma 
Samples may be analysed for ERG expression/fusion status, and possibly other oncology 
biomarkers such as AR and PTEN, which may correlate to drug response. 


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6.7.1.5 
Urine samples for biomarker analysis 
Patients in Part B will be required to provide a urine sample (40 to 50 mL) at Visit 2 and 
discontinuation of study treatment.  These samples may be analysed for ERG 
expression/fusion status and possibly other oncology biomarkers, such as PTEN and AR, 
which may correlate with drug response. 
6.8 
Pharmacogenetics (optional) 
6.8.1 
Collection of pharmacogenetic samples 
See Appendix D (‘Pharmacogenetics Research’) for details. 
For blood volume see Section 7.1. 
6.9 
Health economics 
6.9.1 
Utilities: EQ-5D-5L 
Patient reported health state utility will be assessed at the times outlined in the study plans 
(Table 8 and Table 9) by the EQ-5D-5L, a standardised measure of health status developed by 
the EuroQol Group in order to provide a simple, generic measure of health for clinical and 
economic appraisal.  Applicable to a wide range of health conditions and treatments, it 
provides a simple descriptive profile and a single index value for health status that can be used 
in the clinical and economic evaluation of health care (see Appendix K).  The instrument asks 
patients to respond to 5 different dimensions covering mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression, as well as rate how they feel on the day of assessment via 
a visual analogue scale.  The instrument has been reported to be sensitive to the bowel 
discomfort associated with prostate cancer. 
6.9.2 
Resource use 
The ‘Oncology Hospital Admission’ form will be completed by the Investigator at the visits 
shown in the study plan (Table 8).  Any procedures undertaken, and the reason for the 
procedure, should be captured on the form. 
Resource use relating to analgesic use will be derived from the concomitant medications form. 
If a patient discontinues study treatment for reasons other than RECIST or PCWG-2 
progression, the ‘Oncology Hospital Admission’ form should continue to be administered at 
each clinic visit until progression has been confirmed.  After progression, fewer details will be 
collected on an abridged version of the form (see Table 9). 


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7. 
BIOLOGICAL SAMPLING PROCEDURES 
7.1 
Volume of blood 
The total volume of blood that will be drawn from each patient in each part of this study is 
shown in Table 15 (Part A, Cohort 1), Table 16 (Part A, Cohort 2) and Table 17 (Part B). 
Table 15 
Volume of blood to be drawn from each patient in Cohort 1, Part A 
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
Safety 
Clinical chemistry 
2.7 
12a 
32.4 
 
Haematology 
2.7 
12a 
32.4 
Pharmacogenetics (optional) 
9 
1 
9 
Total 
 
 
73.8b 
a 
12 samples taken at: Visits 1 to 9, discontinuation and follow-up.   
b 
From Visit 8 (Week 16) onwards, a further 5.4 mL blood will be collected (for safety analyses) every 
4 weeks up to Week 52, while the patient is on treatment, whichever comes first, and then every 12 weeks 
for as long as the patient is on treatment.  
 
The total volumes of blood given in Table 14 are based upon a patient remaining in the study 
for 24 weeks.  Subsequent visits beyond Week 24 will result in additional blood sampling as 
indicated in the table footnote. 


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Table 16 
Volume of blood to be drawn from each patient in Cohort 2,  
Part A 
Assessment 
Sample volume 
(mL) 
No. of 
samples 
Total 
volume (mL) 
Safety 
Clinical chemistry 
2.7 
12a 
32.4 
 
Haematology 
2.7 
12a 
32.4 
Pharmacokinetic 
Olaparib (Group 1) 
2.0 
18 
36 
 
Abiraterone (Group 1) 
2.0 
10 
20 
 
Olaparib (Group 2) 
2.0 
9 
18 
 
Abiraterone (Group 2) 
2.0 
20 
40 
Pharmacogenetics 
(Optional) 
9 
1 
9 
Total 
Group 1 
 
 
129.8b 
 
Group 2 
 
 
131.8b 
a 
12 samples taken at: Visits 1 to 9, discontinuation and follow-up.   
b 
From Visit 8 (Week 16) onwards, a further 5.4 mL blood will be collected (for safety analyses) every 
4 weeks up to Week 52, while the patient is on treatment, whichever comes first, and then every 12 weeks 
for as long as the patient is on treatment.  
 
The total volumes of blood given in Table 15 are based upon a patient remaining in the study 
for 24 weeks.  Subsequent visits beyond Week 24 will result in additional blood sampling as 
indicated in the table footnote. 
Table 17 
Volume of blood to be drawn from each patient in Part B 
Assessment 
Sample volume 
(mL) 
No. of 
samples 
Total 
volume (mL) 
Safety 
Clinical chemistry 
2.7 
10a 
27 
 
Haematology 
2.7 
10a 
27 
Biomarker 
PSA 
5 
5b 
25 
 
CTC (enumeration) 
10 
5 
50 
 
CTC (biomarkers) 
10 
2 
20 
 
Exploratory 
11 
2 
22 
Pharmacogenetics 
(Optional) 
9 
1 
9 
Total 
 
 
 
180c 
a 
10 samples taken at: Visits 1 to 7, discontinuation and follow-up.   
b 
5 samples taken at: Visits 1, 3, 4, 5 and 6. 
c 
From Visit 6 (Week 16) onwards, a further 5.4 mL blood will be collected (for safety analyses) every 
4 weeks up to Week 52, while the patient is on treatment, whichever comes first, and then every 12 weeks 


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for as long as the patient is on treatment. In addition, from Visit 7 (Week 24) a 5 mL blood sample will be 
taken every 12 weeks for PSA analysis. 
 
The total volumes of blood given in Table 16 are based upon a patient remaining in the study 
for 24 weeks.  Subsequent visits beyond Week 24 will result in additional blood sampling as 
indicated in the table footnote. 
Clinical chemistry and haematology samples are analysed locally, therefore volumes may vary 
according to local practice. 
7.2 
Handling, storage and destruction of biological samples 
The samples will be used up or disposed of after analyses or retained for further use as 
described here. 
Biological samples (blood, urine and tumour samples) for future research will be retained at a 
secure laboratory on behalf of AstraZeneca for a maximum of 15 years following the Last 
Patient’s Last Visit in the study.  The results from future analysis will be reported separately 
from the CSR. 
7.2.1 
Pharmacokinetic samples 
Pharmacokinetic samples may be disposed of or destroyed or anonymised by pooling.  
Additional analyses may be conducted on the anonymised, pooled PK samples to further 
evaluate and validate the analytical method.  Any results from such analyses may be reported 
separately from the CSR. 
Pharmacokinetic samples will be disposed of after finalisation of the Bioanalytical Report or 
6 months after issuing the draft Bioanalytical Report (whichever is earlier), unless requested 
for future analyses. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR, but 
separately in a Bioanalytical Report. 
7.2.2 
Pharmacogenetic samples (optional) 
For details concerning the coding and storage of pharmacogenetic samples please refer to 
Appendix D ‘Pharmacogenetics Research’. 
7.3 
Labelling and shipment of biohazard samples 
The PI ensures that samples are labelled and shipped in accordance with the Laboratory 
Manual and the Biological Substance, Category B Regulations (materials containing or 
suspected to contain infectious substances that do not meet Category A criteria), see 
Appendix C ‘IATA 6.2 Guidance Document’. 


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Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca or its representative 
and appropriate labelling, shipment and containment provisions are approved. 
7.4 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The PI at each centre keeps full traceability of collected biological samples from the patients 
while in storage at the study site until shipment or disposal (where appropriate) and keeps 
documentation of receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
Quintiles keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. 
Circulating tumour cell samples will be stored at EPIC Sciences (LaJolla, Ca) for up to  
12 months after completion of the study. 
7.5 
Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed, 
AstraZeneca is not obliged to destroy the results of this research. 
The Principal Investigator: 
• 
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca or its representative 
• 
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 
• 
Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destroyed, the action 
documented and the signed document returned to the study site 
• 
Ensures that the patient and AstraZeneca or its representative are informed about 
the sample disposal. 
AstraZeneca or its representative ensures the laboratory(ies) holding the samples is/are 
informed about the withdrawn consent immediately and that samples are disposed 
of/destroyed and the action documented and returned to the study site. 


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Pharmacogenetic samples: Patients may withdraw from the pharmacogenetic research at any 
time, independent of any decision concerning participation in other aspects of the main study.  
Voluntary discontinuation will not prejudice further treatment. 
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca 
policy on Bioethics and Human Biological Samples. 
8.2 
Patient data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
For details regarding pharmacogenetic research and data protection, please see Appendix D 
(‘Pharmacogenetics Research’). 
8.3 
Ethics and regulatory review 
An Ethics Committee (EC) or Institutional Review Board (IRB) should approve the final 
study protocol, including the final version of the Informed Consent Form and any other 
written information and/or materials to be provided to the patients, eg, FACT-P questionnaire.  
The Investigator will ensure the distribution of these documents to the applicable EC/IRB, and 
to the study site staff. 
The opinion of the EC/IRB should be given in writing.  The Investigator should submit the 
written approval to AstraZeneca or its representative before enrolment of any patient into the 
study. 
The EC/IRB should approve all advertising used to recruit patients for the study. 
AstraZeneca or its representative should approve any modifications to the Informed Consent 
Form that are needed to meet local requirements. 
If required by local regulations, the protocol should be re-approved by the EC/IRB annually. 
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations. 
AstraZeneca or its representative, where appropriate, will handle the distribution of any of 
these documents to the national regulatory authorities. 


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AstraZeneca or its representative will provide Regulatory Authorities, ECs/IRBs and PIs with 
safety updates/reports according to local requirements, including SUSARs (Suspected 
Unexpected Serious Adverse Reactions), where relevant. 
Progress reports and notifications of serious and unexpected adverse drug reactions will be 
provided to the EC/IRB according to local regulations and guidelines. 
AstraZeneca or its representative is responsible for informing the Regulatory Authority of 
SAEs/SUSARs as per the EU Clinical Trials Directive and/or local country regulations and 
guidelines. 
8.4 
Informed consent 
The Principal Investigator(s) at each centre will: 
• 
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study 
• 
Ensure each patient is notified that they are free to discontinue from the study at any 
time 
• 
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided 
• 
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study 
• 
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File 
• 
Ensure a copy of the signed Informed Consent Form is given to the patient 
• 
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the informed consent form that is approved by an EC. 
The pharmacogenetic component of the study is optional and will be detailed on a separate 
informed consent form. 
8.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the International 
co-ordinating Investigator and AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol). 


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The amendment is to be approved by the relevant EC and if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be followed 
for revised protocols. 
AstraZeneca or its representative will distribute any subsequent amendments and new versions 
of the protocol to each PI.  For distribution to ECs see Section 8.3. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s EC are to approve the revised Informed Consent Form before the revised 
form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each EC. 
8.6 
Audits and inspections 
Authorised representatives of AstraZeneca or its representative, a regulatory authority, or an 
EC may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, GCP, ICH 
guidelines, and any applicable regulatory requirements.  The Investigator will contact 
AstraZeneca or its representative immediately if contacted by a regulatory agency about an 
inspection at the centre. 
9. 
STUDY MANAGEMENT BY ASTRAZENECA 
This study will be managed by Quintiles, on behalf of AstraZeneca, and Quintiles will act as 
the AstraZeneca representatives. 
9.1 
Pre-study activities 
Before the first patient is entered into the study, it is necessary for a representative of 
AstraZeneca to visit the investigational study site to: 
• 
Determine the adequacy of the facilities 
• 
Determine availability of appropriate patients for the study 
• 
Discuss with the Investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of 
AstraZeneca or its representatives.  This will be documented in a CSA between 
AstraZeneca or its representative and the Investigator. 


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9.2 
Training of study site personnel 
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures, including the 
WBDC system, how to best administer the PRO questionnaires and the IVRS/IWRS system 
utilised. 
The PI will ensure that appropriate training relevant to the study is given to all of these staff, 
and that any new information relevant to the performance of this study is forwarded to the 
staff involved. 
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff). 
Before the first patient is entered into the study the investigational staff will have an 
opportunity to discuss the procedures associated with the collection of blood samples, 
extraction of DNA and host pharmacogenetic research with AstraZeneca personnel or 
delegate.  The ethical considerations specific to genotyping and the importance of the 
informed consent process will be made clear.  The requirements for the collections of the 
patients’ samples will also be made clear. 
9.3 
Monitoring of the study 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 
• 
Provide information and support to the Investigator(s) 
• 
Confirm that facilities remain acceptable 
• 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed 
• 
Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients. This 
will require direct access to all original records for each patient (eg, clinic charts) 
• 
Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the patient. 
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 


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9.3.1 
Source data 
Refer to the CSA for location of source data. 
9.4 
Study agreements 
The PI at each site should comply with all the terms, conditions, and obligations of the CSA 
for this study.  In the event of any inconsistency between this Clinical Study Protocol and the 
CSA, the terms of Clinical Study Protocol shall prevail with respect to the conduct of the 
study and the treatment of patients and in all other respects, not relating to study conduct or 
treatment of patients, the terms of the CSA shall prevail. 
Agreements between AstraZeneca or its representatives and the PI should be in place before 
any study-related procedures can take place, or patients are enrolled. 
9.4.1 
Archiving of study documents 
The Investigator follows the principles outlined in the CSA. 
9.5 
Study timetable and end of study 
The study is expected to start in Q4 2013 for Part A, and Q2 2014 for Part B, and to be 
completed (LPLV) by Q1 2018 (or by Q2 2016 for the primary variable, rPFS). 
The end of the study is defined as ‘the last visit of the last patient undergoing the study’. 
The end of the clinical part of the study is defined as ‘the date of the last patient stopping 
study treatment or the data cut-off for the 60% survival analysis, whichever is the later’. 
The database for Part A and Part B are one database, and therefore the data will be analysed at 
the same time. Part A patients continue beyond their initial 14 days treatment as specified in 
Section 5.5.2. 
The primary analysis will be performed once approximately 100 progression events have 
occurred.  Patients who have progressed will be followed for PFS2 and survival data until 
approximately 60% of patients have died at which point the final analysis will occur and the 
study database will be closed.  Patients who have not progressed at the time of the primary 
analysis will continue to be followed to first disease progression. 
Patients are permitted to continue to receive olaparib beyond the closure of the database if, in 
the opinion of the Investigator, they are continuing to receive benefit from it (see 
Section 5.5.2).  Patients may also continue to receive abiraterone and prednisolone which are 
sourced locally as commercially available materials.  For patients who do continue to receive 
treatment with olaparib beyond the time of this data cut-off, Investigators will continue to 
report all SAEs to AstraZeneca Patient Safety until 30 days after olaparib is discontinued, in 
accordance with Section 6.4.4.  Note: SAEs are not required to be reported for patients who 
continue with abiraterone without olaparib; Investigators should follow local requirements for 
reporting any SAEs to regulatory agencies and/or manufacturers of abiraterone.  Additionally, 


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as stated in Section 6.4.3, any SAE or non-serious AE that is ongoing at the time of this data 
cut-off must be followed up to resolution unless the event is considered by the Investigator to 
be unlikely to resolve, or the patient is lost to follow-up. 
The study may be terminated at individual study sites if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with olaparib. 
10. 
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE 
Data management will be performed by Quintiles. 
The data collected through third party sources will be obtained and reconciled against study 
data. 
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA®).  Medications 
will be classified according to the AstraZeneca Drug Dictionary.  All coding will be 
performed by Quintiles. 
Patient reported outcomes data should be entered as the patients respond.  If 2 adjacent 
responses are marked, then the worst response should be entered.  If 2 responses are marked 
but they are not adjacent, then that item should be missing. 
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail. 
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked. 
Data associated with biological samples will be transferred to laboratories internal or external 
to AstraZeneca. 
For details on the management of pharmacogenetic data, please see Appendix D 
(‘Pharmacogenetics research’).  


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11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA OR DELEGATE 
11.1 
Calculation or derivation of efficacy variable(s) 
11.1.1 
Tumour response rate: malignant soft tissue response (RECIST v1.1) 
Patients will undergo regular tumour assessments until documented objective disease 
progression as defined by RECIST v1.1 for malignant soft tissue disease (see Appendix F).  
Metastatic bone lesions will not be part of this assessment. 
At each visit, the Investigator-assessed RECIST data for a patient will be programmatically 
assigned a response of CR, PR, SD, PD, NED or NE depending on the status of the disease 
compared with baseline and previous assessments. 
Progression of TLs will be calculated in comparison with what the tumour burden was at a 
minimum (ie, smallest sum of diameters previously recorded on study).  In the absence of 
progression, tumour response (CR, PR, SD) will be calculated in comparison to the baseline 
tumour measurements obtained before starting treatment. 
If a patient has had a tumour assessment which cannot be evaluated, then the patient will be 
assigned a visit response of non evaluable (NE) unless there is evidence of progression, in 
which case the response will be assigned as PD. 
For TL measurements, if 1/3 of the TL sizes are missing (either not evaluable or not read, or 
the scan was not done), then a scaling up rule will be applied as follows: 
• 
If 1/3 of lesions recorded at baseline are missing, then the results will be scaled up 
(based on the baseline sizes) to give an estimated sum of diameters and this will be 
used in calculations (this is equivalent to comparing the visit sum of diameters of 
the non-missing lesions to the baseline sum of diameters excluding the lesions that 
are missing and determining at what rate the lesions are changing) 
• 
If >1/3 of lesions recorded at baseline are missing, then the TL response will be NE.  
However, if the sum of non-missing TL diameters would result in PD (ie, if using a 
value of 0 for missing lesions the sum of diameters has still increased by >20% 
compared to the smallest sum of diameters on study and has an absolute increase 
5 mm), PD takes precedence over NE 
• 
A visit response of CR will not be allowed if any of the TL data are missing. 
For patients who only have non-measurable disease at baseline, categorisation of objective 
tumour response assessment will be based on the modified RECIST 1.1 guidelines for 
response for NTLs: CR, PD and Non CR/Non PD or NE. 


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Patients with absence of target and non-target lesions at baseline, and with no progression by 
new lesions at follow-up, will be categorised as ‘no evidence of disease’ (NED).  If there is 
progression due to new soft tissue lesions they will be categorised as PD. 
11.1.2 
Metastatic bone disease status 
Metastatic bone disease status will be reported from the bone lesion assessment on bone scan 
as non-progressive disease or progressive disease, separately from RECIST 1.1 soft tissue and 
PSA response assessments, according to PCWG-2 criteria (see Section 6.3.1.2 for the 
definition of progression on bone scan). 
The date of progression is the date of the first scan which is defined as showing a progression. 
11.1.3 
Radiologic progression-free survival (rPFS) 
The primary endpoint is rPFS (defined by RECIST 1.1 and/or PCWG-2 as assessed by the 
Investigator). 
Progression-free survival (weeks) is defined as the time from randomisation until the date of 
objective disease progression or death (by any cause in the absence of progression) regardless 
of whether the patient withdraws from randomised therapy or receives another anti-cancer 
therapy prior to progression.  Patients who have not progressed (defined as CR, PR or SD by 
RECIST 1.1, or non-PD by PCWG-2 bone scan) or died at the time of analysis will be 
censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 or 
PCWG-2 assessment.  However, if the patient progresses or dies after 2 or more missed 
RECIST 1.1/PCWG-2 visits, the patient will be censored at the time of the latest evaluable 
RECIST 1.1 or PCWG-2 assessment.  If the patient has no evaluable visits or does not have 
baseline data they will be censored at Day 1 unless they die within 2 visits of baseline (in 
which case their date of death will be used). 
The rPFS time will always be derived based on scan/assessment dates not visit dates. 
When the Investigator is in doubt as to whether PD has occurred and therefore reassesses the 
patient at a later date, the date of the initial scan should be declared as the date of progression 
if the repeat scans confirm progression. 
RECIST 1.1/PCWG-2 assessments/scans contributing towards a particular visit may be 
performed on different dates.  The following rules will be applied: 
• 
Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression 
• 
When censoring a patient for rPFS, the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
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11.1.3.1 Time to second progression (PFS2) 
Time from randomisation to PFS2 is defined as the time from the date of randomisation to the 
earliest of the progression event subsequent to that used for the primary variable rPFS, or 
death.  The date of PFS2 will be recorded by the Investigator and defined according to local 
standard clinical practice and may involve any of: objective radiological progression, 
symptomatic progression, PSA or death (see also Section 6.3.1.3).  PFS2 status will be 
reviewed every 12 weeks following the progression event used for the primary variable rPFS 
(the first progression) and status recorded.  Patients alive and for whom a second disease 
progression has not been observed should be censored at the last time known to be alive and 
without a second disease progression (ie, censored at the latest of the rPFS or PFS2 
assessment date if the patient has not had a second progression or death). 
11.1.4 
Overall survival (OS) 
Overall survival (months) is defined as the time from the date of randomisation until death due 
to any cause.  Any patient not known to have died at the time of analysis will be censored 
based on the last recorded date on which the patient was known to be alive.  
Note, survival calls will be made in the 2 weeks following the date of DCO for the analysis, 
and if patients are confirmed to be alive (eg, alive post DCO date or if the death date is post 
the DCO date) these patients will be censored in the analyses as of the date of DCO. 
Patients will enter the OS phase of the study following confirmed progression by the 
Investigator.  All patients will be followed for survival data until approximately 60% of 
patients have died. 
11.1.5 
Objective response rate and associated variables 
For soft tissue disease ORR, only patients with measurable disease (target lesions) at entry 
will be included in the denominator.  A responder will be any patient with a best overall 
response of PR or CR in their soft tissue disease assessed by RECIST 1.1, irrespective of the 
bone scan status assessed by PCWG-2. 
For overall radiological ORR, again only patients with measurable disease (target lesions) at 
entry will be included in the denominator.  A responder demonstrating overall radiological 
response will be any patient with a best overall response of PR or CR in soft tissue disease 
assessed by RECIST 1.1 and also bone scan status of non-PD or NE for their bone assessed by 
PCWG-2.  Soft tissue response rate will thus be equal to or higher than the overall radiological 
ORR. 
Duration of overall radiological response (RECIST 1.1 soft tissue disease response of PR or 
CR, with a PCWG-2 response of non-PD/NE) will be defined as the time from overall 
radiological response until date of documented radiological progression by RECIST 1.1 for 
soft tissue disease or PCWG-2 for bone lesions, or death in the absence of disease 
progression; the end of response should coincide with the date of progression or death from 
any cause used for the rPFS endpoint.  The time of the initial overall radiological response 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
112(134) 
will be defined as the time from randomisation until the earliest of the dates where an overall 
radiological response is seen. 
If a patient does not progress following an overall radiological response, then their DoR will 
be censored at the rPFS censoring time. 
Duration of response will not be defined for those patients who do not have documented 
overall radiological response. 
11.1.6 
Time to subsequent therapies 
Time to first subsequent therapy (TFST) for prostate cancer is defined as the time from 
randomisation to the date of the first subsequent therapy for prostate cancer following 
discontinuation of olaparib.  Similarly, time to second subsequent therapy (TSST) for prostate 
cancer is defined as the time from randomisation to the date of the second subsequent therapy 
for prostate cancer. 
11.2 
Calculation or derivation of safety variable(s) 
11.2.1 
Adverse events 
An AE is the appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s), or medical condition(s) occurring after signing the informed consent.  All AEs 
will be coded using the MedDRA® dictionary to provide the system organ class and preferred 
term for each AE.  AEs will be grouped separately as AE onset before and after first dose of 
study drug. 
Any AE commencing (or worsening) on the same day as the first dose of study treatment, will 
be assumed to occur after study treatment has been administered.  A treatment emergent AE 
(TEAE) will therefore be defined as an AE with the start date on or after the first dose date, 
and up to and including the 30-day (±7 days) follow-up visit after discontinuation of study 
treatment, until the time of the final analysis (rPFS).   
11.2.2 
Other significant adverse events 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and DAEs (discontinuation of IP due to AEs).  
Based on the expert’s judgement, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant adverse 
events (OAEs) and reported as such in the CSR.  A similar review of laboratory/vital 
signs/ECG data will be performed for identification of OAEs. 
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment. 
11.2.3 
Dose-limiting toxicities (DLT) 
Dose-limiting toxicities are defined in Section 3.1.1.4. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
113(134) 
11.2.4 
Concomitant medications 
Concomitant medications will be classified according to the current version of the 
AstraZeneca Drug Dictionary. 
Concomitant medications will be classed as either: 
1. 
Concomitant medications starting prior to first dose (pre-study) 
2. 
Concomitant medications starting on or after first dose date (on study). 
Medications that start on the same day as the first dose of study treatment will be assumed to 
occur after study treatment has been administered, and be classified as on-study. 
11.2.5 
Compliance and exposure 
Study drug exposure (days) will be defined as time from first dose of olaparib to last dose.  
Exposure to abiraterone will be calculated in the same way. 
Exposure will be defined as:  
Last dose date – first dose date + 1. 
If the last dose date is unknown, the soonest available date afterwards where it is confirmed 
that no drug is being taken will be used instead. 
Percentage compliance will be defined as: 
 
{(No. tablets dispensed in period – no. tablets returned from period)/ 
 
  (no. days of study drug exposure in period * expected tablets per day)}   * 100% 
where expected tablets per day will take into account once daily or bid dosing. 
Overall compliance may be calculated over various periods if the dose has been modified, to 
take into account the differing expected tablets per day or the protocol-specified dose 
interruptions.  Missed doses will not be adjusted for; the overall compliance will be reduced. 
11.3 
Calculation or derivation of patient reported outcome variables 
The primary outcome measure for the PRO measures will be BPI-SF. 
11.3.1 
Brief Pain Inventory – Short Form (BPI-SF) 
Scoring of the BPI-SF will be as per the developers’ instructions.  Change in the BPI-SF pain 
and pain interference scores will be calculated as change from baseline at each clinic visit.   
Time to worsening of pain is defined as the time from the date of randomisation to the date of 
first assessment of worsening of pain, or death from any cause (as long as the death occurs 
within 2 BPI-SF assessment visits of the last evaluable assessment of BPI-SF and regardless 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
114(134) 
of whether the patient withdraws from study treatment or receives another anti-cancer therapy.  
Worsening of pain is defined as an increase in worst pain BPI-SF score by at least 2 points on 
the 0 to 10 scale. 
11.3.2 
Worst bone pain item 
The worst bone pain item will be scored as is (0-10 scale, with 10 being worst imaginable 
bone pain).  Change in the worst bone pain item will be calculated as change from baseline at 
each clinic visit. 
Time to worsening of bone pain is defined as the time from the date of randomisation to the 
date of first assessment of worsening of bone pain, or death from any cause (as long as the 
death occurs within 2 PRO assessment visits of the last evaluable assessment of worst bone 
pain and regardless of whether the patient withdraws from study treatment or receives another 
anti-cancer therapy.  Worsening of bone pain is defined as an increase in worst bone pain 
score by at least 2 points. 
11.3.3 
FACT-P 
Scoring of the FACT-P will be as recommended by the developers.  Higher scores equate to 
better quality of life. 
For the FACT-P total score, TOI, FAPSI-8, and PCS, FWB, PWB, EWB and SWB sub-scales, 
changes from baseline for each time point will be calculated for each treatment group. 
A best response of ‘Improved’, ‘No Change’ and ‘Worsened’, defined according to 
Table 18 and Table 19, will be calculated for each patient for scales assessing prostate cancer 
symptoms, impact on physical/functional well-being and overall HRQL (TOI, FAPSI-8, PCS, 
PWB and FWB scales and FACT-P total score). 
If less than 50% of the subscale items are missing from a returned questionnaire, the subscale 
score will be calculated by replacing the missing items with the mean of the non-missing 
items in the scale.  If 50% or more of the items are missing, that visit will be treated as 
missing. 
Table 18 details how responders will be defined for the FACT-P TOI, FAPSI-8, PCS and 
FWB scores (Cella et al 2009).   


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
115(134) 
Table 18 
Definition of visit response for FACT-P, FAPSI-8, TOI, PCS and FWB 
FACT-P scale 
Change from baseline 
Visit response 
FACT-P-Total 
 +6 
Improved 
 
 -6 
Worsened 
 
Otherwise (ie, >-6 and <+6) 
No change 
 
Missing/non-calculable score 
Not evaluable 
FAPSI-8 
 +3 
Improved 
 
 -3 
Worsened 
 
Otherwise (ie, >-3 and <+3) 
No change 
 
Missing/non-calculable score 
Not evaluable 
TOI 
 +5 
Improved 
 
 -5 
Worsened 
 
Otherwise (ie, >-5 and <+5) 
No change 
 
Missing/non-calculable score 
Not evaluable 
PCS 
 +3 
Improved 
 
 -3 
Worsened 
 
Otherwise (ie, >-3 and <+3) 
No change 
 
Missing/non-calculable score 
Not evaluable 
FWB 
 +2 
Improved 
 
 -2 
Worsened 
 
Otherwise (ie, >-2 and <+2) 
No change 
 
Missing/non-calculable score 
Not evaluable 
 
Overall improvement for the FACT-P scores is defined as a change from baseline in the 
required number of points or more, as stated in Table 18 for 2 consecutive visits. 
At the conclusion of the study, the criteria listed in Table 19 will be used to assign a best 
overall response score based on the individual visit responses. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
116(134) 
Table 19 
Overall score response for FACT-P, FAPSI-8, TOI, PCS, FWB 
Overall score response 
Criteria 
Improved 
Two consecutive visit responses of ‘improved’ 
No change 
Does not qualify for overall score response of ‘improved’.  Two 
consecutive visit responses of either ‘no change’, or ‘improved’ 
and ‘no change’ 
Worsened 
Does not qualify for overall score response of ‘improved’ or ‘no 
change’.  A visit response of ‘worsened’ 
Other 
Does not qualify for one of the above 
 
11.4 
Calculation or derivation of pharmacokinetic variables 
The PK analysis of the plasma concentration data for olaparib and abiraterone will be 
performed at (or on behalf of) AstraZeneca R&D.  The actual sampling times will be used in 
the PK calculations, except for the pre-dose sample for which the time will be set to zero.  All 
PK computations will be performed using Phoenix™ for WinNonlin. 
Patients who withdraw from the study following dosing, but prior to study completion, will be 
included in the PK analysis provided they have evaluable profiles over the planned collection 
period.  Patients with partial data will be evaluated on a case-by-case basis to determine if 
sufficient data are available for meaningful analysis. 
If sufficient data are available for estimation, the following multiple-dose PK parameters will 
be calculated for olaparib and abiraterone in Part A: 
• 
Maximum plasma concentration at steady state (Cmax ss) obtained directly from the 
observed concentration versus time data 
• 
Minimum plasma concentration at steady state (Cmin ss) obtained directly from the 
observed concentration versus time data 
• 
Time to reach maximum plasma concentration at steady state (tmax ss) obtained 
directly from the observed concentration versus time data 
• 
Area under the plasma concentration-time curve at steady state (AUCss) calculated 
by linear up/logarithmic down trapezoidal summation of the area under the steady 
state plasma concentration time curve from zero to the end of the dosing interval 
(12 hours for olaparib; 24 hours for abiraterone). 
Additional PK parameters may be determined if deemed appropriate. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
117(134) 
Any value below the limit of quantification (LOQ) in a pre-dose sample will be set to zero; an 
LOQ value elsewhere in the profile will be excluded from the analysis. 
11.5 
Calculation or derivation of biomarker variable(s) 
11.5.1 
Prostate specific antigen 
11.5.1.1 PSA response 
• 
A patient will be regarded as having a single PSA visit response if their PSA level 
at any post-dose visit is reduced by 50% or more compared with baseline 
• 
A patient will be regarded as having a confirmed PSA response if they have a 
reduction in PSA level of 50% or more compared with baseline that is confirmed at 
the next assessment at least 4 weeks later (ie, decrease relative to baseline of at least 
50% documented on 2 consecutive occasions at least 4 weeks apart). 
11.5.1.2 PSA changes on continuous scale 
• 
PSA levels will be evaluated in terms of percentage change from baseline which 
will be derived for each post baseline visit where PSA data are available 
• 
% change = [(post-dose PSA level – baseline PSA level) / baseline PSA level] *100 
• 
Best percentage change from baseline in PSA will be derived as the biggest 
reduction in PSA level compared with baseline (or the smallest increase in the 
absence of a reduction) taking account of all PSA values collected for each patient 
11.5.2 
Circulating tumour cell counts 
• 
Conversion:  change of CTC from 5 at baseline to <5 post baseline 
• 
Change in CTC counts as a continuous variable following treatment with 
olaparib/placebo and abiraterone (calculated as post-dose CTC count - baseline 
CTC count).   
• 
Change in CTC count at 12 weeks. 
11.5.3 
ATM mutation 
Samples will be assessed for ATM mutation.  Full details of categorisation will be given in the 
statistical analysis plan (SAP). 
11.5.4 
BRCA mutation 
Samples will be assessed for BRCA mutation.  Full details of categorisation will be given in 
the SAP. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
118(134) 
11.5.5 
Further biomarker research analysis 
Tumour (where available), blood, urine and CTC samples will be stored for future exploratory 
analysis of biomarkers such as PTEN and AR. 
Methods of analysis for all other biomarker research may include investigation of genetic 
variability, gene expression profiling and/or protein expression profiling. 
11.6 
Calculation or derivation of pharmacogenetic variables 
Please see Appendix D (‘Pharmacogenetics research’) for details. 
11.7 
Calculation or derivation of health economic variables 
11.7.1 
Utilities: EQ-5D-5L 
The EQ-5D-5L index comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression).  For each dimension, respondents select which 
statement best describes their health on that day from a possible 5 options of increasing levels 
of severity (no problems, slight problems, moderate problems, severe problems and unable to/ 
extreme problems).  A unique EQ-5D health state is referred to by a 5-digit code allowing for 
a total of 3125 health states.  For example, state 11111 indicates no problems on any of the 
5 dimensions.  These data will be converted into a weighted health state index by applying 
scores from EQ-5D value sets elicited from general population samples (the base case will be 
the UK valuation set, with other country value sets applied in scenario analyses).  Where 
values sets are not available, the EQ-5D-5L to EQ-5D-3L crosswalk will be applied.  In 
addition to the descriptive system, respondents also assess their health today on a visual 
analogue scale, ranging from 0 (worst imaginable health) to 100 (best imaginable health).  
This score is reported separately.  The evaluable population will comprise the full analysis set. 
The proportion of patients with each score for each item may be summarised for each time 
point and by treatment allocation. 
11.7.2 
Resource use 
Resource use will be analysed from procedures captured on the ‘Oncology Hospital 
Admission’ form and the standard concomitant medication eCRF, and, where required, 
supplemented with data on hospitalisation length of stay logged as part of SAE recording.  
Frequency of palliative interventions and the reasons for the intervention will be estimated 
from the ‘Oncology Hospital Admission’ form.  The evaluable population will comprise the 
full analysis set.  The analysis will be conducted on blinded data. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
119(134) 
12. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION BY ASTRAZENECA OR DELEGATE 
12.1 
Description of analysis sets 
The study physician, pharmacokineticist, and statistician will agree on the strategy for dealing 
with data affected by protocol deviations before any formal statistical analysis is performed. 
12.1.1 
Full analysis set 
Intention to treat (ITT): The primary statistical analysis of the efficacy of olaparib when given 
in addition to abiraterone will include all randomised patients in Part B, regardless of the 
treatment actually received.  Patients who were randomised but did not subsequently go on to 
receive study treatment are included in the full analysis set. 
12.1.2 
PK analysis set 
All patients in Part A (Cohorts 2 and 3, as applicable) of the study who provide at least one 
post-dose analysable plasma sample for PK analysis will be included in the plasma 
concentration listings.  On each sampling occasion, PK parameters will be derived for all 
patients who provide a full PK profile and these parameters will be included in the PK 
parameter listings and summaries.  However, for inclusion in the evaluation of a DDI, patients 
must provide steady state PK profiles both for olaparib/abiraterone alone and in combination, 
and have no protocol violations affecting the PK endpoint. 
The population for the DDI evaluation will be defined by the study team physician, 
pharmacokineticist and statistician prior to any analyses being performed. 
If a patient has a major protocol deviation that affects the evaluability of the PK profile, then 
the patient will not form part of the DDI evaluation. 
Major protocol deviations include changes to the procedures that may impact the quality of 
the data, or any circumstances that can alter the evaluation of the PK.  Examples include, but 
may not be limited to, vomiting following oral dosing occurring within the time frame of 
2 times the median tmax ss, sample processing errors that lead to inaccurate bioanalytical 
results, incomplete dose administered, incomplete PK profile collected, and/or use of 
disallowed concomitant medication.  In the case of a major protocol deviation, affected PK 
data collected will be excluded from the summaries and statistical analyses, but will still be 
reported in the study result listings.  Major deviations will be listed and summarised in the 
CSR. 
12.1.3 
Safety analysis sets 
Part A safety analysis set: All patients in Part A of the study who receive at least 1 dose of 
study treatment.  Treatment group comparisons will be based on the initial dose of study 
treatment actually received. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
120(134) 
Part B safety analysis set: All patients randomised into Part B of the study who receive at 
least 1 dose of study treatment.  Treatment group comparisons will be based on the initial dose 
of study treatment actually received. 
When assessing safety and tolerability, summaries will be produced based on the safety 
analysis sets. 
12.2 
Methods of statistical analyses 
The following text applies to demographic, efficacy and safety analyses only; PK is discussed 
separately. 
Statistical analyses will be performed by Quintiles under the direction of the Biostatistics 
Group, AstraZeneca using SAS® version 9.1 or higher and, where appropriate, additional 
validated software. 
A comprehensive SAP will be prepared before database lock.  For qualitative variables, the 
population size (N for sample size and n for available data) and the percentage (of available 
data) for each class of the variable will be presented.  Quantitative variables will be 
summarised using descriptive statistics, including n, mean, SD, median, minimum, and 
maximum values.  Where appropriate, assessments will be summarised by visit. 
The number of patients who were screened, confirmed eligible (Part A)/randomised (Part B), 
received treatment and completed the study will be produced for each of the treatment groups 
in Part A (using the Part A safety analysis set) and Part B (using the full analysis set).  A 
summary table of analysis sets will be produced.  Demographic and baseline characteristics 
will be summarised using the Part A safety analysis set and the full analysis set, for Parts A 
and B of the study, respectively. 
Treatment duration will be summarised.  Treatment duration is based on the dates of first and 
last dose. 
Study day will be calculated as follows: 
Days prior to first dose: Study day = date – first dose date. 
Days on or after first dose: Study day = date – first dose date + 1. 
In general, missing data will not be imputed.  For the date variables of historical data (ie, any 
data referring to the period prior to the informed consent date), if the year is missing then the 
value will not be imputed.  If the month or day is missing, the value will be imputed: month 
will be imputed with June; day will be imputed as 15th. 
12.2.1 
Efficacy data 
The following efficacy analyses will be performed using the full analysis set. 


