Clinical trial NCT02987543
Conditions: Metastatic Castration-resistant Prostate Cancer
Keywords: metastatic castration-resistant prostate cancer (mCRPC) homologous recombination repair (HRR)
Sponsor: AstraZeneca
Start date: 2017-02-06; Completion date: 2023-02-15
Enrollment: 387 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of olaparib versus enzalutamide or abiraterone acetate in subjects with metastatic castration-resistant prostate cancer who have failed prior treatment with a new hormonal agent and have homologous recombination repair gene mutations.

Detailed description:
This is a prospective, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of olaparib versus enzalutamide or abiraterone in subjects with metastatic castration-resistant prostate cancer (mCRPC) who have failed prior treatment with a new hormonal agent (NHA) and have a qualifying tumor mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway. Subjects will be divided into two cohorts based on HRR gene mutation status.

Approximately 340 subjects will be randomized 2:1 (olaparib : investigator choice of enzalutamide or abiraterone acetate) into the trial.

Arms: arm 1: Olaparib is available as a film-coated tablet containing 150 mg or 100 mg of olaparib. Subjects will be administered study treatment orally at a dose of 300 mg twice daily (bid). The planned dose of 300 mg bid will be made up of two x 150 mg tablets twice daily, with 100 mg tablets used to manage dose reductions arm 2: Enzalutamide:

Enzalutamide is available as capsules or tablets containing 40 mg of enzalutamide. Subjects will be administered study treatment orally at a dose of 160 mg once daily.

Abiraterone acetate with prednisone: Abiraterone acetate is available as tablets containing 250 mg or 500 mg of abiraterone acetate. Subjects will be administered study treatment orally at a dose of 1,000 mg once daily in combination with prednisone 5 mg administered twice daily orally. Prednisolone is permitted for use instead of prednisone if necessary.
Interventions: intervention 1: olaparib intervention 2: enzalutamide intervention 3: abiraterone acetate intervention 4: abiraterone acetate intervention 5: enzalutamide
Intervention descriptions: intervention 1: 300 mg (2x 150 mg tablets) twice daily intervention 2: 160 mg (4 x 40 mg capsules) once daily intervention 3: 1,000 mg (4 x 250 mg tablets) once daily intervention 4: 1,000 mg (2 x 500 mg tablets) once daily intervention 5: 160 mg (4 x 40 mg tablets) once daily

Protocol documents:
Prot_005.pdf: 
 
 
Clinical Study Protocol (CSP), ANGEL 
Version 17.0 
Template Form Doc ID: LDMS_001_00026737 
Parent Doc ID: SOP AZDoc0018580 
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Clinical Study Protocol  
Drug Substance Olaparib 
Study Code 
D081DC00007 
Version 
4.0 
Date 
07 March 2019 
A Phase III, Open Label, Randomized Study to Assess the Efficacy and 
Safety of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone 
Acetate in Men with Metastatic Castration-Resistant Prostate Cancer Who 
Have Failed Prior Treatment with a New Hormonal Agent and Have 
Homologous Recombination Repair Gene Mutations (PROfound) 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden   


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
 
2 (170) 
VERSION HISTORY 
Version 4.0,  07 March 2019 
Changes to the protocol are summarized below. 
• 
Protocol Synopsis (Study site(s) and number of Subjects planned; Study design; Statistical 
methods), Section 1.4 (Study Design), Figure 1 (Study design) and Figure 2 (Study flow 
chart) – 
 
• 
Protocol Synopsis (Study design) – clarification that the study is the PROfound study. 
• 
Protocol synopsis (Duration of treatment), Section 3.9.1 (Procedures for discontinuation of a 
subject from investigational product), Section 4 (Study Schedule – Screening (Part 1 and 
2)/Table 2), Section 4 (Study Schedule – On Study Treatment and Discontinuation/Table 3), 
Section 4 (Study schedule and timing of procedures/Table 4), Section 4 (Study Schedule – 
Subjects switching to olaparib/Table 5), Section 4.2 (Treatment period), Section 4.2.1 
(Subjects who switch to olaparib), Section 4.3 (Follow-up period), Section 5.1.1 (Imaging 
tumor assessments), Section 5.3.3.1 (Assessment of Healthcare Resource Use), Section 7.2 
(Dose and treatment regimens), Section 8.4.1.1 (Radiological Progression Free Survival 
(rPFS)) and Appendix E (Tumor response evaluation) – updated to clarify that after the date 
of DCO for primary analysis, there is no plan for BICR to read scans, and the investigator-
assessed radiographic progression will prevail. 
• 
Protocol Synopsis (Study design; Investigational product, dosage and mode of 
administration), Section 7.1 (Identity of investigational product and comparators/Table 12) 
and Section 7.2 (Dose and treatment regimens) – updated to clarify use of 'enzalutamide 
capsules/tablets’. 
• 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
• 
Protocol synopsis (Target subject population, Biomarker selection) – updated since study 
may use more than one tissue testing laboratory
 
 
 
 
 
 
 
• 
Section 1.2.1 (Rationale for developing the Lynparza Homologous Recombination Repair 
(HRR) Assay) and Section 5.7.6 (Exploratory use of residual biomarker samples and data 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
 
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generated from tumor testing (Optional)) – updated the language for genes analyzed in the 
Lynparza HRR Assay. 
• 
Section 1.3 (Benefit/risk and ethical assessment) – revised Section link from 6.9.2 to 
Section 6.10.2. 
• 
 
 
 
 
 
 
 
 
 
 
 
• 
Table 2 (Study schedule - screening (Part 1 and 2)) and Section 5.7.3.1 (Screening part 1: 
optional blood sample for germline testing) – added clarification that optional blood 
samples for germline testing will not be collected in China. 
• 
 
 
 
 
 
 
 
 
 
 
• 
Table 3 (Study Schedule – On Study Treatment and Discontinuation) and Section 5.6.1 
(Collection of pharmacogenetics samples) – added clarification that pharmacogenetics 
samples will not be collected in China. 
• 
Table 3 (Study Schedule – On Study Treatment and Discontinuation) and Section 5.1.5 
(PSA Assessments) – clarified that the PSA results will not be available for the sites prior to 
final analysis. 
• 
Section 4.2 (Treatment period) – clarified the access to olaparib for subjects randomized to 
the comparator group.  
• 
Section 4.2.1 (Subjects who switch to olaparib) – updated wording for continuing olaparib 
treatment. 
• 
Section 4.3 (Follow-up period) – updated text since the subject’s decision has not been 
captured on the eCRF to date, and clarified that discontinuation is based on BICR and post 
primary analysis by investigator.  
• 
Section 5.1.1 (Imaging tumor assessments/Figure 3) – title updated to reflect that the 
schematic applies for before the primary (rPFS) analysis. 
• 
Section 5.1.2 (Tumor evaluation) – added clarification that scans will not be required after 
primary analysis. 
• 
 
  


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
 
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• 
Section 5.7.2 (Collection, Analysis and Reporting of Tumor Samples) – 
 
 
 Add added clarity on the subject population for the 
confirmed deleterious or suspected deleterious mutation biomarker testing.  
• 
Section 5.7.3.2 (Screening Part 2: Mandatory Blood Sample for Germline Testing) – 
removed the phrase ‘clinical-grade’ describing mandatory HRR germline blood sample, and 
clarified that the retrospective germline testing results are in accordance with the procedures 
for research use 
• 
 
 
• 
Section 5.7.7 (Storage, re-use and destruction of biological sample) – revised wording to 
include local regulation. 
• 
 
 
• 
Section 6.9 (Safety Reporting and Medical Management) – inserted a new sub-section for 
Medication Errors with the reporting description. 
• 
Section 7.7 (Concomitant and other treatments/Palliative radiotherapy) – added clarity that 
the treatment is olaparib. 
• 
Section 8.1 (Statistical considerations) – added clarification of the blinding requirements. 
• 
Section 8.3.1 (Efficacy analysis set) – added clarification on the efficacy analysis sets. 
• 
Section 8.3.2 (Safety analysis set) – clarified the definition of the global 
 safety 
analysis set, and that safety data for subjects switching from investigator choice to olaparib 
will be reported in a separate section. 
• 
Section 8.3.4 (Table 13) – included DoR and patient population as part of the efficacy data 
variable. 
• 
Section 8.4.1.1 (Radiological Progression Free Survival (rPFS)) – revised wording on the 2 
missed visit rule (details will be included in the SAP). 
• 
Section 8.4.2.5 (Duration of Response) – added clarity that DoR is based on subjects with 
confirmed DoR. 
• 
Section 8.4.4.1 (Adverse events) – for accuracy, the description of treatment emergent AE 
(TEAE) has been revised. 
• 
Section 8.5.4 (Subgroup analysis) – added clarification for the analysis. 
• 
 
 
• 
Section 9.3 (Study timetable and end of study) – revised language for clarity. 
• 
Appendix A (Additional Safety Information) – inserted text for the definition of Medication 
Errors. 
• 
Version 3.0, 04 June 2018 – summary of changes for Section 8.5.3.3 has been clarified. 
• 
Minor editorial and formatting updates performed for consistency but not tracked or noted 
as changes to the protocol. 
Version 3.0,  04 June 2018 
Changes to the protocol are summarized below.  


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
 
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• 
Protocol Synopsis, Section 7.1 (Identity of investigational product and comparators) and 
Section 7.2 (Dose and treatment regimens) – Abiraterone acetate 500mg tablets added 
• 
Protocol Synopsis and Section 7.2 (Dose and treatment regimens) – Abiraterone acetate 
dosing instructions clarified 
• 
Section 1.3 (Benefit/risk assessment) - Revised risk-benefit assessment section 
• 
Section 1.4 (Study Design) – Update to screening numbers 
• 
Section 2.4 (Exploratory Objectives) - Added additional Exploratory objectives for ctDNA 
• 
Section 3.1 (Inclusion Criteria) – Updated inclusion criteria #5 and #10 
• 
Section 3.2 (Exclusion Criteria) – Updated exclusion criteria #5 and #8 
• 
Section 3.8.1 (Grapefruit Juice) – Wording strengthened from ‘not recommended’ to 
‘prohibited’ 
• 
Section 5.1.2 (Tumor Evaluation) – Added clarification for if unscheduled bone scan occurs 
prior to week 8 
• 
Section 5.3.1.5 (Analgesic Log) – Clarification that ERT is not integrated with EDC 
• 
Section 5.4.2 (Determination of drug concentration) – Clarification of the lab used 
• 
Section 5.4.3 (Storage and destruction of pharmacokinetic samples) – Change to wording as 
samples cannot be both destroyed and anonymized by pooling. 
• 
Section 5.7.2 (Collection, Analysis and Reporting of Tumor Samples) – Minor edits to 
reference the ‘pathology and genomics manual’ 
• 
 
• 
Section 6.1.1 (Olaparib adverse events of special interest) – Removed requirement to report 
non-serious AESI to Patient Safety function 
• 
Section 7.5 (Compliance) – Clarified instructions for drug accountability of locally supplied 
drug. 
• 
Section 8.4.4 (Safety Endpoints) and Section 8.5.8 (Safety Analyses) – reference to ECG 
removed 
• 
Section 8.5.3.3 (Overall Survival) – Correction to final OS analysis alpha level taking into 
account the correlation between the planned interim and final analyses. 
• 
Table 2 (Study Schedule – Screening (Part 1 and 2)) and Section 5.7.3.1 – Added optional 
blood sample for exploratory germline testing to Screening Part 1 and clarified mandatory 
blood sample for germline testing at Screening Part 2 in Section 5.7.3.2  
• 
Table 2 (Footnote g), Table 3 (Footnote j), Table 4 (Footnote b), Table 5 (Footnote c) – 
removed requirement for additional eCRF page for nausea and vomiting 
• 
Table 2 (Study Schedule – Screening (Part 1 and 2)) and Section 8.5.8.4 (Concomitant 
medications) – clarification regarding concomitant medication collection. 
• 
Table 3 (Footnote c) – update to wording of “approximately 50 subjects assigned to olaparib 
treatment”, to “at least 50 subjects assigned to olaparib treatment”  
• 
Table 3 (Footnote o), Table 4 (Footnote f) and Table 5 (Footnote d) – Clarification regarding 
collection of anti-cancer treatments 
• 
Table 4 (Footnote i), Section 5.3.1.1 (BPI-SF) and Section 5.3.2 (Administration of PRO 
questionnaires) – Clarified instructions for completion of BPI-SF and analgesic log 
• 
Table 4 (Footnote k) – Clarified requirements for collection of opioids after treatment 
discontinuation 
• 
Table 9 (Management of anemia) – updated actions  
• 
Appendix E (Tumor progression evaluation - Schedule of the evaluation) – correction of 
baseline assessment window and clarified footnote in Table 19 and 21 
 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
 
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Version 2.0,  09 March 2017 
Changes to the protocol are summarized below.  
• 
Abbreviation of MGUS was added 
• 
Section 6.3.1 (Time period for collection of adverse events) and Table 2 Study Schedule – 
Screening (Part 1 and 2) footnote g: added the clarification: In screening part 1 only SAEs 
related to study procedures must be reported (AEs do not require reporting). From screening 
part 2 onwards - all AEs/SAEs must be reported. 
• 
Section 7.7 (Concomitant and other treatments)-Administration of other anti-cancer agents: 
delete “corticosteroids for the symptomatic control of brain metastases” because subjects with 
known brain metastases are excluded from the study according to exclusion criteria #13.  
• 
Section 8.4.4.3 (Concomitant medications) and Section 9.4 (Data management by 
AstraZeneca or delegate): updated that medications will be classified according to WHO 
Drug Dictionary. 
• 
Reference: added one reference Sun and Chen, 2010 (referred in section 8.5.6.1 Sensitivity 
analyses for rPFS) 
• 
Appendix F: updated wording related to abstinence  
 
Version 1.0,  19 Oct 2016 
  Initial creation  
This submission document contains confidential commercial information, disclosure of which is 
prohibited without providing advance notice to AstraZeneca and opportunity to object. 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca Standard 
procedures.  The clinical study protocol is publicly registered and the results are disclosed and/or 
published according to the AstraZeneca Global Policy on Bioethics and in compliance with prevailing 
laws and regulations. 


 
 
Clinical Study Protocol (CSP), ANGEL 
Version 17.0 
Template Form Doc ID: LDMS_001_00026737 
Parent Doc ID: SOP AZDoc0018580 
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PROTOCOL SYNOPSIS 
 
A Phase III, Open Label, Randomized Study to Assess the Efficacy and Safety of 
Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men with 
Metastatic Castration-Resistant Prostate Cancer Who Have Failed Prior Treatment with 
a New Hormonal Agent and Have Homologous Recombination Repair Gene Mutations 
 
 
International Co-ordinating Investigator 
 
 
 
 United Kingdom. 
 
International Co-ordinating Investigator 
 
 
  
 USA 
 
 
Study site(s) and number of Subjects planned 
Approximately 340 subjects will be randomized at study sites worldwide. 
 
 
 
Study period 
 
Phase of development 
Estimated date of first subject enrolled 
Q1 2017 
3 
Estimated date of last subject completed 
Q1 2021 
3 
 
Study design 
PROfound is a prospective, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy 
and safety of olaparib versus enzalutamide or abiraterone acetate in subjects with metastatic castration-
resistant prostate cancer (mCRPC) who have failed prior treatment with a new hormonal agent (NHA) 
and have a qualifying tumor mutation in one of 15 genes involved in the homologous recombination 
repair (HRR) pathway. Subjects will be divided into two cohorts based on HRR gene mutation status. 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
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Subjects with mutations in either BRCA1, BRCA2, or ATM will be in Cohort A whereas subjects with 
mutations among 12 other genes involved in the HRR pathway (BARD1, BRIP1, CDK12, CHEK1, 
CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L) will be in Cohort B. 
The primary endpoint of the study is radiographic progression free survival (rPFS) in subjects with 
BRCA1, BRCA2 or ATM mutations (Cohort A). Given the open label design of the study, rigorous 
methodology will be employed to ensure robustness of the primary endpoint assessment with a 
primary analysis of rPFS based on blinded independent central review (BICR) of all subject scans. Key 
secondary endpoints include confirmed objective response rate (Cohort A), rPFS (combined Cohorts A 
+ B), time to pain progression (Cohort A), and overall survival (Cohort A).  
Approximately 340 subjects will be randomized 2:1 (olaparib : investigator choice of enzalutamide or 
abiraterone acetate) into the trial, with ~240 subjects in Cohort A and approximately 100 subjects in 
Cohort B. 
 
 
The treatment groups include olaparib tablets (300 mg bid) or investigator choice 
of either enzalutamide capsules/tablets (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 
mg bid prednisone). The investigator must declare prior to randomization their choice of either 
enzalutamide or abiraterone acetate. 
 
 
The randomization scheme will be stratified based on: 
• 
Prior taxane (yes vs no) 
• 
Measurable disease (yes vs no) 
Randomized study treatment will be given until objective radiographic progression as assessed by 
BICR. Upon BICR progression, subjects randomized to the investigator choice arm will be given the 
option to switch to olaparib. 
Objectives  
Primary Objective: 
Outcome Measure: 
To determine the efficacy (as assessed by 
rPFS) of olaparib versus investigator choice of 
enzalutamide or abiraterone acetate in subjects 
with mCRPC with BRCA1, BRCA2 or ATM 
qualifying mutations (Cohort A)  
• 
rPFS by BICR using RECIST 1.1 (soft tissue) 
and PCWG3 (bone) criteria 
 
 
 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
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Key Secondary Objective: 
Outcome Measure: 
To determine the efficacy (as assessed by 
ORR) of olaparib versus investigator choice of 
enzalutamide or abiraterone acetate in subjects 
with BRCA1, BRCA2 or ATM qualifying gene 
mutations (Cohort A)   
• 
Confirmed ORR by BICR assessment in subjects 
with measurable disease using RECIST 1.1 (soft 
tissue) and PCWG3 (bone) criteria 
To determine the efficacy (as assessed by 
rPFS) of olaparib versus investigator choice of 
enzalutamide or abiraterone acetate in subjects 
with HRR qualifying mutations (Cohort A+B).  
 
 
• 
rPFS by BICR using RECIST 1.1 (soft tissue) 
and PCWG3 (bone) criteria 
To determine the efficacy (as assessed by time 
to pain progression) of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in subjects with BRCA1, 
BRCA2 or ATM qualifying gene mutations 
(Cohort A)   
• 
Pain progression based on BPI-SF item 3 “worst 
pain in 24 hours” and opiate analgesic use (AQA 
score) 
To determine the efficacy (as assessed by 
overall survival) of olaparib versus investigator 
choice of enzalutamide or abiraterone acetate 
in subjects with BRCA1, BRCA2 or ATM 
qualifying gene mutations (Cohort A) 
• 
Overall Survival (OS) 
 
 
 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
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Other Secondary Objectives: 
Outcome Measure: 
To further assess the efficacy of olaparib 
versus investigator choice of enzalutamide or 
abiraterone acetate in subjects with BRCA1, 
BRCA2 or ATM qualifying gene mutations 
(Cohort A) 
• 
Time from randomization to the first SSRE 
• 
Time from partial or complete response in 
subjects with measurable disease (RECIST 1.1) 
to progression by BICR (DoR) 
• 
Time from randomization to opiate use for 
cancer-related pain 
• 
Confirmed ORR (RECIST 1.1) in soft tissue by 
BICR in subjects with measurable disease (Soft 
tissue response) 
• 
Proportion of Subjects achieving a ≥50% 
decrease in PSA from baseline to the lowest post-
baseline PSA result, confirmed by a second 
consecutive PSA assessment at least 3 weeks 
later (PSA50 response) 
• 
Proportion of Subjects achieving a decline in the 
number of CTCs from ≥ 5 cells/7.5mL to < 5 
cells/7.5mL whole blood (CTC conversion rate) 
• 
Time from randomization to second progression 
by investigator assessment of radiological or 
clinical progression or death (PFS2) 
To further assess the effect of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in subjects with BRCA1, 
BRCA2 or ATM qualifying gene mutations 
(Cohort A) on disease-related symptoms and 
health-related quality of life (HRQoL) 
  
• 
Pain severity progression based on BPI-SF Pain 
Severity domain/subscale and opiate analgesic 
use (AQA score) 
• 
Pain interference based on BPI-SF Pain 
Interference domain/subscale 
• 
FACT-P (FACT-P total score, trial outcome 
index [TOI], functional well-being [FWB], 
physical well-being [PWB], prostate cancer 
subscale [PCS], and FACT Advanced Prostate 
Symptom Index 6 [FAPSI 6]) 
• 
Proportion of Subjects with pain (BPI-SF item 3) 
score ≥ 4 points at baseline who have a decrease 
of ≥ 2 points in pain (BPI-SF item 3) and without 
≥ 1 point increase in analgesic score (AQA score) 
at 12 weeks, confirmed at least 3 weeks later 
(Pain palliation) 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
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To assess the efficacy of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in subjects with HRR 
qualifying gene mutations other than BRCA1, 
BRCA2 or ATM (Cohort B). 
 
 
• 
rPFS by BICR using RECIST 1.1 (soft tissue) 
and PCWG3 (bone) criteria 
• 
Confirmed ORR by BICR assessment in subjects 
with measurable disease using RECIST 1.1 (soft 
tissue) and PCWG3 (bone) criteria 
• 
Pain progression based on BPI-SF item 3 "worst 
pain in 24 hours" and opiate analgesic use (AQA 
score) 
• 
OS 
To further assess the efficacy of olaparib 
versus investigator choice of enzalutamide or 
abiraterone acetate in subjects with HRR 
qualifying gene mutations (Cohort A+B). 
 
 
• 
Confirmed ORR by BICR assessment in subjects 
with measurable disease using RECIST 1.1 (soft 
tissue) and PCWG3 (bone) criteria 
• 
Time from randomization to the first SSRE 
• 
Time from partial or complete response in 
subjects with measurable disease (RECIST 1.1) 
to progression by BICR (DoR) 
• 
Time from randomization to opiate use for 
cancer-related pain 
• 
Confirmed ORR (RECIST 1.1) in soft tissue by 
BICR in subjects with measurable disease (Soft 
tissue response) 
• 
Proportion of Subjects achieving a ≥50% 
decrease in PSA from baseline to the lowest post-
baseline PSA result, confirmed by a second 
consecutive PSA assessment at least 3 weeks 
later (PSA50 response) 
• 
Proportion of Subjects achieving a decline in the 
number of CTCs from ≥ 5 cells/7.5mL to < 5 
cells/7.5mL whole blood (CTC conversion rate) 
• 
Time from randomization to second progression 
by investigator assessment of radiological or 
clinical progression or death (PFS2)  
• 
OS 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
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To further assess the effect of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in subjects with HRR 
qualifying gene mutations (Cohort A+B) on 
disease-related symptoms and health-related 
quality of life (HRQoL). 
 
  
  
• 
Pain progression based on BPI-SF item 3 “worst 
pain in 24 hours” and opiate analgesic use (AQA 
score) 
• 
Pain severity progression based on BPI-SF Pain 
Severity domain/subscale and opiate analgesic 
use (AQA score).   
• 
Pain interference based on BPI-SF Pain 
Interference domain/subscale 
• 
FACT-P (FACT-P total score, trial outcome 
index [TOI], functional well-being [FWB], 
physical well-being [PWB], prostate cancer 
subscale [PCS] and FACT Advanced Prostate 
Symptom Index 6 [FAPSI 6])  
• 
Proportion of Subjects with pain (BPI-SF item 3) 
score ≥ 4 points at baseline who have a decrease 
of ≥ 2 points in pain (BPI-SF item 3) and without 
≥ 1 point increase in analgesic score (AQA score) 
at 12 weeks, confirmed at least 3 weeks later 
(Pain palliation) 
To determine the exposure to olaparib in a 
subset of subjects receiving olaparib. 
 
 
• 
Olaparib plasma concentration data 
 
Safety Objective: 
Outcome Measure: 
To evaluate the safety and tolerability of 
olaparib versus investigator choice of 
enzalutamide or abiraterone acetate 
• AEs/SAEs 
• Collection of clinical chemistry/hematology 
parameters 
Target subject population 
All subjects in the study will be selected based on the following 2 criteria: 
Biomarker selection: Documented tumor (tissue) qualifying mutation(s) in one of 15 HRR genes that 
is predicted to be deleterious or suspected deleterious. All subjects must provide a formalin fixed and 
paraffin embedded (FFPE) tumor sample for tissue-based HRR gene panel mutation testing using the 
clinical trial assay (CTA) known as the Lynparza HRR Assay. Foundation Medicine, Inc. (FMI) will 
provide the CTA, a novel next generation sequencing (NGS)-based assay using DNA extracted from 
Formalin Fixed Paraffin Embedded (FFPE) tissue. Tumor tissue samples can be from either primary 
tumor (e.g., transrectal biopsies or radical prostatectomy specimen) or metastatic biopsy. The tumor 
sample will be tested for mutation in 15 pre-specified HRR genes. If the test results indicate that the 
subject has a qualifying mutation in the BRCA1, BRCA2, or ATM genes, the subject is eligible for 
Cohort A of the study. If the results indicate that the subject has a qualifying mutation in any of the 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
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remaining 12 genes (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, 
RAD51B, RAD51C, RAD51D, and RAD54L), then the subject is eligible for Cohort B. 
 
 
Treatment setting: All subjects must have mCRPC and have received and failed prior treatment with 
an NHA (e.g., abiraterone acetate or enzalutamide). Prior receipt of other anti-prostate cancer 
therapies, including docetaxel, cabazitaxel, radium-223, and sipuleucel-T is permitted but not 
required.  Subjects must not have received previous treatment with a DNA-damaging cytotoxic 
chemotherapy (e.g., prior platinum-based chemotherapy and mitoxantrone are not permitted) or a 
PARP inhibitor, including olaparib. 
Duration of treatment 
Until the primary rPFS analysis, all subjects should continue to receive randomized study treatment 
until radiographic progression as assessed by BICR, or until the subject is unable to tolerate study 
treatment. After the date of data cut-off (DCO) for the primary analysis, subjects should receive 
treatment until radiographic progression as assessed by the investigator, or until the subject is unable to 
tolerate study treatment. 
 
 Bone progression requires confirmation by 
a second bone scan at least 6 weeks later. Radiologic assessments will include both bone scans and 
CT/MRI and will be scheduled every 8 weeks (±7 days). All imaging assessments (including 
unscheduled visit scans) will be sent to AstraZeneca appointed central reader on an ongoing basis and 
analysis by BICR will be triggered upon investigator-assessed progression. Results of BICR will be 
immediately reported back to sites. Since the primary analysis of the study is based on BICR, it is 
important that study treatment and scheduled imaging assessments continue until progression by 
BICR. For this same reason, PSA (Prostate Specific Antigen) rise, without evidence of radiographic 
progression, is strongly discouraged as a criterion to stop treatment or to start a new systemic anti-
prostate cancer therapy. 
Upon documentation of radiographic progression by BICR before the primary rPFS analysis, or after 
the primary rPFS analysis based on investigator-assessed radiographic progression, receipt of 
subsequent anti-cancer therapies is allowed at the investigator’s discretion and will be recorded. 
Furthermore, upon BICR-assessed progression, subjects randomized to investigator choice arm will be 
given the option to receive olaparib. 
No restrictions are made to prior or concurrent receipt of bone metastases targeting therapies with 
zoledronic acid or denosumab. 
Investigational product, dosage and mode of administration 
Subjects will receive either olaparib, enzalutamide, or abiraterone acetate. 
Olaparib: Olaparib is available as a film-coated tablet containing 150 mg or 100 mg of olaparib. 
Subjects will be administered study treatment orally at a dose of 300 mg twice daily (bid). The planned 
dose of 300 mg bid will be made up of two x 150 mg tablets twice daily, with 100 mg tablets used to 
manage dose reductions. 


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Subjects should take doses at a similar time each day, with the twice daily doses taken approximately 
12 hours apart. All doses should be taken with a glass of water. The olaparib tablets should be 
swallowed whole and not chewed, crushed, dissolved or divided. Study tablets can be taken with or 
without food. On the PK sampling day subjects should fast from 1 hour before taking the olaparib dose 
to two hours after. 
Enzalutamide: Enzalutamide is available as capsules/tablets containing 40 mg of enzalutamide. 
Subjects will be administered study treatment orally at a dose of 160 mg once daily. Subjects should 
take enzalutamide doses at a similar time each day. Capsules/tablets should be swallowed whole and 
can be taken with or without food, in full accordance with local prescribing information. 
Abiraterone acetate with prednisone: Abiraterone acetate is available as tablets containing 250 mg 
or 500 mg of abiraterone acetate. Subjects will be administered study treatment orally at a dose of 
1,000 mg once daily in combination with prednisone 5 mg administered twice daily orally. Subject 
should take abiraterone acetate doses at a similar time each day. Abiraterone acetate must be taken on 
an empty stomach. No food should be consumed for at least two hours before the dose of abiraterone 
acetate and one hour after the dose of abiraterone acetate. The tablets should be swallowed whole with 
water and not crushed or chewed, in full accordance with local prescribing information. 
Statistical methods 
The primary analysis of rPFS primary endpoint will be performed after approximately 143 progression 
or death events have been accrued in 240 subjects in Cohort A (60% maturity) and would provide 95% 
power to show a statistically significant difference in rPFS at 2-sided 5% alpha level if the assumed 
true treatment effect was a HR=0.53 (corresponding to an assumed increase in median rPFS from 5 
months (enzalutamide or abiraterone acetate) to 9.5 months (olaparib). 
 
 
 
 
It is anticipated that the study accrual period will be approximately 28 months and that 143 progression 
and death events will occur approximately 35 months after the first subject is randomized in the study. 
rPFS will be analyzed using a log rank test stratified by previous taxane (yes, no) and measurable 
disease (yes, no) and the corresponding p value will be generated. The hazard ratio together with its 
corresponding 95% confidence interval will be estimated using a Cox Proportional Hazards Model. 
If the primary analysis of rPFS in Cohort A demonstrates statistical significance, testing of key 
secondary endpoints ORR (Cohort A), rPFS (Cohort A+B), time to pain progression (Cohort A) and 
OS (Cohort A) will be performed in a hierarchical manner using the alpha level recycled from the 
primary endpoint.  
Safety analyses will be presented using the Safety Analysis Set and will be done by means of 
descriptive statistics in Cohorts A, B and A+B. Safety profiles will be assessed in terms of AEs, vital 
signs (including BP and pulse rate), ECG, laboratory data (clinical chemistry and hematology), and 
physical examination. 
Analyses on Cohorts B and A+B will be performed at the time of primary rPFS analysis in Cohort A. 


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Study Code D081DC00007 
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Pharmacokinetic analysis  
The plasma concentration-time data will be analyzed by non-linear mixed effects modelling in order to 
evaluate the pharmacokinetic characteristics of olaparib, quantify variability in the pharmacokinetics, 
identify demographic or pathophysiological covariates which may explain the observed variability and 
explore exposure-response relationships.


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Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
 
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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 1 
VERSION HISTORY .............................................................................................. 2 
PROTOCOL SYNOPSIS ......................................................................................... 7 
TABLE OF CONTENTS ....................................................................................... 16 
1. 
INTRODUCTION ................................................................................................. 27 
1.1 
Background and rationale for conducting this study ............................................. 27 
1.1.1 
Advanced prostate cancer and its treatment ........................................................... 27 
1.1.1.1 
Standard-of-care therapy in mCRPC failing abiraterone or enzalutamide ............ 28 
1.1.1.2 
Standard-of-care therapy in mCRPC who have failed abiraterone acetate 
and/or enzalutamide and docetaxel (+/-cabazitaxel) .............................................. 29 
1.1.2 
Research hypothesis ............................................................................................... 29 
1.1.3 
PARP inhibition as a target for HRR mutation positive mCRPC .......................... 29 
1.1.4 
Pre-clinical experience ........................................................................................... 30 
1.1.5 
Toxicology and safety pharmacology summary .................................................... 30 
1.1.6 
Clinical experience ................................................................................................. 30 
1.1.6.1 
Preliminary Report of Olaparib Activity in Prostate Cancer (Sandhu et al 
2013) ...................................................................................................................... 31 
1.1.6.2 
TOPARP A (Mateo et al 2015) .............................................................................. 31 
1.2 
Rationale for study design, doses and control groups ............................................ 32 
1.2.1 
Rationale for developing the Lynparza Homologous Recombination Repair 
(HRR) Assay .......................................................................................................... 33 
1.3 
Benefit/risk and ethical assessment........................................................................ 33 
1.4 
Study Design .......................................................................................................... 34 
2. 
STUDY OBJECTIVES .......................................................................................... 36 
2.1 
Primary objectives ................................................................................................. 36 
2.2 
Secondary objectives ............................................................................................. 36 
2.3 
Safety objectives .................................................................................................... 39 
2.4 
Exploratory objectives ........................................................................................... 39 
3. 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 41 
3.1 
Inclusion criteria .................................................................................................... 41 
3.2 
Exclusion criteria ................................................................................................... 43 
3.3 
Subject enrollment and randomization .................................................................. 46 


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3.4 
Procedures for handling incorrectly enrolled or randomized Subjects .................. 46 
3.5 
Methods for assigning treatment groups ................................................................ 47 
3.6 
Methods for ensuring blinding ............................................................................... 47 
3.7 
Methods for unblinding .......................................................................................... 47 
3.8 
Restrictions ............................................................................................................ 47 
3.8.1 
Grapefruit juice ...................................................................................................... 48 
3.8.2 
Contraception ......................................................................................................... 48 
3.8.3 
Blood donation ....................................................................................................... 48 
3.9 
Discontinuation of investigational product ............................................................ 48 
3.9.1 
Procedures for discontinuation of a subject from investigational product ............ 49 
3.10 
Criteria for study withdrawal ................................................................................. 49 
3.10.1 
Screen failures ........................................................................................................ 50 
3.10.2 
Withdrawal of the informed consent ...................................................................... 50 
3.11 
Discontinuation of the study .................................................................................. 51 
4. 
STUDY SCHEDULE AND TIMING OF PROCEDURES .................................. 52 
4.1 
Enrollment/screening period .................................................................................. 63 
4.1.1 
Re-Screening .......................................................................................................... 63 
4.2 
Treatment period .................................................................................................... 63 
4.2.1 
Subjects who switch to olaparib ............................................................................ 64 
4.3 
Follow-up period .................................................................................................... 64 
5. 
STUDY ASSESSMENTS ..................................................................................... 65 
5.1 
Efficacy assessments .............................................................................................. 65 
5.1.1 
Imaging tumor assessments ................................................................................... 65 
5.1.1.1 
CT and MRI scans tumor assessments (RECIST 1.1) ........................................... 66 
5.1.1.2 
Bone scans tumor assessment (based on PCWG3 criteria).................................... 67 
5.1.2 
Tumor evaluation ................................................................................................... 67 
5.1.3 
Second progression ................................................................................................ 69 
5.1.4 
Symptomatic skeletal related events (SSRE) ......................................................... 69 
5.1.5 
PSA Assessments ................................................................................................... 69 
5.2 
Safety assessments ................................................................................................. 69 
5.2.1 
Laboratory safety assessments ............................................................................... 69 
5.2.1.1 
Coagulation ............................................................................................................ 70 
5.2.1.2 
Bone marrow or blood cytogenetic samples .......................................................... 70 
5.2.2 
Physical examination ............................................................................................. 71 
5.2.3 
ECG ........................................................................................................................ 71 
5.2.3.1 
Resting 12-lead ECG ............................................................................................. 71 
5.2.4 
Vital signs .............................................................................................................. 71 
5.2.4.1 
Pulse and blood pressure (BP) ............................................................................... 71 
5.2.4.2 
Body temperature ................................................................................................... 71 


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5.3 
Other assessments .................................................................................................. 71 
5.3.1 
Patient reported outcomes ...................................................................................... 71 
5.3.1.1 
BPI-SF .................................................................................................................... 72 
5.3.1.2 
FACT-P .................................................................................................................. 73 
5.3.1.3 
PRO-CTCAE ......................................................................................................... 73 
5.3.1.4 
Patient Global Impression of Change (PGIC)........................................................ 74 
5.3.1.5 
Analgesic Log ........................................................................................................ 74 
5.3.1.6 
Analgesic Use Scoring ........................................................................................... 74 
5.3.1.7 
EQ-5D-5L .............................................................................................................. 75 
5.3.2 
Administration of PRO questionnaires .................................................................. 76 
5.3.3 
Healthcare Resource Use ....................................................................................... 77 
5.3.3.1 
Assessment of Healthcare Resource Use ............................................................... 78 
5.4 
Pharmacokinetics ................................................................................................... 78 
5.4.1 
Collection of samples ............................................................................................. 78 
5.4.2 
Determination of drug concentration ..................................................................... 78 
5.4.3 
Storage and destruction of pharmacokinetic samples ............................................ 78 
5.5 
Pharmacodynamics ................................................................................................ 79 
5.6 
Pharmacogenetics .................................................................................................. 79 
5.6.1 
Collection of pharmacogenetics samples ............................................................... 79 
5.7 
Biomarker analysis ................................................................................................. 79 
5.7.1 
HRR gene panel testing of tumor biopsy sample ................................................... 79 
5.7.2 
Collection, Analysis and Reporting of Tumor Samples ........................................ 79 
5.7.3 
Blood Sample for Germline HRR Testing ............................................................. 80 
5.7.3.1 
Screening Part 1: Optional Blood Sample for Germline Testing .......................... 81 
5.7.3.2 
Screening Part 2: Mandatory Blood Sample for Germline Testing ....................... 81 
5.7.4 
Exploratory blood samples for biomarker analysis (e.g., ctDNA analysis) ........... 81 
5.7.5 
Circulating tumor cells (CTCs) .............................................................................. 81 
5.7.6 
Exploratory use of residual biomarker samples and data generated from 
tumor testing (Optional) ......................................................................................... 82 
5.7.7 
Storage, re-use and destruction of biological samples ........................................... 82 
5.7.8 
Labelling and shipment of biological samples ....................................................... 82 
5.7.9 
Chain of custody of biological samples ................................................................. 82 
5.7.10 
Withdrawal of Informed Consent for donated biological samples ........................ 83 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 83 
6.1 
Definition of adverse events .................................................................................. 83 
6.1.1 
Olaparib adverse events of special interest ............................................................ 83 
6.2 
Definitions of serious adverse event ...................................................................... 84 
6.3 
Recording of adverse events .................................................................................. 84 
6.3.1 
Time period for collection of adverse events ......................................................... 84 
6.3.1.1 
Adverse events after the 30 day follow up period ................................................. 84 
6.3.2 
Follow-up of unresolved adverse events ................................................................ 85 
6.3.3 
Variables ................................................................................................................ 85 


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6.3.4 
Causality collection ................................................................................................ 86 
6.3.5 
Adverse events based on signs and symptoms....................................................... 86 
6.3.6 
Adverse events based on examinations and tests ................................................... 87 
6.3.7 
Hy’s Law ................................................................................................................ 87 
6.3.8 
Disease progression ............................................................................................... 87 
6.3.9 
New cancers ........................................................................................................... 88 
6.3.10 
Lack of efficacy ..................................................................................................... 88 
6.3.11 
Deaths .................................................................................................................... 88 
6.4 
Reporting of serious adverse events....................................................................... 88 
6.5 
Overdose ................................................................................................................ 89 
6.6 
Pregnancy ............................................................................................................... 89 
6.6.1 
Paternal exposure ................................................................................................... 90 
6.7 
Management of toxicities related to olaparib ......................................................... 90 
6.7.1 
Management of hematological toxicity ................................................................. 90 
6.7.1.1 
Management of anemia .......................................................................................... 90 
6.7.1.2 
Management of neutropenia, leukopenia and thrombocytopenia .......................... 91 
6.7.1.3 
Management of prolonged hematological toxicities while on study 
treatment ................................................................................................................ 92 
6.7.2 
Management of non-hematological toxicity .......................................................... 92 
6.7.2.1 
Management of new or worsening pulmonary symptoms ..................................... 92 
6.7.2.2 
Management of nausea and vomiting .................................................................... 93 
6.7.2.3 
Interruptions for intercurrent non-toxicity related events ...................................... 93 
6.8 
Management of toxicities related to enzalutamide and abiraterone acetate........... 94 
6.8.1 
Dose adjustment recommendations for enzalutamide ........................................... 94 
6.8.2 
Dose adjustment recommendations for abiraterone acetate ................................... 94 
6.9 
Medication error ..................................................................................................... 94 
6.10 
Study governance and oversight ............................................................................ 94 
6.10.1 
Steering Committee ............................................................................................... 94 
6.10.2 
Data Monitoring Committee .................................................................................. 95 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 95 
7.1 
Identity of investigational product and comparators.............................................. 95 
7.2 
Dose and treatment regimens ................................................................................. 95 
7.3 
Labelling ................................................................................................................ 97 
7.4 
Storage ................................................................................................................... 97 
7.5 
Compliance ............................................................................................................ 97 
7.6 
Accountability ........................................................................................................ 98 
7.7 
Concomitant and other treatments ......................................................................... 98 
7.7.1 
Other concomitant treatment ................................................................................ 101 


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8. 
STATISTICAL ANALYSES BY ASTRAZENECA .......................................... 101 
8.1 
Statistical considerations ...................................................................................... 101 
8.2 
Sample size estimate ............................................................................................ 101 
8.3 
Definitions of analysis sets .................................................................................. 102 
8.3.1 
Efficacy analysis set ............................................................................................. 102 
8.3.2 
Safety analysis set ................................................................................................ 102 
8.3.3 
PK analysis set ..................................................................................................... 103 
8.3.4 
PRO analysis set .................................................................................................. 103 
8.4 
Outcome measures for analyses ........................................................................... 104 
8.4.1 
Primary Endpoints ............................................................................................... 104 
8.4.1.1 
Radiological Progression Free Survival (rPFS) ................................................... 104 
8.4.2 
Secondary Endpoints ........................................................................................... 105 
8.4.2.1 
Confirmed Overall Objective Response Rate (ORR) .......................................... 105 
8.4.2.2 
Time to Pain Progression ..................................................................................... 105 
8.4.2.3 
Overall Survival ................................................................................................... 106 
8.4.2.4 
Time to first Symptomatic Skeletal –Related Event (SSRE) ............................... 106 
8.4.2.5 
Duration of Response ........................................................................................... 106 
8.4.2.6 
Time to Opiate Use for Cancer Pain .................................................................... 107 
8.4.2.7 
Prostate Specific Antigen (PSA) Response ......................................................... 107 
8.4.2.8 
Circulating Tumor Cell (CTC) Conversion rate .................................................. 107 
8.4.2.9 
Time from randomization to second progression or death (PFS2) ...................... 107 
8.4.2.10 Pain Severity ........................................................................................................ 107 
8.4.2.11 Pain Interference .................................................................................................. 108 
8.4.2.12 FACT-P ................................................................................................................ 108 
8.4.2.13 Pain Palliation ...................................................................................................... 110 
8.4.2.14 Pharmacokinetic Endpoints ................................................................................. 110 
8.4.3 
Exploratory Endpoints ......................................................................................... 110 
8.4.3.1 
PRO-CTCAE ....................................................................................................... 110 
8.4.3.2 
Patient Global Impression of Change (PGIC)...................................................... 110 
8.4.3.3 
Resource Use ....................................................................................................... 110 
8.4.3.4 
EQ-5D-5L ............................................................................................................ 110 
8.4.4 
Safety Endpoints .................................................................................................. 111 
8.4.4.1 
Adverse Events .................................................................................................... 111 
8.4.4.2 
Other significant Adverse Events (OAE) ............................................................ 111 
8.4.4.3 
Concomitant medications ..................................................................................... 111 
8.4.4.4 
Compliance and exposure .................................................................................... 112 
8.5 
Methods for statistical analyses ........................................................................... 112 
8.5.1 
Multiplicity Strategy for Primary Endpoint and Key Secondary endpoints ........ 112 
8.5.2 
Analysis of the primary variable(s) ...................................................................... 113 
8.5.2.1 
Radiological Progression Free Survival ............................................................... 113 
8.5.3 
Analysis of the secondary variable(s) .................................................................. 114 
8.5.3.1 
Confirmed Objective Response Rate (ORR) ....................................................... 114 
8.5.3.2 
Time to Pain Progression: .................................................................................... 115 


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Study Code D081DC00007 
Version 4.0 
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8.5.3.3 
Overall Survival ................................................................................................... 115 
8.5.3.4 
Time to first Symptomatic Skeletal-Related Event (SSRE) ................................ 116 
8.5.3.5 
Duration of Response: .......................................................................................... 116 
8.5.3.6 
Time to Opiate use for Cancer related Pain ......................................................... 116 
8.5.3.7 
Prostate Specific Antigen (PSA) Response ......................................................... 116 
8.5.3.8 
Circulating Tumor Cell (CTC) conversion rate ................................................... 116 
8.5.3.9 
Time from randomization to second progression or death .................................. 117 
8.5.3.10 PK Analysis ......................................................................................................... 117 
8.5.4 
Subgroup analysis ................................................................................................ 117 
8.5.5 
Interim analysis .................................................................................................... 118 
8.5.6 
Sensitivity analysis ............................................................................................... 119 
8.5.6.1 
Sensitivity analyses for rPFS ............................................................................... 119 
8.5.7 
Supportive analyses ............................................................................................. 121 
8.5.7.1 
Patient reported outcomes (PRO) ........................................................................ 121 
8.5.7.2 
EQ-5D-5L ............................................................................................................ 121 
8.5.7.3 
Resource Use ....................................................................................................... 122 
8.5.8 
Safety Analyses .................................................................................................... 122 
8.5.8.1 
Adverse events ..................................................................................................... 122 
8.5.8.2 
Dose-limiting toxicities ........................................................................................ 122 
8.5.8.3 
Laboratory data .................................................................................................... 122 
8.5.8.4 
Concomitant medications ..................................................................................... 122 
8.5.8.5 
Vital signs ............................................................................................................ 123 
8.5.8.6 
Other safety variables ........................................................................................... 123 
8.5.8.7 
Exposure and compliance .................................................................................... 123 
 
 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ........................ 124 
9.1 
Training of study site personnel ........................................................................... 124 
9.2 
Monitoring of the study ....................................................................................... 124 
9.2.1 
Source data ........................................................................................................... 124 
9.2.2 
Study agreements ................................................................................................. 124 
9.2.3 
Archiving of study documents ............................................................................. 125 
9.3 
Study timetable and end of study ......................................................................... 125 
9.4 
Data management by AstraZeneca or delegate .................................................... 125 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 126 
10.1 
Ethical conduct of the study ................................................................................. 126 
10.2 
Subject data protection ......................................................................................... 126 
10.3 
Ethics and regulatory review................................................................................ 127 
10.4 
Informed consent ................................................................................................. 127 
10.5 
Changes to the protocol and informed consent form ........................................... 128 
10.6 
Audits and inspections ......................................................................................... 128 


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11. 
LIST OF REFERENCES ..................................................................................... 129 
 
LIST OF TABLES 
Table 1 
Composite response rates (primary endpoint) by biomarker status 
(Mateo et al 2015)..................................................................................... 32 
Table 2 
Study Schedule – Screening (Part 1 and 2) .............................................. 53 
Table 3 
Study Schedule – On Study Treatment and Discontinuation ................... 55 
Table 4 
Study Schedule – Follow-up Post Discontinuation of Study 
Treatment .................................................................................................. 59 
Table 5 
Study Schedule – Subjects switching to olaparib ..................................... 61 
Table 6 
Requirements for documentation of progression...................................... 68 
Table 7 
Laboratory Safety Variables ..................................................................... 70 
Table 8 
Treatment assignment by Tumor Sample Mutation Result ...................... 79 
Table 9 
Management of anemia ............................................................................ 90 
Table 10 
Management of neutropenia, leukopenia and thrombocytopenia ............. 91 
Table 11 
Dose reductions for olaparib..................................................................... 93 
Table 12 
Identity of investigational product and comparators ................................ 95 
Table 13 
Summary of Outcome Variables and Analysis Populations ................... 103 
Table 14 
Definition of visit response for FACT-P, FAPSI-8, TOI, PCS and 
FWB ....................................................................................................... 109 
Table 15 
 Overall score response criteria .............................................................. 109 
Table 16 
 Summary of Methods of Assessment .................................................... 148 
Table 17  
Evaluation of target lesions .................................................................... 151 
Table 18 
Evaluation of Non-Target Lesions ......................................................... 151 
Table 19 
Overall Visit Soft Tissue Response ........................................................ 152 
Table 20 
Bone progression status .......................................................................... 154 
Table 21 
Overall radiological visit response ......................................................... 155 
Table 22 
Best overall response when confirmation of CR and PR required. ........ 155 


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Study Code D081DC00007 
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LIST OF FIGURES 
Figure 1 
Study Diagram .......................................................................................... 35 
Figure 2 
Study Flow Chart ...................................................................................... 52 
Figure 3 
Assessment of Progression by BICR (prior to primary rPFS 
analysis) .................................................................................................... 66 
Figure 4 
Multiplicity Strategy Maintaining Overall Type I Error Rate ................ 113 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information ................................................................ 135 
Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document ............................................................................... 138 
Appendix C 
Pharmacogenetics Research ................................................................... 139 
Appendix D 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law .......................................................................... 142 
Appendix E 
Guidelines for Evaluation of Objective Tumor Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid 
Tumors) in Soft Tissue and PCWG3 (Prostate Cancer Working 
Group Criteria 3) in Bone Lesions ......................................................... 147 
Appendix F  
Acceptable birth control methods ........................................................... 157 
Appendix G 
Patient Reported Outcomes .................................................................... 158 
Appendix H 
Performance Status (ECOG/KARNOFSKY SCALES) ......................... 170 


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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 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
APTT 
Activated Partial Thromboblastin Time 
AST 
Asparate Aminotransferase 
ATM 
Ataxia Telangiectasia Mutated 
BICR 
Blinded Independent Central Review 
bid 
Twice daily 
BP 
Blood Pressure 
BPI-SF 
Brief Pain Inventory- Short Form 
BRCA1, BRCA2 
Breast Cancer 1 gene or Breast Cancer 2 gene 
BUN 
Blood Urea Nitrogen 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form (electronic/paper) 
CRPC 
Castration-Resistant Prostate Cancer 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
CTA 
Clinical Trial Assay 
CTC 
Circulating Tumor Cells 
CTCAE 
Common Terminology Criteria for Adverse Event 
DAE 
Discontinuation of Investigational Product due to Adverse Event 
DCIS 
Ductal Carcinoma in situ 
DCO 
Data cut-off 
DNA 
Deoxyribonucleic Acid  
DoR 
Duration of Response 


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Abbreviation or 
special term 
Explanation 
DSB 
Double Strand Break 
dUCBT 
Double Umbilical Cord Blood Transplantation 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG 
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group: a performance status using scales 
and criteria to assess how a subject’s disease is progressing 
EQ-5D-5L 
EuroQol 5-dimension, 5-level health state utility index 
FACT-P 
Functional Assessment of Cancer Therapy- Prostate Cancer 
FFPE 
Formalin fixed, paraffin embedded 
FMI 
Foundation Medicine Inc.  
FSH 
Follicle Stimulating Hormone 
FWB 
Functional Well-Being 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
Hb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HRCT 
High Resolution Computed Tomography 
HR 
Hazard Ratio 
HRD 
Homologous Recombination Repair Deficiency 
HRR 
Homologous Recombination Repair 
ICH 
International Conference on Harmonization 
ICI 
International Coordinating Investigator 
IP 
Investigational Product  
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LHRH 
Luteinizing Hormone-Releasing Hormone 
LSLV 
Last Subject Last Visit 
LIMS 
Laboratory Information Management System 
mCRPC 
Metastatic Castration-Resistant Prostate Cancer 
MCV 
Mean Cell Volume 
MDS 
Myelodysplastic Syndrome 


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Study Code D081DC00007 
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Abbreviation or 
special term 
Explanation 
MGUS  
 
Monoclonal Gammopathy of Undetermined Significance   
MRI 
Magnetic Resonance Imaging 
NGS 
Next Generation Sequencing 
NHA 
New Hormonal Agent (abiraterone, enzalutamide) 
NTL 
Non-Target Lesion 
OAE 
Other Significant Adverse Event 
od 
Once daily 
ORR 
Objective response rate 
OS 
Overall survival 
PARP 
Polyadenosine 5’diphosphoribose [poly (ADP ribose)] polymerase 
PCR 
Polymerase Chain Reaction 
PCS 
Prostate Cancer Subscale 
PCWG3 
Prostate Cancer Working Group 3 
PGx 
Pharmacogenetic research 
PGIC 
Patient Global Impression of Change 
PI 
Principal Investigator  
PK 
Pharmacokinetics 
PRO 
Patient Reported Outcome 
PRO-CTCAE 
Patient Reported Outcomes- Common Terminology Criteria for Adverse 
Events 
PSA 
Prostate Specific Antigen 
PWB 
Physical Well-Being 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
Radiographic Progression-Free Survival 
SAE 
Serious Adverse Event  
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvate Transaminase 
SSB 
Single Strand Breaks 
SSRE 
Symptomatic Skeletal Related Event (symptomatic fracture, need for 
radiation to bone metastasis, need for surgery for bone metastasis, spinal 
cord compression) 
TL 
Target Lesion 


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Abbreviation or 
special term 
Explanation 
TOI 
Trial Outcome Index 
TTF 
Time to Treatment Failure 
ULN 
Upper Limit of Normal 
WBDC 
Web Based Data Capture 
 
1. 
INTRODUCTION 
1.1 
Background and rationale for conducting this study 
1.1.1 
Advanced prostate cancer and its treatment  
Prostate cancer has been associated with over-diagnosis and over-treatment in early stages (Shen and 
Kumar 2015), where cure rates are high and average long-term clinical outcomes favorable. However, 
it is a heterogeneous disease and no cure exists for those patients reaching the metastatic castration-
resistant (mCRPC) stage of the disease. With an estimated incidence of 233,000 new cases and 29,480 
deaths in 2014, it is the most frequently diagnosed non-skin cancer and second most frequent cause of 
cancer deaths in US males (American Cancer Society 2014). Similar prostate cancer mortality rates are 
reported for Western Europe (Center et al 2012). Almost all patients dying from prostate cancer will 
have mCRPC, and 90% of overall mortality in mCRPC patients is attributable to the underlying 
malignant disease (Scher et al 2015). 
While a variety of life prolonging agents are approved for mCRPC, a median overall survival of about 
3 years obtained with early treatment initiation such as abiraterone acetate and enzalutamide (Ryan et 
al 2013 and Beer et al 2014) still constitutes a grossly reduced life expectancy when compared to the 
about 15 years of life expectancy for age-matched men (~ 70 years) from the general population (US 
Social Security). Hence a high unmet medical need remains for men with mCRPC for efficacious and 
well tolerated therapies. 
A small percentage of prostate tumors have loss of function mutations in candidate genes involved in 
homologous recombination repair (HRR) of DNA. BRCA1, BRCA2, or ATM are the most well-
characterized and/or frequently mutated HRR genes in prostate cancer and hence form the basis for 
selecting a biomarker-defined target mCRPC population in this phase 3 registration study. The overall 
mutation frequency for these three genes is expected to be less than 15% (Kumar et al 2016, Mateo et 
al 2015 and Robinson et al 2015); furthermore, assuming a technical failure rate of 25% to determine 
BRCA1, BRCA2, or ATM mutations in tumor tissue obtained either by fresh biopsy or using archival 
tissue, only about 1 out of 10 patients with mCRPC will qualify for Cohort A of the proposed 
registration trial. It appears that about half of HRR gene mutations detectable in tumor tissue constitute 
germline mutations (the other half being somatic in nature, i.e., exclusively occurring in tumor tissue; 
Mateo et al 2015). While an adverse prognostic impact of germline BRCA2 mutations has been 
described (Castro et al 2015), it is less clear if other germline or somatic HRR gene mutations are 
associated with similar adverse clinical outcomes. For patients with mCRPC there are no readily 
available clinical parameters known (e.g., age and Gleason score at initial diagnosis, metastatic 


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patterns) to phenotypically differentiate those patients with underlying tumor HRR gene mutations 
from those without HRR gene mutations (Mateo et al 2015).  
However, mCRPC patients with HRR gene mutations have a high propensity to benefit from anti-
cancer therapies resulting in an increased number of DNA double-strand breaks, such as the PARP 
inhibitor olaparib (Mateo et al 2015 and Kaufman et al 2015), and potentially platin compounds 
(Cheng et al 2015). Notably, in the phase II single arm study reported by Mateo et al. high response 
rates, including confirmed RECIST responses of > 50%, were observed with olaparib treatment in 
biomarker-positive patients (tissue HRR mutations) despite these patients having failed both 
abiraterone acetate and/or enzalutamide as well as docetaxel and the majority of them also having 
received cabazitaxel. Conversely, almost no responses were seen in biomarker-negative patients. A 
striking difference in biological activity of olaparib was also seen between biomarker-positive vs. –
negative patients on other clinical outcomes such as radiologic progression free survival and overall 
survival (Mateo et al 2015). This phase 2 study is described in more detail in Section 1.1.6.1. An 
independent phase 2 clinical study reported by Kaufman et al 2015 included mCRPC patients with 
germline BRCA1 or BRCA2 mutations and found a similar rate (50%) of confirmed RECIST responses 
following treatment with olaparib. 
There are no approved targeted treatments for mCRPC patients with tissue mutations of BRCA1, 
BRCA2, ATM or other HRR genes and their treatment is not different from non-selected mCRPC 
patients. 
1.1.1.1 
Standard-of-care therapy in mCRPC failing abiraterone or enzalutamide  
New hormonal agents (NHA) such as abiraterone acetate and enzalutamide are potent, orally available 
treatment options with a favorable tolerability profile and have replaced docetaxel as preferred choice 
of first-line therapy for mCRPC (Flaig et al 2016). Both of these agents have demonstrated robust 
improvements on PFS and OS and have also shown a significantly prolonged time to initiation of 
cytotoxic chemotherapy (Ryan et al 2013 and Beer et al 2014). However, once mCRPC patients have 
failed NHA, the benefit from approved therapeutic options appears substantially diminished and no 
clear single standard of care exists as none of the currently approved agents have been developed for a 
post-NHA setting: 
Taxanes: Unless symptomatic or with high tumor burden, few patients are expected to immediately 
receive docetaxel. For example, 48% of mCRPC patients never received docetaxel at a major U.S. 
academic center (Steinberger et al 2015). 
Efficacy of docetaxel appears markedly reduced when given after NHA as compared to first line use 
(Mezynski et al 2012, Schweizer et al 2014), likely attributable to at least partial cross-resistance 
between taxanes and NHA (van Soest et al 2013). 
The efficacy of docetaxel after failure of abiraterone acetate does not appear to be superior to that of 
enzalutamide (Sun and Chen 2010 and Suzman et al 2014). 
Cabazitaxel appears to have a low real-world usage (Flaig et al 2016) and is approved only after failure 
of docetaxel. 
Both docetaxel and cabazitaxel are administered per i.v. infusion and have boxed warnings for 
hypersensitivity reactions as well as neutropenia/neutropenic deaths.  


