Clinical trial NCT02476968
Conditions: BRCA or HRR+ Mutated Ovarian Cancer Patients
Sponsor: AstraZeneca
Start date: 2015-09-28; Completion date: 2021-12-17
Enrollment: 181 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective, open-label, single arm, multi-center study to assess the real world clinical effectiveness and safety of olaparib maintenance monotherapy as the capsule formulation (in line with the EU approved prescribing information) and will be conducted in platinum-sensitive relapsed high grade epithelial ovarian cancer patients (including patients with primary peritoneal and / or fallopian tube cancer) who carry germline or somatic BRCA mutations (documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious \[known or predicted to be detrimental/lead to loss of function\]).

Detailed description:
The study will recruit approximately 250 patients with sBRCAm disease or gBRCAm disease, with the aim to accrue a minimum of 50 patients with sBRCAm disease.

Patients with an unknown germline BRCA mutated status or gBRCAwt disease or previously identified as having a BRCAm disease by a tumour test will be considered for screening and will undergo, upon informed consent signature, central tumor and blood testing to determine their BRCA mutation status. In addition to central BRCA testing, patients screened for the study with unknown BRCA status or with known gBRCAwt status, for whom an adequate archival tumour tissue sample is available, will be tested for qualifying HRR gene alterations. Patients confirmed to carry a deleterious or suspected deleterious BRCA-independent genetic alteration in any of 13 genes involved in the Homologous Recombination Repair (HRR) pathway (HRRm cohort) will be allowed into an additional exploratory cohort (HRRm cohort). It is expected that approximately 25 patients will be included in the HRRm cohort before the target number of 250 patients with BRCAm disease is reached.

Patients will be assigned olaparib capsules orally 400 mg twice daily. They should initiate olaparib treatment within 8 weeks after their last dose of platinum-containing chemotherapy (last dose is the day of the last infusion) and will be assessed every 4 weeks whilst on treatment.

All patients will have clinical and objective radiological tumour assessments according to modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines at baseline and every 12 weeks relative to date of enrolment, until objective radiological disease progression as determined by the investigator. Patients could continue to receive olaparib for as long as determined by the investigator, until objective radiological disease progression or as long as in the investigator's opinion they are benefiting from treatment in relation to other clinical assessments and they do not meet any other discontinuation criteria. Once a patient has discontinued olaparib she will be managed as per local clinical practice but will remain in the study and data will be collected on subsequent treatments, progression, overall survival and safety.

For exploratory analysis purposes, patients will be asked to provide consent to:

1. Optional tumour samples at baseline and at disease progression
2. An optional blood sample only for patients with a confirmed sBRCAm or HRRm disease

Arms: arm 1: Open Label Drug
Interventions: intervention 1: Olaparib
Intervention descriptions: intervention 1: Olaparib Capsule - 50 mg. Olaparib capsules will be packed in high-density polyethylene (HDPE) bottles with child-resistant closures. Each bottle will contain 120 capsules and 4 bottles will be dispensed for a 4 weekly visit, with a 2 day overage.

Patients will be administered olaparib capsules orally at a dose of 400 mg twice daily.

Eight 50 mg olaparib capsules should be taken at the same time each day approximately 12 hours apart with approximately 240 mL of water.

Protocol documents:
Prot_000.pdf: 
 
 
 
Clinical Study Protocol  
 
Drug Substance 
Olaparib 
 
Study Code 
D0816C00012 
 
Edition Number 
3  
 
Date 
22 July 2016 
 
 
 
An Open Label, Single Arm, Multicentre Study to Assess the Clinical 
Effectiveness and Safety of Lynparza (Olaparib) Capsules Maintenance 
Monotherapy in Platinum Sensitive Relapsed somatic or germline BRCA 
Mutated Ovarian Cancer Patients who are in Complete or Partial Response 
Following Platinum based Chemotherapy (ORZORA) 
 
 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden.   
 
 
This document contains confidential commercial information, disclosure of which is prohibited without providing 
advance notice to AstraZeneca and opportunity to object. 
. 
 


 
 
VERSION HISTORY 
Protocol Edition Number 1, 06 February 2015 
Original Version 
Protocol Edition Number 2, 22 December 2015 
Refer to the Clinical Study Protocol Amendment Number 1.0 for description of change with 
reason. 
Protocol Edition Number 3, 20 July 2016  
Sections: 1.1.4 Homologous recombination repair defects; 5.7.2 Collection of tumour 
sample for HRR testing; 5.7.4 Exploratory use of data generated from 
 
 Central testing of tumour sample (Optional)  
Description of change with reason: new sections added to describe and incorporate new 
exploratory cohort. This exploratory cohort is comprised of patients who carry deleterious 
or suspected deleterious BRCA-independent genetic alteration in any of 13 genes involved 
in the Homologous Recombination Repair (HRR) pathway (HRRm cohort). The real world 
clinical effectiveness and safety of olaparib maintenance therapy will be described for this 
exploratory HRRm cohort. 
 
Sections: 1.2 Research hypothesis; 1.3 Rationale for study design and doses; 1.4 
Benefit/risk and ethical assessment; 1.5 Study Design; Figure 1 Study Flow Chart; 3 Patient 
Selection, Enrolment, Restrictions, Discontinuation and Withdrawal; Figure 2 Screening 
Flow Chart; 5.7.1 Collection of tumour sample for BRCA testing at screening (mandatory); 
5.7.3 Collection of tumour sample for exploratory analysis at screening and at disease 
progression (optional); 5.7.7 Guidance for BRCA and HRR testing  
Description of change with reason: updated to describe and incorporate the exploratory 
HRRm cohort. 
 
Sections: 2.4 Exploratory Objectives; 8 Statistical Considerations; 8.1 Sample Size 
Estimate; 8.4 Methods for statistical analyses; 8.4.1 Analysis of the primary variable; 8.4.2 
Analysis of the secondary variable(s); 8.4.3 Subgroup Analysis 
Description of change with reason: added a new exploratory objective and outcome 
measures to include the planned exploratory research of HRRm cohort and blood samples 
collected for ctDNA. Updated an exploratory objective that will include analysis of HRRm 
cohort. Planned statistical analysis updated to incorporate the new exploratory objectives. 
CCI


Clinical Study Protocol Sy
sis 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
3(96) 
 
Section: 3.1 Inclusion criteria 
Description of change with reason: updated inclusion criterion #3 to describe the 
inclusion criteria for inclusion into the exploratory HRRm cohort. 
 
Section: 4 Study Plan and Timing of Procedures 
Description of change with reason: Table 1 Study Schedule Screening updated to add 
collection of tumour sample for HRR testing. Table 2 Study Schedule – On Study 
Treatment and Discontinuation updated to add collection of blood samples for ctDNA 
analysis. 
 
Section: 4.1 Enrolment/Screening Period 
Description of change with reason: updated to include description of enrolment and 
screening procedures associated with addition of exploratory HRRm cohort and collection 
of optional blood samples for ctDNA analysis. 
 
Section: 5.7.6 Collection of blood sample for ctDNA analysis 
Description of change with reason: new section added to describe collection of blood 
samples for ctDNA analysis to incorporate the addition of optional blood samples collection 
for the exploratory ctDNA analysis. 
 
Sections: 5.7.11 Withdrawal of Informed Consent for donated biological samples; 9.3 
Ethics and Regulatory review 
Description of change with reason: updated to incorporate collection of biological 
samples for exploratory HRRm cohort and optional blood samples for circulating tumour 
DNA (ctDNA) analysis. 
 
Sections: 5.8 Blood Volume; Table 5 Estimated maximum volume of blood to be drawn 
from each patient based on 6 months of treatment 
Description of change with reason: updated to reflect collection of optional blood samples 
for the ctDNA analysis. 
 
Sections: 8.2 Definition of Analysis sets; Table 6 Summary of Outcome Variables and 
Analysis Populations; 8.2.1 Full analysis set; 8.2.2 Safety Analysis Set; 8.2.4 PRO Analysis 


Clinical Study Protocol Sy
sis 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
4(96) 
Set 
Description of change with reason: corrected definitions of analysis sets to align with the 
intended analysis. The efficacy analysis set is replaced by the full analysis set. Updated the 
PRO analysis set. 
 
Sections: Protocol Synopsis; Table of Content; List of Abbreviations; 10 List of References 
Description of change with reason: updated to reflect changes in the protocol text 
incorporating the exploratory HRRm cohort and collection of blood samples for ctDNA 
analysis. 
 
Administrative changes (e.g., correction of typos, clarification in the text) were made 
throughout the Protocol due to inconsistencies identified in the text. 
 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
5(96) 
PROTOCOL SYNOPSIS 
 
An Open Label, Single Arm, Multicentre Study to Assess the Clinical 
Effectiveness and Safety of Lynparza (Olaparib) Capsules Maintenance 
Monotherapy in Platinum Sensitive Relapsed somatic or germline BRCA 
Mutated Ovarian Cancer Patients who are in Complete or Partial Response 
Following Platinum based Chemotherapy (ORZORA) 
 
International Co-ordinating Investigator 
Prof. Sandro Pignata 
National Cancer Institute of Naples  
via Semmola, 80131 Naples, Italy 
Study site(s) and number of patients planned 
The study will be conducted in approximately 8 countries worldwide.  Approximately 60 
centres will be initiated to enrol up to approximately 250 patients with somatic or germline 
BRCA mutated ovarian cancer.  
Patients enrolled in the study will have evidence of a deleterious or suspected deleterious 
germline or somatic BRCA mutation.  In order to avoid including mainly patients with 
previously diagnosed germline BRCA mutated disease, patients previously diagnosed with 
germline BRCA (gBRCA) mutation will not be included in this study. 
Considering the natural BRCA mutation prevalence in this patient population and treatment 
setting, it is estimated that there will be at least 50 patients with somatic BRCA mutated 
(sBRCAm) disease within the planned overall BRCA mutated patient population.  Additional 
sites and countries may be added dependent on recruitment rates.  
An additional exploratory cohort will be comprised of patients who carry a deleterious or 
suspected deleterious BRCA-independent genetic alteration in any of 13 genes involved in the 
Homologous Recombination Repair (HRR) pathway (HRRm cohort). HRR gene mutations 
will be identified using the investigational Next Generation Sequencing (NGS)-based clinical 
trial assay known as the “Lynparza HRR Assay” from 
  
Assuming that approximately 5% of patients with BRCA wild type (BCRAwt) disease 
screened in the study will carry a qualifying genetic alteration in any of the 13 genes involved 
in the HRR pathway (excluding BRCA1 and BRCA2), it is estimated that approximately 25 
patients will be included in the HRRm cohort before the target number of 250 patients with 
BRCAm disease is reached.  
 