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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
121(134) 
12.2.1.1 Radiological progression-free survival 
The primary endpoint of Part B, rPFS (weeks), is defined in Section 11.1.3.  Once 
approximately 100 progression events have occurred, the primary analysis will be performed.  
Radiological progression-free survival will be analysed using a log-rank test.  The hazard ratio 
(HR) and 80% confidence interval (CI) will be estimated from the U and V statistics obtained 
directly from the LIFETEST model with inclusion of STRATA terms for the stratification 
variables (and using the Breslow approach for handling ties). A HR less than 1 will favour 
Olaparib.  
The HR and its confidence interval can be estimated from the log-rank as follows  
(Berry et al 1999, Sellke et al 1983): 
HR = exp(U/V) 
80% CI for HR = (exp{U/V – 1.28/ ¥V}, exp{U/V + 1.28/ ¥V}) 
Where U ¦
−
=
i
i
i
e
d
)
(
1
1
 is the log-rank test statistic( with d1i and e1i the observed and 
expected events in group 1)  and ¥V the standard deviation of the log-rank test statistic as 
produced in the LIFETEST output.   
The HR (Olaparib vs. placebo) together with its corresponding 80% confidence interval (CI) 
and p-value will be presented (a HR less than 1 will favour Olaparib). 
Kaplan-Meier survival curves (product-limit estimates) of rPFS will be presented by treatment 
group, together with a summary of associated statistics (median rPFS time, and 6, 12, 18, 24 
and 30 month survival rate estimates).  Summaries of the number and percentage of patients 
experiencing a rPFS event, and the type of event (RECIST progression, PCWG-2 progression 
or death) will also be presented. 
Listings of rPFS per patient will be produced. 
The assumption of proportionality will be assessed.  Note that in the presence of non-
proportionality, the HR will be interpreted as an average HR over the observed extent of 
follow-up.  Proportionality will be tested firstly by examining plots of complementary log-log 
(event times) versus log (time) and, if these raise concerns, a time-dependent covariate would 
be fitted to assess the extent to which this represents random variation. 
Separate log-rank tests of rPFS will be undertaken using patients who have BRCA or ATM 
mutations, using the same model as for the primary analysis.  If the number of patients in each 
subgroup is small, consideration will be given to merging the subgroups prior to analysis. 
As an exploratory analysis, a Cox proportional hazards model of rPFS may be undertaken 
including some or all of the following factors: PTEN, AR status, disease related biomarkers, 
demographic and disease characteristics. 


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If there are too few events available for a meaningful analysis (it is not considered appropriate 
to present analyses where there are less than 20 events in a subgroup), only descriptive 
statistics will be provided. 
Sensitivity analyses for rPFS 
Sensitivity analyses will be performed to assess the possible presence of time-assessment bias 
(ie, differential assessment times between treatment groups).  Summary statistics for the 
number of weeks between rPFS time and the last evaluable assessment prior to progression 
will be presented for each treatment group. 
(a) 
Evaluation-time bias 
Sensitivity analyses will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled time points.  The midpoint 
between the time of progression and the previous evaluable assessment (RECIST or PCWG-2) 
will be analysed as described for the primary analysis of rPFS.  This approach has been shown 
to be robust to even highly asymmetric schedules (Sun and Chen 2010). 
(b) 
Attrition bias 
Attrition bias will be assessed by repeating the primary rPFS analysis except that the actual 
rPFS event times, rather than the censored time, of patients who progressed or died in the 
absence of progression immediately following 2, or more, non-evaluable tumour assessments 
will be included.  In addition, patients who take subsequent therapy prior to progression or 
death will be censored at their last evaluable assessment prior to taking the subsequent 
therapy. 
(c) 
Censoring bias 
A Kaplan-Meier plot of the time to censoring will be produced, where the censoring indicator 
of the primary rPFS analysis is reversed. 
12.2.1.2 Time to second progression (PFS2) 
The secondary endpoint of PFS2 (weeks), as defined in Section 11.1.3.1, will be analysed 
using the same time-to analysis as rPFS: log-rank test, Kaplan-Meier and summary statistics. 
Listings of PFS2 time per patient will also be produced. 
12.2.1.3 Overall survival (OS) 
The secondary efficacy endpoint for Part B, OS (months), as defined in Section 11.1.4, will be 
performed when approximately 60% of patients have died; patients who have not died at that 
point will be censored. 
The same time-to analyses will be undertaken as for rPFS: log-rank test, Kaplan-Meier and 
summary statistics.  A listing of OS time per patient will also be produced. 


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In addition, to provide further information, listings of first and subsequent therapies will be 
produced. 
Exploratory analyses of OS adjusting for impact of subsequent PARP inhibitor trial or 
treatment (or other potentially active investigational agents) may be performed if a sufficient 
proportion of patients switch. Methods such as Rank Preserving Structural Failure Time 
(RPSFT) (Robins et al 1991), Inverse Probability of Censoring Weighting (Robins 1993) and 
other methods in development will be explored. The decision to adjust and final choice of 
methods will be based on a blinded review of the data and the plausibility of the underlying 
assumptions. Details will be pre-specified in the SAP and Payer analysis plan. 
12.2.1.4 Objective response rate 
The secondary efficacy endpoint for Part B, ORR for soft tissue disease response and overall 
radiological response, will be performed at the time of the rPFS analysis. 
Patients with at least one visit response of CR or PR (the numerator of ORR, as defined in 
Section 11.1.5) will be analysed using logistic regression, adjusting for the same set of 
covariates as for rPFS.  The effect of treatment will be estimated using the adjusted odds ratio 
and its corresponding 80% CIs. 
Objective response rate will be formally analysed for both soft tissue ORR and overall 
radiological ORR using logistic regression.  However, the other associated endpoints (best 
overall soft tissue disease response, best overall radiological response, duration of response, 
time to response) will be summarised only. 
Best objective response (soft tissue disease and overall radiological response) at each 
scheduled visit will be summarised. 
Duration of overall radiological response (months) and time to response (months), are defined 
in Section 11.1.5.  A listing of DoR and time to response per patient will be produced, and the 
data will be summarised. 
12.2.1.5 Time to subsequent therapies 
The TFST and TSST are defined in Section 11.1.6.  A listing of TFST and TSST per patient 
will be produced, and the data will be summarised. 
12.2.2 
Biomarker data (PSA and CTCs) 
Proportion of patients achieving a PSA response will be presented with 80% CIs. 
Proportion of patients achieving a CTC conversion will be presented with 80% CIs. 
PSA percentage change from baseline and change from baseline in CTC counts will be 
summarised as continuous variables using descriptive statistics and presented graphically 
using box plots over time. 


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Change in PSA and CTC counts and best change in these parameters during the study will be 
summarised and presented graphically. 
Summary statistics (n/%) will be presented for ERG fusion positive/negative results, and/or 
ERG expression categories (0 to 3), by treatment group at each visit.  Sample quantity may 
mean that only one ERG measure can be performed. 
Summary statistics (n/%) will also be presented for patients who have BRCA mutations 
compared with those who are BRCA wildtype or information is missing. 
Proportion of patients achieving an ERG fusion positive response will be presented with 80% 
CIs. 
12.2.3 
Patient reported outcomes (PRO) 
The exploratory endpoints in this section are defined in Section 11.3. 
For analysis of the PRO endpoints, BPI-SF, bone pain item and FACT-P, the following 
analysis will be performed. 
Summary statistics for mean score, standard deviation, median and range will be presented by 
treatment group for visits until there are less than one third of patients with evaluable data.  
Box plots will also be presented. 
The proportion of patient with best responses of ‘Improved’, ‘No Change’ and “Worsened” 
will be compared between treatments using logistic regression with the same methods and 
covariates as for the analysis of ORR.  
Time to worsening will be assessed by a Cox proportional hazards model using the same 
methods and covariates as for the primary analysis.  The effect of treatment will be estimated 
by the HR together with its corresponding 80% CI.  Kaplan-Meier plots will also be presented 
by treatment. 
In addition the time to worsening for the subscales of the FACT-P (TOI, FAPSI-8, PCS and 
FWB) will be presented on a forest plot. 
12.2.4 
Safety data 
Safety analyses will be presented using the Safety Analysis Sets and will be done by means of 
descriptive statistics.  Safety profiles will be assessed in terms of AEs, vital signs (including 
BP and pulse rate), ECG, laboratory data (clinical chemistry and haematology), and physical 
examination. 
All data will be summarised and listed appropriately. 
Adverse events will be summarised separately for Parts A and B of the study, and also by dose 
within Part A.  Laboratory data, vital signs, physical examination, body temperature and ECG 
will be summarised separately for Parts A and B by dose group and by study day.  Summaries 


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will be presented for scheduled visits only.  Any unscheduled assessments will be listed.  The 
baseline value is defined as the latest result obtained prior to the start of IP. 
The impact of any major protocol deviations, missing data, and the use of rescue or 
concomitant medication on the robustness of study results will be investigated and any 
methods employed to deal with these will be documented. 
Additional tables, figures, or listings may be produced to aid interpretation. 
Further details of summaries of the safety data will be given in the SAP. 
12.2.4.1 Adverse events 
The number of patients experiencing AEs following administration of olaparib as well as the 
number of AEs experienced will be summarised.  Adverse events will be classified using the 
MedDRA® system of nomenclature (preferred term and system organ class [SOC]).  Adverse 
events reported before administration of olaparib will be listed only and be referred to as 
‘pre-treatment.’ 
Similarly, the number of patients experiencing SAEs, OAEs, AEs that led to withdrawal, AEs 
that led to death and treatment-related AEs and the number of such events will be summarised 
by part, as applicable. 
All AE data will be listed for all patients.  In addition, SAEs, OAEs, and AEs that led to 
withdrawal or death, and treatment-related AEs will be listed. 
12.2.4.2 Dose-limiting toxicities 
Dose-limiting toxicities will be summarised by treatment cohort for Part A. 
12.2.4.3 Laboratory data 
Laboratory data (clinical chemistry and haematology) will be summarised and listed.  Shift 
tables will be provided for select tests, where shift from baseline to the worst value within 
each part of the study and overall will be summarised.  Laboratory data outside the reference 
ranges should be indicated in the listings. 
12.2.4.4 Concomitant medications 
Concomitant medications will be summarised by the coded terms.  The number of patients 
receiving a medication will be summarised overall and for each part of the study.  A 
medication taken during the course of the study is considered concomitant.  A patient is only 
counted once if receiving the medication more than once. 
Disallowed medications will be listed. 


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12.2.4.5 Vital signs 
Vital signs, including BP (mmHg), heart rate (beats/min), body temperature (°C) and weight 
(kg), will be summarised at baseline and each scheduled visit.  In addition, a summary of vital 
signs changes from baseline to each visit will be presented by treatment.  The baseline value is 
the last pre-dose assessment. 
A listing of all vital sign data will also be produced. 
12.2.4.6 Other safety variables 
The remaining safety variables will be presented using summary statistics for quantitative data 
and frequency counts for qualitative parameters. 
12.2.4.7 Exposure and compliance 
Listings and summaries of exposure and compliance will be produced for olaparib and 
abiraterone, by treatment cohorts, for Part A and treatment groups in Part B. 
The number of patients who discontinued study drug, and the reasons, will be summarised by 
treatment group for Part A and B separately.  These data will also be listed. 
12.2.5 
PK data (Part A only) 
The sample bioanalysis for olaparib and abiraterone will be performed by Covance.  The 
merging of PK concentration data with actual PK sampling times will be performed by 
Quintiles Data Management.  The PK analysis will be the responsibility of the 
pharmacokineticist at AstraZeneca.  The PK summaries, figures, and data listings as well as 
the statistical analysis of the PK variables will be the responsibility of the Quintiles 
biostatistician. 
All data received for olaparib and abiraterone will be presented in data listings.  
Pharmacokinetic summaries will be presented for patients in the PK analysis set, as defined in 
Section 12.1.  Data from patients excluded from the PK analysis set will be included in the 
data listings, but not in the summaries.  Extra measurements (such as unscheduled or repeat 
assessments) will also not be included in summary tables, but will be included in patient 
listings. 
For qualitative variables, the population size (N for sample size and n for available data) and 
the percentage (of available data) for each class of the variable will be presented.  Quantitative 
variables will be summarised using descriptive statistics, including n, arithmetic mean, SD, 
coefficient of variation (%CV), median, minimum, and maximum values.  Additionally, 
geometric means and geometric %CV (%GCV) will be reported for PK variables 
(concentrations and all PK parameters, except for tmax ss).  The geometric mean is calculated as 
the exponential of the arithmetic mean calculated from data on a log scale.  The %GCV is 
calculated as 
 where s is the SD of the data on a log scale.  Mean, SD, 
CV%, geometric mean, and %GCV will not be calculated for tmax ss; tmax ss will be summarised 
by median, minimum and maximum values. 
( )
(
)1
exp
100
2 −
⋅
s


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For all data, descriptive statistics except for %CV and %GCV will follow the rounding 
convention of the individual data.  Coefficients of variation (%CV and %GCV) will always be 
reported to 1 decimal place.  Ratios and any corresponding CIs that are obtained during 
inferential statistical analysis shall be reported as a percent with 2 decimal places (eg, 99.88). 
The plasma concentrations for olaparib and abiraterone will be reported to the same precision 
as the source data.  For descriptive statistics of concentrations, non-quantifiable (NQ) values 
of plasma concentrations will be handled as follows: 
• 
If, at a given time point, 50% or less of the plasma concentrations are NQ, the 
mean, SD, geometric mean, %CV, and %GCV will be calculated by substituting the 
LOQ for values which are NQ. 
• 
If more than 50%, but not all, of the concentrations are NQ, the mean, geometric 
mean, SD, %CV, and %GCV will be reported as not calculable (NC). 
• 
If all the concentrations are NQ, the geometric mean and mean will be reported as 
NQ and the SD, %CV, and %GCV as NC. 
The PK parameters will be rounded for reporting purposes both in the summary tables and 
by-patient listings.  For the calculation of descriptive statistics and the statistical analysis, 
rounded values as presented in the data listings will be used.  Except for raw measurements 
(such as Cmax ss and tmax ss), all other derived PK parameters will be reported to 3 significant 
digits. 
The PK data will be presented by treatment group (ie, Group 1 [olaparib alone first, then 
olaparib with abiraterone] and Group 2 [abiraterone alone first, then olaparib with 
abiraterone]). 
The goal of Part A of the study is to determine whether there is any marked evidence of any 
drug interaction between olaparib and abiraterone by determination of steady state exposure to 
olaparib in the presence and absence of abiraterone, and determination of steady state 
exposure to abiraterone in the presence and absence of olaparib.  Cmax ss, AUCss and Cmin ss 
ratios will be calculated for olaparib from Group 1 patients (PK parameter from ‘olaparib 
alone’ profile: PK parameter from ‘olaparib in combination’ profile) and for abiraterone from 
Group 2 patients (PK parameter from ‘abiraterone alone’ profile: PK parameter from 
‘abiraterone in combination’ profile).  These ratios will be summarised for each group and 
displayed graphically.  No statistical analysis of the data will be performed. 
12.2.6 
Health economics data 
12.2.6.1 Utilities: EQ-5D-5L 
Descriptive statistics, graphs and listings will be reported for health state utility index values 
and visual analogue scale by visits as well as change in these scores from baseline.  To 
support future economic evaluations of olaparib, additional appropriate analyses may be 


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undertaken, for example, mean health state utility pre- and post-treatment, and pre- and post-
progression.  Further details will be outlined in the payer analysis plan. 
12.2.6.2 Resource use 
An exploratory health economic analysis of the frequency of metastatic prostate cancer related 
palliative interventions, time to interventions, and reason for the intervention will be 
undertaken.  In addition, length of stay, ICU use, concomitant medications and analgesic use 
will be examined. 
These analyses will examine the impact of disease and treatment on resource use to primarily 
support the economic evaluation of olaparib in castrate resistant metastatic prostate cancer. 
12.2.7 
Interim analyses (Not applicable) 
12.3 
Determination of sample size 
12.3.1 
Part A 
The primary objective of Part A of this study is to assess the safety and tolerability of olaparib 
when combined with abiraterone and to recommend a dose of olaparib for study in Part B.  
Hence the number of patients has been based on the desire to obtain adequate tolerability, 
safety and PK data while exposing as few patients as possible to the IP and procedures. 
Cohorts of 3 to 6 evaluable patients will be required.  The total number of patients will depend 
upon the number of dose escalations/reductions necessary. 
The cohort sizes are based upon accepted methodology for Phase I oncology studies. 
12.3.2 
Part B 
The sample size for Part B of this study was selected to be consistent with the research 
hypothesis as described in Section 1.2.  The sample size calculation is based on the primary 
outcome variable, rPFS. 
In total, 100 rPFS events in the study would have 80% power to show a statistically significant 
rPFS at the 1-sided 10% level if the assumed true treatment effect was HR 0.65; this translates 
to a 3.75 month benefit in median rPFS on olaparib/abiraterone combination over 7 months 
(based on the mean of 2 trials: Antonarakis and Eisenberger 2011 and Scher et al 2012) on 
abiraterone monotherapy if rPFS is exponentially distributed.  Approximately 140 patients 
will be recruited (1:1 ratio) so that data maturity for the rPFS analysis is approximately 70%.  
Assuming 12 months non-linear recruitment, 100 rPFS events are expected to occur 
approximately 24 months after the first patient is enrolled in the study (FPI) (12 month accrual 
+ 12 months follow-up).  This will be the primary analysis of rPFS.  With 100 events, the 
smallest treatment difference that would be statistically significant is rPFS HR = 0.77 (which 
translates to approximately a 2.1 months median difference). 
Overall survival will be analysed after approximately 60% deaths have occurred.  Assuming 
12 months’ non-linear recruitment, 84 death events are expected to occur approximately 


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37 months after FPI.  With 80% power, an improvement in median time to death of 10 months 
on olaparib/abiraterone combination over 17 months on abiraterone alone (HR=0.63) could be 
detected (1-sided, 10% alpha). 
The primary and all secondary efficacy endpoints will be analysed in the full analysis set 
unless otherwise stated.  The safety endpoints will be analysed in the safety analysis set. 
For sample size information relating to the pharmacogenetic component of the study, please 
see Appendix D (‘Pharmacogenetics research’). 
12.4 
Data monitoring committee (Not applicable) 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
13.1 
Medical emergencies and AstraZeneca contacts 
The PI is responsible for ensuring that procedures and expertise are available to handle 
medical emergencies during the study.  A medical emergency usually constitutes a SAE 
and is to be reported as such, see Section 6.4.4. 
In the event of a medical emergency the Investigator may contact the 24-hour Quintiles 
Medical Emergency Contact Centre 
 
13.2 
Overdose 
Investigators should be advised that any patient who receives a higher dose than that intended 
should be monitored closely, managed with appropriate supportive care and followed up 
expectantly. 
There is currently no specific treatment in the event of overdose of olaparib and possible 
symptoms of overdose are not established. 
The primary anticipated complications of olaparib over dosage would consist of bone marrow 
suppression, peripheral neuropathy and mucositis.  Adverse reactions associated with 
overdose should be treated symptomatically and should be managed appropriately. 
• 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose CRF module. 
• 
An overdose without associated symptoms is only reported on the Overdose CRF 
module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
PPD


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Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
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The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with SAE, standard reporting timelines apply, see Section 6.4.4.  For 
other overdoses, reporting should be done within 30 days. 
13.3 
Pregnancy 
13.3.1 
Maternal exposure 
Women are not included in this study. 
13.3.2 
Paternal exposure 
Patients must refrain from fathering a child or donating sperm during the study and for 
3 months following the last dose of olaparib/placebo, since the potential for chromosomal 
aberrations in male gametes, and possible teratogenic effects thereof, has not yet been 
thoroughly investigated. 
Pregnancy of the patients’ partner is not considered to be an AE.  However, the outcome of 
any conception (including spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) from the date of the first dose until 3 months after the last dose 
should, if possible, be followed up and documented. 
Where a report of pregnancy is received, prior to obtaining information on the pregnancy, the 
Investigator must obtain the consent of the subject’s partner. Therefore, the local study team 
should adopt the generic ICF template in line with local procedures and submit it to the 
relevant ECs/IRBs prior to use. 
14. 
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Beltran H, Yelensky R, Frampton GM, Park K, Downing SR, MacDonald TY et al.  Targeted 
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Edition Number 2 
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Brenner et al 2011 
Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q, Asangani IA et al.  Mechanistic rationale for 
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Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M et al.  Germline 
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Cella et al 1993 
Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, et al.  The Functional 
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Cella et al 2009 
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Cleeland 2008 
Cleeland C. The Brief Pain Inventory, User Guide.  1-66. 2008.  
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Cleeland CS, Portenoy RK, Rue M, Mendoza TR, Weller E, Payne Ret al.  Does an oral 
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Di Lorenzo G, Autorino R, Giuliano M, Morelli E, Giordano A, Napodano G et al. Phase II 
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Di Lorenzo et al 2007b 
Di Lorenzo G, Autorino R, Perdona S, De L, Armiento M, Cancello G et al. Docetaxel, 
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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
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Esper et al 1997 
Esper P, Mo F, Chodak G, Sinner M, Cella DF, Pienta KJ.  Measuring quality of life in men 
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Eton and Lepore 2002 
Eton D, Lepore S.  Prostate cancer and health-related quality of life: a review of the literature. 
Psychooncology. 2002;11:307-26. 
Gater et al 2011 
Gater A, Abetz-Webb L, Battersby C, Parasuraman B, McIntosh S, Nathan F et al.  Pain in 
castration-resistant prostate cancer with bone metastases: a qualitative study.  Health Qual 
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Hong et al 2007 
Hong S, Cho K, Cho H, Ahn H, Kim C, Chung B. A prospective, multicenter, open-label trial 
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Lindqvist et al 2008 
Lindqvist O, Rasmussen B, Widmark A.  Experiences of symptoms in men with hormone 
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LoRusso et al 2003 
LoRusso PM, Herbst RS, Rischin D, Ranson M, Calvert H, Raymond E et al.  Improvements 
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Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, et al.  Synthetic 
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Mateo J, Sandhu S, Miranda S, Carreira S, Suneil J, Christy R, et al. DNA repair defects and 
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Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, et al.  Alpha emitter 
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Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
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Robins JM, Tsiatis AA. Correcting for noncompliance in randomized trials using rank 
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Robins 1993 
Robins J. Information recovery and bias adjustment in proportional hazards regression 
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Rosenfeld et al 2004 
Rosenfeld B, Roth AJ, Gandhi S, Penson D.  Differences in health related quality of life of 
prostate cancer patients based on stage of cancer. Psycho-Oncology 2004;13:800-7. 
Ryan et al 2013 
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al.  Abiraterone in 
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Scher et al 2012 
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K et al.  Increased survival with 
enzalutamide in prostate cancer after chemotherapy.  N Engl J Med. 2012 Sep 
27;367(13):1187-97. 
Schiewer et al 2012 
Schiewer MJ, Goodwin JF, Han S, Brenner JC, Augello MA, Dean JL et al.  Dual roles of 
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Sellke, T. and Siegmund, D. Sequential analysis of the proportional hazards model. 
Biometrika 70: 315-326, 1983. 
Skolnik et al 2008 
Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC.  Shortening the timeline of 
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Tester et al 2006 
Tester W, Ackler J, Tijani L, Leighton J.  Phase I/II study of weekly docetaxel and vinblastine 
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Drug Substance Olaparib (AZD2281, KU-0059436)  
Study Code D081DC00008 
Edition Number 2 
Date 20 October 2015 
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Yount et al 2003 
Yount S, Cella D, Banik D, Ashraf T, Shevrin D.  Brief assessment of priority symptoms in 
hormone refractory prostate cancer: the FACT Advanced Prostate Symptom Index (FAPSI). 
Health Qual. Life Outcomes 2003;1: 69. 


 
 
Clinical Study Protocol Appendix B 
 
Drug Substance 
Olaparib (AZD2281, 
KU-0059436) 
 
Study Code 
D081DC00008 
 
Edition Number 
2 
 
Date 
11 December 2103 
 
 
 
 
 
 
 
 
 
 
Appendix B 
Additional Safety Information 
 


Clinical Study Protocol Appendix B 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008 
Edition Number 2 
Date 11 December 2103 
2(3) 
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE) 
Life threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
Examples of such events are: 
• 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation 
• 
Development of drug dependency or drug abuse. 


Clinical Study Protocol Appendix B 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008 
Edition Number 2 
Date 11 December 2103 
3(3) 
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION 
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug. 
• 
Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug? 
• 
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the AE be anticipated from its pharmacological 
properties? 
• 
Dechallenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug? 
• 
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors. 
• 
Rechallenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a rechallenge. 
• 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship? 
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist. 
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE. 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognised feature of overdose of the drug? 
• 
Is there a known mechanism? 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility. 


 
 
Clinical Study Protocol Appendix C 
 
Drug Substance 
Olaparib (AZD2281, 
KU-0059436) 
 
Study Code 
D081DC00008 
 
Edition Number 
2 
 
Date 
11 December 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix C 
International Airline Transportation Association (IATA) 6.2 Guidance 
Document 
 
 


Clinical Study Protocol Appendix C 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
2(3) 
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm).  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus: 
• 
are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
• 
Clinical trial samples will fall into Category B or exempt under IATA regulations 
• 
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm) 
• 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
• 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable 


Clinical Study Protocol Appendix C 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
3(3) 
• 
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used. 
 


 
 
Clinical Study Protocol Appendix D 
 
Drug Substance 
Olaparib (AZD2281, 
KU-0059436) 
 
Study Code 
D081DC00008 
 
Edition Number 
2 
 
Date 
11 December 2013 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix D 
Pharmacogenetics Research 
 


Clinical Study Protocol Appendix D 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
2(7) 
TABLE OF CONTENTS 
PAGE
 
TITLE PAGE.......................................................................................................1 
TABLE OF CONTENTS.....................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS........................... 3 
1. 
BACKGROUND AND RATIONALE.................................................................4 
2. 
GENETIC RESEARCH OBJECTIVES ...............................................................4 
3. 
GENETIC RESEARCH PLAN AND PROCEDURES.........................................4 
3.1 
Selection of genetic research population...............................................................4 
3.1.1 
Study selection record..........................................................................................4 
3.1.2 
Inclusion criteria ..................................................................................................4 
3.1.3 
Exclusion criteria .................................................................................................5 
3.1.4 
Discontinuation of patients from this genetic research..........................................5 
3.2 
Collection of samples for genetic research............................................................5 
3.3 
Coding and storage of DNA samples....................................................................5 
4. 
ETHICAL AND REGULATORY REQUIREMENTS.........................................6 
4.1 
Informed consent .................................................................................................6 
4.2 
Patient data protection..........................................................................................6 
5. 
DATA MANAGEMENT.....................................................................................6 
6. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE ....................................................................................................................7 
7. 
LIST OF REFERENCES .....................................................................................7 
 


Clinical Study Protocol Appendix D 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
3(7) 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event 
BRCA 
Breast cancer genes 
DNA 
Deoxyribonucleic acid 
LIMS 
Laboratory information management system 
 


Clinical Study Protocol Appendix D 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
4(7) 
1. 
BACKGROUND AND RATIONALE 
AstraZeneca intends to perform genetic research in the olaparib clinical development 
programme to explore how genetic variations may affect the clinical parameters associated 
with olaparib and/or agents used in combination or as comparators.  Collection of DNA 
samples from populations with well described clinical characteristics may lead to 
improvements in the design and interpretation of clinical trials and, possibly, to genetically 
guided treatment strategies. 
It is emphasised that AstraZeneca will only look for markers within genes relevant to the 
mode of action of, and response to olaparib and/or abiraterone used in combination or as a 
comparator, and the disease under study within the current Clinical Study Protocol.  BRCA 
genes (genes encoding cancer susceptibility proteins involved in DNA repair) and other genes 
associated with DNA damage repair may be studied.  No other research will be performed on 
the samples. 
BRCA data may be available at the end of the study and sites may request individual patient 
BRCA results to be provided as required.  Sites are responsible for ensuring compliance with 
all associated local procedures for genetic testing if a patient BRCA result is provided. 
2. 
GENETIC RESEARCH OBJECTIVES 
The objective of this research is to collect and store DNA for future exploratory research into 
genes/genetic variation that may influence response (ie, distribution, safety, tolerability and 
efficacy) to study treatments and/or susceptibility to disease. 
3. 
GENETIC RESEARCH PLAN AND PROCEDURES 
3.1 
Selection of genetic research population 
3.1.1 
Study selection record 
All patients will be asked to participate in this genetic research.  Participation is voluntary and 
if a patient declines to participate there will be no penalty or loss of benefit.  The patient will 
not be excluded from any aspect of the main study. 
3.1.2 
Inclusion criteria 
For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described 
in the main body of the Clinical Study Protocol and: 
• 
Provide informed consent for the pharmacogenetic sampling and analyses. 


Clinical Study Protocol Appendix D 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
5(7) 
3.1.3 
Exclusion criteria 
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following: 
• 
Previous allogeneic bone marrow transplant. 
• 
Non-leukocyte depleted whole blood transfusion within 120 days of the date of the 
pharmacogenetic sample collection. 
3.1.4 
Discontinuation of patients from this genetic research 
Specific reasons for discontinuing a patient from this genetic research are: 
Withdrawal of consent for genetic research:  Patients may withdraw from this genetic research 
at any time, independent of any decision concerning participation in other aspects of the main 
study.  Voluntary discontinuation will not prejudice further treatment.  Procedures for 
discontinuation are outlined in Section 7.5 of the main Clinical Study Protocol. 
3.2 
Collection of samples for genetic research 
The blood sample for genetic research will be obtained from the patients at Visit 2.  Although 
genotype is a stable parameter, early sample collection is preferred to avoid introducing bias 
through excluding patients who may withdraw due to an adverse event (AE); such patients 
would be important to include in any genetic analysis.  If for any reason the sample is not 
drawn at Visit 2, it may be taken at any visit until the last study visit.  Only one sample should 
be collected per patient for genetics during the study.  Samples will be collected, labelled, 
stored and shipped as detailed in the Laboratory Manual. 
For blood volume, see Section 7.1 of the Clinical Study Protocol. 
3.3 
Coding and storage of DNA samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 
15 years, from the date of last patient last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached. 
For all samples irrespective of the type of coding used the DNA will be extracted from the 
blood sample.  The DNA sample will be assigned a unique number replacing the information 
on the sample tube.  Thereafter, the DNA sample will be identifiable by the unique DNA 
number only.  The DNA number is used to identify the sample and corresponding data at the 
AstraZeneca genetics laboratories, or at the designated contract laboratory.  No personal 
details identifying the individual will be available to any person (AstraZeneca employee or 
contract laboratory staff working with the DNA.) 


Clinical Study Protocol Appendix D 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
6(7) 
The samples and data for genetic analysis in this study will be single coded.  The link between 
the patient enrolment/randomisation code and the DNA number will be maintained and stored 
in a secure environment, with restricted access WITHIN the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca.  The link will be used 
to identify the relevant DNA samples for analysis, facilitate correlation of genotypic results 
with clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent. 
4. 
ETHICAL AND REGULATORY REQUIREMENTS 
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 8 of the main Clinical Study Protocol. 
4.1 
Informed consent 
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study the patient must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the patient and the original filed at the study centre.  The 
principal investigator(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely discontinue from the genetic aspect of the study at 
any time. 
4.2 
Patient data protection 
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law.  BRCA genotype results may be available at the end of the study and 
can be provided to the investigator if requested by the patient. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data.  Also Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate. 
5. 
DATA MANAGEMENT 
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or third party contracted 
to work with AstraZeneca to analyse the samples. 


Clinical Study Protocol Appendix D 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
7(7) 
Only the date the patient gave consent to participation in the genetic research and the date the 
blood sample was taken from the patient will be recorded in the CRF and database. 
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.  The results from this 
genetic research will be reported separately from the Clinical Study Report for the main study. 
6. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
The number of patients that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A statistical 
analysis plan will be prepared where appropriate. 
7. 
LIST OF REFERENCES 
None 


 
 
Clinical Study Protocol Appendix E 
 
Drug Substance 
Olaparib (AZD2281, 
KU-0059436) 
 
Study Code 
D081DC00008 
 
Edition Number 
3 
 
Date 
15 August 2014 
 
 
 
 
 
 
 
 
 
Appendix E 
Actions Required in Cases of Combined Increase of Aminotransferase and 
Total Bilirubin - Hy’s Law 
 


Clinical Study Protocol Appendix E 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008 
Edition Number 3 
Date 15 August 2014 
2(7) 
TABLE OF CONTENTS 
PAGE
 
TABLE OF CONTENTS.........................................................................................2 
1. 
INTRODUCTION ...................................................................................................3 
2. 
DEFINITIONS.........................................................................................................3 
3. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES...................................3 
4. 
FOLLOW-UP ..........................................................................................................4 
4.1 
Potential Hy’s Law Criteria not met ........................................................................4 
4.2 
Potential Hy’s Law Criteria met ..............................................................................4 
5. 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES...............5 
6. 
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW CRITERIA 
ARE MET BEFORE AND AFTER STARTING STUDY TREATMENT ............6 
7. 
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL 
HY’S LAW ..............................................................................................................6 
8. 
REFERENCES ........................................................................................................7 
 


Clinical Study Protocol Appendix E 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008 
Edition Number 3 
Date 15 August 2014 
3(7) 
1. 
INTRODUCTION 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Product (IP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting adverse events (AE) and serious adverse events (SAE) according to the outcome of 
the review and assessment in line with standard safety reporting processes. 
2. 
DEFINITIONS 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).  The elevations do not have to occur at the same time or within a specified time frame. 
Hy’s Law (HL) 
AST or ALT 3x ULN together with TBL 2xULN, where no other reason, other than the 
IP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  The elevations do not have to occur at the same time 
or within a specified time frame. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
3. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT 3xULN 


Clinical Study Protocol Appendix E 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008 
Edition Number 3 
Date 15 August 2014 
4(7) 
• 
AST 3xULN 
• 
TBL 2xULN 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• 
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix 
for definition) by reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory CRF. 
4. 
FOLLOW-UP 
4.1 
Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
4.2 
Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
• 
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment in the presence of liver metastases (See Section 6) 
• 
Notify the AstraZeneca representative who will then inform the central Study Team. 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will: 
• 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated  
• 
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician 
• 
Complete the three Liver CRF Modules as information becomes available  
• 
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures. 


Clinical Study Protocol Appendix E 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008 
Edition Number 3 
Date 15 August 2014 
5(7) 
5. 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW 
CASES 
The instructions in this section should be followed for all cases where PHL criteria were met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the IP.  
The AstraZeneca Medical Science Director and Global Safety Physician will also be involved 
in this review together with other subject matter experts as appropriate.   
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
• 
If the alternative explanation is an AE/SAE, record the AE/SAE in the CRF 
accordingly and follow the AZ standard processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP: 
• 
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  
− 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
• 
Report a SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above 
• 
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 


Clinical Study Protocol Appendix E 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008 
Edition Number 3 
Date 15 August 2014 
6(7) 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review. 
6. 
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW 
CRITERIA ARE MET BEFORE AND AFTER STARTING 
STUDY TREATMENT 
This section is applicable to patients who meet PHL criteria on study treatment having 
previously met PHL criteria at a study visit prior to starting study treatment. 
At the first on-study treatment occurrence of PHL criteria being met the Investigator will: 
• 
Determine if there has been a significant change in the patients’ condition# 
compared with the last visit where PHL criteria were met#  
− 
If there is no significant change no action is required 
− 
If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described is 
Section 4.2 of this Appendix. 
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty. 
7. 
ACTIONS REQUIRED FOR REPEAT EPISODES OF 
POTENTIAL HY’S LAW 
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.   
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
• 
Was the alternative cause for the previous occurrence of PHL criteria being met 
chronic or progressing malignant disease or did the patient meet PHL criteria prior 
to starting study treatment and at their first on study treatment visit as described in 
Section 6? 