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NHA: Due to at least partial cross-resistance, switching from one NHA to the other is associated with 
reduced efficacy (Cheng et al 2015), with rPFS outcomes similar to those observed with docetaxel in a 
post-NHA setting (Sun and Chen 2010 and Suzman et al 2014). 
Other agents: Sipuleucel-T and radium-223 are rarely used additional therapeutic options; their use is 
either limited regionally (sipuleucel-T: U.S.) and/or restricted to certain patient populations such as 
those with asymptomatic/minimally symptomatic disease (sipuleucel-T) or those with bone-only 
disease and symptoms (radium-223). Efficacy of these agents in a post-NHA setting is unknown. 
In addition to limited efficacy, tolerability issues such as fatigue (Moreira et al 2016) and hematologic 
toxicity from taxanes may further limit use of available options and contribute to short real-world 
estimated median treatment durations between 10 weeks (taxane) and 14 to 17 weeks (NHA) in a 
second line setting (Flaig et al 2016). The median overall survival of patients who have failed NHA 
but have not previously received taxane chemotherapy appears to be between 8.6 months and 12.5 
months (Azad et al 2015 and Mezynski et al 2012) reflecting a high unmet medical need for mCRPC 
patients who fail NHA. 
1.1.1.2 
Standard-of-care therapy in mCRPC who have failed abiraterone acetate 
and/or enzalutamide and docetaxel (+/-cabazitaxel) 
Limited data are available for patients who failed both NHA and at least one taxane-based 
chemotherapy. As expected, in general, responses to treatments decrease with more lines of prior 
therapies, while differences in prognostic baseline factors still confer heterogeneity in clinical response 
measured by rPFS and OS (Caffo et al 2015). Additional data by (Mateo et al 2015 and Azad et al 
2015) indicate a median overall survival of up to 10 months for these very advanced patients, 
reflecting a high unmet medical need for mCRPC patients who have failed prior NHA(s) and prior 
taxane(s). 
1.1.2 
Research hypothesis 
Single agent olaparib at 300 mg bid has superior efficacy and an acceptable tolerability profile as 
compared with enzalutamide or abiraterone acetate in mCRPC patients with deleterious or suspected 
deleterious HRR gene mutations and who have previously failed treatment with an NHA such as 
enzalutamide or abiraterone acetate. The efficacy in this study will be assessed by the primary analysis 
of rPFS defined as the time from randomization until the date of objective radiological disease 
progression or death. Radiological assessments (RECIST 1.1 for soft tissue and PCWG3 for bone) will 
be based upon blinded, independent central review (BICR). 
1.1.3 
PARP inhibition as a target for HRR mutation positive mCRPC 
Investigators should be familiar with the current olaparib (AZD2281) Investigator Brochure (IB). 
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP-ribose)] 
polymerization (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 tumors with deficiencies in 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 DNA double-strand breaks (DSBs) during the 


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process of DNA replication. During the process of cell division, DSBs can be efficiently repaired in 
normal cells by homologous recombination repair (HRR). Tumors with homologous recombination 
deficiencies (HRD), such as mCRPC in patients with BRCA1, BRCA2, ATM or other HRR gene 
mutations, cannot accurately repair the DNA damage, which may become lethal to cells as it 
accumulates. In such tumor types, olaparib may offer a potentially efficacious and less toxic cancer 
treatment compared with currently available taxane-based chemotherapy regimens.  
HRR defective tumors are intrinsically sensitive to PARP inhibitors, both in tumor models in vivo 
(Rottenberg et al 2008, Hay et al 2009) and in the clinic (Fong et al 2009, Tutt et al 2010, Mateo et al 
2015, and Kaufman et al 2015). The main mechanism of action for olaparib results from the trapping 
of inactive PARP onto the single-strand breaks preventing their repair (Helleday 2011 and Murai et al 
2012). Persistence of SSBs during DNA replication results in their conversion into the more serious 
DNA DSBs that would normally be repaired by homologous repair. Olaparib has been shown to inhibit 
selected tumor cell lines in vitro and in xenograft and primary explant models as well as in genetic 
BRCA knockout models, either as a stand-alone treatment or in combination with established 
chemotherapies. 
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 e.g., dog cardiovascular 
and respiratory function tests, and the rat Irwin test. There were no noticeable effects on the 
cardiovascular or respiratory parameters in the anesthetized dog or any behavioral, autonomic or motor 
effects in the rat at the doses studied.  
Rodent and dog toxicology studies have indicated that the primary target organ of toxicity is the bone 
marrow with recovery seen following the 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. 
AstraZeneca considers that the advanced prostate cancer patient population involved in this study falls 
under the advanced cancer, limited life expectancy definition outlined in ICH S9 guideline "Non-
clinical Evaluation For Anticancer Pharmaceuticals" and meets the requirements outlined in the 
guideline. Further information can be found in the current version of the olaparib IB 
1.1.6 
Clinical experience 
Clinical experience with olaparib is fully described in the current version of the olaparib IB. 


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1.1.6.1 
Preliminary Report of Olaparib Activity in Prostate Cancer (Sandhu et al 
2013) 
The first report of olaparib monotherapy activity in advanced prostate cancer came from 3 patients 
with advanced prostate cancer and germline BRCA2 mutations who were treated in Phase I studies. 
Each patient was castration-resistant before the start of olaparib therapy and 1 of them also received 
previous docetaxel and abiraterone acetate. Duration of olaparib treatment (300 mg bid tablet) ranged 
from 11 to 34 months for the 3 patients. The post-NHA post-taxane patient experienced a RECIST 
partial response and a PSA response (from 63 to 3.8 μg/l) under olaparib and remained on treatment 
for > 26 months. 
1.1.6.2 
TOPARP A (Mateo et al 2015) 
TOPARP A was a multicenter phase 2 investigator-initiated single arm study (NCT01682772) in 
mCRPC patients conducted in the United Kingdom. Prior pre-treatment with docetaxel was required 
and almost all patients had at least one prior NHA, which rendered TOPARP A, a third line and above 
setting. Olaparib was administered daily at 400 mg bid tablets. The primary endpoint, composite 
response rate (RR), was defined as either objective response by RECIST 1.1 and/or PSA fall ≥50% 
and/or circulating tumor cell (CTC) count falls from ≥5 to <5/7.5 ml blood (Veridex™). For these 
components to each count as a primary endpoint event, confirmation by a second measurement at least 
4 weeks later was required. The secondary endpoints for the study included safety, tolerability, 
progression-free survival (PFS), and overall survival (OS). Exome, transcriptome, targeted next-
generation sequencing (NGS) and digital PCR tests were conducted from mandated biopsies (in 43 
patients, mCRPC biopsy material was suitable for NGS, in the remaining 6 patients archival tumor 
tissue obtained at initial diagnosis was analyzed). Overall, 50 patients were enrolled; prior treatments 
included docetaxel (100%), cabazitaxel (58%), abiraterone acetate (96%), enzalutamide (28%), and 
palliative radiotherapy (26%). 
Efficacy (overall population) 
In the full population of evaluable patients (n = 49; one patient was lost to follow-up after 1 week and 
deemed non-evaluable by DMC, 16 (32.7%) responded to olaparib (95% CI: 20.0-47.5) by the 
composite response definition with 12 patients on treatment for >6 months.  Six of 32 RECIST 1.1 
measurable patients had radiological responses (18.8 %), and 11 patients had a biochemical response 
defined as a ≥50% decrease in PSA levels. Four of these responses lasted more than 1 year.  
Efficacy by biomarker status 
NGS identified homozygous deletions and/or deleterious mutations in DNA repair genes in 16/49 
(32.7%) cases, including eight (8) patients with BRCA1, BRCA2 and 5 with ATM alterations.  Of the 
sixteen patients with DNA repair mutations, 14 (87.5%) responded to olaparib by the composite 
response definition including all 7/7 patients with BRCA2 loss (4 bi-allelic somatic loss; 3 germline 
mutations) and 4/5 patients with ATM aberrations.  Few responses were observed in biomarker-
negative patients (no DNA repair mutations; 2/33 = 6% RR). Table 1 illustrates composite response 
rates by biomarker status. 


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Table 1 
Composite response rates (primary endpoint) by biomarker 
status (Mateo et al 2015) 
Biomarker 
Responder 
Total (n=49) 
No (n=33) 
Yes (n=16) 
Negative 
31 (93.9%) 
2 (6.1%) 
33  
Positive 
2 (12.5%) 
14 (87.5%) 
16 
 
Median rPFS of the 16 marker positive patients was 9.8 months with a median OS of 13.8 months, as 
opposed to a markedly lower median rPFS of 2.7 months with a median OS of 7.5 months in patients 
without DNA repair gene mutations (Mateo et al 2015).  
Time on treatment ranged from 24 to 48 weeks (mean = 39 and median = 40 weeks) among the 7 
patients with BRCA2 mutations and from 11 to 73 weeks (mean = 43 and median = 57 weeks) among 
the 5 patients with ATM mutations. There were 3 patients still being treated with olaparib among the 
BRCA2 subgroup at data cut-off.  
Safety:  
The most frequently observed AEs (all grades; irrespective of causality) were anemia (76%), fatigue 
(58%), nausea (36%) and arthralgia (30%).  The most common grade >3 adverse events were anemia 
(20%) and fatigue (12%), with 26% of patients requiring a dose reduction.   
1.2 
Rationale for study design, doses and control groups 
Based on data from the TOPARP A study (Mateo et al 2015) a decision was made to require the 
presence of a qualifying tissue HRR gene mutation as an inclusion criterion for patients with mCRPC 
who have failed prior therapy with an NHA. The molecular analysis will be performed by a designated 
central diagnostic provider (Foundation Medicine, Inc.) using an NGS assay, the investigational 
Lynparza HRR Assay. The rationale for only using BRCA1, BRCA2 and ATM tissue mutations for the 
primary endpoint (Cohort A) is based upon the prevalence of these mutations and/or how well 
mutations in these genes are characterized to date. It is expected that qualifying mutations will be 
detectable in the tissue of about one out of 10 mCRPC patients.  
While the TOPARP A trial was limited to patients who had failed both NHA and a taxane, this study 
will also enroll patient not yet having received taxane chemotherapy for mCRPC as there is a medical 
need for patients failing NHA both pre- and post-taxane (see Section 1.1.1.1 and Section 1.1.1.2) and 
as the biological activity of olaparib is expected to be independent of prior taxane therapy.  
The randomization will be 2:1 (olaparib vs. enzalutamide or abiraterone acetate). Enzalutamide and 
abiraterone acetate were chosen as comparators for the following reasons: 


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• 
Enzalutamide and abiraterone acetate are broadly approved for the treatment of mCRPC. 
Switch to the alternate NHA mirrors a relevant real-world scenario for a situation in which 
no single standard of care exists (Vogelzang et al 2016). 
• 
Similar efficacy compared to docetaxel in post-NHA setting (Sun and Chen 2010 and 
Suzman et al 2014), but oral availability and superior tolerability compared to taxanes make 
them the preferred treatment of choice. 
• 
Documented effectiveness both pre and post docetaxel (de Bono et al 2011, Ryan et al 2013, 
Scher et al 2012 and Beer et al 2014). 
Due to the open-label design of the study, rigorous methodology will be employed to ensure 
robustness of the primary endpoint assessment with the primary analysis of rPFS based on blinded 
independent central review (BICR) of all scans. Also, acknowledging the bone predominance of 
mCRPC and the particular challenges of determining bone progression in patients with high skeletal 
tumor burden (Kluetz et al 2013), progression in bone will require confirmation by a repeat scan at 
least 6 weeks later as outlined in detail by PCWG3 criteria (Scher et al 2016).  
The dose used in TOPARP A (400 mg tablets bid) was chosen at a time when information on the 
relative clinical activity with the tablet formulation was not fully complete; as a 300 mg bid tablet dose 
is now considered maximally effective and used across the ongoing olaparib development program, 
this dose has been chosen for this study. 
1.2.1 
Rationale for developing the Lynparza Homologous Recombination Repair 
(HRR) Assay  
AstraZeneca has partnered with Foundation Medicine, Inc.  (FMI) to develop a novel tumor tissue-
based companion diagnostic – the Lynparza HRR Assay – for the detection of mutations in a panel of 
15 HRR genes. The 15 genes that comprise the Lynparza HRR Assay are a subset of the genes covered 
in the FoundationOne® comprehensive cancer panel: a clinical-grade cancer gene profiling test which 
analyzes the coding sequence of 310 cancer-related genes plus introns from select genes for variants 
and/or rearrangements. 
For each patient that passes tissue sample and sequencing quality control, FMI will generate a report 
specifying presence or absence of qualifying HRR gene mutations. A patient has a qualifying mutation 
if any deleterious or suspected deleterious mutation is found in the HRR genes. A mutation is regarded 
as deleterious if it results in protein truncation (which includes nonsense, frameshift, or consensus 
splice site mutations), or select missense mutations well-known to be deleterious in ClinVar/BIC 
databases. Furthermore, larger scale alterations such as genomic truncating rearrangements or 
homozygous deletions will also be classified as qualifying. Patients without qualifying HRR gene 
mutations as determined by the Lynparza HRR Assay will not be eligible for the study. 
1.3 
Benefit/risk and ethical assessment 
As the proposed study will be limited to biomarker-positive patients (i.e., those with qualifying 
mutations in BRCA1, BRCA2, or ATM [Cohort A] or other HRR genes [Cohort B]) for which strong 
clinical activity can be expected (Mateo et al 2015 and Kaufman et al 2015) and as olaparib has been 


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found to be well tolerated across various cancer entities, a positive benefit/risk profile is expected and 
no ethical issues are identified from exposing patients to olaparib within the planned registration trial. 
More detailed information about the known and expected benefits and risks of olaparib may be found 
in the current version of the olaparib IB. 
See Section 6.10.2 for information regarding the Data Monitoring Committee. 
1.4 
Study Design  
This is a prospective, multicenter, open-label, randomized phase 3 trial evaluating the efficacy and 
safety of olaparib (300 mg orally bid) versus investigator choice of either enzalutamide (160 mg orally 
od) or abiraterone acetate (1,000 mg orally od with 5 mg bid prednisone) in approximately 340 
subjects with mCRPC with qualifying HRR gene mutations who have failed prior treatment with an 
NHA. 
 
 Prior to randomization, approximately 5500 subjects will be centrally screened for 
eligibility based on tumor tissue testing using the Lynparza HRR assay (FMI, Cambridge MA). 
Subjects with BRCA1, BRCA2 or ATM qualifying gene mutations will be included in Cohort A 
whereas subjects with mutations among 12 other genes involved in HRR (BARD1, BRIP1, CDK12, 
CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L) will be 
included in Cohort B. Subjects will be randomized 2:1 to either olaparib or predeclared investigator 
choice of either enzalutamide or abiraterone acetate in each of the Cohorts A and B. Randomization 
will be stratified based on prior receipt of taxane chemotherapy (yes vs no) and presence of measurable 
disease at baseline (yes vs no). 


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Figure 1 
Study Diagram 
 
 
 


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2. 
STUDY OBJECTIVES 
2.1 
Primary objectives 
Primary Objective: 
Outcome Measure: 
To determine the efficacy (as assessed by 
rPFS) of olaparib versus investigator choice of 
enzalutamide or abiraterone acetate in subjects 
with mCRPC with BRCA1, BRCA2 or ATM 
qualifying mutations (Cohort A)  
• 
rPFS by BICR using RECIST 1.1 (soft tissue) 
and PCWG3 (bone) criteria 
2.2 
Secondary objectives 
Key Secondary Objective: 
Outcome Measure: 
To determine the efficacy (as assessed by 
ORR) of olaparib versus investigator choice of 
enzalutamide or abiraterone acetate in subjects 
with BRCA1, BRCA2 or ATM qualifying gene 
mutations (Cohort A)   
• 
Confirmed ORR by BICR assessment in subjects 
with measurable disease using RECIST 1.1 (soft 
tissue) and PCWG3 (bone) criteria 
To determine the efficacy (as assessed by 
rPFS) of olaparib versus investigator choice of 
enzalutamide or abiraterone acetate in subjects 
with HRR qualifying mutations (Cohort A+B). 
 
 
• 
rPFS by BICR using RECIST 1.1 (soft tissue) 
and PCWG3 (bone) criteria 
To determine the efficacy (as assessed by time 
to pain progression) of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in subjects with BRCA1, 
BRCA2 or ATM qualifying gene mutations 
(Cohort A)   
• 
Pain progression based on BPI-SF item 3 “worst 
pain in 24 hours” and opiate analgesic use (AQA 
score) 
To determine the efficacy (as assessed by 
overall survival) of olaparib versus investigator 
choice of enzalutamide or abiraterone acetate 
in subjects with BRCA1, BRCA2 or ATM 
qualifying gene mutations (Cohort A) 
• 
Overall survival (OS) 
 
 
 


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Other Secondary Objectives: 
Outcome Measure: 
To further assess the efficacy of olaparib 
versus investigator choice of enzalutamide or 
abiraterone acetate in subjects with BRCA1, 
BRCA2 or ATM qualifying gene mutations 
(Cohort A) 
• 
Time from randomization to the first SSRE 
• 
Time from partial or complete response in 
subjects with measurable disease (RECIST 1.1) 
to progression by BICR (DoR) 
• 
Time from randomization to opiate use for 
cancer-related pain 
• 
Confirmed ORR (RECIST 1.1) in soft tissue by 
BICR in subjects with measurable disease (Soft 
tissue response) 
• 
Proportion of Subjects achieving a ≥50% 
decrease in PSA from baseline to the lowest post-
baseline PSA result, confirmed by a second 
consecutive PSA assessment at least 3 weeks 
later (PSA50 response) 
• 
Proportion of Subjects achieving a decline in the 
number of CTCs from ≥ 5 cells/7.5mL to < 5 
cells/7.5mL whole blood (CTC conversion rate) 
• 
Time from randomization to second progression 
by investigator assessment of radiological or 
clinical progression or death (PFS2) 
To further assess the effect of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in subjects with BRCA1, 
BRCA2 or ATM qualifying gene mutations 
(Cohort A) on disease-related symptoms and 
health-related quality of life (HRQoL) 
  
• 
Pain severity progression based on BPI-SF Pain 
Severity domain/subscale and opiate analgesic 
use (AQA score) 
• 
Pain interference based on BPI-SF Pain 
Interference domain/subscale 
• 
FACT-P (FACT-P total score, trial outcome 
index [TOI], functional well-being [FWB], 
physical well-being [PWB], prostate cancer 
subscale [PCS], and FACT Advanced Prostate 
Symptom Index 6 [FAPSI 6]) 
• 
Proportion of Subjects with pain (BPI-SF item 3) 
score ≥ 4 points at baseline who have a decrease 
of ≥ 2 points in pain (BPI-SF item 3) and without 
≥ 1 point increase in analgesic score (AQA score) 
at 12 weeks, confirmed at least 3 weeks later 
(Pain palliation) 


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To assess the efficacy of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in subjects with HRR 
qualifying gene mutations other than BRCA1, 
BRCA2 or ATM (Cohort B). 
 
 
• 
rPFS by BICR using RECIST 1.1 (soft tissue) 
and PCWG3 (bone) criteria 
• 
Confirmed ORR by BICR assessment in subjects 
with measurable disease using RECIST 1.1 (soft 
tissue) and PCWG3 (bone) criteria 
• 
Pain progression based on BPI-SF item 3 "worst 
pain in 24 hours" and opiate analgesic use (AQA 
score) 
• 
OS 
To further assess the efficacy of olaparib 
versus investigator choice of enzalutamide or 
abiraterone acetate in subjects with HRR 
qualifying gene mutations (Cohort A+B). 
 
 
• 
Confirmed ORR by BICR assessment in subjects 
with measurable disease using RECIST 1.1 (soft 
tissue) and PCWG3 (bone) criteria 
• 
Time from randomization to the first SSRE 
• 
Time from partial or complete response in 
subjects with measurable disease (RECIST 1.1) 
to progression by BICR (DoR) 
• 
Time from randomization to opiate use for 
cancer-related pain 
• 
Confirmed ORR (RECIST 1.1) in soft tissue by 
BICR in subjects with measurable disease (Soft 
tissue response) 
• 
Proportion of Subjects achieving a ≥50% 
decrease in PSA from baseline to the lowest post-
baseline PSA result, confirmed by a second 
consecutive PSA assessment at least 3 weeks 
later (PSA50 response) 
• 
Proportion of Subjects achieving a decline in the 
number of CTCs from ≥ 5 cells/7.5mL to < 5 
cells/7.5mL whole blood (CTC conversion rate) 
• 
Time from randomization to second progression 
by investigator assessment of radiological or 
clinical progression or death (PFS2)  
• 
OS 


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To further assess the effect of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in subjects with HRR 
qualifying gene mutations (Cohort A+B) on 
disease-related symptoms and health-related 
quality of life (HRQoL). 
 
 
  
• 
Pain progression based on BPI-SF item 3 “worst 
pain in 24 hours” and opiate analgesic use (AQA 
score) 
• 
Pain severity progression based on BPI-SF Pain 
Severity domain/subscale and opiate analgesic 
use (AQA score).   
• 
Pain interference based on BPI-SF Pain 
Interference domain/subscale 
• 
FACT-P (FACT-P total score, trial outcome 
index [TOI], functional well-being [FWB], 
physical well-being [PWB], prostate cancer 
subscale [PCS] and FACT Advanced Prostate 
Symptom Index 6 [FAPSI 6])  
• 
Proportion of Subjects with pain (BPI-SF item 3) 
score ≥ 4 points at baseline who have a decrease 
of ≥ 2 points in pain (BPI-SF item 3) and without 
≥ 1 point increase in analgesic score (AQA score) 
at 12 weeks, confirmed at least 3 weeks later 
(Pain palliation) 
To determine the exposure to olaparib in a 
subset of subjects receiving olaparib. 
 
 
• 
Olaparib plasma concentration data 
2.3 
Safety objectives 
Safety Objective: 
Outcome Measure: 
To evaluate the safety and tolerability of 
olaparib versus investigator choice of 
enzalutamide or abiraterone acetate 
• AEs/SAEs 
• Collection of clinical chemistry/hematology 
parameters 
2.4 
Exploratory objectives   
These exploratory objective analyses may be reported separately from the clinical study report. 
Exploratory Objective: 
Outcome Measure: 
To compare the effect of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate on patient-reported 
treatment tolerability and overall health status  
• PRO-CTCAE 
• PGIC 


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To compare the effect of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in subjects with BRCA1, 
BRCA2 or ATM qualifying mutations (Cohort 
A) based on prior receipt of taxane  
• Subgroup analysis of rPFS in subjects with or 
without prior taxane 
To compare the effect of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in subjects with either 
germline or somatic BRCA1, BRCA2 or ATM 
qualifying mutations (Cohort A).  
• Subgroup analysis of rPFS based on whether the 
qualifying mutation is a germline mutation or 
only in the tumor (somatic)  
To compare the effect of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in subjects with BRCA1, 
BRCA2, or ATM qualifying mutations as 
detected by ctDNA analysis. 
 
 
• rPFS analysis in patients with qualifying mutation 
identified by ctDNA test 
To compare the effect of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in subjects with HRR 
qualifying mutations as detected by ctDNA 
analysis. 
 
 
• rPFS analysis in patients with qualifying mutation 
identified by ctDNA test 
To explore methods of estimating OS adjusting 
for the impact of the control arm receiving 
subsequent PARP inhibitors (including 
olaparib), platinum compounds or imbalances 
between the treatment arms for other 
potentially active agents 
• OS adjusted for impact of subsequent PARP 
inhibitors (or other potentially active 
investigational agents) 
To compare the tumour HRR gene mutation 
status in all screened subjects with evaluable 
results from plasma. 
 
 
• Comparison of HRR gene mutation status 
between tumor DNA and plasma derived ctDNA 


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Future exploratory research into factors that 
may influence development of cancer and/or 
response to study treatment (where response is 
defined broadly to include efficacy, tolerability 
or safety) may be performed on the collected 
and stored archival tumor samples that were 
mandatory for entry onto the study or on blood 
samples. 
 
  
• 
Evaluate loss of heterozygosity of HRR genes in 
tumors 
• 
Evaluation of ctDNA collected from plasma at 
baseline and at progression 
• 
CTCs (EPIC assay) 
To collect and store DNA (according to each 
country’s local and ethical procedures) for 
future exploratory research into genes/genetic 
variation that may influence response (i.e., 
distribution, safety, tolerability and efficacy) to 
study treatments and or susceptibility to 
disease (optional) 
• 
Blood sample pharmacogenetics analysis 
To investigate the health economic impact of 
treatment and the disease on hospital related 
resource use and health state utility  
• 
Number, type and reason of hospitalizations and 
hospital attendances, procedures conducted and 
hospital length of stay (HOSPAD) 
• 
EQ-5D-5L 
3. 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL  
Each subject must 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.  
Following written informed consent, all subjects will undergo central HRR gene mutation status 
assessment using the Lynparza HRR Assay (see Section 5.7.1 and Section 5.7.2) and initial eligibility 
criteria review, as defined by the marked criteria (*) in Section 3.1 Inclusion criteria and Section 3.2 
Exclusion criteria, below. 
Subjects should not be pre-screened based on prior germline results since approximately half of 
subjects are expected to carry mutations only in the tumor and not germline.  In addition, subjects may 
undergo testing using HRR Lynparza Assay before progression on NHA. 
3.1 
Inclusion criteria 
For inclusion in the study subjects should fulfill the following criteria: 
1. 
*Provision of informed consent prior to any study-specific procedures.  
2. 
*Male ≥ 18 years of age.  
3. 
*Histologically confirmed diagnosis of prostate cancer. 


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4. 
*Candidate for treatment with enzalutamide or abiraterone acetate with documented 
current evidence of metastatic castration-resistant prostate cancer, where metastatic status 
is defined as at least one (1) documented metastatic lesion on either bone scan or CT/MRI 
scan. Subjects whose disease spread is limited to regional pelvic lymph nodes or local 
recurrence (e.g., bladder, rectum) are not eligible. 
5. 
Subjects must have progressed on prior NHA (e.g., abiraterone acetate and/or 
enzalutamide) for the treatment of metastatic prostate cancer and/or CRPC.  Determination 
of progression is done per local investigator. 
6. 
Serum testosterone levels ≤ 50 ng/dL (≤ 1.75 nmol/L) within (≤) 28 days before 
randomization. 
7. 
*Subjects without prior surgical castration must be currently taking and willing to continue 
luteinizing hormone-releasing hormone (LHRH) analog (agonist or antagonist) therapy 
throughout the duration of study treatment. 
8. 
Radiographic progression at study entry while on androgen deprivation therapy (or after 
bilateral orchiectomy).  Determination of progression is done per local investigator. 
9. 
Qualifying HRR mutation in tumor tissue by the Lynparza HRR Assay (see Section 5.7.1 
and Section 5.7.2). 
− 
Either archival or de novo biopsies are acceptable. 
− 
If subjects have a mutation in one of the 15 HRR genes based on prior prostate 
cancer tissue specimen testing by the commercially available FoundationOne ® 
assay, they must have the mutation confirmed as a qualifying mutation by FMI. 
Residual DNA (stored at FMI) from the original FoundationOne test will be used 
for confirmation. Subjects who do not have sufficient residual DNA from their 
original test will be analysed in-silico for qualifying HRR gene mutations based 
on their original FoundationOne test data, but these subjects must supply 
sufficient formalin fixed, paraffin embedded (FFPE) tumor sample to carry out 
retrospective central confirmation using the Lynparza HRR Assay (see Section 
5.7.2). 
 
 
10. 
Subjects must have normal organ and bone marrow function measured within (≤) 28 days 
prior to administration of study treatment as defined below: 
− 
Hemoglobin ≥ 10.0 g/dL with no blood transfusions in the past 28 days. 
− 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. 
− 
Platelet count ≥ 100 x 109/L. 


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− 
Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  
− 
Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase 
(SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate 
Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present in which case they must be ≤ 5x ULN. 
− 
Subjects must have creatinine clearance estimated of ≥51 mL/min using the 
Cockcroft-Gault equation for males or based on a 24 hour urine test.  
Estimated creatinine clearance = 
(140-age [years]) x weight (kg) 
 
 
 
 
  
serum creatinine (mg/dL) x 72 
11. 
*Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see Appendix H). 
12. 
*Subjects must have a life expectancy ≥ 16 weeks. 
13. 
Must use a condom during treatment and for 3 months after the last dose of olaparib when 
having sexual intercourse with a pregnant woman or with a woman of childbearing 
potential.  Female partners of male subjects should also use a highly effective form of 
contraception ([see Appendix F for acceptable methods]) if they are of childbearing 
potential. 
14. 
*Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations at the institution, 
and completing electronic PRO instruments. 
For inclusion in i) the optional exploratory genetic research, subjects must fulfill the following criteria: 
− 
Provision of informed consent for genetic research. 
If a subject declines to participate in the optional exploratory genetic research, there will be no penalty 
or loss of benefit to the subject. The subject will not be excluded from other aspects of the study. 
3.2 
Exclusion criteria 
Subjects 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 and/or staff at the study site). 
2. 
*Previous randomization in the present study. 
3. 
Participation in another clinical study with an investigational product during the last 30 
days prior to randomization.  
4. 
*Any previous treatment with PARP inhibitor, including olaparib. 


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5. 
*Subjects who have any previous treatment with DNA-damaging cytotoxic chemotherapy, 
except if for non-prostate cancer indication and last dose > 5 years prior to randomization. 
For example, subjects who have received prior mitoxantrone or platinum-based 
chemotherapy for prostate cancer are excluded.  
− 
Prior estramustine is allowed.  
6. 
*Other malignancy (including MDS and MGUS) within the last 5 years except: adequately 
treated non-melanoma skin cancer or other solid tumors including lymphomas (without 
bone marrow involvement) curatively treated with no evidence of disease for ≥5 years. 
7. 
*Subjects with myelodysplastic syndrome/acute myeloid leukemia or with features 
suggestive of MDS/AML. 
8. 
Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged 
by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, 
congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or 
patients with congenital long QT syndrome. 
9. 
Subjects receiving any systemic anti-cancer therapy (except radiotherapy) within 3 weeks 
prior to study treatment. 
− 
Agents to maintain castrate status are authorized as detailed in inclusion criterion 
#7. Agents such as 5-α reductase inhibitors (finasteride, dutasteride), estrogen 
compounds (including estramustine) and megesterol are considered as anti-cancer 
agent and prohibited within 3 weeks prior to study treatment. 
− 
Bone-targeted therapy with denosumab or zoledronic acid is allowed. If subjects 
are being treated with these agents, they should be on a stable regimen when 
entering the study. 
10. 
*Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., 
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout 
period prior to starting olaparib is 2 weeks. 
11. 
*Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or 
moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout 
period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents. 
12. 
*Persistent toxicities ( > grade 2, per the Common Terminology Criteria for Adverse 
Event (CTCAE)) caused by previous cancer therapy, excluding alopecia or toxicities 
related to the use of LHRH agonist or antagonist. 


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13. 
*Subjects with known brain metastases. A scan to confirm the absence of brain metastases 
is not required.  
14. 
*Subjects with spinal cord compression unless considered to have received definitive 
treatment for this and evidence of clinically stable disease for 28 days. 
15. 
Subjects inevaluable for both bone and soft tissue progression as defined by meeting both 
of the following criteria:  
(a) 
A bone scan referred to as a superscan showing an intense symmetric activity in the 
bones. 
(b) 
No soft tissue lesion (measurable or non-measurable) that can be assessed by 
RECIST. 
16. 
Major surgery within 2 weeks of starting study treatment and subjects must have 
recovered from any effects of any major surgery. 
17. 
*Subjects considered a poor medical risk due to a serious, uncontrolled medical disorder, 
non-malignant systemic disease or active, uncontrolled infection.  Examples include, but 
are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) 
myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord 
compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on 
High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that 
prohibits obtaining informed consent. 
18. 
*Subjects unable to swallow orally administered medication and subjects with 
gastrointestinal disorders likely to interfere with absorption of the study medication. 
19. 
*Immunocompromised subjects, e.g., subjects who are known to be serologically positive 
for human immunodeficiency virus (HIV). 
20. 
*Subjects with a known hypersensitivity to olaparib or any of the excipients of the 
product. 
21. 
*Subjects with known active hepatitis (i.e., Hepatitis B or C)    
− 
Active hepatitis B virus (HBV) is defined by a known positive HBV surface 
antigen (HBsAg) result.  Subjects with a past or resolved HBV infection (defined 
as the presence of hepatitis B core antibody and absence of HBsAg) are eligible.   
− 
Subjects positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA.  
22. 
*Previous allogeneic bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT). 


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23. 
*Whole blood transfusions in the last 120 days prior to entry into the study (packed red 
blood cells and platelet transfusions are acceptable, for timing, refer to inclusion criteria 
no.10). 
For procedures for withdrawal of incorrectly enrolled subjects, see Section 3.4. 
3.3 
Subject enrollment and randomization 
Investigator(s) should keep a record, the subject screening log, of subjects who entered pre-study 
screening. 
The Investigator(s) will: 
1. 
Obtain signed informed consent from the potential subject before any study-specific 
procedures are performed. 
2. 
Assign potential subject a unique enrollment number (i.e., E-code) using the centralized 
Interactive Voice/Web Response System (IVRS/IWRS). The E-code is sequentially issued 
and will be used to identify the subject on all study-related documents including the 
electronic case report form (eCRF).  
3. 
Determine subject eligibility. See Sections 3.1 and 3.2.  
4. 
The investigator must declare their choice of either enzalutamide or abiraterone acetate 
using the IVRS/IWRS.  
5. 
Assign eligible subject unique randomization code  
If the subject is found to be ineligible during screening, the subject must be screen failed in the 
IVRS/IWRS. Specific directions concerning the use of the IVRS/IWRS will be provided in a separate 
instruction manual.  If a subject withdraws from participation in the study then his assigned codes 
cannot be reused. 
3.4 
Procedures for handling incorrectly enrolled or randomized 
Subjects 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be enrolled or 
receive study medication.  There can be no exceptions to this rule.  Subjects who are enrolled, but 
subsequently found not to meet all the eligibility criteria must not be randomized or initiated on 
treatment, and must be withdrawn from the study. 
Where a subject does not meet all the eligibility criteria but is randomized in error, or incorrectly 
started on treatment, the Investigator should inform the AstraZeneca study physician immediately, and 
a discussion should occur between the AstraZeneca study physician and the investigator regarding 
whether to continue or discontinue the subject from treatment. The AstraZeneca study physician must 
ensure all decisions are appropriately documented. 


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3.5 
Methods for assigning treatment groups 
Subjects in Cohort A and Cohort B will be randomized in a 2:1 ratio to olaparib or investigator choice 
of enzalutamide or abiraterone acetate.  
The randomization codes will be computer generated using a randomization system (AZRand) and 
loaded into the interactive voice response system/interactive web response system (IVRS/IWRS) 
database. A blocked randomization list will be generated to ensure an approximate balance between 
the olaparib and enzalutamide or abiraterone acetate arms in Cohorts A and B (2:1). The 
randomization will be stratified by previous taxane use (yes, no) and whether subject had measurable 
disease (yes, no). 
Randomization will be done centrally via IVRS/IWRS after subject eligibility is established and prior 
to treatment. Every effort should be made to minimize the time between randomization and starting the 
study drug. It is recommended that subjects commence study drug as soon as possible after 
randomization. 
Separate randomization schedules will be generated for Cohorts A and B as follows: 
1. 
Cohort A: Subjects with mCRPC with previous NHA among subjects with either a 
BRCA1, BRCA2 or ATM qualifying gene mutation. Subjects will be randomized either to 
olaparib or investigator choice of enzalutamide or abiraterone acetate.  
2. 
Cohort B: This cohort will assess olaparib activity among subjects in the same setting but 
with qualifying mutations among 12 other genes involved in the HRR pathway (BARD1, 
BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, 
RAD51D and RAD54L). Subjects will be randomized either to olaparib or investigator 
choice of enzalutamide or abiraterone acetate 
For each subject, the IVRS/IWRS will identify a unique kit ID number corresponding to the 
randomization code matching the treatment arm assigned to the subject. Following treatment 
allocation, the first dose of study medication should be administered to the subject after completion of 
study visit procedures. At subsequent dispensing visits, the subject will be dispensed medication with 
the kit ID as allocated by the IVRS/IWRS.  
If a subject receives incorrect treatment at any time during the study, the center must immediately 
notify the AstraZeneca representative and IVRS/IWRS contact for immediate correction, where 
possible.  
3.6 
Methods for ensuring blinding 
Not applicable. 
3.7 
Methods for unblinding  
Not applicable. 
3.8 
Restrictions 
For restricted medications please see Section 7.7. 


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3.8.1 
Grapefruit juice 
It is prohibited to consume grapefruit juice while on olaparib therapy. 
3.8.2 
Contraception  
Subjects must use a condom during treatment and for 3 months after the last dose of olaparib when 
having sexual intercourse with a pregnant woman or with a woman of childbearing potential.  Female 
partners of male subjects should also use a highly effective form of contraception (as described in 
Appendix F) if they are of childbearing potential.  Subjects should not donate sperm throughout the 
period of taking olaparib and for 3 months following the last dose of olaparib. 
For details of acceptable methods of contraception refer to Appendix F Acceptable Birth Control 
Methods. 
3.8.3 
Blood donation 
Subjects should not donate blood or plasma while participating in this study and for 3 months 
following the last dose of study treatment. 
3.9 
Discontinuation of investigational product 
Subjects may be discontinued from investigational product (IP) in the following situations: 
• 
Subject decision: The subject is at any time free to discontinue treatment, without 
prejudice to future treatment 
• 
Adverse Event 
• 
Severe non-compliance with the study protocol  
• 
Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute myeloid 
leukemia (AML)  
• 
Objective radiographic progression by blinded independent central review (BICR) as 
defined in Section 5.1.2.  
• 
Unequivocal clinical progression: 
− 
Cancer pain requiring initiation of chronic administration of opioids, or 
− 
Immediate need to initiate cytotoxic chemotherapy, radiation therapy, or surgical 
intervention for complications due to tumor progression, or 
− 
Deterioration in ECOG performance status to ≥ Grade 3.  
• 
Initiation of restricted anticancer therapy (see Section 7.7).  
The reason for IP discontinuation will be recorded in the eCRF. 


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3.9.1 
Procedures for discontinuation of a subject from investigational product  
By discontinuing from IP, the subject is not withdrawn from the study. Subjects should be followed for 
progression (if discontinuation in the absence of progression) and OS following treatment 
discontinuation as per the study schedule.  If a subject is withdrawn from study, see Section 3.10. 
Any subject discontinuing investigational product should be seen at 30 days post discontinuation for 
the evaluations outlined in the study schedule (see study schedule Table 3). The subject’s tumor status 
should be assessed clinically and, if appropriate, disease progression should be confirmed by 
radiological assessment. After discontinuation of study medication, the principal Investigator/Sub-
Investigator 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 subject. In addition, they will 
record on the eCRF the date of discontinuation, the reasons, manifestation and treatment at the time of 
discontinuation. If subjects discontinue study treatment, the AstraZeneca monitor must be informed 
immediately. Subjects will be required to attend the treatment discontinuation visit (see study schedule 
Table 3). The subject should return all study medication. 
After discontinuation of the study medication at any point in the study, all ongoing AEs or SAEs must 
be followed until resolution unless, in the Investigator’s opinion the condition is unlikely to resolve 
due to the subjects underlying disease, or the subject is lost to follow up (see Section 6.3.2). All new 
AEs and SAEs occurring during the 30 calendar days after the last dose of study medication must be 
reported (if SAEs, they must be reported to AstraZeneca within 24 hours as described in Section 6.4) 
and followed to resolution as above. Subjects should be seen at least 30 days after discontinuing study 
medication to collect and / or complete AE information. For guidance on reporting adverse events after 
the 30 day follow up period see Section 6.3.1.1. 
After completing the treatment discontinuation visit and the 30 day safety follow-up visit, subjects will 
proceed directly with follow-up visits as defined in the study schedule (see Table 4). For subjects who 
discontinue study treatment after BICR progression, the first 12 week follow-up visit will be 12 weeks 
after the discontinuation of study treatment. Subjects who discontinue therapy prior to radiographic 
progression will continue with follow-up visits every 8 weeks per the original schedule until 
documentation of radiographic progression by BICR (see Table 4). There is no plan for BICR to read 
any scans dated after the date of data cut-off (DCO) for the primary analysis. There will be no need to 
request confirmation of BICR PD after this time point, and the investigator-assessed radiographic 
progression will prevail. 
 
All adverse events occurring after the 30 day 
safety follow-up visit will be assessed at the first follow-up visit.   
While it is preferred that follow-up visits post radiographic progression and discontinuation of study 
treatment are conducted in-person, subjects may proceed with a modified follow-up (i.e., through 
regular telephone contacts, every 12 weeks or a contact at study closure, if agreed to by the subject and 
in compliance with local data privacy laws/practices). All subjects will be followed until death or end 
of study (see Section 9.3). 
3.10 
Criteria for study withdrawal  
The term withdrawal from the study refers to both discontinuation from study treatment and study 
assessments.  
 


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Reasons for withdrawal from the study: 
• 
Voluntary withdrawal by the subject who is at any time free to discontinue their 
participation in the study, without prejudice to further treatment. 
• 
Incorrectly enrolled subjects i.e., the subject does not meet the required 
inclusion/exclusion criteria for the study. 
• 
Subject lost to follow-up. 
• 
Death. 
All subjects, unless they have refused to participate in any further follow–up, will be followed for 
survival up until death or end of study. If a subject wishes to withdraw from the study, this should be 
clearly documented in the eCRF. 
3.10.1 
Screen failures  
Screen failures are subjects who do not fulfill the eligibility criteria for the study, and therefore must 
not be randomized. These subjects should have the reason for study withdrawal recorded as ‘screen 
failed’ (i.e., subject does not meet the required inclusion/exclusion criteria) in IVRS/IWRS.  This 
reason for study withdrawal is only valid for screen failures (not randomized subject). 
In exceptional cases, where a subject has met HRR status and has screened failed eligibility for other 
criteria, the subject may be re-evaluated for study eligibility, as determined by the AstraZeneca 
physician, provided that they have not previously been randomized, assigned or received treatment 
(see Section 4.1.1). 
3.10.2 
Withdrawal of the informed consent 
Subjects are free to withdraw from the study (investigational product and assessments) at any time, 
without prejudice to further treatment. 
A subject who withdraws consent will always be asked about the reason(s) for withdrawal and the 
presence of any adverse events (AE). If the subject prefers not to provide a reason for withdrawal, it 
should be recorded as such. The Investigator will follow up AEs outside of the clinical study. The 
subject will return electronic PRO (ePRO) devices. 
If a subject withdraws from participation in the study, then his/her enrollment/randomization/treatment 
code cannot be reused. Withdrawn subjects will not be replaced.  
If a subject withdraws consent, they will be specifically asked if they are withdrawing consent to: 
• 
further participation in the study including any further follow up (e.g., survival calls)  
• 
the use of any samples (see Section 5.7.4) 
The status of ongoing, withdrawn (from the study) and “lost to follow-up” subjects at the time of an 
overall survival analysis should be obtained by the site personnel by checking the subject notes, 
hospital records, contacting the subject’s general practitioner and checking publicly available death 
registries.  In the event that the subject has actively withdrawn consent to the processing of their 


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personal data, the vital status of the subject can be obtained by site personnel from publicly available 
resources where it is possible to do so under applicable local laws. 
3.11 
Discontinuation of the study 
The study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed at undue risk 
because of clinically significant findings that are not considered to be consistent with continuation of 
the study. 
Regardless of the reason for termination, all data available for the Subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of treatment 
must be documented.   
In terminating the study, the Sponsor will ensure that adequate consideration is given to the protection 
of the subjects’ interests. 


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Date 07 March 2019 
 
 
 
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4. 
STUDY SCHEDULE AND TIMING OF PROCEDURES  
Figure 2 
Study Flow Chart 
 
 
 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
 
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Table 2 
Study Schedule – Screening (Part 1 and 2) 
 
Part 1 
All subjects 
Part 2 
 
Day 
 
-28 to -1 
 
Informed consent 
X 
X 
Demographics 
X 
 
Medical and surgical historya 
 
X 
Family history of cancer 
X 
 
Prior cancer therapies including radiotherapy 
 
X 
Inclusion/exclusion criteria 
X (all * criteria)h 
X 
ECOG Performance status (0-2) 
 
X 
BPI-SF, analgesic log (captured in ePRO)b 
 
X 
Physical examination 
 
X 
Vital signs (includes BP, pulse, and 
temperature), body weight 
 
X 
ECG 
 
X 
Hematology/clinical chemistryc  
 
X 
Blood sample for testosterone 
 
X 
Urinalysis 
 
X 
Tumor tissue sample for HRR statusd, e 
X 
 
Blood sample for germline HRR status testing  
 
X 
Blood sample for biomarker analysis (e.g,. 
ctDNA)k 
X 
 
Blood sample for germline testing (optional, 
subject consent required) j,  
X 
 
Tumor Assessment (Bone scan and CT/MRI)f 
 
X 
Adverse Events (from time of consent)g 
X 
X 
Concomitant medications 
 
Xi 
a 
Includes history of blood transfusion within previous 120 days from randomization and the reasons e.g., 
bleeding or myelosuppression. 
b 
Must be completed by subject daily for 7 consecutive days by prior to randomization 
c 
Coagulation test should be performed at screening and if clinically indicated.  For a list of all required 
laboratory tests please refer to Section 5.2.1. 


Clinical Study Protocol 
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d 
Subjects must have a confirmed qualifying HRR status based on the Lynparza HRR Assay to be eligible for 
the study. Subjects with known HRR status based on FoundationOne® assay may enroll pending 
documented confirmation of the qualifying mutation by FMI (see Section 5.7.2). 
e 
Tissue submitted for central HRR status testing with the Lynparza HRR Assay only after all (*) eligibility 
criteria in Part 1 have been met. 
f 
RECIST 1.1 assessments will be performed using CT scans of the chest, abdomen, and pelvis (or MRI 
where CT is contraindicated). Any other areas of disease involvement should be additionally imaged based 
on the signs and symptoms of individual subjects. Bone scans will be performed as detailed in Section 
5.1.2, consistent with PCWG3 criteria. Baseline assessments should be performed no more than 28 days 
before the date of randomization, and ideally, should be performed as close as possible to the start of study 
treatment. 
g 
In screening part 1, only SAEs related to study procedures must be reported (AEs do not require reporting). 
From screening part 2 onwards - all AEs/SAEs must be reported. 
h 
See Sections 3.1 and 3.2 for marked eligibility (*) criteria.  
i 
Includes all medication being taken from the start of screening part 2 and onwards. 
j  
Optional sample for future germline testing.  Sample will be stored for future testing to explore diagnostic 
test development and thus results will not be available to subjects or their treating physician (see Section 
5.7.3.1).  
 
 
 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
 
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Table 3 
Study Schedule – On Study Treatment and Discontinuation 
Visit Number 
2 
3 
4 
5 
6 
7 
Visit No. 8 
onwards 
Study treatment 
discontinued 
Safety  
Follow-up 
Week 
0 
(Day1) 
4 
8 
12 
16 
20 
24, 
And every 
subsequent 
8 weeks 
Last dose of 
study drug 
30 days after 
last dose 
Visit Window 
 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
Randomization 
X 
 
 
 
 
 
 
 
 
Physical exam a  
Xb 
 
 
 
 
 
 
 
 
Vital signs, body weight 
(includes BP, pulse and 
temperature) a 
Xb 
 
 
 
 
 
 
 
 
ECOG performance status  
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG a 
Xb 
 
 
 
 
 
 
 
 
Blood samples for PK 
analysis (subset of subjects)c  
 
X 
 
 
 
 
 
 
 
CTC blood sample 
(CELLSEARCH® assay) 
X 
 
X 
 
X 
 
X 
X 
 
CTC blood sample 
(EPIC assay)  
X 
 
 
 
 
 
Xe 
 
 
Hematology/clinical 
chemistryf 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis a 
Xb 
 
 
 
 
 
 
 
 


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Version 4.0 
Date 07 March 2019 
 
 
 
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Table 3 
Study Schedule – On Study Treatment and Discontinuation 
Visit Number 
2 
3 
4 
5 
6 
7 
Visit No. 8 
onwards 
Study treatment 
discontinued 
Safety  
Follow-up 
Week 
0 
(Day1) 
4 
8 
12 
16 
20 
24, 
And every 
subsequent 
8 weeks 
Last dose of 
study drug 
30 days after 
last dose 
Visit Window 
 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
Tumor Assessment (bone 
scan and CT/MRI)g h 
 
 
Xh 
 
Xh 
 
Xh 
Xi 
 
SSRE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
PSAj 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Eventsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
including blood transfusions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Opioid usel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPI-SF, analgesic log 
(captured in ePRO)  
To be completed by subject daily for 7 consecutive days every 4 weeks from the date of 
randomization (not required to be at site) 
PRO-CTCAE  
Every 2 weeks (starting on Day 1) for the first 8 weeks, then every 4 weeks 
EQ-5D-5L  
X 
 
X 
 
X 
 
X 
X 
 
FACT-P  
X 
 
X 
 
X 
 
X 
X 
 
Patient Global Impression of 
Change (PGIC)m 
 
 
X 
 
X 
 
X 
X 
 
Healthcare resource usen  
X 
 
X 
 
X 
 
X 
X 
X 
Study treatment 
dispensed/returned  
X 
X 
X 
X 
X 
X 
Xo 
X 
 


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Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
 
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Table 3 
Study Schedule – On Study Treatment and Discontinuation 
Visit Number 
2 
3 
4 
5 
6 
7 
Visit No. 8 
onwards 
Study treatment 
discontinued 
Safety  
Follow-up 
Week 
0 
(Day1) 
4 
8 
12 
16 
20 
24, 
And every 
subsequent 
8 weeks 
Last dose of 
study drug 
30 days after 
last dose 
Visit Window 
 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
Subsequent cancer therapy 
following discontinuation of 
study treatment p 
 
 
 
 
 
 
 
 
X 
Blood sample for 
pharmacogenetics (optional, 
subject consent required)d 
X 
 
 
 
 
 
 
 
 
Blood samples for biomarker 
analysis at progressiond  
 
 
 
 
 
 
Xe 
 
 
a 
To be additionally performed if clinically indicated at any other time. 
b 
If assessed within 7 days before randomization and meets the stated eligibility criteria (if applicable), it does not to be repeated on Day 1 of study 
treatment unless investigator believes that it is likely to have changed significantly.  
c 
PK sampling will be performed in a subset of subjects. At least 50 subjects assigned to olaparib treatment at pre-agreed sites will have PK assessment 
samples taken.  Sampling times: Pre-dose (- 30 min ± 15 min), 30 min ± 15 min, 2 ± 0.5 h, 5 ± 0.5 h, 8± 1 h.  Subjects should fast from 1 hour before 
olaparib dosing to 2 hours after. 
 
 
e 
Blood samples for biomarker analysis (e.g., ctDNA) and EPIC CTC to be taken at objective BICR-assessed radiological disease progression (i.e., not at 
every treatment visit), and post primary analysis, to be taken at investigator-assessed radiographic progression.  
f 
Safety blood samples do not need to be repeated on Day 1 of study treatment if assessed at least 3 weeks after the last dose of chemotherapy but within 7 
days before starting study treatment, unless the investigator believes that it is likely to have changed significantly. Coagulation test should be performed 
at screening and if clinically indicated. For a list of all required laboratory tests please refer to Section 5.2.1. 
g 
Follow-up assessments will be performed every 8 weeks (±7 days) relative to the date of randomization until radiographic progression as assessed by 
BICR, and post primary analysis, as assessed by investigator. Any other sites at which new disease is suspected should also be appropriately imaged. If 
an unscheduled assessment was performed and the subject has not progressed, every attempt should be made to perform the subsequent assessments at 
their scheduled visits. 


Clinical Study Protocol 
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Study Code D081DC00007 
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h 
Bone progression observed by bone scan requires confirmation by bone scan at least 6 weeks later (see Section 5.1.2). Soft tissue progression observed 
by CT or MRI, according to RECIST1.1 criteria, does not require a confirmatory scan. 
i 
Bone scan and CT scans of the chest, abdomen, and pelvis (or MRI where CT is contraindicated) should be conducted at the treatment discontinuation 
visit if radiographic progression has not yet been determined by BICR (including confirmatory scan for bone progression) and it has been ≥ 6 weeks 
since the last radiologic assessment (bone scan and CT/MRI), and post primary analysis, by investigator. 
j 
PSA values while on the study will not be reported to the site prior to final analysis. 
k 
All ongoing adverse events/serious adverse events (AEs/SAEs) and any new AEs/SAEs identified during the 30 calendar days follow up period after last 
dose of study medication must be followed to resolution. 
l 
Opioid use will be captured by the site in the eCRF. 
m 
See Section 5.3.1.4 for more information regarding the Patient Global Impression of Change (PGIC). 
n 
See Section 5.3.3 for more information regarding the healthcare resource use.  
o 
Sufficient study treatment should be dispensed for at least each treatment period plus overage, however additional treatment can be dispensed to subjects 
to last longer in accordance with local practice. 
p 
All anti-cancer treatments (including, but not limited to, chemotherapy and targeted agents), and the investigators opinion of response to them, post 
discontinuation of study treatment need to be recorded. 
 