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Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
6(96) 
 
Study period 
Timeline 
 
Estimated date of first patient enrolled 
Q2 (Q3) 2015 
 
Estimated date of last patient enrolled 
Q3 2017 
 
Estimated date of last patient completed** 
Q3 2018 
 
** 
Estimated date of 150th progression free survival (PFS) event among patients with 
BRCAm disease 
Study phase nomenclature will depend upon local regulatory approval status of olaparib. Pre-
regulatory approval status will define ORZORA a phase IIIb study and IV study prior or post 
regulatory approval accordingly.  Importantly, these differences do not affect study 
methodology.  However the potential need for local regulatory or other agency notification 
should be determined for individual countries.       
Study design 
This is a prospective, open-label, single arm, multi-centre study to assess the clinical 
effectiveness and safety of olaparib maintenance monotherapy and will be conducted in line 
with the European Union (EU) approved prescribing information and indication in patients 
with platinum sensitive relapsed BRCA-mutated (germline and/or somatic) high grade 
epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete 
response or partial response) to platinum-based chemotherapy.  
BRCA mutations are documented germline or somatic mutations in BRCA1 or BRCA2 that are 
predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead 
to loss of function).  
An additional, exploratory cohort of patients with BRCA-independent qualifying alterations in 
genes involved in the HRR pathway will be enrolled into the study (HRRm cohort).  
Qualifying genetic alterations are loss of function (LOF) mutations in any of the 13 genes 
other than BRCA1 and BRCA2 involved in the HRR pathway that are predicted to be 
deleterious or suspected deleterious. These 13 genes are: ATM, BARD1, BRIP1, CDK12, 
CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L.  
The investigational clinical trial assay known as the Lynparza HRR Assay from 
 will be 
used for this testing.  
 
CCI


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
7(96) 
Figure 1 
Study Flow Chart 
 
 
Patients will be assigned olaparib capsules p.o. 400 mg twice daily. They should initiate 
olaparib treatment within 8 weeks after their last dose of platinum-containing chemotherapy 
(last dose is the day of the last infusion). 
All patients will have clinical and objective radiological tumour assessments according to 
modified Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 at baseline and every 
12 weeks relative to date of enrolment, until objective radiological disease progression as 
determined by the investigator. Patients could continue to receive olaparib for as long as 
determined by the investigator, until objective radiological disease progression or as long as in 
the investigator’s opinion they are benefiting from treatment in relation to other clinical 
assessments and they do not meet any other discontinuation criteria. The study will recruit at 
least 50 patients with sBRCAm disease. Once a patient has discontinued olaparib she will be 
managed as per local clinical practice but will remain in the study and data will be collected 
on subsequent treatments, progression, overall survival and safety. 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
8(96) 
Objectives 
Co-Primary Objectives: 
Outcome Measure: 
x 
To assess the real world clinical 
effectiveness of olaparib maintenance 
monotherapy by investigator assessed 
progression free survival (PFS) according 
to modified Response Evaluation Criteria 
In Solid Tumours (RECIST) 1.1 in patients 
with sBRCAm ovarian cancer. 
x 
To assess the real world clinical 
effectiveness of olaparib maintenance 
monotherapy by investigator assessed PFS 
according to RECIST 1.1 in patients with 
BRCAm ovarian cancer. 
Time from study enrolment to disease progression 
(assessed according to RECIST 1.1 guidelines) or 
death.  
 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
9(96) 
Secondary Objectives: 
Outcome Measure: 
To assess the real world clinical effectiveness 
of olaparib maintenance monotherapy in 
patients with BRCAm ovarian cancer and 
patients with sBRCAm ovarian cancer, by 
assessment of: 
a) overall survival (OS),  
b) time to investigator-assessed second 
progression (PFS2), or death. 
a) Time to death 
b) Time to second progression event or death if this 
occurs before second progression event. 
To assess the real world clinical effectiveness 
of olaparib maintenance monotherapy in 
patients with BRCAm ovarian cancer and 
patients with sBRCAm ovarian cancer, by 
assessment of  
a) time to first subsequent therapy or death 
(TFST),  
b) time to second subsequent therapy or death 
(TSST) and,  
c) time to olaparib discontinuation or death 
(TDT). 
a) Time to first subsequent treatment commencement 
or death if this occurs before commencement of first 
subsequent treatment 
b) Time to second subsequent treatment 
commencement or death if this occurs before 
commencement of second subsequent treatment 
c) Time to olaparib discontinuation or death if this 
occurs before discontinuation of olaparib 
maintenance therapy. 
To assess and describe the quality of life (QoL) 
of patients with BRCAm ovarian cancer and 
patients with sBRCAm ovarian cancer. 
Functional Assessment of Cancer Therapy-Ovarian 
(FACT-O), Functional Assessment of Chronic Illness 
Therapy (FACIT)-Fatigue, and ORZORA QoL 
Additional Items Questionnaire   
To describe patterns of routine clinical use of 
olaparib, the nature and patterns of adverse 
events (AEs) of nausea and vomiting and their 
impact on QoL in patients with BRCAm 
ovarian cancer and patients with sBRCAm 
ovarian cancer.   
To describe nausea/vomiting toxicity 
management patterns used in routine clinical 
practice. 
Safety summary tables, Functional Living Index-
Emesis (FLIE) Questionnaire, and concomitant 
medication use.  


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
10(96) 
Safety Objective: 
Outcome Measure: 
To assess the safety and tolerability of olaparib 
maintenance monotherapy in patients with 
BRCAm ovarian cancer and patients with 
sBRCAm ovarian cancer. 
AEs/Serious adverse events (SAEs)/AE of special 
interest (AESI) 
 
 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
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Exploratory Objectives: 
Outcome Measure: 
To describe the longer term safety of olaparib 
monotherapy, including follow up for 
Myelodysplastic Syndrome (MDS)/ Acute 
Myeloid Leukaemia (AML)/ and New primary 
malignancies (other than MDS/AML). 
Collection of long term adverse events, including 
MDS/ AML or new primary malignancies 
To correlate the incidence of side effects and 
QoL according to age and the presence of 
comorbidities. 
Based on collected and summarised outcomes and 
comorbidities 
To describe the clinical effectiveness of 
(response to) subsequent line of treatment and 
correlating it with the progression-free interval 
(PFI) (artificial prolongation of PFI through 
olaparib).  
Description of maximum response to subsequent line 
of treatment  
To describe the efficacy of olaparib according 
to the previous therapy, with or without 
bevacizumab, and according to the PFI 
(recurrence during or after the end of 
bevacizumab maintenance). 
Based on collected and summarised outcomes 
To describe the activity of olaparib according 
to the germline mutational status (BRCA1 vs 
BRCA2), and to the presence of family history 
(yes vs no). 
Based on collected and summarised outcomes and 
family history 
To describe the kinetic of CA-125 progression 
according to Gynecological Cancer InterGroup 
(GCIG) criteria and its correlation with disease 
progression by RECIST 1.1 guidelines during 
olaparib therapy. 
Based on collected and summarised outcomes 
To measure loss of heterozygosity (LOH) for 
the BRCA1 and BRCA2 genes in tumour 
samples and explore any potential association 
with efficacy. 
Based on all available tumour samples collected and 
summarised outcomes. 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
12(96) 
Exploratory Objectives: 
Outcome Measure: 
To describe the real world clinical 
effectiveness and safety of olaparib 
maintenance monotherapy in patients with 
BRCA-independent HRRm ovarian cancer, by 
the following:   
x 
Investigator assessed PFS according to 
RECIST 1.1 
x 
OS 
x 
Safety and tolerability. 
a) Time from study enrolment to disease progression 
(assessed according to RECIST 1.1 guidelines) or 
death 
b) Time to death 
c) AEs, SAEs, AESI 
Potential exploratory research into frequency, 
nature and predictive value of HRR gene 
mutations, including BRCA1 and BRCA2, may 
be performed on the optional collected and 
stored tumour samples available at study entry 
or tumour biopsy samples collected during the 
course of the study.  
These could include studying resistance 
mechanisms to olaparib, future exploratory 
research into factors that may influence 
development of cancer and/or response to 
study treatment.  
To collect and store deoxyribonucleic acid 
(DNA) (according to each country’s local and 
ethical procedures) for future exploratory 
research into genes/genetic variation that may 
influence response to study treatment and or 
susceptibility to disease (optional)*. 
 
To explore the feasibility of reliably measuring 
sBRCAm and HRRm from circulating tumour 
DNA (ctDNA)* 
 
* These exploratory analyses may not be reported in the clinical study report (CSR), if not they will be reported 
separately. 
Target patient population 
Eligible patients will be those with platinum sensitive relapsed (PSR) high grade epithelial 
ovarian cancer, primary peritoneal and/or fallopian tube cancer who are found to carry a 
germline or somatic BRCA mutation known or suspected to be deleterious. 
Patients must have completed at least 2 previous lines of platinum-based therapy (e.g., 
containing carboplatin or cisplatin) before entry to the study and must be considered platinum 
sensitive after the penultimate platinum-based chemotherapy. Eligible patients must be in 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
13(96) 
complete or partial response following platinum-based chemotherapy prior to enrolment in the 
study.  
Only patients with unknown germline BRCA mutation status or patients found to carry 
germline BRCA wild type (gBRCAwt) disease or patients previously identified as having 
BRCAm disease based on a tumour test (with unknown gBRCA or with previously identified 
gBRCAwt status) will be considered for screening. Patients previously diagnosed with 
gBRCAm disease will not be included in this study.  BRCA mutation status will be determined 
or confirmed through central blood and tumour testing (as outlined in Section 5.7.6).  
Exploratory patient population 
Patients screened for the study with unknown BRCA status or with known gBRCAwt status for 
whom an adequate archival tumour tissue sample is available will be tested for qualifying 
HRR gene alterations.  
Patients found not to carry a BRCA mutation in their tumour (tumour BRCAwt), and with 
qualifying BRCA-independent HRR genetic alterations will be included in the study (HRRm 
cohort), and analysed as a separate exploratory cohort.  
Duration of treatment 
Patients should continue to receive olaparib until objective radiological disease progression 
according to RECIST 1.1 guidelines as assessed by the investigator or as long as in the 
investigator’s opinion they are benefiting from treatment and they do not meet any other 
discontinuation criteria as outlined in Section 3.9. Once patients have been discontinued from 
olaparib, other treatment options will be at the discretion of the investigator. 
Investigational product, dosage and mode of administration 
Olaparib will be available as the capsule formulation as follows: 
x Capsules containing 50 mg olaparib. Patients will be administered olaparib orally at a 
dose of 400 mg twice daily (bid), equivalent to a total daily dose of 800 mg. The 
planned dose of 400 mg bid will be made up of eight 50 mg capsules bid.  
Treatment may be interrupted to manage adverse reactions such as nausea, vomiting, 
diarrhoea, and anaemia and dose reduction can be considered. For more information please 
refer to Section 6.8 and the prescribing information (Appendix G) or to the investigator’s 
brochure as appropriate.   
Statistical methods 
No formal sample size calculation is provided for this study. The sample size of 
approximately 250 patients with BRCA mutated ovarian cancer is driven by the need to have 
at least 50 patients with sBRCAm disease, and an adequate number of patients across 
participating countries to allow for individual country and/or regional summaries and to help 