Clinical Study Protocol Appendix E 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008 
Edition Number 3 
Date 15 August 2014 
7(7) 
If No: follow the process described in Section 4.2 of this Appendix 
If Yes: 
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met 
• 
If there is no significant change no action is required 
• 
If there is a significant change follow the process described in Section 4.2 of this 
Appendix 
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty. 
8. 
REFERENCES 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf 
 


 
 
Clinical Study Protocol Appendix F 
 
Drug Substance 
Olaparib (AZD2281, 
KU-0059436) 
 
Study Code 
D081DC00008 
 
Edition Number 
2 
 
Date 
11 December 2013 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix F 
Guidelines for Tumour Assessment: RECIST soft tissue and PCWG2 bone 
lesions 
 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
 
2(15) 
TABLE OF CONTENTS 
PAGE
TITLE PAGE.......................................................................................................1 
TABLE OF CONTENTS.....................................................................................2 
1. 
ASSESSMENT OF MALIGNANT SOFT TISSUE DISEASE BY 
MODIFIED RECIST CRITERIA.........................................................................4 
1.1 
Definition of measurable, non-measurable, target and non-target lesions..............4 
1.1.1 
Measurable lesions...............................................................................................4 
1.1.2 
Non-measurable lesions .......................................................................................4 
1.1.3 
Special cases........................................................................................................5 
1.1.4 
Target lesions.......................................................................................................5 
1.1.5 
Non-target lesions ................................................................................................5 
1.2 
Methods of measurement .....................................................................................5 
1.2.1 
CT and MRI.........................................................................................................6 
1.2.2 
Clinical examination ............................................................................................6 
1.2.3 
Chest X-ray..........................................................................................................6 
1.2.4 
Ultrasound ...........................................................................................................6 
1.2.5 
Endoscopy and laparoscopy .................................................................................6 
1.2.6 
Tumour markers...................................................................................................6 
1.2.7 
Cytology and histology ........................................................................................7 
1.3 
Tumour response evaluation.................................................................................7 
1.3.1 
Schedule of evaluation .........................................................................................7 
1.3.2 
Target lesions.......................................................................................................7 
1.3.2.1 
Documentation of target lesions ...........................................................................7 
1.3.2.2 
Evaluation of target lesions ..................................................................................8 
1.3.3 
Non-target lesions ................................................................................................9 
1.3.3.1 
Evaluation of non-target lesions ...........................................................................9 
1.3.4 
New lesions ....................................................................................................... 10 
1.3.5 
Symptomatic deterioration ................................................................................. 11 
1.3.6 
Evaluation of RECIST visit response for soft tissue lesions................................ 11 
2. 
ASSESSMENT OF BONE LESIONS................................................................11 
2.1 
Schedule of evaluation .......................................................................................12 
2.2 
Assessment of progression in bone lesions ......................................................... 12 
2.3 
Evaluation of PCWG2 response for bone lesions................................................ 12 
3. 
SPECIFICATIONS FOR RADIOLOGICAL IMAGING ...................................13 
3.1 
CT scans ............................................................................................................13 
3.1.1 
Anatomic coverage ............................................................................................ 13 
3.1.2 
Intravenous contrast administration.................................................................... 13 


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Drug Substance Olaparib (AZD2281, KU-0059436) 
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3.1.3 
Slice thickness and reconstruction material ........................................................ 14 
3.2 
MRI scans.......................................................................................................... 14 
3.3 
PET/CT scans ....................................................................................................15 
4. 
REFERENCES ..................................................................................................15 
 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
 
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TUMOUR ASSESSMENTS 
Image based tumour response assessment will be determined by evaluation of soft tissue 
lesions by modified RECIST v1.1 (Response Evaluation Criteria in Solid Tumours) 
(Eisenhauer et al 2009) and a separate bone lesions assessment using bone scans, as described 
in Prostate Cancer Trials Working Group 2 (PGWG2) recommendations (Scher et al 2008, 
Scher et al 2011). 
Note: same method of examination 
The same imaging modality must be used throughout the study to measure disease.  Different 
imaging techniques have differing sensitivities, so any given lesion may have different 
dimensions at any given time if measured with different modalities.  It is therefore not 
acceptable to interchange different modalities throughout this study. 
1. 
ASSESSMENT OF MALIGNANT SOFT TISSUE DISEASE BY 
MODIFIED RECIST CRITERIA 
This section details the implementation of modified RECIST v1.1 guidelines for the study 
with regards to investigator assessment of malignant soft tissue tumour burden. 
Note: In this study, bone lesions will not be included in the RECIST assessment as target 
lesions, non-target-lesions (NTL) or new lesions.  The guidelines for bone lesion 
assessments are defined in Section 2 of this appendix document. 
1.1 
Definition of measurable, non-measurable, target and non-target 
lesions 
Patients with at least one soft lesion (measurable and/or non-measurable) that can be 
accurately assessed at baseline by computerised tomography (CT) or magnetic resonance 
imaging (MRI) will be assessed in accordance with the following guidelines. 
1.1.1 
Measurable lesions 
A lesion, not previously irradiated, that can be measured accurately at baseline as 10 mm in 
the longest diameter (except lymph nodes which must have a short axis 15 mm) with CT or 
MRI and which is suitable for accurate repeated measurements. 
1.1.2 
Non-measurable lesions 
• 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with 10 mm to <15 mm short axis) at baseline.  Nodes with <10 mm 
short axis are considered non-pathological and should not be recorded as NTL 
• 
Truly non-measurable lesions include the following: leptomeningeal disease, 
ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitic 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
 
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involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical examination that are not measurable by CT or MRI 
• 
Previously irradiated lesions as localised post-radiation changes, which affect lesion 
sizes, may occur.  Therefore, lesions that have been previously irradiated will not be 
considered measurable and should be selected as NTLs at baseline and followed up 
as part of the NTL assessment 
• 
Skin lesions assessed by clinical examination 
• 
Brain metastasis. 
1.1.3 
Special cases 
• 
Soft tissue lesion that derives from a lytic bone lesion and meets the definition of 
measurability on CT/MRI can be considered measurable and recorded as a target 
lesion.  The guidelines for bone lesion assessments are defined in Section 2 of this 
appendix document. 
• 
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present 
in the same patient, these non-cystic lesions should be selected as the target lesions 
(TLs). 
1.1.4 
Target lesions 
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline. 
1.1.5 
Non-target lesions 
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline (except bone lesions which will be assessed as defined in Section 2 of this appendix 
document). 
1.2 
Methods of measurement 
The same method of assessment and the same technique should be used to characterise 
each identified and reported lesion at baseline and during follow-up. 
The methods to be used for RECIST assessment are summarised in Table 1 and those 
excluded for tumour assessments in this study are discussed below, with the rationale 
provided. 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
 
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Table 1 
Summary of methods of assessment 
Target lesions 
Non target lesions 
New lesions 
CT (preferred) 
MRI 
 
CT (preferred) 
MRI 
Chest X-ray 
Clinical examination  
CT (preferred) 
MRI 
Chest X-ray 
Ultrasound 
 
1.2.1 
CT and MRI 
Computerised tomography and MRI are generally considered to be the best currently available 
and reproducible methods to measure TLs selected for response assessment and to assess 
NTLs and identification of new lesions. 
In this study it is recommended that CT examinations be used to assess tumour burden.  CT 
examination with intravenous contrast media administration is the preferred method.  MRI 
should be used where CT is not feasible or it is medically contra-indicated.  For assessment of 
brain lesions MRI is the preferred method. 
1.2.2 
Clinical examination 
Clinical examination will not be used for assessment of TLs.  Clinically detected lesions can 
be selected as TLs if they are then assessed by CT or MRI scans.  Clinical examination can be 
used to assess NTLs in patients that also have other lesions assessable by CT or MRI. 
1.2.3 
Chest X-ray 
Chest X-rays will not be used for assessment of TLs as they will be assessed by CT or MRI 
examination.  Chest X-rays can, however, be used to assess NTLs (eg, pleural effusion) and to 
identify the presence of new lesions. 
1.2.4 
Ultrasound 
Ultrasound examination will not be used for assessment of TLs and NTLs as it is not a 
reproducible method, does not provide an accurate assessment of tumour size and it is 
subjective and operator dependent.  Ultrasound examination can, however, be used to identify 
the presence of new lesions.  If new clinical symptoms occur and an ultrasound is performed 
then new lesions should be confirmed by CT or MRI scan. 
1.2.5 
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour measurements. 
1.2.6 
Tumour markers 
Tumour markers will not be used for tumour response assessments per RECIST v1.1. 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib (AZD2281, KU-0059436) 
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In this study PSA and CTC biomarkers are being collected for separate analysis.  However the 
results will not contribute to tumour response based on RECIST v1.1 assessment. 
1.2.7 
Cytology and histology 
Histology will not be used as part of the tumour response assessment per RECIST v1.1.  
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease.  In such circumstances, the cytology is necessary to differentiate between 
response / stable disease (an effusion may be a side effect of the treatment) and progressive 
disease (if the neoplastic origin of the fluid is confirmed).  Where cytology findings are not 
available, any effusion that significantly worsens (from trace to large) or the appearance of a 
clinically significant effusion (requiring change in drug therapy) during the study treatment 
will be considered to be progression of NTLs or disease progression due to new lesions. 
1.3 
Tumour response evaluation 
1.3.1 
Schedule of evaluation 
Baseline tumour assessments should encompass all areas of known predilection for metastases 
in the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual patients and should be performed no more than 
4 weeks (28 days) before the start of study treatment.  On-study assessments should be 
performed every 12 weeks (±1 week) until progression, death or withdrawal of consent. 
Please refer to the study plan in Section 3.1 of the Clinical Study Protocol for the tumour 
assessment schedule. 
Any other sites at which new disease is suspected should also be adequately imaged after 
baseline. 
1.3.2 
Target lesions 
1.3.2.1 
Documentation of target lesions 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved, should be identified as TLs at baseline.  
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions) but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly, should be selected. 
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimetres.  At baseline, the sum of the diameters for all TLs will be calculated and reported 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
 
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as the baseline sum of diameters.  At subsequent assessment visits the sum of diameters for all 
TLs will be calculated and reported as the sum of diameters at that visit. 
Special cases: 
• 
For TLs measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis 
• 
If the CT/MRI slice thickness used is >5mm, the minimum size of measurable 
disease at baseline should be twice the slice thickness of the baseline scan 
• 
If a lesion has completely disappeared, the longest diameter should be recorded as 
0 mm 
• 
If a TL splits into 2 or more parts, then record the sum of the diameters of those 
parts 
• 
If 2 or more TLs merge then the sum of the diameters of the combined lesion should 
be recorded for one of the lesions and 0 mm recorded for the other lesion(s) 
• 
If a TL is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned.  If an accurate measure can be given, this 
should be recorded, even if it is below 5 mm 
• 
If a TL cannot be measured accurately due to it being too large, provide an estimate 
of the size of the lesion 
• 
When a TL has had any intervention eg, radiotherapy, embolisation, surgery etc, 
during the study, the size of the TL should still be provided where possible. 
1.3.2.2 
Evaluation of target lesions 
Table 2 provides the definitions of the criteria used to determine objective tumour visit 
response for TLs. 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
 
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Table 2 
Visit response for target soft tissue lesions 
Complete Response (CR) 
Disappearance of all TLs since baseline.  Any pathological 
lymph nodes selected as TLs must have a reduction in short 
axis to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of TLs, 
taking as reference the baseline sum of diameters. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of TLs, 
taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  The 
appearance of one or more new lesions is also considered 
progression. 
Not Evaluable (NE) 
Only relevant if any of the TLs were not assessed or not 
evaluable or had a lesion intervention at this visit. 
Note: If the sum of diameters meets the progressive disease 
criteria, progressive disease overrides not evaluable as a TL 
response 
 
1.3.3 
Non-target lesions 
1.3.3.1 
Evaluation of non-target lesions 
Note: In this study, bone lesions will not be included in the RECIST assessment as NTL.  The 
guidelines for all other bone lesion assessments are defined in Section 2 of this appendix 
document. 
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline.  Measurements are not required for these lesions but their status should be followed 
at subsequent visits.  At each visit, an overall assessment of the NTL response should be 
recorded by the investigator.  Table 3 provides the definitions of the criteria used to determine 
and record overall response for NTLs at the investigational site at each visit. 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib (AZD2281, KU-0059436) 
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Edition Number 2 
Date 11 December 2013 
 
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Table 3 
Visit response for non-target soft tissue lesions 
Complete Response (CR) 
Disappearance of all NTLs since baseline.  All lymph nodes 
must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD 
Persistence of one or more NTLs. 
Progressive Disease (PD) 
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in one 
lesion only or in several lesions.  In all cases the progression 
MUST be clinically significant for the physician to consider 
changing or stopping therapy.  The appearance of one or 
more new lesions is also considered progression. 
Not Evaluable (NE) 
Only relevant when one or some of the NTLs were not 
assessed and in the investigator’s opinion they are not able to 
provide an evaluable overall NTL assessment at this visit. 
Note: For patients without TLs at baseline, this is relevant if 
any of the NTLs were not assessed at this visit and the 
progression criteria have not been met. 
 
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumour burden has increased sufficiently to merit discontinuation of therapy.  A 
modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status. 
1.3.4 
New lesions 
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new soft-tissue lesions is assessed as progression. 
A soft-tissue lesion identified at a follow up assessment in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease progression. 
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour. 
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan. 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
 
11(15) 
1.3.5 
Symptomatic deterioration 
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy. 
Patients with ‘symptomatic deterioration’ requiring discontinuation of study treatment without 
objective evidence of disease progression at that time should continue to undergo tumour 
assessments where possible until objective disease progression is observed. 
1.3.6 
Evaluation of RECIST visit response for soft tissue lesions 
The RECIST visit response will be derived using the algorithm shown in Table 4. 
Table 4 
Overall visit response for soft tissue lesions 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
NA 
CR 
No 
CR 
CR 
Non-CR/Non PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non PD or NE 
No 
PR 
SD  
Non PD or NE 
No 
SD 
NA 
Non CR/Non PD 
No 
SD (Non CR/non 
PD) 
NE 
Non-PD or NE 
No 
NE 
NA 
NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
NA 
NA 
No 
NED 
CR complete response;  NA not applicable (relevant when no TLs/NTLs at baseline);  NE not evaluable; 
NED no evidence of disease;   PD progressive disease;  PR partial response;  SD stable disease  
2. 
ASSESSMENT OF BONE LESIONS 
In this study, bone lesions will be assessed by bone scintigraphy (bone scans).  Whole body 
anteroposterior (AP) and posteroanterior (PA) bone scans should be performed. 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
 
12(15) 
2.1 
Schedule of evaluation 
A baseline bone scan should be performed a maximum of 4 weeks (28 days) before the start of 
study treatment. 
On-study assessments should be performed every 12 weeks (±1 week) until disease 
progression, discontinuation of study treatment or withdrawal of consent. 
Scans for confirmation of progression will be performed preferably at the next scheduled visit 
and at least 6 weeks after the initial scan where possible progression is identified. 
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
study plan in Section 3.1 of the Clinical Study Protocol for the tumour assessment schedule. 
2.2 
Assessment of progression in bone lesions 
Bone lesions will be assessed by bone scan and will not be part of the RECIST v1.1 malignant 
soft tissue assessment. 
• 
Positive hot spots on a bone scan should be considered significant and unequivocal 
sites of malignant disease to be recorded as metastatic bone lesions. 
Progression on a bone scan is assessed as: 
At the 12 week scan: 
If 2 or more new metastatic bone lesions are observed on the first 12-week scan, the 
confirmatory scan performed, preferably at the next scheduled visit for a bone scan (ie, 
Week 24) and at least 6 weeks later, must show 2 or more additional new metastatic bone 
lesions (for a total of 4 or more new metastatic bone lesions since the baseline assessment) for 
progression to be documented. 
After the 12 week scan: 
If 2 or more new metastatic bone lesions are observed on scans obtained after the first 
12-week assessment, confirmatory scan performed preferably at the next scheduled visit for a 
bone scan (eg, Week 36) and at least 6 weeks later needs to show the persistence of or an 
increase in the number of metastatic bone lesions compared to the prior scan. 
The date of progression is the date of the first scan that shows the change. 
2.3 
Evaluation of PCWG2 response for bone lesions 
Table 5 provides the definitions of the criteria to determine tumour visit response for bone 
lesions. 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
 
13(15) 
Table 5 
Overall PCWG2 response for bone lesions 
 
 
Non –Progressive Disease (non-PD) 
Persistence of one or more bone lesions. 
Progressive Disease (PD) 
Bone lesions fulfilling the requirements for 
new lesions and confirmation of  progression 
Non Evaluable (NE) 
Only relevant if a bone scan is not performed 
at that visit. 
3. 
SPECIFICATIONS FOR RADIOLOGICAL IMAGING 
These notes are recommendations for use in clinical studies.  The use of standardised 
protocols for CT and MRI allows comparability both within and between different studies, 
irrespective of where the examination has been undertaken. 
3.1 
CT scans 
Computerised tomography scans of the chest, abdomen and pelvis should be contiguous 
throughout all the anatomical regions of interest. 
The most critical CT image acquisition parameters for optimal tumour evaluation using 
RECIST v1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval. 
3.1.1 
Anatomic coverage 
Optimal anatomic coverage for most solid tumours is the chest, abdomen and pelvis.  
Coverage should encompass all areas of known predilection for metastases in the disease 
under evaluation and should additionally investigate areas that may be involved based on 
signs and symptoms of individual patients.  Because a lesion later identified in a body part not 
scanned at baseline would be considered as a new lesion representing disease progression, 
careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points.  This will enable better consistency not only of tumour 
measurements but also identification of new disease. 
3.1.2 
Intravenous contrast administration 
Optimal visualisation and measurement of metastases in solid tumours requires consistent 
administration (dose and rate) of intravenous contrast as well as timing of scanning.  
Typically, most abdominal imaging is performed during the portal venous phase and 
(optimally) about the same time frame after injection on each examination.  An adequate 
volume of a suitable contrast agent should be given so that the metastases are demonstrated to 
best effect and a consistent method is used on subsequent examinations for any given patient.  
It is very important that the same technique be used at baseline and on subsequent 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
 
14(15) 
examinations for a given patient.  For patients who develop contraindications to contrast after 
baseline contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or 
non-enhanced) should be performed should also be based on the tumour type, anatomic 
location of the disease and should be optimised to allow for comparison to the prior studies if 
possible.  Each case should be discussed with the radiologist to determine if substitution of 
these other approaches is possible and, if not, the patient should be considered not evaluable 
from that point forward.  Care must be taken in measurement of TLs on a different modality 
and interpretation of non-target disease or new lesions, since the same lesion may appear to 
have a different size using a new modality.  Oral contrast is recommended to help visualise 
and differentiate structures in the abdomen. 
If iodine contrast media is medically contraindicated at baseline or at any time during the 
course of the study, then the recommended methods are:  CT thoracic examination without 
contrast and abdominal and pelvic MRI with contrast.  If MRI cannot be performed then CT 
without intravenous contrast is an option for the thorax, abdomen and pelvic examinations. 
3.1.3 
Slice thickness and reconstruction material 
It is recommended that CT scans be performed at 5 mm contiguous slice thickness and this 
guideline presumes a minimum 5 mm thickness in recommendations for the measurable lesion 
definition.  Exceptionally, particular institutions may perform medically acceptable scans at 
slice thicknesses greater than 5 mm.  If this occurs, the minimum size of measurable lesions at 
baseline should be twice the slice thickness of the baseline scans. 
All window settings should be included in the assessment, particularly in the thorax where 
lung and soft tissue windows should be considered.  When measuring lesions, the TLs should 
be measured on the same window setting for repeated examinations throughout the study.  All 
images from each examination should be included in the assessment and not “selected” 
images of the apparent lesion. 
3.2 
MRI scans 
Magnetic resonance imaging has excellent contrast, spatial and temporal resolution; however, 
there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable 
globally.  The modality used at each visit should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  Generally, axial imaging of 
the abdomen and pelvis with T1 and T2 weighted imaging along with gadolinium-enhanced 
imaging should be performed.  The field of view, matrix, number of excitations, phase encode 
steps, use of fat suppression and fast sequences should be optimised for the specific body part 
being imaged as well as the scanner utilised.  It is beyond the scope of this appendix to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts and diseases.  
Ideally, the same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans.  Body scans should be performed with breath-
hold scanning techniques if possible.  For these reasons, CT is the imaging modality of choice. 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
 
15(15) 
3.3 
PET/CT scans 
At present, low dose or attenuation correction CT portions of a combined PET–CT are of 
limited use in anatomically based efficacy assessments and it is therefore suggested that they 
should not be substituted for dedicated diagnostic contrast enhanced CT scans for tumour 
measurements by RECIST v1.1.  In exceptional situations, if a site can document that the CT 
performed as part of a PET–CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast) then the CT portion of the PET–CT can be used for RECIST measurements.  
However, this is not recommended because the PET portion of the CT introduces additional 
data that may bias an investigator if it is not routinely or serially performed. 
4. 
REFERENCES 
Eisenhauer et al 2009 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al.  New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  European 
Journal of Cancer.  45 (2009) 228-247. 
Scher et al 2008 
Scher HI, Halabi S, Tannock I, et al: Design and end points of clinical trials for patients with 
progressive prostate cancer and castrate levels of testosterone: Recommendations of the 
prostate cancer clinical trials working group. J Clin Oncol 26:1148-1159, 2008 
Scher et al 2011 
Scher HI, Morris MJ, Busch E & Heller G. End Points and Outcones in Castration –Resistant 
Prostate Cancer: From Clinical Trials to Clinical Practice. J Clin Oncol 29:3695-3704. 


 
 
Clinical Study Protocol Appendix G 
 
Drug Substance 
Olaparib (AZD2281, 
KU-0059436) 
 
Study Code 
D081DC00008 
 
Edition Number 
2 
 
Date 
11 December 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix G 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 


Clinical Study Protocol Appendix G 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Code D081DC00008  
Edition Number 2 
Date 11 December 2013 
2(2) 
1. 
ECOG PERFORMANCE STATUS 
 
Patient ability 
 
Score 
Fully active, able to carry on all pre-disease performance without 
restriction 
0 
 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, eg, light house 
work, office work 
1 
Ambulatory and capable of all self-care, but unable to work.  Up 
and about more than 50% of waking hours 
2 
 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours 
3 
 
Completely disabled, unable to carry out any self-care and confined 
totally to bed or chair 
4 
 


 
 
 
Clinical Study Protocol Appendix H 
 
Drug Substance 
Olaparib (AZD2281, 
KU-0059436) 
 
Study Code 
D081DC00008 
 
Edition Number 
2 
 
Date 
11 December 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix H 
Brief Pain Inventory (Short Form) 
 
 


2(3)


3(3)


 
 
Clinical Study Protocol Appendix I 
 
Drug Substance 
Olaparib (AZD2281, 
KU-0059436) 
 
Study Code 
D081DC00008 
 
Edition Number 
2 
 
Date 
11 December 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix I 
Bone Pain Item 
 




 
 
 
Clinical Study Protocol Appendix J 
 
Drug Substance 
Olaparib (AZD2281, 
KU-0059436) 
 
Study Code 
D081DC00008 
 
Edition Number 
2 
 
Date 
11 December 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix J 
FACT-P (Version 4) 
 
 








 
 
 
Clinical Study Protocol Appendix K 
 
Drug Substance 
Olaparib (AZD2281, 
KU-0059436) 
 
Study Code 
D081DC00008 
 
Edition Number 
2 
 
Date 
11 December 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix K 
EQ-5D-5L Health Questionnaire 
 
 


UK (English) v.2 © 2009 EuroQol Group. EQ 5D™is a trade mark of the EuroQol Group
Health Questionnaire
English version for the UK
2(4)


UK (English) v.2 © 2009 EuroQol Group. EQ 5D™is a trade mark of the EuroQol Group
2
Under each heading, please tick the ONE box that best describes your health TODAY  
MOBILITY
I have no problems in walking about   
 
 
 

I have slight problems in walking about  
 
 
 

I have moderate problems in walking about   
 
 

I have severe problems in walking about  
 
 
 

I am unable to walk about  
 
 
 
 
 

SELF-CARE
I have no problems washing or dressing myself  
 
 

I have slight problems washing or dressing myself   
 

I have moderate problems washing or dressing myself  
 

I have severe problems washing or dressing myself  
 

I am unable to wash or dress myself  
 
 
 

USUAL ACTIVITIES (e.g. work, study, housework, 
family or leisure activities)
I have no problems doing my usual activities  
 
 

I have slight problems doing my usual activities  
 
 

I have moderate problems doing my usual activities  
 

I have severe problems doing my usual activities  
 
 

I am unable to do my usual activities  
 
 
 

PAIN / DISCOMFORT
I have no pain or discomfort   
 
 
 
 

I have slight pain or discomfort  
 
 
 
 

I have moderate pain or discomfort   
 
 
 

I have severe pain or discomfort  
 
 
 
 

I have extreme pain or discomfort  
 
 
 
 

ANXIETY / DEPRESSION
I am not anxious or depressed  
 
 
 
 

I am slightly anxious or depressed   
 
 
 

I am moderately anxious or depressed  
 
 
 

I am severely anxious or depressed   
 
 
 

I am extremely anxious or depressed  
 
 
 

3(4)


UK (English) v.2 © 2009 EuroQol Group. EQ 5D™is a trade mark of the EuroQol Group
3
x
We would like to know how good or bad your health is 
TODAY.
x
This scale is numbered from 0 to 100.
x
100 means the best health you can imagine.
0 means the worst health you can imagine.
x
Mark an X on the scale to indicate how your health is TODAY.
x
Now, please write the number you marked on the scale in the 
box below. 
                    
YOUR HEALTH TODAY  = 
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The best health     
you can imagine
The worst health   
you can imagine
4(4)


 
 

Revised Clinical Study Protocol Appendix L
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2FWREHU
 
 
 
 
 
 
 
 
Appendix L
Acceptable Birth Control Methods



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ACCEPTABLE BIRTH CONTROL METHODS
Olaparib is regarded as a compound with medium/high foetal risk
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x
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&HUD]HWWHGHVRJHVWUHO3/86PDOHFRQGRP&HUD]HWWHLVFXUUHQWO\WKHRQO\KLJKO\
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Page 5 of 28


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Page 7 of 28


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	  ). 	, )	  /   ).  0	 		) 	   )	,
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   0		)  .) /,, ) 	 )  00) 		)  	'
02 3 )  0	) 	   <) 	 )  ) >' 	)
 ' .	  		) 	,), ,	) ) 	) ). '	),)
*#! L' 	0	'2 K 0	) 	 ,0 ,)/0 ) ,)/ 	,	 	,  L'
) .) 	, .)	) ). 	, $  	)	 ). )  (;*$# 
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  	, 	' .) ' 		 0 )2
 	 
  	 

F362; 	  G 	  !  	 		 !
		5 	   '		  	 ! 4, F3  	
 	' , 	 		 ! 	  F3  	
		 	* /560! =E>H + /533/5;0? 	 	 	 : 05B>! =E>H
+ 056605EB? 	 	 		 ! 	  F  	 	* 
B/H ="	 	+ >50E1 E>H + >506>533? 	 	 :  DBH ="	
	+ >5/31 E>H + >5//>5/@?5   !  	 4, )
   !  G   	' , 		5
Page 10 of 28


( 	' *)	)) 	 
 	      !"#$%&
	' ()  (    
	 $ 	)  !
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,0 )	 ).	 0)'  )	 	)  )	 /	, ' .	 
		)6
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>	))L) 	)L)  	  =	)0 0
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G) 		 	> ' ). 	, )0 	, N /,)	 ) ) 	) 		 )  
/>2
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P
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0 ).  	2 O),M I)	
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	) 		 )  *	  6
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,)	)	 ! />
P
.) ' ). 	, )	, $ />2
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		M .	'  /.  *	 3 	, K0		) 	 )		 	, 	
*,' ) 	, 	 = =)	)2  ) 	) )/ 	, 		 	) )	 
	, 	' /   )  A'A 2
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  	) )/ 		 	)   )		  ) ,	) 	, 	,' 	  )	)
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 ' 		  	 	 !  !!* 	 )5 	   '		
 	 ! 4, )  	  	'   5
 	 
 	 
 
#		 	  F36 	 :&"//  	5 " !) )) 	 		
	  	  	 	 )!	 	 ,  F36
	  :&"// 	   '  )		 	5 "! 	
  * , 	 ! F36 	  , 		 
		  , 	 	, 	 	) =) '		 	
 ) 	4	 !	 G  	 	 I	?5

	 ! :&"//  	  )' , 	  	 , 		
=) 	 	 G 	)	'  ?5
Page 11 of 28


( 	' *)	)) 	 
 	      !"#$%&
	' ()  (    
	 $ 	)  !
$&
 ! F/0 0@ 	 36 	  ,  ' , F36 ) 
4     	 	 '	 *5 " 	 ! 		  
F0E F0/E 	 )  4,5  	  * 	 		  
		 	   *  	 !  	 G 	
	 5 " !!	 ! 	 	' 	   ! 
	 , 		5
 ' 		 	  ,   	  ! ) #"// #"/ #"0
#"3 " / 	 " 0- 	  	 ,	4  ! 5  	  *
	 		 	 	  *  	 !  ) =) 	 )*
	)		 ? #"// =) 	 )	 	) 	 	
'			? #"/ =) !? #"0 =)  	? #"3 " / 	
" 0-5  		 	   * ! 		  	 
	 , 	 	5
	 ! +
+) .	 	 . ) ) A 		)2
 , 	  +
	
	) //

 !  	!!+
	) !222 )		) ). )-) )'
' *+
K.  		 )	 )-) 	  ) 	) ) ,) 
.))/ .) 	, )		)  .))/A 0	2
' *+
K.  		 )	 )-) 	  ) 	) ) ,) 
.))/ .) 	, )		)  .))/A 0	2 J 	 	   "	 E5
		 ! +
+) .' 		 	 .	 )-) )		)2
 , 	  +
	
Page 12 of 28


( 	' *)	)) 	 
 	      !"#$%&
	' ()  (    
	 $ 	)  !
$$&
	) /0

 !  	!!+
	) !222 )		) ). 	) )'
' *+
*		 /,) )	 	)   ) )-) ,) )	 	) 
  ,0 	 .)  )	  	, 	'   + # + ! 
+ &2  )-) 			  	' )	 ) ,) 
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  ,0 	 .)  )	  	, 	'   + # + ! 
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.))/ .) 	, )		)  .))/A 0	2 J 	 	   "	 E5
		 ! +
+) .' 		 	 .	 	) )		)2
 , 	  +
	
	) /3

 !  	!!+
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' *+
) 		)  )	 		  *	  ). 	, 	' 	 .	  * 	 
)	2
K.  		M )   ) 		 	 	, 	 ).  , 	' 0	 	,' ,)
	 		 	,  .) 	, , 	2
' *+
) 		)  )	 		  *	  ). 	, 	' 	 .	  * 	 
)	2
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	 		 	,  .) 	, , 	2
Page 13 of 28


( 	' *)	)) 	 
 	      !"#$%&
	' ()  (    
	 $ 	)  !
#$&
J 		2	     		   5
	 ! +
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 , 	  +
	
	) /6

 !  	!!+
	) !2 22 =	 ). 
' *+
0 0	 ).  (+(? @  )  Q D -9& ,)  0		 
   )	 ' 	, K0		) /	, ) /	,)	 		) ). 	' 
) ,  ) 	> 	) )	 0) ,	)' ). 2
()) 		  ).   ) 0	 3 ) .)	 . 
,')	,')& ,)  <2 K )  	 ).  ' N
)) 	.)2 Q)/0 .  		 0)  (+(? @ $ Q R -9& )
/) 	' 			 ,)  		 .)  	) < ). # /> 	) )/ .) )
)/ )0'  	, 		 ,)   )	'2 	' 			  
		 	 	,  ) . Q , )0 	) D" -92 ' N	' N
 	 		) ) >' 	)  ) 	 ) )<		 /	, /'
0) 	) -) 	,))'	) / N 	' 			 ) 	)
	) !     .	 	  	)       ) 	2
K.  		 ,  		 .)  /	, 	 )) 	.) /	,)	 	'
			 		)  ) )) 	.) 	  1 ' 	,
K0		) 	' 			 ,)  		 .)  	)  < ). # /> 	) )/
.) ) )/ )0'2 	' 			 ,)  		 	   )2
' *+
0 0	 ).  (+(? @  )  QD K  -9& ,)  0		 
   )	 ' 	, K0		) /	, ) /	,)	 		) ). 	' 
) ,  ) 	> 	) )	 0) ,	)' ). 2 J !  "	
/05
Q)/0 .  		 0)  (+(? @ $ Q R -9& ) /) 	'
			 ,)  		 .)  	) < ). # /> 	) )/ .) ) )/
)0'  	, 		 ,)   )	'2 	' 			   		 	
	,  ) . Q , )0 	) D" -92 ' N	' N  	
		) ) >' 	)  ) 	 ) )<		 /	, /' 0)
Page 14 of 28


( 	' *)	)) 	 
 	      !"#$%&
	' ()  (    
	 $ 	)  !
!$&
	) -) 	,))'	) / N 	' 			 ) 	) 	) ! 
   .	 	  	)       ) 	2
K.  		 ,  		 .)  /	, 	 )) 	.) /	,)	 	'
			 		)  ) )) 	.) 	  1 ' 	,
K0		) 	' 			 ,)  		 .)  	)  < ). # /> 	) )/
.) ) )/ )0'2 	' 			 ,)  		 	   )2
"	 /0
		) ! 			
(	)
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( L />  K D )2
=" &	 0?
@0 )	 )	0 			  0		 	'2
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	.)&  		 ) .)  < ). # />2
K. 	 QL />  K D )2 ) 		 .) < ). # />& 	 Q
S  -  ) )0' ) 	) 	) 0;> ) , 	  
.	 	  	) 0>> ) , 	   ) 	 '  )2
( L D )2
@0 )	 )	0 			 22 	.)&  0		
	'2
K		 ) .)  < ). # />2 	 )0 	) Q S  
-2
) )0' )  	) 0;> ) , 	   .	 	  	)
0>> ) , 	   ) 	  	,  ). 	 Q 2
()) 		  ).   ) 0	 3 ) .)	 . 
,')	,')& ,)  < ')	 	 		 		)2 K )
 	 ).  ' N )) 	.)2
J 	 , 	 ' ) 		)	 * =K0 ,4
2	   	   " &	 3 =( LD )2M?  ,
			 	2 ' !  	! ? !   ;5/>5/5;
!  		) ! 5
		 ! +
+) .	 ,  	M  	 .) ) 	2
 , 	  +
	
	) /;

 !  	!!+
	) %2:22$ ,0 	)  .) )> '
Page 15 of 28


( 	' *)	)) 	 
 	      !"#$%&
	' ()  (    
	 $ 	)  !
%$&
' *+
+)  /, 0& /   .) ?7@ <)-.) 		 
37( 		)  )' )	, <)	)' )> ,  7  *+?
2 I,
0	 '  0 )	, 	'  '    )	 ). 	) 	)
 	,  ). 		 /	, )' . )2
' *+
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 	 " 	  )' )	, <)	)' )> ,  7 
*+?
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). 	) 	)  	,  ). 		 /	, )' . )2
	 ! +
+) .	 ,  	, 	' )' )1	02
 , 	  +
	
	) /@

 !  	!!+
2!2$ ?7@ <)-.) 		
' *+
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 /   .) 	, <) ). ?7@-?7@ .)2 G 	 ).
	)	) /  0  	, 			 '  *&2
' *+
2!2$ ?7@ <)-.) 		 " 	
 /   .) 	, <) ). ?7@-?7@ .) " 	2 G 	
). 	)	) /  0  	, 			 '  *&2
	 ! +
+) .	 ,  	, 	' )' )1	02
 , 	  +
	
Page 16 of 28


( 	' *)	)) 	 
 	      !"#$%&
	' ()  (    
	 $ 	)  !
:$&
	) /B

 !  	!!+
	) 222 7)) ))A. 00
' *+
	 )A> 		 ). *G /  	>  		 /,)  )	0 .) ?7@
<)-.) 		  ) .) 		 /,) ,0 37( 		)  	, 
)  .) 	, ' '2 K. 	,  ). 		  , )  
)	) /  0 	)  	, ) ) 	) '2
' *+
	 )A> 		 ). *G /  	>  		 /,)  )	0 .) ?7@
<)-.) 		  ) .) 		 , 	'   " 	  	,
 )  .) 	, ' '2 K. 	,  ). 		  , )  
)	) /  0 	)  	, ) ) 	) '2
	 ! +
+) .	 ,  	, 	' )' )1	02
 , 	  +
	
	) /D

 !  	!!+
	) # 7.
' *+

)
' *+
B222C
	  	 0>/;
	 N 
	 
 		 
 		 
 
 N    	5 < 	 !
	 	 	' ,  + "# 	 	  	 ! 		 
		 		 	 	 	5 )+  />@ 	
) 0>/;1  /D00 0>/;1 		 
Page 17 of 28


( 	' *)	)) 	 
 	      !"#$%&
	' ()  (    
	 $ 	)  !
$&
B222C
	 ! +
 / . ,   	) )	)) 	) )	 	, ,  	, )' )1	02
 , 	  +
	
	) /E

 !  	!!+
<  	 =  	)
' *+
	O	 	 	 '
 	'
O 7)	) = =7(* G7(*	,
=  	)
	 7T ' *>
=.
(,,  #+@

	
' =)	, ;&
Page 18 of 28
PPD


( 	' *)	)) 	 
 	      !"#$%&
	' ()  (    
	 $ 	)  !
"$&
' *+
	O	 	 	 '
 	'
4	 
'	4 
	 
 
	O	
&	) 
:

	
' =)	, ;&
	 ! +
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 , 	  +
	
Page 19 of 28
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Page 24 of 28










 
 
Clinical Study Protocol Amendment 
 
Amendment Number 
1 
 
Drug Substance 
Olaparib (AZD2281, KU 
0059436) 
 
Study Code 
D081DC00008 
 
Date 
15 August 2014 
 
Protocol Dated 
11 December 2013 
 
 
 
 
 
 
 
 
 
 
A Randomised, Double-Blind, Placebo-Controlled, Multicentre Phase II 
Study to Compare the Efficacy, Safety and Tolerability of Olaparib Versus 
Placebo When Given in Addition to Abiraterone Treatment in Patients 
With Metastatic Castrate-Resistant Prostate Cancer Who Have Received 
Prior Chemotherapy Containing Docetaxel 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
Sponsor: 
AstraZeneca AB, 151 85 Södertälje, Sweden. 
Centres affected by the Amendment: 
All centres. 
The protocol for the study is to be changed as follows: 
Change 1.1: 
Synopsis, Study design 
Change 1.2: 
Synopsis, Statistical methods 
Change 1.3: 
Section 1.1.3, Rationale for olaparib in prostate cancer 
Change 1.4: 
Section 3.1.1, Part A: Safety run-in/dose escalation 
Change 1.5: 
Section 3.1.2, Part B: Randomised part 
Change 1.6: 
Section 3.1, Overall study design and flow chart, Figure 2  
Change 1.7: 
Section 3.1, Overall study design and flow chart, Figure 3 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
2(57) 
Change 1.8: 
Section 3.1, Overall study design and flow chart, Figure 4 
Change 1.9: 
Section 3.1, Overall study design and flow chart, Figure 5 
Change 1.10: Section 3.1, Overall study design and flow chart, Table 4 
Change 1.11: Section 3.1, Overall study design and flow chart, Table 5 
Change 1.12: Section 3.1, Overall study design and flow chart, Table 8 
Change 1.13: Section 3.1, Overall study design and flow chart, Table 9 
Change 1.14: Section 6.2.1, Post-treatment 
Change 1.15: Section 6.4.3, Recording of adverse events 
Change 1.16: Section 6.4.5.2, Clinical chemistry assessments for safety 
Change 1.17: Section 7.1, Volume of blood, Table 14 to 16 
Change 1.18: Section 9.5, Study timetable and end of study 
Change 1.19: Section 12.2.1.1, Radiological progression-free survival 
Change 1.20: Section 12.2.1.2, Time to second progression (PFS2) 
Change 1.21: Section 12.2.1.3, Overall survival (OS) 
Change 1.22: Section 13.3.2, Paternal exposure 
Change 1.23: Section 14, References 
Change 1.24: Appendix A, Signatures, Medical Science Director 
Change 1.25: Appendix A, Signatures, Global Product Statistician 
Change 1.26: Appendix E, Actions required in cases of combined increase of 
aminotransferase and total bilirubin – Hy’s Law, Section 2 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
3(57) 
Change 1.1 
Section of protocol affected: 
Synopsis, Study design 
Previous text: 
Part A: Safety run-in/dose escalation 
Patients will attend the clinic on the first day of study treatment, then at 1, 2, 4, 8 and 
12 weeks, and every 12 weeks thereafter. 
[...] 
Part B: Randomised part 
Patients who have been dosed in Part A of the study may not participate in Part B. 
Patients will receive olaparib or placebo (randomisation ratio 1:1), at the dose determined by 
Part A of the study, and abiraterone 1000 mg once daily.  They will attend the clinic on the 
first day of study treatment, then at 4, 8 and 12 weeks, and every 12 weeks thereafter (every 
24 weeks after Week 72). 
Revised text: 
Part A: Safety run-in/dose escalation 
Patients will attend the clinic on the first day of study treatment, at 1 and 2 weeks, then every 
4 weeks up to Week 52, and every 12 weeks thereafter. 
[...] 
Part B: Randomised part 
Patients who have been dosed in Part A of the study may not participate in Part B. 
Patients will receive olaparib or placebo (randomisation ratio 1:1), at the dose determined by 
Part A of the study, and abiraterone 1000 mg once daily.  They will attend the clinic on the 
first day of study treatment, then every 4 weeks up to Week 52, and every 12 weeks 
thereafter. 
Reason for Amendment: 
To enhance the safety of patients receiving this novel combination therapy, the visit frequency 
is increased to every 4 weeks for the first 52 weeks on the trial, to allow more frequent 
laboratory safety assessments. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
4(57) 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.2 
Section of protocol affected: 
Synopsis, Statistical methods 
Previous text: 
The primary endpoint of Part B is rPFS.  The sample size of 140 patients will have 80% power 
to detect a significant difference at the 1-sided 10% level after 100 events have occurred in the 
full analysis set, if the assumed true treatment effect was hazard ratio (HR) 0.65.  This 
translates to a 3.75 month benefit in median rPFS on olaparib given with abiraterone 
compared to placebo given with abiraterone.  Cox proportional hazards model and Kaplan-
Meier summaries will be undertaken for the primary and sensitivity analyses of rPFS, and all 
other secondary and exploratory time-to endpoints. 
Revised text: 
The primary endpoint of Part B is rPFS.  The sample size of 140 patients will have 80% power 
to detect a significant difference at the 1-sided 10% level after 100 events have occurred in the 
full analysis set, if the assumed true treatment effect was hazard ratio (HR) 0.65.  This 
translates to a 3.75 month benefit in median rPFS on olaparib given with abiraterone 
compared to placebo given with abiraterone.  A log-rank test and Kaplan-Meier summaries 
will be undertaken for the primary and sensitivity analyses of rPFS, and all other secondary 
and exploratory time-to endpoints. 
Reason for Amendment: 
A log-rank test has replaced the Cox proportional hazard model as the primary analysis for the 
time-to-event endpoints, based on recommendations from the United States (US) Food and 
Drug Administration (FDA). 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.3 
Section of protocol affected: 
Section 1.1.3, Rationale for olaparib in prostate cancer 
Previous text: 
This study will evaluate the investigational drug olaparib when given on a background of the 
approved drug abiraterone in patients with metastatic CRPC.  Part A of this study will provide 
an initial assessment of safety/tolerability and potential for pharmacokinetic (PK) interaction 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
5(57) 
between the drugs.  For the randomised phase of this study, only post-chemotherapy CRPC 
patients will be studied (chemotherapy-naive CRPC patients will be recruited in another 
study).  This therefore facilitates a robust assessment of the primary endpoint of radiologic 
progression-free survival (radiologic PFS, rPFS) within a reasonable timeframe for a Phase II 
study. 
Revised text: 
This study will evaluate the investigational drug olaparib when given on a background of the 
approved drug abiraterone in patients with metastatic CRPC.  Part A of this study will provide 
an initial assessment of safety/tolerability and potential for pharmacokinetic (PK) interaction 
between the drugs.  For the randomised phase of this study, only post-chemotherapy CRPC 
patients will be studied.  This therefore facilitates a robust assessment of the primary endpoint 
of radiologic progression-free survival (radiologic PFS, rPFS) within a reasonable timeframe 
for a Phase II study. 
Reason for Amendment: 
Text referring to a separate study to be run in chemotherapy-naive CRPC patients has been 
removed as this study is not currently planned. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.4 
Section of protocol affected: 
Section 3.1.1, Part A: Safety run-in/dose escalation 
Previous text: 
Patients will attend the clinic for assessments on the first day of study treatment, then at 1, 2, 
4, 8 and 12 weeks, and every 12 weeks thereafter.  They will also attend for study treatment 
supplies at 16 weeks and every 4 weeks thereafter. 
Revised text: 
Patients will attend the clinic for assessments on the first day of study treatment, at 1 and 
2 weeks, then every 4 weeks up to Week 52, and every 12 weeks thereafter.  They will also 
attend for study treatment supplies at 16 weeks and every 4 weeks thereafter. 
Reason for Amendment: 
To enhance the safety of patients receiving this novel combination therapy, the visit frequency 
is increased to every 4 weeks for the first 52 weeks on the trial, to allow more frequent 
laboratory safety assessments. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
6(57) 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.5 
Section of protocol affected: 
Section 3.1.2, Part B: Randomised part 
Previous text: 
Patients will receive olaparib/placebo 300 mg bid (or 200 mg bid, if 200 mg bid is the 
maximum tolerated dose in Part A) and abiraterone 1000 mg once daily.  They will attend the 
clinic for assessments on the first day of study treatment, then at 4, 8 and 12 weeks, and every 
12 weeks thereafter (every 24 weeks after Week 72).  They will also attend for study treatment 
supplies at 16 weeks and every 4 weeks thereafter. 
Revised text: 
Patients will receive olaparib/placebo 300 mg bid (or 200 mg bid, if 200 mg bid is the 
maximum tolerated dose in Part A) and abiraterone 1000 mg once daily.  They will attend the 
clinic for assessments on the first day of study treatment, then every 4 weeks up to Week 52, 
and every 12 weeks thereafter.  They will also attend for study treatment supplies at 16 weeks 
and every 4 weeks thereafter. 
Reason for Amendment: 
To enhance the safety of patients receiving this novel combination therapy, the visit frequency 
is increased to every 4 weeks for the first 52 weeks on the trial, to allow more frequent 
laboratory safety assessments. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.6 
Section of protocol affected: 
Section 3.1, Overall study design and flow chart, Figure 2  