 


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Study Code D081DC00007 
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Date 07 March 2019 
 
 
 
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Table 4 
Study Schedule – Follow-up Post Discontinuation of Study Treatment 
Visit Number 
Off-Treatment Follow-Up for 
Progression 
For subjects who discontinue therapy 
prior to BICR progression a 
2nd Progression and 
Survival Follow-Up 
Follow-up after BICR 
radiographic progression 
Visit Frequency 
Every 8 weeks per original schedule 
until radiographic progression  
Every 12 weeks  
Visit Window 
±7da 
±14d 
Adverse Events 
Xb 
Xb 
Tumor Assessment (bone 
scan and CT/MRI) 
Xc 
 
Opioid use k 
Xk 
Xk 
Blood sample for biomarker 
analysis at progression (e.g., 
ctDNA)  
Xd 
 
Healthcare resource use 
X 
 
Secondary malignancies incl. 
MDS/AML e  
X 
X 
Subsequent cancer therapy 
following discontinuation of 
study treatment f 
X 
X 
Time to second progression g 
 
Xg 
Survival h 
 
X 
BPI-SF, analgesic log 
(captured in ePRO) i j 
Every 4 weeks 
Every 4 weeks for 24 weeksj 
PRO-CTCAE j 
Every 4 weeks 
Every 4 weeks for 24 weeksj 
FACT-P j 
X 
Every 8 weeks for 24 weeksj 
EQ-5D-5L j 
X 
Every 8 weeks for 24 weeksj 
a 
Visit schedule for subjects who discontinue study treatment prior to radiographic progression determined by 
BICR. This includes subjects with ≥2 new lesions on a bone scan that has not been confirmed by a second 
scan ≥6 weeks later (see Section 5.1.2). Visits continue every 8 weeks (±7 days) per original study schedule 
until documentation of radiographic progression as assessed by BICR. Following radiographic progression 
subjects move to follow-up for 2nd progression and survival with visits every 12 weeks (±14 days) relative 
to the randomization date. Until the primary rPFS analysis all imaging assessment and study treatment 
should continue until objective disease progression as assessed by BICR. There is no plan for BICR to read 
any scans dated after the date of DCO for the primary analysis. There will be no need to request 
confirmation of BICR PD after this time point, and the investigator-assessed radiographic progression will 
prevail. 
b 
All ongoing adverse events/serious adverse events (AEs/SAEs) and any new AEs/SAEs identified during 
the 30 calendar days follow up period after last dose of study medication must be followed to resolution. 


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Study Code D081DC00007 
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c 
Imaging assessments (CT/MRI and bone scan) will be performed as per the original schedule every 8 weeks 
(±7 days) relative to date of randomization until radiographic progression as assessed by BICR and post 
primary analysis, by investigator.  Bone progression observed by bone scan requires confirmation by bone 
scan at least 6 weeks later (see Section 5.1.2).  Soft tissue progression observed by CT or MRI, according to 
RECIST1.1 criteria, does not require confirmation. 
d 
Blood samples for biomarker analysis (e.g., ctDNA) and EPIC CTC to be taken at objective radiological 
disease progression (i.e., not at every treatment visit), and post primary analysis, at investigator-assessed 
radiographic progression. 
e 
Since some cases of MDS/AML or new primary malignancies develop after discontinuing treatment with 
olaparib, investigators will be asked during the regular follow-up if the subject has developed MDS/AML 
or a new primary malignancy and prompted to report any cases as a SAE (or AE if at least one of the 
criteria for SAE is not met, such as for non-melanoma skin cancers, see Section 6.2) even after 
discontinuation of therapy and regardless of investigator’s assessment of causality or knowledge of the 
treatment arm (see Sections 6.1.1 and 6.3.1.1). 
f 
All anti-cancer treatments post discontinuation of study treatment (including, but not limited to, 
chemotherapy and targeted agents), and the investigators opinion of response need to be recorded. 
g 
Second progression is based on investigator assessment according to local standard clinical practice and 
includes both radiographic and clinical progression.  Second progression status will be reviewed every 12 
weeks following the progression event used for the primary variable PFS (i.e., first progression). 
h 
The status of ongoing, withdrawn (from the study) and “lost to follow-up” subjects at the time of an overall 
survival analysis should be obtained by the site personnel by checking the subjects notes, hospital records, 
contacting the subjects general practitioner and checking publicly available death registries, if allowable per 
local regulations. In the event that the subject has actively withdrawn consent to the processing of their 
personal data the vital status of the subject can be obtained by site personnel from publicly available 
resources where it is possible to do so under applicable local laws (see Section 3.10.2). In addition to their 
regular 12 weekly contact, subjects will be contacted in the 7 days following a specified date (data cut-off 
date) for the survival analysis. 
i 
BPI-SF and analgesic log to be completed by the subject on ePRO device daily, for 7 consecutive days 
every 4 weeks. 
j 
BPI-SF, analgesic log, PRO-CTCAE, FACT-P, and EQ-5D-5L assessments should continue for 24 weeks 
post discontinuation of randomized study treatment.  For subjects who discontinue treatment prior to BICR-
assessed radiographic progression or post primary analysis by investigator-assessed radiographic 
progression, these assessments should continue for 24 weeks post progression. 
k 
Opioid use will be captured by the site in the eCRF.  After treatment discontinuation, only patients with no 
on-treatment opioid use need to be followed until first opioid use.  Continued use does not need to be 
recorded. 
 
 
 
 


Clinical Study Protocol 
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Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
 
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Table 5 
Study Schedule – Subjects switching to olaparib 
Visit Number 
Switch to Olaparib 
Treatment Visits 
Treatment 
Discontinued 
Safety 
Follow-Up 
2nd Progression 
and Survival 
Follow-Up 
Visit Frequency 
Every 4 wks for 24 
weeks, then every 
12 wksa 
Date last dose 
of olaparib 
30 days after 
last dose of 
olaparib 
Every 12 wks 
after last dose of 
olaparib 
Visit Window 
±7d 
±7d 
±7d 
±14d 
Switch to Olaparib ICF 
X 
 
 
 
Physical exam b 
Xb 
 
 
 
Vital signs, body weight 
(includes BP, pulse and 
temperature) b 
Xb 
 
 
 
ECG b 
Xb 
 
 
 
Hematology/clinical 
chemistry 
X 
X 
X 
 
Urinalysis b 
Xb 
 
 
 
Adverse Events c 
X 
X 
X 
 
Concomitant medications 
including blood 
transfusions 
X 
X 
X 
 
Opioid use i 
Xi 
Xi 
Xi 
Xi 
Healthcare resource use 
X 
X 
 
 
Study treatment 
dispensed/returned 
X 
 
 
 
Subsequent cancer 
therapy following 
discontinuation of 
randomized treatment d 
X 
X 
X 
X 
Secondary malignancies 
including MDS/AML e  
X 
X 
X 
X 
Second Progression f 
X 
X 
 
X 
Survival g 
X 
X 
X 
X 
BPI-SF, analgesic usage 
(captured in ePRO) h 
Every 4 weeks for 24 weeks post discontinuation of randomized treatment 
PRO-CTCAE 
Every 4 weeks for 24 weeks post discontinuation of randomized treatment 
FACT-P 
Every 8 weeks for 24 weeks post discontinuation of randomized treatment 


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Study Code D081DC00007 
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a 
Visit schedule for subjects who switch to olaparib post BICR-assessed radiographic progression, or post 
primary analysis by investigator-assessed radiographic progression. Visits every 4 weeks (±7 days) for 24 
weeks following initiation of olaparib, then visits every 12 weeks (±14 days). 
b 
Only required at initiation of olaparib treatment.  To be additionally performed if clinically indicated at any 
other time. 
c 
All ongoing adverse events/serious adverse events (AEs/SAEs) and any new AEs/SAEs identified during 
the 30 calendar days follow up period after last dose of study medication must be followed to resolution. 
d 
All anti-cancer treatments post discontinuation of study treatment (including, but not limited to, 
chemotherapy and targeted agents), and the investigators opinion of response need to be recorded. 
e 
Since some cases [MDS/AML or new primary malignancies] developed after discontinuing treatment with 
olaparib, investigators will be asked during the regular follow-up for overall survival if the subject has 
developed MDS/AML or a new primary malignancy and prompted to report any cases as a SAE (or AE if at 
least one of the criteria for SAE is not met, such as for non-melanoma skin cancers, see Section 6.2) even 
after discontinuation of therapy and regardless of investigator’s assessment of causality or knowledge of the 
treatment arm. 
f 
Second progression is based on investigator assessment according to local standard clinical practice and 
includes both radiographic and clinical progression.  Second progression status will be reviewed every 12 
weeks following the progression event used for the primary variable PFS (i.e., first progression). 
g 
The status of ongoing, withdrawn (from the study) and “lost to follow-up” subjects at the time of an overall 
survival analysis should be obtained by the site personnel by checking the subjects notes, hospital records, 
contacting the subjects general practitioner and checking publicly available death registries. In the event 
that the subject has actively withdrawn consent to the processing of their personal data the vital status of the 
subject can be obtained by site personnel from publicly available resources where it is possible to do so 
under applicable local laws (see Section 3.10.2). In addition to their regular 12 weekly contact, subjects will 
be contacted in the 7 days following a specified date (data cut-off date) for the survival analysis. 
h 
BPI-SF and analgesic log to be completed by the subject on ePRO device daily, for 7 consecutive days 
every 4 weeks. 
i 
Opioid use will be captured by the site in the eCRF.  After treatment discontinuation, only patients with no 
on-treatment opioid use need to be followed until first opioid use.  Continued use does not need to be 
recorded. 
EQ-5D-5L 
Every 8 weeks for 24 weeks post discontinuation of randomized treatment 


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4.1 
Enrollment/screening period 
At screening, consenting subjects are assessed to ensure that they meet eligibility criteria. Subjects 
who do not meet these eligibility criteria must not be randomized. All screening and enrollment 
procedures will be performed according the assessment schedules in Table 2. 
Written informed consent and any locally required privacy act document authorization must be 
obtained prior to performing any protocol-specific procedures, including screening and baseline 
evaluations.    
All subjects are required to consent to supply a sample of their tumor (archived or newly biopsied) (see 
Section 5.7.2) sufficient for testing by the Lynparza HRR Assay, for entry into this study. All subjects 
will also be required to consent to a blood sample for exploratory biomarker research (see Section 
5.7.4). 
Screening evaluations (Part 2) may be performed over more than one visit and should be completed 
within the 28 day period prior to randomization within IVRS/IWRS. The subject will be entered into 
IVRS/IWRS upon enrollment into Screening (Part 1), prior to any other procedures being performed. 
At screening Part 2, the subject will be supplied with an electronic hand-held device to record patient 
reported outcome questionnaires and opiate analgesic use logging (see Section 5.3 for further details). 
Subjects will be asked to complete ePRO for 7 consecutive days before randomization. All efforts 
should be made to ensure that all ePRO data is collected. 
The subject’s eligibility should be evaluated during the screening period with the relevant 
documentation recorded in the subject source records and eCRF. If the subject is determined to be 
ineligible for study, during screening Part 1, they may be withdrawn by way of a telephone contact (for 
collection of SAE information only).  
4.1.1 
Re-Screening 
Subjects who are ineligible for study based on HRR status will be screen failed in the IVRS/IWRS and 
eCRF, should not continue with any remaining screening evaluations and are not permitted to enter the 
main study phase or be re-screened for study.  
Subjects who meet HRR eligibility at screening and screen fail during screening Part 2 may be 
considered for re-screening after discussion with the AstraZeneca physician. 
Where a subject is permitted to re-screen (by the AstraZeneca study physician), the same E-code 
initially assigned by the IVRS/IWRS should be used. The rationale and approval will be documented 
in the investigator study file (ISF). 
4.2 
Treatment period 
All procedures to be conducted during the treatment period will be performed according to the 
assessment schedule (see Table 3). 
Until the primary rPFS analysis, following randomization in IVRS/IWRS, subjects should receive 
assigned study treatment until determined to have objective radiographic progression according to 
Section 5.1.2 by BICR, or until unable to tolerate study treatment (see Section 7.2). After the date of 
DCO for the primary analysis, subjects should receive treatment until radiographic progression as 


Clinical Study Protocol 
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Date 07 March 2019 
 
 
 
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assessed by the investigator. Note that bone progression requires confirmation by a second bone scan ≥ 
6 weeks later (see Section 5.1.2). 
In the absence of tolerability issues, every effort should be made to keep subjects on assigned study 
treatment until progression by BICR. If the investigator makes a decision to initiate alternative anti-
cancer therapy before BICR-assessed radiological progression, unequivocal clinical progression needs 
to be documented as per Section 3.9. If study treatment is discontinued due to unequivocal clinical 
progression (in the absence of BICR-assessed radiographic progression), the investigator should obtain 
imaging scans at the treatment discontinued visit (see Table 3).  This includes confirmatory bone 
scans. Imaging assessments will continue until documentation of progression by BICR, irrespective of 
initiation of subsequent anti-cancer therapy (see Table 4). 
Access to olaparib for subjects randomized to comparator arm will only be possible upon BICR-
assessed progression, or after the date of DCO for the primary analysis, upon investigator-assessed 
radiographic progression, prior to initiation of subsequent anti-cancer therapy (see Section 4.2.1). 
4.2.1 
Subjects who switch to olaparib 
Once subjects on the investigator choice control arm are determined to have objective radiological 
progression by BICR, or after the date of DCO for the primary analysis, subjects are determined to 
have radiographic progression by the investigator, they will be eligible to receive olaparib (300 mg 
bid) and will follow the study schedule as per Table 5, as well as all safety reporting and medical 
management guidance (Section 6) and investigational product use and concomitant medication 
restrictions (Section 7). 
If a subject has been deemed to have objective disease progression according to investigator 
assessment, but not by BICR, he is not eligible to switch to olaparib at that time. Subjects should 
continue to receive randomized study treatment until progression determined by BICR. 
The following criteria must be met in order for a subject to switch to olaparib: 
• 
No intervening anti-cancer therapy following discontinuation of randomized treatment 
• 
Any unresolved toxicities from prior therapy should be controlled, and be no greater than 
CTCAE grade 1 at the time of starting olaparib treatment 
Subjects who switch to olaparib may continue treatment with olaparib as long as in the investigator’s 
opinion they are benefiting from treatment and they do not meet any other discontinuation criteria. 
If subjects are not eligible to switch to olaparib, or choose not to switch, they will enter into the follow-
up phase of the study (see Table 4), and other treatment options should be discussed by the 
investigator. 
4.3 
Follow-up period 
Descriptions of the procedures for this period are included in the study schedule (see Table 4) with 
exceptions of the following specific requirements for the follow-up period: 


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If treatment is discontinued due to BICR-assessed radiographic progression, or after the primary rPFS 
analysis due to investigator-assessed radiographic progression (see Section 5.1.2), the subject may 
select from two follow-up options, in order of preferred approach: 
1. 
The subject will return for all regular clinical visits and perform all scheduled assessments 
until end of study (see Table 4) or, 
2. 
The subject will be followed up every 12 weeks by telephone call until end of study, and 
continuing ePRO completion for the first 6 months after treatment discontinuation. No 
further study procedures will be performed. 
For option 2, AEs including SAEs and subsequent anti-cancer therapies are the minimum elements to 
be collected at each contact. Subjects may switch from a higher contact option to a lower contact 
option, during the follow-up period. Subjects who elect not to undergo follow-up after discontinuing 
from the initial treatment period will be withdrawn from study.   
5. 
STUDY ASSESSMENTS 
The RAVE 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 eCRFs. A copy of the completed eCRFs will be archived at the 
study site. 
5.1 
Efficacy assessments 
5.1.1 
Imaging tumor assessments 
All imaging assessments including unscheduled visit scans should be collected on an ongoing basis 
and sent to an AstraZeneca (AZ) appointed Clinical Research Organization (CRO) to enable 
independent central review. Upon investigator-assessed objective disease progression as defined in 
Section 5.1.2, review of all scans will be conducted by BICR. The results will be reported back to the 
sites. All imaging assessments and study treatment should continue until objective disease progression 
as assessed by BICR (see Figure 3).  
The baseline assessments of all imaging modalities should be performed as close as possible to the 
start of study treatment and no more than 4 weeks (-28 days) before randomization. Following the 
baseline assessment, subsequent assessments should be performed every 8 weeks (± 7 days), relative to 
the date of randomization, until objective radiological disease progression by BICR, even after 
investigator has deemed objective disease progression, irrespective of treatment decisions or dose 
interruptions.  The assessments by different imaging modalities can be done on different days but 
should all be performed within assessment schedule. It is important to follow the imaging assessment 
schedule as closely as possible (see Table 3). If scans are performed outside of scheduled visit window 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D081DC00007 
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interval, and the subject has not progressed, every attempt should be made to perform the subsequent 
scans at their originally scheduled time points. 
In order for subjects randomized to investigator choice arm to be eligible to switch to olaparib, 
scheduled tumor assessments must continue until objective radiological disease progression as 
assessed by BICR, without any intervening systemic anti-cancer therapy following discontinuation of 
randomized study treatment (see Section 4.2.1). 
Until the primary rPFS analysis all imaging assessment and study treatment should continue until 
objective disease progression as assessed by BICR (see Figure 3). There is no plan for BICR to read 
any scans dated after the date of DCO for the primary analysis. There will be no need to request 
confirmation of BICR PD after this time point, and the investigator-assessed radiographic progression 
will prevail. 
Radiological examinations performed during the study should be retained at site as source data. 
Figure 3 
Assessment of Progression by BICR (prior to primary rPFS analysis) 
 
5.1.1.1 
CT and MRI scans tumor assessments (RECIST 1.1) 
The imaging modalities used for RECIST assessment will be CT or MRI scans of the chest, abdomen 
and pelvis. Any other areas of disease involvement should be additionally investigated based on the 
signs and symptoms of individual subjects. At assessments subsequent to baseline, any other sites at 
which new disease is suspected should also be appropriately imaged. The methods of assessment of 
tumor burden used at baseline must be used at each subsequent assessment. In this study, bone lesions 
will not be included in the RECIST soft tissue assessment.  


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5.1.1.2 
Bone scans tumor assessment (based on PCWG3 criteria) 
Bone lesions will be assessed by bone scintigraphy commonly performed with Technetium-99 (bone 
scans). Bone lesions will be assessed by bone scan and will not be part of the RECIST 1.1 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.  
5.1.2 
Tumor evaluation 
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 by bone scan (see Table 6) 
• 
Death. 
RECIST 1.1 criteria will be used to assess subject response to treatment by determining progression 
free survival (PFS) times, objective response rates (ORR), and duration of response (DoR). 
Categorization of objective tumor response assessment will be based on the RECIST 1.1 criteria of 
response: CR (complete response), PR (partial response), SD (stable disease) and PD (progression of 
disease). Target lesion (TL) progression will be calculated in comparison to when the tumor burden 
was at a minimum (i.e., smallest sum of diameters previously recorded on study). In the absence of 
progression, tumor response (CR, PR, and SD) will be calculated in comparison to the baseline tumor 
measurements obtained before starting treatment. 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 tumor burden at the next scheduled assessment or 
sooner if clinically indicated. The RECIST 1.1 guidelines for measurable, non-measurable, target and 
non-target lesions and the objective tumor response criteria are presented in Appendix E. For ORR, a 
visit response of CR or PR must be confirmed by a later scan conducted at least 4 weeks after the 
initial response is observed. 
Bone lesions will be assessed by bone scan and will not be part of the RECIST 1.1 malignant soft 
tissue assessment.  The definition for bone progression is based on PCWG3 criteria.  Positive hot spots 
on the 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 defined as: 
At the 8 week scan: 
If 2 or more new metastatic bone lesions are observed on the first 8-week scan, the confirmatory scan 
performed (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).  
Note - The first bone scan completed after baseline will be considered the ‘8-week scan’ regardless if taken at 
week 8 or at an unscheduled assessment.  
After the 8 week scan: 


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For subjects without progression at the 8 week scan, this scan now serves as new baseline for all 
subsequent scans, i.e., all bone scans after week 8 are compared to the week 8 scan. If 2 or more new 
metastatic bone lesions are observed on scans obtained after the first 8-week assessment (compared to 
week 8 scan), a confirmatory scan performed at least 6 weeks later and preferably no later than the 
next scheduled visit must 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 documenting the 2 new lesions. 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.   
The requirements for determination and confirmation of radiographic progression by either bone scan 
(bone progression) or CT/MRI (soft tissue progression) are summarized in Table 6: 
Table 6 
Requirements for documentation of progression. 
Visit Date 
Criteria for Bone Progression 
Criteria for Soft Tissue Progression 
Week 8 
• 2 or more new lesion compared to 
baseline bone scan. 
• Requires confirmation scan at least 6 
weeks later with > 2 additional lesions 
compared to week 8 scan 
• Progressive disease on CT or MRI 
by RECIST 1.1 
• No confirmation scan required. 
Week 16 or 
later 
• 2 or more new lesions compared to 
week 8 bone scan. 
• Requires confirmation scan at least 6 
weeks later for persistence or increase 
in number of lesions 
• Progressive disease on CT or MRI 
by RECIST 1.1 
• No confirmation scan required. 
 
It is important to follow the assessment schedule as closely as possible.  Please refer to the study 
schedule in Table 3 and Table 4. 
Central reading of scans 
All imaging assessments including unscheduled visit scans should be collected on an ongoing basis 
and sent to an AstraZeneca (AZ) appointed Clinical Research Organization (CRO) to enable blinded 
independent central review (BICR). Upon documentation of radiographic progression by the 
investigator, all imaging assessments for the given subject, including unscheduled visit scans, will be 
reviewed by BICR. Results of this independent review will be communicated to investigators. Subjects 
should continue imaging assessments until BICR-assessed progression (see Section 5.1.1). 
An independent review of all scans used in the assessment of tumors will be conducted prior to the 
primary analysis of rPFS, including for subjects without investigator-assessed progression.  
The primary analysis for this study will be based on the blinded independent central review of all 
radiological scans (CT/MRI and bone scans). 


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After the primary rPFS analysis, central review of scans will no longer be required, and investigators 
will be advised when to stop sending copies of the scans to the CRO conducting the central review. All 
treatment decisions will be based on site assessment of scans after rPFS analysis. Ongoing collection 
of site review tumor assessment is required and must be recorded in the eCRF. 
 
 
 
5.1.3 
Second progression 
Following objective radiographic progression by BICR, copies of the patient’s radiological scans are 
no longer required to be sent for central review. Patients will be assessed every 12 weeks for a second 
progression (using patient’s status at first progression as the reference for assessment of second 
progression).  A patient’s progression status is defined according to local standard clinical practice and 
may involve both radiographic and clinical progression (not PSA progression). RECIST 1.1 and 
PCWG3 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. 
5.1.4 
Symptomatic skeletal related events (SSRE) 
SSREs will be assessed at each visit during the treatment phase, up to and including the study 
treatment discontinued visit (see Table 3). An SSRE is defined as use of radiation therapy to bone in 
order to prevent or relieve skeletal complications, occurrence of new symptomatic pathological bone 
fractures (vertebral or non-vertebral, resulting from minimal or no trauma), occurrence of spinal cord 
compression, or a tumor related orthopedic surgical intervention. 
The occurrence of a SSRE alone, in the absence of disease progression, is discouraged as a reason to 
discontinue treatment or to initiate new systemic anti-cancer therapy. 
5.1.5 
PSA Assessments 
Blood samples will be collected for PSA assessment at baseline and at each visit during the treatment 
phase, up to and including the study treatment discontinued visit (see Table 3). The samples will be 
analyzed by central laboratory. In order to prevent early withdrawal from treatment phase, PSA results 
will not be sent back to sites prior to final analysis. 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory manual. 
5.2 
Safety assessments 
5.2.1 
Laboratory safety assessments 
Blood and urine samples for determination of clinical chemistry, hematology, coagulation, and 
urinalysis will be taken at the times indicated in the Study schedule (see Table 2, Table 3 and Table 5). 
All samples unless otherwise indicated will be centrally assessed by central laboratories. Instructions 
for sample collection, labeling, processing, storage, and shipment will be provided in a separate 
laboratory manual provided to the sites. The volume of blood for collection from each subject for these 
assessments is presented in the laboratory manual. 
Additional safety samples may be collected if clinically indicated at the discretion of the Investigator. 
If applicable, the date, time of collection will be recorded on the appropriate eCRF. 


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The following laboratory variables will be measured: 
Table 7 
Laboratory Safety Variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Hemoglobin (Hb) 
S/P-Creatinine 
B-Leukocyte count 
S/P-Bilirubin, total 
B-Absolute neutrophil count 
S/P-Alkaline phosphatase (ALP) 
B-Absolute lymphocyte count 
S/P-Aspartate transaminase (AST) 
B-Platelet count 
S/P-Alanine transaminase (ALT) 
B-Mean Cell volume (MCV) 
S/P-Albumin 
 
S/P-Calcium 
 
S/P-Potassium 
Urinalysis (dipstick) 
S/P-Sodium 
U-Hb/Erythrocytes/Blood  
S/P-Urea or Blood Urea Nitrogen (BUN) 
U-Protein/Albumin  
S/P-Total Protein 
U-Glucose  
S/P- Lactic dehydrogenase (LDH) 
The Investigator should make an assessment of the available results with regard to clinically relevant 
abnormalities. The laboratory results should be signed and dated and retained at centre as source data for 
laboratory variables.  
 
NB. In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer to Appendix D 
‘Actions required in cases of combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for 
further instructions. 
 
 
5.2.1.1 
Coagulation  
Activated partial thromboplastin time (APTT) will be performed at screening and if clinically indicated   
International normalized ratio (INR) will be performed at screening and if clinically indicated. 
Subjects taking warfarin may participate in this study; however, it is recommended that INR be 
monitored carefully at least once per week for the first month, then monthly if the INR is stable.  
5.2.1.2 
Bone marrow or blood cytogenetic samples  
Bone marrow or blood cytogenetic samples may be collected for subjects with prolonged 
hematological toxicities as defined in Section 6.7.1 
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 Patients Safety database.  These data are not required to be entered into eCRF. 


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The Investigator should assess the available results for clinically relevant abnormalities.  The 
laboratory results should be signed and dated and retained at center as source data for laboratory 
variables.  For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 6.3. 
5.2.2 
Physical examination 
Performed at screening, baseline and as clinically indicated (see Table 2, Table 3 and Table 5). 
5.2.3 
ECG 
5.2.3.1 
Resting 12-lead ECG 
ECGs are required within 7 days prior to starting study treatment and when clinically indicated. 
Twelve-lead ECGs will be obtained after the subject has been rested in a supine position for at least 5 
minutes in each case.  The Investigator or designated physician will review the paper copies of each of 
the timed 12-lead ECGs on each of the study days when they are collected. 
ECGs will be recorded at 25 mm/sec. All ECGs should be assessed locally as to whether they are 
clinically significantly abnormal / not clinically significantly abnormal. If there is a clinically 
significant abnormal finding, the Investigator will record it as an AE on the eCRF. The original ECG 
traces must be stored in the subject medical record as source data. 
5.2.4 
Vital signs 
Weight will be assessed at screening and baseline according to the Study Schedule (see Table 2, Table 
3 and Table 5) and as clinically indicated at any other time.  
 
Any changes in vital signs should be recorded as an AE, if applicable. For information on how AEs 
based on changes in vital signs should be recorded and reported, see Section 6.3. 
5.2.4.1 
Pulse and blood pressure (BP) 
Blood pressure and pulse will be assessed at screening and baseline according to the Study Schedule 
(see Table 2, Table 3 and Table 5) and as clinically indicated at any other time. 
Blood pressure and pulse rate will be measured preferably using a semi automatic BP recording device 
with an appropriate cuff size after 10 minutes rest.   
The date of collection and measurement will be recorded on the appropriate eCRF. 
5.2.4.2 
Body temperature 
Body temperature will be measured in degrees Celsius according to local practice at screening, 
baseline and as clinically indicated (see Table 2, Table 3 and Table 5). 
The date of collection and measurement will be recorded on the appropriate eCRF. 
5.3 
Other assessments 
5.3.1 
Patient reported outcomes 
Patient-reported outcome (PRO) is an umbrella term referring to all outcomes and symptoms that are 
directly reported by the subject. PROs have become a significant endpoint when evaluating the 


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effectiveness of treatments in clinical studies. The following five PRO questionnaires will be 
electronically administered in this study: Brief Pain Inventory- Short Form (BPI-SF), Functional 
Assessment of Cancer Therapy-Prostate Cancer (FACT-P); patient-reported outcomes version of the 
Common Terminology Criteria for Adverse Events (PRO-CTCAE); the Patient Global Impression of 
Change (PGIC); and the EuroQol 5-dimension, 5-level health state utility index (EQ-5D-5L; see 
Appendix G). Analgesic use will be collected using an electronic analgesic-use log using the ERT 
Medication ModuleTM (analgesic log).  
Each center must allocate responsibility for monitoring compliance with completion of the PRO 
questionnaires and the analgesic-use log described in this Section to a specific individual(s) (e.g., a 
Research Nurse). The Clinical Team will arrange for relevant training in the setup of the electronic 
device and training subjects in how to self-administer the questionnaires and analgesic-use log using 
the electronic device. Subjects should complete the questionnaires in accordance with the study 
schedules (see Table 3, Table 4 and Table 5). Subjects must complete the BPI-SF and analgesic log, 
the FACT-P, the PGIC and the EQ-5D-5L prior to completing the PRO-CTCAE. The significance and 
relevance of the data should be explained carefully to participating subjects to ensure they comply with 
data collection. Subjects should complete all required baseline electronic PRO questionnaires and 
analgesic log before any treatment is initiated.  
5.3.1.1 
BPI-SF 
The BPI-SF (see Appendix G) is a validated, 15-item domain-specific instrument designed to assess 
the severity of pain and the impact/interference of pain on daily functions (Cleeland and Ryan 1994). 
The BPI-SF will be scored according to the user guide (Cleeland 2009). All BPI-SF pain items 
including “worst pain” is scored on a 0-10 numeric rating scale (NRS) with 0=No Pain and 10=Worst 
Pain Imaginable. This instrument consists of 2 domains: pain severity and pain interference. The pain 
severity domain consists of 4 items (item #3. Item #4, item #5, and item #6) which assess pain at its 
“worst,” “least,” “average,” and “now” (current pain) respectively on the 11-point NRS. These 4 items 
may be averaged as a composite pain severity score or they may be interpreted individually (Dworkin 
et al 2005, Turk et al 2006, Dworkin et al 2008 and Food and Drug Administration 2009). In this 
study, the “worst pain” (item 3) will be used as a single item in assessing pain progression. A 
composite pain severity score from all the 4 items will also be evaluated as ‘pain severity progression’. 
A 2- or more point change in the average pain severity or in “worst pain” item is considered clinically 
meaningful. 
The pain interference domain includes 7 items: general activity (item #9A), mood (item #9B), walking 
ability (item #9C), normal work (item #9D), relations with other people (item #9E), sleep (item #9F), 
and enjoyment of life (item #9G). The pain interference items are also answered on an 11-point NRS 
from 0 (Does not interfere) to 10 (Completely interferes). Subjects are asked to recall their symptoms 
as well as pain interference with daily activities in the past 24 hours. The pain interference domain is 
scored as the mean of the 7 interference items. Based on the BPI-SF scoring manual, the following 
items are not used in scoring pain severity or pain interference domains: items #1, #2, #7 and #8. Item 
#7 (a free text field) describing pain medication use is captured separately in more detail using the 
Analgesic Log.  
Subjects will complete the BPI-SF daily on the ePRO device for the 7 days prior to day 1 
randomization visit and every 4 weeks as outlined in the study schedule (see Table 3, Table 4 and 
Table 5). The “7 consecutive days prior to randomization” does not have to be the immediately 


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preceding 7 days prior to randomization. These 7 consecutive days can be anywhere within the 28 days 
screening window. Average worst pain, composite pain severity and pain interference will be 
computed when a subject completes the diary for at least 4 of the 7 days. The 4 days do not have to be 
consecutive but should be within the 7 consecutive days timeframe. 
5.3.1.2 
FACT-P 
The FACT-P (Appendix G) is a disease-specific 39-item questionnaire included for the purpose of 
assessing health-related quality of life (HRQoL) and prostate cancer-specific symptoms.  It is a well-
established measure of HRQoL/health status commonly used in prostate cancer clinical studies.  The 
FACT-P was developed specifically for patients with advanced prostate cancer and has been found to 
be reliable and valid in this population (Esper et al 1997).  The FACT-P consists of 5 subscales: 
Physical Well-Being (PWB; 7 items), Functional Well-Being (FWB; 7 items), Emotional Well-Being 
(EWB; 6 items), Social Well-Being (SWB; 7 items), and Additional Concerns or Prostate Cancer 
Subscale (PCS) specific to prostate cancer (12 items).  The PCS relate to prostate-specific questions, 
which include sexuality, bowel/bladder function, and pain (Esper et al 1997). All FACT-P questions 
are scored on a 5-point Likert scale from 0 to 4 (0 being not at all and 4 being very much).  Negatively 
stated items are reversed by subtracting the response from 4.  After reversing proper items, all subscale 
items are summed to a total, which is the subscale score.  For all subscales, symptoms index, and 
individual item scores, the higher the score, the better the HRQoL/symptom. Thus, a score of 0 is a 
severely symptomatic patient, and the highest possible score is an asymptomatic patient. In addition to 
the Total and Subscale scores, the FACT-P also supports the calculation of a Trial Outcome Index 
(TOI) score (the sum of the PWB, FWB and PCS scores), and the FACT Advanced Prostate Symptom 
Index 6 (FAPSI-6), a symptom score made up of 6 items from within the FACT-P (pain – 3 items, 
fatigue – 1 item, weight loss – 1 item, and concerns about the condition getting worse – 1 item). 
Changes from baseline in all of these scores will be assessed, in addition to time to deterioration in the 
scores. The FACT-P will be measured at the times outlined in the study schedules (see Table 3, Table 
4 and Table 5). 
Scoring of the FACT-P will be based on the user manual. Higher scores equate to better quality of life. 
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 
5.3.1.3 
PRO-CTCAE 
The PRO-CTCAE is included to address tolerability from the patients’ perspective. It was developed 
by the National Cancer Institute (NCI). The PRO-CTCAE will only be administered in those countries 
where a linguistically validated version exists. It was developed in recognition that collecting symptom 
data directly from patients using PRO tools can improve the accuracy and efficiency of symptomatic 
AE data collection. This was based on findings from multiple studies demonstrating that physicians 
and nurses underestimate symptom onset, frequency, and severity in comparison with patient ratings 
(Basch et al 2009 and Litwin et al 1998). These symptoms have been converted to patient terms (e.g., 
CTCAE term “myalgia” converted to “aching muscles”). For several symptoms, like fatigue and pain, 
additional questions are asked about symptom frequency, severity, and interference with usual 
activities. The items included in the PRO-CTCAE have undergone extensive qualitative review among 
experts and patients. These items have been extensively evaluated in patients with cancer to be clear, 
comprehensible, and measuring the symptom of interest. In this study, 8 items or symptomatic AEs 


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constituting 15 questions that are considered relevant for the study treatment arms are selected (see 
Appendix G). 
Subjects will complete the PRO-CTCAE every 2 weeks (starting on Day 1) for the first 8 weeks, then 
every 4 weeks thereafter, until 6 months after discontinuation of study treatment (see Table 3, Table 4 
and Table 5). 
5.3.1.4 
Patient Global Impression of Change (PGIC) 
The PGIC item is included to assess how a subject perceives their overall change in health status since 
the start of study treatment. Subjects will choose from response options ranging from “Very Much 
Improved” to “Very Much Worse.” This item is useful in characterizing the overall impact of the 
treatment (see Appendix G). The PGIC assessments will be performed at the times outlined in the 
study schedule (Table 3). 
5.3.1.5 
Analgesic Log  
The analgesic log will be implemented using the ERT Medication Module™, a component of the ERT 
eCOA System that serves for accurately tracking subject consumption of concomitant and/or rescue 
medications. The Medication Module allows medication data capture via the ERT eCOA Universal 
App, followed by the review and management of that data by sites and sponsors. The Medication 
Module provides a consistent, easier-to-use and more efficient tool as compared to paper-based 
reporting. Using the module, subjects will record all analgesic medication dosages & dosage times to 
track pain medications use. The Medication Module includes the following components:  
(a) 
Global Master Medication List –This list will be developed collaboratively by ERT and 
AstraZeneca and will contain all approved analgesic drug names including generic names 
and formulations. The list will be updated over the course of the study via an approval 
workflow process, when necessary. 
(b) 
eCOA Universal App Medication Diary – The medication diary will allow subjects to 
record analgesic medications between visits and identify when any new medications not 
previously approved have been taken. 
(c) 
Medication Report – This interactive report allows sites to see when their subjects have 
taken new medications, resolve those medications through an approval workflow, and 
remotely update the tailored list of medications available on a subjects’ eCOA Universal 
App. 
The Analgesic Log is study specific (not generic) and screenshots will be available and submitted 
along with the CSP to IRB/Ethics Committees. 
5.3.1.6 
Analgesic Use Scoring 
Although information on all analgesics used by patients in pain control will be collected using the 
Analgesic Log, only changes in opiate are considered in pain progression evaluation in line with FDA 
recommendation. Opiates consumed by patients will be converted into oral morphine equivalents as 
defined in Chung et al 2014. The Analgesic Quantification Algorithm (AQA) developed by Chung et 


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al 2014 will be used to quantify and score analgesic use in the study. The AQA is an eight-point scale 
that assigns a score as follows: 
• 
0=No analgesic  
• 
1=Non-opioid analgesics  
• 
2=Weak opioids (e.g., codeine, tramadol)  
• 
3=Strong opioids ≤75 mg oral morphine equivalence (OME) per day  
• 
4=Strong opioids >75–150 mg OME per day 
• 
5=Strong opioids >150–300 mg OME per day 
• 
6=Strong opioids >300–600 mg OME per day 
• 
7=Strong opioids >600 mg OME per day 
Average daily opiate use (based on OME) will be computed using the sum of all opiates used over the 
7 days per the assessment schedule (see Table 3, Table 4 and Table 5). The average daily OME will 
require at least 4 days of data and will be used to assign the AQA score. An increase of 1 point or more 
in the AQA score from a starting value of 1 or higher OR ≥ 2 points in AQA score from a starting 
value of 0 is considered a clinically meaningful increase in opiate use. Similarly, a decrease of 1 point 
or more in the AQA score from a starting value of 2 or higher is considered a clinically meaningful 
decrease in opiate use. 
5.3.1.7 
EQ-5D-5L  
The EQ-5D is a standardized measure of health status developed by the European Quality of Life 
(EuroQoL) Group in order to provide a simple, generic measure of health for clinical and economic 
appraisal (EuroQol Group 1990), see Appendix G. 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 as well as in population health surveys. The 
questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate 
problems, severe problems, and extreme problems) that reflect increasing levels of difficulty (EuroQol 
Group 2013). Since 2009, the EuroQoL group has been developing a more sensitive version of the EQ-
5D (the EQ-5D-5L), which expands the range of responses to each dimension from 3 to 5 levels of 
increasing severity (Herdman et al 2011). Preliminary studies indicate that the 5 level (5L) version 
improves upon the properties of the 3 level (3L) measure in terms of reduced ceiling effect, increased 
reliability, and an improved ability to differentiate between different levels of health (Pickard et al 
2007, Janssen et al 2008a and Janssen et al 2008b). The subject will be asked to indicate his/her 
current health state by selecting the most appropriate level in each of the 5 dimensions. The 
questionnaire also includes a visual analogue scale (VAS), where the subject will be asked to rate 
current health status on a scale of 0 to 100, with zero being the worst imaginable health state.  The EQ-
5D-5L will be measured at the times outlined in the study schedule (see Table 3, Table 4 and Table 5). 


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5.3.2 
Administration of PRO questionnaires 
The PRO instruments will be self-administered by the subjects as ePROs using handheld devices.  The 
analgesic use log using the Medication Module will also be administered electronically alongside the 
ePROs.  
All assessments should be completed according to the following parameters: 
• 
Without assistance from site staff or relatives/friends according to the assessment 
schedules (see Table 3, Table 4 and Table 5). 
• 
Before any other study procedures are conducted at a given visit.  
• 
Before being seen by a study nurse or physician. 
Each center must allocate the responsibility for the administration of the ePROs to a specific individual 
(e.g., a research nurse or study coordinator) and, if possible, assign a backup person to cover if that 
individual is absent.  Approximately 15 to 30 minutes is required for subjects to complete the 
questionnaires.  Subjects may complete some of the ePROs at study sites if the assessment time point 
coincides with a scheduled site visit; otherwise, subjects may complete the ePROs at home. Similarly, 
during the post-progression period, subjects should complete ePROs at home or at the study site if a 
scheduled visit coincides with the time point.  If subjects have had scans or other tests at an outside 
facility or missed a scheduled data collection site visit, ePROs should still be completed by the subject 
at home for that scheduled visit within the window period.  
Subjects should be instructed to complete the BPI-SF (Pain Diary) and the Analgesic Log daily for 7 
consecutive days every 4 weeks (from date of randomization), independent of when site visits are 
scheduled. Baseline BPI-SF (Pain Diary) and Analgesic Log must be completed daily for 7 
consecutive days during the 28 day screening period prior to randomization 
The investigator will arrange for relevant training in the set-up of the electronic device and training 
subjects in how to self-administer the questionnaires and analgesic use log using the electronic device. 
Subjects should complete the questionnaires in accordance with the study schedules (see Table 3, 
Table 4 and Table 5). Subjects must complete the BPI-SF and Analgesic Log, the FACT-P, and the 
PGIC, EQ-5D-5L, prior to completing the PRO-CTCAE. 
The significance and relevance of the data should be explained carefully to participating subjects so 
that they are motivated to comply with data collection. Reminders should be sent to subjects at home 
as needed to ensure compliance with the assessment schedules.  
The following best practice guidelines should be followed when collecting PRO data via an electronic 
device: 
• 
PRO questionnaires must be completed prior to any other study procedures (following 
informed consent) and before discussion of disease progression to avoid bias in subject’s 
responses to the questions. 
• 
When each instrument is due to be completed, the following order should be observed: 
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• 
PRO questionnaires must be completed by the subject in private. 
• 
The research nurse or appointed site staff must explain to subject the value and relevance 
of study participation and inform them that these questions are being asked to find out, 
directly from them, how they feel.  The research nurse or appointed site staff should also 
stress that the information is confidential.  Therefore, if the subjects have any medical 
problems, they should discuss them with the doctor or research nurse separately from the 
ePRO assessment. 
• 
The research nurse or appointed site staff must train the subject on how to use the ePRO 
device, using the materials and training provided by the ePRO vendor, and provide 
guidance on whom to call if there are problems with the device if the subject is 
completing the ePRO at home. 
• 
The research nurse or appointed site staff should remind subjects that there are no right or 
wrong answers. 
• 
The research nurse or appointed staff must avoid clarifying items in order to avoid bias. 
• 
The subject must not receive help from relatives, friends, or clinic staff to answer the 
PRO questionnaires.  If a subject uses visual aids (e.g., spectacles or contact lenses) for 
reading and does not have them when he attends the clinic, the subject will be exempted 
from completing the PROs at the clinic.  
• 
Site staff must not read or complete the PRO questionnaires on behalf of the subject.  If 
the subject is unable to read the questionnaire (e.g., is blind or illiterate), that subject is 
exempted from completing PRO questionnaires and may still participate in the study.  
Subjects exempted in this regard should be flagged appropriately by the site staff. 
• 
The subject should be given sufficient time to complete the PRO questionnaires at his or 
her own speed. 
The research nurse or appointed site staff must monitor compliance to ensure all data is captured.  
Compliance must be checked at each study visit to identify problems early.  If a subject’s compliance 
drops below 85%, they will be flagged in the routine compliance report generated by the ePRO system 
and a check-in call from the site to ask the subject if he or she has any difficulties is highly 
recommended. 
5.3.3 
Healthcare Resource Use 
To explore the impact of treatment and disease on healthcare resource use. Healthcare resource use 
will be captured including inpatient admissions, ICU and length of stay in hospital. Appropriate 
analyses of resource use will be undertaken to examine the impact of disease and treatment on resource 
use to primarily support the health economic evaluation of AstraZeneca therapies. 


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5.3.3.1 
Assessment of Healthcare Resource Use 
The study site staff should complete the “Hospital Admission (HOSPAD)” eCRF at the site at every 
scheduled clinic visit up to and including the study treatment discontinuation follow up visit. If the 
subject discontinues study treatment for reasons other than RECIST progression, the “HOSPAD” 
eCRF should continue to be administered until progression has been determined by BICR or by 
investigator after primary rPFS analysis (see assessment schedule in Table 3, Table 4 and Table 5). 
5.4 
Pharmacokinetics 
5.4.1 
Collection of samples 
PK sampling will be performed in a subset of at least 35 subjects in Cohort A and 15 subjects in 
Cohort B dosed with olaparib and in at least 50 subjects dosed with olaparib in both cohorts at select 
sites. 
 
PK samples are to be taken as a blood sample (2 mL) for determination of olaparib concentrations in 
plasma. At the Week 4 visit, PK samples will be collected at the following times: Pre-dose (- 30 min ± 
15 min), and post dose at 30 min ± 15 min, 2 ± 0.5 h, 5 ± 0.5 h and 8 ± 1h. The actual date and time of 
dosing on the PK study day and the actual date and time of dosing 3 days prior to the pre-dose sample 
must be recorded. 
Samples will be collected, labeled, stored and shipped as detailed in the Laboratory manual. 
5.4.2 
Determination of drug concentration 
Samples for determination of olaparib concentrations in plasma will be analyzed by Covance on behalf 
of AstraZeneca R&D, using a validated bioanalytical method. Full details of the analytical method 
used will be described in a separate bioanalytical report. 
Full instructions for collection, labeling, storage and shipment of samples are provided in the 
Laboratory manual. Results will only be reported for samples shipped within a timeframe for which 
the stability of olaparib in the samples has been validated and shown to be acceptable. 
5.4.3 
Storage and destruction of pharmacokinetic samples 
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or six months 
after issuance of the draft Bioanalytical Report (whichever is earlier) unless requested for future 
analyses, where consented to by the subject.   
Pharmacokinetic samples may be destroyed or anonymized by pooling. Additional analyses may be 
conducted on the anonymized, pooled pharmacokinetic samples to further evaluate and validate the 
analytical method.  Any results from such analyses may be reported separately from the CSR. 
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 Clinical Study Report but 
separately in a Bioanalytical Report. 
Any residual back-up PK samples may be used for future exploratory biomarker research (in this case, 
residual back-up PK samples will be shipped to an AstraZeneca designated biobank; see details in the 
Laboratory Manual). 


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5.5 
Pharmacodynamics 
Pharmacodynamics samples will not be taken during the study 
5.6 
Pharmacogenetics  
5.6.1 
Collection of pharmacogenetics samples 
The subject’s consent to participate in the pharmacogenetic research (PGx) components of the study is 
optional. The background, rationale, objectives, and inclusion/exclusion criteria for the 
pharmacogenetics analysis are detailed in Appendix C: Pharmacogenetics Research. Please refer to 
Appendix C and the Laboratory manual for further information surrounding timing of blood sample 
collection, blood sample storage, and destruction. 
 
 
5.7 
Biomarker analysis  
Biological samples (e.g., archived tumor samples or blood) will be collected as detailed in the 
Laboratory manual in order to carry out prospective and retrospective biomarker screening.  
5.7.1 
HRR gene panel testing of tumor biopsy sample  
All subjects must provide a tumor sample that meets the tissue specifications outlined in the 
Laboratory manual, for tissue based HRR gene panel mutation testing using the Lynparza HRR Assay. 
The tumor sample will be used to test 15 biomarkers simultaneously: BRCA1, BRCA2, ATM, BRIP1, 
BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and 
RAD54L. Subjects who meet all eligibility criteria will be assigned to treatment in the IVRS/IWRS as 
follows: 
Table 8 
Treatment assignment by Tumor Sample Mutation Result 
Tumor Sample Mutation Result 
Treatment Assignment 
BRCA1, BRCA2, ATM 
Cohort A 
BARD1, BRIP1, CDK12, CHEK1, CHEK2, 
FANCL, PALB2, PPP2R2A, RAD51C, RAD51B, 
RAD51D, RAD54L 
Cohort B 
  
5.7.2 
Collection, Analysis and Reporting of Tumor Samples  
Tumor samples will be collected as detailed in the pathology and genomics testing manual. Subjects 
must consent to provide either an archival tumour block, or a de novo tumour biopsy sample for 
analysis. Consideration should be given to the potential benefit to the subject (should he be eligible for 
study) in the context of the risk posed by the biopsy procedure. Tissue biopsy sampling should be 
conducted in accordance with expert guidelines, only by investigators experienced in performing these 
sampling methods in appropriate clinical settings. Samples that meet the minimum tumor content and 
tissue volume as specified in the pathology and genomics testing manual will be shipped at Screening 
Part 1 (post confirmation of other (*) marked eligibility criteria, see Section 3.1 and 3.2) to FMI 
(Cambridge MA, USA) to determine HRR status. 
 
 


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If the first biopsy submitted for testing is inconclusive due to technical test failure, a further biopsy 
sample may be submitted for testing. Submission and testing of new samples can only be performed if 
the original testing failed due to technical failure. Please refer to the pathology and genomics testing 
manual for further details regarding retesting procedures. 
For each subject that passes tissue sample and sequencing quality control, FMI will generate a report 
specifying presence or absence of qualifying HRR gene mutations. A subject has a qualifying mutation 
if any deleterious or suspected deleterious mutation is found in the HRR genes. A mutation is regarded 
as deleterious if it results in protein truncation (which includes nonsense, frameshift, or consensus 
splice site mutations), or select missense mutations well-known to be deleterious in ClinVar/BIC 
databases in certain genes (BRCA1, BRCA2, and ATM). Furthermore, larger scale alterations such as 
genomic truncating rearrangements or homozygous deletions will also be classified as qualifying. 
Subjects without qualifying HRR gene mutations as determined by the Lynparza HRR Assay will not 
be eligible for the study. 
 if a subject has a previously confirmed deleterious or 
suspected deleterious mutation in one of the 15 HRR study genes using the FoundationOne® 
assay: the subject may meet biomarker testing requirements provided all of the following conditions 
are met: 
(a) 
The results are from a prior screening of a prostate cancer tissue specimen by the 
commercially available FoundationOne® assay as performed by FMI (Cambridge, MA, 
USA). No other local testing results or other commercially offered NGS analyses are 
permitted. 
(b) 
Subject to patient consent, residual DNA (stored at FMI) from the original 
FoundationOne® test will be used to confirm presence of a qualifying gene mutation using 
the Lynparza HRR Assay. Subjects who do not have sufficient residual DNA from their 
original test will be analysed in-silico for qualifying HRR gene mutations using data from 
their previous FoundationOne® test. Upon documented confirmation that FMI has re-
evaluated the subject’s mutation and confirms the presence of a qualifying HRR gene 
mutation, the subject may be randomized provided all other eligibility criteria are met. 
(c) 
Subjects who do not have sufficient residual DNA from their original FoundationOne® test 
must confirm availability of sufficient formalin fixed, paraffin embedded (FFPE) tumor 
sample to carry out central confirmation using the Lynparza HRR Assay. The subject is not 
required to wait for the results of the Lynparza HRR Assay to proceed with Screening Part 
2 and randomization, assuming all other eligibility criteria are met. 
 
 the tumor sample for central confirmation should be shipped to 
Foundation Medicine upon enrollment. 
5.7.3 
Blood Sample for Germline HRR Testing 
 


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5.7.3.1 
Screening Part 1: Optional Blood Sample for Germline Testing 
Subjects who consent to provide an optional sample for germline testing will provide a blood sample at 
Screening Part 1. The sample will be stored for future testing to explore diagnostic test development 
and thus results will not be available to subjects, or their treating physician. 
 
 
5.7.3.2 
Screening Part 2: Mandatory Blood Sample for Germline Testing 
A significant proportion of tumor mutations are reflective of pre-existing germline mutations. Subjects 
confirmed to have a qualifying HRR gene mutation, will be required to submit a blood sample at 
screening Part 2 for central germline analysis. The cancer gene profiling test analyzes the coding 
sequence and select introns of hereditary cancer-related genes, including a subset of the 15 clinical 
study genes, for variants and/or rearrangements. The results of retrospective germline testing may be 
made available to the treating physician in accordance with local procedures for research use only.  
5.7.4 
Exploratory blood samples for biomarker analysis (e.g., ctDNA analysis) 
There are two main approaches for the retrieval of tumor material: to obtain contemporary tissue 
biopsies upon disease progression, or to utilize archival specimens from previous stages of the disease. 
The former approach requires invasive biopsies, where tissue may be limited in quantity and quality 
and archival specimens predate progression to mCRPC, and hence, may not reflect tumor evolution 
and alteration of mutational profile that may have occurred in the intervening time span. In order to 
overcome these risks and limitations in the future, exploratory biomarker research will be conducted. 
Testing will include (but is not limited to): 
• 
if there is sufficient ctDNA in plasma for mutation testing,  
• 
if ctDNA in plasma can be used to determine HRR mutation status and  
• 
the correlation between tumor and plasma mutation status 
Subjects must provide a blood sample at screening Part 1 (see Table 2). The sample is requested prior 
to treatment in order to maximize the probability of detecting ctDNA where the tumor burden is 
relatively high. A second sample will be taken at disease progression (see Table 3 and Table 4).  
Please refer to Laboratory manual for further details of biomarker blood sample collection, shipping, 
and storage. 
 
 
5.7.5 
Circulating tumor cells (CTCs) 
Whole blood samples will be taken for analysis of CTC conversion rate using the CellSearch® CTC 
assay at a central lab and the EPIC CTC assay (EPIC, San Diego, CA, USA) for CTC biomarker 
measurement at the times shown in the study schedule (see Table 3 and Table 4). 
 
 
Samples will be shipped under ambient conditions on the day of acquisition to be received by the 
AstraZeneca approved laboratory within 48 hours of blood sampling.  Please refer to the separate 
Laboratory manual for further details of sample collection, shipping, and storage. 


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5.7.6 
Exploratory use of residual biomarker samples and data generated from 
tumor testing (Optional) 
The investigational Lynparza HRR Assay used in this study is being developed for approval as a 
companion diagnostic for olaparib. The Lynparza HRR Assay analyses 15 HRR genes for the presence 
of deleterious or suspected deleterious mutations to determine eligibility for this study. The underlying 
gene panel used in this investigational test is based on the clinical-grade FoundationOne® cancer gene 
profiling test which analyzes the coding sequence of 310 cancer-related genes plus introns from select 
genes for variants and/or rearrangements. A full list of all genes is available in the laboratory manual. 
Subjects will be asked to consent to the use of this additional gene data by AstraZeneca for exploratory 
research, biomarker analysis in relation to olaparib, and development of future diagnostic tests. 
Any residual tumour samples may be used for exploratory research by AstraZeneca (in this case, 
residual samples will be shipped to an AstraZeneca designated Biobank; see details in Laboratory 
manual). 
 
5.7.7 
Storage, re-use and destruction of biological samples 
Biological samples for future research will be retained at AstraZeneca or its designee for a maximum 
of 15 years following the finalization of the Clinical Study Report or as per local regulation, after 
which they will be destroyed. The results of this biomarker research will be reported either in the 
Clinical Study Report itself or as an addendum, or separately in a scientific report or publication. The 
results of this biomarker research may be pooled with biomarker data from other studies with the study 
drug to generate hypotheses to be tested in future research. 
5.7.8 
Labelling and shipment of biological samples 
The Principal Investigator will ensure that samples are labeled 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 B 
‘IATA 6.2 Guidance Document’. 
Any samples identified as Infectious Category A materials are not shipped and no further samples will 
be taken from the subject unless agreed with AstraZeneca and appropriate labeling, shipment and 
containment provisions are approved. 
5.7.9 
Chain of custody of biological samples  
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Principal Investigator at each center keeps full traceability of collected biological samples from 
the subjects while in storage at the center 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. 
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of study 
sites and auditing of external laboratory providers. 
Samples retained for further use are registered in the AstraZeneca Biobank system during the entire 
life cycle. 
 