Clinical Study Protocol Synopsis 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
14(96) 
understand patterns of olaparib use in routine clinical practice across multiple countries with 
the capsule formulation and across various subgroups.  
Assuming that approximately 5% of patients with BRCAwt disease screened in the study will 
carry a qualifying genetic alteration in any of the 13 genes involved in the HRR pathway (i.e., 
BRCA-independent HRRm), it is expected that approximately 25 patients will be included in 
the HRRm cohort before the target number of 250 patients with BRCAm disease is reached.  
Patients enrolled with sBRCAm disease 
Assuming a median PFS value of 11.2 months (as observed in the phase 2 maintenance study), 
and a data cut off at 60% maturity, 30 progression or death events are expected from 50 
patients. Assuming 23 months non-linear recruitment in the sBRCAm cohort, these 30 
progression or death events are expected to occur approximately 32 months after first subject 
is enrolled in the study (FSI).   
All BRCAm patients  
Data will be summarised for all patients who have received at least one dose of olaparib.  The 
sample size of approximately 250 patients is driven by the need to understand patterns of 
olaparib use across multiple countries with the capsule formulation and across various 
subgroups and the primary analysis will be performed after the accumulation of 150 
progression or death events which corresponds to 60% maturity. Assuming a median PFS 
value of 11.2 months and a data cut off at 60% maturity with approximately 23 months of 
non-linear recruitment 150 progression or death events are expected to occur approximately 
32 months after first subject is enrolled in the study (FSI). 
PFS will be presented as a median and 95% confidence interval, with no formal statistical 
comparison between patients with sBRCAm or gBRCAm disease as the single-arm design of 
this study prevents the identification of prognostic or predictive factors. 
Subgroups will be presented, including patients with gBRCAm disease, mutation type 
(BRCA1, or BRCA2 or both), and prior and subsequent Poly-adenosine 5’diphosphoribose 
(ADP) Polymerase (PARP) inhibitor use. 
All time to event endpoints will be described as for PFS.  A summary of PFS2 and OS will be 
produced at the time of the PFS data cut off. QoL and safety data will be summarised.  For 
more information please refer to Section 8. 
Patients enrolled with HRRm disease 
The analyses of PFS, OS and safety data will be repeated for the exploratory cohort of patients 
with BRCA-independent HRRm ovarian cancer.  
 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
15(96) 
TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................... 1 
VERSION HISTORY .............................................................................................. 2 
PROTOCOL SYNOPSIS ......................................................................................... 5 
TABLE OF CONTENTS ....................................................................................... 15 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... 21 
1. 
INTRODUCTION ................................................................................................. 25 
1.1 
Background ............................................................................................................ 25 
1.1.1 
Ovarian cancer and its treatment ............................................................................ 25 
1.1.2 
BRCA mutation positive ovarian cancer ................................................................ 26 
1.1.3 
PARP inhibition as a target for BRCA mutation positive ovarian cancer .............. 26 
1.1.4 
Homologous recombination repair defects ............................................................ 28 
1.1.5 
Pre-clinical experience ........................................................................................... 29 
1.1.6 
Toxicology and safety pharmacology summary .................................................... 29 
1.1.7 
Clinical experience ................................................................................................. 29 
1.2 
Research hypothesis ............................................................................................... 29 
1.3 
Rationale for study design and doses ..................................................................... 30 
1.4 
Benefit/risk and ethical assessment........................................................................ 31 
1.5 
Study Design .......................................................................................................... 32 
2. 
STUDY OBJECTIVES .......................................................................................... 34 
2.1 
Primary objectives ................................................................................................. 34 
2.2 
Secondary objectives ............................................................................................. 34 
2.3 
Safety objectives .................................................................................................... 36 
2.4 
Exploratory objectives ........................................................................................... 36 
3. 
PATIENT SELECTION, ENROLMENT, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL .................................................... 38 
3.1 
Inclusion criteria .................................................................................................... 39 
3.2 
Exclusion criteria ................................................................................................... 41 
3.3 
Patient enrolment ................................................................................................... 41 
3.4 
Procedures for handling incorrectly enrolled patients ........................................... 42 
3.5 
Methods for assigning treatment groups ................................................................ 42 
3.6 
Methods for ensuring blinding ............................................................................... 42 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
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3.7 
Methods for unblinding .......................................................................................... 42 
3.8 
Restrictions ............................................................................................................ 42 
3.9 
Discontinuation of investigational product ............................................................ 42 
3.9.1 
Procedures for discontinuation of a patient from investigational product ............. 43 
3.10 
Criteria for withdrawal ........................................................................................... 44 
3.10.1 
Screen failures ........................................................................................................ 44 
3.10.2 
Withdrawal of the informed consent ...................................................................... 44 
3.11 
Discontinuation of the study .................................................................................. 44 
4. 
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 45 
4.1 
Enrolment/screening period ................................................................................... 52 
4.2 
Treatment period .................................................................................................... 53 
4.3 
Follow-up period .................................................................................................... 53 
4.3.1 
Follow-up 30 days after last dose of investigational product (IP) ......................... 53 
4.3.2 
Survival .................................................................................................................. 53 
4.3.3 
Second progression (PFS2) .................................................................................... 54 
4.3.4 
Patient management post primary analysis ............................................................ 54 
4.3.5 
Patient management post final analysis ................................................................. 54 
5. 
STUDY ASSESSMENTS ..................................................................................... 55 
5.1 
Efficacy assessments .............................................................................................. 55 
5.1.1 
CT and MRI scans tumour assessments ................................................................. 55 
5.1.2 
Tumour Evaluation ................................................................................................ 56 
5.2 
Safety assessments ................................................................................................. 57 
5.2.1 
Laboratory safety assessments ............................................................................... 57 
5.2.2 
Vital signs .............................................................................................................. 58 
5.3 
Other assessments .................................................................................................. 58 
5.3.1 
Patient reported outcomes ...................................................................................... 58 
5.3.2 
Administration of PRO questionnaires FACT-O and FACIT-Fatigue .................. 58 
5.3.3 
Functional Assessment of Cancer Therapy-Ovarian (FACT-O) ........................... 59 
5.3.4 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-
Fatigue) .................................................................................................................. 59 
5.3.5 
ORZORA QoL Additional Items Questionnaire ................................................... 59 
5.3.6 
Functional Living Index-Emesis (FLIE) ................................................................ 60 
5.4 
Pharmacokinetics ................................................................................................... 60 
5.4.1 
Collection of samples ............................................................................................. 60 
5.4.2 
Determination of drug concentration ..................................................................... 60 
5.4.3 
Storage and destruction of pharmacokinetic samples ............................................ 60 
5.5 
Pharmacodynamics ................................................................................................ 60 
5.5.1 
Collection of samples ............................................................................................. 60 
5.5.2 
Storage, re-use and destruction of pharmacodynamic samples ............................. 60 


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5.6 
Pharmacogenetics .................................................................................................. 60 
5.6.1 
Collection of pharmacogenetic samples ................................................................ 60 
5.6.2 
Storage, re-use and destruction of pharmacogenetic samples ............................... 60 
5.7 
Biomarker analysis ................................................................................................. 60 
5.7.1 
Collection of tumour sample for BRCA testing at screening (mandatory) ............ 61 
5.7.2 
Collection of tumour sample for HRR testing ....................................................... 61 
5.7.3 
Collection of tumour sample for exploratory analysis at screening and at 
disease progression (optional) ................................................................................ 62 
5.7.4 
Exploratory use of data generated from 
 Central 
testing of tumor sample (Optional) ........................................................................ 63 
5.7.5 
Collection of blood sample for germline BRCA1 and BRCA2 testing ................... 63 
5.7.6 
Collection of blood sample for ctDNA analysis .................................................... 63 
5.7.7 
Guidance for BRCA and HRR testing .................................................................... 63 
5.7.8 
Storage, re-use and destruction of biological samples ........................................... 64 
5.7.9 
Labelling and shipment of biological samples ....................................................... 65 
5.7.10 
Chain of custody of biological samples ................................................................. 65 
5.7.11 
Withdrawal of Informed Consent for donated biological samples ........................ 65 
5.8 
Blood volume ......................................................................................................... 66 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 67 
6.1 
Definition of adverse events .................................................................................. 67 
6.2 
Definitions of serious adverse event ...................................................................... 68 
6.3 
Adverse events of special interest .......................................................................... 68 
6.4 
Recording of adverse events .................................................................................. 69 
6.4.1 
Time period for collection of adverse events ......................................................... 69 
6.4.2 
Follow-up of unresolved adverse events ................................................................ 69 
6.4.3 
Adverse events after the 30 day follow-up period ................................................. 69 
6.4.4 
Variables ................................................................................................................ 70 
6.4.5 
Causality collection ................................................................................................ 71 
6.4.6 
Adverse events based on signs and symptoms....................................................... 71 
6.4.7 
Hy’s Law ................................................................................................................ 71 
6.4.8 
Disease progression ............................................................................................... 71 
6.4.9 
New cancers ........................................................................................................... 72 
6.4.10 
Lack of efficacy ..................................................................................................... 72 
6.4.11 
Deaths .................................................................................................................... 72 
6.5 
Reporting of serious adverse events....................................................................... 72 
6.6 
Overdose ................................................................................................................ 73 
6.7 
Pregnancy ............................................................................................................... 74 
6.7.1 
Maternal exposure .................................................................................................. 74 
6.7.2 
Paternal exposure ................................................................................................... 74 
6.8 
Management of IP related toxicities, dose interruptions and dose 
reductions ............................................................................................................... 75 
CCI


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Study Code D0816C00012 
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6.9 
Study governance and oversight ............................................................................ 75 
6.9.1 
Steering Committee ............................................................................................... 75 
6.9.2 
Data Monitoring Committee .................................................................................. 75 
6.9.3 
Scientific Advisory Committee .............................................................................. 75 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 75 
7.1 
Identity of investigational product(s) ..................................................................... 75 
7.2 
Dose and treatment regimens ................................................................................. 75 
7.3 
Labelling ................................................................................................................ 76 
7.4 
Storage ................................................................................................................... 76 
7.5 
Compliance ............................................................................................................ 76 
7.6 
Accountability ........................................................................................................ 77 
7.7 
Concomitant and other treatments ......................................................................... 77 
7.7.1 
Surgery and palliative radiotherapy ....................................................................... 79 
7.7.2 
Administration of other anti-cancer agents ............................................................ 79 
7.7.3 
Subsequent therapies for cancer ............................................................................. 79 
7.7.4 
Other concomitant treatment .................................................................................. 79 
7.8 
Post Study Access to Olaparib ............................................................................... 79 
8. 
STATISTICAL CONSIDERATIONS ................................................................... 79 
8.1 
Sample size estimate .............................................................................................. 80 
8.2 
Definitions of analysis sets .................................................................................... 80 
8.2.1 
Full analysis set ...................................................................................................... 81 
8.2.2 
Safety analysis set .................................................................................................. 81 
8.2.3 
PK analysis set ....................................................................................................... 81 
8.2.4 
PRO analysis set .................................................................................................... 81 
8.3 
Outcome measures for analyses ............................................................................. 81 
8.3.1 
Calculation or derivation of efficacy variable(s) ................................................... 81 
8.3.2 
Primary endpoint .................................................................................................... 81 
8.3.3 
Secondary endpoints .............................................................................................. 82 
8.3.4 
Calculation or derivation of health-related quality of life variables ...................... 83 
8.3.5 
Calculation or derivation of safety variable(s) ....................................................... 86 
8.3.6 
Other significant adverse events (OAE) ................................................................ 86 
8.3.7 
Exploratory endpoints ............................................................................................ 86 
8.4 
Methods for statistical analyses ............................................................................. 86 
8.4.1 
Analysis of the primary variable ............................................................................ 87 
8.4.2 
Analysis of the secondary variable(s) .................................................................... 87 
8.4.3 
Subgroup analysis .................................................................................................. 87 
8.4.4 
Interim analysis ...................................................................................................... 88 
8.4.5 
Exploratory analysis (if applicable) ....................................................................... 88 
8.5 
Training of study site personnel ............................................................................. 88 