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
7(57) 
Previous text: 
Figure 2 
Flow chart for Part A, Cohort 1 
  1 week
  2 weeks
  4 weeks
  12 weeks
Discontinuation                   
of study treatments
30-Day follow-up                  
30 ±7 days after last dose of study 
treatment
Visits 5 to 7                       
Weeks 4, 8 and 12                  
Patients visit every 4 weeks
Visit 2                           
Day 1, Week 0                     
Eligibility confirmed                  
Start treatment with olaparib 200 mg bid  
and abiraterone 1000 mg once daily
Visit 1           
Screening         
Day -28 to -1
Visits 3 and 4                     
Weeks 1 and 2                     
Patients visit weekly
Visit 9 onwards
a                         
Week 24 onwards                  
Patients visit every 12 weeks  
Visit 8 onwards
a                         
Week 16 onwards                  
Patients visit every 4 weeks (for study 
treatment supply and AE review only)
 
a 
Unless patients discontinue study treatment, they will remain in the study and be assessed every 12 weeks 
until the database for Part A of the study is closed. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
8(57) 
Revised text: 
Figure 2 
Flow chart for Part A, Cohort 1 
  1 week
  2 weeks
  4 weeks
  12 weeks
Discontinuation                    
of study treatments
30-Day follow-up                   
30 ±7 days after last dose of study 
treatment
Visits 5 to 7                       
Weeks 4, 8 and 12                  
Patients visit every 4 weeks
Visit 2                            
Day 1, Week 0                     
Eligibility confirmed                 
Start treatment with olaparib 200 mg bid 
and abiraterone 1000 mg once daily
Visit 1           
Screening         
Day -28 to -1
Visits 3 and 4                      
Weeks 1 and 2                      
Patients visit weekly
Visit 9 onwards
a                                
Week 24 onwards                   
Patients visit every 12 weeks  
Visit 8 onwards
a                                
Week 16 onwards                   
Patients visit every 4 weeks (for study 
treatment supply, laboratory 
assessments and AE review only)
 
a 
Unless patients discontinue study treatment, they will remain in the study and be assessed every 12 weeks. 
Laboratory assessments will be performed every 4 weeks up to Week 52 while the patient is on 
treatment, whichever comes first, and then every 12 weeks for as long as the patient is on treatment. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
9(57) 
Reason for Amendment: 
To enhance the safety of patients receiving this novel combination therapy, the visit frequency 
is increased to every 4 weeks for the first 52 weeks on the trial, to allow more frequent 
laboratory safety assessments. 
Text referring to patients being assessed every 12 weeks until the database for Part A of the 
study is closed was removed as it was incorrect. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.7 
Section of protocol affected: 
Section 3.1, Overall study design and flow chart, Figure 3 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
10(57) 
Previous text: 
Figure 3 
Flow chart for Part A, Cohort 2, Group 1 
  
Olaparib 300 mg bid only
Olaparib 300 mg bid with abiraterone 1000 mg once daily
Visit 8 onwards                        
Week 16 onwards                      
Patients visit every 4 weeks (for study 
treatment supply and AE review only)
Visit 1               
Screening             
Day -28 to -1
Visits 5 to 7                           
Weeks 4, 8 and 12                      
Patients visit every 4 weeks
Visit 9 onwards                        
Week 24 onwards                      
Patients visit every 12 weeks  
Discontinuation                       
of study treatments
30-Day follow-up                      
30 ±7 days after last dose of study treatment
Visit 3                                               
Week 1                                              
Olaparib PK profiling any day between Days 3 and 7            
Abiraterone 1000 mg once daily to start the day after olaparib PK
Visit 2                                               
Day 1, Week 0                                         
Eligibility confirmed                                      
Start treatment with olaparib 300 mg bid
Visit 4                                               
Week 2                                              
Olaparib and abiraterone PK profiling                        
after dosing olaparib and abiraterone together for at least 5 days
 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
11(57) 
Revised text: 
Figure 3 
Flow chart for Part A, Cohort 2, Group 1 
  
Olaparib 300 mg bid only
Olaparib 300 mg bd with abiraterone 1000 mg once daily
Visit 8 onwardsa                                        
Week 16 onwards                       
Patients visit every 4 weeks (for study 
treatment supply, laboratory assessments 
and AE review only)
Visit 1                
Screening             
Day -28 to -1
Visits 5 to 7                           
Weeks 4, 8 and 12                       
Patients visit every 4 weeks
Visit 9 onwards                        
Week 24 onwards                       
Patients visit every 12 weeks  
Discontinuation                        
of study treatments
30-Day follow-up                       
30 ±7 days after last dose of study treatment
Visit 3                                                 
Week 1                                                
Olaparib PK profiling any day between Days 3 and 7            
Abiraterone 1000 mg once daily to start the day after olaparib PK
Visit 2                                                 
Day 1, Week 0                                          
Eligibility confirmed                                     
Start treatment with olaparib 300 mg bid
Visit 4                                                 
Week 2                                                
Olaparib and abiraterone PK profiling                       
after dosing olaparib and abiraterone together for at least 5 days
 
a 
Laboratory assessments will be performed every 4 weeks up to Week 52 while the patient is on 
treatment, whichever comes first, and then every 12 weeks for as long as the patient is on treatment. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
12(57) 
Reason for Amendment: 
To enhance the safety of patients receiving this novel combination therapy, the visit frequency 
is increased to every 4 weeks for the first 52 weeks on the trial, to allow more frequent 
laboratory safety assessments. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.8 
Section of protocol affected: 
Section 3.1, Overall study design and flow chart, Figure 4 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
13(57) 
Previous text: 
Figure 4 
Flow chart for Part A, Cohort 2, Group 2 
  
Visit 8 onwards                       
Week 16 onwards                      
Patients visit every 4 weeks (for study 
treatment supply and AE review only)
Discontinuation                       
of study treatments
30-Day follow-up                      
30 ±7 days after last dose of study treatment
Visit 1               
Screening             
Day -28 to -1
Abiraterone 1000 mg once daily only
Visit 2                                               
Day 1, Week 0                                        
Eligibility confirmed                                     
Start treatment with abiraterone 1000 mg once daily
Visit 3                                               
Week 1                                              
Abiraterone PK profiling any day between Days 5 and 7         
Olaparib 300 mg bid to start after abiraterone 24 h PK sample
Olaparib 300 mg bid with abiraterone 1000 mg once daily
Visit 4                                               
Week 2                                              
Olaparib and abiraterone PK profiling                       
after dosing olaparib and abiraterone together for at least 3 days
Visits 5 to 7                          
Weeks 4, 8 and 12                     
Patients visit every 4 weeks
Visit 9 onwards                       
Week 24 onwards                      
Patients visit every 12 weeks  
 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
14(57) 
Revised text: 
Figure 4 
Flow chart for Part A, Cohort 2, Group 2 
  
Visit 8 onwards
a                                       
Week 16 onwards                       
Patients visit every 4 weeks (for study 
treatment supply, laboratory assessments 
and AE review only)
Discontinuation                        
of study treatments
30-Day follow-up                       
30 ±7 days after last dose of study treatment
Visit 1               
Screening             
Day -28 to -1
Abiraterone 1000 mg once daily only
Visit 2                                                
Day 1, Week 0                                          
Eligibility confirmed                                     
Start treatment with abiraterone 1000 mg once daily
Visit 3                                                
Week 1                                               
Abiraterone PK profiling any day between Days 5 and 7         
Olaparib 300 mg bd to start after abiraterone 24 h PK sample
Olaparib 300 mg bd with abiraterone 1000 mg once daily
Visit 4                                                
Week 2                                               
Olaparib and abiraterone PK profiling                       
after dosing olaparib and abiraterone together for at least 3 days
Visits 5 to 7                           
Weeks 4, 8 and 12                      
Patients visit every 4 weeks
Visit 9 onwards                        
Week 24 onwards                       
Patients visit every 12 weeks  
 
a 
Laboratory assessments will be performed every 4 weeks up to Week 52 while the patient is on 
treatment, whichever comes first, and then every 12 weeks for as long as the patient is on 
treatment. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
15(57) 
Reason for Amendment: 
To enhance the safety of patients receiving this novel combination therapy, the visit frequency 
is increased to every 4 weeks for the first 52 weeks on the trial, to allow more frequent 
laboratory safety assessments. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.9 
Section of protocol affected: 
Section 3.1, Overall study design and flow chart, Figure 5 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
16(57) 
Previous text: 
Figure 5 
Flow chart for Part B 
 
  4 weeks
  4 weeks
  4 weeks
  12 weeks
  Disease progression or other reason
30-Day follow-up                   
30 ±7 days after last dose of study 
treatment
Visit 5                            
Week 12                          
CT/MRI scan and Bone scan
If treatment 
discontinued due 
to disease 
progression
If treatment discontinued for 
reason other than disease 
progression
Patient followed 
up until confirmed 
disease progression
Survival and PFS2 
follow-up         
Calls to patient 
every 12 weeks
Visit 2                                            
Day 1, Week 0                                      
Randomisation to olaparib with abiraterone               
or placebo witih abiraterone
Visits 3 and 4                      
Weeks 4 and 8                     
Patients visit every 4 weeks
Discontinuation                    
of study treatments
Visit 6 onwards                    
Week 16 onwards                   
Patients visit every 4 weeks (for study 
treatment supply and AE review only)
Visit 1                            
Screening                         
Day -28 to -1                      
CT/MRI scan and Bone scan
Visit 7 onwards                                     
Week 24 onwards                                   
Patients visit every 12 weeks up to and including Week 72, 
then every 24 weeks, until progression                   
CT/MRI scan and Bone scan 
 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
17(57) 
Revised text: 
Figure 5 
Flow chart for Part B 
  4 weeks
  4 weeks
  4 weeks
  12 weeks
  Disease progression or other reason
Visit 1                            
Screening                         
Day -28 to -1                      
CT/MRI scan and Bone scan
Visit 7 onwards                                     
Week 24 onwards                                   
Patients visit every 12 weeks up to and including Week 72, 
then every 24 weeks, until progression                   
CT/MRI scan and Bone scan 
Survival and PFS2 
follow-up         
Calls to patient 
every 12 weeks
Visit 2                                            
Day 1, Week 0                                      
Randomisation to olaparib with abiraterone               
or placebo with abiraterone
Visits 3 and 4                      
Weeks 4 and 8                     
Patients visit every 4 weeks
Discontinuation                    
of study treatments
Visit 6 onwardsa                                 
Week 16 onwards                   
Patients visit every 4 weeks (for study 
treatment supply, laboratory 
assessments and AE review only)
30-Day follow-up                   
30 ±7 days after last dose of study 
treatment
Visit 5                            
Week 12                          
CT/MRI scan and Bone scan
If treatment 
discontinued due 
to disease 
progression
If treatment discontinued for 
reason other than disease 
progression
Patient followed 
up until confirmed 
disease progression
 
a 
Laboratory assessments will be performed every 4 weeks up to Week 52 while the patient is on 
treatment, whichever comes first, and then every 12 weeks for as long as the patient is on 
treatment. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
18(57) 
Reason for Amendment: 
To enhance the safety of patients receiving this novel combination therapy, the visit frequency 
is increased to every 4 weeks for the first 52 weeks on the trial, to allow more frequent 
laboratory safety assessments. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.10 
Section of protocol affected: 
Section 3.1, Overall study design and flow chart, Table 4 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
19(57) 
Previous text: 
Table 4 
Study Plan – Part A, Cohort 1 (Olaparib 200 mg bid + Abiraterone) 
Visit 
1 
Screening 
2 
3 
4 
5 
6 
7 
8+ 
9+ 
Discontin-
uation of IP
30-day 
follow-upj 
Visit window (days) 
–28 to -1 
±0 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
 
 
Week 
 
0 
1 
2 
4 
8 
12 
16+ (every 
4 weeks) 
24+ (every 
12 weeks)
 
 
Day 
- 
1 
8 
15 
29 
57 
85 
113+ 
169+ 
- 
- 
Written informed consent  
X 
 
 
 
 
 
 
 
 
 
 
Demographicsa 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination, 
height and weightb 
X 
 
 
 
 
 
 
 
 
 
X 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
ECOG Performance status 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Collect PSA and BRCA 
status data (local)c 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECGd 
X 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Prior and concomitant 
medicationf 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
AE and SAE reviewg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology, clinical 
chemistry (local)h 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
20(57) 
Table 4 
Study Plan – Part A, Cohort 1 (Olaparib 200 mg bid + Abiraterone) 
Visit 
1 
Screening 
2 
3 
4 
5 
6 
7 
8+ 
9+ 
Discontin-
uation of IP
30-day 
follow-upj 
Visit window (days) 
–28 to -1 
±0 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
 
 
Week 
 
0 
1 
2 
4 
8 
12 
16+ (every 
4 weeks) 
24+ (every 
12 weeks)
 
 
Day 
- 
1 
8 
15 
29 
57 
85 
113+ 
169+ 
- 
- 
PGx blood sample 
(optional)i 
 
X 
 
 
 
 
 
 
 
 
 
Treatment 
dispensed/returned 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE  adverse event;  BRCA  Breast cancer gene;  ECOG  Eastern Cooperative Oncology Group;  ECG  electrocardiogram;  IP  investigational product; 
PSA prostate specific antigen;  PGx  pharmacogenetics;  SAE  serious adverse event 
a 
Demographics include date of birth (if allowed by local regulations), race, and ethnic group. 
b 
Height and weight will be recorded at the first examination only. 
c 
Collect any locally available PSA data for the 12 months prior to study entry, and any locally available BRCA mutation data. 
d 
At screening, a 12-lead ECG will be performed to ensure a QTc value of 470 ms for eligibility.  If the QTc value is >470, the screening ECG may be 
repeated up to 2 times (at least 24 hours apart).  The average of these screening ECGs (up to 3 ECGs) must be 470 ms to confirm patient eligibility. If 
the screening ECG is obtained within 3 days before Day 1 (Visit 2), then the screening ECG will be considered the baseline, and an ECG will not be 
necessary on Day 1.  Failing to meet this time frame, a baseline ECG must be performed on Day 1 (Visit 2).  After baseline, ECGs are only required if 
clinically indicated. 
e 
Including blood pressure (BP), pulse and temperature.  Measurements at Visit 2 must take place before first dose of study drug. 
f 
Concomitant medication should include all medications taken by the patient before and during the study. 
g 
When an AE of nausea or vomiting occurs, there is an additional eCRF for completion. 
h 
The Visit 2 (Day 1) laboratory assessments need only be taken if the screening assessments were collected more than 7 days before Day 1 (Visit 2).  See 
Section 6.4.5 for a complete list of haematology and chemistry assessments. 
i 
Sample will only be collected if separate PGx informed consent has been signed. 
j 
30-day follow-up visit for post-study drug assessment of AEs and concomitant medications as required.  All ongoing AEs/SAEs and any new AEs/SAEs 
identified during the 30-day follow up period must be followed to resolution. 
 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
21(57) 
Revised text: 
Table 4 
Study Plan – Part A, Cohort 1 (Olaparib 200 mg bid + Abiraterone) 
Visit 
1 
Screening 
2 
3 
4 
5 
6 
7 
8+ 
9+j 
Discontin-
uation of IP
30-day 
follow-upk 
Visit window (days) 
–28 to -1 
±0 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
 
 
Week 
 
0 
1 
2 
4 
8 
12 
16+ (every 
4 weeks) 
24+ (every 
12 weeks)
 
 
Day 
- 
1 
8 
15 
29 
57 
85 
113+ 
169+ 
- 
- 
Written informed consent  
X 
 
 
 
 
 
 
 
 
 
 
Demographicsa 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination, 
height and weightb 
X 
 
 
 
 
 
 
 
 
 
X 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
ECOG Performance status 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Collect PSA and BRCA 
status data (local)c 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECGd 
X 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Prior and concomitant 
medicationf 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
AE and SAE reviewg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology, clinical 
chemistry (local)h 
X 
X 
X 
X 
X 
X 
X 
X 
(up to 
Week 52) 
X 
(from 
Week 64) 
X 
X 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
22(57) 
Table 4 
Study Plan – Part A, Cohort 1 (Olaparib 200 mg bid + Abiraterone) 
Visit 
1 
Screening 
2 
3 
4 
5 
6 
7 
8+ 
9+j 
Discontin-
uation of IP
30-day 
follow-upk 
Visit window (days) 
–28 to -1 
±0 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
 
 
Week 
 
0 
1 
2 
4 
8 
12 
16+ (every 
4 weeks) 
24+ (every 
12 weeks)
 
 
Day 
- 
1 
8 
15 
29 
57 
85 
113+ 
169+ 
- 
- 
PGx blood sample 
(optional)i 
 
X 
 
 
 
 
 
 
 
 
 
Treatment 
dispensed/returned 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE  adverse event;  BRCA  Breast cancer gene;  ECOG  Eastern Cooperative Oncology Group;  ECG  electrocardiogram;  IP  investigational product; 
PSA prostate specific antigen;  PGx  pharmacogenetics;  SAE  serious adverse event 
a 
Demographics include date of birth (if allowed by local regulations), race, and ethnic group. 
b 
Height and weight will be recorded at the first examination only. 
c 
Collect any locally available PSA data for the 12 months prior to study entry, and any locally available BRCA mutation data. 
d 
At screening, a 12-lead ECG will be performed to ensure a QTc value of 470 ms for eligibility.  If the QTc value is >470, the screening ECG may be 
repeated up to 2 times (at least 24 hours apart).  The average of these screening ECGs (up to 3 ECGs) must be 470 ms to confirm patient eligibility. If 
the screening ECG is obtained within 3 days before Day 1 (Visit 2), then the screening ECG will be considered the baseline, and an ECG will not be 
necessary on Day 1.  Failing to meet this time frame, a baseline ECG must be performed on Day 1 (Visit 2).  After baseline, ECGs are only required if 
clinically indicated. 
e 
Including blood pressure (BP), pulse and temperature.  Measurements at Visit 2 must take place before first dose of study drug. 
f 
Concomitant medication should include all medications taken by the patient before and during the study. 
g 
When an AE of nausea or vomiting occurs, there is an additional eCRF for completion. 
h 
The Visit 2 (Day 1) laboratory assessments need only be taken if the screening assessments were collected more than 7 days before Day 1 (Visit 2).  
From Visit 8 (Week 16) onwards, laboratory assessments will be performed every 4 weeks up to Week 52, while the patient is on treatment, 
whichever comes first, and then every 12 weeks for as long as the patient is on treatment. See Section 6.4.5 for a complete list of haematology and 
chemistry assessments. 
i 
Sample will only be collected if separate PGx informed consent has been signed. 
j 
Assessments apply to Visit 9 and subsequent visits occurring every 12 weeks thereafter. 
k 
30-day follow-up visit for post-study drug assessment of AEs and concomitant medications as required.  All ongoing AEs/SAEs and any new AEs/SAEs 
identified during the 30-day follow up period must be followed to resolution. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
23(57) 
Reason for Amendment: 
To enhance the safety of patients receiving this novel combination therapy, the visit frequency 
is increased to every 4 weeks for the first 52 weeks on the trial, to allow more frequent 
laboratory safety assessments. 
The footnote ‘Assessments apply to Visit 9 and subsequent visits occurring every 
12 weeks thereafter’ was added to correct an omission in the protocol. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.11 
Section of protocol affected: 
Section 3.1, Overall study design and flow chart, Table 5 
Previous text: 
 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
24(57) 
Table 5 
Study Plan – Part A, Cohort 2 (Olaparib 300 mg bid + Abiraterone) 
Visit 
1 
Screening 
2 
3 
4 
5 
6 
7 
8+ 
9+j 
Discontin-
uation of IP
30-day 
follow-upk
Visit window (days) 
–28 to -1 
±0 
±0 
±0 
±3 
±3 
±7 
±7 
±7 
 
 
Week 
 
0 
1 
2 
4 
8 
12 
16+ 
(every 
4 weeks)
24+ 
(every 
12 weeks)
 
 
Day 
- 
1 
3-7 
12-14 
29 
57 
85 
113+ 
169+ 
- 
- 
Written informed  
X 
 
 
 
 
 
 
 
 
 
 
Demographicsa 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination, 
height and weightb 
X 
 
 
 
 
 
 
 
 
 
X 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
ECOG Performance 
Status 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Collect PSA and 
BRCA status data 
(local)c 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECGd 
X 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Prior and concomitant 
medicationf 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
AE and SAE reviewg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
25(57) 
Table 5 
Study Plan – Part A, Cohort 2 (Olaparib 300 mg bid + Abiraterone) 
Visit 
1 
Screening 
2 
3 
4 
5 
6 
7 
8+ 
9+j 
Discontin-
uation of IP
30-day 
follow-upk
Visit window (days) 
–28 to -1 
±0 
±0 
±0 
±3 
±3 
±7 
±7 
±7 
 
 
Week 
 
0 
1 
2 
4 
8 
12 
16+ 
(every 
4 weeks)
24+ 
(every 
12 weeks)
 
 
Day 
- 
1 
3-7 
12-14 
29 
57 
85 
113+ 
169+ 
- 
- 
Haematology, clinical 
chemistry (local)h 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
PK profile 
 
 
Xl,m,n 
Xl,m,n 
 
 
 
 
 
 
 
PGx blood sample 
(optional)i 
 
X 
 
 
 
 
 
 
 
 
 
Olaparib/abiraterone 
dispensed/returned 
 
X 
Xl 
Xl 
X 
X 
X 
X 
X 
 
 
Patient complicance 
questionnaireo 
 
X 
X 
X 
 
 
 
 
 
 
 
AE  Adverse event;  BRCA  Breast cancer gene;  ECOG  Eastern Cooperative Oncology Group;  ECG  electrocardiogram;  IP  investigational product; 
PSA  prostate specific antigen;  PGx  pharmacogenetics;  SAE  serious adverse event 
a 
Demographics include date of birth (if allowed by local regulations), race, and ethnic group. 
b 
Height and weight will be recorded at the first examination only. 
c 
Collect any locally available PSA data for the 12 months prior to study entry, and any locally available BRCA mutation data. 
d 
At screening, a 12-lead ECG will be performed to ensure a QTc value of 470 ms for eligibility.  If the QTc value is >470, the screening ECG may be 
repeated up to 2 times (at least 24 hours apart).  The average of these screening ECGs (up to 3 ECGs) must be 470 ms to confirm patient eligibility.  If 
the screening ECG is obtained within 3 days before Day 1 (Visit 2), then the screening ECG will be considered the baseline, and an ECG will not be 
necessary on Day 1.  Failing to meet this time frame, a baseline ECG must be performed on Day 1 (Visit 2).  After baseline, ECGs are only required if 
clinically indicated. 
e 
Including blood pressure (BP), pulse and temperature.  Measurements at Visit 2 must take place before first dose of study drug. 
f 
Concomitant medication should include all medications taken by the patient before and during the study.  
g 
When an AE of nausea or vomiting occurs, there is an additional eCRF for completion. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
26(57) 
h 
The Visit 2 (Day 1) laboratory assessments need only be taken if the screening assessments were collected more than 7 days before Day 1 (Visit 2).  See 
Section 6.4.5 for a complete list of haematology and chemistry assessments. 
i 
Sample will only be collected if separate PGx informed consent has been signed. 
j 
Assessments apply to Visit 9 and subsequent visits occurring every 12 weeks thereafter. 
k 
30-day follow-up visit for post-study drug assessment of AEs and concomitant medications as required.  All ongoing AEs/SAEs and any new AEs/SAEs 
identified during the 30-day follow up period must be followed to resolution. 
l 
Group 1: Olaparib (300 mg bid) dosing starts Day 1.  Olaparib steady state PK profile collected any day between Days 3 and 7 after morning dose. 
Abiraterone (1000 mg) dosing to start the day after the olaparib PK profile has been collected. 
Continue dosing both drugs together for at least 5 days then collect both olaparib and abiraterone PK profiles.  See Table 6 
 
Group 2: Abiraterone (1000 mg) dosing starts Day 1.  Abiraterone steady state PK profile collected any day between Days 5 and 7 after morning dose. 
Olaparib dosing (300 mg bid) to start after the abiraterone PK profile has been collected (immediately after the 24-hour sample). 
Continue dosing both drugs together for at least 3 days then collect both olaparib and abiraterone PK profiles.  See Table 7. 
m 
Blood samples for determination of olaparib to be collected pre-dose and at 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after morning dose on each sampling day. 
n 
Blood samples for determination of abiraterone to be collected pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after morning dose on each sampling 
day. 
o 
Patients will be asked to complete a questionnaire to assess their study treatment compliance from Day 1 until after the PK profiling has been completed. 
 
Revised text: 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
27(57) 
Table 5 
Study Plan – Part A, Cohort 2 (Olaparib 300 mg bid + Abiraterone) 
Visit 
1 
Screening 
2 
3 
4 
5 
6 
7 
8+ 
9+j 
Discontin-
uation of IP
30-day 
follow-upk
Visit window (days) 
–28 to -1 
±0 
±0 
±0 
±3 
±3 
±7 
±7 
±7 
 
 
Week 
 
0 
1 
2 
4 
8 
12 
16+ 
(every 
4 weeks) 
24+ 
(every 
12 weeks)
 
 
Day 
- 
1 
3-7 
12-14 
29 
57 
85 
113+ 
169+ 
- 
- 
Written informed  
X 
 
 
 
 
 
 
 
 
 
 
Demographicsa 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination, 
height and weightb 
X 
 
 
 
 
 
 
 
 
 
X 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
ECOG Performance 
Status 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Collect PSA and 
BRCA status data 
(local)c 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECGd 
X 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Prior and concomitant 
medicationf 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
AE and SAE reviewg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
28(57) 
Table 5 
Study Plan – Part A, Cohort 2 (Olaparib 300 mg bid + Abiraterone) 
Visit 
1 
Screening 
2 
3 
4 
5 
6 
7 
8+ 
9+j 
Discontin-
uation of IP
30-day 
follow-upk
Visit window (days) 
–28 to -1 
±0 
±0 
±0 
±3 
±3 
±7 
±7 
±7 
 
 
Week 
 
0 
1 
2 
4 
8 
12 
16+ 
(every 
4 weeks) 
24+ 
(every 
12 weeks)
 
 
Day 
- 
1 
3-7 
12-14 
29 
57 
85 
113+ 
169+ 
- 
- 
Haematology, clinical 
chemistry (local)h 
X 
X 
X 
X 
X 
X 
X 
X 
(up to 
Week 52) 
X 
(from 
Week 64) 
X 
X 
PK profile 
 
 
Xl,m,n 
Xl,m,n 
 
 
 
 
 
 
 
PGx blood sample 
(optional)i 
 
X 
 
 
 
 
 
 
 
 
 
Olaparib/abiraterone 
dispensed/returned 
 
X 
Xl 
Xl 
X 
X 
X 
X 
X 
 
 
Patient complicance 
questionnaireo 
 
X 
X 
X 
 
 
 
 
 
 
 
AE  Adverse event;  BRCA  Breast cancer gene;  ECOG  Eastern Cooperative Oncology Group;  ECG  electrocardiogram;  IP  investigational product; 
PSA  prostate specific antigen;  PGx  pharmacogenetics;  SAE  serious adverse event 
a 
Demographics include date of birth (if allowed by local regulations), race, and ethnic group. 
b 
Height and weight will be recorded at the first examination only. 
c 
Collect any locally available PSA data for the 12 months prior to study entry, and any locally available BRCA mutation data. 
d 
At screening, a 12-lead ECG will be performed to ensure a QTc value of 470 ms for eligibility.  If the QTc value is >470, the screening ECG may be 
repeated up to 2 times (at least 24 hours apart).  The average of these screening ECGs (up to 3 ECGs) must be 470 ms to confirm patient eligibility.  If 
the screening ECG is obtained within 3 days before Day 1 (Visit 2), then the screening ECG will be considered the baseline, and an ECG will not be 
necessary on Day 1.  Failing to meet this time frame, a baseline ECG must be performed on Day 1 (Visit 2).  After baseline, ECGs are only required if 
clinically indicated. 
e 
Including blood pressure (BP), pulse and temperature.  Measurements at Visit 2 must take place before first dose of study drug. 
f 
Concomitant medication should include all medications taken by the patient before and during the study.  
g 
When an AE of nausea or vomiting occurs, there is an additional eCRF for completion. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
29(57) 
h 
The Visit 2 (Day 1) laboratory assessments need only be taken if the screening assessments were collected more than 7 days before Day 1 (Visit 2).  
From Visit 8 (Week 16) onwards, laboratory assessments will be performed every 4 weeks up to Week 52, while the patient is on treatment, 
whichever comes first, and then every 12 weeks for as long as the patient is on treatment. See Section 6.4.5 for a complete list of haematology and 
chemistry assessments. 
i 
Sample will only be collected if separate PGx informed consent has been signed. 
j 
Assessments apply to Visit 9 and subsequent visits occurring every 12 weeks thereafter. 
k 
30-day follow-up visit for post-study drug assessment of AEs and concomitant medications as required.  All ongoing AEs/SAEs and any new AEs/SAEs 
identified during the 30-day follow up period must be followed to resolution. 
l 
Group 1: Olaparib (300 mg bid) dosing starts Day 1.  Olaparib steady state PK profile collected any day between Days 3 and 7 after morning dose. 
Abiraterone (1000 mg) dosing to start the day after the olaparib PK profile has been collected. 
Continue dosing both drugs together for at least 5 days then collect both olaparib and abiraterone PK profiles.  See Table 6. 
Group 2: Abiraterone (1000 mg) dosing starts Day 1.  Abiraterone steady state PK profile collected any day between Days 5 and 7 after morning dose. 
Olaparib dosing (300 mg bid) to start after the abiraterone PK profile has been collected (immediately after the 24-hour sample). 
Continue dosing both drugs together for at least 3 days then collect both olaparib and abiraterone PK profiles.  See Table 7. 
m 
Blood samples for determination of olaparib to be collected pre-dose and at 0.5, 1, 2, 3, 4, 6, 8 and 12 hours after morning dose on each sampling day. 
n 
Blood samples for determination of abiraterone to be collected pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after morning dose on each sampling 
day. 
o 
Patients will be asked to complete a questionnaire to assess their study treatment compliance from Day 1 until after the PK profiling has been completed. 
 
 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
30(57) 
Reason for Amendment: 
To enhance the safety of patients receiving this novel combination therapy, the visit frequency 
is increased to every 4 weeks for the first 52 weeks on the trial, to allow more frequent 
laboratory safety assessments. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.12 
Section of protocol affected: 
Section 3.1, Overall study design and flow chart, Table 8 
Previous text: 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
31(57) 
Table 8 
Study Plan – Part B, Randomised Part 
Visit 
 
1 
Screening 
2 
3 
4 
5 
6+ 
7+o 
Discontin-
uation of IP 
30-day 
follow-upp 
Visit window 
-28 to -1 
±0 
±3 
±3 
±3 
±7 
±7 
 
 
Week 
 
0 
4 
8 
12 
16+ (every 
4 weeks) 
24+ (every 
12 weekso) 
 
 
Day 
- 
1 
29 
57 
85 
113+ 
169+ 
- 
- 
Written informed consent 
including consent for archival 
tissue sample provision 
X 
 
 
 
 
 
 
 
 
Demographicsa 
X 
 
 
 
 
 
 
 
 
Physical examination, height 
and weightb 
X 
 
 
 
 
 
 
 
X 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
CT or MRI scan of the chest, 
abdomen and pelvis 
(RECIST 1.1)c 
X 
 
 
 
X 
 
X 
 
 
Bone scand 
X 
 
 
 
X 
 
X 
 
 
Collect PSA and BRCA status 
data (local)e 
X 
 
 
 
 
 
 
 
 
12-lead ECGf 
X 
 
 
 
 
 
 
 
 
Vital signsg 
X 
X 
X 
X 
X 
 
X 
X 
X 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
32(57) 
Table 8 
Study Plan – Part B, Randomised Part 
Visit 
 
1 
Screening 
2 
3 
4 
5 
6+ 
7+o 
Discontin-
uation of IP 
30-day 
follow-upp 
Visit window 
-28 to -1 
±0 
±3 
±3 
±3 
±7 
±7 
 
 
Week 
 
0 
4 
8 
12 
16+ (every 
4 weeks) 
24+ (every 
12 weekso) 
 
 
Day 
- 
1 
29 
57 
85 
113+ 
169+ 
- 
- 
Prior and concomitant 
medicationh 
X 
X 
X 
X 
X 
 
X 
X 
X 
AE and SAE reviewi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood samples for haematology 
and clinical chemistry (local)j 
X 
X 
X 
X 
X 
 
X 
X 
X 
CTC blood sample 
(Veridex assay, central)k 
X 
X 
X 
 
X 
 
 
X 
 
CTC blood sample 
(EPIC assay, central)k 
 
X 
 
 
X 
 
 
 
 
PSA blood sample (local) 
 
X 
X 
X 
X 
 
X 
 
 
PGx blood sample (optional)l 
 
X 
 
 
 
 
 
 
 
Blood biomarker sample 
(mandatory) 
 
X 
 
 
 
 
 
X 
 
Urine biomarker sample 
(mandatory) 
 
X 
 
 
 
 
 
X 
 
Archival tumour sample (where 
available) 
 
X 
 
 
 
 
 
 
 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
33(57) 
Table 8 
Study Plan – Part B, Randomised Part 
Visit 
 
1 
Screening 
2 
3 
4 
5 
6+ 
7+o 
Discontin-
uation of IP 
30-day 
follow-upp 
Visit window 
-28 to -1 
±0 
±3 
±3 
±3 
±7 
±7 
 
 
Week 
 
0 
4 
8 
12 
16+ (every 
4 weeks) 
24+ (every 
12 weekso) 
 
 
Day 
- 
1 
29 
57 
85 
113+ 
169+ 
- 
- 
BPI-SF instrument and 
individual bone pain itemm 
 
X 
X 
X 
X 
 
X 
X 
X 
FACT-Pm,n 
 
X 
X 
X 
X 
 
X 
X 
X 
EQ-5D-5L questionnairen 
 
X 
X 
X 
X 
 
X 
X 
X 
Oncology resource usen 
 
X 
X 
X 
X 
 
X 
X 
X 
Randomisation to study 
treatment 
 
X 
 
 
 
 
 
 
 
Treatment dispensed/returned 
 
X 
X 
X 
X 
X 
X 
X 
 
AE  Adverse event;  BPI-SF  Brief Pain Inventory – Short Form;  BRCA  Breast cancer gene;  CT  Computed tomography; 
ECOG  Eastern Cooperative Oncology Group;  ECG  electrocardiogram;  EQ-5D-5L EuroQuol-5 Dimensions, five-level; 
FACT-P  Functional Assessment of Cancer Therapy – Prostate Cancer;  IP  investigational product;  MRI  magnetic resonance imaging;   
PSA  prostate specific antigen;  PGx  pharmacogenetics;  SAE  serious adverse event 
a 
Demographics include date of birth (if allowed by local regulations), race and ethnic group. 
b 
Height and weight will be recorded at the first examination only. 
c 
Baseline assessments should be performed no more than 28 days before the date of randomisation, and ideally should be performed as close to the date 
of randomisation as possible. 
Follow up assessments will be performed every 12 weeks (±1 week) relative to the date of randomisation up to and including Week 72.  Thereafter, 
assessments will be conducted every 24 weeks until objective progression. 
Bone lesion PCWG-2 assessments will be performed using bone scan (preferably whole body). 
Malignant soft tissue RECIST v1.1 assessments will be performed using CT or MRI scans of chest, abdomen, pelvis. 
d 
Bone scan required to confirm progression due to new bone lesions, preferably at the next scheduled visit for a bone scan and at least 6 weeks later. 
e 
Collect any locally available PSA data for the 12 months prior to study entry, and any locally available BRCA mutation data. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
34(57) 
f 
At screening, a 12-lead ECG will be performed to ensure a QTc value of 470 ms for eligibility.  If the QTc value is >470, the screening ECG may be 
repeated up to 2 times (at least 24 hours apart).  The average of these screening ECGs (up to 3 ECGs) must be 470 ms to confirm patient eligibility.  If 
the screening ECG is obtained within 3 days before Day 1 (Visit 2), then the screening ECG will be considered the baseline, and an ECG will not be 
necessary on Day 1.  Failing to meet this time frame, a baseline ECG must be performed on Day 1 (Visit 2).  After baseline, ECGs are only required if 
clinically indicated. 
g 
Including blood pressure (BP), pulse and temperature.  Measurements at Visit 2 must take place before first dose of study drug. 
h 
Concomitant medication should include all medications taken by the patient before and during the study. 
i 
When an AE of nausea or vomiting occurs, there is an additional eCRF for completion. 
j 
The Visit 2 (Day 1) laboratory assessments need only be taken if the screening assessments were collected more than 7 days before Day 1 (Visit 2).  See 
Section 6.4.5 for a complete list of haematology, chemistry assessments. 
k 
Visit 2 (Day 1) sample to be collected pre-dose.   
l 
Sample will only be collected if separate PGx informed consent has been signed. 
m 
The patient should complete the PRO questionnaires in a quiet place before any investigations have been carried out.  Site personnel should not 
influence the patient’s answers to the questions.  Please refer to Section 6.5. 
n 
If the patient discontinues study treatment for reasons other than RECIST or PCWG-2 progression, the ‘Oncology Hospital Admission’ form, FACT-P 
and EQ-5D-5L should continue to be administered until progression has been confirmed.  After progression, see Table 9. 
o 
Assessments apply to Visit 7 and subsequent visits occurring every 12 weeks up to and including Week 72, and every 24 weeks thereafter. 
p 
30-day follow-up visit for post-study drug assessment of AEs and concomitant medications as required.  All ongoing AEs/SAEs and any new AEs/SAEs 
identified during the 30-day follow up period must be followed to resolution. 
 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
35(57) 
Revised text: 
Table 8 
Study Plan – Part B, Randomised Part 
Visit 
 