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5.7.10 
Withdrawal of Informed Consent for donated biological samples  
If a Subject withdraws consent to the use of donated biological samples, the samples will be disposed 
of/destroyed, and the action documented.  If samples are already analyzed, AstraZeneca is not obliged 
to destroy the results of this research. 
The Principal Investigator: 
• 
Ensures Subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca 
• 
Ensures that biological samples from that Subject, 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 of/destroyed, the action documented 
and the signed document returned to the study site 
• 
Ensures that the Subject and AstraZeneca are informed about the sample disposal. 
AstraZeneca ensures the central 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. 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The Principal Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this Section. 
6.1 
Definition of adverse events 
An adverse event 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 (e.g., 
nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation 
(e.g., laboratory findings, electrocardiogram).  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. 
6.1.1 
Olaparib adverse events of special interest 
Adverse events of special interest [AESI] are events of scientific and medical interest specific to the 
further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. An AESI may be serious or non-serious. Adverse 
Events of Special Interest for olaparib are the Important Potential Risks of MDS/AML, new primary 
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A questionnaire will be sent to any investigator reporting an AESI, as an aid to provide further detailed 
information on the event.  During the study there may be other events identified as AESIs that require 
the use of a questionnaire to help characterize the event and gain a better understanding regarding the 
relationship between the event and study treatment. 
6.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, and 
washout, follow-up), that fulfills one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-subject hospitalization or prolongation of existing hospitalization  
• 
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 jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above 
For further guidance on the definition of an SAE, see Appendix A to the Clinical Study Protocol. 
6.3 
Recording of adverse events 
6.3.1 
Time period for collection of adverse events 
Adverse Events, including Serious Adverse Events, will be collected from the time of signature of 
informed consent throughout the treatment period up to and including the 30-day follow-up period*.  
All ongoing and any new AEs/SAEs identified during the 30 calendar days follow-up period after the 
last dose of study medication, must be followed to resolution. After any interim analysis, any ongoing 
AEs/SAEs need to be unlocked and followed for resolution. 
*Exception: In screening part 1, only SAEs related to study procedures must be reported (AEs do not 
require reporting). From screening part 2 onwards - all AEs/SAEs must be reported. 
6.3.1.1 
Adverse events after the 30 day follow up period  
For Pharmacovigilance purposes and characterization, any SAE of MDS/AML or new primary 
malignancy occurring after the 30 day follow up period should be reported to AstraZeneca Patient 
Safety regardless of investigator’s assessment of causality or knowledge of the treatment arm.  
Investigators will be asked during the regular follow up for overall survival if the subject has 
developed MDS/AML or a new primary malignancy and prompted to report any such cases.   
At any time after a subject has completed the study, if an Investigator learns of any SAE including 
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causally related to the investigational product, the investigator should notify AstraZeneca, Patient 
Safety. 
If subjects who are gaining clinical benefit are allowed to continue study treatment post data cut off 
and/or post study completion then all SAEs must continue to be collected and reported to Patient 
Safety within the usual timeframe. 
Otherwise, after study treatment completion (i.e., 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 subjects. This includes new AEs/SAEs in subjects still being followed up for survival but 
who have completed the post treatment follow up period (30 days). 
6.3.2 
Follow-up of unresolved adverse events 
Any SAE or non-serious adverse event that is ongoing at the time of the 30-day follow up, must be 
followed up to resolution unless the event is considered by the investigator to be unlikely to resolve, or 
the subject is lost to follow up. AstraZeneca retains the right to request additional information for any 
subject with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
6.3.3 
Variables  
The following variables will be collected for each AE; 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
CTCAE grade and changes in CTCAE grade 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the Investigational Product (yes or no), comparator 
drug (yes/no) 
• 
Action taken with regard to investigational product/comparator drug 
• 
Outcome. 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
AE is serious due to 
• 
Date of hospitalization 
• 
Date of discharge 


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• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to Study procedure(s) 
• 
Causality assessment in relation to Other medication 
• 
Description of AE. 
Severity of AE 
For each episode of an adverse event, all changes to the CTCAE grade attained as well as the highest 
attained CTC grade 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 6.2.  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 an SAE unless it meets the criteria shown in Section 6.2. On the 
other hand, a stroke that results in only a limited degree of disability may be considered a mild stroke 
but would be an SAE when it satisfies the criteria shown in Section 6.2. 
The grading scales found in the National Cancer Institute (NCI) CTCAE 4.03 will be utilized for all 
events with an assigned CTCAE grading. For those events without assigned CTCAE grades the 
recommendation is that the CTCAE criteria that convert mild, moderate and severe events into 
CTCAE grades should be used. 
A copy of the CTCAE version can be downloaded from the Cancer Therapy Evaluation program 
website (http://ctep.cancer.gov). 
6.3.4 
Causality collection 
The Investigator will assess causal relationship between Investigational Product and each Adverse 
Event, 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/comparator drug?’ 
For SAEs causal relationship will also be assessed for other medication and study procedures   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 A to the Clinical Study 
Protocol. 
6.3.5 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the subject or reported in response to the open question from the 
study personnel: ‘Have you had any health problems since the previous visit/you were last asked?’, or 
revealed by observation will be collected and recorded in the CRF.  When collecting AEs, the 
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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. 
6.3.6 
Adverse events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarized in the clinical 
study report.  Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs 
and ECG abnormalities should therefore only be reported as AEs if one of the following is met: 
• 
Any criterion for an SAE is fulfilled. 
• 
Causes study treatment discontinuation. 
• 
Causes study treatment interruption. 
• 
Causes study treatment dose reduction. 
• 
The investigator believes that the abnormality should be reported as an AE. 
If the deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, the 
sign or symptom will be reported as an AE and the associated laboratory result/vital sign will be 
considered as additional information.  Wherever possible the reporting Investigator uses the clinical, 
rather than the laboratory term (e.g., anemia versus low hemoglobin 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. 
6.3.7 
Hy’s Law 
Cases where a subject 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 D for further instruction on cases of increases in liver biochemistry 
and evaluation of Hy’s Law. 
6.3.8 
Disease progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to the 
disease for which the investigational product is being studied.  It may be an increase in the severity of 
the disease under study and/or increases in the signs and symptoms of the cancer.  The development of 
new, or progression of existing metastasis to the primary cancer under study should be considered as 
disease progression and not an AE.  Events, which are unequivocally due to disease progression, 
should not be reported as an AE during the study. 


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6.3.9 
New cancers 
The development of a new primary cancer (including skin cancer) should be regarded as an AE (see 
Section 6.1.1 Olaparib Adverse Events of Special Interest).  New primary malignancies are those that 
are not the primary reason for the administration of the study treatment and have developed after the 
inclusion of the subject 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. 
6.3.10 
Lack of efficacy 
When there is deterioration in the cancer, for which the study treatment(s) is being used, 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 study treatment 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. 
6.3.11 
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 study treatment, must be reported as follows: 
• 
Death clearly the result of disease progression should be reported to the study monitor at the 
next monitoring visit and should be documented in the DEATH eCRF but should not be 
reported as an 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 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 eCRF’. 
• 
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 within the usual timeframes. 
6.4 
Reporting of serious adverse events 
All SAEs must be reported, whether or not considered causally related to the investigational product, 
or to the study procedure(s)*. All SAEs will be recorded in the CRF. 
*Exception: In screening part 1, only SAEs related to study procedures must be reported.  
If any SAE occurs in the course of the study, then Investigators or other site personnel must inform the 
appropriate AstraZeneca representatives within one day i.e., immediately but 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 
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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 adverse events 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 within one calendar day 
i.e., immediately but 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. 
The AstraZeneca representative will advise the Investigator/study site personnel how to proceed. 
Investigators or other site personnel send relevant CRF modules by fax to the designated AstraZeneca 
representative.  
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca drug 
and the EU Summary of Product Characteristics (SPC) for the active comparator product. 
6.5 
Overdose 
There is currently no specific treatment in the event of overdose with olaparib and possible symptoms 
of overdose are not established.  
Study treatment must only be used in accordance with the dosing recommendations in this protocol. 
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol should be 
reported as an overdose. The Maximum Tolerated Dose is 300 mg bid (tablet). 
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 CRF 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 the Investigator 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 relevant 
information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  For 
other overdoses, reporting must occur within 30 days. 
6.6 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. 


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6.6.1 
Paternal exposure  
Subjects should refrain from fathering a child or donating sperm during the study and for 3 months 
following the last dose. 
Pregnancy of the subject’s partners is not considered to be an adverse event. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or 
congenital abnormality) should if possible be followed up and documented.  
The outcome of any conception occurring from the date of the first dose until 3 months after the last 
dose should be followed up and documented. 
6.7 
Management of toxicities related to olaparib 
Any toxicity observed during the course of the study could be managed by interruption of the dose of 
study treatment or dose reductions. Repeat dose interruptions are allowed as required, for a maximum 
of 4 weeks on each occasion. If the interruption is any longer, the study team must be informed. 
Olaparib can be dose reduced to 250 mg twice daily as a first step and to 200 mg twice daily as a 
second step. If the reduced dose of 200 mg twice daily is not tolerable, no further dose reduction is 
allowed and study treatment should be discontinued.   
For management of toxicities for subjects treated with abiraterone acetate or enzalutamide see Section 
6.8.  
Once dose is reduced, escalation is not permitted. 
6.7.1 
Management of hematological toxicity 
6.7.1.1 
Management of anemia 
Table 9 
Management of anemia 
Hemoglobin 
Action to be taken 
Hb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2) 
Give appropriate supportive treatment, continue to monitor and investigate 
causality.  
• 
For first incidence: investigator judgement to continue olaparib 
with or without supportive treatment (e.g., transfusion) or 
interrupt dose for a maximum of 4 weeks.  
• 
For repeat incidence (after recovery of first event) 
• 
If Hb < 10 but ≥ 9 g/dl investigator judgement to continue 
olaparib with supportive treatment (e.g., transfusion) or 
dose interrupt (for max of 4 weeks) and upon recovery dose 
reduction may be considered (to 250 mg twice daily as a 
first step and to 200 mg twice daily as a second step). 
• 
If Hb < 9 but ≥ 8 g/dl, dose interrupt (for max of 4 weeks) 
until Hb ≥ 9 g/dl and upon recovery dose reduction may be 
considered (to 250 mg twice daily as a first step and to 
200 mg twice daily as a second step).  


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Table 9 
Management of anemia 
Hemoglobin 
Action to be taken 
Hb < 8 g/dl 
(CTCAE Grade 3) 
Give appropriate supportive treatment (e.g., transfusion), continue to 
monitor and investigate causality.  
Interrupt olaparib for a maximum of 4 weeks until improved to Hb ≥ 9 
g/dl. 
Upon recovery dose reduce olaparib 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 (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed. In some cases management of 
anemia may require blood transfusions. For cases where subjects develop prolonged hematological 
toxicity (≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anemia and/or 
development of blood transfusion dependence) , refer to Section 6.7.1.3 for the management of this. 
6.7.1.2 
Management of neutropenia, leukopenia and thrombocytopenia 
Table 10 
Management of neutropenia, leukopenia and thrombocytopenia 
Toxicity 
Study treatment dose adjustment 
CTCAEa Grade 1-2 
Investigator judgement to continue study treatment or if dose interruption, 
this should be for a maximum of 4 weeks; appropriate supportive 
treatment and causality investigation 
CTCAE Grade 3-4 
Dose interruption until recovered to CTCAE grade 1 or better for a 
maximum of 4 weeks. If repeat CTCAE grade 3-4 occurrence, dose reduce 
olaparib to 250 mg twice daily as a first step and 200 mg twice daily as a 
second step. 
 
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by the 
investigator with close follow-up and interruption of study drug if CTC grade 3 or worse neutropenia 
occurs. 
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not recommended, 
however, if a subject 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 h (7 days for pegylated G-CSF) of the last dose of study 
treatment unless absolutely necessary. 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 
For cases where subjects develop prolonged hematological toxicity (≥2 week interruption/delay in 
study treatment due to CTC grade 3 or worse), refer to Section 6.7.1.3. 


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6.7.1.3 
Management of prolonged hematological toxicities while on study treatment 
If a subject develops prolonged hematological toxicity such as: 
• 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anemia and/or 
development of blood transfusion dependence 
• 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse neutropenia 
(ANC < 1 x 109/L) 
• 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets < 50 x 
109/L) 
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If any 
blood parameters remain clinically abnormal after 4 weeks of dose interruption, the subject should be 
referred to hematologist for further investigations. Bone marrow analysis and/or blood cytogenetic 
analysis should be considered at this stage according to standard hematological practice. Study 
treatment should be discontinued if blood counts do not recover to CTC grade 1 or better within 4 
weeks of dose interruption. 
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should be 
reported as an SAE and full reports must be provided by the investigator to AstraZeneca Patient 
Safety. Olaparib treatment should be discontinued if subject’s diagnosis of MDS and/or AML is 
confirmed. 
6.7.2 
Management of non-hematological toxicity 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion. If the 
interruption is any longer than this the study monitor must be informed.  Where toxicity reoccurs 
following re-challenge with study treatment, and where further dose interruptions are considered 
inadequate for management of toxicity, then the subject should be considered for dose reduction or 
must permanently discontinue study treatment. 
Study treatment can be dose reduced to 250 mg bd as a first step and to 200 mg bd as a second step. 
Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse event occurs which the 
investigator considers to be related to administration of study treatment. 
6.7.2.1 
Management of new or worsening pulmonary symptoms  
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities occur in the 
absence of a clear diagnosis, an interruption in study treatment dosing is recommended and further 
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 Study Physician. 


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6.7.2.2 
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 subjects and 36% in the placebo 
treated subjects and vomiting was reported in 34% of the olaparib treated subjects and 14% in the 
placebo treated subjects. These events 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 for nausea and within the first 6 months of treatment for vomiting. For nausea, the 
incidence generally plateaus at around 9 months, and for vomiting at around 6 to 7 months. 
No routine prophylactic anti-emetic treatment is required at the start of study treatment, however, 
subjects 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.  Alternatively, olaparib 
tablets can be taken with a light meal/snack (i.e., 2 pieces of toast or a couple of biscuits). 
As per international guidance on anti-emetic use in cancer subjects (ESMO, NCCN), generally a single 
agent antiemetic should be considered e.g., dopamine receptor antagonist, antihistamines or 
dexamethasone. 
6.7.2.3 
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 subject 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. 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF.  
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 needle biopsy procedure. 
Study treatment should be discontinued for a minimum of 3 days before a subject undergoes radiation 
treatment. Study treatment should be restarted within 4 weeks as long as any bone marrow toxicity has 
recovered. 
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, subjects should be 
advised to use caution while driving or using machinery if these symptoms occur.  
Table 11 
Dose reductions for olaparib 
Initial Dose 
Following re-challenge post 
interruption: Dose reduction 1 
Dose reduction 2 
300 mg twice daily 
250 mg twice daily 
200 mg twice daily 
 


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6.8 
Management of toxicities related to enzalutamide and abiraterone 
acetate 
Detailed here, as guidance, are approved toxicity management guidelines for abiraterone acetate and 
enzalutamide (US Prescribing Information). 
For toxicity management please adhere to these guidelines or, where appropriate, to local approved or 
clinical practice guidelines.   
6.8.1 
Dose adjustment recommendations for enzalutamide 
If subject experiences a ≥ Grade 3 toxicity or an intolerable side effect, interrupt enzalutamide 
treatment for one week or until symptoms improve to ≤ Grade 2, then resume at the same or a reduced 
dose (120 mg or 80 mg), per investigator discretion. 
6.8.2 
Dose adjustment recommendations for abiraterone acetate 
In subjects with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the dose of 
abiraterone acetate to 250 mg once daily.  Permanently discontinue treatment with abiraterone acetate 
in subjects with baseline moderate hepatic impairment if ALT and/or AST > 5xULN or total bilirubin 
> 3xULN. 
In subjects who develop hepatotoxicity during treatment, i.e., ALT and/or AST > 5xULN or total 
bilirubin > 3xULN, interrupt abiraterone acetate treatment until values return to subject’s baseline 
value or to AST and ALT ≤2.5xULN and total bilirubin ≤ 1.5xULN.  Treatment may be restarted at 
investigator discretion at a reduced dose of 750 mg as first step and 500 mg as second step.  If 
hepatotoxicity recurs at the reduced dose of 500 mg once daily, treatment should be discontinued with 
no further dose reductions. 
Permanently discontinue abiraterone acetate treatment for subjects with concurrent elevation of ALT > 
3xULN and total bilirubin > 2xULN in the absence of biliary obstruction of other causes responsible 
for the concurrent elevation. 
6.9 
Medication error 
If a medication error occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day i.e., immediately but 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 relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up Fatal/Life-Threatening) 
or 5 (other serious initial and follow up) calendar days if there is an SAE associated with the 
medication error (see Section 6.3.1) and within 30 days for all other medication errors. 
The definition of a Medication Error can be found in Appendix A. 
6.10 
Study governance and oversight 
6.10.1 
Steering Committee 
A Steering Committee will be responsible for supervising the progress of the trial. This committee will 
include experts in prostate cancer and the Sponsor’s representatives. 


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6.10.2 
Data Monitoring Committee 
This study will use an external Independent Data Monitoring Committee (IDMC) to perform interim 
reviews of accumulating study safety data. This committee will be composed of therapeutic area 
experts and a statistician, who are not employed by AstraZeneca, and do not have any major conflict of 
interest. Following the review, the IDMC will recommend whether the study should continue 
unchanged, be terminated, or be modified in any way. Once the IDMC has reached a recommendation, 
a report will be provided to AstraZeneca. A separate IDMC charter will be developed which will 
contain details of the IDMC members and clearly define the responsibilities of the IDMC. 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational product and comparators 
The AstraZeneca Pharmaceutical Technology and Development R&D Supply Chain will supply 
olaparib. Abiraterone acetate and enzalutamide will be sourced locally or centrally and should be 
administered according to local prescribing information, including any treatment restrictions.  
Abiraterone acetate must be dosed with prednisone in accordance with the approved label 
(prednisolone is permitted for use instead of prednisone if necessary).   
Table 12 
Identity of investigational product and comparators 
Investigational product 
Dosage form and strength 
Olaparib 
100 and 150 mg tablets 
Abiraterone acetateb 
250 mg and/or 500 mg tablets 
Enzalutamide 
40 mg capsules/tablets 
 
a 
Descriptive information for olaparib can be found in the olaparib IB.  Manufacturer will be included in the 
quality section of the IMPD.  
b 
With prednisone 
For all centers, olaparib tablets 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 will be required for dispensing in order to 
make up the desired dose. 
7.2 
Dose and treatment regimens 
Subjects will be randomized to receive either olaparib or investigator choice of abiraterone acetate or 
enzalutamide in a 2:1 ratio, respectively.  Subjects will continue to receive study treatment until BICR-
assessed radiographic progression, or after the date of DCO for the primary analysis until 
investigator-assessed radiographic progression, as long as they do not meet any of the criteria for 
treatment discontinuation.  
Olaparib is available as film-coated tablet containing 150 mg or 100 mg of olaparib. 


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Subjects will be administered olaparib orally twice daily at 300 mg bid continually.  Two x 150 mg 
olaparib tablets should be taken at the same time each day, approximately 12 hours apart with one 
glass of water.  If required, dose reductions to 250 mg bid and a further dose reduction to 200 mg bid 
are permitted, however once dose reduced, no return to the higher dose will be allowed. 
The tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Olaparib tablets 
can be taken with or without food.  On PK sampling days, subjects should fast from 1 hour before 
olaparib dosing to 2 hours after. 
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 subject enrolled on the study miss a 
scheduled dose for whatever reason (e.g., as a result of forgetting to take the tablets or vomiting), the 
subject 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 subject should take their allotted dose at the next scheduled time. 
Enzalutamide will be administered orally at 160 mg once daily.  Four x 40 mg capsules/tablets should 
be taken a similar time each day.  Capsules/tablets should be swallowed whole and can be taken with 
or without food, in full accordance with local prescribing information. 
Abiraterone acetate will be administered orally at 1,000 mg once daily.  Four x 250 mg or two x 
500 mg tablets should be taken at a similar time each day in combination with prednisone 5 mg 
administered orally twice daily (each prednisone dose approximately 12 hours apart). Subjects should 
take abiraterone acetate doses at a similar time each day. Abiraterone acetate must be taken on an 
empty stomach. No food should be consumed for at least two hours before the dose of abiraterone 
acetate and one hour after the dose of abiraterone acetate. The tablets should be swallowed whole with 
water and not crushed or chewed, in full accordance with local prescribing information. 
Dose Reductions  
For guidance on dose reductions for management of AEs refer to Section 6.7 (for olaparib) and 
Section 6.8 (for enzalutamide and abiraterone acetate). 
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors and strong 
CYP2C8 inhibitors (for enzalutamide) cannot be avoided see Section 7.7. 
Renal Impairment    
If subsequent to study entry and while still on study therapy, a subject’s estimated CrCl falls below the 
threshold for study inclusion (≥51 ml/min), retesting should be performed promptly.  
 
A dose reduction is recommended for subjects who develop moderate renal impairment (calculated 
creatinine clearance by Cockcroft-Gault equation of between 31 and 50 ml/min) for any reason during 
the course of the study: the dose of olaparib should be reduced to 200 mg bid. 
 
Because the CrCl determination is only an estimate of renal function, in instances where the CrCl falls 
to between 31 and 50 mL/min, the investigator should use his or her discretion in determining whether 
a dose change or discontinuation of therapy is warranted. 
 


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Olaparib has not been studied in subjects with severe renal impairment (creatinine clearance 
≤ 30 ml/min) or end-stage renal disease; if subjects develop severe impairment or end stage disease it 
is recommended that olaparib be discontinued. 
7.3 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local regulatory 
guidelines.  The labels will fulfill GMP Annex 13 requirements for labelling.  Label text will be 
translated into local language. 
Each bottle/pack of IMP will have an investigational product label permanently affixed to the outside 
stating that the material is for clinical study/investigational use only and should be kept out of reach 
and sight of children. The label will include a space for the enrollment code (E-code) to be completed 
at the time of dispensing. 
Specific dosing instructions will not be included on the label; the site must complete the ‘Subject 
Dispensing Card’ with the details of the dosing instructions at the time of dispensing. 
The subject emergency contact details will not be on the label, but can be found in the informed 
consent and the ‘Subject Dispensing Card’.  For emergency purposes, the subject must be in 
possession of the emergency contact details at all times. 
7.4 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the bottle specifies the appropriate storage. 
7.5 
Compliance 
The administration of all study drugs (including investigational products) should be recorded in the 
appropriate Sections of the eCRF. 
Subjects should be given clear instructions on how and when to take their study treatment. Subjects 
will self-administer study treatment. 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 staff will make tablet/capsule counts at regular intervals 
during treatment. Compliance will be assessed by the tablet /capsule count and the information will be 
recorded in the appropriate Section of the eCRF. After the tablet/capsule count has been performed, the 
remaining tablets/capsules will not be returned to the subject but will be retained by the Investigative 
site until reconciliation is completed by the study monitor. All subjects should return their 
bottles/packs of study medication at the appropriate scheduled visit, when new bottles/packs will be 
dispensed. Subjects will be instructed to notify study site personnel of missed doses. Dates of missed 
or held doses will be recorded on the eCRF. 
*Exception: Tablet/capsule counts do not have to be recorded on eCRF for locally supplied drug, but 
all study drug usage, including any missed doses, still needs to be recorded on appropriate section of 
eCRF. 
Subjects must return all containers and any remaining tablets at the end of the study. 


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7.6 
Accountability 
The study drug 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 subjects in accordance with the protocol. 
The study personnel will account for all study drugs dispensed to and returned from the subject. 
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. 
Dispensing and accountability records will continue to be collected for as long as subjects continue to 
receive study treatment, although they will not be entered on the database after the database has closed. 
Study site personnel, if applicable, or the AZ monitor will account for all study drugs received at the 
site, unused study drugs and for appropriate destruction.  Certificates of delivery, and destruction 
should be signed.  
7.7 
Concomitant and other treatments  
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 case report form (CRF). 
Medications that may NOT be administered 
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (except LHRH 
agonist/antagonist which is required during treatment phase), biological therapy or other novel agent, 
incl. corticosteroids if given for anti-cancer indication) is to be permitted while the subject is receiving 
study medication. 
Live virus and live bacterial vaccines should not be administered whilst the subject is receiving study 
medication and during the 30 day follow-up period. An increased risk of infection by the 
administration of live virus and bacterial vaccines has been observed with conventional chemotherapy 
drugs and the effects with olaparib are unknown. 


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Restricted concomitant medications 
Strong or Moderate CYP3A inhibitors  
Known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, boosted protease 
inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors 
(ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) should not be taken with olaparib. 
If there is no suitable alternative concomitant medication, then the dose of olaparib should be reduced 
for the period of concomitant administration. The dose reduction of olaparib should be recorded in the 
CRF with the reason documented as concomitant CYP3A inhibitor use.  
• 
Strong CYP3A inhibitors – reduce the dose of olaparib to 100 mg bid for the duration of 
concomitant therapy with the strong inhibitor and for 5 half lives afterwards. 
• 
Moderate CYP3A inhibitors - reduce the dose of olaparib to 150 mg bid for the duration 
of concomitant therapy with the moderate inhibitor and for 3 half lives afterwards. 
• 
After the washout of the inhibitor is complete, the olaparib dose can be re-escalated. 
Strong or Moderate CYP3A inducers 
Strong (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine, 
enzalutamide and St John’s Wort) and moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil) 
of CYP3A should not be taken with olaparib. 
If the use of any strong or moderate CYP3A inducers are considered necessary for the subject’s safety 
and welfare this could diminish the clinical efficacy of olaparib. 
If a subject requires use of a strong or moderate CYP3A inducer then they must be monitored carefully 
for any change in efficacy of olaparib. 
Refer to local prescribing information for guidance on dose modification for abiraterone acetate and 
enzalutamide in situations where co-administration with strong CYP3A4 inducers cannot be avoided. 
Strong CYP2C8 inhibitors 
Co-administration of enzalutamide with strong CYP2C8 inhibitors may increase exposure to 
enzalutamide and thus should be avoided if possible.  If subjects must be co-administered a strong 
CYP2C8 inhibitor, reduce the enzalutamide dose to 80 mg once daily (or per local prescribing 
information if different).  If co-administration of the strong inhibitor is discontinued, the enzalutamide 
dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor. 
P-gp inhibitors 
It is possible that co-administration of P-gp inhibitors (e.g., amiodarone, azithromycin) may increase 
exposure to olaparib. Caution should therefore be observed. 
Effect of olaparib on other drugs 
Based on limited in vitro data, olaparib may increase the exposure to substrates of CYP3A4, P-gp, 
OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K.  


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Based on limited in vitro data, olaparib may reduce the exposure to substrates of CYP3A4, 2B6, 2C9, 
2C19 and P-gp.  
Caution should therefore be observed if substrates of these isoenzymes or transporter proteins are co-
administered. 
Examples of substrates include: 
• 
CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot alkaloids, 
fentanyl, pimozide, sirolimus, tacrolimus and quetiapine 
• 
CYP2B6 – bupropion, efavirenz 
• 
CYP2C9 – warfarin  
• 
CYP2C19 - lansoprazole, omeprazole, S-mephenytoin 
• 
P-gp - simvastatin, pravastatin, digoxin, dabigatran, colchicine 
• 
OATP1B1 - bosentan, glibenclamide, repaglinide, statins and valsartan 
• 
OCT1, MATE1, MATE2K – metformin 
• 
OCT2 - serum creatinine 
• 
OAT3 -furosemide, methotrexate 
Anticoagulant Therapy 
Subjects who are taking warfarin may participate in this trial; however, it is recommended that 
international normalized ratio (INR) be monitored carefully at least once per week for the first month, 
then monthly if the INR is stable. Subcutaneous heparin and low molecular weight heparin are 
permitted. 
Anti-emetics/Anti-diarrheals 
From screening part 2 onwards, should a subject develop nausea, vomiting and / or diarrhea, then these 
symptoms should be reported as AEs (see Section 6.3) and appropriate treatment of the event given. 
Palliative radiotherapy  
Palliative radiotherapy may be used for the treatment of pain at the site of bony metastases that were 
present at baseline, provided the investigator does not feel that these are indicative of clinical disease 
progression during the study period.  Olaparib should be discontinued for a minimum of 3 days before 
a subject undergoes therapeutic palliative radiation treatment.  Olaparib should be restarted within 4 
weeks as long as any bone marrow toxicity has recovered.   


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Administration of other anti-cancer agents 
Continuous androgen deprivation therapy (ADT) with an LHRH agonist/antagonist (unless bilateral 
orchiectomy) must be continued during the trial. Since LHRH is standard of care, it will not be 
provided nor reimbursed.  
Subjects must not receive any other concurrent anti-cancer therapy, including investigational agents, 
while on study treatment. Subjects may continue the use of bisphosphonates or denosumab for bone 
disease provided the dose is stable before and during the study and they were started at least 4 weeks 
prior to beginning study treatment. 
Subsequent therapies for cancer  
Details of first and subsequent therapies for cancer and/or details of surgery for the treatment of the 
cancer, after discontinuation of treatment, will be collected.  Reasons for starting subsequent anti-
cancer therapies including access to other PARP inhibitors or investigational drugs will be collected 
and included in the exploratory assessments of OS. 
7.7.1 
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the subject’s 
safety and well-being, may be given at the discretion of the Investigator and recorded in the 
appropriate Sections of the eCRF. 
In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the study 
period must be recorded in the eCRF. 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA 
8.1 
Statistical considerations 
• 
All personnel involved with the analysis of the study will remain blinded at aggregate 
level until database lock and protocol violations identified. Prior to the database lock, any 
analysis tasks being performed will use a dummy random scheme. 
• 
Analyses will be performed by AstraZeneca or its representatives. 
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first subject randomized and 
any subsequent amendments will be documented, with final amendments completed prior to 
unblinding of the data. 
8.2 
Sample size estimate 
The sample size of 240 subjects randomized in a 2:1 ratio to olaparib tablets (300 mg orally bid) versus 
predeclared investigator choice of either enzalutamide (160 mg orally od) or abiraterone acetate 
(1,000 mg orally od with 5 mg bid prednisone) in Cohort A of this study was selected to be consistent 
with the research hypothesis as described in Section 1.1.2. The primary endpoint of the study is rPFS. 
It is expected that the targeted sample size of 240 subjects in Cohort A with approximately 143 rPFS 
events (60% maturity) will provide 95% power to demonstrate a statistical significant difference in 


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rPFS at a 2-sided alpha level of 5% assuming true treatment effect was a HR=0.53. This translates to 
an approximately 4.5-month improvement in median rPFS over an assumed 5-month median rPFS on 
enzalutamide or abiraterone acetate assuming rPFS is exponentially distributed. The smallest treatment 
difference that would be statistically significant at the final analysis is a HR of 0.71. It is anticipated 
that the study accrual period will be approximately 28 months and that 143 progression and death 
events will occur approximately 35 months after the first subject is randomized in the study.  
Cohort B of the study will consist of approximately 100 subjects with qualifying HRR mutations other 
than BRCA1, BRCA2 and ATM. These subjects will be randomized in a 2:1 ratio to olaparib tablets 
versus predeclared investigator choice of either enzalutamide or abiraterone acetate. 
8.3 
Definitions of analysis sets 
8.3.1 
Efficacy analysis set 
Cohort A Full Analysis Set (FAS):  
The primary statistical analysis of the efficacy of olaparib in comparison to investigator choice of either 
enzalutamide or abiraterone acetate in Cohort A will include all subjects who randomized in Cohort A as 
part of the global enrollment regardless of the treatment actually received. The global recruitment to the 
study closed when approximately 340 subjects were randomized. Subjects who were randomized in 
Cohort A as part of the global enrollment but did not subsequently go on to receive study treatment are 
included in the full analysis set (FAS) on Cohort A. All efficacy and health- related quality of life 
(HRQoL) data will be analyzed using the Full Analysis Set. 
 
 
  
 
 
Cohort B Full Analysis Set (FAS):  
The analysis of the efficacy of olaparib in Cohort B will include all subjects randomized to olaparib or 
investigator choice of either enzalutamide or abiraterone acetate in Cohort B as part of the global 
enrollment regardless of the treatment actually received. Subjects who were randomized in Cohort B 
but did not subsequently go on to receive study treatment are included in the FAS of Cohort B. All 
efficacy and HRQoL data will be analyzed using the Full Analysis Set. 
Cohort A+B Full Analysis Set (FAS):  
The analysis based on Cohort A+B will include subjects from both Cohort A Full Analysis Set and 
Cohort B Full Analysis Set. 
8.3.2 
Safety analysis set 
All subjects who are randomized as part of the global enrollment and received at least one dose of 
randomized study treatment in Cohort A or in Cohort B, will be included in the safety analysis set in 
the respective cohorts. If a subject receives at least one dose of olaparib study treatment they will be 
summarized in the olaparib arm for safety summaries (e.g., olaparib arm will include subjects 


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randomized to olaparib who receive at least one dose of olaparib or those subjects who receive at least 
one dose of olaparib study treatment in error at any time). If a subject randomized to olaparib receives 
only investigator choice of either enzalutamide or abiraterone acetate then they will be summarized as 
part of the investigator choice arm. Safety data captured on subjects receiving investigator choice who 
have subsequently switched to olaparib upon progression will be summarized per the treatment at the 
time of the onset of safety condition or lab result and reported in a separate section. 
 
 
 
8.3.3 
PK analysis set 
All subjects who have received at least one dose of study medication and provided at least one post-dose 
analyzable plasma sample for PK analysis will be included in the PK analysis set. Subjects with major 
protocol deviations including changes to the procedures that may impact the quality of the data, or any 
circumstances that can alter the evaluation of the PK may be excluded from the PK analysis set. 
8.3.4 
PRO analysis set 
The analysis of Patient Reported Outcomes will be based on the Full Analysis Set as defined in 
Section 8.3.1 for the respective Cohorts A and B.  
Table 13 
Summary of Outcome Variables and Analysis Populations 
Outcome Variable 
Populations 
Efficacy Data 
FAS 
- 
rPFS 
 
- 
Time to pain progression 
- 
Overall survival (OS) 
- 
Time from randomization to the date of opiate 
use for cancer-related pain.  
- 
PFS2 
 
Efficacy Data 
- 
ORR 
- 
DoR 
 
Subjects with measurable disease (FAS) 
Subjects with measurable disease at baseline that 
have a confirmed response (FAS) 
Demography 
FAS 
Disposition 
FAS 
Plasma concentration 
PK Analysis Set 
HRQoL data 
FAS  
Safety Data 
Safety Analysis Set 
- Compliance and Exposure 
 


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Table 13 
Summary of Outcome Variables and Analysis Populations 
Outcome Variable 
Populations 
- Adverse Events 
 
- Lab measurements 
 
- Vital Signs 
 
- Concomitant Medications 
 
 
8.4 
Outcome measures for analyses 
8.4.1 
Primary Endpoints 
8.4.1.1 
Radiological Progression Free Survival (rPFS)  
Progression-free survival is defined as the time from randomization until the date of objective disease 
progression (see Section 5.1.1.1 and Table 6) or death (by any cause in the absence of progression) 
regardless of whether the subject withdraws from randomized therapy or receives another anti-cancer 
therapy prior to progression. Subjects who have not progressed (defined as CR, PR or SD by RECIST 
1.1 for soft tissue disease, or non-PD for bone disease, see Section 5.1.2 and Appendix E) at the time 
of analysis will be censored at the time of the latest date of their last evaluable RECIST assessment or 
bone scan. However, if the subject progresses or dies after 2 or more missed radiologic assessments, 
the subject will be censored at the time of the latest evaluable RECIST 1.1 or bone scan assessment 
prior to the two missed visits. If the subject 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 subject at 
a later date, the date of the initial scan should be declared as the date of progression if the repeat scans 
confirm progression. 
CT/MRI and bone scans contributing towards a particular visit may be performed on different dates. 
The following rules will be applied: 
• 
For BICR (RECIST 1.1 and PCWG3) assessments, the date of progression will be 
determined based on the earliest of the scan dates of the component that triggered the 
progression for the adjudicated reviewer selecting PD or of the reviewer who read 
baseline first if there is no adjudication for ICR data.  
• 
For investigator assessments, the date of progression will be determined based on the 
earliest of the dates of the component that triggered the progression 
• 
For BICR and investigator assessments, when censoring a subject for rPFS, the subject 
will be censored at the latest of the dates contributing to a particular overall visit 
assessment. 


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The primary analysis will be based on the blinded independent central review (BICR) of the 
radiological scans. There is no plan for BICR to read any scans dated after the date of DCO for the 
primary analysis. There will be no need to request confirmation of BICR PD after this time point, and 
the investigator-assessed radiographic progression will prevail. 
 
A charter 
for the BICR will be developed in advance of the start of study. A sensitivity analysis based on the 
programmatically derived rPFS based on investigator recorded assessments will be performed. 
8.4.2 
Secondary Endpoints 
8.4.2.1 
Confirmed Overall Objective Response Rate (ORR) 
For the secondary endpoint ORR assessed by BICR (RECIST 1.1 and PCWG3), only subjects with 
measurable disease (target lesions) at entry will be included in the analysis. A responder will be any 
subject with a confirmed best overall response of PR or CR in their soft tissue disease assessed by 
RECIST 1.1, in the absence of progression on bone scan assessed by PCWG3. A subject will be 
classified as a responder if the RECIST 1.1 criteria for a CR or PR are satisfied (as well as the absence 
of confirmed progression on bone scan assessed by PCWG3) at any time up to and including the 
defined analysis cut-off point. For each treatment group, the objective response rate (ORR) is the 
number of subjects with a CR and PR divided by the number of subjects in the treatment group in the 
FAS with measurable disease at baseline.  
 
ORR will also be defined on the basis of RECIST only (soft tissue disease only). Additionally, 
analyses will also be performed on ORR assessed by investigator. 
8.4.2.2 
Time to Pain Progression 
Time to pain progression is defined as time from randomization to time point at which worsening in 
pain is observed for asymptomatic subjects and symptomatic subjects (at baseline) as follows: 
Asymptomatic subjects at baseline (average BPI-SF Item 3 score of 0 and not taking opioids) 
• 
Increase of 2 or more points in the average (i.e., average of 7-day assessments) “worst 
pain in 24 hours” (BPI-SF item 3) from baseline observed at 2 consecutive follow-up 
assessments/visits (separated by 3-4 weeks) 
Or 
• 
Initiation of opioid use for pain  
Symptomatic subjects at baseline (average BPI-SF Item 3 score >0 and/or currently taking opioids) 
• 
Increase of 2 or more points in the average (i.e., average of 7-day assessments) “worst 
pain in 24 hours” (BPI-SF item 3) from baseline observed at 2 consecutive follow-up 
assessments/visits (separated by 3-4 weeks) and an average worst pain score ≥4, and no 
decrease in average (i.e., average of 7-day assessments) opioid use measured as 1 or more 
points decrease in AQA score from a starting value of 2 or higher  
Or 


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• 
Increase in the average (i.e., average of 7-day assessments) opioid use measured as 1 or 
more points increase (or at least 2 points increase if the starting value is 0) in the AQA 
score from baseline observed at 2 consecutive follow-up assessments/visits (separated by 
3-4 weeks)  
Subjects satisfying one or more of the criteria above will be considered to have pain progression. 
Subjects who do not satisfy any of the criteria above will be censored at the time of the last known 
assessment that showed an absence of pain progression.  
Details on the BPI-SF and Analgesic score are provided in Sections 5.3.1.1 and 5.3.1.5, respectively. 
8.4.2.3 
Overall Survival 
Overall survival is defined as the time from the date of randomization until death due to any cause 
regardless of whether the subject withdraws from randomized therapy or receives another anti-cancer 
therapy. Any subject not known to have died at the time of analysis will be censored based on the last 
recorded date on which the subject was known to be alive. Note: Survival calls will be made in the 
week following the date of DCO for the analysis, and if subjects are confirmed to be alive or if the 
death date is post the DCO date these subjects will be censored at the date of DCO. See Section 3.10.2 
for methods that can be used to determine status of subjects who withdraw consent or are lost to follow 
up. 
8.4.2.4 
Time to first Symptomatic Skeletal –Related Event (SSRE)  
Time from randomization to first symptomatic skeletal–related event as defined by any of the 
following or a combination: 
• 
Use of radiation therapy to prevent or relieve skeletal symptoms. 
• 
Occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral). 
Radiologic documentation is required. 
• 
Occurrence of spinal cord compression. Radiologic documentation required. 
• 
Orthopedic surgical intervention for bone metastasis. 
Subjects who have not experienced any of the above conditions will be censored at time of death, or 
time of analysis if the subject is living. 
8.4.2.5 
Duration of Response 
Duration of response (DOR) will be defined as the time from the date of first documented confirmed 
response (by BICR using RECIST 1.1 and PCWG3) until date of documented progression (by BICR) 
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 
PFS endpoint. The time of the initial response will be defined as the latest of the dates contributing 
towards the first visit response of PR or CR. If a subject does not progress following a response, then 
their duration of response will use the PFS censoring date as the date at which that subject is censored 
for DOR. The time to response is the time from randomization to the first onset of an objective tumor 
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8.4.2.6 
Time to Opiate Use for Cancer Pain 
Time to Opiate use is defined as the time from randomization to the date of opiate use for cancer-
related pain on subjects who have not received any opiates at baseline. Subjects who have not received 
opiates during the study or died prior to receiving opiates will be considered censored at the last known 
on study date of no opiate use.  
8.4.2.7 
Prostate Specific Antigen (PSA) Response 
PSA response is defined as the proportion of subjects achieving a ≥50% decrease in PSA from baseline 
to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 
weeks later 
• 
A subject 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 subject 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 3 weeks later (i.e., decrease relative to baseline of at least 50% documented on 2 
consecutive occasions at least 3 weeks apart).  
8.4.2.8 
Circulating Tumor Cell (CTC) Conversion rate 
Defined as the proportion of subjects achieving a decline in the number of CTCs from ≥5 cells/7.5 mL 
at baseline to <5 cells/7.5 mL post baseline.   
8.4.2.9 
Time from randomization to second progression or death (PFS2) 
Defined as the time from the date of randomization to the earliest of the investigator assessed 
progression event (subsequent to that used for the primary variable PFS) or death. 
8.4.2.10 Pain Severity 
The BPI-SF pain severity domain/subscale consists of 4 items (#3, #4, #5, and #6) that assess pain at 
its “worst,” “least,” “average,” and “now” (current pain) respectively on an 11-point numeric rating 
scale (NRS). A pain severity subscale or composite score from all the 4 items (a mean score) will be 
evaluated as time to ‘pain severity’ progression and assessed from the time of randomization as 
follows for asymptomatic and symptomatic subjects: 
Asymptomatic subjects at baseline (average “pain severity” subscale score of 0 and not taking 
opioids) 
• 
Increase of ≥ 2 points in the average “pain severity” subscale score from baseline observed at 
2 consecutive follow-up assessments/visits (separated by 3-4 weeks) 
Or 
• 
Initiation of opioid use for pain. 
Symptomatic subjects at baseline (average “pain severity” subscale score >0 and/or currently taking 
opioids) 


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• 
Increase of ≥ 2 points in the average “pain severity” subscale score from baseline observed at 
2 consecutive follow-up assessments/visits (separated by 3-4 weeks) and an average “pain 
severity” subscale score ≥4, and no decrease in average opioid use measured as 1 or more 
points decrease in AQA score from a starting value of 2 or higher   
Or 
• 
Increase in the average (i.e., average of 7-day assessments) opioid use measured as 1 or more 
points increase (or at least 2 points increase if the starting value is 0) in the AQA score from 
baseline observed at 2 consecutive follow-up assessments/visits (separated by 3-4 weeks).  
8.4.2.11 Pain Interference 
The BPI-SF pain interference domain includes 7 items: general activity (item #9A), mood (item #9B), 
walking ability (item #9C), normal work (item #9D), relations with other people (item #9E), sleep 
(item #9F), and enjoyment of life (item #9G). The pain interference domain is scored as the mean of 
the 7 interference items. The mean can be used if more than 50% of the total items, or 4 of 7, have 
been completed on a given administration (Cleeland 2009). Absolute and change from baseline scores 
of pain interference will be evaluated. 
8.4.2.12 FACT-P 
For the FACT-P total score, TOI, FAPSI-6, PCS, PWB, and FWB sub-scales, absolute and change 
from baseline scores for each time point will be calculated for each treatment group. 
A best response of ‘Improved’, ‘No Change’ and ‘Worsened’, defined according to Table 14 and Table 
15, will be calculated for each subject for scales assessing prostate cancer symptoms, impact on 
functional well-being etc: FACT-P Total, TOI, FAPSI-6, PCS, PWB, and FWB subscales. 
Table 14 details how responders will be defined for the FACT-P total, TOI, FAPSI-6, PCS, PWB, and 
FWB scores (Cella et al 2009). 
  


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Table 14 
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 (i.e., >-6 and <+6) 
No change 
Missing/non-calculable score 
Not evaluable 
FAPSI-6 
≥ +3 
Improved 
≤ -3 
Worsened 
Otherwise (i.e., >-3 and <+3) 
No change 
Missing/non-calculable score 
Not evaluable 
TOI 
≥ +5 
Improved 
≤ -5 
Worsened 
Otherwise (i.e., >-5 and <+5) 
No change 
Missing/non-calculable score 
Not evaluable 
PCS 
≥ +3 
Improved 
≤ -3 
Worsened 
Otherwise (i.e., >-3 and <+3) 
No change 
Missing/non-calculable score 
Not evaluable 
FWB, PWB 
≥ +2 
Improved 
≤ -2 
Worsened 
Otherwise (i.e., >-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 14 for 2 consecutive visits. 
The criteria listed in Table 15 will be used to assign a best overall response score based on the 
individual visit responses. 
Table 15 
 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 
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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 
 
8.4.2.13 Pain Palliation 
Pain Palliation is defined for subjects with a BPI-SF “worse pain” item #3 score ≥4 points at baseline 
and is assessed as the proportion of subjects with a decrease of ≥ 2 points in BPI-SF item #3 score at 
12 weeks, confirmed at least 3 weeks later, without a ≥ 1 point increase (or ≥ 2 increase if starting 
value is 0) in AQA analgesic score. 
8.4.2.14 Pharmacokinetic Endpoints 
Olaparib concentrations in plasma will be measured at Week 4 (Visit 3) pre-dose (- 30 min ± 15 min) 
and at 30 min ± 15 min, 2 ± 0.5 h, 5 ± 0.5 h, and 8± 1 h postdose.  
8.4.3 
Exploratory Endpoints 
8.4.3.1 
PRO-CTCAE 
The PRO-CTCAE consists of nominal categories (e.g., “none” to “very severe” for some items in the 
questionnaire) as described in the Appendix G. 
8.4.3.2 
Patient Global Impression of Change (PGIC) 
The response options of the PGIC are scored as follows: Very Much Improved (+3), Much Improved 
(+2), Minimally Improved (+1), No Change (0), Minimally Worse (-1), Much Worse (-2) and Very 
Much Worse (-3).  
8.4.3.3 
Resource Use 
To investigate the impact of treatment and disease on health care resource, the following variables will 
be captured:  
• 
Planned and unplanned hospital attendances beyond trial protocol mandated visits 
(including physician visits, emergency room visits, day cases and admissions)  
• 
Primary sign or symptom the subject presents with  
• 
Length of hospital stay  
• 
Length of any time spent in an intensive care unit (ICU).  
8.4.3.4 
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 


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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). 
8.4.4 
Safety Endpoints 
Safety and tolerability will be assessed in terms of physical examination, AEs, deaths, laboratory data 
and vital signs.  These will be collected for all subjects.   
8.4.4.1 
Adverse Events 
An AE is the appearance of or worsening of any pre-existing condition, 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. 
8.4.4.2 
Other significant Adverse Events (OAE) 
During the evaluation of the AE data, an AstraZeneca or designated CRO medically qualified expert 
will review the list of AEs that were not reported as SAEs and DAEs.  Based on the expert’s 
judgement, significant adverse events of particular clinical importance may, after consultation with the 
Global Subject Safety Physician, be considered OAEs and reported as such in the Clinical Study 
Report.  A similar review of laboratory/vital signs/ECG data will be performed for identification of 
OAEs. 
Examples of these are marked hematological and other laboratory abnormalities, and certain events 
that lead to intervention (other than those already classified as serious), dose reduction or significant 
additional treatment. 
8.4.4.3 
Concomitant medications 
Concomitant medications will be classified according to the current version of the WHO 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. 


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8.4.4.4 
Compliance and exposure 
Study drug exposure (days) will be defined as time from first dose of olaparib to last dose. Exposure to 
investigator choice 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. 
8.5 
Methods for statistical analyses 
A comprehensive SAP will be prepared before first subject randomized. 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 summarized using 
descriptive statistics, including n, mean, SD, median, minimum, and maximum values. Where 
appropriate, assessments will be summarized by visit. 
The number of subjects who were screened, randomized to treatment (either Cohort A or Cohort B), 
received treatment and completed the study will be produced for each of the Cohorts and treatment 
groups using the full analysis set. A summary table of analysis sets will be produced. Demographic 
and baseline characteristics will be summarized using the full analysis set, for Cohorts A and B of the 
study, respectively. 
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. 
The treatment comparison is olaparib versus investigator choice. Results of statistical analyses will be 
presented using corresponding 2-sided confidence intervals and 2-sided p-values, where appropriate.  
8.5.1 
Multiplicity Strategy for Primary Endpoint and Key Secondary endpoints 
rPFS (Cohort A) is considered the primary endpoint in the study. 
Upon achieving statistical significance on the primary endpoint rPFS in Cohort A, testing of each of 
the secondary endpoints, ORR (Cohort A), rPFS (Cohort A + B), time to pain progression (Cohort A), 


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and overall survival (Cohort A) will be performed sequentially with the 2-sided 5% level of alpha 
recycled from the primary rPFS (Cohort A) endpoint.  
Figure 4 
Multiplicity Strategy Maintaining Overall Type I Error Rate 
               
 
 
 
 
8.5.2 
Analysis of the primary variable(s) 
8.5.2.1 
Radiological Progression Free Survival  
The primary analysis of rPFS will be performed when approximately 143 progression and death events 
(60% maturity) in cohort A have occurred based on BICR (RECIST 1.1 and PCWG3) assessment. This 
will be considered the primary rPFS analysis.  
rPFS will be analyzed using a log rank test stratified by previous taxane (yes, no) and measurable 
disease (yes, no) [when analyzing rPFS in Cohort A+B as part of a secondary analysis, an additional 
stratum for cohort will be used if sufficient events exist within strata] and a corresponding p-value will 
be generated. If there are less than 5 rPFS events within each stratum, then the levels of strata will be 
collapsed until the minimum 5 event criterion is achieved for the primary rPFS endpoint. All analyses 
in Cohort A, B and A+B (secondary analyses) will be conducted in accordance with the corresponding 
final pooling strategy. Further details of the pre-defined pooling strategy indicating the order in which 
the levels of stratum will be collapsed will be documented in the SAP. The hazard ratio (HR) and 
confidence interval will be estimated using a Cox Proportional Hazards Model (with ties=Efron and 
the stratification variables as covariates) and the 2-sided CI will be calculated using a profile likelihood 


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approach. Stratification variables will be defined according to data from the interactive voice/web 
response system (IVRS/IWRS). 
The HR (olaparib vs. investigator choice) together with its corresponding 95% confidence intervals 
(CI) and p-value will be presented (a HR less than 1 will favor olaparib).  
Any subjects mis-stratified in the IVRS/IWRS will be included in the stratified log rank test using the 
baseline data collected in the IVRS/IWRS. 
A Kaplan-Meier (KM) plot of rPFS will be presented by treatment group. Summaries of the number 
and percentage of subjects experiencing a progression or death event, and the type of event (RECIST 
1.1 or bone progression or death) will be provided along with median rPFS for each treatment arm. 
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 producing 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.   
The primary analysis will be based on the BICR assessment of rPFS using all scans regardless of 
whether they were scheduled or not.  
The estimated rPFS rates at 6 months and 12 months will be summarized (using the KM curve) and 
presented by treatment group. 
Additionally, the rPFS endpoint will be analyzed in Cohort B and Cohort A+B as part of secondary 
analyses. 
8.5.3 
Analysis of the secondary variable(s) 
Analyses of secondary endpoints will be performed at the time of the primary rPFS analysis including 
an interim analysis for OS. The final analysis of OS will occur upon achieving ~60% maturity in 
Cohort A. 
All time to event analyses in Cohort A, B and A+B will be conducted in accordance with the final 
pooling strategy for stratification factors in the primary analysis of rPFS as indicated in Section 8.5.2 
where less than 5 events for a time to event endpoint within each stratum, will result in collapsing of 
strata until the minimum 5 event criterion is achieved.  Unstratified analyses will be conducted for any 
secondary endpoints that still do not conform to the 5 event rule per stratum. This will also be 
supported by unstratified sensitivity analyses of the primary endpoint.  Additional sensitivity analyses 
may also be conducted as required.  Further details of the pre-defined pooling strategy indicating the 
order in which the levels of stratum will be collapsed will be documented in the SAP. 
8.5.3.1 
Confirmed Objective Response Rate (ORR) 
ORR will be assessed based on BICR assessed RECIST and bone scan data (using all scans regardless 
of whether they were scheduled or not) in subjects with measurable disease in FAS. ORR will be 
compared between olaparib and investigator choice using a logistic regression model adjusting for the 
stratification variable, previous taxane (yes, no).  The results of the analysis will be presented in terms 
of an odds ratio (an odds ratio greater than 1 will favor olaparib) together with its associated profile 
likelihood 95% CI (e.g., using the option ‘LRCI’ in SAS procedure GENMOD) and p-value (based on 


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twice the change in log-likelihood resulting from the addition of a treatment factor to the model). 
Statistically significant difference in ORR will be demonstrated using a 2-sided 5% alpha level based 
on the multiplicity strategy described in section 8.5.1.    
If there are not enough responses for a meaningful analysis using logistic regression then a Fisher’s 
exact test using mid p-values will be presented. The mid-p-value modification of the Fisher exact test 
amounts to subtracting half of the probability of the observed table from Fisher's p-value. 
Fisher’s exact test mid p-value  =  Two sided p-value 
-  
Table probability 
2 
Summaries will be produced that present the number and percentage of subjects with a tumor response 
(CR/PR) per BICR and investigator assessment.  
For each treatment arm, best objective response (BoR) will be summarized by n (%) for each category 
(CR, PR, SD, PD and NE).  No formal statistical analyses are planned for BoR. 
Analysis of ORR will be performed in Cohorts A, B and A+B. 
8.5.3.2 
Time to Pain Progression: 
Time to pain progression will be analyzed at the time of the primary rPFS analysis using the same 
methods as in the analysis of rPFS. The p-value will be based on the stratified log rank test using 
previous taxane use and measurable disease as strata and HR and 95% CI will be based on the Cox 
model. A 2-sided 5% alpha level will be used to test time to pain progression based on multiplicity 
strategy. 
A Kaplan-Meier (KM) plot of time to pain progression will be presented by treatment group. 
Summaries of the number and percentage of subjects experiencing pain progression will be provided 
along with median time to pain progression for each treatment arm. 
Analysis of Pain progression will be performed in Cohorts A, B and A+B. 
8.5.3.3 
Overall Survival 
Analysis of the secondary efficacy endpoint OS, as defined in Section 8.4.2.3, will be performed at the 
time of the primary analysis of rPFS with approximately 49% maturity in Cohort A (approximately 
117 events) expected at this point in time and will be considered an interim OS analysis. As per the 
multiplicity strategy described in Section 8.5.1, testing of the OS endpoint will utilize the alpha level 
recycled from rPFS primary endpoint and the secondary endpoints ORR (Cohort A), rPFS (Cohort 
A+B), and time to pain progression (Cohort A) using a 2-sided 5% alpha spend. Using an O’Brien-
Fleming spending function, the interim analysis will use approximately 0.012 alpha level with 80% 
information fraction and a final OS analysis will use as alpha level of 0.021 with approximately 146 
events (61% maturity) estimated to occur approximately 48 months after first subject randomized in 
the study. The p-value will be based on the stratified log rank test using previous taxane use and 
measurable disease as strata. HR and 95% CI will be based on the Cox model. 
A Kaplan-Meier (KM) plot of OS will be presented by treatment group. Summaries of the number and 
percentage of deaths and those alive and censored will be provided along with median time to death for 
each treatment arm. 


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OS analysis will be repeated in Cohorts B and Cohort A+B using a 2-sided alpha level. 
Exploratory analyses of OS in Cohort A adjusting for impact of subsequent PARP inhibitor trial or 
treatment (or other potentially active investigational agents) may be performed if a sufficient proportion 
of subjects 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. 
8.5.3.4 
Time to first Symptomatic Skeletal-Related Event (SSRE) 
Time to SSRE will be analyzed using the same methods as in the analysis of the primary endpoint 
rPFS. 
A Kaplan-Meier (KM) plot of time to SSRE will be presented by treatment group. Summaries of the 
number and percentage of subjects with symptomatic skeletal related events and those who are 
censored will be provided along with median time to symptomatic skeletal related events for each 
treatment arm. 
8.5.3.5 
Duration of Response: 
Descriptive data will be provided for the duration of response in responding subjects, including the 
associated Kaplan-Meier curves (without any formal comparison of or p-value attached). 
8.5.3.6 
Time to Opiate use for Cancer related Pain 
Time to opiate use will be analyzed at the time of the primary rPFS analysis using the same methods as 
in the analysis of rPFS. The, p-value will be based on the stratified log rank test using previous taxane 
use and measurable disease as strata and HR and 95% CI will be based on the Cox model. A 2-sided 
5% alpha level will be used to test time to opiate use based on multiplicity strategy. 
A Kaplan-Meier (KM) plot of time to opiate use will be presented by treatment group. Summaries of 
the number and percentage of subjects using opiates will be provided along with median time to opiate 
use for each treatment arm. 
8.5.3.7 
Prostate Specific Antigen (PSA) Response 
Proportion of subjects achieving a PSA response and subjects with a confirmed PSA response will be 
presented with 95% CIs. Best PSA percentage change from baseline and percentage change at 12 
weeks will be summarized as continuous variables using descriptive statistics and will be graphically 
displayed using waterfall plots. 
8.5.3.8 
Circulating Tumor Cell (CTC) conversion rate 
Proportion of subjects achieving a CTC conversion will be presented with 95% CIs. Change from 
baseline in CTC counts will be summarized as continuous variables using descriptive statistics and will 
be displayed graphically using waterfall plots. 