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Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
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8.6 
Monitoring of the study ......................................................................................... 89 
8.6.1 
Source data ............................................................................................................. 89 
8.6.2 
Study agreements ................................................................................................... 89 
8.6.3 
Archiving of study documents ............................................................................... 89 
8.7 
Study timetable and end of study ........................................................................... 89 
8.8 
Data management by AstraZeneca ........................................................................ 90 
9. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 91 
9.1 
Ethical conduct of the study ................................................................................... 91 
9.2 
Patient data protection ............................................................................................ 91 
9.3 
Ethics and regulatory review.................................................................................. 91 
9.4 
Informed consent ................................................................................................... 92 
9.5 
Changes to the protocol and informed consent form ............................................. 93 
9.6 
Audits and inspections ........................................................................................... 93 
10. 
LIST OF REFERENCES ....................................................................................... 93 
 
 
LIST OF TABLES 
Table 1 
Study Schedule Screening ........................................................................ 45 
Table 2 
Study Schedule – On Study Treatment and Discontinuation ................... 47 
Table 3 
Study Schedule – Follow-up Post Discontinuation of Olaparib ............... 50 
Table 4 
Laboratory Safety Variables ..................................................................... 57 
Table 5 
Estimated maximum volume of blood to be drawn from each 
patient based on 6 months of treatment .................................................... 67 
Table 6 
Summary of Outcome Variables and Analysis Populations ..................... 80 
Table 7 
Health-Related QoL .................................................................................. 84 
Table 8 
Health-Related Quality of Life: Change rates - overall score. ................. 85 
 
LIST OF FIGURES 
Figure 1 
Study Flow Chart ...................................................................................... 32 
Figure 2 
Screening Flow Chart ............................................................................... 39 
 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
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LIST OF APPENDICES 
Appendix A 
Signatures 
Appendix B 
Additional Safety Information Further Guidance On The Definition Of A 
Serious Adverse Event (SAE) A Guide To Interpreting The Causality 
Question 
Appendix C 
International Airline Transportation Association (IATA) 6.2 Guidance 
Document 
Appendix D 
Actions Required In Cases Of Combined Increase Of Aminotransferase 
And Total Bilirubin – HY’s Law 
Appendix E 
Acceptable Birth Control Methods 
Appendix F 
Guidance Of Evaluation Of Objective Tumour Response Using Modified 
RECIST 1.1 Criteria (Response Evaluation Criteria In Solid Tumours) 
Appendix G 
Prescribing Information 
Appendix H 
FACT-O, ORZORA QoL Additional Items Questionnaire, FACIT Fatigue 
Scale, And Functional Living Index Emesis (FLIE) 
 


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Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
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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 
ACMG 
American College of Medical Genetics and Genomics  
AE 
Adverse Event (see definition in Section 6.1) 
AESI 
Adverse Event of Special Interest (see Section 6.3) 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukaemia  
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
Bid 
Twice a day 
BP 
Blood Pressure 
BRACAnalysis® 
Gene sequencing and large rearrangement analysis for Hereditary Breast 
and Ovarian Cancer, registered trademark of Myriad Genetics, Inc. 
BRCA  
Breast cancer susceptibility gene (in accordance with scientific convention, 
gene and mutation is italicised whereas protein is not italicised) 
BRCAm 
gBRCA and/or sBRCA mutated 
BRCAwt 
gBRCA and/or sBRCA wild type 
BUN 
Blood Urea Nitrogen 
CHO 
Chinese Hamster Ovary 
CI 
Confidence Interval 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
ctDNA 
Circulating Tumour DNA 
DAE 
Discontinuation of Investigational Product due to Adverse Event 


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Edition Number 3 
Date 22 July 2016 
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Abbreviation or 
special term 
Explanation 
DCO 
Data Cut-Off 
DNA 
Deoxyribonucleic Acid  
DoR 
Duration of Response 
DSB 
Double Strand Break 
DUS 
Disease Under Study 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
eCRF 
electronic Case Report Form 
ENGOT 
European Network of Gynaecological Oncological Trial Groups 
EU 
European Union 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue  
FACT-O 
Functional Assessment of Cancer Therapy-Ovarian 
FAS 
Full Analysis Set 
FFPE 
Formalin-Fixed, Paraffin-Embedded 
FLIE 
Functional Living Index-Emesis 
FSI 
First Subject In (enrolled) 
gBRCA 
germline BRCA 
gBRCAm 
germline BRCA mutated 
gBRCAwt 
Germline BRCA wild type 
GCIG 
Gynecological Cancer InterGroup 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
Hb 
Haemoglobin 
HIV  
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
HRD 
Homologous Recombination Deficiency 
HRQoL 
Health-Related Quality of Life 
HRR 
Homologous Recombination Repair 
HRRm 
Qualifying mutation in the tumour of any of 15 genes involved in DNA 
homologous recombination repair  
HRT 
Hormone Replacement Therapy 
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Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
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Abbreviation or 
special term 
Explanation 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
INR 
International Normalised Ratio 
International 
Co-ordinating 
investigator 
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the Investigators and/or 
activities internationally.  
IP 
Investigational Product  
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
KM 
Kaplan Meier 
LOF 
Loss of Function 
LOH 
Loss of Heterozygosity 
MCV 
Mean Cell Volume 
MDS 
Myelodysplastic Syndrome  
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NGS 
Next Generation Sequencing 
NTL 
Non-Target Lesion 
OAE 
Other Significant Adverse Event (see definition in Section 8.3.6) 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PARP 
Poly-adenosine 5’diphosphoribose (ADP) Polymerase / Polymerisation 
PD 
Progression of Disease 
PFI 
Progression-Free Interval 
PFS 
Progression Free Survival during initial olaparib maintenance therapy 
PFS2 
Progression Free Survival following initial olaparib maintenance and 
subsequent chemotherapy  
PI 
Principal Investigator  
p.o. 
Administered by mouth  
PR 
Partial Response 
PRO 
Patient Reported Outcome 


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Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
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Abbreviation or 
special term 
Explanation 
PSR 
Platinum Sensitive Relapsed 
QoL 
Quality of Life 
RECIST 
Response Evaluation Criteria In Solid Tumours 
SAE 
Serious Adverse Event (see definition in Section 6.2) 
SAP 
Statistical Analysis Plan 
sBRCAm 
Somatic tumour BRCA mutated (mutation detected in the tumour but not in 
the germline) 
sBRCAwt 
Somatic tumour BRCA wild type 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvate Transaminase 
SSB 
Single Strand Breaks 
TDT 
Time to Discontinuation of Treatment or Death 
TFST 
Time to First Subsequent Therapy (Treatment) or Death 
TL 
Target Lesion 
TOI 
Trial Outcome Index 
TSST 
Time to Second Subsequent Therapy (Treatment) or Death 
ULN 
Upper Limit of Normal 
US 
United States 
WBDC 
Web Based Data Capture 
wt 
Wild type.  
Patients without evidence of BRCA 1 or BRCA 2 deleterious or suspected 
deleterious mutations for a given gene or set of genes (e.g. BRCA 1 or 
BRCA 2) 
 
 
 


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Drug Substance Olaparib  
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Edition Number 3 
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1. 
INTRODUCTION 
1.1 
Background  
1.1.1 
Ovarian cancer and its treatment 
Ovarian cancer is the fifth most common cause of death from cancer in women 
(Colombo et al 2010; NCCN Clinical Practice Guidelines in Oncology 2013). In the European 
Community, approximately 28,000 new cases of ovarian cancer and approximately 17,000 
deaths are reported annually, ranking ovarian cancer as the leading cause of death from 
gynaecological cancer. The incidence rates of ovarian cancer increase with age and are highest 
in the eighth decade of life (50.8/100,000 and 50.3/100,000 in age groups 80-84 and 85+, 
respectively) 
(Howlader et al 2014). In the United States (US), nearly 80% of the patients are diagnosed 
with advanced disease (regional or distant), while only 15% are diagnosed at the localized 
stage (Howlader et al 2014). Approximately 44% of women diagnosed with ovarian cancer (at 
any stage) survive 5 years from diagnosis, while among those diagnosed at the distant stage of 
the disease 5-year survival is ~27% (Siegel et al 2014). In Europe, an average 5-year relative 
survival (~42%) is similar to that found in the US (Sant et al 2009).  
The standard therapy for advanced ovarian cancer consists of radical debulking surgery 
followed by post-operative platinum-based first-line chemotherapy.  Since 1996, platinum and 
paclitaxel combination therapy has become the standard-of-care first-line chemotherapy 
regimen (McGuire et al 1996).  Worldwide, the use of carboplatin has replaced that of 
cisplatin because of carboplatin’s superior tolerability profile together with equal 
effectiveness.  However, the success of this approach is limited and approximately 70% of 
patients fail to achieve complete responses, or eventually relapse, after a varying disease-free 
interval. 
Should a relapse or a progression after first-line therapy occur, cure of the disease is rarely 
possible.  In these cases, second-line chemotherapy is usually offered, with a palliative intent.  
Recurrence-free interval influences the choice of possible second-line chemotherapy, 
specifically the value of platinum re-exposure (Blackledge et al 1989, Gore et al 1990, 
Markman et al 1991) and is of prognostic importance for the ongoing course of the illness 
(Eisenhauer et al 1997). Patients with ovarian cancer who developed recurrence >6 months 
after completion of first line platinum chemotherapy are characterised as having platinum 
sensitive disease. 
For patients with platinum sensitive disease, response rates of 20% to 30% may be seen with 
platinum re-treatment in those with a platinum-free interval of 6 to 12 months.  In those 
patients with treatment-free intervals of >12 months, response rates in the range of 30% to 
70% may be seen, and some patients may benefit from durable second remissions.  
Carboplatin in combination with gemcitabine, pegylated liposomal doxorubicin or paclitaxel 
represents the main treatment options for patients with relapsed platinum sensitive disease, 
being repeated as long as the patients remain platinum sensitive. 