1 
Screening 
2 
3 
4 
5 
6+ 
7+o 
Discontin-
uation of IP 
30-day 
follow-upp 
Visit window 
-28 to -1 
±0 
±3 
±3 
±3 
±7 
±7 
 
 
Week 
 
0 
4 
8 
12 
16+ (every 
4 weeks) 
24+ (every 
12 weekso) 
 
 
Day 
- 
1 
29 
57 
85 
113+ 
169+ 
- 
- 
Written informed consent 
including consent for archival 
tissue sample provision 
X 
 
 
 
 
 
 
 
 
Demographicsa 
X 
 
 
 
 
 
 
 
 
Physical examination, height 
and weightb 
X 
 
 
 
 
 
 
 
X 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
 
X 
 
X 
X 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
CT or MRI scan of the chest, 
abdomen and pelvis 
(RECIST 1.1)c 
X 
 
 
 
X 
 
X 
 
 
Bone scand 
X 
 
 
 
X 
 
X 
 
 
Collect PSA and BRCA status 
data (local)e 
X 
 
 
 
 
 
 
 
 
12-lead ECGf 
X 
 
 
 
 
 
 
 
 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
36(57) 
Table 8 
Study Plan – Part B, Randomised Part 
Visit 
 
1 
Screening 
2 
3 
4 
5 
6+ 
7+o 
Discontin-
uation of IP 
30-day 
follow-upp 
Visit window 
-28 to -1 
±0 
±3 
±3 
±3 
±7 
±7 
 
 
Week 
 
0 
4 
8 
12 
16+ (every 
4 weeks) 
24+ (every 
12 weekso) 
 
 
Day 
- 
1 
29 
57 
85 
113+ 
169+ 
- 
- 
Vital signsg 
X 
X 
X 
X 
X 
 
X 
X 
X 
Prior and concomitant 
medicationh 
X 
X 
X 
X 
X 
 
X 
X 
X 
AE and SAE reviewi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood samples for haematology 
and clinical chemistry (local)j 
X 
X 
X 
X 
X 
X 
(up to 
Week 52) 
X 
(from 
Week 64) 
X 
X 
CTC blood sample 
(Veridex assay, central)k 
X 
X 
X 
 
X 
 
 
X 
 
CTC blood sample 
(EPIC assay, central)k 
 
X 
 
 
X 
 
 
 
 
PSA blood sample (local) 
 
X 
X 
X 
X 
 
X 
 
 
PGx blood sample (optional)l 
 
X 
 
 
 
 
 
 
 
Blood biomarker sample 
(mandatory) 
 
X 
 
 
 
 
 
X 
 
Urine biomarker sample 
(mandatory) 
 
X 
 
 
 
 
 
X 
 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
37(57) 
Table 8 
Study Plan – Part B, Randomised Part 
Visit 
 
1 
Screening 
2 
3 
4 
5 
6+ 
7+o 
Discontin-
uation of IP 
30-day 
follow-upp 
Visit window 
-28 to -1 
±0 
±3 
±3 
±3 
±7 
±7 
 
 
Week 
 
0 
4 
8 
12 
16+ (every 
4 weeks) 
24+ (every 
12 weekso) 
 
 
Day 
- 
1 
29 
57 
85 
113+ 
169+ 
- 
- 
Archival tumour sample (where 
available) 
 
X 
 
 
 
 
 
 
 
BPI-SF instrument and 
individual bone pain itemm 
 
X 
X 
X 
X 
 
X 
X 
X 
FACT-Pm,n 
 
X 
X 
X 
X 
 
X 
X 
X 
EQ-5D-5L questionnairen 
 
X 
X 
X 
X 
 
X 
X 
X 
Oncology resource usen 
 
X 
X 
X 
X 
 
X 
X 
X 
Randomisation to study 
treatment 
 
X 
 
 
 
 
 
 
 
Treatment dispensed/returned 
 
X 
X 
X 
X 
X 
X 
X 
 
AE  Adverse event;  BPI-SF  Brief Pain Inventory – Short Form;  BRCA  Breast cancer gene;  CT  Computed tomography; 
ECOG  Eastern Cooperative Oncology Group;  ECG  electrocardiogram;  EQ-5D-5L EuroQuol-5 Dimensions, five-level; 
FACT-P  Functional Assessment of Cancer Therapy – Prostate Cancer;  IP  investigational product;  MRI  magnetic resonance imaging;   
PSA  prostate specific antigen;  PGx  pharmacogenetics;  SAE  serious adverse event 
a 
Demographics include date of birth (if allowed by local regulations), race and ethnic group. 
b 
Height and weight will be recorded at the first examination only. 
c 
Baseline assessments should be performed no more than 28 days before the date of randomisation, and ideally should be performed as close to the date 
of randomisation as possible. 
Follow up assessments will be performed every 12 weeks (±1 week) relative to the date of randomisation up to and including Week 72.  Thereafter, 
assessments will be conducted every 24 weeks until objective progression. 
Bone lesion PCWG-2 assessments will be performed using bone scan (preferably whole body). 
Malignant soft tissue RECIST v1.1 assessments will be performed using CT or MRI scans of chest, abdomen, pelvis. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
38(57) 
d 
Bone scan required to confirm progression due to new bone lesions, preferably at the next scheduled visit for a bone scan and at least 6 weeks later. 
e 
Collect any locally available PSA data for the 12 months prior to study entry, and any locally available BRCA mutation data. 
f 
At screening, a 12-lead ECG will be performed to ensure a QTc value of 470 ms for eligibility.  If the QTc value is >470, the screening ECG may be 
repeated up to 2 times (at least 24 hours apart).  The average of these screening ECGs (up to 3 ECGs) must be 470 ms to confirm patient eligibility.  If 
the screening ECG is obtained within 3 days before Day 1 (Visit 2), then the screening ECG will be considered the baseline, and an ECG will not be 
necessary on Day 1.  Failing to meet this time frame, a baseline ECG must be performed on Day 1 (Visit 2).  After baseline, ECGs are only required if 
clinically indicated. 
g 
Including blood pressure (BP), pulse and temperature.  Measurements at Visit 2 must take place before first dose of study drug. 
h 
Concomitant medication should include all medications taken by the patient before and during the study. 
i 
When an AE of nausea or vomiting occurs, there is an additional eCRF for completion. 
j 
The Visit 2 (Day 1) laboratory assessments need only be taken if the screening assessments were collected more than 7 days before Day 1 (Visit 2).  
From Visit 6 (Week 16) onwards, laboratory assessments will be performed every 4 weeks up to Week 52, while the patient is on treatment, 
whichever comes first, and then every 12 weeks for as long as the patient is on treatment. See Section 6.4.5 for a complete list of haematology, 
chemistry assessments. 
k 
Visit 2 (Day 1) sample to be collected pre-dose.   
l 
Sample will only be collected if separate PGx informed consent has been signed. 
m 
The patient should complete the PRO questionnaires in a quiet place before any investigations have been carried out.  Site personnel should not 
influence the patient’s answers to the questions.  Please refer to Section 6.5. 
n 
If the patient discontinues study treatment for reasons other than RECIST or PCWG-2 progression, the ‘Oncology Hospital Admission’ form, FACT-P 
and EQ-5D-5L should continue to be administered until progression has been confirmed.  After progression, see Table 9. 
o 
With the exception of laboratory assessments (see Footnote j for details), assessments apply to Visit 7 and subsequent visits occurring every 12 
weeks up to and including Week 72, and every 24 weeks thereafter. 
p 
30-day follow-up visit for post-study drug assessment of AEs and concomitant medications as required.  All ongoing AEs/SAEs and any new AEs/SAEs 
identified during the 30-day follow up period must be followed to resolution. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
39(57) 
Reason for Amendment: 
To correct an omission in the original protocol, and to bring the protocol in line with project 
standards, additional ECOG assessments have been added in Table 8 (Part B Randomised 
Part). 
To enhance the safety of patients receiving this novel combination therapy, the visit frequency 
is increased to every 4 weeks for the first 52 weeks on the trial, to allow more frequent 
laboratory safety assessments. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.13 
Section of protocol affected: 
Section 3.1, Overall study design and flow chart, Table 9 
Previous text:


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
40(57) 
Table 9 
Study plan – Randomised part (follow-up post discontinuation of study treatment) 
Visit 
Off treatment follow-up for: 
Patients who have discontinued 
study treatment due to 
reasons other than disease 
progression 
 
Visits every 12 weeks 
Follow up for 1st progression 
Time to second progression (PFS2) and survival for: 
Patients who have discontinued study treatment due to 
disease progression 
Patients who have progressed off treatment 
Patients followed up by telephone every 12 weeks 
post discontinuation of study treatment 
Visit window 
±7 days 
±7 days 
CT or MRI scan of the chest, 
abdomen and pelvis (RECIST 1.1)a 
X 
 
Bone scan (PCWG-2)a 
X 
 
BPI-SF and bone pain item 
X 
 
BPI-SF worst pain item and worst 
bone pain itemb 
 
X 
PSA blood sample (local)c 
X 
 
Subsequent cancer therapy following 
discontinuation of study treatmentd 
X 
X 
EQ-5D-5L questionnaire 
X 
 
FACT-P 
X 
 
Oncology resource usee 
X 
Xb 
Time to second progression 
 
X 
Survivalf,g 
X 
X 
BPI-SF  Brief Pain Inventory – Short Form;  CT  CT  Computed tomography;  MRI  magnetic resonance imaging;   


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
41(57) 
PCWG-2  Prostate Cancer Working Group 2;  PFS2  second progression;  PSA prostate specific antigen 
a 
Patients will continue to be assessed by objective tumour assessments every 12 weeks (±1 week) relative to date of randomisation up to and including 
Week 72, then every 24 weeks until progression, via RECIST 1.1 and PCWG-2.   
b 
Administered by the Investigator over the telephone. 
c 
Scheduled PSA samples will not be collected during the PFS2 and OS follow-up, but a standard of care local PSA value should be collected at the time 
of PFS2 and included on the database. 
d 
All anti-cancer treatments (including, but not limited to, chemotherapy and targeted agents), and the Investigator’s opinion of response to them, plus the 
date of progression post discontinuation of study treatment, need to be recorded. 
e 
The full ‘Oncology Hospital Admission’ form will be completed until rPFS; thereafter, an abridged version will be completed. 
f 
The status of ongoing, withdrawn (from the study) and ‘lost to follow-up’ patients at the time of an OS analysis should be obtained by the site personnel 
by checking the patients notes, hospital records, contacting the patient’s general practitioner and checking publicly available death registries.  In the 
event that the patient has actively withdrawn consent to the processing of their personal data the vital status of the patient can be obtained by site 
personnel from publicly available resources where it is possible to do so under applicable local laws (see Section 3.1.5). 
g 
In addition to their regular 12 weekly contact, patients will be contacted in the 7 days following a specified date (data cut off date) for each survival 
analysis. 
 
Revised text: 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
42(57) 
Table 9 
Study plan – Randomised part (follow-up post discontinuation of study treatment) 
Visit 
Off treatment follow-up for: 
Patients who have discontinued 
study treatment due to 
reasons other than disease 
progression 
 
Visits every 12 weeks 
Follow up for 1st progression 
Time to second progression (PFS2) and survival for: 
Patients who have discontinued study treatment due to 
disease progression 
Patients who have progressed off treatment 
Patients followed up by telephone every 12 weeks 
post discontinuation of study treatment 
Visit window 
±7 days 
±7 days 
ECOG Performance Status 
X 
X 
CT or MRI scan of the chest, 
abdomen and pelvis (RECIST 1.1)a 
X 
 
Bone scan (PCWG-2)a 
X 
 
BPI-SF and bone pain item 
X 
 
BPI-SF worst pain item and worst 
bone pain itemb 
 
X 
PSA blood sample (local)c 
X 
 
Subsequent cancer therapy following 
discontinuation of study treatmentd 
X 
X 
EQ-5D-5L questionnaire 
X 
 
FACT-P 
X 
 
Oncology resource usee 
X 
Xb 
Time to second progression 
 
X 
Survivalf,g 
X 
X 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
43(57) 
BPI-SF  Brief Pain Inventory – Short Form;  CT  CT  Computed tomography;  MRI  magnetic resonance imaging;   
PCWG-2  Prostate Cancer Working Group 2;  PFS2  second progression;  PSA prostate specific antigen 
a 
Patients will continue to be assessed by objective tumour assessments every 12 weeks (±1 week) relative to date of randomisation up to and including 
Week 72, then every 24 weeks until progression, via RECIST 1.1 and PCWG-2.   
b 
Administered by the Investigator over the telephone. 
c 
Scheduled PSA samples will not be collected during the PFS2 and OS follow-up, but a standard of care local PSA value should be collected at the time 
of PFS2 and included on the database. 
d 
All anti-cancer treatments (including, but not limited to, chemotherapy and targeted agents), and the Investigator’s opinion of response to them, plus the 
date of progression post discontinuation of study treatment, need to be recorded. 
e 
The full ‘Oncology Hospital Admission’ form will be completed until rPFS; thereafter, an abridged version will be completed. 
f 
The status of ongoing, withdrawn (from the study) and ‘lost to follow-up’ patients at the time of an OS analysis should be obtained by the site personnel 
by checking the patients notes, hospital records, contacting the patient’s general practitioner and checking publicly available death registries.  In the 
event that the patient has actively withdrawn consent to the processing of their personal data the vital status of the patient can be obtained by site 
personnel from publicly available resources where it is possible to do so under applicable local laws (see Section 3.1.5). 
g 
In addition to their regular 12 weekly contact, patients will be contacted in the 7 days following a specified date (data cut off date) for each survival 
analysis. 
 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
44(57) 
Reason for Amendment: 
To correct an omission in the original protocol, and to bring the protocol in line with project 
standards, additional ECOG assessments have been added in Table 9 (Randomised Part, 
follow-up discontinuation of study treatment). 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.14 
Section of protocol affected: 
Section 6.2.1, Post-treatment 
Previous text: 
For patients who discontinue study treatment in Part A, there will be no further follow-up or 
data collection after their 30-day follow-up visit. 
The database for Part A of the study will be closed after the decision has been made whether 
or not to proceed with Part B of the study.  Patients are permitted to continue to receive study 
treatment beyond the closure of the database if, in the opinion of the Investigator, they are 
continuing to receive benefit from treatment with olaparib/placebo and abiraterone (see 
Sections 5.5.2 and 9.5). 
Patients who discontinue study treatment in Part B will be followed up until disease 
progression.  Thereafter, they will be followed up for PFS2 and survival in accordance with 
the study plan (see Table 8). 
Dispensing and accountability records will continue to be collected after follow-up for as long 
as patients continue to receive IP. 
Revised text: 
For patients who discontinue study treatment in Part A, there will be no further follow-up or 
data collection after their 30-day follow-up visit. 
Patients who discontinue study treatment in Part B will be followed up until disease 
progression.  Thereafter, they will be followed up for PFS2 and survival in accordance with 
the study plan (see Table 8). 
Dispensing and accountability records will continue to be collected after follow-up for as long 
as patients continue to receive IP. 
Reason for Amendment: 
Text relating to the closure of the Part A database has been removed because there is no plan 
to close the database for Part A after the decision on Part B dose is taken, and text is 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
45(57) 
contradictory to text in Section 3.1.2. The remainder of this paragraph is not needed as it 
duplicates text in Section 5.5.2. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.15 
Section of protocol affected: 
Section 6.4.3, Recording of adverse events 
Previous text: 
[...] 
NB. Cases where a patient shows an AST or ALT 3xULN or total bilirubin 2xULN may 
need to be reported as SAEs, please refer to Appendix E ‘Actions required in cases of 
combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for further 
instructions. 
Revised text: 
[...] 
NB. Cases where a patient shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT 3xULN together with total bilirubin 2xULN 
may need to be reported as SAEs.  Please refer to Appendix E ‘Actions required in cases of 
combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’for further 
instructions on cases of increases in liver biochemistry and evaluation of Hy’s Law. 
Reason for Amendment: 
To reflect a change in AstraZeneca’s operating procedure on Hy’s Law 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.16 
Section of protocol affected: 
Section 6.4.5.2, Clinical chemistry assessments for safety 
Previous text: 
[...] 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
46(57) 
NB. In case a patient shows an AST or ALT 3xULN total bilirubin 2xULN please refer to 
Appendix E ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions. 
Revised text: 
[...] 
NB. In case a patient shows an AST or ALT 3xULN together with total bilirubin 2xULN 
please refer to Appendix E ‘Actions required in cases of combined increase of 
Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions. 
Reason for Amendment: 
To reflect a change in AstraZeneca’s operating procedure on Hy’s Law. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.17 
Section of protocol affected: 
Section 7.1, Volume of blood, Table 14 to 16 
Previous text: 
Table 14 
Volume of blood to be drawn from each patient in Cohort 1, Part A 
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
Safety 
Clinical chemistry 
2.7 
10a 
27 
 
Haematology 
2.7 
10a 
27 
Pharmacogenetics (optional) 
9 
1 
9 
Total 
 
 
63b 
a 
10 samples taken at: Visits 1 to 9, discontinuation and follow-up.   
b 
For every additional 12 weeks that patients remain in the study after Visit 9, a further 5.4 mL blood will be 
collected (for safety analyses). 
[...] 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
47(57) 
Table 15 
Volume of blood to be drawn from each patient in Cohort 2, Part A 
Assessment 
Sample volume 
(mL) 
No. of 
samples 
Total volume 
(mL) 
Safety 
Clinical chemistry 
2.7 
10a 
27 
 
Haematology 
2.7 
10a 
27 
Pharmacokinetic 
Olaparib (Group 1) 
2.0 
18 
36 
 
Abiraterone (Group 1) 
2.0 
10 
20 
 
Olaparib (Group 2) 
2.0 
9 
18 
 
Abiraterone (Group 2) 
2.0 
20 
40 
Pharmacogenetics 
(Optional) 
9 
1 
9 
Total 
Group 1 
 
 
119b 
 
Group 2 
 
 
121b 
a 
10 samples taken at: Visits 1 to 9, discontinuation and follow-up.   
b 
For every additional 12 weeks that patients remain in the study after Visit 9, a further 5.4 mL blood will be 
collected (for safety analyses).  
 
[...] 
Table 16 
Volume of blood to be drawn from each patient in Part B 
Assessment 
Sample volume 
(mL) 
No. of 
samples 
Total volume 
(mL) 
Safety 
Clinical chemistry 
2.7 
8a 
21.6 
 
Haematology 
2.7 
8a 
21.6 
Biomarker 
PSA 
5 
5b 
25 
 
CTC (enumeration) 
10 
5 
50 
 
CTC (biomarkers) 
10 
2 
20 
 
Exploratory 
11 
2 
22 
Pharmacogenetics 
(Optional) 
9 
1 
9 
Total 
 
 
 
169.2c 
a 
8 samples taken at: Visits 1 to 7, discontinuation and follow-up.   
b 
5 samples taken at: Visits 1, 3, 4, 5 and 6. 
c 
For every additional visit where blood samples are collected after Visit 7, a further 10.4 mL blood will be 
collected (for safety and PSA analyses). 
 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
48(57) 
Revised text: 
Table 14 
Volume of blood to be drawn from each patient in Cohort 1, Part A 
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
Safety 
Clinical chemistry 
2.7 
12a 
32.4 
 
Haematology 
2.7 
12a 
32.4 
Pharmacogenetics (optional) 
9 
1 
9 
Total 
 
 
73.8b 
a 
12 samples taken at: Visits 1 to 9, discontinuation and follow-up.   
b 
From Visit 8 (Week 16) onwards, a further 5.4 mL blood will be collected (for safety analyses) every 
4 weeks up to Week 52, while the patient is on treatment, whichever comes first, and then every 12 
weeks for as long as the patient is on treatment.  
[...] 
Table 15 
Volume of blood to be drawn from each patient in Cohort 2, Part A 
Assessment 
Sample volume 
(mL) 
No. of 
samples 
Total volume 
(mL) 
Safety 
Clinical chemistry 
2.7 
12a 
32.4 
 
Haematology 
2.7 
12a 
32.4 
Pharmacokinetic 
Olaparib (Group 1) 
2.0 
18 
36 
 
Abiraterone (Group 1) 
2.0 
10 
20 
 
Olaparib (Group 2) 
2.0 
9 
18 
 
Abiraterone (Group 2) 
2.0 
20 
40 
Pharmacogenetics 
(Optional) 
9 
1 
9 
Total 
Group 1 
 
 
129.8b 
 
Group 2 
 
 
131.8b 
a 
12 samples taken at: Visits 1 to 9, discontinuation and follow-up.   
b 
From Visit 8 (Week 16) onwards, a further 5.4 mL blood will be collected (for safety analyses) every 
4 weeks up to Week 52, while the patient is on treatment, whichever comes first, and then every 
12 weeks for as long as the patient is on treatment.  
[...] 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
49(57) 
Table 16 
Volume of blood to be drawn from each patient in Part B 
Assessment 
Sample volume 
(mL) 
No. of 
samples 
Total volume 
(mL) 
Safety 
Clinical chemistry 
2.7 
10a 
27 
 
Haematology 
2.7 
10a 
27 
Biomarker 
PSA 
5 
5b 
25 
 
CTC (enumeration) 
10 
5 
50 
 
CTC (biomarkers) 
10 
2 
20 
 
Exploratory 
11 
2 
22 
Pharmacogenetics 
(Optional) 
9 
1 
9 
Total 
 
 
 
180c 
a 
10 samples taken at: Visits 1 to 7, discontinuation and follow-up.   
b 
5 samples taken at: Visits 1, 3, 4, 5 and 6. 
c 
From Visit 6 (Week 16) onwards, a further 5.4 mL blood will be collected (for safety analyses) every 
4 weeks up to Week 52, while the patient is on treatment, whichever comes first, and then every 
12 weeks for as long as the patient is on treatment. In addition, from Visit 7 (Week 24) a 5 mL blood 
sample will be taken every 12 weeks for PSA analysis. 
 
Reason for Amendment: 
To enhance the safety of patients receiving this novel combination therapy, the visit frequency 
is increased to every 4 weeks for the first 52 weeks on the trial, to allow more frequent 
laboratory safety assessments. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.18 
Section of protocol affected: 
Section 9.5, Study timetable and end of study 
Previous text: 
The database for Part A of the study will be closed after the decision has been made whether 
or not to proceed with Part B of the study. 
Revised text: 
The database for Part A and Part B are one database, and therefore the data will be 
analysed at the same time. Part A patients continue beyond their initial 14 days 
treatment as specified in Section 5.5.2. 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
50(57) 
Reason for Amendment: 
Text has been revised to correct erroneous wording and to clarify wording. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.19 
Section of protocol affected: 
Section 12.2.1.1, Radiological progression-free survival 
Previous text: 
The primary endpoint of Part B, rPFS (weeks), is defined in Section 11.1.3.  Once 
approximately 100 progression events have occurred, the primary analysis will be performed.  
Radiological progression-free survival will be analysed using a Cox proportional hazards 
model with a factor for treatment group.  The hazard ratio (HR) and 80% confidence interval 
(CI) will be estimated from the model (using ties=Efron).  The CI will be calculated using a 
profile likelihood approach.  The p-value will be based on twice the change in log-likelihood 
resulting from the addition of treatment factor to a model that contains no factors. 
[...] 
[...] 
[...] 
Separate Cox proportional hazards models of rPFS will be undertaken using patients who are 
positive for ERG expression/fusion status and also for patients who have BRCA mutations, 
including the same factors as for the primary analysis.  If the number of patients in each 
subgroup is small, consideration will be given to merging the subgroups prior to analysis. 
As an exploratory analysis, a Cox proportional hazards model of rPFS may be undertaken 
including some or all of the following factors: PTEN, AR status, disease related biomarkers, 
demographic and disease characteristics. 
If there are too few events available for a meaningful analysis (it is not considered appropriate 
to present analyses where there are less than 20 events in a subgroup), only descriptive 
statistics will be provided. 
Revised text: 
The primary endpoint of Part B, rPFS (weeks), is defined in Section 11.1.3.  Once 
approximately 100 progression events have occurred, the primary analysis will be performed.  
Radiological progression-free survival will be analysed using a log-rank test.  The hazard 
ratio (HR) and 80% confidence interval (CI) will be estimated from the U and V statistics 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
51(57) 
obtained directly from the LIFETEST model with inclusion of STRATA terms for the 
stratification variables (and using the Breslow approach for handling ties). A HR less 
than 1 will favour Olaparib.  
The HR and its confidence interval can be estimated from the log-rank as follows (Berry 
et al 1999, Sellke et al 1983): 
HR = exp(U/V) 
80% CI for HR = (exp{U/V – 1.28/ ¥V}, exp{U/V + 1.28/ ¥V}) 
Where U ¦
−
=
i
i
i
e
d
)
(
1
1
 is the log-rank test statistic( with d1i and e1i the observed and 
expected events in group 1)  and ¥V the standard deviation of the log-rank test statistic 
as produced in the LIFETEST output.   
The HR (Olaparib vs. placebo) together with its corresponding 80% confidence interval 
(CI) and p-value will be presented (a HR less than 1 will favour Olaparib). 
[...] 
[...] 
[...] 
Separate log-rank tests of rPFS will be undertaken using patients who are positive for ERG 
expression/fusion status and also for patients who have BRCA mutations, using the same 
model as for the primary analysis.  If the number of patients in each subgroup is small, 
consideration will be given to merging the subgroups prior to analysis. 
Reason for Amendment: 
A log-rank test has replaced the Cox proportional hazard model as the primary analysis for the 
time-to-event endpoints, based on recommendations from the US FDA. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.20 
Section of protocol affected: 
Section 12.2.1.2, Time to second progression (PFS2) 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
52(57) 
Previous text: 
The secondary endpoint of PFS2 (weeks), as defined in Section 11.1.3.1, will be analysed 
using the same time-to analysis as rPFS: Cox proportional hazard model, Kaplan-Meier and 
summary statistics. 
Revised text: 
The secondary endpoint of PFS2 (weeks), as defined in Section 11.1.3.1, will be analysed 
using the same time-to analysis as rPFS: log-rank test, Kaplan-Meier and summary statistics. 
Reason for Amendment: 
A log-rank test has replaced the Cox proportional hazard model as the primary analysis for the 
time-to-event endpoints, based on recommendations from the US FDA. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.21 
Section of protocol affected: 
Section 12.2.1.3, Overall survival (OS) 
Previous text: 
The secondary efficacy endpoint for Part B, OS (months), as defined in Section 11.1.4, will be 
performed when approximately 60% of patients have died; patients who have not died at that 
point will be censored. 
The same time-to analyses will be undertaken as for rPFS: Cox proportional hazard model, 
Kaplan-Meier and summary statistics.  A listing of OS time per patient will also be produced. 
Revised text: 
The secondary efficacy endpoint for Part B, OS (months), as defined in Section 11.1.4, will be 
performed when approximately 60% of patients have died; patients who have not died at that 
point will be censored. 
The same time-to analyses will be undertaken as for rPFS: log-rank test, Kaplan-Meier and 
summary statistics.  A listing of OS time per patient will also be produced. 
Reason for Amendment: 
A log-rank test has replaced the Cox proportional hazard model as the primary analysis for the 
time-to-event endpoints, based on recommendations from the US FDA. 
Persons who initiated the Amendment: 
AstraZeneca 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
53(57) 
Change 1.22 
Section of protocol affected: 
Section 13.3.2, Paternal exposure 
Previous text: 
Patients must refrain from fathering a child or donating sperm during the study and for 
3 months following the last dose of olaparib/placebo, since the potential for chromosomal 
aberrations in male gametes, and possible teratogenic effects thereof, has not yet been 
thoroughly investigated. 
Pregnancy of the patients’ partner is not considered to be an AE.  However, the outcome of 
any conception (including spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) from the date of the first dose until 3 months after the last dose 
should, if possible, be followed up and documented. 
Revised text: 
Patients must refrain from fathering a child or donating sperm during the study and for 
3 months following the last dose of olaparib/placebo, since the potential for chromosomal 
aberrations in male gametes, and possible teratogenic effects thereof, has not yet been 
thoroughly investigated. 
Pregnancy of the patients’ partner is not considered to be an AE.  However, the outcome of 
any conception (including spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) from the date of the first dose until 3 months after the last dose 
should, if possible, be followed up and documented. 
Where a report of pregnancy is received, prior to obtaining information on the 
pregnancy, the Investigator must obtain the consent of the subject’s partner. Therefore, 
the local study team should adopt the generic ICF template in line with local procedures 
and submit it to the relevant ECs/IRBs prior to use. 
Reason for Amendment: 
To provide clarification on when and how to use the consent form for pregnant partners of 
male participants. 
Persons who initiated the Amendment: 
AstraZeneca 


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
54(57) 
Change 1.23 
Section of protocol affected: 
Section 14, References 
Previous text: 
None 
Revised text: 
[...] 
Berry et al 1999 
Berry G, Kitchin RM & Mock PA. A comparison of two simple hazard ratio estimators based 
on the logrank test. Statistics in Medicine 1991; 10:749-755. 
[...] 
Sellke et al 1983 
Sellke, T. and Siegmund, D. Sequential analysis of the proportional hazards model. 
Biometrika 70: 315-326, 1983. 
Reason for Amendment: 
Two new references have been added to the protocol to support the change in statistical 
methodology to be used in the primary analysis for the time-to-event endpoints. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.24 
Section of protocol affected: 
Appendix A, Signatures, Medical Science Director 




Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
56(57) 
Previous text: 
AstraZeneca Research and Development 
site representative 
 
 
 
 
 
 
 
AstraZeneca R&D 
Alderley Park, Macclesfield 
Cheshire, SK10 4TG 
UK 
 
 
Date 
(Day Month Year) 
Revised text: 
AstraZeneca Research and Development 
site representative 
 
 
 
 
Helen Mann MSc 
Global Product Statistician 
 
AstraZeneca R&D 
Alderley Park, Macclesfield 
Cheshire, SK10 4TG 
UK 
 
  
Date 
(Day Month Year) 
Reason for Amendment: 
To reflect a change in study personnel. 
Persons who initiated the Amendment: 
AstraZeneca 
Change 1.26 
Section of protocol affected: 
Appendix E, Actions required in cases of combined increase of aminotransferase and total 
bilirubin – Hy’s Law, Section 2 
PPD
PPD
PPD


Clinical Study Protocol Amendment 1 
Drug Substance Olaparib (AZD2281, KU 0059436) 
Study Code D081DC00008 
Date 15 August 2014 
57(57) 
Previous text: 
2 
DEFINITIONS 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT)  3x Upper Limit of 
Normal (ULN) and Total Bilirubin (TBL)  2xULN at any point during the study irrespective 
of an increase in Alkaline Phosphatase (ALP).  The elevations do not have to occur at the 
same time or within a specified time frame. 
Hy’s Law (HL) 
AST or ALT  3x ULN and TBL  2xULN, where no other reason, other than the IMP, can 
be found to explain the combination of increases, eg, elevated ALP indicating cholestasis, 
viral hepatitis, another drug.  The elevations do not have to occur at the same time or within a 
specified time frame. 
Revised text: 
2 
DEFINITIONS 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP). 
Hy’s Law (HL) 
AST or ALT 3x ULN together with TBL 2xULN, where no other reason, other than the 
IP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, 
on the same day) the elevation in TBL, but there is no specified timeframe within which 
the elevations in transaminases and TBL must occur. 


 
 
Clinical Study Protocol Amendment No 1 Appendix A
 
Drug Substance 
Olaparib (AZD2281, 
KU-0059436) 
 
Study Code 
D081DC00008 
 
Edition Number 
1 
 
Date 
15 August 2014 
 
Protocol Dated 
11 December 2013 
 
 
 
 
 
 
 
 
 
Appendix A 
Signatures 
 









SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D081DC00008
Edition Number
Final v2.0
Date
23OCT2017
A Randomised, Double-Blind, Placebo-Controlled, Multicentre Phase II 
Study to Compare the Efficacy, Safety and Tolerability of Olaparib Versus 
Placebo When Given in Addition to Abiraterone Treatment in Patients 
With Metastatic Castrate-Resistant Prostate Cancer Who Have Received 
Prior Chemotherapy Containing Docetaxel








Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
5
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................3
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................4
TABLE OF CONTENTS.....................................................................................5
LIST OF ABBREVIATIONS ..............................................................................9
AMENDMENT HISTORY................................................................................13
1.
STUDY DETAILS.............................................................................................14
1.1
Study objectives................................................................................................. 14
1.1.1
Primary Objective ..............................................................................................14
1.1.2
Secondary Objectives.........................................................................................14
1.1.3
Exploratory Objectives....................................................................................... 16
1.2
Study design ...................................................................................................... 17
1.2.1
Part A: Safety run-in/dose escalation..................................................................18
1.2.2
Part B: Randomised part ....................................................................................19
1.3
Number of subjects ............................................................................................19
1.3.1
Part A: Safety run-in/dose escalation..................................................................19
1.3.2
Part B: Randomised part ....................................................................................20
2.
ANALYSIS SETS .............................................................................................21
2.1
Definition of analysis sets .................................................................................. 21
2.1.1
Full analysis set..................................................................................................21
2.1.2
PK analysis set...................................................................................................21
2.1.3
Safety analysis sets ............................................................................................ 21
2.2
Violations and deviations ................................................................................... 21
2.2.1
Part A ................................................................................................................21
2.2.2
Part B.................................................................................................................22
3.
PRIMARY AND SECONDARY VARIABLES.................................................23
3.1
Derivation of RECIST visit responses – malignant soft tissue ............................23
3.1.1
RECIST Target lesions (TLs).............................................................................23
3.1.2
RECIST Non-Target Lesions (NTLs) and new lesions. ......................................27
3.1.3
RECIST overall visit response ...........................................................................28
3.1.4
RECIST Best objective response........................................................................29
3.2
Evaluation of PCWG2 progression status – bone lesions....................................30
3.3
Primary variable – radiologic progression free survival (rPFS)...........................31


Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
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3.4
Secondary outcome variables.............................................................................33
3.4.1
Time to second progression (PFS2)....................................................................33
3.4.2
Overall survival (OS).........................................................................................33
3.4.3
Objective response rate (ORR) and associated variables.....................................34
3.4.4
Time to subsequent therapies .............................................................................35
3.5
Safety................................................................................................................. 35
3.5.1
Dose limiting toxicities (DLTs)..........................................................................35
3.5.2
Adverse Events ..................................................................................................36
3.5.3
Laboratory data..................................................................................................36
3.5.4
Vital signs..........................................................................................................37
3.5.5
Electrocardiograms (ECG).................................................................................37
3.5.6
Physical examination .........................................................................................38
3.5.7
Duration of exposure..........................................................................................38
3.6
Pharmacokinetic variables and PK analysis methods..........................................39
3.7
Calculation or derivation of biomarker variable(s).............................................. 40
3.7.1
Prostate specific antigen..................................................................................... 40
3.7.1.1
PSA response.....................................................................................................40
3.7.1.2
PSA changes on continuous scale.......................................................................40
3.7.2
Circulating tumour cell counts (CTCs)...............................................................40
3.7.3
ATM mutation ...................................................................................................41
3.7.4
BRCA mutation .................................................................................................41
3.7.5
Composite BRCA/ATM mutation......................................................................42
3.7.6
Composite HRR mutation (excluding BRCA1, BRCA2 and ATM)....................43
3.8
Exploratory variables ......................................................................................... 43
3.8.1
Patient reported outcomes (PRO) and HRQL .....................................................43
3.8.1.1
Functional Assessment of Cancer therapy – Prostate Cancer (FACT-P) .............43
3.8.1.2
Brief Pain Inventory – short form (BPI-SF)........................................................49
3.8.1.3
Bone pain item...................................................................................................50
3.8.2
Health economics...............................................................................................51
3.8.2.1
Utilities: EQ-5D-5L ...........................................................................................51
3.8.2.2
Resource use...................................................................................................... 52
4.
ANALYSIS METHODS....................................................................................52
4.1
General principles.............................................................................................. 52
4.2
Analysis methods...............................................................................................53
4.2.1
Multiplicity........................................................................................................53
4.2.2
Analysis of the primary efficacy variable (rPFS)................................................54
4.2.2.1
Sensitivity analyses............................................................................................56
4.2.3
Analysis of the secondary outcome variables......................................................57
4.2.3.1
Time to second progression (PFS2)....................................................................57
4.2.3.2
Overall survival (OS).........................................................................................57
4.2.3.3
Objective response rate (ORR) and associated variables.....................................57


Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
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4.2.3.4
Time to first subsequent therapy or death (TFST) and time to second 
subsequent therapy or death (TSST)...................................................................58
4.2.4
Tolerability and safety........................................................................................58
4.2.4.1
Adverse events (AE) ..........................................................................................58
4.2.4.2
Dose-limiting toxicities......................................................................................62
4.2.4.3
Exposure and compliance...................................................................................62
4.2.4.4
Laboratory data.................................................................................................. 62
4.2.4.5
Concomitant medications...................................................................................63
4.2.4.6
Vital signs.......................................................................................................... 63
4.2.5
Biomarkers ........................................................................................................ 63
4.2.6
Patient reported outcomes (PRO) and HRQL ..................................................... 64
4.2.6.1
FACT-P .............................................................................................................64
4.2.6.2
BPI-SF...............................................................................................................65
4.2.6.3
Bone Pain ..........................................................................................................66
4.2.7
Health economics data ....................................................................................... 66
4.2.7.1
Utilities: EQ-5D-5L ...........................................................................................66
4.2.7.2
Resource use...................................................................................................... 66
4.2.8
Demographic data and baseline data...................................................................66
4.2.9
Statistical analysis of PK data ............................................................................67
5.
INTERIM ANALYSES (NOT APPLICABLE)..................................................71
6.
CHANGES OF ANALYSIS FROM PROTOCOL .............................................71
7.
REFERENCES ..................................................................................................71
8.
APPENDIX (NOT APPLICABLE).................................................................... 73
LIST OF TABLES
Table 1
Primary objectives.................................................................................14
Table 2
Secondary objectives.............................................................................14
Table 3
Exploratory objectives...........................................................................16
Table 4
TL visit responses .................................................................................24
Table 5
Example of scaling-up...........................................................................27
Table 6
Overall visit response for soft tissue lesions ..........................................29
Table 7
Overall PCWG-2  progression status (bone)..........................................31
Table 8
Overall radiological visit response.........................................................32
Table 9 
Description of ATM mutation categories...............................................41
Table 10 
Description of BRCA mutation categories.............................................41
Table 11 
Description of composite BRCA/ATM mutation categories ..................42
Table 12 
Description of composite HRR categories .............................................43


Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
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Table 13 
Definition of visit response for FACT-P, FAPSI-8, FAPSI-6, TOI, 
PCS, FWB, PWB and SWB ..................................................................45
Table 14 
Overall score response for FACT-P, FAPSI-8, FAPSI-6, TOI, 
PCS, FWB, PWB, SWB........................................................................47
LIST OF FIGURES
Figure 1
Multiple Testing Procedure...................................................................54


Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
9
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse event 
ALT
Amean
Alanine aminotransferase
Arithmetic mean
ATM
Ataxia telangiectasia mutated 
AST
Aspartate aminotransferase
AUCss
Area under the plasma concentration-time curve across the dosing interval 
at steady state
AUC0-t
Area under the plasma concentration-time curve from time zero to last 
quantifiable concentration
Bid
Twice daily (Latin: bis die)
BOR
Best objective response
BP
Blood pressure
BPI-SF
Brief Pain Inventory – Short Form
BRCA
Breast cancer gene, i.e., BRCA1 and BRCA2
CI
Confidence interval
CLss/F
Apparent clearance of drug from the body as steady state
Css,max
Maximum plasma concentration at steady state
Css,min
Minimum plasma concentration at steady state
CR
Complete response
CRPC
Castrate-resistant prostate cancer
CSR
Clinical Study Report
CT
Computed tomography
CTC
Circulating tumour cell
CTCAE
Common Terminology Criteria for Adverse Event
%CV
% Coefficient of variation 
DAE
Discontinuation of Investigational Product due to Adverse Event
DCO
Data cut-off
DDI
Drug-drug interaction
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid


Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
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Abbreviation or 
special term
Explanation
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EQ-5D-5L
EuroQuol-5 Dimensions, five level
EWB
Emotional well-being
FACIT
Functional assessment of chronic illness
FACT-P
Functional Assessment of Cancer Therapy – Prostate Cancer
FAPSI-6
Functional Assessment of Prostate Cancer Symptoms Index 6
FAPSI-8
Functional Assessment of Prostate Cancer Symptoms Index 8
FPI
First patient in
FWB
Functional well-being
Gmean
Geometric mean
GSD
Geometric standard deviation factor
%GCV
% Geometric coefficient of variation
HR
Hazard ratio
HRR
Homologous recombination repair
HRQL
Health-Related Quality of Life
ICU
Intensive care unit
IP
Investigational Product 
ITT
Intention to treat
LD
Longest diameter
LOQ
Limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model for repeated measures
MRI
Magnetic resonance imaging
MTP
Multiple testing procedure
NA
Not applicable
NC
Not calculable
NCA
Non-compartmental analysis
NE
Not-evaluable
NED
No evidence of disease


Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
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Abbreviation or 
special term
Explanation
NGS
Next-generation sequencing
NQ
Non-quantifiable
NRS
Numerical rating scale
NTL
Non-target lesion
OAE
Other Significant Adverse Event
ORR
Objective response rate
OS
Overall survival
PARP
Polyadenosine 5’-diphosphoribose polymerase
PCS
Prostate cancer symptoms
PCWG-2
Prostate Cancer Working Group 2
PD
Progressive disease
PFS2
Second progression
PID
Percent intended dose
PK
Pharmacokinetics
PR
Partial response
PRO
Patient Reported Outcome
PSA
Prostate specific antigen
PWB
Physical well-being
QTc
Corrected QT interval
RDI
Relative dose intensity
RECIST 1.1
Response Evaluation Criteria in Solid Tumours version 1.1
REML
Restricted maximum likelihood
rPFS
Radiologic progression-free survival
RPFST
Rank preserving structural failure time
RR
Respiratory rate
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Stable disease
SD
Standard deviation based on non log-transformed data
SI
International system of units (systeme international)
SOC
System organ class
SRC
Safety Review Committee


Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
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Abbreviation or 
special term
Explanation
SWB
Social well-being
TFST
Time to first subsequent therapy
TL
Target lesion
tss,max
Time to reach maximum plasma concentration at steady state
tss,last
Time to last quantifiable plasma concentration at steady state
TOI
Trial outcome index
TSST
Time to second subsequent therapy


Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
13
AMENDMENT HISTORY
Date
Brief description of change
10OCT2017
SAP v2.0 vs SAP v1.0
!
Replaced efficacy analysis use of Cox’s proportional hazards modelling with 
the log rank test. Added 95% CI for HR to be reported.
!
Two-sided 5% significance level for the endpoint testing replaced with 1-sided 
2.5%.
!
No interim analysis for PFS2 and OS is planned. Both endpoints will be tested 
at the time of rPFS analysis. 
!
Updated primary efficacy subgroup analysis plans by inclusion of the other 
(beside ATM, BRCA1/2) genes mutation statuses from the HRR group, and 
exclusion of ERG expression/fusion status. The minimum 20 endpoint events 
per subgroup/arm condition replaced with minimum 5 events.
!
The PTEN and AR marker factors were excluded from the current exploratory 
analysis. Any futures exploratory analysis and outcome variables were left yet 
to be defined. No exploratory analysis is planned to assess an impact from 
possible treatment switching on the OS adjustment.
!
In the PK analysis, the DDI ratio was changed from mono:combination to 
combination:mono for olaparib and abiraterone. 
!
Updated modelling approach in PRO supportive analysis
!
List of important deviation categories for Part B was extended. Table 7 
(Overall PCWG-2 response), Table 8 (Overall radiological visit response 
classification), and Table 14 (Overall score response) content updated. The 
FACT-P missing data subscale scoring details updated, and HRQL visit 
response extended with PWB and SWB scores. Weight (part of vital signs) 
levels were recorded at the baseline only. In the summary of deaths the number 
of categories increased.
!
Completed list of the SAP v2.0 changes from the CSP
!
Global product statistician and study statistician changed
!
Added 80% CI to the sensitivity analysis.


Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
14
1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary Objective
Table 1
Primary objectives
Primary objective
Primary outcome variable
Part A, Safety run-in:
To assess the safety and tolerability of olaparib 
when given in addition to abiraterone and to 
recommend, by assessment of dose-limiting 
toxicities (DLTs) and other safety and tolerability 
data, a dose of olaparib for further study when 
given in addition to abiraterone.
Assessment of adverse events (AEs) graded by 
common terminology criteria for adverse events 
(CTCAE v4.0), vital signs (including blood 
pressure (BP), pulse), and evaluation of 
laboratory parameters (clinical chemistry and 
haematology).
Incidence of DLTs during the initial evaluation 
period.
Part B:
To compare the efficacy of olaparib when given 
in addition to abiraterone, with placebo given in 
addition to abiraterone, by assessment of 
radiologic progression-free survival (rPFS) using 
Response Evaluation Criteria in Solid Tumours 
version 1.1 (RECIST 1.1) and Prostate Cancer 
Working Group 2 (PCWG-2) criteria.
rPFS, defined as the time from randomisation to 
disease progression according to RECIST 1.1 (for 
soft tissue disease) and/or PCWG-2 criteria (for 
bone disease), or death.
1.1.2
Secondary Objectives
Table 2
Secondary objectives
Secondary objective
Secondary outcome variables
Part A, Safety run-in:
To evaluate the presence of any drug interaction 
between olaparib and abiraterone by 
determination of steady state exposure to olaparib 
in the presence and absence of abiraterone, and 
determination of steady state exposure to 
abiraterone in the presence and absence of 
olaparib.
Olaparib and abiraterone pharmacokinetic steady 
state (PK) parameters (where the data allow): 
maximum plasma concentration at steady state 
(Css,max), time to reach maximum plasma 
concentration at steady state (tss,max), minimum 
plasma concentration at steady state (Css,min), area 
under the plasma concentration-time curve at 
steady state (AUCss), area under the plasma 
concentration-time curve from time zero to time 
of last quantifiable concentration (AUC0-t), time 
to last quantifiable plasma concentration at steady 
state (tss,last), along with ratios for Css,max, Css,min and 
AUCss of drug in combination versus 
monotherapy.


Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
15
Table 2
Secondary objectives
Secondary objective
Secondary outcome variables
Part B:
To compare the safety and tolerability of olaparib 
when given in addition to abiraterone, with 
placebo given in addition to abiraterone.
Assessment of AEs graded by CTCAE v4.0, vital 
signs (including BP, pulse), and evaluation of 
laboratory parameters (clinical chemistry and 
haematology).
To assess the anti-tumour activity of olaparib 
when given in addition to abiraterone, compared 
with placebo given in addition to abiraterone, by 
measurement of changes in circulating prostate 
specific antigen (PSA) and circulating tumour 
cells (CTCs), calculation of overall radiological 
objective response rate (ORR) (by RECIST 1.1 
and PCWG-2 bone scan criteria) and malignant 
soft tissue ORR (by RECIST 1.1), duration of 
response (DOR), time to first subsequent therapy 
(TFST) for prostate cancer, and time to second 
subsequent therapy (TSST) for prostate cancer.
Absolute and percentage change from baseline in 
PSA levels and PSA response.
Change and best change from baseline in CTC 
numbers, and CTC conversion rates.
Tumour response in terms ORR (malignant soft 
tissue response and overall radiological response 
[malignant soft tissue response by RECIST 1.1, 
overall radiological response by RECIST 1.1 and 
PCWG-2]) and DOR.
TFST, defined as the time from randomisation 
until the first subsequent therapy for prostate 
cancer, and TSST, defined as the time from 
randomisation until the second subsequent
therapy for prostate cancer.
To assess the efficacy of olaparib when given in 
addition to abiraterone, compared with placebo 
given in addition to abiraterone, by assessment of 
overall survival (OS).
OS, defined as time from randomisation to the 
date of death from any cause.
To assess the efficacy of olaparib when given in 
addition to abiraterone, compared with placebo 
given in addition to abiraterone, by assessment of 
time from randomisation to second progression 
(PFS2).
PFS2.  Progression defined by local standard 
clinical practice.  May involve any of: objective 
radiological progression, symptomatic 
progression, rises in PSA or death.
To investigate BRCA and ATM mutation as 
candidate predictors of response to olaparib. In 
addition to BRCA and ATM mutations, mutations 
in 12 other homologous recombination repair 
(HRR) genes will be explored. Note: This 
objective is dependent upon the number of 
evaluable samples obtained from the study.
BRCA, ATM, and HRR mutation status; if the 
number of events in these groups is sufficient then 
the primary analysis of rPFS will be repeated in 
all BRCA and/or ATM, and HRR mutation 
patients.


Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
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1.1.3
Exploratory Objectives
Table 3
Exploratory objectives
Exploratory objectives
Exploratory outcome variables
To explore the effects of olaparib on pain and 
other prostate cancer-related symptoms compared 
to placebo.
Change from baseline in worst pain, general pain 
and pain interference in daily activities scales of 
the Brief Pain Inventory – Short Form (BPI-SF) 
and the worst bone pain item.
Change from baseline in the Functional 
Assessment of Prostate Cancer Symptoms Index 8 
(FAPSI-8), as derived from 8 items within the 
Functional Assessment of Cancer Therapy –
Prostate Cancer (FACT-P), Functional 
Assessment of Prostate Cancer Symptoms Index 6 
(FAPSI-6) and the Prostate Cancer Symptoms
(PCS), as derived from the 12 items in the 
prostate specific module of the FACT-P.
To explore the effects of olaparib on health-
related quality of life (HRQL) compared to 
placebo.
Change from baseline, as measured by the FACT-
P scales: functional well-being (FWB), physical 
well-being (PWB), emotional well-being (EWB), 
social well-being (SWB), the FACT-P total score, 
and the trial outcome index (TOI) score (the sum 
of the PWB, FWB and PCS scores).
To assess the time to deterioration in pain.
Time to deterioration in the BPI-SF worst pain 
item and time to deterioration in the worst bone 
pain item.
To assess time to deterioration in HRQL.
Time to deterioration in HRQL, as measured by 
FACT-P TOI score.
To explore the impact of treatment and disease 
state on health state utility.
EuroQuol-5 Dimensions, five level (EQ-5D-5L) 
health state utility index.
To investigate the impact of treatment and disease 
progression on metastatic castrate-resistant 
prostate cancer (CRPC) management resource 
use.
Resource use will be captured, focussing on 
in-patient and ICU admissions, length of stay, 
palliative interventions and reason for admission 
into hospital and interventions.  
Future exploratory research into factors that may 
influence development of cancer and/or response 
to treatment (where response is defined broadly to 
include efficacy, tolerability or safety) may be 
performed on the collected and stored archival 
tumour samples (where available), blood samples 
(mandatory), urine and CTC samples 
(mandatory).*
Analysis and outcome variables yet to be defined.




Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
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1.2.1
Part A: Safety run-in/dose escalation
Patients will attend the clinic for assessments on the first day of study treatment, at 1 and 2 
weeks, then every 4 weeks up to Week 52, and every 12 weeks thereafter. They will also 
attend for study treatment supplies at 16 weeks and every 4 weeks thereafter.
Cohort 1 (up to 6 patients)
At least 3 and up to 6 evaluable patients will be enrolled in Cohort 1.  Patients will receive 
olaparib 200 mg bid and abiraterone 1000 mg once daily. Dose-limiting toxicities (DLTs) 
from all patients will be assessed by a Safety Review Committee (SRC) after a minimum of 
3 patients have received a minimum of 14 days’ treatment.
Cohort 2 (12 patients)
If the combination of olaparib 200 mg bid and abiraterone 1000 mg once daily is tolerated, a 
cohort of 12 patients (split into 2 groups of 6 patients) will be treated with olaparib 300 mg 
bid given in addition to abiraterone 1000 mg once daily, and will be evaluated for safety, 
tolerability and PK.  Patients will be recruited to Group 1 and Group 2 concurrently, 
recruitment will alternate between Group 1 and Group 2.
Group 1:
Patients will receive olaparib alone (300 mg bid) for between 3 and 7 days.  Blood samples 
will be collected to determine the steady state PK profile for olaparib; this may be done on any 
day between Days 3 and 7, starting after the morning dose.
Patients will then receive abiraterone (1000 mg once daily) starting from the day after the 
olaparib PK profile has been collected.  Olaparib and abiraterone will continue to be dosed in 
combination for at least 5 days, then blood samples will be collected again to determine both 
olaparib and abiraterone PK profiles.
Group 2:
Patients will receive abiraterone alone (1000 mg once daily) for between 5 and 7 days.  Blood 
samples will be collected to determine the steady state PK profile for abiraterone (any day 
between Days 5 and 7).
Patients will receive olaparib (300 mg bid) starting immediately after the 24-hour abiraterone 
PK sample has been collected.  Olaparib and abiraterone will continue to be dosed in 
combination for at least 3 days, then blood samples will be collected again to determine both 
olaparib and abiraterone PK profiles.
Dose-limiting toxicities will be assessed by the SRC after a minimum of 14 days’ treatment 
with both olaparib and abiraterone.  If <2 DLTs occur in the first 9 patients that have 
completed at least 14 days’ dosing with both olaparib and abiraterone, then the randomised 
part of the study, Part B, may commence with this dose combination and the remaining 
3 patients to be dosed in Part A may be recruited in parallel with Part B.  If 2 or more DLTs 


Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
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occur then all 12 patients must be dosed before a decision is made to progress to Part B.  If 
<4 DLTs occur in this cohort of 12 patients (Groups 1 and 2), then the randomised part of the 
study, Part B, will commence with this dose combination.
Cohort 3 (12 patients)
If 4 or more DLTs occur in Cohort 2, a further 12-patient cohort may be recruited and treated 
with olaparib 200 mg bid in combination with abiraterone 1000 mg once daily and evaluated 
for safety, tolerability and PK as described for Cohort 2.
If Cohort 3 is dosed and there are <4 DLTs, then Part B may proceed using a 200 mg bid dose 
of olaparib.  If 4 or more DLTs are observed, then the study will be terminated.
1.2.2
Part B: Randomised part
Progression to Part B will be based on a review of all available safety, tolerability and PK data 
from Part A of the study.  This will be performed when sufficient evaluable patients in both of 
the patient groups in Part A Cohort 2 (or Cohort 3 if necessary) have completed a minimum of 
14 days’ treatment.  The selection of the dose for Part B will be taken by the SRC and 
AstraZeneca. This review may be conducted on pre-database lock data that have not been 
formally analysed.
Patients will receive olaparib at the dose determined by Part A of the study, and abiraterone 
1000 mg once daily.
Patients will be evaluated until disease progression regardless of whether study treatment is 
discontinued.  The collection of Response Evaluation Criteria in Solid Tumours version 1.1 
(RECIST 1.1)/prostate cancer working group 2 (PCWG-2) data will then stop and patients 
will be followed for second progression (PFS2) and survival.
The primary analysis will be performed once approximately 100 progression events have 
occurred.
1.3
Number of subjects
1.3.1
Part A: Safety run-in/dose escalation
The primary objective of Part A of this study is to assess the safety and tolerability of olaparib 
when combined with abiraterone and to recommend a dose of olaparib for study in Part B.  
Hence the number of patients has been based on the desire to obtain adequate tolerability, 
safety and PK data while exposing as few patients as possible to the investigational product 
(IP) and procedures.
Cohorts of 3 to 6 evaluable patients will be required.  The total number of patients will depend 
upon the number of dose escalations/reductions necessary.
The cohort sizes are based upon accepted methodology for Phase I oncology studies.


Statistical Analysis Plan 
Study Code D081DC00008
Edition Number 2.0
Date 23OCT2017
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1.3.2
Part B: Randomised part
The sample size for Part B of this study was selected to be consistent with the hypothesis that 
administration of olaparib when given in addition to abiraterone will result in greater efficacy, 
as determined by radiological progression free survival (rPFS), in patients with metastatic 
CRPC than treatment with abiraterone alone.  
In total, 100 rPFS events in the study would provide approximately 80% power to show a 
statistically significant rPFS at the 1-sided 10% level if the assumed true treatment effect was 
a hazard ratio (HR) of 0.65; this translates to a 3.75 month benefit in median rPFS on 
olaparib/abiraterone combination over 7 months (based on the mean of 2 trials: de Bono et al 
2011 and Scher et al 2012) on abiraterone monotherapy if rPFS is exponentially distributed.
Given the number of rPFS events stays unchanged, the power to find the proposed effect size 
to be significant at the 1-sided 2.5% level drops down to approximately 58% and the smallest 
detectable effect becomes HR=0.67 (which translates to a 3.4 months improvement in the 
olaparib/abiraterone combination over the abiraterone/placebo arm).
Approximately 140 patients will be recruited (1:1 ratio) so that data maturity for the rPFS
analysis is approximately 70% at the time of the primary analysis.  Assuming 12 months non-
linear recruitment, 100 rPFS events are expected to occur approximately 24 months after the 
first patient is enrolled in the study (FPI) (12 months accrual + 12 months follow-up).  This 
will be the primary analysis of rPFS.  With 100 events, the smallest treatment difference that 
would be statistically significant at the 1-sided 10% level is rPFS HR= 0.77 (which translates 
to approximately a 2.1 months median difference). `
Overall survival will be analysed at the time of the rPFS primary analysis. At this time we 
expect approximately 60% of the patients to have died (84 deaths). Eighty four death events 
gives 80% power, to show a statistically significant OS effect at the 10% 1-sided level if the 
true hypothesised improvement in median time to death of 10 months on olaparib/abiraterone 
combination over 17 months on abiraterone alone (HR=0.63). Keeping the event number 
fixed, the power to detect a similar effect at the 1-sided 2.5% significance goes down to 
approximately 56%. Note, if the true OS improvement is similar to the anticipated rPFS 
improvement (approximately 4 months median improvement represented by a HR of 0.81) 
then this study is not powered to detect an OS difference at the 1-sided 10% significance level.
The primary and all secondary efficacy endpoints will be analysed in the full analysis set 
unless otherwise stated.  The safety endpoints will be analysed in the safety analysis set.
For sample size information relating to the pharmacogenetic component of the study, please 
see the clinical study protocol Appendix D (‘Pharmacogenetics research’).


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2.
ANALYSIS SETS
2.1
Definition of analysis sets
The study physician, pharmacokineticist, and statistician will agree on the strategy for dealing 
with data affected by protocol deviations before any formal statistical analysis is performed 
and prior to the unblinding of part B.
2.1.1
Full analysis set
Intention to treat (ITT): The primary statistical analysis of the efficacy of olaparib when given 
in addition to abiraterone will include all randomised patients in Part B, regardless of the 
treatment actually received.  Patients who were randomised but did not subsequently go on to 
receive study treatment are included in the full analysis set.
2.1.2
PK analysis set
All patients who receive at least one dose of olaparib per the protocol, for whom there are at 
least one reportable PK concentration and who have no important protocol deviations or 
adverse events that impact PK on all PK Days, will be included in the PK analysis set.
2.1.3
Safety analysis sets
Part A safety analysis set: All patients in Part A of the study who receive at least 1 dose of 
olaparib.  Treatment group comparisons will be based on the initial dose of olaparib actually 
received.
Part B safety analysis set: All patients randomised into Part B of the study who receive at 
least 1 dose of olaparib/placebo.  Treatment group comparisons will be based on the initial 
dose of olaparib/placebo actually received.
When assessing safety and tolerability, summaries will be produced based on the safety 
analysis set.
2.2
Violations and deviations
Deviations from the inclusion/exclusion criteria detailed in section 4 of the protocol are not 
allowed in either part of the study and will be considered important deviations.
2.2.1
Part A
Protocol deviations will be assessed on an ongoing basis to ensure there are sufficient 
evaluable patients for the decision points detailed in Section 1.2.1.
Important protocol deviations include changes to the procedures that may impact the quality 
of the data or any circumstances that can alter the evaluation of the PK. Examples include, but 
are not be limited to, sample processing errors that lead to inaccurate bioanalytical results, 
incomplete dose administered, incomplete PK profile collected, and/or use of disallowed 
concomitant medication. In the case of an important protocol deviation which could impact 


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the robustness of the data, affected PK data collected will be excluded from the descriptive 
summary statistics but will still be reported in the study result listings. Important deviations 
will be listed and discussed in the CSR.
2.2.2
Part B
The important protocol deviations will be listed and summarised by randomised treatment 
group. None of the deviations will lead to any patients being excluded from any of the 
analysis sets described in Section 2.1. If the deviations are serious enough to have the 
potential to impact the primary analysis, sensitivity analyses may be performed.
The following general categories will be considered important deviations and be listed and 
discussed in the CSR as appropriate for study.
!
Patients randomised but who did not receive olaparib/matching placebo.
!
Patients who deviate from entry criteria, which will be documented ahead of 
database lock. 
!
Baseline RECIST scan > 28 days before study treatment is started.
!
Baseline RECIST scans after randomisation.
!
Patients who have RECIST scans outside of a scheduled visit window on > 2 
occasions.
!
Disallowed concomitant medication use.
The categorisation of these as important deviations is not automatic and will depend on 
duration and the perceived effect on efficacy and safety. In addition to the programmatic 
determination of the deviations above, monitoring notes or summaries will be reviewed to 
determine any important post entry deviations that are not identifiable via programming, and 
to check that those identified via programming are correctly classified. The final classification 
will be made prior to database lock and all decisions will be made whilst blinded to study 
treatment allocation. For example, details of disallowed concomitant medication use will be 
reviewed by a physician using blinded data and may be determined as key.
Misrandomisations in terms of errors in treatment dispensing, in addition to incorrect 
stratifications, will also be summarised and listed separately to the important protocol 
deviations. A misrandomisation is when a patient is not randomised or treated according to the 
randomisation schedule. It is envisaged that there will be 2 sub categories of this:
(a) Patients who receive no treatment whatsoever for a period of time due to errors in 
dispensing of medication. Note, this is not due to tolerability issues where patients may stop 
taking drug.


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(b) The patient receives a treatment pack with a different code to their randomisation code. 
However, the actual treatment may still match the randomised treatment. For example, a 
patient is given randomisation code 0001, which according to the randomisation schedule is 
olaparib. However, at the randomisation visit they are given treatment pack 0003, but this still 
contains olaparib.
The summary will include all patients with a dispensing error but will also include 
information on how many of those patients received at least one dose of the wrong treatment 
(olaparib/placebo) at any time. Patients who receive the wrong treatment at any time will be 
included in the safety analysis set as described in Section 2.1. During the study, decisions on 
how to handle misrandomisations will be made on an individual basis with written instruction 
from the study team leader and/or statistician.
3.
PRIMARY AND SECONDARY VARIABLES
For Part A, the primary assessment is the safety and tolerability of olaparib when given in 
addition to abiraterone and to recommend, by assessment of DLTs and other safety and 
tolerability data, a dose of olaparib for further study when given in addition to abiraterone.  
See section 3.3 of this SAP for further details.
For Part B, the primary assessment of efficacy is rPFS, defined as disease progression 
according to RECIST 1.1 (for soft tissue disease) and/or PCWG-2 criteria (for bone disease), 
or death. To ensure comparability, identical imaging techniques should be used for the 
assessment of response at baseline and throughout the study. Further details of the methods 
used to determine the RECIST response are detailed below and also in Appendix F of the 
clinical study protocol.
3.1
Derivation of RECIST visit responses – malignant soft tissue
For all patients, RECIST version 1.1 will be used to determine each patient’s visit response. It 
will also be used to determine if and when a patient has progressed and also their best 
objective response.
Baseline radiological tumour assessments are to be performed no more than 28 days before 
the start of randomised treatment.  Tumour assessments are then performed every 12 weeks 
following randomisation up to and including Week 72.  Thereafter, assessments will be 
conducted every 24 weeks until objective progression.
At each visit, an overall visit response will be determined programmatically - using the 
information from target lesions (TL), non-target lesions (NTL) and new lesions.  RECIST 
outcomes will be calculated using a computer program.
3.1.1
RECIST Target lesions (TLs)
Measurable disease is defined as having at least one measurable lesion which is ≥10 mm in 
the longest diameter (except lymph nodes which must have short axis ≥15 mm) with CT or 


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MRI.  A patient can have a maximum of 5 measurable lesions recorded at baseline and these 
are referred to as TLs.  If more than 1 baseline scan is recorded then measurements from the 
one that is closest to randomisation will be used to define the baseline sum of TLs.
Table 4 provides details for TL visit responses.
Table 4
TL visit responses
Visit Reponses
Description
Complete Response (CR)
Disappearance of all target lesions.  Any pathological 
lymph nodes selected as target lesions must have a 
reduction in short axis to <10mm.
Partial response (PR)
At least a 30% decrease in the sum of diameters of target
lesions, taking as reference the baseline sum of diameters 
as long as criteria for PD are not met.
Progressive disease (PD)
A ≥20% increase in the sum of diameters of target lesions 
and an absolute increase of ≥5mm, taking as reference 
the smallest sum of diameters since treatment started 
including the baseline sum of diameters.
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD
Not applicable (NA)
No target lesions are recorded at baseline
Not-Evaluable (NE)
Only relevant if any of the TLs were not assessed or not 
evaluable or had a lesion intervention at this visit.
Note: If the sum of diameters meets the progressive 
disease criteria, progressive disease overrides not 
evaluable as a TL response
Rounding of TL data
For calculation of progressive disease (PD) and partial response (PR) for TLs percentage 
changes from baseline and previous minimum should be rounded to 1 decimal place before 
assigning a TL response.  For example 19.95% should be rounded to 20.0% but 19.94% 
should be rounded to 19.9%.
Missing TL data 
For a visit to be evaluable then all TL measurements should be recorded.  However, a visit 
response of PD should still be assigned if any of the following occurred:
!
A new lesion is recorded


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!
A NTL visit response of PD is recorded
!
The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute 
increase of ≥5mm, from nadir even assuming the non-recorded TLs have 
disappeared
If any TL measurements are missing, the visit response will automatically be set to not-
evaluable (NE) unless lesion measurements are missing due to an intervention (such as 
irradiation/palliative surgery/embolisation) during the course of the study, in which case they 
will be handled using the 3 steps outlined below.
TL Visit responses subsequent to CR
A complete response (CR) response can only be followed by CR, PD or NE. If a CR has 
occurred then the following rules at the subsequent visits must be applied:
!
Step 1: If all lesions meet the CR criteria (i.e., 0 mm or < 10 mm for lymph nodes) 
then response will be set to CR irrespective of whether the criteria for PD of TL is 
also met i.e. if a lymph node longest diameter (LD) increases by 20% but remains < 
10 mm.
!
Step 2: If some lesion measurements are missing but all other lesions meet the CR 
criteria (i.e. 0 mm or < 10 mm for lymph nodes) then response will be set to NE 
irrespective of whether when referencing the sum of TL diameters the criteria for 
PD is also met.
!
Step 3: If not all lesions meet the CR criteria and the sum of lesions meets the 
criteria for PD then response will be set to PD
!
Step 4: If after steps 1 – 3 a response can still not be determined the response will 
be set to remain as CR
Lymph nodes
For lymph nodes, if the size reduces to < 10mm then these are considered non-pathological.  
However a size will still be given and this size should still be used to determine the TL visit 
response as normal.  In the special case where all lymph nodes are <10mm and all other TLs 
are 0mm then although the sum may be >0mm the calculation of TL response should be over-
written as a CR.
TL too big to measure
If a TL becomes too big to measure this should be indicated in the database and a size (‘x’) 
above which it cannot be accurately measured should be recorded.  If using a value of x in the 
calculation of TL response would not give an overall visit response of PD, then this will be 
flagged and reviewed by the study team blinded to treatment assignment.  It is expected that a 
visit response of PD will remain in the vast majority of cases.


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TL too small to measure
If a TL becomes too small to measure a value of 5mm will be entered into the database and 
used in TL calculations, unless the radiologist has indicated and entered a smaller value that 
can be reliably measured.  If a TL response of PD results then this will be reviewed by the 
study team blinded to treatment assignment.
Irradiated lesions/lesion intervention
Previously irradiated lesions (i.e., lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment.
Any TL (including lymph nodes), which has had intervention during the study (for example, 
irradiation/palliative surgery/embolisation), should be handled in the following way and once
a lesion has had intervention then it should be treated as having intervention for the remainder 
of the study noting that an intervention will most likely shrink the size of tumours:
!
Step 1: the diameters of the TLs (including the lesions that have had intervention) 
will be summed and the calculation will be performed in the usual manner.  If the 
visit response is PD this will remain as a valid response category.
!
Step 2: If there was no evidence of progression after step 1, treat the lesion diameter 
(for those lesions with intervention) as missing and scale up as described below.  If 
the scaling-up results in a visit response of PD then the patient would be assigned a 
TL response of PD.
Note: scaling up will only be performed if ∀1/3 of the TL measurements have been 
set to missing following an intervention.  If > 1/3 of TL measurements are set to 
missing then TL response will be set to NE).
!
Step 3: If after both steps PD has not been assigned, then if appropriate, a scaled 
sum of diameters will be calculated, treating the lesion with intervention as missing, 
and PR or stable disease (SD) then assigned as the visit response.  Patients with 
intervention are evaluable for CR as long as all non-intervened lesions are 0 (or 
<10mm for lymph nodes) and the lesions that have been patient to intervention also 
has a value of 0 recorded.  If scaling-up is not appropriate due to too few non-
missing sizes then the visit response will be set to NE.
At subsequent visits the above steps will be repeated to determine the TL and overall visit 
response.  When calculating the previous minimum (the nadir), lesions with intervention 
should be treated as missing and scaled up where appropriate (as per step 2 above).
Table 5 provides an example of scaling-up.


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Table 5
Example of scaling-up
Lesion
Longest diameter at baseline 
visit
Longest diameter at follow-up 
visit
1
7.2
7.1
2
6.7
6.4
3
4.3
4.0
4
8.6
8.5
5
2.5
Missing
Sum
29.3
26
Lesion 5 has received intervention prior to the follow-up visit and has been set to missing.  
The sum of lesions 1-4 at the follow-up is 26 cm.  The sum of the corresponding lesions at 
baseline visit is 26.8 cm.  Scale up as follows to give an estimated TL sum of 28.4cm:
cm
4.
28
3.
29
8.
26
26
#
∃
Lesions that split in two
If a TL splits in two, then the LDs of the split lesions should be summed and reported as the 
LD for the lesion that split.
Lesions that merge
If two TLs merge, then the LD of the merged lesion should be recorded for one of the TL 
sizes and the other TL size should be recorded as 0cm.
Change in method of assessment of target lesions
If a change in method of assessment occurs between CT and MRI this will be considered 
acceptable and no adjustment within the programming is needed.  
3.1.2
RECIST Non-Target Lesions (NTLs) and new lesions.
Non-target lesion response will be derived based on the Investigator’s overall assessment of 
NTLs as follows:
Progressive disease:
Unequivocal progression of existing NTLs, which may be due 
to an important progression in one lesion only or in several 
lesions.  In ALL cases the progression must be clinically 
significant for the physician to consider changing (or stopping) 
therapy.


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Complete response:
Disappearance of all NTLs present at baseline with all lymph 
nodes non-pathological in size (<10mm short axis).
Non-CR/Non-PD:
Persistence of one or more NTLs with no evidence of 
progression.
Not evaluable:
Only relevant when one or some of the NTLs have not been 
assessed and in the Investigator’s opinion they are not able to 
provide an evaluable overall NTL assessment.
Not applicable:
Only relevant if there are no NTLs at baseline
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumour burden has increased sufficiently to merit discontinuation of therapy.  A 
modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status.
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
1 or more new soft-tissue lesions is assessed as progression.
A soft-tissue lesion identified at a follow up assessment in an anatomical location that was not 
scanned at baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: i.e., not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.
Patients with ‘symptomatic deterioration’ requiring discontinuation of study treatment without 
objective evidence of disease progression at that time should continue to undergo tumour 
assessments where possible until objective disease progression is observed.
3.1.3
RECIST overall visit response
Table 6 defines how the previously defined TL and NTL visit responses will be combined 
with new lesion information to give an overall visit response.


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Table 6
Overall visit response for soft tissue lesions
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non-CR/Non PD
No
PR
CR
NE
No
PR
PR
Non PD or NE
No
PR
SD 
Non PD or NE
No
SD
NA
Non CR/Non PD
No
SD (Non CR/non PD)
NE
Non-PD or NE
No
NE
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
NA
NA
No
NED
3.1.4
RECIST Best objective response
RECIST best objective response (BOR) for soft tissue represents the best response for 
malignant soft tissue a patient has had during their time in the study up until disease 
progression, or last evaluable assessment in the absence of progression.
Each patient will be assigned a best objective response of CR, PR, SD, PD, NE or no evidence 
of disease (NED), which will be calculated as follows:
CR:
Any overall visit response of CR
PR:
Any overall visit response of PR in the absence of CR
SD:
Stable disease recorded at least 12 weeks - 1 week, i.e. at least 77 days 
after the date of randomisation in the absence of CR/PR. Stable disease 
recorded for less than 77 days is assigned to NE.
PD:
Progression or Death in the absence of CR/PR or SD
NED:
No evidence of disease at all visits
NE:
No evidence of CR/PR or SD or PD or Death


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3.2
Evaluation of PCWG2 progression status – bone lesions
Metastatic bone disease status will be reported from the bone lesion assessment on bone scan 
as non-progressive disease (non-PD), PD and NE, separately from RECIST 1.1 soft tissue and 
PSA response assessments, according to PCWG-2 criteria.
Bone lesions will be assessed by bone scintigraphy (bone scans).  Guidelines for the 
assessment of bone lesions are presented in protocol Appendix F.  A baseline bone scan 
should be performed no more than 28 days before randomisation, and ideally should be 
performed as close as possible to the start of study treatment.  Subsequent assessments will be 
performed every 12 weeks (±1 week) from the start of treatment until disease progression, 
death, or withdrawal of consent (every 24 weeks after Week 72).
Bone lesions will be assessed by bone scan and will not be part of the RECIST v1.1 malignant 
soft tissue assessment.  Positive hot spots (if considered to constitute bone metastases) are on 
the bone scan should be considered significant and unequivocal sites of malignant disease to 
be recorded as metastatic bone lesions.
If an unscheduled assessment, e.g., confirmation of progression scan, is performed and there is 
no evidence of disease progression, every attempt should be made to perform the subsequent 
assessments at their scheduled visits while the patient remains on study treatment.
Progression on a bone scan is assessed as:
!
At the 12 week scan:
If 2 or more new metastatic bone lesions are observed on the first 12-week scan, the 
confirmatory scan performed, preferably at the next scheduled visit for a bone scan 
(i.e., Week 24) and at least 6 weeks later (week 18 or later), must show 2 or more 
additional new metastatic bone lesions (for a total of 4 or more new metastatic bone 
lesions since the baseline assessment) for progression to be documented.  
As bone scans at Week 12 do not have a PCWG-2 response (because a 
confirmatory scan is required), they will be classified as non-PD, unless Bone 
Lesion Status cannot be determined from that scan.
!
After the 12 week scan:
If 2 or more new metastatic bone lesions are observed on scans obtained after the 
first 12-week assessment, confirmatory scan performed preferably at the next 
scheduled visit for a bone scan (e.g., Week 36) and at least 6 weeks later needs to 
show the persistence of or an increase in the number of metastatic bone lesions 
compared to the prior scan.
Additionally, for any scan with 2 or more new bone lesions that does not have a 
subsequent scan, the response will be classified as non-PD, however is unusable 
and deemed not contributing for the primary endpoint.


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The date of progression is the date of the first scan that shows the change.
If the Investigator is in doubt as to whether progression has occurred, it is advisable to 
continue study treatment and reassess the bone lesion status at the next scheduled assessment, 
or sooner if clinically indicated.
It is important to follow the assessment schedule as closely as possible.
Table 7 provides the definitions of the criteria to determine tumour visit response for bone 
lesions.
Table 7
Overall PCWG-2 progression status (bone)
Non–progressive disease (non-PD)
Persistence of one or more bone lesions, disappearance of all 
bone lesions or a bone scan with 2 or more new lesions that is 
not confirmed.
Progressive disease (PD)
Bone lesions fulfilling the requirements for new lesions and 
confirmation of progression
Non evaluable (NE)
Bone scan not performed at the visit or image quality not 
sufficient for evaluation
Disease progression will only occur when a response of progressive disease is recorded at two 
visits at least 6 weeks apart. The date of the progression is designated as the first scan showing 
2 or more new bone lesions. 
Disease progression and the date of disease progression will be recorded on 
the eCRF by the investigator. Progression will be determined by the 
investigator using the definition of progression on bone scan as described 
above and in Appendix F of the clinical study protocol.
3.3
Primary variable – radiologic progression free survival (rPFS)
The primary endpoint in Part B is rPFS (defined by RECIST 1.1 and/or PCWG-2 as assessed 
by the Investigator, and expressed in months). The visit responses for the soft tissue 
assessment (based on RECIST 1.1) will be used in conjunction with the PCWG-2 bone scan 
evaluations assessed by the investigator, in that a patient is progression-free only if they are 
not PD by RECIST 1.1 or PCWG-2.
Table 8 defines how the visit responses for soft tissue (according to RECIST1.1 criteria) and 
bone (according to PCWG-2 criteria) will be combined with bone lesion information to give 
an overall radiological visit response.