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8.5.3.9 
Time from randomization to second progression or death 
Time from randomization to second progression or death will be analyzed using the same methods as 
in the analysis of the primary endpoint rPFS. The HR and corresponding 95% confidence interval will 
be based on the Cox model using previous taxane use and measurable disease as strata.  
A Kaplan-Meier (KM) plot of time to second progression or death will be presented by treatment 
group. Summaries of the number and percentage of subjects with second progression or death and 
those who are censored will be provided along with median time to second progression or death for 
each treatment arm.  
8.5.3.10 PK Analysis  
The PK analysis of the plasma concentration data for olaparib will be performed at AstraZeneca 
Research & Development or by a clinical research organization identified by AstraZeneca Research & 
Development. The actual sampling times will be used in the PK calculations. For each subject 
providing a complete set of PK samples, non-linear mixed effects modeling will be used to estimate 
steady state maximum observed plasma concentration, AUC, and minimum observed plasma 
concentration. 
The plasma concentration-time data will be analyzed by non-linear mixed effects modeling in order to 
evaluate the PK characteristics of olaparib, quantify variability in the PK, identify demographic or 
pathophysiological covariates which may explain the observed variability and explore exposure-
response relationships. The relationship between exposure to olaparib and pharmacodynamics response 
(safety and/or efficacy) will be investigated if deemed appropriate. The population 
PK/pharmacodynamic modeling will be reported separately from the CSR. 
The plasma concentration data will be listed within the clinical study report and the pre-dose and post-
dose olaparib plasma concentrations will be summarized, using summary statistics, as detailed in the 
statistical analysis plan.  
8.5.4 
Subgroup analysis 
Subgroup analyses will be conducted for rPFS endpoint in Cohort A. The purpose of the subgroup 
analyses is to assess the consistency of treatment effect across potential or expected prognostic factors.  
If there are too few responders or events available for a meaningful analysis of a particular subgroup (it 
is not considered appropriate to present analyses where there are less than 5 events in a subgroup), the 
relationship between that subgroup and the endpoint will not be formally analyzed.  In this case, only 
descriptive summaries will be provided. 
The following subgroups of the full analysis set in Cohort A will be analyzed for rPFS for stratification 
factors 
• 
Previous taxane use (yes, no) 
• 
Measurable disease at baseline (yes, no) 
Values collected on the eCRF will be used to define subgroups for stratification factors. 


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Additional subgroups of interest include: 
• 
HRR mutation type, e.g., BRCA1, BRCA2, BRCA1 and BRCA2 (both), ATM  
• 
Germline versus somatic mutation type 
• 
Visceral disease at baseline (yes, no) 
• 
ECOG performance status at baseline (0, 1, or 2). 
Other baseline variables may also be assessed if there is clinical justification. 
Additionally, time to pain progression will be assessed in the subgroup of subjects who have not taken 
any analgesics at baseline.  
In each subgroup, the HRs for radiological progression by BICR (olaparib: investigator choice) and 
associated 2-sided CIs will be calculated from a Cox proportional hazards model (ties = Efron) that 
contains the treatment term, factor and treatment-by-factor interaction term.  The treatment effect HRs 
for each treatment comparison along with their confidence intervals will be obtained for each level of 
the subgroup from this single model.  The HRs and 95% CIs will be presented on a forest plot 
including the HR and 95% CI from the overall population (using the primary analysis).   
No adjustment to the significance level for testing of subgroups will be made since all these subgroup 
analyses will be considered exploratory and may only be supportive of the primary analysis of rPFS. 
The presence of quantitative interactions will be assessed by means of an overall global interaction 
test.  This will be performed in the overall population by comparing the fit of a Cox proportional 
hazards model including treatment, all covariates (stratification factors), and all covariate-by-treatment 
interaction terms, with one that excludes the interaction terms and will be assessed at the 2-sided 10% 
significance level. If the fit of the model is not significantly improved then it will be concluded that 
overall the treatment effect is consistent across the subgroups. 
If the global interaction test is found to be statistically significant, an attempt to determine the cause 
and type of interaction will be made. Stepwise backwards selection will be performed on the saturated 
model, whereby (using a 10% level throughout) the least significant interaction terms are removed 
one-by-one and any newly significant interactions re-included until a final model is reached where all 
included interactions are significant and all excluded interactions are non-significant.  Throughout this 
process all main effects will be included in the model regardless of whether the corresponding 
interaction term is still present.  This approach will identify the factors that independently alter the 
treatment effect and prevent identification of multiple correlated interactions.  
Any quantitative interactions identified using this procedure will then be tested to rule out any 
qualitative interaction using the approach of Gail and Simon (Gail and Simon 1985). 
8.5.5 
Interim analysis 
An interim analysis of OS will be performed at the time of the primary rPFS analysis in Cohort A 
(approximately 35 months after first subject randomized into the study).  Approximately 117 deaths 
(49% maturity) are expected to be accrued in Cohort A at the time of interim OS analysis.  Using 


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O’Brien-Fleming spending function an alpha level of 0.012 will be spent at the interim analysis with 
80% information fraction (117/146 events) at the interim OS analysis.  
This study will use an external Independent Data Monitoring Committee (IDMC) to perform interim 
reviews of accumulating study safety data. This committee will be composed of therapeutic area 
experts and a statistician, who are not employed by AZ, and do not have any major conflicts of 
interest. Following the review, the IDMC will recommend whether the study should continue 
unchanged, be terminated, or be modified in any way. Once the IDMC has reached a recommendation, 
a report will be provided to AstraZeneca. The report will only include the recommendation and any 
potential protocol amendments and it will not contain any unblinded information or reference to the 
confidential considerations of the committee to have led to their recommendation. A separate IDMC 
charter will be developed which will contain details of the IDMC members and clearly define the 
responsibilities of the IDMC. 
In addition to the periodic review of safety data by an IDMC, the safety of all AstraZeneca clinical 
studies is closely monitored on an on-going basis by AstraZeneca representatives in consultation with 
the Subject Safety Department. Issues identified will be addressed; this could involve, for instance, 
amendments to the study protocol and letters to investigators. 
8.5.6 
Sensitivity analysis 
8.5.6.1 
Sensitivity analyses for rPFS 
Sensitivity analyses will be performed to assess the possible presence of time-assessment bias (i.e., 
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 PCWG3) will be analyzed 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 subjects who progressed or died in the absence of progression 
immediately following 2, or more, non-evaluable tumor assessments will be included. In addition, 
subjects 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. 
(d)  
Ascertainment bias 


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Analysis of rPFS will be based on investigator assessment. 
(e)  
Sensitivity analysis using unequivocal clinical progression in addition to radiological 
progression 
 
Repeating primary rPFS analysis with the addition of unequivocal progression as an event. Where 
unequivocal clinical progression is defined as, cancer pain requiring initiation of opioids, need to 
initiate cytotoxic chemotherapy, radiation therapy or surgical intervention for complications due to 
tumor progression or deterioration in ECOG performance to >= Grade 3. 
(f)  
Sensitivity analysis for confirmation of bone progression 
Repeat primary rPFS analysis with revised confirmation criteria for bone progression where bone 
progression accompanied by unequivocal clinical progression does not require a confirmatory bone 
scan.  
(g)  
Sensitivity analysis censoring subjects with subsequent therapy or discontinuation of study 
drug 
Repeat primary rPFS analysis censoring subjects with subsequent therapy or discontinuation of study 
drug prior to progression.  
(h) 
Sensitivity analysis for enrichment of subjects on Cohort B 
If enrichment on Cohort B (subjects with non BRCA/ATM HRR+ gene mutations) subjects is 
required then a sensitivity analysis of rPFS in Cohort A+B will be conducted in which a weighted 
estimate of the overall HR (HRcohort A+B) will be calculated using the estimated HR in Cohort B 
(HRcohort B), the estimated HR in Cohort A (HRcohort A) and the estimated HR in HRR+ 
unknown subgroup if exists (HR HRR unknown): 
 
ln(HRcohort A+B) = w1ln(HRcohort A) + w2ln(HRcohort B) + w3ln(HR HRR unknown) where 
weights w1 , w2 and  w3 (proportion of Cohort A subjects, Cohort B subjects and HRR unknown 
subjects, respectively) will be estimated from the subjects enrolled prior to enrichment occurring (i.e., 
in the non-enriched portion of the trial). 
 
For calculation of confidence intervals, the overall variance (log scale) will take into account the 
variance of all groups (that are independent), and thus be calculated as: 
 
var(ln(HRcohort A+B)) = w12var(ln(HRcohort A)) + w22var(ln(HRcohort B)) + 
w32var(ln(HR HRR unknown)) 
 
The 100(1-α) % confidence interval will be calculated as: 
 
exp[ ln(HR cohort A+B) ± Z1-α/2 √ var(ln(HRcohort A+B))] 
 
The weighted hazard ratio (HR; olaparib: enzalutamide or abiraterone) for treatment will be estimated 
together with two-sided 95% confidence interval. If there are less than 5 events in the HRR unknown 
subgroup then Cohort A and HRR unknown group will be combined. 


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8.5.7 
Supportive analyses 
All exploratory analyses will be performed at the time of the primary rPFS analysis. 
8.5.7.1 
Patient reported outcomes (PRO) 
The secondary endpoints BPI-SF (Pain Severity domain), BPI-SF (Pain interference domain), Pain 
Palliation, FACT-P (FACT-P Total score, TOI, FWB, PWB, PCS and FAPSI 6 and exploratory 
endpoints), PRO-CTCAE and PGIC are described in Sections 8.4.2 and 8.4.3. 
PRO endpoints that are continuous in nature (e.g., BPI-SF, FACT-P, Pain interference) will be 
summarized using means, standard deviation, median and range by treatment group for each visit until 
there are less than one third of subjects with evaluable data. For the FACT-P total score, TOI, FAPSI-
6, PCS, FWB, PWB, BPI-SF item #3 (worst pain in 24 hours), pain severity (BPI-SF pain severity 
domain), and pain interference, absolute and change from baseline scores for each time point will be 
calculated for each treatment group. 
The proportion of subjects with best responses of ‘Improved’, ‘No Change’ and “Worsened” on 
FACT-P and subscales (FWB, PWB, PCS, FAPSI 6) scores including TOI will be compared between 
treatments using logistic regression with the same methods and covariates as for the analysis of ORR. 
Responses on the PRO-CTCAE and PGIC will be summarized descriptively as number of subject and 
corresponding percentages for each category in the questionnaire at each visit by treatment group. 
Time to pain progression will be repeated as a sub-group analysis restricted to subjects who are non-
opiate users at baseline. 
Time to pain severity progression will be analyzed using the same methodology as in time to pain 
progression without any adjustments for multiplicity. Proportion of subjects with pain palliation will 
be summarized with corresponding 95% confidence intervals 
Summary measures of overall compliance and compliance over time will be derived separately for 
BPI-SF, FACT-P, PGIC, PRO-CTCAE.  
Overall compliance will be defined as the number of subjects who provided both a baseline and at least 
one post baseline assessment for which there were sufficient data recorded for the visit to be evaluable 
for at least one subscale, divided by the number of subjects randomized.  
Compliance over time is calculated separately for each visit, including baseline, as the number of 
subjects with an evaluable form at the time point (as defined above), divided by number of subjects 
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. 
Analyses of PRO endpoints will be performed in Cohorts A and A+B. 
8.5.7.2 
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- 


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and post-treatment, and pre- and post- progression. Further details will be outlined in the payer analysis 
plan. 
8.5.7.3 
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. 
8.5.8 
Safety Analyses 
Safety analyses will be presented using the Safety Analysis Set 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), laboratory data (clinical chemistry and hematology), and physical examination. 
Adverse events will be summarized separately for Cohorts A, B and A+B of the study and by treatment 
group. Laboratory data, vital signs, physical examination, body temperature and ECG will be 
summarized separately by Cohorts A, B and A+B, Treatment group and Visit. 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. 
Additional tables, figures, or listings may be produced to aid interpretation. Further details of 
summaries of the safety data will be provided in the SAP. 
8.5.8.1 
Adverse events 
The number of subjects experiencing AEs following administration of olaparib and investigator choice 
of enzalutamide and abiraterone acetate as well as the number of AEs experienced will be summarized. 
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 subjects experiencing SAEs, OAEs, AEs that led to withdrawal, AEs that led 
to death and treatment-related AEs with corresponding number of such events will be summarized by 
Cohort A, B and Cohort A+B and treatment, as applicable. 
8.5.8.2 
Dose-limiting toxicities 
Dose-limiting toxicities will be summarized by treatment cohort and treatment. 
8.5.8.3 
Laboratory data 
Laboratory data (clinical chemistry and hematology) will be summarized. Shift tables will be provided 
for select tests, where shift from baseline to the worst value within the study will be summarized. 
Laboratory data outside the reference ranges will be indicated. 
8.5.8.4 
Concomitant medications 
Concomitant medications will be summarized by the coded terms. The number of subjects receiving a 
medication will be summarized by Cohort A, B and Cohort A+B and treatment group. A medication 


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taken from the start of the screening part 2 and onwards is considered concomitant. A subject is only 
counted once if receiving the medication more than once. 
Disallowed medications will be listed. 
8.5.8.5 
Vital signs 
Vital signs, including BP (mmHg), body temperature (°C) and weight (kg), will be summarized at 
baseline. The baseline value is the last pre-dose assessment. 
8.5.8.6 
Other safety variables 
The remaining safety variables will be presented using summary statistics for quantitative data and 
frequency counts for qualitative parameters. 
8.5.8.7 
Exposure and compliance 
Listings and summaries of exposure and compliance will be produced for olaparib and investigator 
choice by Cohort A, B and Cohort A+B.  
The number of subjects who discontinued study drug, and the reasons, will be summarized by Cohort 
A, B and Cohort A+B and treatment separately. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA 
9.1 
Training of study site personnel 
Before the first subject 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 and the IVRS/ IWRS/WBDC/and/or ePRO 
system(s) utilized. 
The Principal Investigator 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 Principal Investigator will maintain a record of all individuals involved in the study (medical, 
nursing and other staff). 
9.2 
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 subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (e.g., clinic charts). 
• 
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject. 
The AstraZeneca representative will be available between visits if the Investigator(s) or other staff at 
the center needs information and advice about the study conduct. 
9.2.1 
Source data 
Refer to the Clinical Study Agreement (CSA) for location of source data.     
9.2.2 
Study agreements 
The Principal Investigator at each center should comply with all the terms, conditions, and obligations 
of the CSA or equivalent, for this study. In the event of any inconsistency between this CSP and the 


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CSA the terms of CSP shall prevail with respect to the conduct of the study and the treatment of 
subjects and in all other respects, not relating to study conduct or treatment of subjects, the terms of the 
CSA shall prevail. Agreements between AstraZeneca and the Principal Investigator should be in place 
before any study-related procedures can take place, or any subjects are enrolled. 
9.2.3 
Archiving of study documents 
The investigator follows the principles outlined in the CSA. 
9.3 
Study timetable and end of study 
The end of this study is defined as ‘the last visit of the last subject undergoing the study’. 
There will be a final data cut-off defined as the time of final OS analysis (see Section 8.5.3.3).  At this 
time point, the clinical study database will close to new data.  Subjects 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 study treatment.  AstraZeneca will continue to 
supply olaparib for subjects in the study.  NHA will be continued by local supply under standard of 
care. For subjects who do continue to receive olaparib treatment beyond the time of this data cut-off, 
Investigators will continue to report all SAEs to AstraZeneca Patient Safety until 30 days after study 
treatment is discontinued, in accordance with Section 6.4 (Reporting of Serious Adverse Events). If an 
Investigator learns of any SAEs, including death, at any time after a subject 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.  Additionally as 
stated in Section 6.3 (Recording of adverse events), any SAE or non-serious adverse event 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 subject is lost to follow-up. 
The study is expected to start in Q1 2017 and to end by Q1 2021. 
The study may be terminated at individual centres 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. 
9.4 
Data management by AstraZeneca or delegate 
Data management will be performed by a chosen vendor according to the Data Management Plan. 
Data entered in the WBDC system or data captured electronically will be immediately saved to the 
applicable database and changes tracked to provide an audit trail. 
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 WHO Drug Dictionary.  All coding will be performed by the Medical 
Coding Team at the chosen vendor. 
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the study 
database will be available in an audit trail. 


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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.  The Data Management Plan will also clarify the roles and responsibilities of the various 
functions and personnel involved in the data management process. 
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. 
Serious Adverse Event (SAE) Reconciliation 
SAE reconciliation reports are produced and reconciled with the Subject Safety database and/or the 
investigational site.  
Data Management of genotype data 
See Appendix C – Pharmacogenetics Research. 
Data associated with human biological samples 
Data associated with biological samples will be transferred from laboratory (ies) internal or external to 
AstraZeneca. 
Management of external data 
Data from external providers (e.g., central laboratories) will be validated as appropriate to ensure it is 
consistent with the clinical data and included in the final database. In the case of biomarker (tumour 
tissue or blood for exploratory analyses) data, the results of any analyses will not be recorded in the 
database, but information relating to the processing of the sample, including the original date of biopsy 
(historical tumour tissue sample and the actual date the sample(s) were collected) will be recorded in 
the eCRF and database. 
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
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 ICH/Good Clinical Practice, applicable regulatory 
requirements and the AstraZeneca policy on Bioethics and Human Biological Samples. 
10.2 
Subject 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.  
AstraZeneca will not provide individual genotype results from PGx to subjects, any insurance 
company, any employer, their family members, general physician or any other third party, unless 
required to do so by law. 
Precautions are taken to preserve confidentiality and prevent genetic data being linked to the identity 
of the Subject. In exceptional circumstances, however, certain individuals might see both the genetic 
data and the personal identifiers of a Subject. For example, in the case of a medical emergency, an 


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AstraZeneca Physician or an Investigator might know a Subject’s identity and also have access to his 
or her genetic data. Also Regulatory authorities may require access to the relevant files, though the 
Subject’s medical information and the genetic files would remain physically separate. 
10.3 
Ethics and regulatory review 
An Ethics Committee 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 
subjects.  The Investigator will ensure the distribution of these documents to the applicable Ethics 
Committee, and to the study site staff. 
The opinion of the Ethics Committee should be given in writing. The Investigator should submit the 
written approval to AstraZeneca before enrollment of any subject into the study.  
The Ethics Committee should approve all advertising used to recruit subjects for the study. 
AstraZeneca 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 Ethics Committee annually. 
Before enrollment of any subject 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 will handle the distribution of any of these documents to the national regulatory 
authorities. 
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal Investigators with 
safety updates/reports according to local requirements. 
10.4 
Informed consent 
The Principal Investigator(s) at each center will: 
• 
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study, information about alternative 
treatment with non-investigational drugs. 
• 
Ensure each subject is notified that they are free to discontinue from the study at any time. 
• 
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided. 
• 
Ensure each subject 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 subject. 


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• 
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the informed consent form that is approved by an Ethics Committee. 
10.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the International co-ordinating 
Investigators 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). 
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be followed for 
revised protocols. 
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to each 
Principal Investigator(s). For distribution to Ethics Committee see Section 10.3. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca and the 
centre’s Ethics Committee 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 
Ethics Committee. 
10.6 
Audits and inspections 
Authorized representatives of AstraZeneca, a regulatory authority, or an Ethics Committee may 
perform audits or inspections at the center, 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, analyzed, 
and accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements.  The 
Investigator will contact AstraZeneca immediately if contacted by a regulatory agency about an 
inspection at the center. 


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11. 
LIST OF REFERENCES 
American Cancer Society 2014 
American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014. 
Azad et al 2015 
Azad AA, Eigl BJ, Murray RN, Kollmannsberger C, Chi KN. Efficacy of enzalutamide following 
abiraterone acetate in chemotherapy-naïve metastatic castration-resistant prostate cancer subjects. Eur 
Urol. 2015 Jan;67(1):23-9. 
Basch et al 2009 
Basch E, Jia X, Heller G, Barz A, Sit L, Fruscione M, et al. Adverse symptom event reporting by 
patients vs clinicians: relationship with clinical outcomes. J Natl Cancer Inst. 2009;101:1624-32. 
Beer et al 2014 
Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in 
metastatic prostate cancer before chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33. 
Caffo et al 2015 
Caffo O, De Giorgi , Fratino L, Alesini D, Zagonel V, Facchini G et al. Clinical outcomes of 
castration-resistant prostate cancer treatments administered as third or fourth line following failure of 
docetaxel and other second-line treatment: Results of an Italian multicentre study. Eur Urol. 2015;68 
(1):147-53. 
Castro et al 2015 
Castro E, Goh C, Leongamornlert D, Saunders E, Tymrakiewicz M, Dadaev T, et al. Effect of BRCA 
mutations on metastatic relapse and cause-specific survival after radical treatment for localised 
prostate cancer. Eur Urol. 2015 Aug;68(2):186-93. 
Cella et al 2009 
Cella D, Nichol MB, Eton D, Nelson JB, Mulani P. Estimating clinically meaningful changes for the 
Functional Assessment of Cancer Therapy-Prostate: results from a clinical trial of patients with 
metastatic hormone-refractory prostate cancer. Value Health. 2009 Jan-Feb;12(1):124-9. 
Center et al 2012 
Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, et al. International variation in 
prostate cancer incidence and mortality rates. Eur Urol. 2012 Jun;61(6):1079-92. 
Cheng et al 2015 
Cheng HH, Pritchard CC, Boyd T, Nelson PS, Montgomery B. Biallelic inactivation of BRCA2 in 
platinum-sensitive metastatic castration-resistant prostate cancer. Eur Urol. 2016 Jun;69(6):992-5. 
Cheng et al 2015 
Cheng HH, Gulati R, Azad A, Nadal R, Twardowski P, Vaishampayan UN, et al. Activity of 
enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment 
with abiraterone and/or docetaxel. Prostate Cancer Prostatic Dis. 2015 Jun;18(2):122-7. 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
 
130 (170) 
Chung et al 2014 
Chung KC, Barlev A, Braun AH, Qian Y, Zagari M. Assessing analgesic use in patients with advanced 
cancer: development of a new scale--the Analgesic Quantification Algorithm. Pain Med 2014;15:225-
32. 
Cleeland 2009 
Cleeland CS. The Brief Pain Inventory User Guide. 2009;1-63. 
Cleeland and Ryan 1994 
Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med 
Singapore 1994 March;23(2):129-138. 
de Bono et al 2011 
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L et al. Abiraterone and increased 
survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. 
Dworkin et al 2005 
Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP et al. Core outcome 
measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9-19. 
Dworkin et al 2008 
Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT et al. Interpreting the clinical 
importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain 
2008 Feb;9(2):105-21. 
Esper et al 1997 
Esper P, Mo F, Chodak G, Sinner M, Cella DF, Pienta KJ. Measuring quality of life in men with 
prostate cancer using the Functional Assessment of Cancer Therapy-Prostate instrument. Urology. 
1997;50:920-8. 
EuroQol Group 1990 
EuroQol Group. EuroQol - a new facility for the measurement of health-related quality of life. Health 
Policy 1990;16(3):199-208. 
EuroQol Group 2013 
EuroQol Group. EQ-5D-5L user guide: basic information on how to use the EQ-5D-5L instrument, 
version 2.0, October 2013. Available from: URL: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/UserGuide_EQ-5D-
5L_v2.0_October_2013.pdf. Accessed 21 November 2013. 
Fong et al 2009 
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) 
polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123-34. 
Flaig et al 2016 
Flaig TW, Potluri RC, Ng Y, Todd MB, Mehra M. Treatment evolution for metastatic castration-
resistant prostate cancer with recent introduction of novel agents: retrospective analysis of real-world 
data. Cancer Med. 2016 Feb;5(2):182-91. 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
 
131 (170) 
Food and Drug Administration 2009 
Food and Drug Administration: Guidance for Industry on Patient-Reported Outcome Measures: Use in 
Medical Product Development to Support Labeling Claims; Availability. Federal Register 
2009;74:65132-3. 
Gail and Simon 1985 
Gail M, & Simon R. Testing for qualitative interactions between treatment effects and patient subsets. 
Biometrics 1985; 41:361-72. 
Hay et al 2009 
Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, et al. Poly(ADP-ribose) polymerase-
1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays 
tumor relapse in combination with carboplatin. Cancer Res. 2009;69(9):3850-5.  
Helleday 2011 
Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the 
misunderstandings. Mol Oncol. 2011; 5: 387-393. 
Herdman et al 2011 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and preliminary 
testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20(10):1727-36. 
Janssen et al 2008a 
Janssen MF, Birnie E, Haagsma JA, Bonsel GJ. Comparing the standard EQ-5D three-level system 
with a five-level version. Value Health 2008;11(2):275-84. 
Janssen et al 2008b 
Janssen MF, Birnie E, Bonsel GJ. Quantification of the level descriptors for the standard EQ-5D three-
level system and a five-level version according to two methods. Qual Life Res 2008;17(3):463-73. 
Kaufman et al 2015 
Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña  J et al. 
Olaparib monotherapy in subjects with advanced cancer and a germline BRCA1, BRCA2 mutation. J 
Clin Oncol. 2015 Jan 20;33(3):244-50. 
Kluetz et al 2013 
Kluetz PG, Ning YM, Maher VE, Zhang L, Tang S, Ghosh D et al. Abiraterone acetate in combination 
with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer: U.S. 
Food and Drug Administration drug approval summary. Clin Cancer Res. 2013 Dec 15;19(24):6650-6. 
Kumar et al 2016 
Kumar A, Coleman I, Morrissey C, Zhang X, True LD, Gulati R et al. Substantial interindividual and 
limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat 
Med. 2016 Apr;22(4):369-78. 
Litwin et al 1998 
Litwin MS, Lubeck DP, Henning JM, Carroll PR. Differences in urologist and patient assessments of 
health related quality of life in men with prostate cancer: results of the CaPSURE database. J Urol 
1998;159:1988-92. 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D081DC00007 
Version 4.0 
Date 07 March 2019 
 
 
 
132 (170) 
Mateo et al 2015 
Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R et al. DNA repair defects and 
PARP inhibition in metastatic prostate cancer. N Engl J Med. 2015 Oct 29;373(18):1697-708. 
Mezynski et al 2012 
Mezynski J, Pezaro C, Bianchini D, Zivi A, Sandhu S, Thompson E, et al. Antitumor activity of 
docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-
resistance? Ann Oncol. 2012 Nov;23(11):2943-7. 
Moreira et al 2016 
Moreira RB, Debiasi M, Maluf FC, Bellmunt J, Fay AP, Choueiri TK, et al. Differential side effects 
profile in mCRPC subjects treated with abiraterone or enzalutamide: A meta-analysis of randomized 
controlled trials. J Clin Oncol 34, 2016 (suppl 2S; abstr 73) 
Murai et al 2012 
Murai J, Huang SN, Das BB, Renaud A, Zhnag, Y, Doroshow, JH, et al. Trapping of PARP1 and 
PARP2 by Clinical PARP Inhibitors. AACR; 72(21); 5588–99. 
Pickard et al 2007 
Pickard AS, De Leon MC, Kohlmann T, Cella D, Rosenbloom S. Psychometric comparison of the 
standard EQ-5D to a 5 level version in cancer patients. Med Care 2007;45(3):259-63. 
Robins et al 1991 
Robins JM, Tsiatis AA. Correcting for noncompliance in randomised trials using rank preserving 
structural failure time models. Commun Stat Theory Methods. 1991; 20:2609-2631. 
Robins 1993 
Robins J. Information recovery and bias adjustment in proportional hazards regression analysis of 
randomised trials using surrogate markers. Proceedings of the Biopharmaceutical Section, ASA. 1993; 
24-33. 
Robinson et al 2015 
Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM et al. Integrative clinical 
genomics of advanced prostate cancer. Cell. 2015 May 21;161(5):1215-28. 
Rottenberg et al 2008 
Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, et al. High 
sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in 
combination with platinum drugs. Proc Natl Acad Sci. 2008;105(44):17079-84. 
Ryan et al 2013 
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic 
prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. 
Sandhu et al 2013 
Sandhu SK, Omlin A, Hylands L, Miranda S, Barber LJ, Riisnaes R et al. Poly (ADP-ribose) 
polymerase (PARP) inhibitors for the treatment of advanced germline BRCA2 mutant prostate cancer. 
Ann Oncol. 2013 May;24(5):1416-8. 


Clinical Study Protocol 
Drug Substance Olaparib  
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Date 07 March 2019 
 
 
 
133 (170) 
Scher et al 2012 
Scher HI, Fizazi K, Saad F, M., Taplin ME, Sternberg CN, Miller K et al. Increased Survival with 
Enzalutamide in Prostate Cancer after Chemotherapy. N Engl J Med 2012; 367:1187-1197. 
Scher et al 2015 
Scher HI, Solo K, Valant J, Todd MB, Mehra M. Prevalence of prostate cancer clinical states and 
mortality in the United States: Estimates using a dynamic progression model. PLoS One. 2015 Oct 
13;10(10):e0139440. 
Scher et al 2016 
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K et al. Trial Design and Objectives for 
Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical 
Trials Working Group 3. J Clin Oncol. 2016 Apr 20;34(12):1402-18. 
Schweizer et al 2014 
Schweizer MT, Zhou XC, Wang H, Bassi S, Carducci MA, Eisenberger MA, et al. The influence of 
prior abiraterone treatment on the clinical activity of docetaxel in men with metastatic castration-
resistant prostate cancer. Eur Urol. 2014 Oct;66(4):646-52. 
Shen and Kumar 2015 
Shen X, Kumar P. Trade-off between treatment of early prostate cancer and incidence of advanced 
prostate cancer in the prostate screening era. J Urol. 2015 Dec 2. pii: S0022-5347(15)05348-3.  
Steinberger et al 2015 
Steinberger AE, Ledet EM, Luk E, Cotogno P, Stolten M, Desmond D, et al.  
Characterizations of clinical and therapeutic histories for men with prostate cancer-specific 
mortality. Clin Genitourin Cancer. 2015 Nov 11. pii: S1558-7673(15)00302-X. doi: 
10.1016/j.clgc.2015.11.003 
Sun and Chen 2010 
Sun X, Chen C. Comparison of Finkelstein’s Method With the Conventional Approach for Interval-
Censored Data Analysis. Stat Biopharm Res. 2010; 2:97-108 
Suzman et al 2014 
Suzman DL, Luber B, Schweizer MT, Nadal R, Antonarakis ES. Clinical activity of enzalutamide 
versus docetaxel in men with castration-resistant prostate cancer progressing after abiraterone. 
Prostate. 2014 Sep; 74(13):1278-85. 
Turk et al 2006 
Turk DC, Dworkin RH, Burke LB, Gershon R, Rothman M, Scott J et al. Developing patient-reported 
outcome measures for pain clinical trials: IMMPACT recommendations. Pain 2005 Dec 5;125(3):208-
15. 
Tutt et al 2010 
Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN et al. Oral poly(ADP-ribose) 
polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast 
cancer: a proof-of-concept trial. Lancet. 2010 Jul; 376(9737):235-44.  


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134 (170) 
US Social Security 
U.S. Social security administration Online: Life expectancy calculator. Available from: URL: 
https://www.socialsecurity.gov/OACT/population/longevity.html. Accessed 5 February 2016. 
van Soest et al 2013 
van Soest RJ, van Royen ME, de Morrée ES, Moll JM, Teubel W, Wiemer EA et al. Cross-resistance 
between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence 
choices in metastatic castration-resistant prostate cancer. Eur J Cancer. 2013 Dec;49(18):3821-30. 
Vogelzang et al 2016 
Vogelzang NJ, Armstrong AJ, Higano CS, Sartor AO, Pieczonka CM, Concepcion RS et al. Treatment 
patterns for metastatic castration-resistant prostate cancer (mCRPC) in oncology (ONC) urology 
(URO) practices: Data from the PROCEED registry. J Clin Oncol 34, 2016 (suppl; abstr e16503).


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Appendix A 
Additional Safety Information 
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 
(e.g., hepatitis that resolved without hepatic failure). 
Hospitalization 
Out subject treatment in an emergency room is not in itself a serious AE, although the reasons for it 
may be (e.g., bronchospasm, laryngeal edema).  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, 
hospitalization, 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. 
• 
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 (e.g., neutropenia or anemia requiring blood transfusion, etc.) or convulsions 
that do not result in hospitalization 
Development of drug dependency or drug abuse 
A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors 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? 


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• 
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? 
• 
De-challenge 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 etiology such as the 
underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-challenge. 
• 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship. 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression ‘reasonable 
possibility’ of a causal relationship is meant to convey, in general, that there are facts (evidence) or 
arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough information to 
make an informed judgment.  With limited or insufficient information in the case, it is likely that the 
event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of effect should 
be classified as no reasonable possibility. 
Medication error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in the 
treatment process for an AstraZeneca study drug that either causes harm to the participant or has the 
potential to cause harm to the participant.   
A medication error is not lack of efficacy of the drug, but rather a human or process related failure 
while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error.   
• 
occurred 
• 
was identified and intercepted before the participant received the drug 
• 
did not occur, but circumstances were recognize that could have led to an error 


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Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion 
• 
Dispensing error e.g., medication prepared incorrectly, even if it was not actually given to 
the participant 
• 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• 
Drug not taken as indicated e.g., tablet dissolved in water when it should be taken as a solid 
tablet  
• 
Drug not stored as instructed e.g., kept in the fridge when it should be at room temperature  
• 
Wrong participant received the medication (excluding IVRS/IWRS errors) 
• 
Wrong drug administered to participant (excluding IVRS/IWRS errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error  
• 
Participant accidentally missed drug dose(s) e.g., forgot to take medication 
• 
Accidental overdose (will be captured as an overdose) 
• 
Participant failed to return unused medication or empty packaging 
• 
Errors related to background and rescue medication, or standard of care medication in open 
label studies, even if an AZ product  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the medication 
error. 
 


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Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
Labelling and shipment of biohazard samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  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 e.g., 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 e.g., 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.  
• 
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. 
• 
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. 


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Appendix C 
Pharmacogenetics Research 
Background and Rationale 
AstraZeneca intends to perform genetic research in the olaparib clinical development program 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. 
Future research may suggest other genes or gene categories as candidates for influencing not only 
response to olaparib and/or agents used in combination or as comparators but also susceptibility to 
disease and/or response for which olaparib may be evaluated. Thus, this genetic research may involve 
study of additional un-named genes or gene categories for the purpose of diagnostic development or 
other exploratory research, but only as related to disease susceptibility and drug action. 
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 (i.e., distribution, safety, tolerability and efficacy) 
to olaparib. 
Study selection record 
Subjects will be asked to participate in this genetic research.  Participation is voluntary and if a subject 
declines to participate there will be no penalty or loss of benefit.  The subject will not be excluded 
from any aspect of the main study. 
Inclusion criteria 
For inclusion in this genetic research, subjects must fulfill all of the inclusion criteria described in the 
main body of the Clinical Study Protocol and: 
• 
Provide informed consent for the genetic sampling and analyses. 
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 in 120 days of genetic sample collection 
Discontinuation of Subjects from this genetic research 
Specific reasons for discontinuing a subject from this genetic research are: 
Withdrawal of consent for genetic research:  Subjects 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 3.10.2 of the main study protocol. 


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Collection of samples for genetic research 
The blood sample for genetic research will be obtained from the subjects at Visit 2 (day 0) baseline. 
Although genotype is a stable parameter, early sample collection is preferred to avoid introducing bias 
through excluding subjects who may withdraw due to an adverse event (AE), such subjects would be 
important to include in any genetic analysis. If for any reason the sample is not drawn at baseline, it 
may be taken at any visit until the last study visit. Only one sample should be collected per subject for 
genetics during the study. See the laboratory manual for blood volume, and sample management 
details. 
Coding and storage of DNA samples 
The processes adopted for the coding and storage of samples for genetic analysis are important to 
maintain Subject confidentiality. Samples will be stored for a maximum of 15 years, from the date of 
last Subject 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.) 
The samples and data for genetic analysis in this study will be single coded.  The link between the 
subject enrollment/randomization 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. 
Ethical and Regulatory Requirements 
The principles for ethical and regulatory requirements for the study, including this genetics research 
component, are outlined in Section 10 of the protocol. 
Informed Consent 
The genetic component of this study is optional and the subject 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 subject must sign and date both the consent for the main study and the 
genetic component of the study.  Copies of signed and dated consent forms must be given to the 
subject and the original filed at the study center.  The investigator(s) is responsible for ensuring that 
consent is given freely and that the Subject understands that they may freely discontinue from the 
genetic aspect of the study at any time. 


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Subject Data Protection 
AstraZeneca will not provide individual genotype results to subjects, any insurance company, any 
employer, their family members, general physician or any other third party, unless required to do so by 
law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to the 
identity of the subject.  In exceptional circumstances, however, certain individuals might see both the 
genetic data and the personal identifiers of a Subject.  For example, in the case of a medical 
emergency, an AstraZeneca Physician or an investigator might know a subject’s identity and also have 
access to his or her genetic data.  Also Regulatory authorities may require access to the relevant files, 
though the subject’s medical information and the genetic files would remain physically separate. 
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 analyze the samples. 
The results from this genetic research may be reported in the CSR for the main study, or in a separate 
report as appropriate. 
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.  
Statistical Methods and Determination of Sample Size 
The number of subjects 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. 


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Appendix D 
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately report cases 
of Hy’s Law.  It is not intended to be a comprehensive guide to the management of elevated liver 
biochemistries. Specific guidance on the managing liver abnormalities can be found in Section 6.3.7 of 
the protocol. 
During the course of the study the Investigator will remain vigilant for increases in liver biochemistry.  
The investigator is responsible for determining whether a subject 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 Medicinal Product (IMP).  
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. 
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 IMP, can 
be found to explain the combination of increases, e.g., elevated ALP indicating cholestasis, viral 
hepatitis, another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e., on the same 
day) the elevation in TBL, but there is no specified timeframe within which the elevations in 
transaminases and TBL must occur. 
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 subject who meets any of the following identification criteria in isolation or in combination: 
• 
ALT ≥ 3xULN 
• 
AST ≥ 3xULN 
• 
TBL ≥ 2xULN 


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When a subject meets any of the identification criteria, in isolation or in combination, the central 
laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca representative).  
The Investigator will also remain vigilant for any local laboratory reports where the identification 
criteria are met, where this is the case the Investigator will: 
• 
Notify the AstraZeneca representative. 
• 
Request a repeat of the test (new blood draw) by the central laboratory. 
• 
Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result. 
When the identification criteria are met from central or local laboratory results the Investigator will 
without delay: 
• 
Determine whether the subject meets PHL criteria (see Definitions within this Appendix for 
definition) by reviewing laboratory reports from all previous visits (including both central and 
local laboratory results). 
Follow-up 
Potential Hy’s Law Criteria not met 
If the subject does not meet PHL criteria the Investigator will: 
• 
Inform the AstraZeneca representative that the subject has not met PHL criteria. 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in the 
Clinical Study Protocol. 
Potential Hy’s Law Criteria met 
If the subject does meet PHL criteria the Investigator will: 
• 
Determine whether PHL criteria were met at any study visit prior to starting study treatment 
(See Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment). 
• 
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 subjects’ follow-up and the continuous review of data.  Subsequent to this contact the 
Investigator will: 
• 
Monitor the subject until liver biochemistry parameters and appropriate clinical symptoms and 
signs return to normal or baseline levels, or as long as medically indicated.  


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• 
Investigate the etiology of the event and perform diagnostic investigations as discussed with 
the Study Physician. This includes deciding which the tests available in the Hy’s law lab kit 
should be used.  
• 
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. 
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this Section should be followed for all cases where PHL criteria are 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 IMP.  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 IMP: 
• 
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 an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above. 


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• 
Continue follow-up and review according to agreed plan.  Once the necessary supplementary 
information is obtained, repeat the review and assessment to determine whether HL criteria are 
met.  Update the SAE report according to the outcome of the review. 
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment  
This Section is applicable to subjects with liver metastases 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 subjects’ 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 in Potential 
Hy’s Law Criteria met of this Appendix. 
# A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of the 
individual liver biochemistry parameters (ALT, AST or total bilirubin) 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. 
Actions Required for Repeat Episodes of Potential Hy’s Law 
This Section is applicable when a subject 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 found to be 
the disease under study e.g., chronic or progressing malignant disease, severe infection or liver 
disease or did the subject meet PHL criteria prior to starting study treatment and at their first 
on study treatment visit as described in Actions Required When Potential Hy’s Law Criteria 
are Met Before and After Starting Study Treatment? 
If no: follow the process described in Potential Hy’s Law Criteria met of this Appendix 
If yes: determine if there has been a significant change in the subject’s condition# compared with when 
PHL criteria were previously met 
• 
If there is no significant change no action is required. 


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• 
If there is a significant change follow the process described in Potential Hy’s Law Criteria met. 
A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of the 
individual liver biochemistry parameters (ALT, AST or total bilirubin) 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. 
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  


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Appendix E 
Guidelines for Evaluation of Objective Tumor Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumors) in Soft Tissue and PCWG3 (Prostate Cancer 
Working Group Criteria 3) in Bone Lesions 
INTRODUCTION 
This appendix details the implementation of RECIST 1.1 Guidelines (Eisenhauer et al 2009) and 
PCWG3 guidelines (Scher et al 2016) for the D081DC00007 study with regards to assessment of 
tumor burden including protocol-specific requirements for this study. 
ASSESSMENT OF SOFT TISSUE DISEASE USING RECIST 1.1 
CRITERIA 
Definition of measurable, non-measurable, target and non-target lesions 
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 the bone 
lesion section of this appendix document. 
Measurable: 
A lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the 
longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed 
tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated 
measurements. 
Non-measurable: 
• 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with ≥10 to <15mm short axis at baseline*). 
• 
Truly non-measurable lesions include the following: leptomeningeal disease, ascites, 
pleural / pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, abdominal masses/abdominal organomegaly identified by physical 
examination that is not measurable by CT or MRI. 
• 
Previously irradiated lesions**. 
*Nodes with <10mm short axis are considered non-pathological and should not be recorded or 
followed as NTL. 
**Localized post-radiation changes which affect lesion sizes may occur.  Therefore, lesions that have 
been previously irradiated will not be considered measurable and must be selected as Non-Target 
Lesions (NTL) at baseline and followed up as part of the NTL assessment. 


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Special Cases: 
• 
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 subject, these should be selected as target lesions. 
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 target lesions (TL) 
at baseline. 
Non-Target lesions: 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline 
(except bone lesions which will be assessed as defined in bone lesion section of this appendix). 
Methods of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and recorded lesion at baseline and during follow-up visits. 
A summary of the methods to be used for RECIST assessment is provided below and those excluded 
from tumor assessments for this study are highlighted, with the rationale provided. 
Table 16 
 Summary of Methods of Assessment 
Target Lesions  
Non-Target Lesions 
New Lesions 
CT (preferred) 
MRI 
CT (preferred) 
MRI  
X-ray, Chest x-ray 
CT (preferred) 
MRI  
X-ray, Chest x-ray 
Ultrasound 
FDG-PET 
 
CT and MRI  
CT and MRI are generally considered to be the best currently available and reproducible methods to 
measure TL selected for response assessment and to assess NTL and identification of any new lesions.  
In the D081DC00007 study it is recommended that CT examinations of the chest, abdomen and pelvis 
will be used to assess tumor burden at baseline and follow-up visits.  CT examination with intravenous 
(i.v.) contrast media administration is the preferred method.  MRI should be used where CT is not 
feasible or it is medically contra-indicated.  For brain lesion assessment, MRI is the preferred method. 
Every effort should be made to maintain the radiologic imaging modality used at baseline throughout 
subsequent assessments.  
Chest X-ray 


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In the D081DC00007 study, chest x-ray assessment will not be used for assessment of TL as they will 
be assessed by CT examination or MRI examination.  Chest X-ray can, however, be used to assess 
NTL and to identify the presence of new lesions. 
Ultrasound  
In the D081DC00007 study, ultrasound examination will not be used for assessment of TL and NTL as 
it is not a reproducible method, does not provide an accurate assessment of tumor 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 examination. 
Endoscopy and laparoscopy  
In the D081DC00007 study, endoscopy and laparoscopy will not be used for tumor assessments as 
they are not validated in the context of tumor assessment. 
Tumor markers  
In the D081DC00007 study tumor markers will not be used for tumor response assessments as per 
RECIST 1.1. 
In this study the following marker (PSA) are being collected for separate analysis.  However, the 
results will not contribute to tumor response based on RECIST 1.1 assessment. 
Cytology and histology  
In the D081DC00007 study histology and will not be used for tumor response assessments as per 
RECIST 1.1 and tumor response assessments will be performed on radiological criteria only.   
FDG-PET scan  
In the D081DC00007 study FDG-PET scans may be used as a method for identifying new lesions, 
according with the following algorithm:  New lesions will be recorded where there is positive FDG 
uptake* not present on baseline FDG-PET scan or in a location corresponding to a new lesion on 
CT/MRI at the same follow-up visit.  If there is no baseline FDG-PET scan available, and no evidence 
of new lesions on CT/MRI scans then follow-up CT/MRI assessments should be continued, scheduled 
as per protocol or clinical indicated, in order to confirm new lesions. 
* A positive FDG-PET scan lesion should be reported only when an uptake greater than twice that of 
the surrounding tissue is observed. 
Tumor response evaluation  
Schedule of evaluation 
Baseline 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 subjects and should be performed no more than 28 days before randomization. 
Follow-up assessments will be performed every 8 weeks (± 7 days) after randomization until objective 
disease progression by BICR as defined by RECIST 1.1 (soft tissue) or PCWG3 (bone), and after the 


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date of DCO for the primary analysis, by investigator-assessed radiographic progression. Any other 
sites at which new disease is suspected should also be adequately imaged at follow-up. 
If an unscheduled assessment was performed and the subject has not progressed, every attempt should 
be made to perform the subsequent assessments at their originally scheduled visits.  This schedule is to 
be followed in order to minimize any unintentional bias caused by some subjects being assessed at a 
different frequency than other subjects. 
Target lesions (TL) 
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 TL 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 millimeters.  At 
baseline the sum of the diameters for all TL will be calculated and reported as the baseline sum of 
diameters.  At follow-up visits the sum of diameters for all TL will be calculated and reported as the 
follow-up sum of diameters. 
Special cases: 
• 
For TL 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 two or more parts, then record the sum of the diameters of those parts.  
• 
If two or more TL 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 5mm should be assigned.  If an accurate measure can be given, this should be recorded, 
even if it is below 5mm. 
• 
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 e.g., radiotherapy, embolization, surgery etc., during 
the study, the size of the TL should still be provided where possible. 


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Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor visit response for 
TL. 
Table 17  
Evaluation of target lesions 
Complete Response (CR) 
Disappearance of all target lesions since baseline.  Any 
pathological lymph nodes selected as target lesions must have a 
reduction in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of TL, 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 target lesions, 
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 5mm. 
Not Evaluable (NE) 
Only relevant if any of the target lesions 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 target lesion 
response 
 
Non-Target lesions (NTL) 
Evaluation of non-target lesions 
All other lesions (or sites of disease), except for bone lesions, not recorded as TL should be identified 
as NTL 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.  This section provides the definitions of the criteria used to determine and 
record overall response for NTL at the investigational site at each visit. 
Table 18 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions since baseline. All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
Non CR/Non PD 
Persistence of one or more NTL  
Progression (PD) 
Unequivocal progression of existing non-target lesions.  
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. 


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Not Evaluable (NE) 
Only relevant when one or some of the non-target lesions were not 
assessed and, in the Investigator's opinion, they are not able to 
provide an evaluable overall non-target lesion assessment at this 
visit. 
Note:  For subjects without target lesions at baseline, this is 
relevant if any of the non-target lesions were not assessed at this 
visit and the progression criteria have not been met. 
 
To achieve ‘unequivocal progression’ on the basis of non-target lesions, there must be an overall level 
of substantial worsening in non-target disease such that, even in presence of SD or PR in target lesions, 
the overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. 
New Lesions 
Details of any new soft tissue lesions will also be recorded with the date of assessment.  The presence 
of one or more new lesions is assessed as progression.  
A 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 tumor. 
If a new lesion is equivocal, for example because of its small size, the treatment and tumor 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. 
Evaluation of Overall Visit Soft Tissue Response 
The overall visit response will be derived using the algorithm shown in Table 19. 
Table 19 
Overall Visit Soft Tissue Response 
Target lesions 
Non-Target lesions 
New Lesions 
Overall soft tissue 
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) 


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Table 19 
Overall Visit Soft Tissue Response 
Target lesions 
Non-Target lesions 
New Lesions 
Overall soft tissue 
response 
NA 
NA 
No 
NED 
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 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable, NA = not applicable (only relevant if there were no TL and/or NTLs at baseline), NED = No Evidence 
of Disease (only relevant when there is no TL and NTL from baseline). 
ASSESSMENT OF BONE LESION PROGRESSION USING PCWG3 
CRITERIA 
Bone lesions will be assessed by bone scan and will not be part of the RECIST v1.1 malignant soft 
tissue assessment. 
Method of assessment 
Bone lesions identified on a whole body isotopic bone scan at baseline should be recorded and 
followed by the same method as per baseline assessment.   
In the D081DC00007 study isotopic bone scans will be used as a method of assessment to identify the 
presence of new bone lesions at follow-up visits.  New lesions will be recorded where a positive and 
unequivocal hot-spot that was not present on the baseline bone scan assessment is identified on a bone 
scan performed at any time during the study.  The Investigator should consider the positive hot-spot to 
be a significant new site of malignant disease and represent true disease progression in order to record 
the new lesion.   
Tumor progression evaluation 
Schedule of the evaluation 
Baseline assessments should be performed no more than 28 days before the start of study treatment. 
Follow-up assessments will be performed every 8 weeks (± 7 days) after randomization until objective 
disease progression by BICR as defined by RECIST 1.1 (soft tissue) or PCWG3 (bone).  
If an unscheduled assessment was performed and the subject has not progressed, every attempt should 
be made to perform the subsequent assessments at their originally scheduled visits.  This schedule is to 
be followed in order to minimize any unintentional bias caused by some subjects being assessed at a 
different frequency than other subjects. 
Documentation of lesions 


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All bone lesions (or sites of disease) should be identified at baseline.  Their status should be followed 
at subsequent visits.  At each visit an overall assessment of the bone lesion progression should be 
recorded by the Investigator.  This section provides the definitions of the criteria used to determine and 
record bone progression at the investigational site at each visit. 
Progression on a bone scan is identified using PCWG3 as follow: 
• 
At the 8 week scan: 
2 or more new metastatic bone lesions are observed on the first 8-week scan compared to 
the baseline assessment. The confirmatory scan, performed at least 6 weeks later and 
preferably no later than the next scheduled visit for a bone scan (i.e,, Week 16), 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. 
Note - The first bone scan completed after baseline will be considered the ‘8-week scan’ 
regardless if taken at week 8 or at an unscheduled assessment. 
• 
After the 8 week scan: 
2 or more new metastatic bone lesions are observed compared to the 8‑week assessment. 
The confirmatory scan, performed at least 6 weeks later and preferably at the next 
scheduled visit for a bone scan, must show the persistence of or an increase in the number 
of metastatic bone lesions compared to the prior scan for progression to be documented. 
The date of progression is the date of the scan that first documents the second lesion. 
Evaluation of bone progression status 
Table 20 provides the definitions for the visit bone progression status for bone lesions. 
Table 20 
Bone progression status 
Non Progressive Disease (Non-
PD) 
No evidence of progression, or appearance of one new bone 
lesion, or non-fulfillment of the progression criteria including new 
lesions without confirmation of progression.  
Progressive Disease (PD) 
Bone lesions fulfilling the requirements for at least 2 new lesions 
and confirmation of progression. 
Not Evaluable (NE) 
Only relevant if a follow-up bone scan is not performed 
OVERALL RADIOLOGICAL VISIT ASSESSMENT 
Table 21 provides the definitions how the visit responses for soft tissue (according to RECIST1.1 
criteria) and bone progression status (according to PCWG3 criteria) are combined to give an overall 
radiological objective visit response. 


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Table 21 
Overall radiological visit response 
Overall visit soft 
tissue response 
(RECIST 1.1) 
Bone progression status 
(PCWG3) 
Bone lesions at visit 
Present/Absent 
Overall radiological 
visit response 
CR 
Non-PD 
Absent 
CR 
CR 
Non-PD 
Present 
PR 
CR 
NE 
- 
PR 
PR 
Non-PD or NE 
Any 
PR 
SD 
Non-PD or NE 
Any 
SD 
NED 
Non-PD or NE 
Any 
Non-PD 
NE 
Non-PD or NE 
Any 
NE 
PD  
Any 
Any 
PD 
Any 
PD 
Any 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable, NED = No Evidence of Disease (only relevant when there is no TL and NTL from baseline). 
CONFIRMATION OF RESPONSE  
In the D081DC00007 study, imaging for confirmation of response (CR or PR) should be performed at 
the next scheduled RECIST and PCWG3 assessment, i.e., 8 weeks (and must not be less than 4 weeks 
later) following the date the criteria for response were first met. 
Table 22 
Best overall response when confirmation of CR and PR required. 
Overall radiological 
response First time 
point 
Overall radiological 
response subsequent time 
point 
Best Overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD or PD 
CR 
PD  
SD or PD 
CR 
NE 
SD or NE  
PR 
CR 
PR 
PR  
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD or PD 
PR 
NE 
SD or NE 


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Overall radiological 
response First time 
point 
Overall radiological 
response subsequent time 
point 
Best Overall response 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable. 
a  
if a CR is truly met at first time point, then any disease seen at subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after 
CR). Best response would depend on whether minimum duration for SD was met. However, sometimes 
‘CR’ may be claimed when subsequent scan suggest small lesions were likely still present and in fact the 
subject had PR, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
CENTRAL REVIEW 
The Contract Research Organization (CRO) appointed by AstraZeneca to perform the independent 
central review for this study will provide specification for radiological imaging protocols in standard 
acquisition guidelines documentation.  
REFERENCES 
Eisenhauer et al 2009 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R.  New response evaluation 
criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer 45 (2009) 228-247 
Scher et al 2016 
Scher HI, Morris MJ, Stadler WM et al. Trial design and objectives for castration-resistant prostate 
cancer: Updated recommendations from the Prostate Cancer Clinical Trials Working Group 3.  J Clin 
Oncol 34 (2016)  


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Appendix F  
Acceptable birth control methods 
Olaparib is regarded as a compound with medium/high foetal risk. 
Subjects must use a condom during treatment and for 3 months after the last dose of olaparib when 
having sexual intercourse with a pregnant woman or with a woman of childbearing potential.  Female 
partners of male subjects should also use a highly effective form of contraception if they are of 
childbearing potential (as listed below).  Male subjects should not donate sperm throughout the period 
of taking olaparib and for 3 months following the last dose of olaparib. 
 Acceptable Non-hormonal birth control methods include: 
• 
Total/True abstinence: When the subject refrains from any form of sexual intercourse and this is in 
line with their usual and/or preferred lifestyle; this must continue for the total duration of the trial 
and for at least 3 months after the last dose of study drug. [Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods, or declaration of abstinence solely for the 
duration of a trial) and withdrawal are not acceptable methods of contraception]  
• 
Vasectomized sexual partner PLUS male condom.  With participant assurance that partner 
received post-vasectomy confirmation of azoospermia. 
• 
Tubal occlusion PLUS male condom  
• 
IUD PLUS male condom.  Provided coils are copper-banded. 
Acceptable hormonal methods: 
• 
Normal and low dose combined oral pills PLUS male condom.  
• 
Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only highly efficacious 
progesterone based pill. 
• 
Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom. 
• 
Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom.  
• 
Norelgestromin / EE transdermal system PLUS male condom.  
• 
Intrauterine system [IUS] device (e.g., levonorgestrel releasing IUS -Mirena®) PLUS male 
condom.  
• 
Intravaginal device (e.g., EE and etonogestrel) PLUS male condom.  