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1.1.2 
BRCA mutation positive ovarian cancer 
An important risk factor for ovarian cancer is genetic predisposition with BRCA1 or BRCA2 
mutations (i.e., germline BRCA mutated [gBRCAm]) which account for the majority of 
hereditary ovarian cancers.  If a lifetime risk for ovarian cancer among women in the general 
population is estimated to be 1.4 percent (14 out of 1,000), a woman with BRCA1 or BRCA2 
deleterious mutation has a lifetime risk of 15 to 40 percent (150–400 out of 1,000) (NCI; 
BRCA1 and BRCA2: Cancer Risk and Genetic Testing).  BRCA mutated ovarian cancer 
patients can also develop ovarian cancer earlier in their life than those without the mutation.  
Deficiency in BRCA function is thought to arise when the relevant second copy of the gene is 
lost (loss of heterozygosity) in tumorigenesis (George et al 2014). 
If all ovarian cancer patients underwent germline BRCA (gBRCA) testing, current estimates 
indicate that 13% to 14% of the overall ovarian cancer population would have gBRCA1/2 
mutations (Alsop et al 2012, Zhang et al 2011), and the proportion of patients with gBRCA 
mutations may be as high as 22% in patients with high grade epithelial ovarian cancer.  In 
addition, a population of ovarian cancer patients whose tumours harbour BRCA1 and BRCA2 
mutations that are not detected in the germline (~7% of unselected patients) also exist and are 
defined as somatic BRCA mutations (sBRCAm) (Hennessy et al 2010).  Based on the above 
overall incidence of gBRCA and sBRCA mutations reported separately, it would be expected 
that about 30% of patients with BRCA mutated (BRCAm) disease overall have a somatic 
mutation.   
Ovarian cancer patients with BRCA mutated disease seem to have a better prognosis compared 
with the overall relapsed ovarian cancer patient population but the pattern of disease is similar, 
with patients eventually dying from their disease.  Patients with BRCA mutation represent a 
small, well defined and medically recognised subpopulation.  
Throughout the protocol the term ‘BRCA mutation’ is used to refer to a BRCA1 or BRCA2 
mutation (detected either in the germline or in the tumour) classified as ‘deleterious’ or 
‘suspected deleterious’ in accordance with the American College of Medical Genetics and 
Genomics (ACMG) recommendations for standards for interpretation and reporting of 
sequence variants (Richards et al 2008). 
Where reference is made to germline BRCA mutations specifically, the abbreviation gBRCAm 
is used. Where reference is made to patients who harbour a tumour BRCA mutation but are 
known not to harbour a germline BRCA mutation, the abbreviation sBRCAm is used to 
indicate a somatic tumour BRCA mutation.  In addition, mutated or wild type (wt) may be 
designated by BRCAm and BRCAwt, respectively.  Patients are classified as BRCA mutated by 
virtue of having BRCA mutated status in either their blood or tumour sample.   
1.1.3 
PARP inhibition as a target for BRCA mutation positive ovarian cancer 
Investigators should be familiar with the current olaparib (AZD2281, KU-0059436) 
Investigator’s Brochure (IB) or Prescribing Information (Appendix G) as applicable 
depending on country specific marketing authorisation status. 


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Edition Number 3 
Date 22 July 2016 
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Olaparib is a potent Polyadenosine 5’diphosphoribose [poly (ADP ribose)] polymerisation 
(PARP) inhibitor (PARP-1, -2 and -3) that is being developed as an oral therapy, both as a 
monotherapy (including maintenance) and for combination with chemotherapy and other anti-
cancer agents. 
PARP inhibition is a novel approach to targeting tumours with deficiencies in 
deoxyribonucleic acid (DNA) repair mechanisms.  PARP enzymes are essential for repairing 
DNA single strand breaks (SSBs).  Inhibiting PARPs leads to the persistence of SSBs, which 
are then converted to the more serious DNA double strand breaks (DSBs) during the process 
of DNA replication.  During the process of cell division, DSBs can be efficiently repaired in 
normal cells by homologous recombination repair (HRR).  Tumours with homologous 
recombination deficiencies (HRD), such as ovarian cancers in patients with BRCA mutations, 
cannot accurately repair the DNA damage, which may become lethal to cells as it 
accumulates.  In such tumour types, olaparib may offer a potentially efficacious and less toxic 
cancer treatment compared with currently available chemotherapy regimens.  
BRCA1 and BRCA2 defective tumours are intrinsically sensitive to PARP inhibitors, both in 
tumour models in vivo (Rottenberg et al 2008, Hay et al 2009) and in the clinic 
(Fong et al 2009). The mechanism of action for olaparib results from the trapping of inactive 
PARP onto the single-strand breaks preventing their repair (Helleday 2011; 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 HRR.  Olaparib has been shown to inhibit 
selected tumour cell lines in vitro and in xenograft and primary explant models as well as in 
genetic BRCA knock out models, either as a stand-alone treatment or in combination with 
established chemotherapies. 
The phase II study D0810C00019 was a randomised, double-blind, placebo-controlled study 
to evaluate maintenance treatment with olaparib (capsule formulation) in patients with 
platinum sensitive relapsed high grade epithelial ovarian cancer who had received SUHYLRXV
platinum regimens and were in partial or complete response following their last platinum-
containing regimen.  The primary endpoint was investigator-assessed progression free survival 
(PFS).   
In total, 265 patients were randomised to olaparib 400 mg bid (136) or placebo (129).  The 
primary analysis was carried out following 154 PFS events and demonstrated that 
maintenance treatment with olaparib led to a significant PFS improvement vs placebo (hazard 
ratio [HR] 0.35; 95% confidence interval [CI] 0.25-0.49; p<0.00001) (Ledermann et al 2012).  
A subgroup analysis (pre-specified in the statistical analysis plan [SAP]) suggested that 
olaparib may lead to a greater clinical benefit in patients with a known gBRCAm status was 
determined retrospectively for all consenting patients (n=166) using blood samples taken 
before randomisation.  Tumour BRCAm status was determined from archival tumour samples 
of 196 patients.  Since germline BRCA wild type (gBRCAwt) patients may develop somatic 
tumour BRCA mutations, efficacy analyses were performed by known gBRCA mutation status 
and known total BRCA mutation status.  gBRCAm patients had the greatest PFS benefit with 
olaparib maintenance vs placebo (HR, 0.17; 95% CI 0.09-0.31; median: 11.2 vs 4.1 months; 


Clinical Study Protocol 
Drug Substance Olaparib  
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Date 22 July 2016 
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p<0.001).  The PFS benefit was consistent when sBRCAm ovarian cancers (18 patients with 
sBRCAm disease) were included to reach an overall sample of 136 patients with BRCAm 
disease (HR, 0.18; 95% CI 0.11-0.31; median: 11.2 vs 4.3 months; p<0.0001).  In an interim 
analysis of overall survival (OS; 58% maturity), OS HRs from the gBRCAm subgroup was 
0.85; 30% gBRCAm placebo patients received a subsequent PARP inhibitor.  The analysis of 
all BRCAm patients was less confounded and resulted in an OS HR of 0.73 (95% CI 0.45-
1.17; median: 34.9 vs 31.9 months; p=0.19).  Olaparib tolerability was similar in BRCAm 
patients and the overall population.  
1.1.4 
Homologous recombination repair defects 
As described above, PARP inhibition induces synthetic lethality in tumour cells with HRR 
deficiencies, such as BRCA1/2 mutations (BRCAm).  PARP inhibitors may also induce 
lethality in tumour cells that have BRCA1/2-unrelated deficiencies in the DNA damage repair 
mechanism.  BRCA-independent defects include loss-of-function (LOF) mutations in other 
genes that encode proteins involved in DNA damage repair by HRR (HRRm).  
AstraZeneca has partnered with 
 to develop a novel tumour 
tissue-based companion diagnostic – the clinical trial assay known as “Lynparza HRR Assay” 
– for the detection of mutations in a set of 15 HRR genes including BRCA1, BRCA2, and 
13 other genes (ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, 
RAD51B, RAD51C, RAD51D, RAD54L).The Lynparza HRR Assay is based on the clinical-
grade next generation sequencing (NGS) 
 cancer gene-profiling test, which 
analyses the coding sequence of 310 cancer-related genes plus select introns from 35 genes for 
variants and/or rearrangements.  
A patient is classified “positive” (i.e., HRRm) if any deleterious or suspected deleterious 
genetic alteration is found in the 13 HRR genes, other than BRCA1 and BRCA2 (i.e., BRCA-
independent HRRm).  Classification of genetic alterations is in accordance with the American 
College of Medical Genetics and Genomic standards and guidelines for the interpretation of 
sequence variants (Richards et al 2015).  A genetic alteration 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 genetic alterations such as genomic truncating 
rearrangements or homozygous deletions will also be classified as “positive”. Patients that do 
not meet such criteria are labelled as biomarker “negative”.   
Tumour samples from BRCAwt patients participating in Study D0810C00019 were analysed 
to determine the presence of exploratory, candidate biomarkers of sensitivity to olaparib.  Of 
the 95 BRCAwt patients for whom comprehensive NGS tumour profiling was completed, 
21 patients (22%) had at least one LOF mutation in a candidate HRR gene (BRCAwt HRRm 
subset); however, analyses of PFS, OS, time to first and second subsequent therapy have not 
been performed for BRCA-independent HRRm patients because there were insufficient events 
in this patient subset.  Further clinical studies are needed to fully characterize the activity of 
olaparib in patients with a HRRm pattern (Hodgson et al 2015).  
CCI
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Furthermore, in the phase II Trial of PARP Inhibition in Prostate Cancer, in patients with 
metastatic castration-resistant prostate cancer no longer responding to standard treatments, 
16 of 49 patients presented genetic alterations in the HRR pathway.  Of these 16 patients, 
14 patients (88%) had a response to olaparib (Mateo et al 2015).  
1.1.5 
Pre-clinical experience 
The pre-clinical experience is fully described in the current version of the olaparib 
Investigational Brochure (IB) and the Prescribing Information (Appendix G) as applicable 
depending on country specific marketing authorisation status. 
1.1.6 
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 anaesthetised dog or any 
behavioural, 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 withdrawal of olaparib.  Ex vivo studies have 
confirmed that olaparib is cytotoxic to human bone marrow cells. 
Olaparib was not mutagenic in the Ames test but was clastogenic in the Chinese hamster 
ovary (CHO) chromosome aberration test in vitro.  When dosed orally, olaparib also induced 
micronuclei in the bone marrow of rats.  This profile is consistent with the potential for 
genotoxicity in man. 
Reproductive toxicology data indicate that olaparib can have adverse effects on embryofoetal 
survival and development at dose levels that do not induce significant maternal toxicity.  
Further information can be found in the current version of the olaparib IB and the Prescribing 
Information (Appendix G) as applicable depending on country specific marketing 
authorisation status. 
1.1.7 
Clinical experience 
Clinical experience with olaparib is fully described in the current version of the olaparib IB 
and the Prescribing Information (Appendix G) as applicable depending on country specific 
marketing authorisation status. 
1.2 
Research hypothesis 
Olaparib administered as monotherapy as a treatment in routine clinical practice in the 
maintenance setting in line with the approved indication in the European Union (EU) exhibits 
the level of clinical effectiveness, safety and tolerability that are consistent with those seen in 
controlled clinical trials to date within the olaparib clinical development programme in the 
same treatment setting. Patients with somatic BRCA deleterious or suspected deleterious 
mutated disease (sBRCAm) appear to have consistent outcomes with those reported previously 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
30(96) 
in patients with gBRCAm ovarian cancer. The capsule formulation is appropriate to use in this 
clinical setting in patients with BRCA mutated relapsed ovarian cancer who have a complete 
or partial response to platinum-based chemotherapy. 
The exploratory HRRm cohort will assess olaparib activity among patients with ovarian 
cancer who carry LOF genetic alterations among 13 genes, other than BRCA1 and BRCA2 
(i.e., BRCA-independent HRRm), involved in the HRR pathway, as identified on an archival 
tumour sample by the Lynparza HRR Assay (see Section 1.1.4).  
1.3 
Rationale for study design and doses  
Based on the results of a pivotal phase II trial (D0810C00019), described in more detail above 
(Section 1.1.3), olaparib as the capsule formulation at a daily recommended dose of 400 mg 
twice daily (a total daily dose of 800 mg) has been approved in EU as monotherapy for the 
maintenance treatment of adult patients with platinum sensitive relapsed (PSR) BRCA mutated 
(germline and/or somatic) high grade epithelial ovarian, fallopian tube, or primary peritoneal 
cancer who are in response (complete response or partial response) to platinum-based 
chemotherapy. 
AstraZeneca in cooperation with the European Network of Gynaecological Oncological Trial 
Groups (ENGOT) is also conducting currently a phase III trial (D0816C00002) to confirm the 
outcomes of olaparib as maintenance monotherapy in patients with PSR BRCA mutation 
positive ovarian cancer. The phase III confirmatory trial is being conducted with the new 
tablet formulation. 
The phase II study D0810C000019 demonstrated the efficacy of olaparib maintenance when 
using the capsule formulation (8 capsules twice daily).  A more patient friendly tablet 
formulation (2 tablets twice daily) has been developed and currently studied in a phase III 
ongoing study investigating the efficacy of the tablet formulation when given as a 
maintenance therapy to patients with BRCA mutated platinum sensitive relapsed ovarian 
cancer.   
Further information is provided in the IB or the Prescribing Information (Appendix G) as 
applicable depending on country specific marketing authorisation status. 
The findings from study D0810C00019 are supported by clinical data from over 350 
additional patients with BRCAm ovarian cancer in 6 other olaparib trials demonstrating 
consistent response rates.  Details are available in the IB and the Prescribing Information 
(Appendix G) as applicable depending on country specific marketing authorisation status.  
The current study will allow patients to complete their platinum-containing regimen prior to 
enrolment and then initiate maintenance treatment with olaparib as per the EU approved 
indication and according to normal clinical practice. This study is the first study to explore the 
use of olaparib in a clinical setting very near to expected routine clinical practice and to 
provide valuable further insight into patients’ benefit and tolerability, quality of life and 
clinical management in this treatment setting. 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
31(96) 
In order to avoid including mainly patients with previously diagnosed gBRCA mutated 
disease, only patients with unknown germline BRCA mutation status or patients found to carry 
gBRCAwt disease or patients previously identified as having BRCAm disease based on a 
tumour test (with unknown gBRCA mutation status or with previously identified gBRCAwt 
status) will be considered for screening.  Patients previously diagnosed with gBRCAm disease 
will not be included in this study. 
The study will explore whether patients presenting with BRCA-independent qualifying 
alterations in any of the 13 HRR genes tested by the Lynparza HRR Assay (HRRm 
exploratory cohort) may benefit from treatment with olaparib, using the same maintenance 
treatment regimen as approved by the European Medicines Agency for patients with sBRCAm 
or gBRCAm ovarian cancer.  
1.4 
Benefit/risk and ethical assessment 
Olaparib is considered to have a positive benefit-risk profile in this study target population of 
relapsed BRCA mutated platinum sensitive ovarian cancer patients based on the randomised 
phase II data in the same patient population (see Section 1.3) demonstrating a large and 
clinically meaningful prolongation of progression free survival, with an acceptable tolerability 
profile for use in the maintenance setting. Platinum-containing therapy is considered the 
treatment of choice for patients with recurrent platinum sensitive ovarian cancer, including 
those patients with BRCAm ovarian cancer, however the duration of response (DoR) and the 
prolongation of the progression free interval are usually brief and these chemotherapy 
regimens cannot be continued until progression as they are associated with neurological, renal 
and haematological toxicity and cannot generally be tolerated for more than about 6 cycles.  
Since chemotherapy is not a viable treatment option in the maintenance setting, there is a need 
for a well-tolerated maintenance treatment (following completion of chemotherapy) that can 
be taken until disease progression to extend the progression free interval in this patient 
population.   
Patients with BRCAm ovarian cancer, however, represent a targeted and clinically identifiable 
subpopulation.  
The current study design will allow patients to complete their standard platinum-containing 
regimen prior to enrolment and then initiate maintenance treatment with olaparib as per its 
EU-approved indication and according to normal clinical practice. Considering that ovarian 
cancer is the leading cause of death from gynaecological tumours in the Western world, the 
clinically meaningful efficacy benefit of olaparib in the targeted BRCA mutated patient 
population and the known tolerability profile of olaparib monotherapy used according to EU-
approved indication and restrictions, the current study is considered to have a positive benefit-
risk profile. Refer to the current IB or the Prescribing Information (Appendix G) as applicable 
depending on country specific marketing authorisation status for a complete description of the 
safety and tolerability profile.  