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Table 8
Overall radiological visit response
RECIST1.1 visit 
response (soft 
tissue/visceral)
PCWG-2 progression 
status (bone)
Bone lesions
Present/Absent
Overall radiological 
visit response
CR
Non-PD
Absent
CR
CR
Non-PD
Present
PR
CR
NE a
Any b
PR
PR
Non-PD or NE a
Any
PR
SD
Non-PD or NE a
Any
SD
NED c
Non-PD
Any
non-PD
NED c
NE a
Any
NE
NE d
Non-PD or NE a
Any
NE
PD 
Any
Any
PD
Any
PD
Any
PDe
a  -   From an imaging point of view, a PCWG2 visit response of ‘NE’ will mainly be because a patient did not 
have a scan at all at that time-point or a bone scan was done however there were issues with the image 
quality, e.g. poor contrast, the wrong acquisition parameter was used.
b -   ‘Any’ refers to any result whether measured or missing.
c -   NED – No evidence of soft tissue disease at all visits.
d -   NE – Not evaluable.
e -
Following the confirmation of PD at the subsequent bone scan, the overall radiological visit response of 
progression for the visit will be programmatically derived as PD using the  Progression Date (Previous 
Bone scan date where new lesions first seen) captured on the eCRF.
Radiologic progression-free survival (months) is defined as the time from randomisation until 
the date of objective disease progression or death (by any cause in the absence of progression) 
regardless of whether the patient withdraws from randomised therapy or receives another anti-
cancer therapy prior to progression.
Patients will undergo tumour assessments at baseline, and thereafter every 12 weeks following 
randomisation up to and including Week 72 (every 24 weeks thereafter), until objective 
disease progression or death. The rPFS time will always be derived based on scan/assessment 
dates, not visit dates.
Patients who are not known to have progressed (defined as CR, PR, SD or NED by RECIST 
1.1 and/or non-PD by PCWG-2 bone scan) or died at the time of analysis will be censored at 
the time of the latest date of assessment from either their last evaluable RECIST 1.1 
assessment or their last evaluable PCWG-2 assessment.  Also, if the patient progresses or dies 
after 2 or more missed visits (i.e. 2 or more visits where neither a RECIST 1.1 visit scan nor a 
PCWG-2 visit scan were done; not evaluable scans that were completed are not considered 
“missed”) the patient will be censored at the time of the latest evaluable RECIST 1.1 or 


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PCWG-2 assessment.  If the patient has no evaluable visits or does not have baseline data they 
will be censored at Day 1 unless they die within 2 visits of baseline (in which case their date 
of death will be used).
When the Investigator is in doubt as to whether PD has occurred and therefore reassesses the 
patient at a later date, the date of the initial scan should be declared as the date of progression 
if the repeat scans confirm progression.
If a patient discontinues treatment prior to progression then the patient will continue to be 
followed until evidence of objective disease progression as defined by RECIST 1.1 or 
PCWG-2 occurs and their rPFS time will be derived as defined above.
RECIST 1.1/PCWG-2 assessments/scans contributing towards a particular visit may be 
performed on different dates. The following rules will be applied:
!
Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression
!
When censoring a patient for rPFS, the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment.
3.4
Secondary outcome variables 
3.4.1
Time to second progression (PFS2)
PFS2 (months) is defined as the time from the date of randomisation to the earliest of the 
progression event subsequent to that used for the primary variable rPFS, or death.  The date of 
PFS2 will be recorded by the Investigator and defined according to local standard clinical 
practice and may involve any of: objective radiological progression, symptomatic progression, 
rises in PSA or death.  This is calculated for Part B only.
PFS2 status will be reviewed every 12 weeks following the progression event used for the 
primary variable rPFS (the first progression) and investigator opinion of progression status 
(progressed or non-progressed) at each assessment will be recorded in the electronic case 
report form (eCRF).  RECIST 1.1 and PCWG-2 assessments will not be required for 
assessment of PFS2.  Patients alive and for whom a second disease progression has not been 
observed should be censored at the last time known to be alive and without a second disease 
progression (i.e., censored at the latest of the rPFS or PFS2 assessment date if the patient has 
not had a second progression or death).
PFS2 status will be assessed during the 2 weeks following the DCO.
3.4.2
Overall survival (OS)
Overall survival (months) is defined as the time from the date of randomisation until death due 
to any cause. Any patient not known to have died at the time of analysis will be censored 
based on the last recorded date on which the patient was known to be alive. This is calculated 
for Part B only.  This should be based on information in the date subject last known to be alive 


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variable recorded within the survival status module of the eCRF (SUR_DAT, recorded within 
the SURVIVE module of the eCRF).
Note, survival calls will be made in the 2 weeks following the date of data cut-off (DCO) for 
the analysis, and if patients are confirmed to be alive (or if the death date is post the DCO 
date) these patients will be censored in the analyses as of the date of DCO.  Death dates may 
be found by checking publicly available death registries.  
Patients will enter the OS phase of the study following confirmed progression by the 
Investigator. All patients will be followed for survival data until approximately 60% of 
patients have died.
3.4.3
Objective response rate (ORR) and associated variables
Objective response rate (ORR) rate is defined as the number (%) of patients with at least one 
visit response of CR or PR.  Data obtained up until progression, or last evaluable assessment 
in the absence of progression, will be included in the assessment of response rate.  This will be 
irrespective of whether or not patients discontinued treatment. Any responses observed after 
the start of the first cancer therapy subsequent to treatment discontinuation will not be 
included.
For soft tissue disease ORR, only patients with measurable disease (target lesions) at entry 
will be included in the denominator.  A responder will be any patient with a RECIST best 
overall response of PR or CR in their soft tissue disease assessed by RECIST 1.1, irrespective 
of the bone scan status assessed by PCWG-2.
A soft tissue visit response of CR is defined when all TL and NTL lesions present at baseline 
have disappeared (with the exception of lymph nodes which must be <10 mm to be considered 
non-pathological) and no new lesions have developed since baseline.  A soft tissue visit 
response of PR is defined when the sum of diameters of the TLs has decreased by 30% or 
more compared with baseline (with no evidence of progression) and the NTLs are at least 
stable with no evidence of new lesions.
For overall disease ORR, again only patients with visceral measurable disease (TLs) at entry 
will be included in the denominator whether or not they have documented metastatic bone 
scan at entry. A responder demonstrating overall radiological response will be any patient 
with a best overall response of PR or CR in soft tissue disease assessed by RECIST 1.1 and 
also bone scan status of non-PD or NE for their bone scans assessed by PCWG-2.  Soft tissue 
response rate will thus be equal to or higher than the overall radiological ORR.
Duration of overall radiological response (RECIST 1.1 soft tissue disease response of PR or 
CR, with a PCWG-2 response of non-PD/NE) will be defined as the time from overall 
radiological response until date of documented radiological progression by RECIST 1.1 or 
PCWG-2, or death in the absence of disease progression; the end of response should coincide 
with the date of progression or death from any cause used for the rPFS endpoint.  The time of 
the initial overall radiological response will be defined as the latest of the dates contributing 


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towards the first visit where an overall radiological response is seen. The time to the initial 
overall radiological response will be defined as the time from randomisation until the earliest 
of the dates where an overall radiological response is seen.
If a patient does not progress following an overall radiological response, then their duration of 
response (DOR) will be censored at the rPFS censoring time.
Duration of response will not be defined for those patients who do not have documented 
overall radiological response or visceral measurable disease at entry.
3.4.4
Time to subsequent therapies
Subsequent anti-cancer therapies, which does not include radiotherapy, will be reviewed prior 
to unblinding to assess which represent clinically important treatments intended to control 
prostate cancer. As a supportive summary to rPFS, time to start of first subsequent anti-cancer 
therapy or death (TFST) will be assessed. TFST is defined as the time from randomisation to 
the earlier of first subsequent anti-cancer therapy start date following study treatment 
discontinuation, or death. Any patient not known to have died at the time of the analysis and 
not known to have had a further intervention of this type will be censored at the last known 
time to have not received subsequent therapy, i.e. the last follow-up visit where this was 
confirmed.
As a supportive summary to rPFS, time to start of second subsequent anti-cancer therapy or 
death (TSST) will be assessed. TSST is defined as the time from randomisation to the earlier 
of the second subsequent anti-cancer therapy start date following study treatment 
discontinuation, or death. Any patient not known to have died at the time of the analysis and 
not known to have had a further intervention of this type will be censored at the last known 
time to have not received second subsequent therapy, i.e. the last follow-up visit where this 
was confirmed.
3.5
Safety
3.5.1
Dose limiting toxicities (DLTs)
Dose limiting toxicities will be reviewed in Part A, the incidence of DLTs will be summarised 
by cohort and listed.
A DLT is defined as any toxicity which is not a recognised adverse effect of abiraterone or 
prednisolone, and not attributable to the disease or disease-related processes under 
investigation, which occurs during a minimum of 14 days’ treatment and which includes:
Haematological toxicity ≥ common terminology criteria for adverse events (CTCAE) Grade 4 
present for more than 4 days
%
Except anaemia
Non-haematological toxicity ≥ CTCAE Grade 3 including:


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%
Infection including febrile neutropenia
%
Corrected QT interval (QTc) prolongation (> 500 msec)
Any other toxicity that is greater than that at baseline, is clinically significant and/or 
unacceptable, does not respond to supportive care, results in a disruption of dosing schedule of 
7 days or more, or is judged to be a DLT by the SRC.
3.5.2
Adverse Events
The definitions of adverse events (AEs) and serious AEs (SAEs) are given in Sections 6.4.1 
and 6.4.2 of the clinical study protocol.  AEs will be listed for each patient and summarised by 
treatment received according to the system organ class (SOC) and preferred term assigned to 
the event using the Medical Dictionary for Regulatory Activities (MedDRA).  AEs will be 
graded according to the National Cancer Institute CTCAE (version 4.0).  The CTCAE grade 
will be assigned by the investigator as will an assessment of causality. All summaries will 
include treatment emergent events, defined as adverse events with an onset date on or after the 
first dose and up to and including 30 days following the date of last dose of study medication, 
unless otherwise stated
Grouped AEs
Specific preferred terms describing similar clinical concepts will be considered collectively as 
Grouped AEs. An AstraZeneca medically qualified expert after consultation with the Global 
Patient Safety Physician will confirm the list of Grouped AEs and the specific preferred terms 
contributing to each grouping at blind data review.
AEs of special interest
Adverse events of special interest (AESIs) for olaparib are events of scientific and medical 
interest specific to the further understanding of the olaparib safety profile. An AESI may be 
serious or non-serious.  For olaparib these AESI’s have been identified as the Important 
Potential Risks of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), new 
primary malignancy (other than MDS/AML), pneumonitis and diffuse alveolar damage. The 
preferred terms associated with these AESIs are listed in Appendix B.
Some clinical concepts (including Grouped AEs and some selected individual preferred terms) 
are considered “AEs of interest”.  An AstraZeneca medically qualified expert after 
consultation with the Global Patient Safety Physician will confirm the list of AEs of special 
interest (to include Grouped AEs and the specific preferred terms) at prior to unblinding.
3.5.3
Laboratory data
Blood samples will be used for determination of clinical chemistry and haematology. Clinical 
chemistry and haematology will be taken at all scheduled visits. The laboratory parameters to 
be collected are given in the protocol Section 6.4.5 of the clinical study protocol.


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Change from baseline in haematology and clinical chemistry variables will be calculated for 
each post-dose visit on treatment. Baseline will be the last non-missing assessments prior to 
initiation of olaparib/placebo, in most cases this will be the assessments performed on Day 1. 
CTCAE grades will be defined at each visit according to the CTCAE grade criteria using AZ 
standard ranges as required, after conversion of laboratory results to corresponding SI units. 
The following parameters have CTCAE grades defined for both high and low values: 
potassium, sodium, magnesium and calcium so high and low CTCAE grades will be 
calculated. CTCAE grades are not defined for total protein, urea nitrogen, absolute eosinophil 
count, absolute basophil count, absolute monocyte count.
Absolute values will be compared to the AZ standard reference range and classified as low 
(below lower limit), normal (within range or on limits of range) and high (above upper limit). 
The maximum or minimum on-treatment value (depending on the direction of an adverse 
effect) will be defined for each laboratory parameter as the maximum (or minimum) post-dose 
value at any time.
The denominator used in laboratory summaries will only include evaluable patients, in other 
words those who had sufficient data to have the possibility of an abnormality. For example:
!
If a CTCAE criterion involves a change from baseline, evaluable patients would 
have both a pre-dose and at least 1 post-dose value recorded
!
If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post dose-value recorded
Any data collected at unscheduled visits (including retests) will be listed, included in the 
derivation of baseline and also in the derivation of maximum overall CTCAE grade during 
treatment and maximum value during treatment, but will not be included in any summaries by 
visit.
3.5.4
Vital signs
Vital sign assessments (resting blood pressure [BP], pulse rate, body temperature), including 
weight, will be performed as per the study. Height will be assessed at screening only.
Change from baseline in vital signs variables will be calculated for each post-dose visit on 
treatment. The denominator in vital signs data should include only those patients with 
recorded data. Any data collected at unscheduled visits will be listed and included in the 
derivation of baseline, but will not be included in any summaries by visit.
3.5.5
Electrocardiograms (ECG)
Twelve-lead ECG will be performed as per the study plan. Patients should be supine and at 
rest 5 minutes prior to recording the ECG. At each time point the Investigator’s assessment of 
the ECG (normal, borderline or abnormal) and heart rate, duration of QRS complex, 
respiratory rate (RR), pulse rate and QT intervals will be collected. 


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For triplicate ECGs, the mean of the 3 ECG assessments will be used to determine the value at 
that time point.
QTcF will be derived during creation of the reporting database using the reported ECG values 
(RR and QT).
QTcF = QT / RR^ (1/3) where RR is in seconds
3.5.6
Physical examination
A physical examination will be performed as per the study plan.
3.5.7
Duration of exposure
Study drug exposure (days) will be defined as time from first dose of olaparib, up to and 
including the, last day that the dose of olaparib was greater than 0mg. Exposure to abiraterone 
will be calculated in the same way.
Exposure will be defined as: Last dose date – first dose date + 1.
Actual exposure (days) to study drug, defined as time from first dose of olaparib, up to and 
including the, last day of dosing minus total number of days where the dose was 0 (including 
missed or forgotten doses), will also be calculated.  Actual exposure to abiraterone will be 
calculated in the same way.
The number of days each patient took the assigned dose of study drug in part B, (this will 
depend on the result of part A but is assumed to be 300mg olaparib/placebo b.i.d), will also be 
calculated and summary statistics of this data will be presented.  
Percentage compliance will be defined as: 
{(No. tablets dispensed in period – no. tablets returned from period)/
  (no. days of study drug exposure in period * expected tablets per day)}   * 100%
where expected tablets per day will take into account once daily or bid dosing.
Overall compliance may be calculated over various periods if the dose has been modified, to 
take into account the differing expected tablets per day or the protocol-specified dose 
interruptions.  Missed doses will not be adjusted for; the overall compliance will be reduced.
For summaries, compliance will be capped at 100%, however uncapped compliance rates will 
be listed by subject.
Dose intensity
Relative dose intensity (RDI) is the percentage of the actual dose intensity delivered relative 
to the intended dose intensity through to treatment discontinuation. Percentage intended dose 
(PID) is the percentage of the actual dose delivered relative to the intended dose through to 
progression. Both will be derived using study treatment data up to two years or until the date 


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of objective disease progression (whichever is earliest) as defined by RECIST and/or PCWG-
2 criteria using the investigator site assessments. If the investigator considered that it was in 
the patient’s best interest to continue study treatment past this time, this was not included in 
the derivation of dose intensity.
RDI and PID will be defined as follows:
•
RDI = 100% * d/D, where d is the actual cumulative dose delivered up to the earlier of 
progression (or a censoring event) or the actual last day of dosing and D is the 
intended cumulative dose up to the earlier of progression (or a censoring event) or the 
actual last day of dosing plus the protocol-defined post-dose rest period.
•
PID = 100% * d/D, where d is the actual cumulative dose delivered up to progression 
(or a censoring event) and D is the intended cumulative dose up to progression (or a 
censoring event). D is the total dose that would be delivered, if there were no 
modification to dose or schedule.
3.6
Pharmacokinetic variables and PK analysis methods
The PK analysis of the plasma concentration data for olaparib and abiraterone will be 
performed by Covance Clinical Pharmacokinetic Alliance (CPKA) on behalf of AstraZeneca 
R&D. The actual sampling times will be used in the PK calculations, except for the pre-dose 
sample for which the time will be set to zero. All PK computations will be performed using 
Phoenix™WinNonLin® v6.4 for non-compartmental analysis (NCA).
Patients who withdraw from the study following dosing, but prior to study completion, will be 
included in the PK analysis provided they have evaluable profiles over the planned collection 
period.  Patients with partial data will be evaluated on a case-by-case basis to determine if 
sufficient data are available for meaningful analysis.
Where plasma concentration-time data allow the following steady state PK parameters will be 
determined in Part A for olaparib (Cohort 2 Group 1 Visits 3 and 4 and Cohort 2 Group 2 
Visit 4) and abiraterone (Cohort 2 Group 1 Visit 4 and Cohort 2 Group 2 Visits 3 and 4):
Css,max, Css,min, tss,max, AUCss, AUC0-t, tss,last, CLss/F and ratios of Css,max, Css,min and AUCss for 
each analyte in combination compared to monotherapy.
Plasma concentrations that are non-quantifiable (NQ) (i.e. are below the LOQ limit of 
quantification) from the time of pre-dose sampling (t=0) up to the time of the first quantifiable 
concentration will be set to a value of zero. After this time point, NQ plasma concentrations 
will be set to missing for all concentration profiles. Where two or more consecutive 
concentrations are NQ at the end of a profile, the profile will be deemed to have terminated 
and therefore any further quantifiable concentrations will be set to missing for the calculation 
of the PK parameters unless it is considered to be a true characteristic of the profile of the 
drug. If an entire concentration-time profile is NQ, the profile will be excluded from the PK 
analysis.


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Css,max, Css,min, tss,max and tss,last will be determined by visual inspection of the concentration-
time profiles. Css,min will be taken as the concentration in the pre-dose sample taken 
immediately prior to dosing on the PK day. AUCss will be calculated using the linear 
trapezoidal method when concentrations are increasing and the logarithmic trapezoidal 
method when concentrations are decreasing (linear up, log down). The minimum requirement 
for the calculation of AUCss will be the inclusion of at least three consecutive plasma 
concentrations above the lower limit of quantification (LLOQ), with at least one of these 
concentrations following Css,max. The apparent steady state clearance (CLss/F) will be 
determined from the ratio of dose/AUCss. Ratios of Css,max, Css,min and AUCss for each analyte 
in combination compared to monotherapy will be determined in Phoenix using non log-
transformed parameter data .
3.7
Calculation or derivation of biomarker variable(s)
3.7.1
Prostate specific antigen
The distribution of the PSA data will be assessed prior to unblinding and if necessary, a log-
transformation may be applied. 
3.7.1.1
PSA response
!
A patient will be regarded as having a single PSA visit response if their PSA level 
at any post-dose visit is reduced by 50% or more compared with baseline
!
A patient will be regarded as having a confirmed PSA response if they have a 
reduction in PSA level of 50% or more compared with baseline that is confirmed at 
the next assessment at least 4 weeks later (i.e., decrease relative to baseline of at 
least 50% documented on 2 consecutive occasions at least 4 weeks apart).
3.7.1.2
PSA changes on continuous scale
!
PSA levels will be evaluated in terms of percentage change from baseline which 
will be derived for each post baseline visit where PSA data are available
!
% change = [(post-dose PSA level – baseline PSA level) / baseline PSA level] *100
!
Best percentage change from baseline in PSA will be derived as the biggest 
reduction in PSA level compared with baseline (or the smallest increase in the 
absence of a reduction) taking account of all PSA values collected for each patient.
3.7.2
Circulating tumour cell counts (CTCs)
!
Conversion: change of circulating tumour cells (CTC) from ≥5 at baseline to <5 
post baseline
!
Absolute change in CTC counts as a continuous variable following treatment with 
olaparib/placebo and abiraterone (calculated as post-dose CTC count - baseline 
CTC count).  


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!
Absolute change in CTC count at 12 weeks.
3.7.3
ATM mutation
Patient tumour samples will be assessed for the presence of Ataxia telangiectasia (ATM) 
mutation utilising a targeted NGS assay (Foundation Medicine). Results from the tumour 
analysis will be used to classify the data into the categories as listed in Table 9 to define the 
subgroups for analysis. The tumour-derived ATM mutation call may be supplemented by 
germline data if that becomes available during study (e.g. if noted on eCRF). The presence of 
ATM mutation from any source is dominant (whether considered of germline origin or 
tumour-specific).
Table 9
Description of ATM mutation categories
Category
Description
Detected
Patient with a deleterious or suspected deleterious ATM 
mutation identified in their tumour.
Variant of unknown significance 
(VUS)
Patient who was not ATM mutated as defined above, but 
tumour analysis indicated the presence of a variant of 
unknown significance.
Not Detected
Patient who was not ATM mutated/ATM VUS as defined 
above, but tumour analysis was performed successfully 
and no mutation was detected
Failed
Patient for whom a tumour sample was analysed but the 
analysis failed to provide sufficient data to enable 
classification of their ATM mutation status.
Status unknown
Patient did not have an ATM result recorded from tumour 
analysis.
3.7.4
BRCA mutation
Patient tumour samples will be assessed for the presence of breast cancer gene (BRCA1 or 
BRCA2) mutation utilising a targeted NGS assay (Foundation Medicine). Results from the 
tumour analysis will be used to classify the data into the categories as listed in Table 10 to 
define the subgroups for analysis. The tumour-derived BRCA mutation call may be 
supplemented by germline data if that becomes available during study (e.g. if noted on eCRF). 
The presence of BRCA mutation from any source is dominant (whether considered of 
germline origin or tumour-specific).  
Table 10
Description of BRCA mutation categories
Category
Description
Detected
Patient with a deleterious or suspected deleterious BRCA 
(BRCA1 or BRCA2) mutation identified in their tumour.


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Category
Description
Variant of unknown significance 
(VUS)
Patient who was not BRCA mutated as defined above, but 
tumour analysis indicated the presence of a variant of 
unknown significance.
Not Detected
Patient who was not BRCA mutated/BRCA VUS as 
defined above, but tumour analysis was performed 
successfully and no mutation was detected
Failed
Patient for whom a tumour sample was analysed but the 
analysis failed to provide sufficient data to enable 
classification of their BRCA mutation status.
Status Unknown
Patient did not have a BRCA result recorded from tumour 
analysis or a BRCA result recorded in the eCRF.
3.7.5
Composite BRCA/ATM mutation
Results from the tumour analysis for BRCA1, BRCA2 and ATM mutation as described above 
in sections 3.7.3 and 3.7.4 will be used to classify the data into composite categories as shown 
in Table 11 to define the subgroups for the analysis.
Table 11
Description of composite BRCA/ATM mutation categories
Category
Description 
Detected
Patient with a deleterious or suspected 
deleterious mutation identified in their 
tumour in at least one of the BRCA1, 
BRCA2 and ATM genes.
Variant of unknown significance (VUS) 
Patient was not mutated as defined above, 
but tumour analysis indicated the presence 
of a variant of unknown significance in at 
least one of the BRCA1, BRCA2 and 
ATM genes. 
Not Detected  
Patient was not mutated/VUS as defined 
above, but tumour analysis was performed 
successfully and no mutation was detected 
in the BRCA1, BRCA2 and ATM genes.
Failed
Patient for whom a tumour sample was 
analysed but the analysis failed to provide 
sufficient data to enable classification of 
their mutation status. 
Status Unknown
Patient did not have a result recorded 
from tumour analysis or a result recorded 
in the eCRF. 


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3.7.6
Composite HRR mutation (excluding BRCA1, BRCA2 and ATM)
Patient tumour samples will also be assessed for the presence of an additional panel of 12 
HRR gene mutations (denoted as follows: BARD1, BRIP1, CDK12, CHEK1, CHEK2, 
FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L) utilising a 
targeted NGS assay (Foundation Medicine). Results from the tumour analysis will be used to 
classify the data into composite HRR categories as shown in Table 12 to define the subgroups 
for the analysis.
Table 12
Description of composite HRR mutation categories
Category
Description 
Detected
Patient with a deleterious or suspected 
deleterious mutation identified in their 
tumour in at least one of the 12 HRR 
genes (as denoted above).
Variant of unknown significance (VUS) 
Patient was not mutated as defined above, 
but tumour analysis indicated the presence 
of a variant of unknown significance in at 
least one of the 12 HRR genes. 
Not Detected  
Patient was not mutated/VUS as defined 
above, but tumour analysis was performed 
successfully and no mutation was detected 
in all 12 HRR genes.
Failed
Patient for whom a tumour sample was 
analysed but the analysis failed to provide 
sufficient data to enable classification of 
their mutation status. 
Status Unknown
Patient did not have a result recorded 
from tumour analysis.
3.8
Exploratory variables
3.8.1
Patient reported outcomes (PRO) and HRQL
Patient reported outcomes (PRO) will be measured using the Brief Pain Inventory – short 
form (BPI-SF), and the individual item on bone pain and the Functional Assessment of Cancer 
Therapy - Prostate Cancer (FACT-P;- Esper et al 1997, Cella et al 1993) questionnaires.
3.8.1.1
Functional Assessment of Cancer therapy – Prostate Cancer (FACT-P)
The patient-reported FACT-P will be used to assess health-related quality of life.  The 
questionnaire will be administered in Part B of the study, at baseline, Week 4, 8 and 12 and 
then continue to be administered to all patients (who have not withdrawn consent) every 12 
weeks.


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The following outcome measures will be calculated from the FACT-P questionnaire, the 
resulting value is the total score for the associated questions or scaled scores:
!
Physical well-being subscale (PWB) (Questions GP1 to GP7)
!
Social/family well-being subscale (SWB) (Questions GS1 to GS7)
!
Emotional well-being subscale (EWB) (Questions GE1 to GE6)
!
Functional well-being subscale (FWB) (Questions GF1 to GF7)
!
Prostate cancer subscale (PCS) (Questions C2, C6, P1 to P8, BL2 and BL5)
!
Trial Outcome Index (TOI), sum of PWB, FWB and PCS
!
Functional Assessment of Prostate Cancer Symptoms Index 8 (FAPSI-8) (Questions 
P1 to P3, GP1, C2, P7, P8 and GE6)
!
Functional Assessment of Prostate Cancer Symptoms Index 6 (FAPSI-6) (Questions 
P1 to P3, GP1, C2 and GE6).
!
FACT-P total score (sum of scores of all the sub-scales)
Items to be reversed:
!
Each question in the FACT-P questionnaires has a choice of 5 responses, “Not at 
all”, “A little bit”, “Somewhat”, “Quite a bit” and “Very much”.  The scores range 
from 0 (“Not at all”) to 4 (“Very much”) for positively phrased questions.  
Negatively phrased questions have a reverse scoring, from 0 (“Very much”) to 4 
(“Not at all”).  This results in a consistent approach, where higher scores indicate a 
better quality of life.
!
Note, questions that are reversed (via subtraction of the response from 4) are: 
GP1-7, GE1, GE3-6, C2, P1-3, P6-P8 and BL2.
Missing data
As per the FACIT scoring guidelines (Cella et al 1993, Cella 1994, Esper et al 1997),
!
More than 80% of questions in a questionnaire must be completed for the 
questionnaire to have the FACT-P total score evaluable. If 80% or less of questions 
are completed, the FACT-P total scores will not be calculated.
!
For each domain (PWB, SWB, EWB, FWB and PCS) if more than 50% of the items 
were answered (e.g., a minimum of 4 of 7 items, 4 of 6 items, etc), the subscale 
score will be calculated by multiplying the sum of subscale by the number of items 
in the subscale, then dividing by the number of items actually answered:


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Subscale score= (sum of item scores x N of items in subscale)/ N of items answered   
!
If at least 50% of the domain items are missing, that domain will be treated as 
missing and thus NE. The total score for each variable (FACT-P TOI and FACT-P 
total) is then calculated as the sum of the un-weighted prorated scores. If a domain 
score is NE, any health related quality of life (HRQL) variable which these domains 
contribute to is also termed NE. For example, for the FACT-P TOI variable, if PWB 
is NE at a visit, the FACT-P TOI variable is also NE at this visit. Also, the FACT-P 
total score cannot be computed if any of the domain scores is NE.
Visit responses
The last non-missing assessment before randomisation will be assigned to be the baseline 
assessment. At each post-baseline visit, the following criteria as listed below in Table 13 will 
be used to assign a visit response for the FACT-P total score, FACT-P TOI, FAPSI-8, FAPSI-
6, PCS and FWB scores (Cella et al 2009). This response should be maintained for 2 
consecutive visits.
Table 13
Definition of visit response for FACT-P, FAPSI-8, FAPSI-6, TOI, PCS, 
FWB, PWB and SWB
FACT-P scale
Possible scores
Change from baseline
Visit response
FACT-P-Total
0-156
≥ +6
Improved
≤ -6
Worsened
Otherwise (i.e., >-6 and <+6)
No change
Missing/non-calculable score
Not evaluable
FAPSI-8
0-32
≥ +3
Improved
≤ -3
Worsened
Otherwise (i.e., >-3 and <+3)
No change
Missing/non-calculable score
Not evaluable
FAPSI-6
0-24
≥ +3
Improved
≤ -3
Worsened
Otherwise (i.e., >-3 and <+3)
No change
Missing/non-calculable score
Not evaluable
TOI
0-104
≥ +5
Improved
≤ -5
Worsened
Otherwise (i.e., >-5 and <+5)
No change
Missing/non-calculable score
Not evaluable
PCS
0-48
≥ +3
Improved
≤ -3
Worsened


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FACT-P scale
Possible scores
Change from baseline
Visit response
Otherwise (i.e., >-3 and <+3)
No change
Missing/non-calculable score
Not evaluable
FWB
0-28
≥ +2
Improved
≤ -2
Worsened
Otherwise (i.e., >-2 and <+2)
No change
Missing/non-calculable score
Not evaluable
PWB
0-28
≥ +2
Improved
≤ -2
Worsened
Otherwise (i.e., >-2 and <+2)
No change
Missing/non-calculable score
Not evaluable
SWB
0-28
≥ +2
Improved
≤ -2
Worsened
Otherwise (i.e., >-2 and <+2)
No change
Missing/non-calculable score
Not evaluable
Note for some patients it will not be immediately possible to obtain a visit response for a 
particular subscale, for example:
!
Patients with no baseline score for a particular subscale, or no baseline data at all
!
Patients whose baseline subscale score is too close to the maximum or minimum 
possible score to allow an increase or decrease of the specific size to be observed.
%
For patients whose baseline score is greater than the maximum possible score 
for that subscale minus the score needed to satisfy improvement, the best visit 
response possible will be “No Change”.
%
For patients whose baseline score is less than the threshold needed for 
worsening (e.g., a baseline FACT-P TOI < 5) all post-baseline visit responses 
will be considered not-calculable.
For those patients who meet the criteria above (where it is not possible to improve or worsen), 
descriptive data will be provided.  
At the conclusion of the study, the criteria listed in Table 14 will be used to assign a best 
overall response score based on the individual visit responses.


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Table 14
Overall score response for FACT-P, FAPSI-8, FAPSI-6, TOI, PCS, FWB, 
PWB, SWB
Overall score response
Criteria
Improved
Two consecutive visit responses of ‘improved’
No change
Does not qualify for overall score response of ‘improved’.  Two 
consecutive visit responses of either ‘no change’, or ‘improved’ 
and ‘no change’
Worsened
Does not qualify for overall score response of ‘improved’ or ‘no 
change’.  A visit response of ‘worsened’
Other
Does not qualify for one of the above
Not evaluable
Missing or non-calculable scores
Time to deterioration for FACT-P
Time to deterioration of HRQL as measured by FACT-P TOI will be defined as the interval 
from the date of randomisation to the first assessment of worsened without an improvement in 
the next 12 weeks in FACT-P TOI, or the date of death (by any cause in the absence of 
symptom deterioration). Time to deterioration as measured by the FACT-P total score and 
FAPSI-6, FAPSI8, PCS, FWB, PWB and SWB will be derived similarly.
A worsening is as described in Table 13 for example, for FACT-P TOI a decrease in score 
from baseline of ≥ 5, or “Subject too affected by symptoms of disease under investigation” 
answered as the reason for not completing HRQL at a post-baseline visit will constitute a 
deterioration.  Improvement is also as defined within Table 13.
A deterioration followed by an improvement within 12 weeks means that this first 
deterioration cannot be used in determining the time to deterioration of symptoms.  However, 
if a subsequent worsening is seen, with no improvement in the following 12 weeks, this 
second deterioration will be used to derive the time to deterioration.
Radiologic progression or a reason for not completing the questionnaire of “Subject 
unwilling”, “Subject too sick, other than disease under investigation” or “Administrative 
failure to distribute questionnaire to Subject” will not be considered as deterioration in
symptoms.
Note, under the same principles applied to the primary outcome variable (rPFS), time to 
deterioration will be derived regardless of whether the patient withdraws from randomised 
therapy or receives another anti-cancer therapy prior to symptom deterioration.  In addition, if 
a patient either meets the criteria for deterioration after 2 or more missed HRQL, then the 
patient will be censored at the time of the latest evaluable HRQL assessment. These patients 
will be presented as “Censored FACT-P TOI Score” in summaries.


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A number of situations will lead to a patient’s time to deterioration of HRQL endpoints being 
censored.  These are:
!
Patients who have not met the criteria for symptom deterioration or died at the time 
of analysis will be censored at the time of the latest evaluable HRQL assessment:
%
The censoring date will be the date of the last assessment that led to evaluable 
being assigned for FACT-P TOI. These patients will be presented as alive and 
deterioration-free in summaries.
%
Patients with no evaluable baseline or post-baseline data will be censored at 
Day 1 unless they die within 2 visits of baseline. These patients will be 
presented as alive and deterioration-free in summaries.
!
Patients whose baseline subscale score is close to the minimum possible
%
For patients whose baseline score is less than the threshold needed for 
worsening (e.g., a baseline FACT-P TOI of < 6), time to deterioration will be 
censored at Day 1 unless they die within 2 visits of baseline. Patients who 
haven’t died will be presented as “Censored FACT-P TOI Score” in 
summaries.
The time to deterioration of HRQL will be derived based on assessment dates, not visit dates, 
unless the subject is too affected by symptoms of disease under investigation, in which case 
there are no assessment dates and visit dates will be used.
PRO Compliance
Summary measures of overall compliance and compliance over time will be derived for the 
FACT-P. These will be based upon:
•
Received forms = number of FACT-P forms received back plus the number not
received back where the reason was ‘Subject too heavily affected by symptoms of 
disease under investigation’.
•
Expected forms = number of patients still under HRQL follow-up at the specified 
assessment time excluding patients in countries with no available translation. For 
patients that have progressed, the latest of progression and safety follow-up will be 
used to assess whether the patient is still under HRQL follow-up at the specified 
assessment time. Date of study discontinuation will be mapped to the nearest visit date 
to define the number of expected forms.
•
Evaluable forms = subset of expected FACT-P forms with at least one subscale that 
can be determined; or where REVPRDI form is ticked ‘Subject too affected by 
symptoms of disease under investigation’.


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Thus the overall compliance rate is defined as number of patients with an evaluable baseline 
and at least one evaluable follow-up form (as defined above), divided by the number of 
patients expected to have completed at least a baseline FACT-P form. 
Compliance over time will be calculated separately for each visit, including baseline, as the 
number of patients with an evaluable form at the time point (as defined above), divided by 
number of patients still expected to complete forms at that visit. Similarly the evaluability rate 
over time will be calculated separately for each visit, including baseline, as the number of 
evaluable forms (per definition above), divided by the number of received forms.
3.8.1.2
Brief Pain Inventory – short form (BPI-SF)
The BPI-SF will be used to assess the impact of pain on daily life.  Worst pain, general pain 
and pain’s interference with daily life will be assessed during Part B of the study at baseline, 
Week 4, 8 and 12 and then continue to be administered to all patients (who have not 
withdrawn consent) every 12 weeks.
The BPI-SF comprises a total of 15 items measuring 2 domains: pain severity and pain 
interference.  Items measuring pain severity (including ‘worst pain’) are rated on an 11-point 
numerical rating scale (NRS) ranging from 0=No pain to 10=Pain as bad as you can imagine.  
All BPI-SF items are measured using a 24-hour recall period.
The following outcome measure will be calculated for the BPI-SF:
!
Pain severity (Questions 3, 4, 5 and 6)
!
Pain Interference (Question 9 A-G)
Note that the database contains an item number in addition to the Question number.  For each 
outcome measure the mean score of non-missing items will be calculated.  For pain 
interference at least 50% of the items must have a response for a mean score to be calculated.  
The individual responses to the questions comprising the pain severity domain will also be 
summarised.
Absolute change in the BPI-SF pain and pain interference scores will be calculated as change 
from baseline at each clinic visit.
Time to deterioration in BPI-SF
Time to deterioration (or worsening of pain) is defined as the time from the date of 
randomisation to the date of first assessment of worsening of pain, or death from any cause (as 
long as the death occurs within 2 BPI-SF assessment visits of the last evaluable assessment of 
BPI-SF and regardless of whether the patient withdraws from study treatment or receives 
another anti-cancer therapy). “Subject too heavily affected by symptoms of disease under 
investigation” answered as the reason for not completing HRQL at a post-baseline visit will 
also signify a clinically important deterioration in BPI-SF. Worsening of pain is defined as an 
increase in worst pain BPI-SF score by at least 2 points on the 0 to 10 scale.


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Note, under the same principles applied to time to deterioration for FACT-P, time to 
deterioration in BPI-SF will be derived regardless of whether the patient withdraws from 
randomised therapy or receives another anti-cancer therapy prior to symptom deterioration.  In 
addition, if a patient either meets the criteria for deterioration, or dies after 2 or more missed 
HRQL assessments, then the patient will be censored at the time of the latest evaluable HRQL 
assessment. These patients will be presented as “Censored BPI-SF Worst Pain Score” or 
“Censored Death” in summaries.
A number of situations will lead to a patient’s time to deterioration of HRQL endpoints being 
censored.  These are:
!
Patients who have not met the criteria for symptom deterioration or have not died at 
the time of analysis will be censored at the time of the latest evaluable HRQL 
assessment:
%
The censoring date will be the date of the last assessment that led to evaluable 
being assigned for BPI-SF. These patients will be presented as alive and 
deterioration-free in summaries.
%
Patients with no evaluable baseline or post-baseline data will be censored at 
Day 1 unless they die within 2 visits of baseline. These patients will be 
presented as alive and deterioration-free in summaries.
The time to deterioration of HRQL will be derived based on assessment dates, not visit dates, 
unless the subject is too affected by symptoms of disease under investigation, in which case 
there are no assessment dates and visit dates will be used.
PRO Compliance
Summary measures of overall compliance and compliance over time will be derived for the 
BPI-SF. These will be based upon the compliance derivations described for FACT-P.
3.8.1.3
Bone pain item
The bone pain item is an individual question asking patients to rate their worst bone pain 
severity on a 0 to 10 point scale.  This will be summarised as captured on the eCRF.  Absolute 
change in the worst bone pain item will be calculated as change from baseline at each clinic 
visit.
Time to deterioration in bone pain item
Time to deterioration (or worsening of bone pain) is defined as the time from the date of 
randomisation to the date of first assessment of worsening of bone pain, or death from any 
cause (as long as the death occurs within 2 PRO assessment visits of the last evaluable 
assessment of worst bone pain and regardless of whether the patient withdraws from study 
treatment or receives another anti-cancer therapy). “Subject too heavily affected by symptoms 
of disease under investigation” answered as the reason for not completing HRQL at a post-


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baseline visit will also signify a clinically important deterioration in bone pain. Worsening of 
bone pain is defined as an increase in worst bone pain score by at least 2 points.
Note, under the same principles applied to time to deterioration for FACT-P, time to 
deterioration in bone pain will be derived regardless of whether the patient withdraws from 
randomised therapy or receives another anti-cancer therapy prior to symptom deterioration.  In 
addition, if a patient either meets the criteria for deterioration, or dies after 2 or more missed 
HRQL, then the patient will be censored at the time of the latest evaluable HRQL assessment. 
These patients will be presented as “Censored Worst Bone Pain Score” or “Censored Death” 
in summaries.
A number of situations will lead to a patient’s time to deterioration of HRQL endpoints being 
censored.  These are:
!
Patients who have not met the criteria for symptom deterioration or died at the time 
of analysis will be censored at the time of the latest evaluable HRQL assessment:
%
The censoring date will be the date of the last assessment that led to evaluable 
being assigned for bone pain. These patients will be presented as alive and 
deterioration-free in summaries.
%
Patients with no evaluable baseline or post-baseline data will be censored at 
Day 1 unless they die within 2 visits of baseline. These patients will be 
presented as alive and deterioration-free in summaries.
The time to deterioration of HRQL will be derived based on assessment dates, not visit dates, 
unless the subject is too affected by symptoms of disease under investigation, in which case 
there are no assessment dates and visit dates will be used.
PRO Compliance
Summary measures of overall compliance and compliance over time will be derived for the 
bone pain item. These will be based upon the compliance derivations described for FACT-P.
3.8.2
Health economics
3.8.2.1
Utilities: EQ-5D-5L
The euroqol-5 dimensions, five level (EQ-5D-5L) index comprises 5 dimensions of health 
(mobility, self-care, usual activities, pain/discomfort and anxiety/depression). For each 
dimension, respondents select which statement best describes their health on that day from a 
possible 5 options of increasing levels of severity (no problems, slight problems, moderate 
problems, severe problems and unable to/ extreme problems). A unique EQ-5D health state is 
referred to by a 5-digit code allowing for a total of 3125 health states.  For example, state 
11111 indicates no problems on any of the 5 dimensions. These data will be converted into a 
weighted health state index by applying scores from EQ-5D value sets elicited from general 
population samples (the base case will be the UK valuation set, with other country value sets 
applied in scenario analyses). Where values sets are not available, the EQ-5D-5L to EQ-5D-


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3L crosswalk will be applied. In addition to the descriptive system, respondents also assess 
their health today on a visual analogue scale, ranging from 0 (worst imaginable health) to 100 
(best imaginable health). This score is reported separately. The evaluable population will 
comprise the full analysis set.
The proportion of patients with each score for each item may be summarised for each time 
point and by treatment allocation.
Further Payer required analyses such as mapping quality of life instruments unto utilities will 
be described in detail in the Payer analysis plan.
3.8.2.2
Resource use
Resource use will be analysed from procedures captured on the ‘Oncology Hospital 
Admission’ form and the standard concomitant medication eCRF, and, where required, 
supplemented with data on hospitalisation length of stay logged as part of SAE recording.  
Frequency of palliative interventions and the reasons for the intervention will be estimated 
from the ‘Oncology Hospital Admission’ form. The evaluable population will comprise the 
full analysis set. The analysis will be conducted on blinded data. 
Further Payer required analyses involving resource use will be described in detail in the Payer 
analysis plan.
4.
ANALYSIS METHODS
4.1
General principles
The DCO date for the statistical analysis for the primary objective of the study will be 
established when ~100 confirmed progression events are expected to have occurred.
The study will be centrally unblinded after database lock, but patients and Investigators will 
remain blinded. As per the protocol (Section 6.3.5), after the primary rPFS analysis, patients 
who are still receiving olaparib can either choose to discontinue from the study or, where the 
Investigator believes patients are gaining clinical benefit, patients may continue to receive
olaparib. All patients will receive follow-up care in accordance with standard local clinical 
practice. Patients that are on placebo will not be offered olaparib as a study treatment.
Serious adverse events will continue to be reported to AstraZeneca Patient Safety Department,
for any patients who continue on olaparib until 30 days after study treatment is discontinued,
in accordance with protocol Section 6.4.4. Additionally, as stated, any SAE or non-serious AE 
that is ongoing at the end of the study must be followed up to resolution unless the event is
considered by the Investigator to be unlikely to resolve, or the patient is lost to follow-up. If
an Investigator learns of any SAEs, including death, at any time after a patient has completed
the study, and he/she considers there is a reasonable possibility that the event is causally
related to the investigational product, the Investigator should notify AstraZeneca, Patient
Safety.