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Appendix G 
Patient Reported Outcomes 


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Appendix H 
Performance Status (ECOG/KARNOFSKY SCALES) 
Example of performance status (ECOG/KARNOFSKY SCALE) 
 
 

SAP_015.pdf: 
Statistical Analysis Plan, ANGEL
Version number 4.0
Form Doc Number: LDMS_001_00026934
Parent Doc Number: 
Statistical Analysis Plan
Study Code
D081DC00007
Edition Number
4.0
Date
4 July 2019
A Phase III, Open Label, Randomized Study to Assess the Efficacy and
Safety of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone
Acetate in Men with Metastatic Castration-Resistant Prostate Cancer Who
Have Failed Prior Treatment with a New Hormonal Agent and Have
Homologous Recombination Repair Gene Mutations (PROfound)


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
2
A Phase III, Open Label, Randomized Study to Assess the Efficacy and
Safety of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone
Acetate in Men with Metastatic Castration-Resistant Prostate Cancer Who
Have Failed Prior Treatment with a New Hormonal Agent and Have
Homologous Recombination Repair Gene Mutations (PROfound)
Date


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
3
A Phase III, Open Label, Randomized Study to Assess the Efficacy and
Safety of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone
Acetate in Men with Metastatic Castration-Resistant Prostate Cancer Who
Have Failed Prior Treatment with a New Hormonal Agent and Have
Homologous Recombination Repair Gene Mutations (PROfound)
Date


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
4
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................3
TABLE OF CONTENTS.....................................................................................4
LIST OF ABBREVIATIONS ..............................................................................8
AMENDMENT HISTORY................................................................................ 11
1.
STUDY DETAILS............................................................................................. 21
1.1
Study objectives.................................................................................................21
1.1.1
Primary Objective .............................................................................................. 21
1.1.2
Secondary Objectives......................................................................................... 21
1.1.3
Safety Objectives ............................................................................................... 27
1.1.4
Exploratory Objectives....................................................................................... 27
1.2
Study design ......................................................................................................29
1.3
Number of patients............................................................................................. 30
2.
ANALYSIS SETS ............................................................................................. 31
2.1
Definition of analysis sets .................................................................................. 31
2.1.1
Full analysis set..................................................................................................31
2.1.2
Evaluable for response (EFR) analysis set.......................................................... 31
2.1.3
Safety analysis set.............................................................................................. 31
2.1.4
Safety switch analysis set................................................................................... 32
2.1.5
PK analysis set...................................................................................................32
2.2
Violations and deviations ................................................................................... 33
3.
PRIMARY AND SECONDARY VARIABLES................................................. 35
3.1
Derivation of RECIST visit responses – malignant soft tissue ............................ 35
3.1.1
Target lesions (TLs) – site investigator data ....................................................... 36
3.1.2
Non-target lesions (NTLs) and new lesions – site investigator data .................... 40
3.1.3
Overall visit response – site investigator data ..................................................... 42
3.1.4
Bone Lesion Progression using PCWG3 ............................................................ 42
3.1.5
Blinded Independent Central Review (BICR) with RECIST 1.1 and 
PCWG3 criteria..................................................................................................44
3.2
Primary endpoint- Radiological Progression Free Survival (rPFS)...................... 44


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
5
3.3
Secondary endpoints .......................................................................................... 46
3.3.1
Confirmed Overall Objective Response Rate (ORR) ..........................................46
3.3.2
Analgesic Use Scoring ....................................................................................... 47
3.3.3
Time to Pain Progression (TTPP).......................................................................48
3.3.4
Brief Pain Inventory – short form (BPI-SF)........................................................ 51
3.3.5
Pain Palliation....................................................................................................55
3.3.6
Overall Survival.................................................................................................57
3.3.7
Time to first Symptomatic Skeletal –Related Event (SSRE)............................... 57
3.3.8
Duration of Response (DoR).............................................................................. 57
3.3.9
Time to Opiate Use for Cancer Pain...................................................................58
3.3.10
Prostate Specific Antigen (PSA) Response......................................................... 58
3.3.11
PSA changes on continuous scale.......................................................................58
3.3.12
Circulating Tumor Cell (CTC) Conversion rate.................................................. 59
3.3.13
Time from randomization to second progression or death (PFS2)....................... 59
3.3.14
Functional Assessment of Cancer Therapy- Prostate Cancer (FACT-P).............. 60
3.3.15
Pharmacokinetic Endpoint ................................................................................. 65
3.4
Exploratory endpoints ........................................................................................ 65
3.4.1
PRO-CTCAE.....................................................................................................65
3.4.2
Patient Global Impression of Change (PGIC)..................................................... 65
3.4.3
Health Economics .............................................................................................. 65
3.4.3.1
Resource use......................................................................................................65
3.4.3.2
EQ-5D-5L..........................................................................................................66
3.5
Safety................................................................................................................. 67
3.5.1
General considerations for safety assessments.................................................... 67
3.5.2
Handling of partial dates .................................................................................... 68
3.5.3
Adverse Events ..................................................................................................69
3.5.4
Concomitant medications................................................................................... 69
3.5.5
Laboratory assessments...................................................................................... 70
3.5.6
Exposure............................................................................................................70
3.5.7
Dose intensity ....................................................................................................71
3.5.8
Vital signs..........................................................................................................71
3.5.9
Physical examination ......................................................................................... 71
3.5.10
ECG................................................................................................................... 71
4.
ANALYSIS METHODS.................................................................................... 72
4.1
General principles.............................................................................................. 72
4.2
Analysis methods............................................................................................... 73
4.2.1
Multiplicity........................................................................................................79
4.2.2
Analysis of the primary efficacy variable (rPFS)................................................ 80
4.2.2.1
Subgroup analysis.............................................................................................. 81
4.2.2.2
Sensitivity analysis............................................................................................. 85
4.2.3
Analysis of secondary variables .........................................................................86
4.2.3.1
Confirmed Objective response rate (ORR) ......................................................... 87
4.2.3.2
Time to pain progression (TTPP) .......................................................................88


Statistical Analysis Plan 
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Edition Number 4.0
Date 4 July 2019
6
4.2.3.3
Overall survival..................................................................................................89
4.2.3.4
Time to first Symptomatic Skeletal-Related Event (SSRE).................................90
4.2.3.5
Duration of Response......................................................................................... 90
4.2.3.6
Time to Opiate use for Cancer related Pain......................................................... 90
4.2.3.7
Prostate specific antigen (PSA) response............................................................ 90
4.2.3.8
Circulating Tumor Cell (CTC) conversion rate................................................... 91
4.2.3.9
Time from randomization to second progression or death (PFS2)....................... 91
4.2.3.10
FACT-P ............................................................................................................. 91
4.2.3.11
Pharmacokinetic analysis ................................................................................... 93
4.2.4
Concordance between BICR and investigator assessments .................................94
4.2.4.1
Concordance between BICR and investigator assessments for rPFS................... 94
4.2.4.2
Concordance between BICR and investigator assessments for Overall 
Radiological Objective Response .......................................................................94
4.2.5
Safety analysis ...................................................................................................94
4.2.5.1
Adverse events...................................................................................................95
4.2.5.2
Laboratory assessments...................................................................................... 99
4.2.5.3
Vital signs..........................................................................................................99
4.2.5.4
Exposure............................................................................................................99
4.2.6
Concomitant medications................................................................................. 100
4.2.7
Supportive analysis .......................................................................................... 100
4.2.7.1
Resource Use ................................................................................................... 100
4.2.7.2
Patient reported outcomes (PRO) ..................................................................... 100
4.2.7.3
EQ-5D-5L........................................................................................................ 101
4.2.8
Demographic and baseline data........................................................................ 101
5.
INTERIM ANALYSES ................................................................................... 102
6.
CHANGES OF ANALYSIS FROM PROTOCOL ........................................... 103
7.
REFERENCES ................................................................................................ 104
8.
APPENDIX (NOT APPLICABLE).................................................................. 105
LIST OF TABLES
Table 1
Primary objectives.................................................................................21
Table 2
Key secondary objectives......................................................................21
Table 3
Other secondary objectives....................................................................23
Table 4
Safety objectives ...................................................................................27
Table 5
Exploratory objectives...........................................................................27
Table 6
Summary of primary and secondary outcome variables and 
analysis populations ..............................................................................32
Table 7
TL Visit Responses (RECIST 1.1).........................................................36


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Edition Number 4.0
Date 4 July 2019
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Table 8
NTL Visit Responses ............................................................................40
Table 9
Overall visit soft tissue responses..........................................................42
Table 10
Bone progression status.........................................................................43
Table 11
Overall radiological visit response.........................................................46
Table 12
Definition of visit response for FACT-P, FAPSI-6, FACT-G, TOI, 
PCS, FWB and PWB.............................................................................61
Table 13
Overall score response criteria...............................................................63
LIST OF FIGURES
Figure 1
Overall study design..............................................................................30
Figure 2
Multiplicity strategy maintaining overall Type I error rate.....................80


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
8
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse event 
ALT
Alanine aminotransferase
AQA
Analgesic Quantification Algorithm
ATM
Ataxia telangiectasia mutated
AST
Aspartate aminotransferase
BICR
Blinded Independent Central Review
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
CR
Complete response
CRPC
Castration-resistant prostate cancer
CSP
Clinical study protocol
CSR
Clinical Study Report
CT
Computed tomography
CTC
Circulating tumor 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
DNA
Deoxyribonucleic acid
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EFR
Evaluable for response
EQ-5D-5L
EuroQuol-5 Dimensions, five level
EWB
Emotional well-being


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
9
Abbreviation or 
special term
Explanation
FACIT
Functional assessment of chronic illness
FACT-G
Functional Assessment of Cancer Therapy - General
FACT-P
Functional Assessment of Cancer Therapy - Prostate Cancer
FAPSI-6
FACT Advanced Prostate Symptom Index 6
FAS
Full analysis set
FMI
Foundation Medicine Inc.
FWB
Functional well-being
HRR
Homologous recombination repair
HR
Hazard ratio
HRQL
Health-Related Quality of Life
ICU
Intensive care unit
IDMC
Independent Data Monitoring Committee
IP
Investigational product
IPCW
Inverse Probability of Censoring Weighting
IPD
Important protocol deviation
KM
Kaplan-Meier
LD
Longest diameter
LLOQ
Lower 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
NE
Not-evaluable
NED
No evidence of disease
NHA
New hormonal agent  
NQ
Non-quantifiable
NR
Not Reportable
NS
No Sample
NTL
Non-target lesion
OAE
Other Significant Adverse Event


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
10
Abbreviation or 
special term
Explanation
OME
Oral morphine equivalence
ORR
Objective response rate
OS
Overall survival
PARP
Polyadenosine 5’-diphosphoribose polymerase
PCS
Prostate cancer subscale
PCWG-3
Prostate Cancer Working Group 3
PD
Progressive disease
PFS2
Second progression
PGIC
Patient Global Impression of Change
PID
Percentage intended dose
PK
Pharmacokinetics
PR
Partial response
PRO
Patient Reported Outcome
PSA
Prostate specific antigen
PWB
Physical well-being
RDI
Relative dose intensity
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
rPFS
Radiologic progression-free survival
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Stable disease
SOC
System organ class
SSRE
Symptomatic Skeletal –Related Event
SWB
Social well-being
TL
Target lesion
TOI
Trial outcome index
VAS
Visual analogue scale


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
11
AMENDMENT HISTORY
Date
Brief description of change
4 July 2019
SAP v4.0 vs SAP v3.0

Clarified concomitant medications will be summarized for Cohort A 
FAS and Cohort B FAS in addition to Cohort A+B FAS

Updated rPFS censoring to censor at the time of the earliest date of their 
last evaluable RECIST 1.1 assessment (taking the latest target lesion, 
non-target lesion or new lesion scan date) or bone scan assessment that 
showed Non-PD. The definition now uses the bone scan visit response 
description rather than the bone scan visit definition.

Section 3.2.2 Analgesic Use Scoring
-
Moved AQA missing data imputation rules from TTPP section to 
this section
-
Added additional information for the imputation rules for OME and 
AQA scores. If “other” medications are clearly identified as non-
opioid the OME score will be set to 0.
-
Added additional information for AQA score imputation. If 
additional pain medications taken alongside “Other” over the 7 
days of assessments, and they are all non-opioids, then AQA score 
of 1 will be assigned (i.e. non-opioid analgesics)

Moved Time to pain progression section to Section 3.3.3 (previously 
Section 3.3.4) 

Section 3.3.3 Time to pain progression (TTPP):
-
Removed the text which required the 2 consecutive subsequent 
assessments to be separated by 3-4 weeks. The requirement is 2 
consecutive follow-up assessments (with at least 2 weeks between 
the end of the initial visit and the start of the subsequent visit). 
-
Added additional information regarding how the average BPI-SF 
worst pain [Item 3] and the average AQA score are derived
-
Added additional information regarding baseline, assessments on or 
before the date of first treatment will be considered screening
-
Added definition of a missed visit for pain progression
-
Added additional clarity to show that olaparib is a considered a 
subsequent therapy for patients who switch from investigators 
choice of NHA to olaparib upon progression
-
Added additional information for the censoring rules for time to 
pain progression

Section 3.3.4 Brief Pain Inventory – short form (BPI-SF):
-
Updated pain severity subscale/domain to include average pain 
severity definition
-
Removed the text which required the 2 consecutive subsequent 
assessments to be separated by 3-4 weeks. The requirement is 2 


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
12
Date
Brief description of change
consecutive follow-up assessments (with at least 2 weeks between 
the end of the initial visit and the start of the subsequent visit). 
-
Clarified that the date of pain severity progression will be  the 
earliest of the assessments contributing to the average. 
-
Added additional information regarding how the average BPI-SF 
“pain severity” subscale score and the average AQA score are 
derived
-
Added additional information regarding baseline, assessments on or 
before the date of first treatment will be considered screening
-
Added definition of a missed visit for pain severity progression
-
Added additional clarity to show that olaparib is a considered a 
subsequent therapy for patients who switch from investigators 
choice of NHA to olaparib upon progression
-
Added additional information for the censoring rules for time to 
pain severity progression

Section 3.3.5 Pain Palliation:
-
Updated pain severity subscale/domain to include average pain 
severity definition
-
Clarified pain palliation uses the average BPI-SF worst pain [Item 
3]
-
Updated confirmation visit definition to clarify start date of 
subsequent visit – start date of initial visit must be >= 14 days
-
Added additional information regarding how the average BPI-SF 
worst pain [Item 3] and the average AQA score are derived
-
Added additional information regarding baseline, assessments on or 
before the date of first treatment will be considered screening
-
Added definition of a missed visit for pain palliation
-
Added additional clarity to show that olaparib is a considered a 
subsequent therapy for patients who switch from investigators 
choice of NHA to olaparib upon progression

Updated FACT-P TOI worsening examples to reflect the criteria in 
Table 12

Clarified the p-values reported for the interaction testing subgroups will 
represent those from the final model resulting from stepwise backwards 
selection; the 'selection model'

Removed the cumulative incidence function from the cumulative 
incidence plot for AESIs in Section 4.2.5.1 Adverse events

Updated Section 6 Changes of Analysis from Protocol
29 April 2019
SAP v3.0 vs SAP 2.0


Added clarification to the origin (eCRF or IVRS) of measurable disease 


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
13
Date
Brief description of change
and prior taxane use throughout

Changed ‘Investigator choice’ to ‘Investigator choice of NHA’ 
throughout

Added clarity throughout for rPFS, sensitivity analysis and all secondary 
endpoints to show they will all use the same strata as the primary rPFS 
analysis as determined by the pooling strategy 

Specified that there needs to be at least 5 responses to perform logistic 
regression analyses throughout, otherwise a fisher’s exact test will be 
used

Added text throughout for PRO endpoints to show analyses will include 
data until the start date of subsequent anti-cancer therapy for patients 
who receive a subsequent anti-cancer therapy (note that radiotherapy is 
not considered a subsequent anti-cancer therapy).

Section 2.1 (Definition of analysis sets)
-
Clarified ORR, DoR and BoR will use the EFR analysis set
-
Added EFR analysis set for Cohort A, B and A+B
-
Update to Table 6 to reflect the addition of EFR analysis set

Added IPD for patients who were randomized to investigators choice of 
NHA and started olaparib treatment before disease progression 
determined by BICR

Removed partial date imputation rule from Section 3 and added to 
Section 3.3.6 (Overall survival) only

Update to Table 9 – overall visit soft tissue responses

Removed BICR adjudication details from SAP, this can be found in 
imaging charter

Clarified BICR will be carried out on PCWG-3 assessments too

Section 3.2 (rPFS)
-
Update to rPFS censoring approach for censoring patients who have 
not progressed or died at the time of analysis and for censoring 
patients who progress or die immediately after 2 or more consecutive 
missed visits. The updated approach will take the earliest date of 
their last evaluable RECIST 1.1 assessment (taking the latest target 
lesion, non-target lesion or new lesion scan date) or bone scan 
assessment that showed fewer than 2 new lesions
-
Update to Table 11 – overall radiological visit response 
-
Text added describing how RECIST 1.1 and PCWG3 assessments 
will be merged for BICR and investigator assessments 

Updated ORR to use the EFR analysis set

Section 3.3.3 (BPI-SF)
-
Added clarification to regarding visits separated by 3-4 weeks
-
Added definition of completed questionnaire to PRO compliance 
-
Text added regarding completion rate definition and PRO patient 


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
14
Date
Brief description of change
disposition tables.

Section 3.3.4 (Time to pain progression)
-
Added clarification regarding visits separated by 3-4 weeks
-
Added text to show the date of pain progression is the earliest date 
when the average is taken (i.e. average of 7-day assessments) 
“worst pain in 24 hours” (BPI-SF item 3)
-
Added missing data imputation rule for AQA 

Added clarification regarding visits separated by 3-4 weeks to section 
3.3.5 (Pain palliation) 

Clarified survival calls will be made for the primary rPFS analysis, final 
OS analysis 

Section 3.3.8 (Duration of response)
-
Update to DoR to use the EFR analysis set
-
Update to censoring rule 
-
Added clarification to time to response definition
-
Unconfirmed response definition added in

Clarified which analysis set will be used for PSA response, PSA 
changes on a continuous scale, CTC conversion rate and CTC counts on 
a continuous scale

Added text to show patients data will only be included until the start 
date of the subsequent anti-cancer therapy for patients who receive a 
subsequent anti-cancer therapy for PSA response, PSA changes on a 
continuous scale, CTC conversion rate and CTC counts on a continuous 
scale

Section 3.3.14 (FACT-P)
-
Clarified that improvement rates and time to deterioration will be 
performed for FACT-G
-
Clarification to Table 13 to show consecutive visits need to be at 
least 3 weeks apart
-
Clarification to time to deterioration to show there must be no 
improvement between subsequent visits 
-
Removed reference to ‘patient is too affected by symptoms’

Text added to general considerations for safety regarding visit windows 
and methods for handing data in visit based summaries

Removed compliance definition and summary

Clarified exposure will not be calculated for prednisone/prednisolone 

Added percentage intended dose definition and summary 

Update to Table 14 to include all planned analyses and cohorts

Section 4.2.2
-
Clarified that the pooling strategy will be employed for Cohort A, 
Cohort B and Cohort A+B separately


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
15
Date
Brief description of change
-
Added text to show all sensitivity analyses and secondary 
endpoints (except for ORR which only includes prior taxane) will 
use the same strata as the primary model
-
Clarified that the rPFS analysis and KM plot will be produced for 
confirmed FMI F1CDx patients and confirmed myriad gBRCAm 
patients

Section 4.2.2.1 (Subgroup analysis)
-
Update to subgroup analysis to only provide descriptive statistics if 
there are less than 5 events across both treatment groups 
-
Clarification added to stratification factors
-
Clarification added to show which HRR gene mutation subgroups 
will be performed in the FAS, confirmed F1CDx patients and 
confirmed myriad gBRCAm patients 
-
Clarified that the results for HRR gene mutation subgroups will be 
displayed for one level only
-
Removed germline vs somatic subgroup
-
Added KM plots for selected subgroups
-
Added text to show that the consistency of treatment effect between 
subgroups will not use HRR gene mutation subgroups

Section 4.2.2.2 (Sensitivity analysis)
-
Added information for previous evaluable assessment to select 
sensitivity analyses
-
Added KM plot to censoring bias and ascertainment bias sensitivity 
analysis 
-
Clarified how unequivocal clinical progression is determined 

Removed text which stated that for the key secondary analyses, the 
subgroup analyses specified for the primary analysis and the sensitivity 
analyses for HRR mutation status will be repeated

Section 4.2.3.1 (Confirmed objective response rate)
-
Added BOR analysis on soft tissue using RECIST 1.1
-
Added all ORR analysis will be repeated for patients with an 
unconfirmed response
-
Added text to show that the confirmed ORR logistic regression will 
be produced for confirmed FMI F1CDx patients and confirmed 
myriad gBRCAm patients
-
Added subgroup analysis for confirmed ORR

Added logistic regression for pain progression, pain severity, pain 
palliation

Added text to show analysis of  pain progression, pain severity and pain 
palliation will be repeated for patients who are non-opiate users at 
baseline

Added text to show TTPP will be produced for confirmed FMI F1CDx 


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
16
Date
Brief description of change
patients and confirmed myriad gBRCAm patients

Added missing data summary and listing for time to pain progression

Clarified that the OS analysis, not including the KM plot, will be 
produced for confirmed FMI F1CDx patients and confirmed myriad 
gBRCAm patients

Added DoR analysis for patients with an unconfirmed response 

Clarified that PSA waterfall plots will be created for best percentage 
change and percentage change at Week 12

Added visit window around the Week 12 visit for PSA

Clarified CTC waterfall plots and summaries will be produced for best 
change from baseline and best percentage change from baseline

Updated text to show FACT-P scores will be presented by treatment 
group for all visits until there are less than the minimum of 20 or 1/3 of 
patients dosed

Update to FACT-P to use the logistic regression methods described for 
TTPP

Added prior taxane and measurable disease at baseline into the MMRM 
model for FACT-P

Removed text ‘The population PK/pharmacodynamic modelling will be 
reported separately from the CSR.’

Clarified that the overall summary AE table will be produced for 
confirmed FMI F1CDx patients and confirmed myriad gBRCAm 
patients

Updated concomitant and disallowed medications to be summarized 
using the FAS

Added summary for disallowed medications 

Removed concomitant medication summary for patients who switch 
from investigators choice of NHA to olaparib

Added text to show PRO-CTCAE will be summarized for only patients 
in countries (Argentina Australia, Austria, Canada [English-speaking 
sites], Germany, Japan, Spain, United Kingdom and United States) 
where the questionnaire was administered

Clarified which demographic and baseline data will be summarised for 
the FAS, confirmed FMI F1CDx patients, confirmed myriad gBRCAm 
and the patients who switch from investigators choice of NHA to 
olaparib
09 November 2018
SAP v2.0 vs SAP v1.0

Replaced the use of ‘subjects’ with ‘patients’ throughout

Added additional Exploratory objectives for ctDNA to reflect the 
clinical study protocol (CSP)

Updated Full Analysis Set definitions to explicitly describe by cohort


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
17
Date
Brief description of change

Added Safety switch analysis set

Updated Table 6 to contain all primary and secondary endpoints with 
analysis populations

Section 2.2 (Violations and deviations):
-
Removed repeated important protocol deviations 
-
Text relating to mis-randomizations in treatment dispensing 
removed since these are covered within retained list of important 
protocol deviations
-
Added text describing a deviation bias sensitivity analysis

Added partial date imputation rules to primary and secondary variables 
section

New sections added to section 3.1, including Target lesions, Non-target 
lesions, Overall visit response and Bone lesion progression using 
PCWG3

Section 3.2 (Primary endpoint- Radiological Progression Free Survival 
[rPFS]):
-
Updated definition of radiological progression-free survival to also 
refer to censoring 
-
Updated definition of censored patients to include patients who have 
not died at time of analysis
-
Added detail for allowable intervals for 8 weekly scheduled scans

Section 3.3.1 (Confirmed Overall Objective Response Rate [ORR])
-
Added definition of an unconfirmed response
-
Added rules for non-consecutive visits

Added section 3.2.2 for Analgesic Use Scoring

Section 3.3.3 (Brief Pain Inventory – short form [BPI-SF]):
-
Clarified all items must be non-missing for pain severity score
-
Time to pain progression and pain palliation moved to sections 3.3.4 
and 3.3.5 

Calculation for overall survival calculation added in for clarification 

Section 3.3.8 (Duration of Response [DOR]):
-
Added text to DOR definition clarifying patients must have 
measurable disease at baseline and have a confirmed response
-
Added DOR calculation
-
Added text to show response must be confirmed

Added section 3.3.10 (Time to Opiate Use for Cancer Pain)

Text added regarding missing PSA data

Added section 3.3.11 (PSA changes on continuous scale)

Text added to clarify CTC conversion rate can be at any visit post 
baseline


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
18
Date
Brief description of change

Text added regarding missing CTC values

Detail added concerning second progression

Section 3.3.14 (Functional Assessment of Cancer Therapy- Prostate 
Cancer [FACT-P]):
-
Added FACT-G score throughout
-
Added clarification for missing data in FACT-G and TOI subscales
-
Updated the definition of visit response in Table 12
-
Updated text for time to deterioration for FACT-P

Added text for length of hospital stay and length of ICU stay

Added Section 3.5.1 (General considerations for safety assessments) and 
Section 3.5.2 (Handling of partial dates)

Clarified definition of treatment emergent AEs

Updated concomitant medication coding dictionary to WHO drug 
dictionary 

Added exposure calculation for patients who switch 

Added detail to Compliance and Exposure regarding Missed or 
Forgotten doses and Safety Follow-up 

Updated baseline definition for PRO endpoints

Section 4.2.2 (Analysis of the primary efficacy variable [rPFS]):
-
Updated to show the hypothesis of superiority of olaparib compared 
to investigator choice will be tested using a log rank test, and 
removed reference to p-value from Cox Proportional Hazards 
Model
-
Updated pooling strategy 
-
Added detail to the assessment of proportionality

Section 4.2.2.1 (Subgroup analysis):
-
Added Cohort A+B 
-
Detailed the HRR gene mutation combinations 
-
Added additional subgroups

Removed sensitivity analysis for enrichment (h) since no enrichment 
was implemented

Added text to repeat HRR mutation subgroup analysis for key secondary 
endpoints

Added text for analysis of soft tissue ORR and text for all ORR analyses 
to be repeated using investigator assessed response

Clarified the subgroup analysis detailed for rPFS will be repeated for 
overall survival at the final analysis only

Added Section 4.2.3.5 (Duration of Response) and Section 4.2.3.6 
(Time to Opiate use for Cancer related Pain)

Added text for percentage change from baseline to be summarized for 


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
19
Date
Brief description of change
CTC counts

Added supportive analyses for FACT-P

Added detail to pharmacokinetic analysis section regarding the 
summary table and listing

Added Section 4.2.4 (Concordance between BICR and investigator 
assessments)

Corrected criteria for death summaries that display deaths > 30 days 
after last treatment dose

Removed Section 4.2.4.2 (Dose limiting toxicities)

Text added to Section 4.2.5.1 (Adverse events) regarding a new listing 
and separate summaries for patients who switch

Added shift table to Section 4.2.5.2 (Laboratory assessments) for 
patients who switch 

Section 4.2.5.3 (Concomitant medications):
-
Updated text to clarify summaries will be for Cohort A+B only
-
Added summary for patients who switch from investigators choice 
of treatment to olaparib

Added vital signs summary for patients who switch from investigators 
choice of treatment to olaparib

Section 4.2.5.5 (Compliance and exposure):
-
Updated text to clarify summaries will be for Cohort A+B only
-
Added text relating to summaries for subset of patients with any 
qualifying HRR mutation by the FMI central tumor test
-
Added text relating to summaries for patients who switch from 
investigators choice of treatment to olaparib

Section 4.2.6 (Supportive analysis):
-
Updated text to clarify that resource use and EQ 5D 5L may be 
reported outside of the CSR
-
Added AQA and FACT-G to PRO summaries
-
Added absolute and change from baseline mean (± standard 
deviation) plots for FACT-P total score, FACT-G total score, TOI, 
FAPSI-6, PCS, FWB, PWB, EWB, SWB, BPI-SF item #3 (worst 
pain in 24 hours), pain severity (BPI-SF pain severity domain), pain 
interference and AQA score
-
Added additional supportive analyses for BPI-SF (BPI-SF Item 3, 
pain severity score and pain interference score)
-
Added text detailing which cohorts will be presented for PRO 
endpoints and that the analysis will not be performed for patients 
who switch from investigators choice to olaparib

Updated list of demographic and baseline data that will be listed to meet 
ICH requirements

Added summaries to Section 4.2.7 (Demographic and baseline data) for 


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
20
Date
Brief description of change
patients who switch from investigator choice of treatment to olaparib

Added text to Section 6 (Changes of Analysis from Protocol) based on 
the above


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
21
1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary Objective
Table 1
Primary objectives
Primary objective
Primary outcome measures
To determine the efficacy (as assessed by 
radiographic Progression- Free Survival 
(rPFS)) of olaparib versus investigator choice 
of enzalutamide or abiraterone acetate in 
patients with metastatic Castration-Resistant 
Prostate Cancer (mCRPC) with BRCA1, 
BRCA2 or ATM qualifying mutations (Cohort 
A)

rPFS by blinded independent 
central review (BICR) using 
Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1, soft 
tissue) and Prostate Cancer 
Working Group 3 (PCWG3, bone) 
criteria
1.1.2
Secondary Objectives
Table 2
Key secondary objectives
Key Secondary Objectives
Key secondary outcome measures
To determine the efficacy (as assessed by 
Objective Response Rate [ORR]) of olaparib 
versus investigator choice of enzalutamide or 
abiraterone acetate in patients with BRCA1, 
BRCA2 or ATM qualifying gene mutations 
(Cohort A)
 

Confirmed ORR by BICR 
assessment in patients with 
measurable disease at baseline
using RECIST 1.1 (soft tissue) and 
PCWG3 (bone) criteria
To determine the efficacy (as assessed by 
rPFS) of olaparib versus investigator choice 
of enzalutamide or abiraterone acetate in 
patients with Homologous Recombination 
Repair (HRR) qualifying mutations (Cohort 
A+B)

rPFS by BICR using RECIST 1.1 
(soft tissue) and PCWG3 (bone) 
criteria
To determine the efficacy (as assessed by 
time to pain progression) of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in patients with BRCA1, 
BRCA2 or ATM qualifying gene mutations 
(Cohort A)

Pain progression based on Brief 
Pain Inventory- Short Form 
(BPI-SF) item 3 “worst pain in 24 
hours” and opiate analgesic use 
(AQA score)


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
22
Table 2
Key secondary objectives
Key Secondary Objectives
Key secondary outcome measures
To determine the efficacy (as assessed by
overall survival) of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in patients with BRCA1, 
BRCA2 or ATM qualifying gene mutations 
(Cohort A)

verall survival OS)


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
23
Table 3
Other secondary objectives
Other Secondary Objectives
Other secondary outcome measures
To further assess the efficacy of olaparib 
versus investigator choice of enzalutamide or 
abiraterone acetate in patients with BRCA1, 
BRCA2 or ATM qualifying gene mutations 
(Cohort A)

Time from randomization to the 
first Symptomatic Skeletal –
Related Event (SSRE)

Time from partial or complete 
response in patients with 
measurable disease at baseline 
(RECIST 1.1) to progression by 
BICR (Duration of Response 
[DoR])

Time from randomization to opiate 
use for cancer-related pain

Confirmed ORR (RECIST 1.1) in 
soft tissue by BICR in patients with 
measurable disease at baseline 
(Soft tissue response)

Proportion of Patients achieving a 
≥50% decrease in Prostate Specific 
Antigen (PSA) from baseline to the 
lowest post-baseline PSA result, 
confirmed by a second consecutive 
PSA assessment at least 3 weeks 
later (PSA50 response)

Proportion of Patients achieving a 
decline in the number of 
Circulating Tumor Cells (CTCs) 
from ≥ 5 cells/7.5mL to < 5 
cells/7.5mL whole blood (CTC 
conversion rate)

Time from randomization to 
second progression by investigator 
assessment of radiological or 
clinical progression or death 
(PFS2)


Statistical Analysis Plan 
Study Code D081DC00007
Edition Number 4.0
Date 4 July 2019
24
Table 3
Other secondary objectives
Other Secondary Objectives
Other secondary outcome measures
To further assess the effect of olaparib versus
investigator choice of enzalutamide or 
abiraterone acetate in patients with BRCA1, 
BRCA2 or ATM qualifying gene mutations 
(Cohort A) on disease-related symptoms and 
Health-Related Quality of Life (HRQoL)

Pain severity progression based on 
BPI-SF Pain Severity 
domain/subscale and opiate 
analgesic use (AQA score)

Pain interference based on BPI-SF 
Pain Interference domain/subscale

Functional Assessment of Cancer 
Therapy- Prostate cancer [FACT-P] 
(FACT-P total score, Trial 
Outcome Index [TOI], Functional 
Well-Being [FWB], Physical Well-
Being [PWB], Prostate Cancer 
Subscale [PCS], and FACT 
Advanced Prostate Symptom Index 
6 [FAPSI 6])

Proportion of Patients with pain 
(BPI-SF item 3) score ≥ 4 points at 
baseline who have a decrease of ≥ 
2 points in pain (BPI-SF item 3) 
and without ≥ 1 point increase in 
analgesic score (AQA score) at 12 
weeks, confirmed at least 3 weeks 
later (Pain palliation)
To assess the efficacy of olaparib versus
investigator choice of enzalutamide or
abiraterone acetate in patients with HRR
qualifying gene mutations other than BRCA1,
BRCA2 or ATM (Cohort B)
 

rPFS by BICR using RECIST 1.1 
(soft tissue) and PCWG3 (bone) 
criteria

Confirmed ORR by BICR 
assessment in patients with 
measurable disease at baseline
using RECIST 1.1 (soft tissue) and 
PCWG3 (bone) criteria

Pain progression based on BPI-SF 
item 3 "worst pain in 24 hours" and 
opiate analgesic use (AQA score)

OS


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Table 3
Other secondary objectives
Other Secondary Objectives
Other secondary outcome measures
To further assess the efficacy of olaparib
versus investigator choice of enzalutamide or
abiraterone acetate in patients with HRR 
qualifying gene mutations (Cohort A+B)
 

Confirmed ORR by BICR 
assessment in patients with 
measurable disease at baseline
using RECIST 1.1 (soft tissue) and 
PCWG3 (bone) criteria

Time from randomization to the 
first SSRE

Time from partial or complete 
response in patients with 
measurable disease at baseline 
(RECIST 1.1) to progression by 
BICR (DoR)

Time from randomization to opiate 
use for cancer-related pain

Confirmed ORR (RECIST 1.1) in 
soft tissue by BICR in patients with 
measurable disease at baseline
(Soft tissue response)

Proportion of Patients achieving a 
≥50% decrease in PSA from 
baseline to the lowest post-baseline 
PSA result, confirmed by a second 
consecutive PSA assessment at 
least 3 weeks later (PSA50
response)

Proportion of Patients achieving a 
decline in the number of CTCs 
from ≥ 5 cells/7.5mL to < 5 
cells/7.5mL whole blood (CTC 
conversion rate)

Time from randomization to 
second progression by investigator 
assessment of radiological or 
clinical progression or death 
(PFS2)

OS


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Table 3
Other secondary objectives
Other Secondary Objectives
Other secondary outcome measures
To further assess the effect of olaparib versus
investigator choice of enzalutamide or
abiraterone acetate in patients with HRR 
qualifying gene mutations (Cohort A+B) on
disease-related symptoms and Health-Related
Quality of Life (HRQoL)
 

Pain progression based on BPI-SF 
item 3 “worst pain in 24 hours” and 
opiate analgesic use (AQA score)

Pain severity progression based on 
BPI-SF Pain Severity 
domain/subscale and opiate 
analgesic use (AQA score)

Pain interference based on BPI-SF 
Pain Interference domain/subscale

FACT-P (FACT-P total score, Trial 
Outcome Index [TOI], Functional 
Well-Being [FWB], Physical Well-
Being [PWB], Prostate Cancer 
Subscale [PCS] and FACT 
Advanced Prostate Symptom Index 
6 [FAPSI 6])

Proportion of Patients with pain 
(BPI-SF item 3) score ≥ 4 points at 
baseline who have a decrease of ≥ 
2 points in pain (BPI-SF item 3) 
and without ≥ 1 point increase in 
analgesic score (AQA score) at 12 
weeks, confirmed at least 3 weeks 
later (Pain palliation)
To determine the exposure to olaparib in a 
subset of patients receiving olaparib
 

Olaparib plasma concentration data


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1.1.3
Safety Objectives
Table 4
Safety objectives
Safety objective
Safety outcome measures
To evaluate the safety and tolerability of 
olaparib versus investigator choice of 
enzalutamide or abiraterone acetate (Cohort 
A+B)

Adverse events (AEs)/ serious 
adverse eventsSAEs)

Collection of clinical 
chemistry/haematology parameters
1.1.4
Exploratory Objectives
These exploratory objective analyses may be reported separately from the clinical study 
report.
Table 5
Exploratory objectives
Exploratory objective
Exploratory outcome measures
To compare the effect of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate on patient-reported 
treatment tolerability and overall health status 
(Cohort A)

Patient Reported Outcomes-
Common Terminology Criteria for 
Adverse Events PRO-CTCAE)

Patient Global Impression of 
Change (PGIC)
To compare the effect of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in patients with BRCA1, 
BRCA2 or ATM qualifying mutations (Cohort 
A) based on prior receipt of taxane

Subgroup analysis of rPFS in 
patients with or without prior 
taxanes
To compare the effect of olaparib versus 
investigator choice of enzalutamide or 
abiraterone acetate in patients with either 
germline or somatic BRCA1, BRCA2 or ATM 
qualifying mutations (Cohort A)

Subgroup analysis of rPFS by 
BICR based on whether the 
qualifying mutation is a germline 
mutation or only in the tumor 
(somatic)
To compare the effect of olaparib versus
investigator choice of enzalutamide or
abiraterone acetate in patients with BRCA1, 
BRCA2, or ATM qualifying mutations as
detected by ctDNA analysis
 

rPFS analysis in patients with 
qualifying mutation identified by 
ctDNA test


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Table 5
Exploratory objectives
Exploratory objective
Exploratory outcome measures
To compare the effect of olaparib versus
investigator choice of enzalutamide or
abiraterone acetate in patients with HRR
qualifying mutations as detected by ctDNA
analysis
 

rPFS analysis in patients with 
qualifying mutation identified by 
ctDNA test
To explore methods of estimating OS 
adjusting for the impact of the control arm 
receiving subsequent PARP inhibitors 
(including olaparib), platinum compounds or 
imbalances between the treatment arms for 
other potentially active agents (Cohort A)

OS adjusted for impact of 
subsequent PARP inhibitors (or 
other potentially active 
investigational agents)
To compare the tumor HRR gene mutation 
status in all screened patients with evaluable 
results from plasma (Cohort A+B)
 

Comparison of HRR gene mutation 
status between tumor DNA and 
plasma derived ctDNA
Future exploratory research into factors that 
may influence development of cancer and/or 
response to study treatment (where response 
is defined broadly to include efficacy, 
tolerability or safety) may be performed on 
the collected and stored archival tumor 
samples that were mandatory for entry onto 
the study or on blood samples (Cohort A+B)
 

Evaluate loss of heterozygosity of 
HRR genes in tumors

Evaluation of ctDNA collected 
from plasma at baseline and at 
progression

CTCs (EPIC assay)
To collect and store DNA (according to each 
country’s local and ethical procedures) for 
future exploratory research into genes/genetic 
variation that may influence response (i.e., 
distribution, safety, tolerability and efficacy) 
to study treatments and or susceptibility to 
disease (optional) (Cohort A+B)

Blood sample pharmacogenetics 
analysis


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Table 5
Exploratory objectives
Exploratory objective
Exploratory outcome measures
To investigate the health economic impact of 
treatment and the disease on hospital related 
resource use and health state utility 
(Cohort A)

Number, type and reason of 
hospitalizations and hospital 
attendances, procedures conducted 
and hospital length of stay 
(HOSPAD)

EuroQol 5-dimension, 5-level 
health state utility index EQ-5D-
5L)
Some of these exploratory analyses may be reported separately from the CSR.
1.2
Study design
This is a prospective, multi-centre, open-label, randomized phase 3 trial evaluating the 
efficacy and safety of olaparib (300 mg orally bid) versus investigator choice of either 
enzalutamide (160 mg orally od) or abiraterone acetate (1,000 mg orally od with 5 mg bid 
prednisone) in approximately 340 patients with metastatic castration-resistant prostate cancer 
(mCRPC) with qualifying homologous recombination repair (HRR) gene mutations who have 
failed prior treatment with a new hormonal agent (NHA).
 
 Prior to 
randomization, it was anticipated that approximately 5500 patients will be centrally screened 
for eligibility based on tumor tissue testing using the Lynparza HRR assay (Foundation 
Medicine Inc. (FMI), Cambridge MA). Patients with BRCA1, BRCA2 or ATM qualifying gene 
mutations will be included in Cohort A whereas patients with mutations among 12 other genes 
involved in HRR (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, 
RAD51B, RAD51C, RAD51D, and RAD54L) will be included in Cohort B. Patients will be 
randomized 2:1 to either olaparib or pre-declared investigator choice of either enzalutamide or 
abiraterone acetate in each of the Cohorts A and B. Randomization will be stratified based on 
prior receipt of taxane chemotherapy (yes vs no) and presence of measurable disease at 
baseline (yes vs no). Figure 1 illustrates the overall study design. The global recruitment to the 
study closed when approximately 340 patients were randomized in Cohorts A and B.


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Figure 1
Overall study design
1.3
Number of patients
The sample size for Cohort A was based on the research hypothesis that single agent olaparib 
at 300 mg bid has superior efficacy and an acceptable tolerability profile as compared with 
enzalutamide or abiraterone acetate in mCRPC patients with deleterious or suspected 
deleterious HRR gene mutations and who have previously failed treatment with an NHA such 
as enzalutamide or abiraterone acetate. 
Approximately 240 patients will be randomized in Cohort A in a 2:1 ratio to olaparib tablets 
(300 mg orally bid) versus pre-declared investigator choice of either enzalutamide (160 mg 
orally od) or abiraterone acetate (1,000 mg orally od with 5 mg bid prednisone). The primary 
endpoint of the study is rPFS as assessed by BICR.
It is expected that the targeted sample size of 240 patients in Cohort A with approximately 
143 rPFS events (60% maturity) will provide 95% power to demonstrate a statistically 
significant difference in rPFS at a 2-sided alpha level of 5% assuming the true treatment effect 
was a hazard ratio (HR)=0.53. This translates to an approximately 4.5 month improvement in 
median rPFS over an assumed 5 month median rPFS on enzalutamide or abiraterone acetate 
assuming rPFS is exponentially distributed. The smallest treatment difference that would be 
statistically significant at the final analysis is a HR of 0.71. It is anticipated that the study 
accrual period will be approximately 28 months and that 143 progression and death events 
will occur approximately 35 months after the first patient is randomized in the study. 
To predict the data cut-off date (DCO) when 143 rPFS events will be first observed in Cohort 
A, the blinded grouped time to event data will be modelled on an ongoing basis through the 
trial. Once the DCO is set, data will be collected and cleaned while recognised that there may 
ultimately be fewer or more events than specified.


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Cohort B of the study will consist of approximately 100 patients with qualifying HRR 
mutations other than BRCA1, BRCA2 and ATM as assessed by the FMI central tumor test.
These patients will be randomized in a 2:1 ratio to olaparib tablets versus predeclared 
investigator choice of either enzalutamide or abiraterone acetate.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
Full analysis set
Cohort A Full Analysis Set (Cohort A FAS):
The primary statistical analysis of the efficacy of olaparib in comparison to investigator choice 
of either enzalutamide or abiraterone acetate in Cohort A, will include all patients who were 
randomized in Cohort A as part of the global enrollment regardless of the treatment actually 
received. Patients who were randomized in Cohort A as part of the global enrollment but did 
not subsequently go on to receive study treatment are included in the full analysis set (FAS) 
on Cohort A. Efficacy and health- related quality of life (HRQoL) data (except for ORR, DoR 
and BoR) will be analyzed using the full analysis set.  See Table 6 for details.
Cohort B Full Analysis Set (Cohort B FAS):
The analysis of the efficacy of olaparib in Cohort B will include all patients randomized to 
olaparib or investigator choice of either enzalutamide or abiraterone acetate in Cohort B as 
part of the global enrolment regardless of the treatment actually received. Patients who were 
randomized in Cohort B but did not subsequently go on to receive study treatment are 
included in the FAS on Cohort B. Efficacy and HRQoL data (except for ORR, DoR and BoR)
will be analyzed using the full analysis set.
Cohort A+B Full Analysis Set (Cohort A+B FAS):
The analysis based on Cohort A+B will include patients from both Cohort A full analysis set 
and Cohort B full analysis set.
2.1.2
Evaluable for response (EFR) analysis set
This is a subset of the FAS, who have measurable disease at baseline as per the RECIST 1.1 
criteria. Measurable disease will be defined using the BICR assessment for analyses of BICR 
data, as well as using the investigator assessment data for analyses of investigator assessment
The EFR set will be defined for Cohort A, Cohort B and Cohort A+B separately. ORR, DoR 
and BoR will be analyzed using the EFR set. 
2.1.3
Safety analysis set
All patients who were randomized as part of the global enrollment and received at least one 
dose of randomized study treatment in Cohort A or in Cohort B, will be included in the safety 


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analysis set. If a patient receives at least one dose of olaparib study treatment they will be 
summarized in the olaparib arm for safety summaries (e.g. olaparib arm will include patients 
randomized to olaparib who receive at least one dose of olaparib or those patients randomized 
to investigator choice arm who receive at least one dose of olaparib study treatment in error at 
any time). If a patient randomized to olaparib receives only investigator choice of either 
enzalutamide or abiraterone acetate then they will be summarized as part of the investigator 
choice arm. Safety data captured on patients receiving investigator choice who have 
subsequently switched to olaparib upon progression will be summarized per the treatment at 
the time of the onset of safety condition or lab result and reported in a separate section.
2.1.4
Safety switch analysis set
All patients randomised to investigator choice, who received at least one dose of study 
treatment in Cohort A or in Cohort B, who have subsequently switched to olaparib upon 
progression and received at least one dose of olaparib will be included in the safety switch 
analysis set. 
2.1.5
PK analysis set
All patients who have received at least one dose of study medication and provided at least one 
post-dose analyzable plasma sample for PK analysis will be included in the PK analysis set. 
Patients with major protocol deviations including changes to the procedures that may impact 
the quality of the data, or any circumstances that can alter the evaluation of the PK may be 
excluded from the PK analysis set. These deviations and changes will be specified in a 
separate protocol deviation specification document. 
Table 6
Summary of primary and secondary outcome variables and analysis populations
Outcome Variables
Analysis Populations
Efficacy Data
-
rPFS (Cohort A, Cohorts A+B, Cohort B)
-
Time to pain progression (Cohort A, 
Cohorts A+B, Cohort B)
-
Overall survival (Cohort A, Cohorts A+B, 
Cohort B)
-
Time from randomization to first 
symptomatic skeletal–related event 
(Cohort A, Cohort A+B)
-
Time from randomization to the date of 
opiate use for cancer-related pain. (Cohort 
A, Cohorts A+B)
-
PSA Response (Cohort A, Cohorts A+B)
-
CTC conversion rate (Cohort A, 
Cohorts A+B)
-
PFS2 (Cohort A, Cohorts A+B)
Cohort A FAS, Cohort B FAS, Cohort A+B FAS


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Table 6
Summary of primary and secondary outcome variables and analysis populations
Outcome Variables
Analysis Populations
-
ORR (Cohort A, Cohorts A+B, Cohort B)
Cohort A EFR, Cohort B EFR, Cohort A+B EFR 
(Subjects with measurable disease at baseline)
-
Duration of Response (Cohort A, 
Cohorts A+B, Cohort B)
Cohort A EFR, Cohort B EFR, Cohort A+B EFR 
(Subjects with measurable disease at baseline)
Demography (Cohort A, Cohort A+B, Cohort B)
Cohort A FAS, Cohort B FAS, Cohort A+B FAS
Disposition (Cohort A, Cohorts A+B, Cohort B)
Cohort A FAS, Cohort B FAS, Cohort A+B FAS, 
Safety switch analysis set  
Plasma concentration
PK
HRQoL (Cohort A, Cohorts A+B)
Cohort A FAS, Cohort A+B FAS
Safety data (Cohorts A+B)
-
Compliance and exposure
-
Adverse events
-
Lab measurements
-
Vital signs
Safety analysis set, Safety switch analysis set
-
Concomitant medications
Cohort A FAS, Cohort B FAS, Cohort A+B FAS
2.2
Violations and deviations
The important protocol deviations (IPD) will be listed and summarised by randomized 
treatment group. None of the deviations will lead to any patients being excluded from the 
efficacy or safety analysis sets. 
The following general categories will be considered IPDs:

Patients randomized but who did not receive olaparib/investigators choice of NHA. 

Patients who deviate from key entry criteria per the Clinical Study Protocol:
1) Histologically confirmed diagnosis of prostate cancer.
2) Candidate for treatment with enzalutamide or abiraterone acetate with 
documented current evidence of metastatic castration-resistant prostate cancer, 
where metastatic status is defined as at least one (1) documented metastatic lesion 
on either bone scan or CT/MRI scan. Subjects whose disease spread is limited to 
regional pelvic lymph nodes or local recurrence (e.g. bladder, rectum) are not 
eligible.


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3) Subjects must have progressed on prior NHA (e.g. abiraterone acetate and/or 
enzalutamide) for the treatment of metastatic prostate cancer and/or CRPC. 
Determination of progression is done per local investigator.
4) Qualifying HRR mutation in tumor tissue by the Lynparza HRR Assay.

Baseline RECIST or Bone scan > 42 days before start date of randomized treatment, 
or no baseline RECIST 1.1 or no bone scan assessment on or before date of 
randomization.

Persistently missing important protocol required safety assessments (hematology, 
liver function test, chemistry panel) and potentially having major impact to patient 
safety (clinical review on a case by case base).

Received prohibited other anti-cancer agents during study treatment period.

Met study treatment discontinuation criteria but continued study treatment and 
potentially had major impact to patients’ safety according to clinical judgement.

Patients randomized who received their randomized study treatment at an incorrect 
dose or received an alternative study treatment to that which they were randomized.

Patients assigned to the incorrect cohort. 

Patients who were randomized to investigators choice of NHA and started olaparib 
treatment before disease progression determined by BICR.
The categorisation of these as IPDs 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 important.
A ‘deviation bias’ sensitivity analysis will be performed on the rPFS endpoint excluding 
patients with deviations that may affect the efficacy of the trial therapy if > 10% of patients in 
either treatment group have IPDs.
The need for such a sensitivity analysis will be determined following review of the protocol 
deviations ahead of database lock, and will be documented prior to the primary analysis being 
conducted.


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3.
PRIMARY AND SECONDARY VARIABLES
The primary assessment of efficacy is rPFS, defined as disease progression according to 
RECIST 1.1 (for soft tissue disease) and/or PCWG-3 criteria (for bone disease), or death by 
any cause, whichever comes first. 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 and PCWG3 progression are 
detailed below and also in Appendix E of the clinical study protocol. The primary analysis 
will be based on BICR of the radiological scans.
For efficacy analyses, when an event has occurred, every attempt will be made to establish the 
exact date of the event and enter this into the database. If this is not possible, partial dates will 
be accepted. If the date of event is not known, then the patient will have an imputed event date 
as the day of their last known alive event free date prior to DCO.
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.
3.1
Derivation of RECIST visit responses – malignant soft tissue
For all patients, the RECIST tumor response data will be used to determine each patient’s visit 
response according to RECIST version 1.1. It will also be used to determine if and when a 
patient has progressed in accordance with RECIST and their best objective response to study 
treatment.
The baseline assessments of all imaging modalities should be performed as close as possible 
to the start of study treatment and no more than 4 weeks (-28 days) before randomization.
Following the baseline assessment, subsequent assessments should be performed every 8 
weeks (± 7 days), relative to the date of randomization, until objective radiological disease 
progression by BICR, even after the investigator has deemed objective disease progression, 
irrespective of treatment decisions or dose interruptions. 
If a patient has been deemed to have objective disease progression according to investigator 
assessment, but not by BICR, he is not eligible to switch to olaparib at that time. Patients 
should continue to receive randomized study treatment until progression determined by BICR.
If an unscheduled assessment was performed and the subject has not progressed, every 
attempt should be made to perform the subsequent assessments at their originally scheduled 
visits. This schedule is to be followed in order to minimize any unintentional bias caused by 
some subjects being assessed at a different frequency than other subjects.


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3.1.1
Target lesions (TLs) – site investigator data
Measurable disease is defined as having at least one measurable lesion, not previously 
irradiated, which is ≥ 10 mm in the longest diameter (LD), (except lymph nodes which must 
have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging 
(MRI) and which is suitable for accurate repeated measurements. A patient can have a 
maximum of five measurable lesions recorded at baseline with a maximum of two lesions per 
organ (representative of all lesions involved and suitable for accurate repeated measurement) 
and these are referred to as target lesions (TLs). If more than one baseline scan is recorded 
then measurements from the one that is closest and prior to randomisation will be used to 
define the baseline sum of TLs. 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.
All other lesions (or sites of disease) not recorded as TL should be identified as non-target 
lesions (NTLs) at baseline.  Measurements are not required for these lesions, but their status 
should be followed at subsequent visits.
Note: For patients who do not have measurable disease at entry (i.e. no TLs) but have non-
measurable disease, evaluation of overall visit responses will be based on the overall NTL 
assessment and the absence/presence of new lesions (see section 3.1.3 for further details). If a 
patient does not have measurable disease at baseline then the TL visit response will be not 
applicable (NA).
Table 7
TL Visit Responses (RECIST 1.1)
Visit Responses
Description
Complete response (CR)
Disappearance of all TLs.  Any pathological lymph nodes 
selected as TLs must have a reduction in short axis to 
<10mm.
Partial response (PR)
At least a 30% decrease in the sum of diameters of TLs, 
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 TLs 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.


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Visit Responses
Description
Not evaluable (NE)
Only relevant in certain situations (i.e. if any of the TLs 
were not assessed or not evaluable or had a lesion 
intervention at this visit; and scaling up could not be 
performed for lesions with interventions).  Note: If the 
sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a TL 
response.
Not applicable (NA)
No TLs are recorded at baseline.
Rounding of TL data
For calculation of PD and PR for TLs percentage changes from baseline and previous 
minimum should be rounded to one 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

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
Note: the nadir can only be taken from assessments where all the TLs had a LD recorded. 
If there is at least one TL measurement missing and a visit response of PD cannot be assigned, 
the visit response is NE.
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. 


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TL visit responses subsequent to CR
CR, PD or NE. can only follow a CR.  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. 0mm or < 10mm 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 LD increases by 20% but remains < 10mm. 

Step 2:  If some lesion measurements are missing but all other lesions meet the CR 
criteria (i.e. 0mm or < 10mm for lymph nodes) then response will be set to NE 
irrespective of whether, when referencing the sum of TL diameters, the criteria for 
PD are also met. 

Step 3:   If not all lesions meet the CR criteria (i.e. a pathological lymph node 
selected as TL has short axis >10mm or the reappearance of previously disappeared 
lesion) or a new lesion appears 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
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.  
TL too small to measure
If a TL becomes too small to measure then this will be indicated as such on the case report 
form and a value of 5mm will be entered into the database and used in TL calculations. 
However a smaller value may be used if the radiologist has not indicated ‘too small to 
measure’ on the case report form and has 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 / embolization), should be handled in the following way and 


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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 if 1/3 of the TLs have missing 
measurements then scale up as described in the ‘Scaling’ section below.  If the 
scaling results in a visit response of PD then the patient would be assigned a TL 
response of PD.  

Step 3: If, after both steps, PD has not been assigned, then, if appropriate (i.e. if 
1/3 of the TLs have missing measurements), the scaled sum of diameters 
calculated in step 2 should be used, and PR or 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 
subject to intervention have a value of 0 (or <10mm for lymph nodes) recorded.  If 
scaling up is not appropriate due to too few non-missing measurements then the 
visit response will be set as NE.
At subsequent visits, the above steps will be repeated to determine the TL and overall visit 
response.  When calculating the previous minimum, lesions with intervention should be 
treated as missing and scaled up (as per step 2 above).
Scaling (applicable only for irradiated lesions/lesion intervention)
If > 1/3 of TL measurements are missing (because of intervention) then the TL response will 
be NE, unless the sum of diameters of non-missing TL would result in PD (i.e. if using a value 
of 0 for missing lesions, the sum of diameters has still increased by 20% or more compared to 
nadir and the sum of TLs has increased by ≥5mm from nadir).  
If ≤ 1/3 of the TL measurements are missing (because of intervention) then the results will be 
scaled up (based on the sizes at the nadir visit 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 nadir sum of diameters excluding the lesions with missing 
measurements.
Example of scaling
Lesion 5 is missing at the follow-up visit; it had a nadir measure of 29.3cm. 
The sum of lesions 1-4 at the follow-up is 26 cm.  The sum of the corresponding lesions at the 
nadir visit is 26.8 cm.