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
32(96) 
An additional exploratory patient cohort will be enrolled in the study, comprised of patients 
with BRCAwt status, and BRCA-independent HRRm ovarian cancer. These patients will be 
treated and followed up in the same manner as patients with sBRCAm and gBRCAm disease.  
1.5 
Study Design  
This is a prospective, open-label, single arm, multi-centre study to assess the real world 
clinical effectiveness and safety of olaparib maintenance monotherapy as the capsule 
formulation in relapsed high grade epithelial ovarian cancer patients (including patients with 
primary peritoneal and / or fallopian tube cancer) who carry germline or somatic BRCA 
mutations (documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or 
suspected deleterious [known or predicted to be detrimental/lead to loss of function]) who 
have responded following platinum based chemotherapy. 
Figure 1 
Study Flow Chart 
 
Patients will be assigned to olaparib capsules p.o. 400 mg twice daily. They should initiate 
olaparib treatment within 8 weeks after their last dose of chemotherapy (last dose is the day of 
the last infusion). 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
33(96) 
All patients will have clinical and objective radiological tumour assessments according to 
modified Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 guidelines at baseline 
and every 12 weeks relative to date of enrolment, until objective radiological disease 
progression as determined by the investigator. Patients could continue to receive olaparib for 
as long as determined by the investigator, until objective radiological disease progression or as 
long as in the investigator’s opinion they are benefiting from treatment in relation to other 
clinical assessments and they do not meet any other discontinuation criteria. 
The study will recruit approximately 250 patients with sBRCAm disease or gBRCAm disease, 
with aim to accrue a minimum of 50 patients with sBRCAm disease. Patients found or known 
to carry a deleterious or suspected deleterious mutation in the tumour will be eligible to 
continue study screening procedures. They will provide a blood sample to determine their 
mutated or wild type germline BRCA status (in the latter case, confirming a somatic mutation). 
BRCA mutated disease will be determined or confirmed through central blood and tumour 
testing (as outlined in Section 5.7.6).  
Any counselling procedures required before such testing will be carried out in accordance 
with local hospital practice.  For more information please see Section 5.7.6. 
Based on the respective frequencies of gBRCA and sBRCA mutations in patients with ovarian 
cancers, it is expected that approximately 25% of the patients eligible to enter the study with 
BRCA mutated disease will harbour a somatic mutation. The recruitment of patients with 
gBRCAm disease may be capped if, after enrolling 150 patients onto the study, less than 50 
patients are confirmed to have sBRCAm disease.   
Additionally, an exploratory cohort of patients with tumour BRCAwt status, who are found to 
carry one or more BRCA-independent qualifying genetic alterations in the 13 HRR genes 
tested by the Lynparza HRR Assay will be enrolled in the study (HRRm cohort).  It is 
expected that approximately 450 patients with tumour BRCAwt status will be screened using 
the Lynparza HRR Assay and approximately 5% of those screened will be enrolled into the 
study based on presence of BRCA-independent qualifying HRR mutation.  Recruitment into 
this HRRm cohort will not interfere with the planned recruitment of approximately 250 
patients with BRCAm ovarian cancer. 
Once a patient has discontinued olaparib she will be managed as per local clinical practice but 
will remain in the study and data will be collected on subsequent treatments, progression and 
survival. 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
34(96) 
2. 
STUDY OBJECTIVES 
2.1 
Primary objectives 
Co-Primary Objectives: 
Outcome Measure: 
x 
To assess the real world clinical 
effectiveness of olaparib maintenance 
monotherapy by investigator assessed 
progression free survival (PFS) according 
to modified Response Evaluation Criteria 
In Solid Tumours (RECIST) 1.1 in patients 
with sBRCAm ovarian cancer.  
x 
To assess the real world clinical 
effectiveness of olaparib maintenance 
monotherapy by investigator assessed PFS 
according to RECIST 1.1 in patients with 
BRCAm ovarian cancer 
Time from study enrolment to disease progression 
(assessed according to RECIST 1.1 guidelines) or 
death.  
2.2 
Secondary objectives 
Secondary Objective: 
Outcome Measure: 
To assess the real world clinical effectiveness 
of olaparib maintenance monotherapy in 
patients with BRCAm ovarian cancer and 
patients with sBRCAm ovarian cancer, by 
assessment of: 
a) overall survival (OS),  
b) time to investigator-assessed second 
progression (PFS2), or death. 
a) Time to death 
b) Time to second progression event or of death if 
this occurs before second progression event. 
To assess the real word clinical effectiveness 
of olaparib maintenance monotherapy in 
patients with BRCAm ovarian cancer and 
patients with sBRCAm ovarian cancer, by 
assessment of  
a) time to first subsequent therapy or death 
(TFST),  
b) time to second subsequent therapy or death 
(TSST) and,  
c) time to olaparib discontinuation or death 
(TDT). 
a) Time to first subsequent treatment commencement 
or death if this occurs before commencement of first 
subsequent treatment 
b) Time to second subsequent treatment 
commencement or death if this occurs before 
commencement of second subsequent treatment 
c) Time to olaparib discontinuation or death if this 
occurs before discontinuation of olaparib 
maintenance therapy. 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
35(96) 
Secondary Objective: 
Outcome Measure: 
To assess and describe the quality of life (QoL) 
of patients with BRCAm ovarian cancer and 
patients with sBRCAm ovarian cancer. 
Functional Assessment of Cancer Therapy-Ovarian 
(FACT-O), Functional Assessment of Chronic Illness 
Therapy (FACIT)-Fatigue, and ORZORA QoL 
Additional Items Questionnaire.   
To describe patterns of routine clinical use of 
olaparib, the nature and patterns of adverse 
events (AEs) of nausea and vomiting and their 
impact on QoL in patients with BRCAm 
ovarian cancer and patients with sBRCAm 
ovarian cancer.  
To describe nausea/vomiting toxicity 
management patterns used in routine clinical 
practice. 
Safety summary tables, Functional Living Index-
Emesis (FLIE) Questionnaire, and concomitant 
medication use.  


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
36(96) 
2.3 
Safety objectives 
Safety Objective: 
Outcome Measure: 
To assess the safety and tolerability of olaparib 
maintenance monotherapy in patients with 
BRCAm ovarian cancer and patients with 
sBRCAm ovarian cancer. 
AEs/serious adverse events (SAEs)/AEs of special 
interest (AESI) 
 
 
2.4 
Exploratory objectives 
Exploratory Objectives: 
Outcome Measure: 
To describe the longer term safety of olaparib 
monotherapy, including follow up for 
Myelodysplastic Syndrome (MDS)/ Acute 
Myeloid Leukaemia (AML)/ New primary 
malignancies. 
Collection of long term adverse events, including 
MDS/AML or new primary malignancies 
To correlate the incidence of side effects and 
QoL according to age and the presence of 
comorbidities. 
Based on collected and summarised outcomes and 
comorbidities 
To describe the clinical effectiveness of 
(response to) subsequent line of treatment and 
correlating it with the progression-free interval 
(PFI) (artificial prolongation of PFI through 
olaparib).  
Description of maximum response to subsequent line 
of treatment  
To describe the efficacy of olaparib according 
to the previous therapy, with or without 
bevacizumab, and according to the PFI 
(recurrence during or after the end of 
bevacizumab maintenance). 
Based on collected and summarised outcomes 
To describe the activity of olaparib according 
to the germline mutational status (BRCA1 vs 
BRCA2), and to the presence of family history 
(yes vs not). 
Based on collected and summarised outcomes and 
family history 
To describe the kinetic of CA-125 progression 
according to Gynecological Cancer InterGroup 
(GCIG) criteria and its correlation with disease 
progression by RECIST 1.1 guidelines during 
olaparib therapy. 
Based on collected and summarised outcomes 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
37(96) 
Exploratory Objectives: 
Outcome Measure: 
To measure loss of heterozygosity (LOH) for 
the BRCA1 and BRCA2 genes in tumour 
samples and explore any potential association 
with efficacy. 
Based on all available tumour samples collected and 
summarised outcomes. 
To describe the real world clinical 
effectiveness and safety of olaparib 
maintenance monotherapy in patients with 
BRCA-independent HRRm ovarian cancer, by 
the following:   
x 
Investigator assessed PFS according to 
RECIST 1.1 
x 
OS 
x 
Safety and tolerability. 
a) Time from study enrolment to disease progression 
(assessed according to RECIST 1.1 guidelines) or 
death 
b) Time to death 
c) AEs, SAEs, AESI 
Potential exploratory research into frequency, 
nature and predictive value of HRR gene 
mutations, including BRCA1 and BRCA2, may 
be performed on the optional collected and 
stored tumour samples available at study entry 
or tumour biopsy samples collected during the 
course of the study.  
These could include studying resistance 
mechanisms to olaparib, future exploratory 
research into factors that may influence 
development of cancer and/or response to 
study treatment.  
To collect and store deoxyribonucleic acid 
(DNA) (according to each country’s local and 
ethical procedures) for future exploratory 
research into genes/genetic variation that may 
influence response to study treatment and or 
susceptibility to disease (optional)*. 
 