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Study day will be calculated as follows:
Days prior to first dose: Study day = date – first dose date.
Days on or after first dose: Study day = date – first dose date + 1.
Where month is derived, days will be divided by 30.4375.
In general, missing data will not be imputed.  For the date variables of historical data (i.e., any 
data referring to the period prior to the informed consent date), if the year is missing then the 
value will not be imputed.  If the month or day is missing, the value will be imputed: month 
will be imputed with June; day will be imputed as 15th.
Efficacy data will be summarised and analysed on the full analysis set.  Safety data will be 
summarised and analysed on the respective safety population.
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of study treatment.
All descriptive statistics will be presented by treatment group.  Continuous variables will be 
summarised by the number of observations, mean, standard deviation, median, minimum, and 
maximum.  Categorical variables will be summarised by frequency counts and percentages for 
each category.  Unless otherwise stated, percentages will be calculated out of the population 
total for the corresponding treatment group.
Data for exploratory PRO endpoints will be analysed descriptively on an ITT basis. For PRO 
endpoints, data will be presented in terms of minimum, maximum, mean, standard deviation 
and median scores together with 95% confidence interval (CIs) at each visit as well as change 
from baseline to end of treatment.
4.2
Analysis methods
4.2.1
Multiplicity
In order to describe the nature of the benefits of olaparib treatment, rPFS, PFS2, TFST, TSST, 
radiological ORR, soft tissue ORR, time to deterioration in FACT-P TOI and OS will be 
tested at a 1-sided significance level of 2.5%.
However if strong results are observed for the primary analysis (rPFS 1-sided p-value < 0.025) 
then a multiple testing strategy will be implemented in order to describe the nature of the 
benefits of olaparib treatment.
In order to strongly control the type I error at 2.5% 1-sided, the multiple testing procedure will 
be employed across the primary endpoint and secondary endpoints intended for key label 
claims (i.e. PFS2 and OS).  There is no requirement to adjust for multiplicity due to rPFS 


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interim analyses, since there are no planned interim rPFS analyses with the opportunity to 
make an early claim of efficacy.
A hierarchical testing strategy will be employed where rPFS is tested first using the full test 
mass (full test mass = alpha) and key secondary endpoints of PFS2 and OS will then be tested 
using a multiple testing procedure (MTP) with a recycling strategy (i.e., the MTP will recycle 
the test mass to the endpoint not yet rejected in the hierarchy outlined in Figure 1).
Figure 1
Multiple Testing Procedure
PFS2 will only be tested if statistical significance is shown for rPFS. OS will only be tested if 
the null hypothesis (of no difference) is rejected for PFS2. 
All planned analyses will be performed, regardless of the outcome of the MTP. If the full test 
mass has been used on an earlier test in the MTP, any claims regarding the statistical 
significance of a subsequent analysis in the MTP will be affected. Both PFS2 and OS will be 
tested at the time of the primary analyses of rPFS.
4.2.2
Analysis of the primary efficacy variable (rPFS)
The primary endpoint of Part B is rPFS (months). Once approximately 100 progression events 
have occurred, the primary analysis will be performed.  Radiological progression-free survival 
will be analysed using the log rank test.  The HR 80% CI and 95% CI will be estimated from 
the U and V statistics obtained directly from PROC LIFETEST in SAS (as below) using the 
Breslow approach for handling ties. A HR less than 1 will favour olaparib.
The HR and its confidence intervals will be estimated from the log-rank test as follows (Berry 
et al 1991, Sellke et al 1983):
HR = exp(U/V)
80% CI for HR = (exp{U/V – 1.28/√V}, exp{U/V + 1.28/√V})
95% CI for HR = (exp{U/V – 1.96/√V}, exp{U/V + 1.96/√V})


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Where U=Σi(d1i-e1i) is the log-rank test statistic (with d1i and e1i the observed and expected 
events in group 1) and √V the standard deviation of the log-rank test statistic as produced in 
the LIFETEST output. The syntax for running LIFETEST is as follows.
PROC LIFETEST DATA=XXX METHOD=KM;
  ODS OUTPUT LOGUNICHISQ=XX;
  TIME TIMEVAR*CENSORED(1);
  TEST TREAT; 
RUN;
In addition, a one-sided p-value will be calculated to test the hypothesis of HR<1 (olaparib
improves survival) versus the hull hypothesis of HR=1(no treatment effect). The one-sided p-
value will be found using a Z-score test statistic calculated as Z =log(HR)/SE(log(HR)) which 
equates to Z=(U/V)/(1/√V)=U/√V.
Kaplan-Meier survival curves (product-limit estimates) of rPFS will be presented by treatment 
group, together with a summary of associated statistics (median rPFS time, and 6-, 12-, 18-, 
24-month survival rate estimates).  Summaries of the number and percentage of patients 
experiencing a rPFS event, and the type of event (RECIST progression, PCWG-2 progression, 
both or death) will also be presented.
Listings of rPFS per patient will be produced.
The assumption of proportionality will be assessed.  Note that in the presence of 
non-proportionality, the HR will be interpreted as an average HR over the observed extent of 
follow-up.  Proportionality will be tested firstly by examining plots of complementary log-log 
(event times) versus log (time) and, if these raise concerns, a time-dependent covariate would 
be fitted into the Cox proportional hazards model with treatment factor to assess the extent to 
which this represents random variation.
Separate log rank tests comparing rPFS between treatments in following subsets of the full 
analysis set based on key baseline demographics and disease characteristics (e.g. Age, Race, 
ECOG) as well as ATM, BRCA, composite BRCA/ATM, and composite HRR mutation 
categories (Sections 3.7.3, 3.7.4, 3.7.5, and 3.7.6). The listed gene mutation statuses will be 
aggregated to the Detected and the Other subgroups, where the latter pools together: Not 
Detected, VUS, Failed, and Status Unknown subtypes. The HRR mutation status will be 
aggregated to the Detected, Not Detected, and Unknown subgroups, where the last category 
pools together VUS, Failed, and Status Unknown subtypes. The results will be presented on a 
forest plot. If there are too few events available for a meaningful subgroup analysis (it is not 
considered appropriate to present analyses with less than 5 events within each treatment arm 
within the subgroup), only descriptive statistics will be provided along with the number (%) of 
patients and events.
The primary rPFS analysis will also be repeated for patients who had not responded to 
treatment with abiraterone by Week 12 (Visit 5), a non-responder is defined as in Section 


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3.7.1.1. Patients who had responded to treatment at this time will be excluded from the 
analysis.
Summaries of the number and percentage of patients who miss two or more consecutive 
disease assessments (RECIST & bone) and the number of patients who miss one disease 
assessment (RECIST & bone) will be presented for each treatment group.
In addition, duration of follow-up will be summarised using medians:
!
In censored (not died) patients only: Time from randomisation to date of censoring 
(date last known to be alive)
!
In all patients: Time from randomisation to the date of death or to the date of 
censoring for censored patients.
For the subset of patients who have measureable disease at baseline, summary statistics for the 
change from baseline in the sum of the target lesion LDs will be presented.  
Additionally, summaries will be provided showing the reason for progression, i.e. new lesion, 
progression of target lesions, progression of non-target lesions or a combination of these.  The 
reasons will be summarised separately for patients with RECIST only progressions and those 
with bone and RECIST progressions.
Summary statistics for the number of months between rPFS time and the last evaluable 
assessment prior to progression will be presented for each treatment group for subjects who 
have progressed.
4.2.2.1
Sensitivity analyses
To assess the sensitivity of the primary rPFS analysis, the following supportive analyses will 
be performed:
!
To assess time evaluation bias (i.e., differential assessment times between treatment 
groups), the primary rPFS analysis, will be repeated, but using the midpoint 
between the time that progression was detected (as calculated for the primary 
endpoint) and the previous evaluable assessment (RECIST or PCWG-2).  
!
To assess attrition bias, the primary rPFS analysis will be repeated, but the actual 
rPFS event times, rather than the censored times, of patients who progressed or died 
in the absence of progression immediately following 2, or more, NE tumour 
assessments will be included.  In addition, patients who take subsequent therapy 
prior to progression or death will be censored at their last evaluable assessment 
prior to taking the subsequent therapy. 
!
To assess censoring bias, a Kaplan-Meier plot of the time to censoring will be 
produced, where the censoring indicator of the primary rPFS analysis is reversed.


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!
An analysis excluding patients with deviations that may affect the efficacy of the 
trial therapy will be performed if > 10% of patients:
o
did not have the intended disease or indication or
o
did not receive any randomised therapy
Using the same methodology as described for the primary analysis of rPFS.  The 
HR and its corresponding 80% and 95% CI will be presented.
!
The primary rPFS analysis will be repeated using only PCWG-2 progression events 
to address any possible bias introduced as a result of including any soft tissue 
progressions as assessed by RECIST 1.1 in the primary definition of rPFS. 
4.2.3
Analysis of the secondary outcome variables
4.2.3.1
Time to second progression (PFS2)
The secondary endpoint of PFS2 (months) will be analysed using the same time-to analysis as 
rPFS: log rank test, Kaplan-Meier and summaries of associated statistics (median second 
progression time, and 6-, 12-, 18-, 24-month survival rate estimates).
The type of progression event will also be summarised by treatment group.
4.2.3.2
Overall survival (OS)
The secondary efficacy endpoint for Part B, OS (months), will be performed at the time of the 
analysis of rPFS when approximately 60% of patients have died; patients who have not died at 
that point will be censored.  Overall survival will be analysed using the same approach as for 
rPFS: log rank test, Kaplan-Meier and summaries of associated statistics (median second 
progression time, and 6-, 12-, 18-, 24-month survival rate estimates). A listing of OS time per
patient will also be produced.
4.2.3.3
Objective response rate (ORR) and associated variables
The secondary efficacy endpoint for Part B, ORR for soft tissue disease response and overall 
radiological response, will be performed at the time of the rPFS analysis. A summary of ORR 
will be presented by treatment group.  Objective response rate will be formally analysed for 
both soft tissue ORR and overall radiological ORR using logistic regression, with treatment 
group as a factor.  The effect of treatment will be estimated using the adjusted odds ratio and 
its corresponding 80% CIs and 95% CIs. Only patients with measurable disease (target lesions) 
at baseline will be included in the analysis
The other associated endpoints (best overall soft tissue disease response, best overall 
radiological response, DOR, time to response) will be summarised only.
Best objective response (soft tissue disease and overall radiological response) at each 
scheduled visit will be summarised. 


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4.2.3.4
Time to first subsequent therapy or death (TFST) and time to second 
subsequent therapy or death (TSST)
TFST and TSST will be analysed at the same time as the primary analysis of rPFS using the 
same methodology and model. Patients who did not receive randomised treatment will be 
censored on the date of randomisation. The HRs for the treatment effect together with 80% 
and 95% CIs will be presented.  Kaplan-Meier plots will be presented by treatment arm. 
Summary tables of first and second subsequent therapies event type by treatment arm will be 
provided.
A listing of TFST and TSST, per patient, will also be produced. 
Relevant parametric analyses of time to event endpoints required for Payer reimbursement 
submissions will be outlined in a separate Payer analysis plan.
4.2.4
Tolerability and safety
Summaries will be presented for scheduled visits only.  Any unscheduled assessments will be 
listed.  The baseline value is defined as the latest result obtained prior to the start of IP.
4.2.4.1
Adverse events (AE)
Adverse events will be summarised separately for Parts A and B of the study, and also by dose 
for AEs occurring within Part A.
All AEs, both in terms of MedDRA preferred term and CTCAE grade, will be listed and 
summarised descriptively by count (n) and percentage (%) and dose (Part A) or treatment 
group (Part B). MedDRA dictionary will be used for coding.  Any AE occurring before 
olaparib/placebo treatment (i.e., before Study Day 1) will be included in the AE listings, but 
will not be included in the summary tables (unless otherwise stated).  These will be referred to 
as ‘pre-treatment’.
An overall summary of the number and percentage of patients in each category will be 
presented for Parts A and B and an overall summary of the number of episodes in each 
category will be presented for Part B only.
Frequencies and percentages of patients reporting each preferred term will be presented for
Part B only. Total number of events will also be reported separately. 
All reported AEs will be included in listings along with the date of onset, date of resolution (if 
AE is resolved), investigator’s assessment of severity and relationship to study drug.  
Summary information (the number and percent of patients by treatment) will be tabulated for:
!
All AEs 
!
All AEs causally related to olaparib/placebo


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!
AEs with CTCAE grade 3 or higher
!
AEs with CTCAE grade 3 or higher, causally related to olaparib/placebo
!
AEs with outcome of death
!
AEs with outcome of death causally related to olaparib/placebo
!
All SAEs
!
All SAEs causally related to olaparib/placebo 
!
AEs leading to discontinuation of olaparib/placebo
!
AEs leading to discontinuation of olaparib, causally related to olaparib/placebo
!
Other significant AEs
!
Other significant AEs causally related to olaparib/placebo
Key patient information tables will be produced for:
!
AEs causally related to olaparib
!
AEs with outcome of death
!
All SAEs
!
AEs leading to discontinuation of olaparib/placebo
!
Other significant AEs
In addition, a truncated AE table of most common AEs, showing all events that occur in at 
least 5% of patients overall will be summarised by preferred term, by decreasing frequency for 
Part B only.  This cut-off may be modified after review of the data.
For Part B, each AE event rate (per 1000 patient years) will also be summarised by preferred 
term within each system organ class.  For each preferred term, the event rate will be presented 
and will be defined as the number of patients with that AE divided by the sum of the duration 
of therapy (for patients without the event) and the time to the AE (for patients with the event) 
in each group multiplied by 1000.
Adverse events will be assigned CTCAE grades (National Cancer Institute CTCAE version
4.0) and summaries of the number and percentage of patients will be provided by maximum 
reported CTCAE grade, SOC, preferred term and actual treatment group. Fluctuations 
observed in CTCAE grades during study will be listed.


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Adverse events with CTCAE grade 3 or higher will be summarised as the number and 
percentage of patients by SOC, preferred term and actual treatment group for Part B only.
Causally related adverse events will be summarised as the number and percentage of patients 
by SOC, preferred term and actual treatment group for Part B only.
Causally related adverse events of CTCAE grade 3 or higher will be summarised for the 
number and percentage of patients by SOC, preferred term and actual treatment group for Part 
B only.
Summaries of the number and percentage of patients with AEs leading to dose change of 
olaparib/placebo and also dose interruptions of olaparib/placebo will be presented by preferred 
term and treatment group for Part B only.  
Summaries of the number and percentage of patients with AEs which started prior to first dose 
or > 30 days following date of last dose will be presented by preferred terms and treatment 
group for Part B only.
A summary of deaths will be provided with number and percentage of patients by study part 
and actual treatment group (Part B), categorised as:
!
Related to disease under investigation
!
AE outcome=death
!
Both related to disease under investigation and with AE outcome=death
!
Unrelated to AE or disease under investigation
!
Deaths ≥ 30 days after last treatment dose, related to disease under investigation
!
AE with outcome=death ≥30 days after last treatment dose
!
Deaths ≥ 30 days after last treatment dose, related to AE or disease under 
investigation
!
Deaths ≥ 30 days after last treatment dose, unrelated to AE or disease under 
investigation
!
Patients with unknown reason for death, and
!
Other deaths (not captured above).
Causally related adverse events with an outcome of death will be summarised for the number 
and percentage of patients by SOC, preferred term and actual treatment group for Part B only.


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Causally related serious adverse events will be summarised for the number and percentage of 
patients by SOC, preferred term and actual treatment group for Parts A and B.
Adverse events leading to discontinuation of olaparib/placebo will be summarised for the 
number and percentage of patients by SOC, preferred term and actual treatment group for Part 
B only.
Causally related adverse events leading to discontinuation of olaparib/placebo will be 
summarised for the number and percentage of patients by SOC, preferred term and actual 
treatment group for Part B only.
In addition, AEs with outcome of death, SAEs, OAEs, AEs leading to discontinuation of 
treatment and AEs causally related to olaparib/placebo will be listed in key patient 
information tables for Parts A and B. 
Listings of AE data will also be produced for Parts A and B.
Summary of long term tolerability
For Part B only, to assess long term tolerability, prevalence plots, life table plots and 
cumulative incidence plots will be presented for:
!
Nausea
!
Vomiting
!
Any other events considered important after review of the safety data, provided 
there are ≥10 events.
A prevalence plot provides information on the extent to which the events may be an ongoing 
burden to patients.  The prevalence at time t after first dose of study treatment is calculated as 
the number of patients experiencing the event divided by the number of patients receiving 
study treatment or in safety follow-up at time t; generally, t is categorised by each day after 
dosing.  The prevalence is plotted over time split by treatment group.  Multiple occurrences of 
the same event are considered for each patient but a patient is only counted in the numerator 
whilst they are experiencing one of the occurrences of the event.
For each AE, median time to first onset of the AE will be presented for patients in the safety 
analysis set by actual treatment group.  Patients who did not experience the AE will be 
censored at the end of their safety follow-up.  Summary tables of time to first onset for each 
AE will also be produced (e.g. 1-28 days, 29-56 days, 57-84 days, 85-112 days, >112 days).  
Median duration of the AE will be presented for patients who experienced each AE.
A life table plot can be used to describe the time to onset of the event and specifically when 
patients are at most risk of first experiencing the event.  The hazard, or in other words, the 
probability of having an AE in a specified time period (e.g. 0-1 months, 1-3 months, 3-6 


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months, etc.) given that the patient reaches that time period without having an event is plotted 
for each time period split by treatment.
A cumulative incidence plot is a plot of the raw cumulative incidence and cumulative 
incidence function over time with the treatment groups presented on separate plots.  The raw 
cumulative incidence is the actual probability that a patient will have experienced their first 
occurrence of the event by a given time point.  The cumulative incidence function estimates 
the cumulative incidence if the DCO had not been imposed and all patients had completed 
safety follow-up (O’Neill 1987).
4.2.4.2
Dose-limiting toxicities
The incidence of DLTs will be summarised by treatment cohort for Part A.
4.2.4.3
Exposure and compliance
Listings and summaries of exposure, actual exposure, and compliance will be produced for 
olaparib and abiraterone, by treatment cohorts, for Part A and treatment groups in Part B. RDI, 
PID will also be summarised, but not listed.
Compliance for olaparib will be derived as per section 3.5.7 details. Compliance for 
abiraterone will be summarised using the eCRF measurement ‘Study drug administered 
according to protocol’.
The number of patients with study drug interruptions or reductions for olaparib/placebo, and 
the reasons, will be summarised by treatment group for Part B only. These data will also be 
listed.
Treatment duration will be summarised. Treatment duration is based on the dates of first and 
last dose.
For patients on study treatment at the time of the rPFS analysis, the DCO date will be used to 
calculate exposure.
4.2.4.4
Laboratory data
Laboratory data (clinical chemistry and haematology) will be summarised. Laboratory data 
will be summarised separately for Parts A and B by dose group and by study day.
For all continuous laboratory assessments, absolute value, change from baseline and 
percentage change from baseline will be summarised using descriptive statistics at each 
scheduled assessment time by actual treatment group.  For categorical laboratory assessments, 
shift from baseline will be summarised using frequency and proportion at each scheduled 
assessment time by actual treatment group.
Shift tables for laboratory values by worst CTCAE grade will be produced, within each part of 
the study and overall, and for specific parameters separate shift tables indicating hyper- and 
hypo- directionality of change will be produced.  For parameters with no CTCAE grading, 


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shift tables from baseline to worst value on-treatment will be provided (i.e., on-treatment is 
defined as data collected up until the last dose of olaparib/placebo).  A scatter plot of ALT 
versus total bilirubin, both expressed as multiples of upper limit of normal range, will be 
produced. The scatter plot will be repeated for AST versus total bilirubin.
Liver biochemistry test results over time for patients with elevated ALT or AST, and elevated 
total bilirubin (at any time) will be plotted for Part B only.  
Box-plots of change from baseline will be presented.
All laboratory summaries will be presented by actual treatment group.
4.2.4.5
Concomitant medications
Concomitant medications will be summarised by the coded terms.  Astra Zeneca drug 
dictionary (AZDD)  will be used for concomitant medication coding.  The number of patients 
receiving a medication will be summarised overall and for each part of the study.  A 
medication taken during the course of the study is considered concomitant. A patient is only 
counted once if receiving the medication more than once.  Allowed and disallowed 
medications will be summarised separately with allowed concomitant medications 
summarised for Part B only.
4.2.4.6
Vital signs
Vital signs, including BP (mmHg), heart rate (beats/min) and body temperature (°C) actual 
values and change from baseline values, will be summarised separately for Parts A and B by 
dose group and by study day. Vital signs will be summarised at baseline and each scheduled 
visit. The baseline value is the last pre-dose assessment. Descriptive statistics will include 
number of non-missing patients (n), mean, standard deviation, median, first and third quartiles 
(Q1 and Q3), minimum and maximum.
Box-plots of absolute values by study day by treatment group, and change from baseline by 
study day by treatment group will also be produced for pulse rate, systolic BP, diastolic BP 
and temperature for Part B only.
4.2.5
Biomarkers
All Biomarkers analysis will be performed for Part B only.
!
Proportion of patients achieving a PSA response (single visit response and also a 
confirmed response) with 80% CIs and best percentage change from baseline values 
will be presented.
!
PSA absolute change and percentage change from baseline values will be presented.
!
CTC change from baseline values will be presented.


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!
Proportion of patients achieving a CTC conversion with 80% CIs and best change 
from baseline will be presented.
4.2.6
Patient reported outcomes (PRO) and HRQL
The analysis population for HRQL data will be the subset of the FAS (ITT) set.
4.2.6.1
FACT-P
Summary statistics for FACT-P score will be presented by treatment group (including means, 
standard deviation, median and range) for all visits until there are less than one third of 
patients with evaluable data.  
Time to FACT-P deterioration will be analysed using the same methodology and model as 
described for the primary analysis of rPFS.  However sensitivity analyses will not be 
performed.
FACT-P improvement rates will be analysed using a logistic regression model with treatment 
group as a factor.  If the overall response rate is < 5%, no analysis will be performed.  (Note 
that if the response rate in only one of the treatment groups is < 5% but ≥ 5% in the other 
treatment group then the analysis will still be performed). If the expected response rate is low 
(< 20%) a Fisher’s exact test will be considered and mid p-values used.
The results of the analysis will be presented in terms of an odds ratio together with its 
associated profile likelihood CIs and p-values (based on twice the change in log-likelihood 
resulting from the addition of a treatment factor to the model).
FACT-P compliance (overall compliance and by visit compliance) will be summarised for 
each treatment group.
Descriptive statistics will be reported for the FACT-P by visits as well as change in these 
scores from baseline.  These will also be reported for PWB, FWB, PCS and the individual 
items for PCS.  Summary tables of FACT-P best change rates (improvement, worsening, and 
no change) will be provided.
Supportive analyses
Supportive analyses will be performed for the FACT-P total score, and scales (TOI, FAPSI-6)
for both improvement rates, time to deterioration and best change rates (best overall response). 
Compliance will be analysed for the FACT-P total only.   
Change from baseline in the FACT-P total score, and scales (TOI, FAPSI-6) will be analysed 
using a mixed model for repeated measures (MMRM) analysis of all the post-baseline FACT-
P (or equivalent) scores for each visit. The study discontinuation visit and the safety follow-up 
visit will be excluded from this analysis. Restricted maximum likelihood (REML) estimation 
will be used. The model will include treatment, visit and treatment by visit interaction as 
explanatory variables and the baseline FACT-P total score as a covariate, along with the
baseline FACT-P total score by visit interaction. Treatment, visit, treatment by visit 


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interaction, baseline FACT-P total score, and the baseline FACT-P score by visit interaction
will be fixed effects in the model. The treatment by visit interaction will remain in the model 
regardless of significance.
An unstructured covariance matrix will be used to model the within-subject error and the 
Kenward-Roger approximation will be used to estimate the degrees of freedom. The following
provides sample code for implementing the MMRM analysis:
proc mixed data= FACTP method = reml;
class TRT VISIT SUBJECT;
model CHBL = TRT VISIT TRT*VISIT BL BL*VISIT / s ddfm=kr;
repeated VISIT / type=UN subject=SUBJECT;
lsmeans TRT / at means pdiff diff alpha=0.05 cl;
where TRT is the randomised treatment, VISIT is the visit, CHBL is the change from baseline 
in the FACT-P total score, and BL is the baseline FACT-P total score.
For the estimation of TRT*VISIT means an additional model will be run using all visits and 
the following lsmeans statement:
lsmeans TRT*VISIT / slice=VISIT pdiff diff alpha=0.05 cl;
If the fit of the unstructured covariance structure fails to converge, the following covariance 
structures will be tried in order until convergence is reached: Toeplitz with heterogeneity, 
autoregressive with heterogeneity, Toeplitz, and autoregressive.  
The adjusted mean estimates and corresponding 95% confidence intervals will be presented 
by visit for each treatment group.
The minimally important difference in score is ≥20%, ≥50% is an important difference and 
≥80% a large difference. 
4.2.6.2
BPI-SF
Summary statistics for BPI-SF pain severity scale and pain interference scale, means, standard
deviations, medians and ranges will be presented by treatment group for visits until there are 
less than 20% of patients with evaluable data. 
Analysis of time to deterioration, and change from baseline in the aforementioned BPI-SF 
scores will be carried out, as described for FACT-P in Section 4.2.7.1. Supportive analyses 
will also be repeated, including MMRM for the worst pain severity score (item nbr 3) and the 
total pain severity score (item numbers 3-6).
BPI-SF compliance (overall compliance and by visit compliance) will be summarised for each 
treatment group.


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4.2.6.3
Bone Pain
Summary statistics for mean bone pain score, standard deviation, median and range will be 
presented by treatment group for visits until there are less than 20% of patients with evaluable 
data. 
Analysis of time to deterioration, improvement rates and change from baseline in bone pain
score will be carried out as described for FACT-P in Section 4.2.7.1. Supportive analyses will
also be repeated, including MMRM.
Bone pain compliance (overall compliance and by visit compliance) will be summarised for 
each treatment group.
4.2.7
Health economics data
4.2.7.1
Utilities: EQ-5D-5L
Descriptive statistics will be reported for health state utility index values and visual analogue 
scale by visits as well as change in these scores from baseline.  To support future economic 
evaluations of olaparib, additional appropriate analyses may be undertaken, for example, 
mean health state utility pre- and post-treatment, and pre- and post-progression.  Further 
details will be outlined in the Payer analysis plan.
4.2.7.2
Resource use
An exploratory health economic analysis of the frequency of metastatic prostate cancer related 
palliative interventions, time to interventions, and reason for the intervention will be 
undertaken.  In addition, length of stay, intensive care unit (ICU) use, concomitant 
medications and analgesic use will be examined.
These analyses will examine the impact of disease and treatment on resource use to primarily 
support the economic evaluation of olaparib in castrate resistant metastatic prostate cancer.
4.2.8
Demographic data and baseline data
The following baseline characteristics will be listed for each patient and summarised for all 
patients in the safety analysis set (Part A) and the FAS (Part B) (unless otherwise specified):
The following collected data will be listed.
!
Patient disposition (including confirmed eligible (Part A)/randomised (Part B), 
received treatment and completed the study) 
!
Important deviations
!
Inclusion in analysis populations
!
Demographics (age, age group, race and ethnicity)


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!
Patient characteristics at baseline (height, weight, and body mass index (BMI) 
!
Patient recruitment by country and centre (presented for Part B only)
!
Previous disease related treatment modalities
!
Previous radiotherapy (tabulated for Part B only and not listed)
!
Disease characteristics at baseline (ECOG performance status at baseline, PSA at 
baseline, ATM mutation status at screening BRCA status, time since original 
diagnosis, histology type at diagnosis, tumour grade at diagnosis, AJCC stage at 
diagnosis and Gleason score at diagnosis)
!
Extent of disease
!
Time from prior disease progression to randomisation (Part B only)
!
Post-discontinuation disease-related anticancer therapy (Part B only)
!
Current signs and symptoms at baseline
!
Current and past medical history
!
Relevant surgical history (presented for Part B only and not listed)
!
Physical examination at baseline (presented for Part B only)
Patients who were unblinded (a) prior to disease progression and (b) prior to or on the day of 
treatment discontinuation will be summarised by treatment group and listed.
4.2.9
Statistical analysis of PK data
The PK analysis will be performed for Part A only.
PK descriptive statistics and precision of data for reporting
All plasma concentration data received for olaparib and abiraterone and all derived reportable 
PK parameters will be presented in data listings for the safety analysis set.  All plasma 
concentrations, Css,max and Css,min will be reported to the same precision as the source data (3 
significant figures).  All other PK parameters will be listed to 3 significant figures except for 
tss,max and tss,last which will be presented to 2 decimal places.
Reportable pharmacokinetic concentration and parameter summary data will be presented for 
patients in the PK analysis set.  Extra measurements (such as unscheduled or repeated 
assessments) will be included in the patient listings but will only be included in summary 
tables and figures if the extra measurement is used in the PK analysis e.g. if a repeat value is 
substituted for the original at the discretion of the PK scientist.


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The exclusion of any patients from the PK analysis set or from the analysis in a specific 
treatment period will be agreed by the study physician, statistician and PK Scientist during the 
data review meeting (DRM) held once all data is clean and final. Any data to be excluded 
from the PK analysis and/or summary tables and corresponding figures will be flagged with 
the reasons by the PK Scientist in the PK handover document and flagging file for 
programming and these data will be flagged in the listings and the appropriate footnotes 
added.
Quantitative PK variables for olaparib and abiraterone will be summarised using descriptive 
statistics by Cohort, Group and treatment period (Visit/Day)) (Cohort 2 Group 1 Visits 3 and 4 
and Cohort 2 Group 2 for olaparib and Cohort 2 Group 1 Visit 4 and Cohort 2 Group 2 Visits 
3 and 4 for abiraterone).
The PK parameters AUC, AUCss, AUC0-t, Css,max, and Css,min will present:
-
Number of observations (n)
-
Geometric mean (Gmean, calculated as exp[μ], where μ is the mean of the data on a
log scale)
-
Geometric coefficient of variation (%GCV, calculated as 100 √ [exp(s2)-1], where s is 
the standard deviation of the data on a log scale)
-
Arithmetic mean (Amean, calculated using non log-transformed data)
-
Standard Deviation (SD, using non log-transformed data)
-
%CV (using non log-transformed data)
-
Median
-
Minimum (min)
-
Maximum (max)
Plasma concentrations of olaparib and abiraterone at each time point will use the same 
summary statistics with the addition of n> LLOQ and Gmean error bars calculated as exp[μ ± 
s], where μ and s are the mean and standard deviation of the log-transformed data, 
respectively. These Gmean error bars will be labelled ‘Gmean +/- GSD’.
CLss/F will present only n, Amean, SD, %CV, median, min and max.
tss,maxand tss,last will present only n, median, min and max  
The descriptive statistics for all PK data will be presented to 4 significant figures except for 
min and max which will be presented to 3 significant figures and n and n>LLOQ which will 
be presented as a whole integer.
Reporting of plasma concentrations that are Below Limit of Quantification (BLQ) 
Individual olaparib and abiraterone concentrations below their Lower Limit of Quantification 
(LLOQ) of the bioanalytical assay will be reported as NQ (Not Quantifiable) in the listings 
with the LLOQ defined in the footnotes of the relevant TFLs. Individual plasma 
concentrations that are Not Reportable will be reported as NR and those that are missing will 


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be reported as NS (No Sample) in the listings. Plasma concentrations that are NQ, NR or NS 
will be handled as follows for the provision of descriptive statistics.
Descriptive Statistics 
• Any values reported as NR or NS will be excluded from the summary tables and 
figures.
• At a time point where less than or equal to 50% of the concentration values are NQ, 
all NQ values will be substituted with the LLOQ concentration, and all descriptive 
statistics will be calculated accordingly. 
• At a time point where more than half (but not all) of the values are NQ, the Gmean,
Gmean with range, %GCV, Amean, SD, and %CV will be set to NC. The maximum 
value will be reported from the individual data, and the minimum and median will be 
set to NQ. 
• If all concentrations are NQ at a time point, the Gmean, Amean, minimum, median 
and maximum will be reported as NQ, and the Gmean with range, %GCV, SD, and 
%CV will be reported as NC. 
• The number of values above LLOQ (n >LLOQ) will be reported for each time point 
together with the total number of collected values. 
Three observations > LLOQ are required as a minimum for a plasma concentration or PK 
parameter to be summarised. Two values are presented as a minimum and maximum with the 
other summary statistics as NC. For consistency, the same plasma concentration values are used in 
the mean data graphs as those given in the descriptive statistics summary table for each time point. 
Evaluation of DDI
A secondary objective of Part A of the study is to evaluate the presence of any drug 
interaction between olaparib and abiraterone by looking for any marked difference in steady 
state exposure when each is dosed in the presence and absence of the other. Css,max, AUCss and 
Css,min ratios will be calculated using non log-transformed parameter data for olaparib from 
Cohort 2 Group 1 patients (olaparib + abiraterone treatment : olaparib alone treatment) and for 
abiraterone from Cohort 2 Group 2 patients (abiraterone + olaparib treatment : abiraterone 
alone treatment). These PK parameter ratios will be summarised for each Group and displayed 
graphically. No formal statistical analysis of the PK data will be performed. The study was not 
sized to show statistically significant differences.
PK figures
The following PK figures will be provided:
!
Plot of individual steady state plasma concentrations (μg/ml) of olaparib versus time 
following 300mg twice daily dosing of olaparib – Cohort 2 – 1 semilogarithmic plot 
per subject for Group 1 Visits 3 and 4 and 1 semilogarithmic plot per subject for 
Group 2 Visit  4  (Safety Analysis Set)


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!
Plot of individual steady state plasma concentrations (μg/ml) of abiraterone versus 
time following 1000mg once daily dosing of abiraterone – Cohort 2 – 1 
semilogarithmic plot per subject for Group 1 Visit 4 and 1 semilogarithmic plot per 
subject for Group 2 Visits 3 and  4 (Safety Analysis Set)
!
Combined plot of individual steady state olaparib plasma concentrations (μg/mL) 
versus time following 300mg twice daily dosing of olaparib – Cohort 2 - 1 linear plot 
per treatment for Group 1 Visit 3, Group 1 Visit 4 and Group 2 Visit 4 (Safety 
Analysis Set)
!
Combined plot of individual steady state abiraterone plasma concentrations (ng/mL) 
versus time following 1000mg once daily dosing of abiraterone – Cohort 2 - 1 linear 
plot per treatment for Group 1 Visit 4 , Group 2 Visit 3 and Group 2 Visit 4 (Safety 
Analysis Set)
!
Plot of Gmean (+/- GSD) steady state olaparib plasma concentrations (μg/mL) vs time 
following 300mg twice daily dosing of olaparib – Cohort 2 – 1 semilogarithmic plot 
and 1 linear plot  (PK Analysis Set)
!
Plot of Gmean steady state olaparib plasma concentrations (μg/mL) vs time following 
300mg twice daily dosing of olaparib – Cohort 2 – 1 semilogarithmic plot (PK 
Analysis Set)
!
Plot of Gmean (+/- GSD) steady state abiraterone plasma concentrations (ng/mL) 
versus time following 1000mg once daily dosing of abiraterone – Cohort 2 – 1 
semilogarithmic plot and 1 linear plot  (PK Analysis Set)
!
Plot of Gmean steady state abiraterone plasma concentrations (ng/mL) versus time 
following 1000mg once daily dosing of abiraterone – Cohort 2 – 1 semilogarithmic 
plot (PK Analysis Set)
!
Line plots of individual and Gmean olaparib steady state pharmacokinetic parameters 
alone and in combination with abiraterone following 300mg twice daily dosing of 
olaparib – Cohort 2 Group 1 (PK Analysis Set)
!
Line plots of individual and Gmean abiraterone steady state pharmacokinetic 
parameters alone and in combination with olaparib following 1000mg once daily 
dosing of abiraterone – Cohort 2 Group 2 (PK Analysis Set)
!
Scatter plot for the individual and Gmean ratio of steady state pharmacokinetic 
parameters of olaparib in combination with abiraterone : alone (Visit 4:Visit 3) 
following 300mg twice daily dosing of olaparib – Cohort 2 Group 1 (PK Analysis Set)
!
Scatter plot for the individual and Gmean ratio of steady state pharmacokinetic 
parameters of abiraterone in combination with olaparib : alone (Visit 4:Visit 3) 


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following 1000mg once daily dosing of abiraterone – Cohort 2 Group 2 (PK Analysis 
Set)
5.
INTERIM ANALYSES (NOT APPLICABLE)
6.
CHANGES OF ANALYSIS FROM PROTOCOL
!
Changed the description of the log-rank test such that it does not suggest using a 
stratified log-rank test. The randomisation was not stratified and the primary 
analysis will not be stratified. Added 95% CI for HR to be reported. The 30-month 
survival rates will not be provided in the associated statistics.
!
Updated primary efficacy subgroup analysis plans by inclusion of the other (beside 
ATM, BRCA1/2) genes mutation statuses from the HRR group, and exclusion of 
ERG expression/fusion status. The minimum 20 endpoint events per subgroup/arm 
condition replaced with minimum 5 events.
!
The PTEN and AR marker factors were excluded from the current exploratory 
analysis. Any futures exploratory analysis and outcome variables were left yet to be 
defined. No exploratory analysis is planned to assess an impact from possible 
treatment switching on the OS adjustment.
!
For the PRO endpoints, the time to worsening will be analysed similar as in primary 
analysis, and not as planned with a Cox PH model.
!
In the PK analysis, the DDI ratio was changed from mono:combination to 
combination:mono for olaparib and abiraterone.
!
New category (‘Not applicable (NA)’) was added to the TLs and NTLs response 
outcomes. Weight (part of vital signs) levels were recorded at the baseline only.
7.
REFERENCES
Berry et al 1991
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8.
APPENDIX (NOT APPLICABLE)