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Scale up as follows to give an estimated TL sum of 28.4cm:
cm
4.
28
3.
29
8.
26
26


CR will not be allowed as a TL response for visits where there is missing data.  Only PR, SD 
or PD (or NE) could be assigned as the TL visit response in these cases.  However, for visits 
with 1/3 lesion assessments not recorded, the scaled up sum of TLs diameters will be 
included when defining the nadir value for the assessment of progression.
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 TLs
CT, MRI and clinical examination are the only methods of assessment that can be used within 
a trial, with CT and MRI being the preferred methods and clinical examination only used in 
special cases. 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.  
If a change in method involves clinical examination (e.g. CT changes to clinical examination 
or vice versa), any affected lesions should be treated as missing.  
3.1.2
Non-target lesions (NTLs) and new lesions – site investigator data
At each visit, the investigator should record an overall assessment of the NTL response. This 
section provides the definitions of the criteria used to determine and record overall response 
for NTL at the investigational site at each visit.
NTL response will be derived based on the overall assessment of NTLs as follows:  
Table 8
NTL Visit Responses
Visit Responses
Description
Complete response (CR)
Disappearance of all NTLs present at baseline with all 
lymph nodes non-pathological in size (<10 mm short 
axis).


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Visit Responses
Description
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.
Non-CR/Non-PD
Persistence of one or more NTLs with no evidence of 
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.
Not applicable (NA)
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 the presence of SD or PR in 
TLs, the overall tumour burden has increased sufficiently to merit a determination of disease 
progression.  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 
one or more new lesions is assessed as progression.
A 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.
New lesions will be identified via a Yes/No tick box (excluding bone lesions). The absence 
and presence of new lesions at each visit should be listed alongside the TL and NTL visit 
responses.
A new lesion indicates progression so the overall visit response will be PD irrespective of the 
TL and NTL response.
If the question ‘Any new lesions since baseline (excluding bone lesions)’ has not been 
answered with Yes or No and the new lesion details are blank this is not evidence that no new 
lesions are present, but should not overtly affect the derivation.   


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Symptomatic progression is not a descriptor for progression of NTLs: it is a reason for 
stopping study therapy and will not be included in any assessment of NTLs.
Patients with ‘symptomatic progression’ requiring discontinuation of 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
Overall visit response – site investigator data
Table 9 defines how the previously defined TL and NTL visit responses will be combined 
with new lesion information to give an overall visit response.
Table 9
Overall visit soft tissue responses
Target lesions
Non-Target lesions
New Lesions
Overall soft tissue 
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 PDa or NE
No
PR
SD 
Non PDa or NE
No
SD
NA
Non CR/Non PD
No
SD
NA
NA
No
NED
NE
Non PDa or NE
No
NE
NA
NE
No 
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
a Non PD = CR or Non CR/Non PD or NA.
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable, NA = not applicable (only relevant if there were no TL and/or NTLs at baseline), NED = No Evidence 
of Disease (only relevant when there is no TL and NTL from baseline).
3.1.4
Bone Lesion Progression using PCWG3
Bone lesions will be assessed by bone scan and will not be part of the RECIST v1.1 malignant 
soft tissue assessment. If more than one baseline scan is recorded then measurements from the 
one that is closest and prior to randomization will be used. 


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All bone lesions (or sites of disease) should be identified at baseline. Their status should be 
followed at subsequent visits. At each visit an overall assessment of the bone lesion 
progression should be recorded by the Investigator.
Progression on a bone scan is identified using PCWG3 as follows: 

At the Week 8 scan: 
Two or more new metastatic bone lesions are observed on the first 8-week scan 
compared to the baseline assessment. The confirmatory scan, performed at least 6 
weeks later and preferably no later than the next scheduled visit for a bone scan (ie, 
Week 16), must show two or more additional new metastatic bone lesions (for a total 
of four or more new metastatic bone lesions since the baseline assessment) for 
progression to be documented.
Note - The first bone scan completed after baseline will be considered the ‘8-week 
scan’ regardless if taken at week 8 or at an unscheduled assessment.

After the Week 8 scan: 
Two or more new metastatic bone lesions are observed compared to the 8-week 
assessment. The confirmatory scan, performed at least 6 weeks later and preferably at 
the next scheduled visit for a bone scan, must show the persistence of or an increase 
in the number of metastatic bone lesions compared to the prior scan for progression to 
be documented. 
The date of progression is the date of the scan that first documents the second lesion.
Table 10 provides the definitions for the visit bone progression status for bone lesions.
Table 10
Bone progression status 
Non Progressive Disease (Non-PD)
No evidence of progression, or appearance of 
one new bone lesion, or non-fulfilment of the 
progression criteria including new lesions 
without confirmation of progression.
Progressive Disease (PD)
Bone lesions fulfilling the requirements for at 
least 2 new lesions and confirmation of 
progression.
Not Evaluable (NE)
Only relevant if no evaluable follow-up bone 
scan is available


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3.1.5
Blinded Independent Central Review (BICR) with RECIST 1.1 and PCWG3 
criteria
A planned BICR of all radiological imaging data will be carried out using RECIST version 1.1 
for soft tissue lesions and PCWG3 for bone lesions. All radiological scans for all patients 
(including those at unscheduled visits, or outside visit windows) will be collected on an 
ongoing basis and sent to an AstraZeneca appointed Contract Research Organization (CRO) 
for central analysis. The imaging scans will be reviewed by two independent radiologists 
using both RECIST 1.1 and PCWG3 and will be adjudicated, if required (i.e. two reviewers’ 
review the scans and adjudication is performed by a separate reviewer in case of a 
disagreement in a timepoint assessment). For each patient, the BICR will define the overall 
visit response (i.e. the response obtained overall at each visit by assessing TLs, NTLs and new 
lesions) data and no programmatic derivation of visit response is necessary.  RECIST 
assessments/scans contributing towards a particular visit may be performed on different dates 
and for the central review the date of progression for each reviewer will be provided based on 
the earliest of the scan dates of the component that triggered the progression. The records 
from the selected reviewer will be used to report all BICR information including dates of 
progression, visit response, censoring and changes in target lesion dimensions. Endpoints (of 
ORR, rPFS and DoR) will be derived programmatically from this information.
The independent review charter contains the details of the BICR conducted by the 
AstraZeneca- appointed Contract Research Organisation (CRO) and has been developed in 
advance at the start of the study. The BICR will provide RECIST measurements and response 
and PCWG3 progression status for each visit (i.e. for visits where progression is/is not 
identified) for each patient at the time of the primary DCO. After the primary rPFS analysis, 
BICR review of scans will no longer be required. 
3.2
Primary endpoint- Radiological Progression Free Survival (rPFS)
The analysis of the primary endpoint, rPFS of cohort A, will be based on tumor assessments 
determined by BICR using RECIST 1.1 (soft tissue) and PCWG3 (bone) criteria. There is no 
plan for BICR to read any scans dated after the date of DCO for the primary analysis. There 
will be no need to request confirmation of BICR PD after this time point, and the investigator-
assessed radiographic progression will prevail. 
 
 A sensitivity analysis based on the programmatically derived rPFS 
based on investigator recorded assessments will be performed.
Radiological progression-free survival is defined as the time from randomization until the date 
of objective disease progression (soft tissue or bone) or death (by any cause in the absence of 
progression) regardless of whether the patient withdraws from randomized therapy or receives
another anti-cancer therapy prior to progression (i.e. date of rPFS event or censoring – date of 
randomization + 1).
Patients who have not progressed (defined as CR, PR or SD by RECIST 1.1 for soft tissue 
disease, or Non-PD for bone disease) or died at the time of analysis will be censored at the 


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time of the earliest date of their last evaluable RECIST 1.1 assessment (taking the latest target 
lesion, non-target lesion or new lesion scan date) or bone scan assessment that showed Non-
PD. Else the latest of the previous RECIST1.1 assessment and bone scan if done at the same 
visit
However, if the patient progresses or dies immediately after 2 or more consecutive missed 
visits for either soft tissue or bone assessments, the patient will be censored at the earliest of 
the previous RECIST 1.1 assessment (taking the latest target lesion, non-target lesion or new 
lesion scan date) or previous bone scan assessment prior to the two consecutive missed visits 
(if RECIST and bone scan done at different visits).  Else the latest of the previous RECIST1.1 
assessment and bone scan if done at the same visit. 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).
With 8 weekly scheduled scans, the allowable interval from the previous radiographic 
assessment (earliest of the previous RECIST 1.1 assessment or previous bone scan 
assessment) equates to 18 weeks (126 days), allowing for early and late visits (i.e. 2 x 8 weeks 
+ 1 week for an early assessment + 1 week for a late assessment), or 17 weeks if immediately 
after the baseline scan (as no need to allow for an early assessment).
The rPFS time will always be derived based on scan 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.
CT/MRI and bone scans contributing towards a particular visit may be performed on different 
dates. The following rules will be applied:

For BICR (RECIST 1.1 and PCWG3) assessments, the date of progression will be 
determined based on the earliest of the scan dates of the component that triggered 
the progression for the adjudicated reviewer selecting PD, or of the reviewer with 
the earliest date of progression if there is no adjudication for BICR data.

For investigator assessments, the date of progression will be determined based on 
the earliest of the dates of the component that triggered the progression 

For BICR and investigator assessments, when censoring a patient for rPFS, the 
patient will be censored at the earliest of the of the previous RECIST 1.1 
assessment (taking the latest target lesion, non-target lesion or new lesion scan date) 
or previous bone scan assessment.
Table 11 provides the definitions how the visit responses for soft tissue (according to 
RECIST1.1 criteria) and bone progression status (according to PCWG3 criteria) are combined 
to give an overall radiological objective visit response.


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Table 11
Overall radiological visit response
Overall visit soft
tissue response
(RECIST 1.1)a
Bone progression 
status
(PCWG3)b
Bone lesions at visit
Present/Absent
Overall radiological
visit response
CR
Non-PD
Absent
CR
CR
Non-PD
Present
PR
CR
NE
-
PR
PR
Non-PD or NE
Any
PR
SD
Non-PD or NE
Any
SD
NED
Non-PD
Any
Non-PD
NED
NE
Any
NE
NE
Non-PD or NE
Any
NE
PD
Any
Any
PD
Any
PD
Any
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable (if an assessment is missing, it will be considered NE), NED = No Evidence of Disease (only relevant 
if there were no TL and NTLs at all visits)
a See section 3.1.3.
b See section 3.1.4.
In order to derive an overall radiological response, the BICR RECIST 1.1 and PCWG3 
assessments will be merged by the BICR visit number. The investigator assessments cannot 
be merged by visit number, they will instead be merged using windows around the protocolled 
visit schedule as described in the ADaM specification.
3.3
Secondary endpoints 
3.3.1
Confirmed Overall Objective Response Rate (ORR)
For patients in the EFR analysis set (who have measurable disease at baseline determined by 
BICR), objective response rate assessed by BICR (RECIST 1.1 and PCWG3), is defined as 
the number (%) of patients with at least one visit response of CR or PR, in their soft tissue 
disease assessed by RECIST 1.1, in the absence of progression on bone scan assessed by 
PCWG3. For each treatment group, the objective response rate (ORR) is the number of 
patients with a CR and PR divided by the number of patients in the treatment group .
A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit and 
confirmed by repeat imaging not less than 4 weeks after the visit when the response was first 
observed with no evidence of progression between the initial and CR/PR confirmation visit. 
Data obtained up until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR. Patients who discontinue randomized treatment 
without progression, receive a subsequent anti-cancer therapy (note that for this analysis 


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radiotherapy is not considered a subsequent anti-cancer therapy) and then respond will not be 
included as responders in the ORR.
In patients without a confirmed response, an unconfirmed response of CR/PR means that a 
response of CR/PR is recorded but either no confirmation assessment is performed or a 
confirmation assessment is performed but response is not confirmed.
In the case where a patient has two non-consecutive visit responses of PR, then, as long as the 
time between the 2 visits of PR is greater than 4 weeks and there is no PD between the PR 
visits, the patient will be defined as a confirmed responder. Similarly, if a patient has visit 
responses of CR, NE, CR, then, as long as the time between the 2 visits of CR is greater than 4 
weeks, then a best confirmed response of CR will be assigned.
Overall response rate based on soft tissue will be defined on the basis of RECIST 1.1 only. 
ORR will also be calculated based on investigator assessment using the EFR analysis set with 
measurable disease at baseline determined by investigator assessment.
3.3.2
Analgesic Use Scoring
The Analgesic Quantification Algorithm (AQA) developed by Chung et al 2014 will be used 
to quantify and score analgesic use in the study. The AQA is an eight-point scale that assigns 
a score as follows:

0=No analgesic

1=Non-opioid analgesics

2=Weak opioids (e.g. codeine, tramadol)

3=Strong opioids ≤75 mg oral morphine equivalence (OME) per day

4=Strong opioids >75–150 mg OME per day

5=Strong opioids >150–300 mg OME per day

6=Strong opioids >300–600 mg OME per day

7=Strong opioids >600 mg OME per day
Average daily opiate use (based on OME) will be computed using the sum of all opiates used 
over the 7 days per the assessment schedule. The average daily OME will require at least 4 
days of data and will be used to assign the AQA score. An increase of 1 point or more in the 
AQA score from a starting value of 1 or higher OR ≥ 2 points in AQA score from a starting 
value of 0 is considered a clinically meaningful increase in opiate use. Similarly, a decrease of 
1 point or more in the AQA score from a starting value of 2 or higher is considered a clinically 
meaningful decrease in opiate use.


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3.3.3
Time to Pain Progression (TTPP)
Time to pain progression (based on average BPI-SF worst pain [Item 3] and analgesic [AQA] 
score) is defined as time from randomization to time point at which worsening in pain (based 
on BPI-SF worst pain [Item 3]) is observed (i.e. date of pain progression – date of 
randomization + 1) for asymptomatic patients and symptomatic patients (at baseline) as 
follows:
Asymptomatic patients at baseline (average BPI-SF worst pain [Item 3] score of 0 and not 
taking opioids)

Increase of 2 or more points from baseline in the average BPI-SF worst pain [Item 
3] score observed at 2 consecutive follow-up assessments/visits (with at least 2 
weeks between the end of the initial visit and the start of the subsequent visit). The 
date of pain progression will be the earliest date of the assessments contributing to 
the average of 7-day assessments for BPI-SF [Item 3].
Or

Initiation of opioid use for pain.
Symptomatic patients at baseline (average BPI-SF Item 3 score >0 and/or currently taking 
opioids)

Increase of 2 or more points from baseline in the BPI-SF worst pain [Item 3] score 
observed at 2 consecutive follow-up assessments/visits (with at least 2 weeks 
between the end of the initial visit and the start of the subsequent visit) and an 
average worst pain score ≥4, and no decrease in average opioid use measured as 1 
or more points decrease in AQA score from a starting value of 2 or higher. The date 
of pain progression will be the earliest date of the assessments contributing to the 
average of 7-day assessments for BPI-SF worst pain [Item 3].
Or

Increase in the average opioid use measured as 1 or more points increase (or at least 
2 points increase if the starting value is 0) in the AQA score from baseline observed 
at 2 consecutive follow-up assessments/visits (with at least 2 weeks between the end 
of the initial visit and the start of the subsequent visit). 
Information on all analgesics used by patients in pain control will be collected using the 
analgesic log. For the purposes of pain severity progression, only information on the actual 
pain medication collected with the analgesic log will be used.
Any BPI-SF worst pain [Item 3] or analgesic log assessments on or before the date of first 
treatment will be considered a screening assessment. 


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The window for the visits following baseline will be constructed in such a way that the upper 
limit of the interval falls half way between the two visits (the lower limit of the first post-
baseline visit will be Day 2). If an even number of days exists between two consecutive visits 
then the upper limit will be taken as the midpoint value minus 1 day.  Study day will be 
calculated in relation to date of first treatment. For example:
•
Day 29, visit window 2 – 42
•
Day 57, visit window 43 – 70
•
Day 85, visit window 71 – 98
For the Week 4 (Day 29) visit, if there are overlapping screening measurements in the week 4 
window on Day 2, 3, 4 etc, resulting in 2 sets of observations in the Week 4 window, then the 
set of assessments closest to the target day will be used.
Where the average of BPI-SF worst pain [Item 3] score and average AQA score are taken over 
7 days for each visit, the 7 day window for both BPI-SF worst pain [Item 3] score and AQA 
score will start from the date of first entry of the BPI-SF worst pain [Item 3] for that visit. For 
example, if there are medications entered in the analgesic log prior to the first entry of BPI-SF 
worst pain [Item 3], the data will not be used in the average AQA score. Additionally, if there 
are medications entered in the analgesic log after the 7 day period, these will not be used in the 
average AQA score. 
To calculate the average BPI-SF worst pain [Item 3] score over 7 days, there must be at least 4 
days with the BPI-SF worst pain [Item 3] completed. The denominator for the average BPI-SF 
worst pain [Item 3] over 7 days will be the number of days the BPI-SF worst pain [Item 3] is 
filled in. 
To calculate the average AQA score, there must be at least 4 out of the 7 days with evaluable 
data. To count a day as having evaluable data, at least the BPI-SF worst pain [Item 3] or the 
analgesic log must be filled in. The denominator for the average AQA score will be the 
number of days either the BPI-SF worst pain [Item 3] or the analgesic log is filled in.
Pain progression is set to missing at a visit if there are < 4 days data for BPI-SF worst pain 
[Item 3] and the average AQA score does not meet the progression criteria.  If average AQA 
score meets the progression criteria regardless of available BPI-SF worst pain [Item 3] then 
the visit is set to progression.
For patients who receive a subsequent anti-cancer therapy, data will only be included until the 
start date of the subsequent anti-cancer therapy. Note that for this analysis radiotherapy is not 
considered a subsequent anti-cancer therapy. For patients who switch from investigators 
choice of NHA to olaparib upon progression, olaparib will be considered subsequent therapy. 
Patients who do not satisfy the pain progression criteria for asymptomatic patients and 
symptomatic patients (at baseline) will be censored as follows:


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
If a patient meets the criteria for pain progression after 2 or more missed visits 
(visits which showed < 4 days of BPI-SF worst pain [Item 3] assessments and the 
average AQA score does not meet the progression criteria), then the patient will be 
censored at the time of the latest evaluable average BPI-SF worst pain [Item 3] 
assessment (the earliest date of the assessments contributing to the average will be 
used).

Patients who have not met the criteria for pain progression at the time of analysis

The censoring date will be the date of the latest evaluable average BPI-SF 
worst pain [Item 3] assessment (the earliest date of the assessments contributing 
to the average will be used).

Patients with no evaluable baseline or post-baseline data will be censored at 
Day 1. 

Patients who receive subsequent anti-cancer therapy

The censoring date will be the date of the latest evaluable average BPI-SF 
worst pain [Item 3] assessment prior to the start date of subsequent anti-cancer 
therapy (the earliest date of the assessments contributing to the average will be 
used).

Patients with no evaluable baseline or post-baseline data will be censored at 
Day 1.

Patients who are randomized but do not receive study treatment will be censored at 
Day 1.
Missing data 
Analgesic or pain medication use allows patients to add new medications as “Other” to the 
handheld device. 
In the case where there are reconciled or unreconciled “other” pain medication entries in the 
analgesic log and the OME value is missing, but the medication is clearly identified as a non-
opioid, then the OME value will be set to 0. OME values will not be imputed for reconciled 
“other” medications which are not clearly identified as non-opioids.
In the case where there are unreconciled “other” pain medication entries which are not clearly 
identified as non-opioids, OME values will be imputed at two levels while AQA scores will 
be imputed where OME values cannot be assigned as follows:
Daily completion level: 


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
If additional pain medications were taken alongside “Other” for a specific day, the 
highest OME value of the pain medications (based on completed entries) will be 
selected as the imputed value for each unreconciled “other” entry for the specific 
day.
7-day completion period level: 

If no additional pain medications were taken alongside “Other” for a specific day, 
the highest OME value of pain medications (based on completed entries) across the 
7 days of assessments will be selected as the imputed value for each unreconciled 
“other” entry.
AQA score level: 

If no additional pain medications were taken alongside “Other” across the 7 days of 
assessments, the highest AQA value from all previous visits will be selected as 
imputed AQA value for the time point. 

If additional pain medications taken alongside “Other” over the 7 days of 
assessments, and they are all non-opioids, then AQA score of 1 will be assigned 
(i.e. non-opioid analgesics).

Where no AQA score can be imputed, the AQA value for that visit will be 
considered missing.
3.3.4
Brief Pain Inventory – short form (BPI-SF)
The BPI-SF will be used to assess the impact of pain on daily life. The BPI-SF comprises a 
total of 15 items measuring 2 domains: pain severity and pain interference.
Pain severity subscale/domain
The BPI-SF pain severity domain/subscale consists of 4 items (#3, #4, #5, and #6) that assess 
pain at its “worst,” “least,” “average,” and “now” (current pain) respectively on an 11-point 
numeric rating scale (NRS) ranging from 0=No pain to 10=Pain as bad as you can imagine. 
Pain severity subscale or composite score from all the 4 items will be calculated as a mean 
score where all items must be non-missing. The average pain severity subscale/domain score 
at each visit will be calculated as the average of 7 days starting from the date of the first BPI-
SF pain severity domain/subscale entry. There must be at least 4 out of the 7 days with a non-
missing pain severity subscale score to calculate the average pain severity subscale/domain 
score. 
Time to pain severity progression
Time to ‘pain severity’ progression will be assessed from the date of randomization (i.e. date 
of pain severity progression – date of randomization +1) as follows for asymptomatic and 
symptomatic patients:


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Asymptomatic patients at baseline (average “pain severity” subscale score of 0 and not taking 
opioids)

Increase of ≥ 2 points in the average “pain severity” subscale score from baseline 
observed at 2 consecutive follow-up assessments/visits (with at least 2 weeks 
between the end of the initial visit and the start of the subsequent visit). The date of 
pain severity progression will be the earliest date of the assessments contributing to 
the average of 7-day assessments.
Or

Initiation of any opioid use for pain
Symptomatic patients at baseline (average “pain severity” subscale score >0 and/or currently 
taking opioids)

Increase of ≥ 2 points in the average “pain severity” subscale score from baseline 
observed at 2 consecutive follow-up assessments/visits (with at least 2 weeks 
between the end of the initial visit and the start of the subsequent visit) and an 
average “pain severity” subscale score ≥4, and no decrease in average opioid use, 
measured as 1 or more points decrease in AQA score from a starting value of 2 or 
higher. The date of pain severity progression will be the earliest date of the 
assessments contributing to the average of 7-day assessments.
Or

Increase in the average (i.e. average of 7-day assessments) opioid use measured as 1 
or more points increase (or at least 2 points increase if the starting value is 0) in the 
AQA score from baseline observed at 2 consecutive follow-up assessments/visits 
(with at least 2 weeks between the end of the initial visit and the start of the 
subsequent visit). The date of pain severity progression will be the earliest date of 
the assessments contributing to the average of 7-day assessments.
Information on all analgesics used by patients in pain control will be collected using the 
analgesic log. For the purposes of pain severity progression, only information on the actual 
pain medication collected with the analgesic log will be used. For AQA imputation rules for 
missing data, see section 3.3.3.
Any BPI-SF “pain severity” subscale or analgesic log assessments taken on or before the date 
of first dose will be considered a screening assessment. 
The window for the visits following baseline will be constructed in such a way that the upper 
limit of the interval falls half way between the two visits (the lower limit of the first post-
baseline visit will be Day 2). If an even number of days exists between two consecutive visits 
then the upper limit will be taken as the midpoint value minus 1 day.  Study day will be 
calculated in relation to date of first treatment. For example:


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•
Day 29, visit window 2 – 42
•
Day 57, visit window 43 – 70
•
Day 85, visit window 71 – 98
For the Week 4 (Day 29) visit, if there are overlapping screening measurements in the week 4 
window on Day 2, 3, 4 etc, resulting in 2 sets of observations in the Week 4 window, then the 
set of assessments closest to the target day will be used.
Where the average of BPI-SF “pain severity” subscale score and average AQA score are taken 
over 7 days for each visit, the 7 day window for both BPI-SF “pain severity” subscale score 
and average AQA score will start from the date of first entry of the BPI-SF “pain severity” 
subscale for that visit. For example, if there are medications entered in the analgesic log prior 
to the first entry of BPI-SF “pain severity” subscale, the data will not be used in the average 
AQA score. Additionally, if there are medications entered in the analgesic log after the 7 day 
period, these will not be used in the average AQA score. 
To calculate the average BPI-SF “pain severity” subscale score, there must be at least 4 days 
with the BPI-SF “pain severity” subscale completed. The denominator for the average BPI-SF 
“pain severity” subscale will be the number of days the BPI-SF “pain severity” subscale is 
calculated. 
To calculate the average AQA score, there must be at least 4 out of the 7 days with evaluable 
data. To count a day as having evaluable data, at least the BPI-SF “pain severity” subscale 
score or the analgesic log must be filled in. The denominator for the average AQA score will 
be the number of days either the BPI-SF “pain severity” subscale score or the analgesic log is 
filled in.
Pain severity progression is set to missing at a visit if there are < 4 days data for “pain 
severity” subscale score and the average AQA score does not meet the progression criteria.  If 
average AQA score meets the progression criteria regardless of available BPI-SF “pain 
severity” subscale score then the visit is set to progression.
For patients who receive a subsequent anti-cancer therapy data will only be included until the 
start date of the subsequent anti-cancer therapy. Note that for this analysis radiotherapy is not 
considered a subsequent anti-cancer therapy. For patients who switch from investigators 
choice of NHA to olaparib upon progression, olaparib will be considered subsequent therapy.
A number of situations will lead to a patient’s time to pain severity progression being 
censored.  These are:

If a patient meets the criteria for pain severity progression after 2 or more missed 
visits (visits which showed < 4 days of BPI-SF “pain severity” subscale assessments 
and the average AQA score does not meet the progression criteria), then the patient 
will be censored at the time of the latest evaluable average BPI-SF “pain severity” 
subscale assessment (the earliest date of the assessments contributing to the average 
will be used). 


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
Patients who have not met the criteria for pain severity progression at the time of 
analysis 

The censoring date will be the date of the latest evaluable average BPI-SF “pain 
severity” subscale assessment (the earliest date of the assessments contributing 
to the average will be used).

Patients with no evaluable baseline or post-baseline data will be censored at 
Day 1. 

Patients who receive subsequent anti-cancer therapy

The censoring date will be the date of the latest evaluable average BPI-SF “pain 
severity” subscale assessment prior to the start date of subsequent anti-cancer 
therapy (the earliest date of the assessments contributing to the average will be 
used). 

Patients with no evaluable baseline or post-baseline data will be censored at 
Day 1.

Patients who are randomized but do not receive study treatment will be censored at 
Day 1.
Pain interference domain
The BPI-SF pain interference domain includes 7 items: general activity, mood, walking 
ability, normal work, relations with other people, sleep, and enjoyment of life. The pain 
interference domain is scored as the mean of the 7 interference items. At least 50% of the 
items, or 4 out of 7, must have a response for a mean score to be calculated. The average pain 
interference subscale score at each visit will be calculated as the average of 7 days starting 
from the date of the first entry. There must be at least 4 out of the 7 days with a non-missing 
pain interference subscale score to calculate the average pain interference subscale score.
PRO compliance
Summary measures of overall compliance and compliance over time will be derived for 
BPI-SF. These will be based upon the following definitions:

Received form: a form that has been received and has a completion date and at least 
one individual item completed. 

Expected form: a form that is expected to be completed at a scheduled assessment 
time e.g. a form from a patient who has not withdrawn from the study at the 
scheduled assessment time but 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 BPI-SF follow-up 


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at the specified assessment time. Date of study discontinuation will be mapped to 
the nearest visit date to define the number of expected forms.  BPI-SF forms are to 
be completed for 6 months after either progression or treatment discontinuation 
(whichever comes second).

Evaluable form: a form with a completion date and at least one subscale that is non-
missing. 

Completed questionnaire: a form with all questions completed

Overall BPI-SF compliance rate is defined as the total number of evaluable forms 
across all time points, divided by total number of forms expected to be received 
across all time points multiplied by 100. 

Overall patient compliance rate is defined for each randomized treatment group as 
the total number of patients with both an evaluable baseline and at least one 
evaluable follow-up form (as defined above), divided by the total number of 
patients expected to have completed at least a baseline BPI-SF form multiplied by 
100. 
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. Completion 
rate will be calculated separately for each visit, including baseline, as the number of 
completed questionnaires (per definition above), divided by the number of received 
questionnaires. Finally, patient disposition of PRO assessments over time will be computed 
cumulatively at each visit using tables and bar charts. Descriptive summaries for patient/form 
disposition will include patients expected to provide PRO assessments and patients 
unexpected to provide PRO assessment due to death, disease progression and other reasons 
respectively at each visit.
3.3.5
Pain Palliation
Pain Palliation is defined for patients with an average BPI-SF worst pain [Item 3] score ≥ 4 
points at baseline and is assessed as the proportion of patients with a decrease of ≥2 points in 
BPI-SF worst pain [Item 3] score at 12 weeks, confirmed at least 2 weeks later, without a ≥1 
point increase (or ≥2 increase if starting value is 0) in AQA analgesic score. 
Note: Confirmation at least 2 weeks later: (start date of subsequent visit – end date of initial 
visit is >= 14 days).
Information on all analgesics used by patients in pain control will be collected using the 
analgesic log. For the purposes of pain severity progression, only information on the actual 


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pain medication collected with the analgesic log will be used. For AQA imputation rules for 
missing data, see section 3.3.3.
Any BPI-SF worst pain [Item 3] or analgesic log assessments on or before the date of first 
treatment will be considered a screening assessment. 
The window for the visits following baseline will be constructed in such a way that the upper 
limit of the interval falls half way between the two visits (the lower limit of the first post-
baseline visit will be Day 2). If an even number of days exists between two consecutive visits 
then the upper limit will be taken as the midpoint value minus 1 day.  Study day will be 
calculated in relation to date of first treatment. For example:
•
Day 29, visit window 2 – 42
•
Day 57, visit window 43 – 70
•
Day 85, visit window 71 – 98
For the Week 4 (Day 29) visit, if there are overlapping screening measurements in the week 4 
window on Day 2, 3, 4 etc, resulting in 2 sets of observations in the Week 4 window, then the 
set of assessments closest to the target day will be used.
Where the average of BPI-SF worst pain [Item 3] score and average AQA score are taken over 
7 days for each visit, the 7 day window for both BPI-SF worst pain [Item 3] score and average 
AQA score will start from the date of first entry of the BPI-SF worst pain [Item 3] for that 
visit. For example, if there are medications entered in the analgesic log prior to the first entry 
of BPI-SF worst pain [Item 3], the data will not be used in the average AQA score. 
Additionally, if there are medications entered in the analgesic log after the 7 day period, these 
will not be used in the average AQA score. 
To calculate the average BPI-SF worst pain [Item 3] score over 7 days, there must be at least 4 
days with the BPI-SF worst pain [Item 3] completed. The denominator for the average BPI-SF 
worst pain [Item 3] over 7 days will be the number of days the BPI-SF worst pain [Item 3] is 
filled in. 
To calculate the average AQA score, there must be at least 4 out of the 7 days with evaluable 
data. To count a day as having evaluable data, at least the BPI-SF worst pain [Item 3] or the 
analgesic log must be filled in. The denominator for the average AQA score will be the 
number of days either the BPI-SF worst pain [Item 3] or the analgesic log is filled in.
Pain palliation is set to missing at a visit if there are < 4 days data for BPI-SF worst pain [Item 
3].
For patients who receive a subsequent anti-cancer therapy, data will only be included until the 
start date of the subsequent anti-cancer therapy. Note that for this analysis radiotherapy is not 
considered a subsequent anti-cancer therapy. For patients who switch from investigators 
choice of NHA to olaparib upon progression, olaparib will be considered subsequent therapy.


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3.3.6
Overall Survival
Overall survival is defined as the time from the date of randomization until death due to any
cause regardless of whether the patient withdraws from randomized therapy or receives 
another anti-cancer therapy (i.e. date of death or censoring – date of randomization + 1). 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 variable is recorded within the 
survival status module of the eCRF (SUR_DAT, recorded within the SURVIVE module of the 
eCRF).
For overall survival, if a partial date exists when an event has occurred then the following 
imputation method will be used: if month is missing, then impute month with January. If the 
day is missing, then impute day with 01. Then choose the latest date from the imputed event 
date and the patient’s last known alive date+1 as the final imputed event date. 
Note: Survival calls will be made in the week following the date of DCO for the primary rPFS 
analysis, final OS analysis 
, and if patients are confirmed to be 
alive or if the death date is post the DCO date these patients will be censored at the date of 
DCO.
3.3.7
Time to first Symptomatic Skeletal –Related Event (SSRE)
Time from randomization to first symptomatic skeletal–related event as defined by any of the 
following or a combination:

Use of radiation therapy to prevent or relieve skeletal symptoms

Occurrence of new symptomatic pathological bone fractures (vertebral or 
nonvertebral). Radiologic documentation is required.
A pathological fracture, as determined by investigator, is defined as associated with 
low or no trauma and deemed to have occurred at a site of bone metastasis

Occurrence of spinal cord compression. Radiologic documentation required

Orthopedic surgical intervention for bone metastasis
Patients who have not experienced any of the above conditions will be censored at time of 
death, or time of last SSRE assessment.
3.3.8
Duration of Response (DoR)
For patients in the EFR analysis set (who have measurable disease at baseline determined by 
BICR) and have a confirmed response (CR or PR as described in section 3.3.1), duration of 
response (DoR) will be defined as the time from the date of first documented confirmed 
response until date of documented progression or death in the absence of disease progression 
(i.e. date of rPFS event or censoring – date of first confirmed response + 1).


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The time of the first confirmed response will be defined as the latest of the dates contributing 
towards the first visit response of confirmed PR or CR. The end of response will be defined as 
the date of progression or death from any cause used for the rPFS endpoint. If a patient does 
not progress following a response, then their duration of response will use the rPFS censoring 
date as the date at which that patient is censored for DoR. However, if the date of rPFS 
censoring is on or before the date of the first confirmed response then the patient will be 
censored at Day 1 for DoR.
The time to response is the time from randomization to the first onset of a confirmed objective 
tumor response (i.e. date of first confirmed response – date of randomization + 1).
An unconfirmed response is defined in section 3.3.1. Duration of response will also be 
calculated for patients with an unconfirmed response for BICR and investigator assessments 
separately. 
3.3.9
Time to Opiate Use for Cancer Pain
Time to Opiate use is defined as the time from randomization to the date of opiate use for 
cancer-related pain on subjects who have not received any opiates at baseline. Subjects who 
have not received opiates during the study or died prior to receiving opiates will be censored 
at the last study assessment date prior to DCO where no opiate use was recorded.
3.3.10
Prostate Specific Antigen (PSA) Response
PSA response is defined as the proportion of patients achieving a ≥50% decrease in PSA from 
baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA 
assessment at least 3 weeks later. For patients who receive a subsequent anti-cancer therapy 
(note that for this analysis radiotherapy is not considered a subsequent anti-cancer therapy), 
data will only be included until the start date of the subsequent anti-cancer therapy. All 
patients in the FAS will be included, regardless of having a baseline PSA measurement.  

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 3 weeks later (i.e., decrease relative to baseline of at 
least 50% documented on 2 consecutive occasions at least 3 weeks apart).
For the calculation of PSA responses, values of the form of “< x” (i.e. below the lower limit of 
quantification) or > x (i.e. above the upper limit of quantification) will be imputed as “x”.
3.3.11
PSA changes on continuous scale
PSA changes on a continuous scale will be evaluated in patients in the FAS who have a valid 
baseline and post-baseline PSA measurement. Patients without a baseline PSA measurement 
and/or a post-baseline PSA measurement will be excluded from the analysis. For patients who 


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receive a subsequent anti-cancer therapy (note that for this analysis radiotherapy is not 
considered a subsequent anti-cancer therapy), data will only be included until the start date of 
the subsequent anti-cancer therapy.

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:

Percentage change from baseline = [(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.
For the calculation of PSA changes on a continuous scale, values of the form of “< x” (i.e. 
below the lower limit of quantification) or > x (i.e. above the upper limit of quantification) 
will be imputed as “x”.
3.3.12
Circulating Tumor Cell (CTC) Conversion rate
Defined as the proportion of patients achieving a decline in the number of CTCs from ≥5 
cells/7.5 mL at baseline to <5 cells/7.5 mL at any visit post baseline. For patients who receive 
a subsequent anti-cancer therapy (note that for this analysis radiotherapy is not considered a 
subsequent anti-cancer therapy), data will only be included until the start date of the 
subsequent anti-cancer therapy. All patients in the FAS will be included for CTC conversion 
rate, regardless of having a baseline CTC measurement.
For the calculation of CTC conversion rates, CTC values of the form of “< x” (i.e. below the 
lower limit of quantification) or > x (i.e. above the upper limit of quantification) will be 
imputed as “x”.
CTC counts on a continuous scale will be evaluated in patients in the FAS who have a valid 
baseline and post-baseline CTC measurement. For patients who receive a subsequent anti-
cancer therapy (note that for this analysis radiotherapy is not considered a subsequent anti-
cancer therapy), data will only be included until the start date of the subsequent anti-cancer 
therapy. Patients without a baseline CTC measurement and/or a post-baseline CTC 
measurement will be excluded from the analysis.
3.3.13
Time from randomization to second progression or death (PFS2)
Defined as the time from the date of randomization to the earliest of the investigator assessed 
progression event (subsequent to that used for the primary variable rPFS) or death (i.e. date of 
PFS2 event or censoring – date of randomisation + 1). The date of second progression will be 
recorded by the investigator and defined according to local standard clinical practice and may 
involve any of; objective radiological, symptomatic progression or death. The date of the 
PFS2 assessment and investigator opinion of progression status (progressed or non-
progressed) at each assessment will be recorded in the electronic case report form (eCRF). 


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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 date by investigator assessment or PFS2 assessment date if 
the patient has not had a second progression or death). However, if the patient experiences a 
second progression or dies after two or more visits where there was no evaluable PFS2 
assessment (i.e. the evaluable PFS2 assessment was greater than 196 days since the prior 
evaluable assessment, based on two 12-weekly visits plus two allowed 2 week visit windows) 
the patient will be censored at the time of the prior evaluable PFS2 assessment.
3.3.14
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, at baseline, Week 8, 16 and 24 and then continue to be 
administered to all patients (who have not withdrawn consent) every 8 weeks.
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)

Total Functional Assessment of Cancer Therapy- General (FACT-G) score, sum of 
PWB, SWB, EWB and FWB

Trial Outcome Index (TOI), sum of PWB, FWB and PCS

Functional Assessment of Prostate Cancer Symptoms Index 6 (FAPSI-6) (Questions 
P1 to P3, GP1, C2 and GE6)

Total FACT-P 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.


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
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 functional assessment of chronic illness (FACIT) scoring guidelines (Cella et al 
1993, Cella et al 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. Similarly, FACT-G 
total score and and TOI score require more than 80% of the relevant questions to be 
completed for the score to be evaluable. 

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:
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-G, 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 randomization will be assigned to be the baseline 
assessment.
At each post-baseline visit, the following criteria as listed below in Table 12 will be used to 
assign a visit response for the FACT-P total score, TOI, FACT-G, FAPSI-6, PCS, PWB and 
FWB scores (Cella et al 2009).  This response should be maintained for 2 consecutive visits.
Table 12
Definition of visit response for FACT-P, FAPSI-6, FACT-G, TOI, PCS, 
FWB and PWB
FACT-P scale
Change from baseline
Visit response
FACT-P-Total
≥ +10
Improved
≤ -10
Worsened


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Table 12
Definition of visit response for FACT-P, FAPSI-6, FACT-G, TOI, PCS, 
FWB and PWB
FACT-P scale
Change from baseline
Visit response
Otherwise (i.e. >-10 and 
<+10)
No change
Missing/non-calculable score
Not evaluable
FAPSI-6
≥ +3
Improved
≤ -3
Worsened
Otherwise (i.e. >-3 and <+3)
No change
Missing/non-calculable score
Not evaluable
TOI
≥ +9
Improved
≤ -9
Worsened
Otherwise (i.e. >-9 and <+9)
No change
Missing/non-calculable score
Not evaluable
FACT-G
≥ + 7
Improved
≤ - 7
Worsened
Otherwise (i.e. >-7 and <+7)
No change
Missing/non-calculable score
Not evaluable
PCS, FWB, PWB
≥ +3
Improved
≤ -3
Worsened
Otherwise (i.e. >-3 and <+3)
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”.


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
For patients whose baseline score is less than the threshold needed for 
worsening (e.g., a baseline FACT-P TOI < 9) 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 13 will be used to assign a best 
overall response score based on the individual visit responses. For patients who receive a 
subsequent anti-cancer therapy (note that for this analysis radiotherapy is not considered a 
subsequent anti-cancer therapy), data will only be included until the start date of the 
subsequent anti-cancer therapy.
Table 13
Overall score response criteria
Best overall response
Criteria
Improved
Two consecutive visit responses of ‘improved’. 
Consecutive visits need to be at least 3 weeks apart.
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’
Not evaluable
Missing or non-calculable scores
Other
Does not qualify for one of the above
Time to deterioration for FACT-P
Time to deterioration in HRQL as measured by FACT-P total score will be defined as the 
interval from the date of randomization until the date of the first clinically meaningful 
deterioration that is confirmed at a subsequent visit at least 3 weeks apart with no 
improvement in between the visits (except if it was the patient’s last available assessment) or 
death (by any cause) in the absence of a clinically meaningful deterioration, regardless of 
whether the patient discontinues study drug(s) prior to the deterioration in FACT-P total score. 
Death will be included as an event only if it occurs within 2 PRO assessment visits from the 
last available PRO assessment. For patients who receive a subsequent anti-cancer therapy 
(note that for this analysis radiotherapy is not considered a subsequent anti-cancer therapy), 
data will only be included until the start date of the subsequent anti-cancer therapy. Time to 
deterioration as measured by FACT-P TOI, FACT-G, FAPSI-6, PCS, PWB and FWB will be 
derived similarly.


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A worsening is as described in Table 12, for example, for FACT-P TOI a decrease in score 
from baseline of ≥ 9 will constitute a deterioration. Improvement is also as defined in Table 
12.
Radiologic progression 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 prior to symptom deterioration. A number of situations will lead to a patient’s time to 
deterioration of HRQL endpoints being censored.  These are:

If a patient either dies or meets the criteria for deterioration 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 e.g. “Censored 
FACT-P total score” in summaries.

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 total score. 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 (in which case their date of 
death will be used). These patients will be presented as censored in summaries.

Patients who receive subsequent anti-cancer therapy

The censoring date will be the date of the last assessment prior to the start date 
of subsequent anti-cancer therapy that led to evaluable being assigned for 
FACT-P total score. 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 (in which case their date of 
death will be used). These patients will be presented as censored 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 total score 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 Total Score” in 
summaries.


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The time to deterioration of HRQL will be derived based on assessment dates, not visit dates.
PRO compliance
Summary measures of overall compliance and compliance over time will be derived for the 
FACT-P. These will be based upon the compliance derivations described for BPI-SF.
3.3.15
Pharmacokinetic Endpoint
Olaparib plasma concentrations will be measured at Week 4 (Visit 3) pre-dose (- 30 min ± 15 
min) and at 30 min ± 15 min, 2 ± 0.5 hour, 5 ± 0.5 hour, and 8± 1 hour post-dose.
3.4
Exploratory endpoints
3.4.1
PRO-CTCAE
The PRO-CTCAE consists of nominal categories (e.g. “none” to “very severe” for some items 
in the questionnaire) it will be collected every 2 weeks (starting day 1) for first 8 weeks and 
every 4 weeks thereafter until 6 months after discontinuation of study treatment.
PRO Compliance
Summary measures of overall compliance and compliance over time will be derived for the 
PRO-CTCAE. These will be based upon the compliance derivations described for BPI-SF.
3.4.2
Patient Global Impression of Change (PGIC)
The PGIC item is included to assess how a patient perceives their overall change in health 
status since the start of study treatment. Patients will choose from response options ranging 
from “Very Much Improved” to “Very Much Worse.” This item is useful in characterizing the 
overall impact of the treatment. The PGIC assessments will be performed on week 8 and 
every 8 weeks thereafter.
PRO Compliance
Summary measures of overall compliance and compliance over time will be derived for the 
PGIC. These will be based upon the compliance derivations described for BPI-SF.
3.4.3
Health Economics 
3.4.3.1
Resource use
To investigate the impact of treatment and disease on health care resource, the following 
variables will be captured:

Planned and unplanned hospital attendances beyond trial protocol mandated visits 
(including physician visits, emergency room visits, day cases and admissions)

Primary sign or symptom the patient presents with

Length of hospital stay


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
Length of any time spent in an intensive care unit (ICU)
The study site staff will complete the “Hospital Admission (HOSPAD)” eCRF at the site at 
every scheduled clinic visit up to and including the study treatment discontinuation follow up 
visit. If the subject discontinues study treatment for reasons other than RECIST progression, 
the “HOSPAD” eCRF should continue to be administered until progression has been 
determined by BICR.
Where admitted overnight, the length of hospital stay will be calculated as the difference 
between the date of hospital discharge (or death date) and the start date of hospitalisation or 
start of study drug if the start of study drug is after start date of hospitalisation (length of 
hospital stay = end date of hospitalisation – start date of hospitalisation + 1). Patients with 
missing discharge dates will be calculated as the difference between the last day with 
available data and the start date of hospitalisation. The length of ICU stay will be calculated 
using the same method.
Further Payer required analyses involving resource use will be described in detail in the Payer 
analysis plan.
3.4.3.2
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 (VAS), ranging from 0 (worst imaginable health) to 100 (best imaginable 
health).
Measurements are collected on study day 1 and every 8 weeks thereafter until 24 weeks 
following radiographic progression.
Further analyses involving each of the 5 dimensions of health, the EQ-5D-VAS and utilities 
will be needed to support Payer dossiers and will be described in detail in the payer analysis 
plan.
PRO Compliance
Summary measures of overall compliance and compliance over time will be derived for the 
EQ-5D-5L. These will be based upon the compliance derivations described for BPI-SF.


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3.5
Safety
3.5.1
General considerations for safety assessments
Baseline will generally be the last value obtained prior to the first dose of study medication. 
Alternatively, if two visits are equally eligible to assess patient status at baseline (e.g., 
screening and baseline assessments both on the same date prior to first dose with no washout 
or other intervention in the screening period), the average can be taken as a baseline value.  
For non-numeric laboratory tests (i.e. some of the urinalysis parameters) where taking an 
average is not possible then the best value would be taken as baseline as this is the most 
conservative.  In the scenario where there are two assessments on day 1, one with time 
recorded and the other without time recorded, the one with time recorded would be selected as 
baseline. 
Time windows will be defined for any presentations that summarise values by visit.   The 
following conventions will apply: 

The time windows will be exhaustive so that data recorded at any time point has the 
potential to be summarised.   Inclusion within the time window will be based on the
actual date and not the intended date of the visit.

All unscheduled visit data have the potential to be included in the summaries.

The window for the visits following baseline will be constructed in such a way that 
the upper limit of the interval falls half way between the two visits (the lower limit 
of the first post-baseline visit will be Day 2). If an even number of days exists 
between two consecutive visits then the upper limit will be taken as the midpoint 
value minus 1 day.  For example, the visit windows for laboratory assessment data 
(with 4 weeks between scheduled assessments) are:

Day 29, visit window 2 – 42

Day 57, visit window 43 – 70

Day 85, visit window 71 – 98

For summaries showing the maximum or minimum values, the maximum/minimum 
value recorded on treatment will be used (regardless of where it falls in an interval).

Listings should display all values contributing to a time point for a patient.

For visit based summaries

If there is more than one value per patient within a time window then the
closest value to the scheduled visit date will be summarised, or the earlier, in 
the event the values are equidistant from the nominal visit date.  The listings 
will highlight the value for the patient that contributed to the summary table, 
wherever feasible.  Note: in summaries of extreme values all post baseline 


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values collected are used including those collected at unscheduled visits 
regardless of whether or not the value is closest to the scheduled visit date.

To prevent very large tables or plots being produced that contain many cells 
with meaningless data, for each treatment group, visit data should only be 
summarised if the number of observations is greater than the minimum of 20 
and > 1/3 of patients dosed.

For summaries at a patient level, all values will be included, regardless of whether 
they appear in a corresponding visit based summary, when deriving a patient level 
statistic such as a maximum.
Where safety data are summarised over time, study day will be calculated in relation to date of 
first treatment.  
Missing safety data will generally not be imputed.  However, safety assessment values of the 
form of “< x” (i.e. below the lower limit of quantification) or > x (i.e. above the upper limit of 
quantification) will be imputed as “x” in the calculation of summary statistics but displayed as 
“< x” or “> x” in the listings. Additionally, adverse events that have missing causality (after 
data querying) will be assumed to be related to study drug.
For laboratory data the following applies:

Numerical summaries will provide the mean, standard deviation, median, minimum, 
maximum, and lower and upper quartile for visit based tabular summaries.  
3.5.2
Handling of partial dates
For missing start dates for AEs and concomitant medications/procedures, the following will be 
applied:

Missing day - Impute the 1st of the month unless month is the same as month of first 
dose of study drug then impute first dose date.

Missing day and month – impute 1st January unless year is the same as first dose date 
then impute first dose date.

Completely missing date – impute first dose date unless the end date is less than the 
first dose date, in which case impute the 1st January of the same year as the end date. 
When imputing a start date ensure that the new imputed date is sensible e.g. is prior to the end 
date of the AE.
For missing stop dates of AEs or concomitant medications/procedures, the following will be 
applied:

Missing day - Impute the last day of the month unless month is the same as month of 
the last dose of study drug then impute last dose date.


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
Missing day and month – impute 31st December unless year is the same as last dose 
date then impute last dose date.

Completely missing date – do not impute.
The imputation of dates will be used to decide if an observation is treatment emergent for 
adverse events or concomitant medications.  The imputed dates are not used to calculate 
durations. Where partial dates occur, listings will contain the date collected in the partial form.
3.5.3
Adverse Events
The definitions of adverse events (AEs) and serious AEs (SAEs) are given in Sections 6.1 and 
6.2 of the clinical study protocol.  AEs and SAEs will be collected throughout the study, from 
date of informed consent until 30 days after the last dose of study treatment (or end of follow-
up period). Events will be defined as treatment emergent if they onset, or worsen (by 
investigator report of a change in intensity), on or after the first dose date, and up to and 
including 30 days following the date of last dose of study medication. The Medical Dictionary 
for Regulatory Activities (MedDRA) (using the latest or current MedDRA version) will be 
used to code the AEs. AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for AEs (CTCAE Version 4.03).
Other significant Adverse Events (OAE)
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs or discontinuations of IP due to AEs (DAEs). 
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 AEs 
(OAEs) and reported as such in the Clinical Study Report. A similar review of laboratory/vital 
signs/ECG data will be performed for identification of OAEs.
AEs of special interest
Adverse events of special interest (AESI) are events of scientific and medical interest specific 
to the further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. An AESI may be serious or non-serious.
Adverse events of special interest for olaparib are:

Important Potential Risks of MDS/AML

New primary malignancy (other than MDS/AML)

Pneumonitis
3.5.4
Concomitant medications
Concomitant medications will be classified according to the current version of the WHO Drug 
Dictionary.


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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.
3.5.5
Laboratory assessments
Blood samples for determination of clinical chemistry, hematology and coagulation will be 
taken at each scheduled visit and urine samples to determine urinalysis will be taken at 
screening and Day 1 visits. The laboratory parameters to be collected are given in Section 
5.2.1 of the protocol.
3.5.6
Exposure
Study drug exposure (days) for olaparib will be defined as time from first dose of olaparib, up 
to and including the, last day of dosing of olaparib.  Exposure to investigators choice of 
enzalutamide or abiraterone acetate will be calculated in the same way using enzalutamide or 
abiraterone acetate only.  Exposure to prednisone/prednisolone will not be calculated. 
Exposure will be defined as:
Last dose date – first dose date + 1.
Exposure to olaparib for patients randomised to investigator choice of treatment, who have 
subsequently switched to olaparib upon progression will be defined as:
Last dose date of olaparib – first dose date of olaparib + 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.
Actual exposure of olaparib/investigators choice of NHA:

Actual exposure = intended exposure – total duration of dose interruptions, where 
intended exposure will be calculated as above and a dose interruption is defined as 
any length of time where the patient has not taken any of the planned daily dose.
Missed or forgotten doses
Missed and forgotten doses should be recorded on the EX, EX1 and EX2 modules for 
olaparib, enzalutamide and abiraterone respectively as drug interrupted with the reason 
recorded as “Subject forgot to take dose”. These missed or forgotten doses will not be 
included as dose interruptions in the summary tables but the information will appear in the 
listing for dosing.  However, these missed and forgotten doses will be considered in the 
derivation of actual exposure.


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Safety Follow-up
Total Safety Follow-up = min((last dose date + 30 days), date of withdrawal of consent, date 
of death, date of DCO, date of first dose of subsequent anti-cancer therapy) – first dose date 
+1.
3.5.7
Dose intensity
Relative dose intensity (RDI) is the percentage of the actual dose delivered relative to the 
intended dose through to treatment discontinuation. RDI will be defined as follows:

RDI = 100% * d/D, where d is the actual cumulative dose delivered up to the actual 
last day of dosing and D is the intended cumulative dose up to the or the actual last 
day of dosing. D is the total dose that would be delivered, if there were no 
modification to dose or schedule. 
Percentage intended dose (PID) is the percentage of the actual dose delivered relative to the 
intended dose through to progression.  PID will be defined as follows:

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.
Intensity of olaparib, enzalutamide, and abiraterone acetate will be summarised separately. 
The intended cumulative dose is defined as 300mg olaparib twice daily, 160mg enzalutamide
once daily and 1000mg abiraterone acetate once daily.
3.5.8
Vital signs
Vital signs, including BP (mmHg), pulse rate (beats/minute), body temperature (°C) and 
weight (kg), will be assessed at screening, baseline and as clinically indicated and will be 
summarized at baseline. Changes in vital signs should be recorded as an AE, if applicable.
3.5.9
Physical examination
Physical examination assessments will be performed at screening, day 1 and as clinically 
indicated.
3.5.10
ECG
Resting 12-lead ECGs will be performed within 7 days prior to starting study treatment and 
when clinically indicated. Measurements should be taken after the patient has been rested in a 
supine position for at least 5 minutes. All ECGs will be assessed locally to determine whether 
they are clinically significantly abnormal / not clinically significantly abnormal. If there is a 
clinically significant abnormal finding, it will be recorded as an AE by the Investigator. 


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4.
ANALYSIS METHODS
4.1
General principles
The DCO date for the statistical analysis for the primary objective of the study will be when 
approximately 143 rPFS events in Cohort A, are expected to have occurred.
This study is comparing olaparib to investigators choice of NHA. Results of statistical 
analyses will be presented using corresponding 2-sided 95% confidence intervals and 2-sided 
p-values, where appropriate.
Efficacy data will be summarised and analysed on the full analysis set.  Safety data, including 
exposure data, will be summarised and analysed on the safety population. Study population 
and demography data will be summarised on the full analysis set.
Descriptive statistics will be used for all variables, as appropriate. Continuous variables will 
be summarised by the number of observations, mean, standard deviation, median, upper and 
lower quartiles, 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 and for each treatment group and will be rounded to 1 
decimal place. 
For continuous data, the mean and median will be rounded to 1 additional decimal place 
compared to the original data. The standard deviation will be rounded to 2 additional decimal 
places compared to the original data. Minimum and maximum will be displayed with the same 
accuracy as the original data. 
All analyses will be performed in SAS version 9.2 or later.
In general, for efficacy endpoints the last non missing measurement prior to randomization 
will be considered the baseline measurement. However, if an evaluable assessment is only 
available after randomization but before the first dose of randomized treatment then this 
assessment will be used as baseline. For safety and PRO endpoints, the last observation before 
the first dose of study treatment will be considered the baseline measurement unless otherwise 
specified. For assessments on the day of first dose where time is not captured, a nominal pre-
dose indicator, if available, will serve as sufficient evidence that the assessment occurred prior 
to first dose. If neither time nor a nominal pre-dose indicator are present assessments will be 
considered pre-dose if such procedures are required by the protocol to be conducted before 
first dose. 
In all summaries change from baseline variables will be calculated as the post-treatment value 
minus the value at baseline. The percentage change from baseline will be calculated as 
(postbaseline value - baseline value) / baseline value x 100.


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4.2
Analysis methods
Table 14
Pre-planned statistical and sensitivity analyses to be conducted 
Endpoints analysed
Cohort
Notes
Radiologic progression-free survival
Cohort A
Cohort B
Cohort A+B

Stratified log-rank test: 
-Primary analysis (based on BICR 
[RECIST 1.1 and PCWG3] assessments 
and stratified in accordance with the 
pooling strategy defined in section 4.2.2

Hazard ratio using Cox proportional 
hazards model (with ties=Efron and the 
stratification variables determined by the 
pooling strategy as covariates)

Plots and summaries of number (%) 
patients with progression or death events 
using Kaplan-Meier (KM) method.