To explore the feasibility of reliably measuring 
sBRCAm and HRRm from circulating tumour 
DNA (ctDNA)* 
 
*  
These exploratory analyses may not be reported in the clinical study report (CSR), if not they will be 
reported separately. 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
38(96) 
3. 
PATIENT SELECTION, ENROLMENT, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL  
Each patient should meet all of the inclusion and none of the exclusion criteria for this study.  
These are designed in line with the EU approved indication for patients carrying BRCA 
mutated ovarian cancer. Under no circumstances can there be exceptions to this rule. 
Patients with unknown germline BRCA mutation status, or patients found to carry gBRCAwt 
disease, or patients previously identified as having BRCAm disease based on a tumour test 
(with unknown gBRCA mutation status or with previously identified gBRCAwt status) will be 
considered for screening.  
Patients previously diagnosed with gBRCAm disease will not be included in this study. 
Patients with unknown BRCA mutation status who are considered for inclusion in this trial 
should be identified early so that the appropriate BRCA mutation screening procedures can be 
put in place in a timely manner.  
In order to optimise the screening of patients and potential timely treatment initiation with 
study drug, patients may start the screening procedure from the end of cycle 3 of their current 
chemotherapy, if they are responding to treatment in the opinion of the investigator.  
BRCA mutation status will be determined or confirmed through central blood and tumour 
testing as outlined in Figure 2 (see also Section 5.7.6).  
Exploratory HRRm patient cohort 
Patients screened for the study with unknown BRCA status or with known gBRCAwt status, 
for whom an adequate archival tumour tissue sample is available, will be tested for qualifying 
HRR gene alterations, as defined in Section 1.1.4.  
Patients found not to carry a BRCA mutation in their tumour (tumour BRCAwt), and with 
qualifying BRCA-independent HRR genetic alterations will be included in the study (HRRm 
cohort), and analysed as a separate exploratory cohort.  
Patients previously identified as having BRCAm based on a tumour test will not be screened 
for HRR gene mutations. 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
39(96) 
Figure 2 
Screening Flow Chart 
 
  
*Undetermined: the central tumour BRCA testing was unable to determine the presence or absence of 
BRCA mutation. 
3.1 
Inclusion criteria 
Screening procedures described in Section 3 should be strictly complied with.  For inclusion 
in the study patients should fulfil the following criteria: 
1. 
Provision of informed consent prior to any study specific procedures  
2. 
Age 18 years or over 
3. 
Documented germline or somatic mutation in BRCA1 or BRCA2 genes that is predicted 
to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to 
loss of function) [Genetic counselling for patients with germline BRCA mutations 
should be performed according to local regulations] 
Or 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
40(96) 
Tumour BRCAwt status and documented qualifying mutation in any of 13 genes 
involved in the HRR pathway, excluding BRCA1 and BRCA2 (ATM, BARD1, BRIP1, 
CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, 
and RAD54L), identified by the Lynparza HRR Assay in archival tumour tissue (i.e., 
BRCA-independent HRRm) 
4. 
Patients with platinum sensitive relapsed high grade epithelial ovarian cancers 
(including primary peritoneal and/or fallopian tube cancer): 
 
Platinum sensitive disease is defined as disease progression 6 months after 
completion of their last dose of platinum based chemotherapy 
5. 
Patients should have received at least 2 previous lines of platinum containing therapy 
prior to enrolment: 
 
For the last chemotherapy course immediately prior to enrolment on the study, 
patients must be, in the opinion of the investigator, in response (partial or 
complete radiological response) and no evidence of a rising CA-125, following 
completion of this chemotherapy course. 
6. 
Patients must have normal organ and bone marrow function measured within 28 days of 
enrolment, as defined below: 
 
Haemoglobin JG/ZLWKQRElood transfusions in the past 28 days 
 
Absolute neutrophil count (ANC) [9/L 
 
Platelet count [9/L 
7. 
Total bilirubin [LQVWLWXWLRQDOXSSHUOLPLWRIQRUPDO8/1, Aspartate 
aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase [SGOT]) / 
Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase [SGPT]) 
2.5 x institutional ULN unless liver metastases are present in which case they must be 
5x ULN 
8. 
Creatinine clearance > 50 ml/min (calculated) 
9. 
Patients must be postmenopausal or have evidence of non-childbearing status for 
women of childbearing potential. 
Postmenopausal is defined as any of the following: 
x Amenorrhoea for 1 year or more following cessation of exogenous hormonal 
treatments 
x For women under 50 years old, luteinizing hormone (LH) and follicle 
stimulating hormone (FSH) levels in the post-menopausal range  
x Radiation-induced oophorectomy, with interval of 1 year or more since last 
menses 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
41(96) 
x Chemotherapy-induced menopause, with interval of 1 year or more since last 
menses  
x Surgical sterilisation (bilateral oophorectomy or hysterectomy).  
 
3.2 
Exclusion criteria 
Screening procedures described in Section 3 should be strictly complied with and patients 
should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Patients previously diagnosed with gBRCAm disease 
2. 
Participation in another clinical study with an investigational product during the most 
recent chemotherapy course  
3. 
Patients with a known hypersensitivity to olaparib or any of the excipients of the 
product  
4. 
Patients receiving any systemic chemotherapy or radiotherapy (except for palliative 
reasons) or major surgery within 3 weeks prior to olaparib treatment. Major surgery 
within 3 weeks of starting study treatment and patients must have recovered from any 
effects of any major surgery 
5. 
Persistent toxicities Common Terminology Criteria for Adverse Event (CTCAE) grade 
2 caused by previous cancer therapy, excluding alopecia 
6. 
Patients with myelodysplastic syndrome/acute myeloid leukaemia 
7. 
Immuno-compromised patients e.g., Human Immunodeficiency Virus (HIV) requiring 
treatment or active Hepatitis B or C 
8. 
Patients with symptomatic uncontrolled brain metastases. The patient can receive a 
stable dose of corticosteroids before and during the study as long as these were started 
at least 4 weeks prior to treatment. Patients with spinal cord compression unless 
considered to have received definitive treatment for this and evidence of clinically 
stable disease (SD) for 28 days 
9. 
Patients considered to be at a high medical risk due to a serious, uncontrolled medical 
disorder, systemic disease or active, uncontrolled infection  
10. 
Currently pregnant (confirmed with a positive pregnancy test) or breastfeeding. 
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4. 
3.3 
Patient enrolment 
Investigator(s) should keep a record of the patient screening log, of patients who entered pre-
study screening. 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
42(96) 
The Investigator(s) will: 
x 
Obtain signed informed consent from the potential patient before any 
study specific procedures are performed. 
x 
Assign potential patient a unique enrolment number, beginning with ‘E#’. 
This number is obtained through Interactive Voice/Web response System 
(IVRS/IWRS). 
x 
Determine patient eligibility. See Section 3. 
x 
If patient meets eligibility criteria enrol patient through IVRS/IWRS to 
dispense the IP. 
If a patient withdraws from participation in the study, then her enrolment number cannot be 
reused. 
3.4 
Procedures for handling incorrectly enrolled patients 
Where a patient does not meet all the eligibility criteria but is incorrectly enrolled and 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 patient from treatment.  The AstraZeneca 
study physician must ensure all decisions are appropriately documented. 
3.5 
Methods for assigning treatment groups 
Not applicable. 
3.6 
Methods for ensuring blinding 
Not applicable. 
3.7 
Methods for unblinding  
Not applicable. 
3.8 
Restrictions 
Patients of childbearing potential and their partners, who are sexually active, must agree to the 
use of two highly effective forms of contraception in combination throughout the period of 
taking treatment and for at least one month after last dose of study drug. 
For details refer to Appendix E. 
3.9 
Discontinuation of investigational product 
Patients may be discontinued from investigational product (IP) in the following situations: 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
43(96) 
x 
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment 
x 
Adverse Event 
x 
Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute 
myeloid leukaemia (AML) 
x 
Severe non-compliance with the study protocol  
x 
Disease progression (unless in the investigator’s opinion the patient is benefiting 
from the treatment and does not meet any other discontinuation criteria) 
 
3.9.1 
Procedures for discontinuation of a patient from investigational product  
By discontinuing from IP, the patient is not withdrawn from the study unless the patient 
withdraws consent to participation in the study.  If a patient is withdrawn from study, see 
Section 3.10. 
At any time, patients are free to discontinue investigational product or withdraw from the 
study, without prejudice to further treatment.  A patient that decides to discontinue IP will 
always be asked about the reason(s) and the presence of any adverse events.  Any patient 
discontinuing IP should be seen at 30 days post last dose of IP for the evaluations outlined in 
the study schedule. After discontinuation of IP, the Principal Investigator (PI)/Sub-
Investigator will perform the observation(s), test(s) and evaluation(s) consistent with the 
current standard of care as well as give appropriate medication and all possible measures for 
the safety of the patient. Patients who discontinue treatment prior to documented progression 
should continue to be followed for first progression as per the protocol recommended 
schedule.  Once progressed, all patients should be followed for PFS2 and OS as per the 
protocol schedule.  In addition, they will record on the electronic case report form (eCRF) the 
date of discontinuation, the reasons, manifestation and treatment at the time of 
discontinuation. If patients discontinue olaparib, the study monitor must be informed 
immediately. Patients will be required to attend the treatment discontinuation visit. The patient 
should return all IP. 
After discontinuation of olaparib 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 patients underlying disease, or the patient is lost to follow up (see 
Section 4.3.1). All new AEs and SAEs occurring during the 30 calendar days after the last 
dose of olaparib must be reported (if SAEs, they must be reported to AstraZeneca within 24 
hours as described in Section 6.5) and followed to resolution as above. Patients should be seen 
at least 30 days after discontinuing the last IP dose to collect and / or complete AE 
information. Any untoward adverse event occurring subsequent to that the investigator 
assesses as possibly related to the study medication should also be reported as an adverse 
event. Cases of MDS, AML or new primary cancers, as well as pneumonitis should be 
reported also after the 30-day follow-up AE reporting period. 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
44(96) 
Any patient who has not yet shown disease progression at withdrawal from IP should continue 
to be followed as detailed in Table 3. 
All patients should be followed for survival, up to the final analysis. 
3.10 
Criteria for withdrawal  
3.10.1 
Screen failures  
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be enrolled.  These patients should have the reason for study withdrawal 
recorded as ‘Did not meet Eligibility Criteria’ (i.e., patient does not meet the required 
inclusion/exclusion criteria), and screening failure/ study withdrawal should be noted in 
IVRS/IWRS.  This reason for study withdrawal is only valid for screen failures (not enrolled 
patients). Patients who were screen failures may be re-enrolled and re-screened if in the 
opinion of the Investigator, the reason(s) for earlier withdrawal no longer applies. Patients 
cannot re-enter the study if dosed and subsequently withdrawn from the study. 
3.10.2 
Withdrawal of the informed consent 
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment. 
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow up AEs outside of the clinical study.   
If a patient withdraws from participation in the study, then her unique enrolment number 
cannot be reused. Withdrawn patients will not be replaced.  
3.11 
Discontinuation of the study 
The study may be stopped if, in the judgment of AstraZeneca, trial patients 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 patient at the time of 
discontinuation of follow-up must be recorded in the eCRF. 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 patients’ interests. 
 