Stratified log tank test and cox proportional 
hazards model will be repeated for 
confirmed FMI F1CDx patients and 
confirmed myriad gBRCAm patients.

KM plot will be produced for confirmed 
FMI F1CDx patients and confirmed myriad 
gBRCAm patients.
rPFS sensitivity analysis: 
(a) Evaluation-time bias
(b) Attrition bias
(c) Censoring bias
(d) Ascertainment bias
(e) Sensitivity analysis using unequivocal 
clinical progression in addition to 
radiological progression
(f)
Sensitivity analysis for confirmation of 
bone progression
(g) Sensitivity analysis censoring patients 
with subsequent therapy or 
discontinuation of study drug
Cohort A
Cohort B
Cohort A+B

Stratified log-rank test stratified in 
accordance with the pooling strategy (all 
sensitivity analyses except for censoring 
bias)

Hazard ratio using Cox proportional 
hazards model with ties=Efron and the 
stratification variables determined by the 
pooling strategy as covariates (all 
sensitivity analyses except for censoring 
bias)

KM plot (censoring bias and ascertainment 
bias only)


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Endpoints analysed
Cohort
Notes
rPFS subgroup analysis (based on BICR 
assessments):

Previous taxane use (yes, no)

Measurable disease at baseline (yes, no)

Metastases at baseline: bone only vs 
visceral vs other

ECOG performance status at baseline 
(0, 1, or 2)

Age at randomisation (<65, ≥65)

Region (Asia, Europe, North and South 
America)

Race (White, Black/African-American, 
Asian, Other) 

Baseline PSA (above/below median 
baseline PSA of the patients across both 
treatment groups)
Cohort A
Cohort A+B

HRs and associated 2-sided CIs will be 
estimated using a Cox proportional hazards 
model (with the Efron method being used 
for handling ties) that contains the 
treatment term, factor and treatment-by-
factor interaction term

If there are less than 5 events across both 
treatment arms in a subgroup then 
descriptive statistics will be provided 
instead.

KM plots for the following subgroups:

Previous taxane use (yes, no)

Measurable disease at baseline (yes, no)

Metastases at baseline: bone only vs 
visceral vs other

Baseline PSA (above/below median 
baseline PSA of the patients across both 
treatment groups)
rPFS subgroup analysis (based on BICR 
assessments):
HRR gene mutations in the full analysis set 
and confirmed FMI F1CDx patients:

BRCA1 and/or BRCA2

BRCA1 and/or BRCA2 and/or ATM

BRCA1 and/or BRCA2 and/or ATM
and/or CDK12

BARD1 and/or BRIP1 and/or CHEK1
and/or CHEK2 and/or FANCL and/or 
PALB2 and/or PPP2R2A and/or 
RAD51B and/or RAD51C and/or 
RAD51D and/or RAD54L

BRCA1 and/or BRCA2 and/or CDK12

Any single HRR mutation 

Each individual gene in patients with 
single HRR gene mutations only 
HRR gene mutations in confirmed myriad 
gBRCAm patients:

BRCA1 only

BRCA2 only
Cohort A+B

HRs and associated 2-sided CIs will be 
estimated using a Cox proportional hazards 
model (with the Efron method being used 
for handling ties) that contains the 
treatment term, factor and treatment-by-
factor interaction term

If there are less than 5 events across both 
treatment groups in a subgroup then 
descriptive statistics will be provided 
instead.

KM plots for all combinations of  HRR 
gene mutations in the full analysis set only.


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Endpoints analysed
Cohort
Notes
Confirmed objective response rate

BICR assessment using RECIST and 
bone scan data

BICR assessment using RECIST soft 
tissue only

Investigator assessment using RECIST 
and bone scan data

Investigator assessment using RECIST 
soft tissue only
Cohort A
Cohort B
Cohort A+B

Odds ratio using logistic regression 
adjusted for prior taxane. If there are not at 
least 5 responses across both treatment 
groups, then a Fisher’s exact test using mid 
p-values will be used.

Logistic regression for confirmed ORR 
using BICR assessment (RECIST and bone 
scan data) will be repeated for confirmed 
FMI F1CDx patients and confirmed myriad 
gBRCAm patients.
Confirmed objective response rate subgroup 
analysis:

Each individual gene in patients with 
single HRR gene mutations only 
Cohort A+B

Odds ratio using logistic regression 
adjusting for treatment, factor and treatment 
by factor interaction
Unconfirmed objective response rate

BICR assessment using RECIST and 
bone scan data

BICR assessment using RECIST soft 
tissue only

Investigator assessment using RECIST 
and bone scan data

Investigator assessment using RECIST 
soft tissue only
Cohort A
Cohort B
Cohort A+B

Odds ratio using logistic regression 
adjusted for prior taxane. If there are not at 
least 5 responses across both treatment 
groups then a Fisher’s exact test using mid 
p-values will be used 
Time to pain progression:

All patients in FAS 

Patients in FAS who have not taken any 
analgesics at baseline
Cohort A
Cohort B
Cohort A+B

Stratified log rank test stratified in 
accordance with the pooling strategy

Hazard ratio using a Cox proportional 
hazards model (with ties=Efron and the 
stratification variables determined by the 
pooling strategy as covariates)

Plots and summaries of number (%) 
patients with events using KM method.

Stratified log tank test and cox proportional 
hazards model will be repeated for 
confirmed FMI F1CDx patients and 


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Endpoints analysed
Cohort
Notes
confirmed myriad gBRCAm patients.
Proportion of patients with pain
progression:

All patients in FAS 

Patients in FAS who have not taken any 
analgesics at baseline
Cohort A
Cohort B
Cohort A+B

Odds ratio using logistic regression 
adjusted for the stratification variables 
determined by the pooling strategy
Overall survival
Cohort A
Cohort B
Cohort A+B

Stratified log rank test stratified in 
accordance with the pooling strategy 

Hazard ratio using a Cox proportional 
hazards model (with ties=Efron and the 
stratification variables determined by the 
pooling strategy as covariates) 

Plots and summaries of number (%) 
patients with events using KM method.

Stratified log tank test and cox proportional 
hazards model will be repeated for 
confirmed FMI F1CDx patients and 
confirmed myriad gBRCAm patients.
Time to first Symptomatic Skeletal-Related 
Event
Cohort A
Cohort A+B

Stratified log-rank test stratified in 
accordance with the pooling strategy

Hazard ratio using a Cox proportional 
hazards model (with ties=Efron and the 
stratification variables determined by the 
pooling strategy as covariates)

Plots and summaries of number (%) 
patients with events using KM method.
Duration of Response:

Confirmed response

Unconfirmed response
Cohort A
Cohort B
Cohort A+B

Summarized using descriptive statistics

KM plots
Time to Opiate use for Cancer related Pain
Cohort A
Cohort A+B

Stratified log-rank test stratified in 
accordance with the pooling strategy

Hazard ratio using a Cox proportional 
hazards model (with ties=Efron and the 
stratification variables determined by the 


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Endpoints analysed
Cohort
Notes
pooling strategy as covariates)

Plots and summaries of number (%) 
patients with events using KM method.
Prostate Specific Antigen (PSA) Response
Cohort A
Cohort A+B

Summarized using descriptive statistics

Waterfall plots

Best percentage change from baseline

Percentage change from baseline at 
Week 12

Confirmed PSA best response presented 
with 95% CIs
Circulating Tumor Cell (CTC) conversion 
rate
Cohort A
Cohort A+B

Summarized using descriptive statistics

Waterfall plots

Best change from baseline

Best percentage change from baseline

Proportion of patients achieving CTC 
conversion at any time presented with 95% 
CIs
Time from randomization to second 
progression or death
Cohort A
Cohort A+B

Stratified log-rank test stratified in 
accordance with the pooling strategy

Hazard ratio using a Cox proportional 
hazards model (with ties=Efron and the 
stratification variables determined by the 
pooling strategy as covariates)

Plots and summaries of number (%) 
patients with events using KM method.


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Endpoints analysed
Cohort
Notes
Time to deterioration in FACT-P (FACT-P 
total score, FACT-G total score, TOI, 
FAPSI-6, FWB, PWB, PCS)
Cohort A
Cohort A+B

Stratified log rank test stratified in 
accordance with the pooling strategy 

Hazard ratio using a Cox proportional 
hazards model (with ties=Efron and the 
stratification variables determined by the 
pooling strategy as covariates)

Forest plot
FACT-P (FACT-P total score, FACT-G 
total score, TOI, FAPSI-6, FWB, PWB, 
PCS)
Cohort A
Cohort A+B

Summary statistics by treatment group

Change from baseline using a MMRM 
which includes 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 and the stratification 
variables prior taxane and measurable 
disease as determined by the pooling 
strategy
FACT-P improvement rate (FACT-P total 
score, FACT-G total score, TOI, FAPSI-6, 
FWB, PWB, PCS)

Odds ratio using logistic regression 
adjusted for the stratification variables 
determined by the pooling strategy. If there 
are not at least 5 responses across both 
treatment groups then a Fisher’s exact test 
using mid p-values will be used.
BPI-SF (worst pain [Item 3], pain severity 
domain and pain interference domain)
Cohort A
Cohort A+B

Change from baseline using a MMRM 
which includes 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 and the stratification 
variables prior taxane and measurable 
disease as determined by the pooling 
strategy


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Endpoints analysed
Cohort
Notes
Time to pain severity

All patients in FAS 

Patients in FAS who have not taken any 
analgesics at baseline
Cohort A
Cohort A+B

Stratified log rank test stratified in 
accordance with the pooling strategy 

Hazard ratio using a Cox proportional 
hazards model (with ties=Efron and the 
stratification variables determined by the 
pooling strategy as covariates)

Plots and summaries of number (%) 
patients with events using KM method
Proportion of patients with pain severity

All patients in FAS 

Patients in FAS who have not taken any 
analgesics at baseline
Cohort A
Cohort A+B

Odds ratio using logistic regression 
adjusted for the stratification variables 
determined by the pooling strategy
Proportion of patients with pain palliation

All patients in FAS 

Patients in FAS who have not taken any 
analgesics at baseline
Cohort A
Cohort A+B

Odds ratio using logistic regression 
adjusted for the stratification variables 
determined by the pooling strategy
4.2.1
Multiplicity
The multiple testing procedure (MTP) (as shown in Figure 2) will define which significance 
levels should be applied to the interpretation of the raw p-values for the primary endpoint of 
rPFS and the key secondary endpoints. 
Hypotheses will be tested using a MTP with an alpha-exhaustive recycling strategy (Burman 
et al 2009). Upon achieving statistical significance on the primary endpoint rPFS in Cohort A, 
testing of each of the secondary endpoints, ORR (Cohort A), rPFS (Cohort A+B), time to pain 
progression (Cohort A), and overall survival (Cohort A) will be performed sequentially with 
the 2-sided 5% level of alpha recycled from the primary rPFS (Cohort A) endpoint. This 
testing procedure stops when the entire test mass is allocated to non-rejected hypotheses.  
Implementation of this pre-defined ordered testing procedure, including recycling, will 
strongly control type I error at 5% (2-sided), among all key hypotheses.
Note that two analyses of OS are planned:
1.
An initial look at the time of the primary rPFS analysis, and
2.
A final analysis at approximately 61% maturity.
Using an O’Brien-Fleming spending function, the initial look will use approximately 0.012 
one sided alpha level with 80% information fraction and a final OS analysis will use as alpha 
level of 0.021 with approximately 146 events (61% maturity) estimated to occur 


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approximately 48 months after first patient randomized in the study. The actual information 
fraction will be calculated based on the observed number of OS events at the time of the initial 
look and the this will determine the one-side alpha level for the analysis.
Figure 2
Multiplicity strategy maintaining overall Type I error rate
4.2.2
Analysis of the primary efficacy variable (rPFS)
The primary analysis of radiologic progression-free survival will be performed when 
approximately 143 rPFS events (60% maturity) in cohort A have occurred based on BICR 
(RECIST 1.1 and PCWG3) assessment. 
The primary analysis will be based on the BICR assessment of rPFS using all scans regardless 
of whether they were scheduled or not. The hypothesis of superiority of olaparib compared to 
investigator choice will be tested using a log rank test with the Breslow method for handling 
ties, stratified by the variables determined by the pooling strategy described below. 
The effect of olaparib versus investigator choice of NHA will be estimated by the hazard ratio 
and corresponding 95% confidence interval. This analysis will be performed using a Cox 
Proportional Hazards Model with the Efron approach being used for handling ties and the 
stratification variables determined by the pooling strategy being used as covariates. The 2-
sided 95% confidence intervals will be calculated using the profile likelihood method and a 
HR less than 1 will favour olaparib.


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Any patients mis-stratified in the IVRS/IWRS will be included in the stratified log rank test 
using the baseline data collected in the IVRS/IWRS.
Although it is expected that there will be enough rPFS events in each strata (where strata are 
defined as categories formed from – prior taxane * measurable disease * treatment) to allow a 
meaningful analysis, if any stratum for either treatment arm contains less than 5 events, then a 
pooling strategy will be employed. The order of preference for pooling will be (prior taxane * 
treatment), (measurable disease * treatment), unstratified. In addition, for analyses on Cohort 
A+B, Cohort will be added as a stratification factor provided that the addition does not lead to 
<5 events in any strata. Prior taxane and measurable disease will use data collected via IVRS. 
The pooling strategy will be employed for Cohort A, Cohort B and Cohort A+B separately. 
All sensitivity analyses and secondary endpoints (except for ORR which only includes prior 
taxane) will use the same strata as the primary model, for that endpoint, unless there are <5 
events per stratum and then an unadjusted model will be used.
Kaplan-Meier (KM) 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-
and 12-month survival rate estimates).  Summaries of the number and percentage of patients 
experiencing an rPFS event, and the type of event (RECIST progression, PCWG-3 
progression, both or death) will also be presented.
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 producing plots of complementary log-log 
(event times) versus log (time) and, if these raise concerns, a time dependent covariate would 
be fitted (adding a treatment-by-time or treatment-by-ln(time) interaction term) to assess the 
extent to which this represents random variation. If qualitative non-proportionality is observed 
then using stratification rather than covariate adjustment will be considered.
Additionally, the rPFS endpoint will be analyzed in Cohort B and Cohort A+B as part of 
secondary analyses. The rPFS analysis, along with Kaplan Meier curves, will also be 
produced for confirmed FMI F1CDx patients and confirmed myriad gBRCAm patients in 
Cohort A, Cohort B and Cohort A+B. 
4.2.2.1
Subgroup analysis
Subgroup analyses will be conducted for rPFS endpoint. The purpose of the subgroup 
analyses is to assess the consistency of treatment effect across potential or expected prognostic 
factors. If there are too few responders or events available for a meaningful analysis of a 
particular subgroup (it is not considered appropriate to present analyses where there are less 
than 5 events across both treatment groups per subgroup), the relationship between that 
subgroup and the endpoint will not be formally analyzed. In this case, only descriptive 
summaries will be provided.
The following subgroups of the full analysis set in Cohort A and Cohort A+B will be analyzed 
for rPFS for stratification factors


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
Previous taxane use (yes, no)

Measurable disease at baseline (yes, no)
Values collected on the eCRF will be used to define subgroups for stratification factors.
Additional subgroups of interest include:

HRR gene mutations in the FAS , each individual gene, and pre-specified 
combinations:

BRCA1 and/or BRCA2 - Cohort A+B

BRCA1 and/or BRCA2 and/or ATM - Cohort A+B

BRCA1 and/or BRCA2 and/or ATM and/or CDK12 - Cohort A+B

BARD1 and/or BRIP1 and/or CHEK1 and/or CHEK2 and/or FANCL and/or 
PALB2 and/or PPP2R2A and/or RAD51B and/or RAD51C and/or RAD51D 
and/or RAD54L - Cohort A+B

BRCA1 and/or BRCA2 and/or CDK12 - Cohort A+B

Any single HRR mutation* - Cohort A+B

Each individual gene in patients with single HRR gene mutations only -
Cohort A+B
* This will include all patients who only have a single HRR gene mutation in the FAS. 
There will be two levels for this subgroup, patients with a single HRR gene mutation 
and patients who do not have a single HRR gene mutation i.e. patients with co-
mutations.
There will be two levels per subgroup (or gene for each individual gene category): yes 
and no (patients with specified HRR gene mutations and patients not confirmed to 
have specified gene mutations respectively).

Metastases at baseline: bone only vs visceral vs other - Cohort A and Cohort A+B

ECOG performance status at baseline (0, 1, or 2) - Cohort A and Cohort A+B

Age at randomisation (<65, ≥65) - Cohort A and Cohort A+B

Region (Asia, Europe, North and South America) - Cohort A and Cohort A+B

Race (White, Black/African-American, Asian, Other) - Cohort A and Cohort A+B

Baseline PSA (above/below median baseline PSA of the patients across both 
treatment groups) - Cohort A and Cohort A+B
The following subgroups will be analysed for confirmed FMI F1CDx patients: 


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
BRCA1 and/or BRCA2 - Cohort A+B

BRCA1 and/or BRCA2 and/or ATM - Cohort A+B

BRCA1 and/or BRCA2 and/or ATM and/or CDK12 - Cohort A+B

BARD1 and/or BRIP1 and/or CHEK1 and/or CHEK2 and/or FANCL and/or 
PALB2 and/or PPP2R2A and/or RAD51B and/or RAD51C and/or RAD51D 
and/or RAD54L - Cohort A+B

BRCA1 and/or BRCA2 and/or CDK12 - Cohort A+B

Any single HRR mutation* - Cohort A+B

Each individual gene in patients with single HRR gene mutations only -
Cohort A+B
* This will include all patients who only have a single HRR gene mutation for 
confirmed FMI F1CDx patients. There will be two levels for this subgroup, patients 
with a single HRR gene mutation and patients who do not have a single HRR gene 
mutation i.e. patients with co-mutations.
There will be two levels per subgroup (or gene for each individual gene category): yes 
and no (patients with specified HRR gene mutations and patients not confirmed to 
have specified gene mutations respectively). 
The following subgroups will be analysed for confirmed myriad gBRCAm patients in patients: 

BRCA1 only

BRCA2 only
There will be two levels per gene: yes and no (patients with specified HRR gene mutations 
and patients not confirmed to have specified gene mutations respectively). 
In each subgroup, the HRs for radiological progression by BICR (olaparib vs investigator 
choice of NHA) and associated 2-sided CIs will be estimated using a Cox proportional 
hazards model (with the Efron method being used for handling ties) that contains the 
treatment term, factor and treatment-by-factor interaction term. For all subgroups except the 
HRR gene mutation subgroups, the treatment effect HRs for each treatment comparison along 
with their confidence intervals will be obtained for each level of the subgroup from this single 
model. For the HRR gene mutation subgroups, the treatment effect HRs for each treatment 
comparison along with their confidence intervals will only be displayed for the subgroup level 
containing patients who have the specified HRR gene mutations.  The HRs and 95% CIs will 
be presented on a forest plot including the HR and 95% CI from the overall population (using 
the primary analysis). No adjustment to the significance level for testing of subgroups will be 
made since all these subgroup analyses will be considered exploratory as supportive of the 
primary analysis of rPFS. 
In addition, KM plots will be produced for the following subgroups in the full analysis set: 

Previous taxane use (yes, no) Cohort A and Cohort A+B


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
Measurable disease at baseline (yes, no) Cohort A and Cohort A+B

HRR gene mutations in the full analysis set, each individual gene, and pre-specified 
combinations:

BRCA1 and/or BRCA2 - Cohort A+B

BRCA1 and/or BRCA2 and/or ATM - Cohort A+B

BRCA1 and/or BRCA2 and/or ATM and/or CDK12 - Cohort A+B

BARD1 and/or BRIP1 and/or CHEK1 and/or CHEK2 and/or FANCL and/or 
PALB2 and/or PPP2R2A and/or RAD51B and/or RAD51C and/or RAD51D 
and/or RAD54L - Cohort A+B

BRCA1 and/or BRCA2 and/or CDK12 - Cohort A+B

Any single HRR mutation - Cohort A+B

Each individual gene in patients with single HRR gene mutations only -
Cohort A+B

Metastases at baseline: bone only vs visceral vs other - Cohort A and Cohort A+B

Baseline PSA (above/below median baseline PSA of the patients across both 
treatment groups) - Cohort A and Cohort A+B
Consistency of treatment effect between subgroups
The presence of quantitative interactions will be assessed by means of an overall global 
interaction test. This will be performed in the overall population by comparing the fit of a Cox 
proportional hazards model including treatment, all covariates (stratification factors), and all 
covariate-by-treatment interaction terms, with one that excludes the interaction terms. This 
will not include the HRR mutation subgroups. This will be assessed at the 2-sided 10% 
significance level. If the fit of the model is not significantly improved then it will be 
concluded that overall the treatment effect is consistent across the subgroups.
If the global interaction test is found to be statistically significant, an attempt to determine the 
cause and type of interaction will be made. Stepwise backwards selection will be performed 
on the saturated model, whereby (using a 10% level throughout) the least significant 
interaction terms are removed one-by-one and any newly significant interactions re-included 
until a final model is reached where all included interactions are significant and all excluded 
interactions are non-significant. All main effects will be included in the model regardless of 
whether the corresponding interaction term is still present. This approach will identify the 
factors that independently alter the treatment effect and prevent identification of multiple 
correlated interactions. The p-values reported will represent those from the final model 
resulting from stepwise backwards selection; the 'selection model'.  
Any quantitative interactions identified using this procedure will then be tested to rule out any 
qualitative interaction using the approach of Gail and Simon (Gail and Simon 1985).


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4.2.2.2
Sensitivity analysis
Sensitivity analyses may be performed to assess the possible presence of time-assessment bias 
(i.e., 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. For all sensitivity analyses, the same methodology 
and model will be used as per the primary rPFS analysis, including stratification factors in 
accordance with the final pooling strategy. The HR and associated 95% CI will be reported. 
Median rPFS will be presented by treatment group.
The following sensitivity analyses will be evaluated:
(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 PCWG3) 
will be analyzed as described for the primary analysis of rPFS. The previous evaluable 
assessment will be the latest of the previous RECIST 1.1 assessment or previous bone scan 
assessment. Note that midpoint values resulting in non-integer values should be rounded 
down. For patients whose death was treated as a rPFS event, the date of death will be used to 
derive the rPFS time used in the analysis.  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 tumor 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, where the last evaluable assessment is the latest of the previous RECIST 1.1 
assessment or previous bone scan assessment.
(c) Censoring bias
A KM plot of the time to censoring will be produced where the censoring indicator of the
primary rPFS analysis is reversed.
(d) Ascertainment bias
Analysis of rPFS will be based on investigator assessment. A KM plot will also be produced 
for investigator assessment. 
(e) Sensitivity analysis using unequivocal clinical progression in addition to radiological 
progression


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Repeating primary rPFS analysis based on BICR assessed RECIST and bone scan data with 
the addition of unequivocal progression as an event. Where unequivocal clinical progression is 
defined as, cancer pain requiring initiation of opioids, need to initiate cytotoxic chemotherapy, 
radiation therapy or surgical intervention for complications due to tumor progression or 
deterioration in ECOG performance to >= Grade 3. Unequivocal clinical progression will be 
determined using the dose discontinuation module (DOSDISC) where patients discontinue 
due to “Unequivocal clinical progression”.
(f) Sensitivity analysis for confirmation of bone progression
Repeat primary rPFS analysis based on BICR assessed RECIST and bone scan data with 
revised confirmation criteria for bone progression where bone progression accompanied by 
unequivocal clinical progression does not require a confirmatory bone scan. Unequivocal 
clinical progression will be determined using the dose discontinuation module (DOSDISC)
where patients discontinue due to “Unequivocal clinical progression”.
(g) Sensitivity analysis censoring patients with subsequent therapy or discontinuation of study 
drug
Repeat primary rPFS analysis censoring patients with subsequent therapy or discontinuation 
of study drug prior to progression (censoring at the earliest date of the first day of subsequent 
therapy or the last day of study drug).
As a key sensitivity analysis to the primary endpoint of rPFS, the primary analysis will be 
repeated excluding any patients who did not have a qualifying gene mutation confirmed 
positive by the FMI F1CDx or the Myriad gBRCAm test (where these tests have been 
performed to support companion diagnostic development), see section 4.2.2. Similarly, the 
analysis will be repeated in all the 15 HRR qualifying gene mutations (Cohort A+B), see 
section 4.2.2.1 for specification of these outputs.
4.2.3
Analysis of secondary variables 
Analyses of secondary endpoints will be performed at the time of the primary rPFS analysis 
including an interim analysis for OS. The final analysis of OS will occur upon achieving 
approximately 146 deaths (61% maturity) in Cohort A.
All time to event analyses in Cohort A, B and A+B will be conducted in accordance with the 
final pooling strategy for stratification factors in the primary analysis of rPFS, where less than 
5 events for a time to event endpoint within each stratum, will result in collapsing of strata 
until the minimum 5 event criterion is achieved. Unstratified analyses will be conducted for 
any secondary endpoints that still do not conform to the 5 event rule per stratum. This will 
also be supported by unstratified sensitivity analyses of the primary endpoint. Additional 
sensitivity analyses may also be conducted as required.


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4.2.3.1
Confirmed Objective response rate (ORR)
Objective response rate will be assessed based on BICR assessed RECIST and bone scan data 
(using all scans regardless of whether they were scheduled or not) in patients in the EFR 
analysis set (patients with measurable disease at baseline determined by BICR) .
The ORR will be compared between olaparib and investigator choice using a logistic 
regression model adjusting for previous taxane (yes, no) collected via IVRS. The results of the 
analysis will be presented in terms of an odds ratio, with an odds ratio greater than 1 favouring 
olaparib, together with the associated 95% profile likelihood CI and p-value (based on twice 
the change in log-likelihood resulting from the addition of a treatment factor to the model). A 
statistically significant difference in ORR will be demonstrated using a 2-sided 5% alpha level 
based on the multiplicity strategy described in section 4.2.1.
If there are not at least 5 responses across both treatment groups then a Fisher’s exact test 
using mid p-values will be presented. The mid-p-value modification of the Fisher exact test 
amounts to subtracting half of the probability of the observed table from Fisher's p-value.
Fisher’s exact test mid p-value = Two sided p-value – (Table probability ÷ 2)
Summaries of number (%) of patients with a tumor response (BICR and investigator 
assessment of CR or PR) will be presented.
Best objective response (BOR) will be assessed based on BICR assessed RECIST and bone 
scan data in patients in the EFR analysis set (patients with measurable disease at baseline 
determined by BICR) in the full analysis set. For each treatment group BOR will be 
summarised by n (%) of patients for each category (CR, PR, SD, PD and NE), no formal 
statistical analyses for BOR are planned. For patients with a BOR of SD, the number and 
percentage of patients who had an unconfirmed response of CR/PR will be displayed. BOR 
will be repeated based on soft tissue response only using RECIST 1.1. 
Analysis of ORR will be performed in Cohorts A, B and A+B for the EFR analysis set.  
Additionally, analysis of soft tissue ORR will be performed in Cohorts A, and A+B for the 
EFR analysis set.  All ORR analyses will be repeated for patients with an unconfirmed 
response of CR/PR. 
All analyses will be repeated using investigator assessed response for patients in the EFR 
analysis set (patients with measurable disease at baseline determined by investigator 
assessment).
The confirmed ORR logistic regression will also be produced for confirmed FMI F1CDx 
patients and confirmed myriad gBRCAm patients. 
Subgroup analysis


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The analysis of confirmed ORR will be repeated in Cohort A+B EFR set using the logistic 
regression methodology above adjusting for treatment, factor and treatment by factor 
interaction for the following subgroup:

Each individual gene in patients with single HRR gene mutations only 
There will be two levels per gene, yes and no (patients with specified HRR gene mutation and 
patients not confirmed to have specified gene mutation respectively). The results of the 
analysis will be presented in terms of an odds ratio, with an odds ratio greater than 1 favouring 
olaparib, together with the associated 95% profile likelihood CI. No adjustment to the 
significance level for testing of subgroups will be made since all these subgroup analyses will 
be considered exploratory as supportive of the confirmed ORR analysis.
If there are not at least 5 responses across both treatment groups for a subgroup, then the 
relationship between that subgroup and the endpoint will not be formally analyzed. In this 
case, only descriptive summaries will be provided.
4.2.3.2
Time to pain progression (TTPP)
Time to pain progression will be analyzed at the time of the primary rPFS analysis using the 
same methods as in the analysis of rPFS. The HR and 95% confidence interval will be based 
on the cox proportional hazards model and the p-value on the stratified log rank test stratified 
in accordance with the pooling strategy described in section 4.2.2 with previous taxane and 
measurable disease as stratification variables. A 2-sided 5% alpha level will be used to test 
time to pain progression based on the multiplicity strategy. 
TTPP will also be assessed in the subgroup of patients who have not taken any analgesics at 
baseline. In addition, TTPP will be produced for confirmed FMI F1CDx patients and 
confirmed myriad gBRCAm patients. 
A KM plot of time to pain progression will be presented by treatment group. Summaries of the 
number and percentage of patients experiencing pain progression will be provided along with 
median time to pain progression for each treatment arm.
The proportion of patients with pain progression will be compared between olaparib and 
investigator choice using logistic regression adjusting for the stratification variables 
determined by the pooling strategy. The results of the analysis will be presented in terms of an 
odds ratio, with an odds ratio less than 1 favouring olaparib, together with the associated 95% 
profile likelihood CI and p-value (based on twice the change in log-likelihood resulting from 
the addition of a treatment factor to the model). If there are not at least 5 responses across both 
treatment groups then a Fisher’s exact test using mid p-values will be presented. The mid-p-
value modification of the Fisher exact test amounts to subtracting half of the probability of the 
observed table from Fisher's p-value.
Fisher’s exact test mid p-value = Two sided p-value – (Table probability ÷ 2)
This will be repeated patients who are non-opiate users at baseline.


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Analysis of Pain progression will be performed in Cohorts A, B and A+B.
Missing data
Tabular summaries will be presented to show the percentage of randomized patients with one 
or more reconciled or unreconciled “Other” pain medication as well as all imputed OME 
values by assessment level for each visit for the full analysis set. Percentage of patients with 
imputed AQA values as applicable will be included in the summary tables. 
The sensitivity and robustness of the imputation approaches will be assessed by producing a 
listing of all patients with one or more imputed OME values. The listing will include: 
i)
Highest OME value of pre-selected pain medications from Master List 
ii)
Highest OME value of reconciled “Other” pain medication
iii)
Highest imputed OME value of unreconciled “Other” pain medication.
4.2.3.3
Overall survival
Analysis of the secondary efficacy endpoint overall survival will be performed at the time of 
the primary analysis of rPFS with approximately 117 (49%) events in Cohort A expected at 
this point in time and will be considered an interim OS analysis. As per the multiplicity 
strategy, testing of the OS endpoint will utilize the alpha level recycled from rPFS primary 
endpoint and the secondary endpoints ORR (Cohort A), rPFS (Cohort A+B), and time to pain 
progression (Cohort A) using a 2-sided 5% alpha spend. 
The p-value will be based on the stratified log rank test stratified in accordance with the 
pooling strategy described in section 4.2.2 . HR and 95% CI will be based on the Cox model.
A KM plot of OS will be presented by treatment group. Summaries of the number and 
percentage of deaths and those alive and censored will be provided along with median time to 
death for each treatment arm.
An interim overall survival analysis will take place at the time of the primary rPFS analysis, 
and a final OS analysis will happen when approximately 146 (61%) of events have occurred. 
Note that if OS is not tested at the initial look then no formal testing of OS will occur at the 
final analysis of OS.
Exploratory analyses of OS in Cohort A, 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 (IPCW) 
(Robins 1993) and other methods in development may 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.


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Overall survival analysis will be performed in Cohorts A, B, and A+B. Overall survival 
analysis (not including the KM plot) will be repeated for the subset of patients positive by 
F1CDx and myriad gBRCAm. The subgroup analyses specified for rPFS will be repeated for 
OS for the final analysis only. 
4.2.3.4
Time to first Symptomatic Skeletal-Related Event (SSRE)
Time to SSRE will be analyzed using the same methods as in the analysis of the primary 
endpoint rPFS.
A KM plot of time to SSRE will be presented by treatment group. Summaries of the number 
and percentage of patients with symptomatic skeletal related events and those who are 
censored will be provided along with median time to symptomatic skeletal related events for 
each treatment arm for Cohort A and Cohort A+B only.
4.2.3.5
Duration of Response
Duration of response will be assessed in patients in the EFR analysis set (patients with 
measurable disease at baseline determined by BICR) for Cohorts A, B and A+B. 
Descriptive data will be provided for the duration of response in responding subjects, 
including the associated KM curves (without any formal comparison of or p-value attached). 
Descriptive data for onset of response will also be provided. DoR will be repeated for patients 
with an unconfirmed response. 
4.2.3.6
Time to Opiate use for Cancer related Pain
Time to opiate use will be analyzed at the time of the primary rPFS analysis using the same 
methods as in the analysis of rPFS. The, p-value will be based on the stratified log rank test 
stratified in accordance with the pooling strategy described in section 4.2.2 HR and 95% CI 
will be based on the Cox model. A 2-sided 5% alpha level will be used to test time to opiate 
use based on multiplicity strategy.
A KM plot of time to opiate use will be presented by treatment group. Summaries of the 
number and percentage of subjects using opiates will be provided along with median time to 
opiate use for each treatment arm.
Time to opiate use analysis will be performed in Cohort A and Cohort A+B only.
4.2.3.7
Prostate specific antigen (PSA) response
Proportion of patients achieving a PSA response and patients with a confirmed PSA response 
will be presented with 95% CIs. Best PSA percentage change from baseline will be 
summarized as continuous variables using descriptive statistics and will be graphically 
displayed using waterfall plots for Cohort A and Cohort A+B only. In addition percentage 
change from baseline at Week 12 will be summarized as continuous variables using 
descriptive statistics and will be graphically displayed using waterfall plots for Cohort A and 
Cohort A+B only. 


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For the Week 12 visit, a window of +/- 7 days will be applied to the scheduled visit Day 85. If 
there is more than one value per patient within the time window, then the closest value to the 
scheduled visit date will be summarised.
4.2.3.8
Circulating Tumor Cell (CTC) conversion rate
Proportion of patients achieving a CTC conversion will be presented with 95% CIs. 
Best change from baseline and best percentage change from baseline in CTC counts will be 
summarized as continuous variables using descriptive statistics and will be displayed 
graphically using waterfall plots for Cohort A and Cohort A+B only.
4.2.3.9
Time from randomization to second progression or death (PFS2)
Time from randomization to second progression or death will be analysed using the same 
methods as in the analysis of the primary endpoint rPFS. The HR and corresponding 95% 
confidence interval will be based on the Cox model including the stratification variables 
determined by the pooling strategy as covariates. 
A KM plot of time to second progression or death will be presented by treatment group. 
Summaries of the number and percentage of patients with second progression or death and 
those who are censored will be provided along with median time to second progression or 
death for each treatment arm for Cohort A and Cohort A+B only.
4.2.3.10
FACT-P
Summary statistics for FACT-P (FACT-P Total score, TOI, FACT-G, FWB, PWB, PCS and 
FAPSI 6) score will be presented by treatment group (including means, standard deviation, 
median and range) for all visits until there are less than the minimum of 20 or 1/3 of patients 
dosed with evaluable data. Absolute and change from baseline scores for each time point will 
be calculated for each treatment group. 
The proportion of patients with best responses of ‘Improved’, ‘No Change’ and “Worsened” 
on FACT-P total score and subscales (FWB, PWB, PCS, FAPSI 6, FACT-G) scores including 
TOI will be compared between treatments using logistic regression with the same methods 
and covariates as for the logistic regression analysis of pain progression in section 4.2.3.2.
The analysis of FACT-P (FACT-P Total score, TOI, FACT-G, FWB, PWB, PCS and FAPSI 
6) will be performed in Cohort A and Cohort A+B only.
FACT-P compliance (overall compliance and by visit compliance) will be summarised for 
each treatment group
Supportive analyses
Supportive analyses will be performed for the FACT-P total score, and scales (FACT-G total 
score, TOI, FAPSI-6, FWB, PWB, PCS). Compliance will be analysed for the FACT-P total 
only.


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Change from baseline in the FACT-P total score, and scales (FACT-G total score, TOI, 
FAPSI-6, FWB, PCS) will be analyzed 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 and the stratification variables prior taxane and measurable disease determined by 
the pooling strategy described in section 4.2.2. Treatment, visit, treatment by visit interaction, 
baseline FACT-P total score, baseline FACT-P score by visit interaction, prior taxane and 
measurable disease 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 PRIOR MEASURE / 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, BL is the baseline FACT-P total score, PRIOR is prior taxane use 
collected via IVRS and MEASURE is measurable disease at baseline collected via IVRS. 
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.
Finally, exploratory descriptive item analysis based on responses at each visit as appropriate 
will be summarized for overall impact of treatment side effects (FACT-P item GP5, “I am 
bothered by my side effects of treatment) in Cohort A and Cohort A+B.


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4.2.3.11
Pharmacokinetic analysis
The plasma concentration data will be listed within the clinical study report. The pre-dose and 
post-dose olaparib plasma concentrations will be summarized by nominal sample time, using 
summary statistics, as detailed below: 

Number of observations (n)

n > lower limit of quantification (LLOQ)

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 (using non log-transformed data)

%CV (using non log-transformed data)

Median

Minimum (min)

Maximum (max)
Reporting of plasma concentrations that are Below Limit of Quantification (BLQ) 
Individual olaparib and abiraterone concentrations below their 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 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, 
%CV, Amean and standard deviation will be set to Not Calculable (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 standard deviation, 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.


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Three observations > LLOQ are required as a minimum for a plasma concentration to be 
summarised. Two values are presented as a minimum and maximum with the other summary 
statistics as NC.
4.2.4
Concordance between BICR and investigator assessments
4.2.4.1
Concordance between BICR and investigator assessments for rPFS
Concordance between BICR and investigator assessments for rPFS will be summarised by 
concordance status (concordant or discordant) and type of concordance (according to timing 
and type of progression event (RECIST and/or bone scan) by treatment group and overall. 
The concordance rate will be derived as the proportion of patients where BICR and 
investigator have agreed on rPFS status (event or censored).
4.2.4.2
Concordance between BICR and investigator assessments for Overall 
Radiological Objective Response
Concordance between BICR and investigator assessments for best radiological objective 
response status (response [CR and PR] or non-response [SD, PD, NE and non-PD] categories) 
and best radiological objective response type (CR, PR, SD, PD, NE and non-PD), according to 
RECIST1.1 criteria and bone progression status (according to PCWG3 criteria) will be 
summarised in a shift table by treatment group and overall for subjects with measurable 
disease (as determined by BICR).
The concordance rate will be derived as the proportion of patients where BICR and 
investigator, have agreed on response [CR and PR] or non-response [SD, PD, NE and
non-PD].
A listing will be created including concordance between BICR and investigator reviews of 
overall visit response including progression type separately by BICR and investigator 
assessments, if responses between BICR and investigator assessments are concordant, 
summarised by subject, treatment group and visit.
4.2.5
Safety analysis
Safety analyses will be presented using the Safety Analysis Set and will be investigated using 
descriptive statistics. Safety profiles will be assessed in terms of AEs, vital signs (including 
BP and pulse rate), laboratory data (clinical chemistry and hematology), and physical 
examination.
Summaries will be presented for Cohort A+B and 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.
Summaries for patients who switch from investigators choice of NHA to olaparib following
objective disease progression will be summarised separately for Cohort A+B. 


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4.2.5.1
Adverse events
Adverse events will be summarized for Cohort A+B of the study and by treatment group. 
Separate summaries will be produced for Olaparib post switch from investigator choice.
All AEs, both in terms of MedDRA preferred term and CTCAE grade, will be listed and 
summarised descriptively by count (n) and percentage (%) and treatment group.  MedDRA 
dictionary will be used for coding.  Any AE occurring before olaparib/investigators choice of 
NHA (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 as will an overall summary of the number of episodes in each category. An overall 
summary of the number and percentage of patients in each category will be presented for 
confirmed FMI F1CDx patients and confirmed myriad gBRCAm patients.
Frequencies and percentages of patients reporting each preferred term will be presented. 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.  A 
separate listing will be produced for AEs that are on-going in patients who switch from 
investigator choice to olaparib at the start date of olaparib.
Summary information (the number and percent of patients by treatment) will be tabulated by 
system organ class (SOC), preferred term and treatment group for:

All AEs 

All AEs causally related to olaparib/ investigators choice of NHA

AEs with CTCAE grade 3 or higher

AEs with CTCAE grade 3 or higher, causally related to olaparib/ investigators 
choice of NHA

AEs with outcome of death

AEs with outcome of death causally related to olaparib/ investigators choice of 
NHA

All SAEs

All SAEs causally related to olaparib/ investigators choice of NHA

AEs leading to discontinuation of olaparib/ investigators choice of NHA


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
AEs leading to discontinuation of olaparib, causally related to olaparib/investigators 
choice of NHA

AEs leading to dose reduction of olaparib/ investigators choice of NHA t

AEs leading to dose interruption of olaparib/ investigators choice of NHA

Other significant AEs

Other significant AEs causally related to olaparib/ investigators choice of NHA
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/ investigators choice of NHA

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. 
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 
4.03) 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.
AEs which started prior to first dose or > 30 days following date of last dose will be listed 
only.
Deaths
A summary of deaths will be provided with number and percentage of patients by cohort and 
actual treatment group categorised as:

Related to disease under investigation,


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
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, cohort and actual treatment group.
Causally related serious adverse events will be summarised for the number and percentage of 
patients by SOC, preferred term, cohort and actual treatment group.
Adverse events leading to discontinuation of olaparib/ investigators choice of NHA will be 
summarised for the number and percentage of patients by SOC, preferred term, cohort and 
actual treatment group for.
Causally related adverse events leading to discontinuation of olaparib/investigators choice of 
NHA will be summarised for the number and percentage of patients by SOC, preferred term, 
cohort and actual treatment group.
In addition, AEs with outcome of death, SAEs, OAEs, AEs leading to discontinuation of 
treatment and AEs causally related to olaparib/investigators choice of NHA will be listed in 
key patient information tables. 
Listings of AE data will also be produced.
Adverse events of special interest (AESI)
Preferred terms used to identify adverse events of special interest (as defined in section 3.5.3) 
will be listed before DBL and documented in the Study Master File. Grouped summary tables 
of certain MedDRA preferred terms will be produced and may also show the individual 
preferred terms which constitute each AESI grouping. Groupings will be based on preferred 


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terms provided by the medical team prior to DBL, and a listing of the preferred terms in each 
grouping will be provided. 
Summaries of the above-mentioned grouped AE categories will include number (%) of 
patients who have: 

At least one AESI presented by outcome 

At least one AESI causally related to study medication 

At least one AESI leading to discontinuation of study medication 
A summary of total duration (days) of AESI will be provided for events which have an end 
date and will be supported by summaries of ongoing AESIs at death and, separately, at data 
cut-off.
Summary of long term tolerability
To assess long term tolerability, provided that there are a sufficient number of patients with 
events to warrant it, prevalence plots, life table plots and cumulative incidence plots will be 
presented for each of the AESI grouped terms and 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 arm. 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. These plots will only be 
produced for AESIs that have ≥10 events.
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 
months, etc.) given that the patient reaches that time period without having an event is plotted 
for each time period split by treatment. These plots will only be produced for AESIs that have 
≥10 events.
A cumulative incidence plot is a plot of the raw cumulative incidence over time. 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. These plots will only be produced for AESIs 
that have ≥10 events.


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4.2.5.2
Laboratory assessments
Laboratory data (clinical chemistry and haematology) will be summarized. Shift tables will be 
provided for select tests, where shift from baseline to the worst value within the study will be 
summarized. Laboratory data outside the reference ranges will be indicated.
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, 
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/ investigators choice of NHA).  A 
scatter plot of alanine aminotransferase (ALT) versus total bilirubin, both expressed as 
multiples of upper limit of normal range, will be produced.  The scatter plot will be repeated 
for aspartate aminotransferase (AST) versus total bilirubin.
Shift tables and plots will be repeated for olaparib post switch from investigator choice, where 
the baseline is defined as the last observation before the first dose of olaparib (generally the 
measurement at the study treatment discontinuation visit).
4.2.5.3
Vital signs
Vital signs, including BP (mmHg), body temperature (°C), pulse (beats/minute) and weight 
(kg), will be summarized at baseline for Cohort A+B by treatment group, including a separate 
summary for patients who switch from investigators choice of NHA to olaparib. The baseline 
value is the last pre-dose assessment.
4.2.5.4
Exposure
Summaries of duration of exposure and cumulative exposure over time will be produced for 
Cohort A+B by treatment group.
The number of patients with study drug reductions, interruptions, or discontinuation and the 
reasons, will be summarised for Cohort A+B by treatment group.
These summaries will be repeated for the subset of patients who switch from investigators 
choice of NHA to olaparib.
These data will also be listed.
Summary statistics (mean, standard deviation, median, quartiles, minimum, maximum) will be 
presented for RDI and PID. 


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4.2.6
Concomitant medications
Concomitant medications will be summarized by the coded terms. The number of patients 
receiving a medication will be summarized for Cohort A+B FAS by treatment group. A 
medication taken from the start of the screening part 2 and onwards is considered 
concomitant. A patient is only counted once if receiving the medication more than once.
Disallowed medications will be summarised and listed.
4.2.7
Supportive analysis
4.2.7.1
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.
Resource use may be reported outside of the CSR.
4.2.7.2
Patient reported outcomes (PRO)
The Patient reported outcome endpoints, BPI-SF (Pain Severity domain), BPI-SF (Pain 
interference domain), Pain Palliation, AQA score, FACT-P (FACT-P Total score, FACT-G 
total score, TOI, FWB, PWB, PCS and FAPSI 6 and exploratory endpoints [EWB, SWB]), 
PRO-CTCAE and PGIC are described in Section 3.
The PRO endpoints that are continuous will be summarised using means, standard deviations, 
medians and ranges by treatment group and at each visit until there are less than the minimum 
of 20 or 1/3 of patients dosed with evaluable data. For the FACT-P total score, FACT-G total 
score, TOI, FAPSI-6, PCS, FWB, PWB, EWB, SWB, BPI-SF item #3 (worst pain in 24 
hours), pain severity (BPI-SF pain severity domain), pain interference and AQA score, 
absolute and change from baseline scores for each time point will be calculated for each 
treatment group. The absolute scores and change from baseline scores will also be 
summarised descriptively based on plots of unadjusted mean.
Responses on the PRO-CTCAE and PGIC will be summarised descriptively as number of 
patient and corresponding percentages for each category in the questionnaire at each visit by 
treatment group. PRO-CTCAE will be summarized for only patients in countries (Argentina 
Australia, Austria, Canada [English-speaking sites], Germany, Japan, Spain, United Kingdom 
and United States) where the questionnaire was administered.
Time to pain severity progression and the proportion of patients with pain severity will be 
analysed using the same methodology as in time to pain progression without any adjustments 
for multiplicity. This will be repeated for patients who are non-opiate users at baseline.


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Proportion of patients with pain palliation will be summarized with corresponding 95% 
confidence intervals. This will also be compared between olaparib and investigator choice 
using the same logistic regression model as pain progression (section 4.2.3.2). This will be 
repeated patients who are non-opiate users at baseline.
Time to deterioration in FACT-P (FACT-P Total score, FACT-G total score, TOI, FWB, 
PWB, PCS and FAPSI 6) will be analysed using the same methodology as in time to pain 
progression without any adjustments for multiplicity. Proportion of patients with deterioration 
in FACT-P scores will be summarized with corresponding 95% confidence intervals. The HRs 
and 95% CIs will be presented on a forest plot.
Summary measures of overall compliance and compliance over time will be derived 
separately for BPI-SF, FACT-P, PGIC, PRO-CTCAE.
Supportive analysis for BPI-SF (average BPI-SF worst pain [Item 3], average pain severity 
score and average pain interference score) will be analyses using the same methodology as the 
supportive MMRM described in section 4.2.3.10 for FACT-P.
The analysis of PRO endpoints will be performed in Cohort A and Cohort A+B only. The 
analysis will not include data after patients have received subsequent anti-cancer therapy. 
4.2.7.3
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.
EQ-5D-5L may be reported outside of the CSR.
4.2.8
Demographic and baseline data
The following collected data will be listed.

Patient disposition (received treatment and completed the study) 

Important deviations

Inclusion in analysis populations

Demographics (age, age group, race and ethnicity)
The following will be summarized for the full analysis set for Cohort A, B and A+B:

Patient disposition 

Important protocol deviations

HRR gene mutations (single gene mutations and co-mutations will be summarized)

Stratification factors according to the IVRS/IWRS and eCRF

Inclusion in analysis populations


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
Demographics (age, age group, race and ethnicity)

Patient characteristics at baseline (weight)

Patient recruitment by country and centre

Previous disease-related treatment modalities

Previous disease-related chemotherapy treatments

Previous/current/post treatment radiotherapy

Disease characteristics at baseline

Extent of disease at baseline

Demographic characteristics

Time from most recent disease progression to randomisation

Post-discontinuation disease-related anticancer therapy

Past/current medical history

Past medical history of opioid use

Relevant surgical history at baseline
The following will be summarized for confirmed FMI F1CDx patients and confirmed myriad 
gBRCAm patients for Cohort A, B and A+B:

Patient disposition 

HRR gene mutations (single gene mutations and co-mutations will be summarized)

Inclusion in analysis populations

Demographics (age, age group, race, ethnicity and weight)

Disease characteristics at baseline 
The following will be summarized for patients who switch from investigators choice of NHA 
to olaparib for Cohort A+B:

Patient disposition 
5.
INTERIM ANALYSES
An interim analysis of OS will be performed at the time of the primary rPFS analysis in 
Cohort A (approximately 35 months after first patient randomized into the study). 
Approximately 117 deaths (49% maturity) are expected to be accrued in Cohort A at the time 
of interim OS analysis. The alpha spending for the OS analysis is described in 4.2.3.3.
This study will use an external Independent Data Monitoring Committee (IDMC) to perform 
interim reviews of accumulating study safety data. The IDMC will not be involved in the 
interim analysis of OS because it is at the time of the primary rPFS analysis when the study 
will be unblinded.  This committee will be composed of two therapeutic area experts and a 
statistician, who are not employed by AZ, and do not have any major conflicts of interest. 
Following the review, the IDMC will recommend whether the study should continue 
unchanged, be terminated, or be modified in any way. Once the IDMC has reached a 
recommendation, a report will be provided to AstraZeneca. The report will only include the 


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recommendation and any potential protocol amendments and it will not contain any unblinded 
information or reference to the confidential considerations of the committee to have led to 
their recommendation. A separate IDMC charter will be developed which will contain details 
of the IDMC members and clearly define the responsibilities of the IDMC.
In addition to the periodic review of safety data by an IDMC, the safety of all AstraZeneca 
clinical studies is closely monitored on an on-going basis by AstraZeneca representatives in 
consultation with the Patient Safety Department. Issues identified will be addressed; this could 
involve, for instance, amendments to the study protocol and letters to investigators.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
Section 5.3.1.2 of the protocol details the FACT-P subscales and derivations. The SAP 
includes FACT-G in addition to the subscales outlined in the protocol. 
Section 8.3 of the protocol defines the safety analysis set. An additional safety analysis set has 
been added to the SAP for patients who switch from investigators choice of NHA to olaparib.
Section 8.4.1.1 states  that subjects who have not progressed (defined as CR, PR or SD by 
RECIST 1.1 for soft tissue disease, or non-PD for bone disease, see Section 5.1.2 and 
Appendix E) at the time of analysis will be censored at the time of the latest date of their last 
evaluable RECIST assessment or bone scan. However, if the subject progresses or dies after 2 
or more missed radiologic assessments, the subject will be censored at the time of the latest 
evaluable RECIST 1.1 or bone scan assessment prior to the two missed visits. The censoring 
approach has been updated in the SAP to take the earliest date of their last evaluable RECIST 
1.1 assessment (taking the latest target lesion, non-target lesion or new lesion scan date) or 
bone scan assessment that showed Non-PD.
Section 8.4.2.2 of the protocol defines 2 consecutive visits as being separated by 3-4 weeks. 
This has been updated in the SAP to state 2 consecutive visits (with at least 2 weeks between 
the end of the initial visit and the start of the subsequent visit). 
Section 8.4.2.4 of the protocol details that patients who have not experienced any 
symptomatic skeletal–related event will be censored at time of death, or time of analysis if the 
patient is living. This has been updated in the SAP to censor the patients at time of death, or 
time of last SSRE assessment.
Section 8.4.2.5 of the protocol details duration of response will be defined as the time from the 
date of first documented response (by BICR using RECIST 1.1 and PCWG3) until date of 
documented progression (by BICR) or death in the absence of disease progression. The text 
has been updated in the SAP to show patients must have a confirmed response. 
Section 8.4.2.10 of the protocol defines 2 consecutive visits as being separated by 3-4 weeks. 
This has been updated in the SAP to state 2 consecutive visits (with at least 2 weeks between 
the end of the initial visit and the start of the subsequent visit). 


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Section 8.4.2.12 of the protocol displays the definition of visit response for FACT-P, 
FAPSI-8, TOI, PCS and FWB.  The SAP has updated the criteria in this table and added 
FACT-G.
Section 8.4.2.13 of the protocol specifies the confirmation visit for pain palliation must be at 
least 3 weeks later. This has been updated in the SAP to 2 weeks instead of 3 weeks. 
Section 8.2.5 of the protocol specifics demographic and baseline characteristics will be 
summarized using the full analysis set, for Cohorts A and B of the study, respectively. This 
has been updated in the SAP to include Cohort A+B.
Section 8.5.8 of the protocol details adverse events and laboratory data will be summarised for 
Cohort A, Cohort B and Cohort A+B. This has been updated in the SAP to be produced for 
Cohort A+B only.
Section 8.5.8.4 of the protocol details concomitant medications will be summarised for Cohort 
A, Cohort B and Cohort A+B. This has been updated in the SAP to be produced for Cohort 
A+B only.
Section 8.5.8.7 of the protocol details listings and summaries for compliance and exposure 
will be produced for Cohort A, Cohort B and Cohort A+B. This has been updated in the SAP 
to be produced for Cohort A+B only. 
7.
REFERENCES
Burman et al 2009
Burman CF, Sonesson C, Guilbaud O. A recycling framework for the construction of 
Bonferroni based multiple tests. Stat Med 2009;28:739-61.
Cella et al 1993
Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, et al.  The Functional 
Assessment of Cancer Therapy scale: development and validation of the general measure.  
J Clin Oncol. 1993 Mar;11(3):570-9.
Cella et al 1994
Cella, D.F. Manual: Functional Assessment of Cancer Therapy (FACT) Scales and Functional 
Assessment of HIV Infection (FAHI) Scale, Chicago: Rush-Presbyterian-St Luke’s Medical 
Center. 1994.
Cella et al 2009
Cella D, Nichol MB, Eton D, Nelson JB, Mulani P.  Estimating clinically meaningful changes 
for the Functional Assessment of Cancer Therapy-Prostate: results from a clinical trial of 
patients with metastatic hormone-refractory prostate cancer. 
Value Health 2009; Jan-Feb;12(1):124-9.


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Study Code D081DC00007
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105
Chung et al 2014
Chung KC, Barlev A, Braun AH, Qian Y, Zagari M. Assessing analgesic use in patients with 
advanced cancer: development of a new scale--the Analgesic Quantification Algorithm. Pain 
Med 2014;15:225- 32.
Esper et al 1997
Esper P, Mo F, Chodak G, Sinner M, Cella DF, Pienta KJ. Measuring quality of life in men 
with prostate cancer using the Functional Assessment of Cancer Therapy-Prostate instrument. 
Urology 1997;50:920-8.
Pintilie
Pintilie M. Competing risks: A practical perspective. Wiley.
Robins et al 1991
Robins JM, Tsiatis AA. Correcting for noncompliance in randomised trials using rank 
preserving structural failure time models. Commun Stat Theory Methods. 1991; 20:2609-
2631.
Robins 1993
Robins J. Information recovery and bias adjustment in proportional hazards regression 
analysis of randomised trials using surrogate markers. Proceedings of the Biopharmaceutical 
Section, ASA. 1993; 24-33.
Sun and Chen 2010
Sun X, Chen C. Comparison of Finkelstein’s Method With the Conventional Approach for 
IntervalCensored Data Analysis. Stat Biopharm Res. 2010; 2:97-108 
8.
APPENDIX (NOT APPLICABLE)