 


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Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
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4. 
STUDY PLAN AND TIMING OF PROCEDURES 
Table 1 
Study Schedule Screening 
 
Part 1 
 
BRCA testing 
Part 2 
Patients with known  
tumour BRCA 
mutation  
 
Post-cycle 3 of 
ongoing 
chemotherapy to  
-28 daysa 
-28 to –1 days 
Informed consent 
Xb 
Xi 
Demographics 
 
X 
Medical and surgical history 
 
X 
Inclusion/exclusion criteria 
 
X 
ECOG Performance Status (0-2) 
 
X 
Vital signs, body weight, (includes blood pressure 
[BP] and pulse) 
 
X 
Haematology / clinical chemistryc 
 
X 
Pregnancy test 
 
X 
Tumour Assessment (CT or MRI according to 
RECIST 1.1 guidelines)d 
 
X 
Blood sample for disease specific marker (CA-125) 
 
X 
Tumour sample for determination of tumour BRCA 
status 
Xe 
Xe 
Blood sample for determination of gBRCA status 
Xf 
Xf 
Tumour sample for HRR testing  
Xg 
 
Adverse Events (from time of consent) 
Xh 
Xh 
Relevant concomitant medications 
 
X 
Optional tumour sample for exploratory analysis 
 
Xj 
a 
The post cycle 3 of ongoing chemotherapy to -28 day time period is to allow patients with unknown 
BRCA mutation status who are considered for inclusion in this trial to be identified early so that the 
appropriate BRCA mutation screening procedures can be put in place in a timely manner. In order to 
optimize the screening of patients and potential timely treatment initiation with study drug patients may 
start the screening procedure from the end of cycle 3 of their current chemotherapy if they are, in the 
opinion of the investigator, in partial or complete response.  
b 
Informed consent for BRCA testing and HRR testing only.   
c 
Coagulation tests will only be required if clinically indicated.   
d 
Computed Tomography (CT)/ Magnetic Resonance Imaging (MRI) of the chest, abdomen and pelvis 
not more than 28 days prior to starting olaparib and as close as possible to the start of olaparib.  


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
46(96) 
e 
As part of the study screening procedures, an archival tumour sample should be provided for central 
determination or confirmation of BRCAm status. If an archival tumour sample is not available, a fresh 
biopsy should be provided (see Sections 5.7.1 and 5.7.6 for further details). 
x 
For patients with unknown BRCAm status and patients with previously identified gBRCAwt 
status, tumour BRCAm status will be determined by central laboratory testing on tumour 
samples.  
x 
Patients who have been previously identified as having BRCA mutations in the tumour, 
determined in a local test, can enter screening Part 2; however confirmatory central test from 
tumour should be completed prior to enrolment. 
f  
Blood samples for central determination of gBRCA status will be collected from patients who are found 
to carry a tumour BRCA mutation based on the central tumour test (see Sections 5.7.4 and 5.7.7).  
x 
This result will be used to confirm patients’ germline or somatic BRCA mutated disease, and 
the test should be completed prior to study enrolment.  
x 
Patients who have been previously identified as having BRCA mutations in the tumour and 
enter the study at Part 2 screening as either known somatic patients based on the local testing, 
or tumour BRCA with unknown germline status, can be enrolled into the study after central 
confirmation of their BRCA tumour mutation status and blood sample collection for central 
confirmation of the germline or somatic BRCA mutation status. 
g 
As part of the study screening procedures, if available, an archival tumour sample should be provided 
for central determination of BRCA-independent HRR mutation status.  If an adequate archival tumour 
sample is not available for this test, it will not be conducted (see Section 5.7.2 for further details).  
h 
Only SAE’s related to screening procedures will be collected at this visit. 
i  
Informed consent for participation in the main study, including optional consent for tumour and blood 
samples for exploratory analysis. 
j  
All patients are requested to provide samples of their most recently available tumour tissue for 
exploratory testing (optional and subject to specific informed consent). This is to be provided in addition 
to the diagnostic samples for tumour BRCA and HRR testing (see Section 5.7.3).  
 
 
 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
47(96) 
Table 2 
Study Schedule – On Study Treatment and Discontinuation  
Visit Number 
2 
3 
Visit No. 4 onwards  
Subsequent on treatment visits every 4 weeksa 
Tumour assessment visits every 12 weeksa,b 
Discontinuation of 
olaparib  
Safety Follow-up 30 days 
after last dose of IP 
Day 
1 
29 
Day 1of next visit period 
(Visit 4 equals day 57 (week 8) then visit 5 
equals day 85 (week 12) etc.) 
 
 
Visit Window 
 
 
±3d 
±3d 
±7d 
±7d 
Enrolment 
X 
 
 
 
 
Haematology / clinical 
chemistryc 
Xc 
Xc 
X 
X 
X 
Blood sample for disease 
specific marker (CA-125) 
Xi 
Xi 
Xi 
Xi 
 
Blood samples for ctDNA 
analysis 
 
Xj 
 
 
 
Tumour Assessment (CT or 
MRI according to RECIST 
1.1 guidelines)b 
 
Every 12 weeks until PD 
 
 
FACT-Og 
X 
X 
X 
X 
X 
FACIT-Fatigueg 
X 
X 
X 
X 
X 
ORZORA QoL Additional 
Items Questionnaire g 
X 
X 
X 
X 
X 
Adverse Eventsd 
X 
X 
X 
X 
X 
FLIEg, h 
Xh 
Xh 
X 
X 
X 
Concomitant medications 
including blood transfusions 
X 
X 
X 
X 
X 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
48(96) 
Table 2 
Study Schedule – On Study Treatment and Discontinuation  
Visit Number 
2 
3 
Visit No. 4 onwards  
Subsequent on treatment visits every 4 weeksa 
Tumour assessment visits every 12 weeksa,b 
Discontinuation of 
olaparib  
Safety Follow-up 30 days 
after last dose of IP 
Day 
1 
29 
Day 1of next visit period 
(Visit 4 equals day 57 (week 8) then visit 5 
equals day 85 (week 12) etc.) 
 
 
Visit Window 
 
 
±3d 
±3d 
±7d 
±7d 
Olaparib 
dispensed/returnede 
X 
X 
X 
X 
 
Subsequent cancer therapy 
following discontinuation of 
olaparibf 
 
 
 
 
X 
Optional tumour sample on 
progression j 
 
 
 
X 
 
a 
Visit to take place on Day 1 of a 4 week (28 day) visit period up to 52 weeks (if not progressed and still on treatment) as per IB or prescribing 
information as applicable based on country specific marketing authorisation status, then on day 1 of a 12 week visit period relative to date of enrolment.  
Visits for patients who remain on treatment post progression should take place every 12 weeks. 
b 
Follow-up tumour assessment visits will be performed every 12 weeks (±1 week) relative to date of enrolment. Follow-up CT or MRI assessments will 
cover chest (in those patients with disease in the chest or upper abdomen lymphadenopathy at baseline), abdomen and pelvis. Any other sites at which 
new disease is suspected should also be appropriately imaged.  Patients will be followed until disease progression according to RECIST 1.1 guidelines. 
If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent assessments at 
their scheduled visits.  
c 
Safety blood samples do not need to be repeated on Day 1 of olaparib treatment if assessed within 7 days before starting olaparib, unless the investigator 
believes that it is likely to have changed significantly.  Coagulation tests only required if clinically indicated.  For a list of all required laboratory tests 
please refer to Section 5.2.1  
d 
When an AE for nausea and vomiting occurs, an additional eCRF will require completion.  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 as per Section 6.4.3. 
e 
Sufficient olaparib should be dispensed for at least each treatment period plus overage, however additional treatment can be dispensed to patients to last 
longer in accordance with local practice. 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
49(96) 
f 
Post discontinuation of olaparib all anti-cancer treatments (including, but not limited to, chemotherapy and targeted agents), and the investigator’s 
opinion of response to them plus the date of progression need to be recorded. 
g 
QoL questionnaires will be collected at baseline, at Day 29, then every 12 weeks (+/- 7 days) for 24 months or the data cut off for the primary analysis, 
whichever comes first. In addition, QoL questionnaires will be collected at the discontinuation of study treatment visit and 30 days post last dose. 
h 
In addition to the outlined QoL collection frequency, in the first month from starting the study treatment, the FLIE questionnaire will be administered to 
the patient weekly, in person or over the phone. 
i  
Assessment of CA-125 will be at the discretion of the investigator, according to the local clinical practice.  
j 
To be collected only for patients that have confirmed sBRCAm or HRRm ovarian cancer (optional and subject to specific informed consent). If 
confirmation of the sBRCAm status is not obtained by Day 29, these blood samples can be taken at a later study visit. 
h 
Optional and subject to specific informed consent.  
 
 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
50(96) 
Table 3 
Study Schedule – Follow-up Post Discontinuation of Olaparib 
Visit Number 
Off treatment follow-up  
Olaparib discontinued due to reasons other 
than disease progression 
Follow-up for patients beyond 1st disease progression (PFS1) 
 
 
Follow up for 1st progression 
Tumour assessment visits every 12 weeksa 
Every 12 weeks post discontinuation of olaparib 
 
Visit Window 
±7d 
±7d 
Tumour Assessment (CT 
or MRI according to 
RECIST 1.1 guidelines) a 
Every 12 weeks until PD, one 
additional RECIST 1.1 assessment 
required after PD declared by the 
investigator 
 
Blood sample for disease 
specific marker (CA-125) 
Xg 
 
FACT-Of 
X 
X 
FACIT-Fatiguef 
X 
X 
ORZORA QoL Additional 
Items Questionnaire f 
X 
X 
Adverse Eventse 
Xe 
Xe 
FLIEf 
X 
X 
Subsequent cancer therapy 
following discontinuation 
of olaparibb 
X 
X 
Time to second 
progression 
 
X 
Survivalc,d 
X 
X 
a 
RECIST 1.1 follow-up assessments will be performed as per the original schedule every 12 weeks (±1 week) relative to date of enrolment. Follow-up 
assessment will include CT or MRI assessments of abdomen and pelvis for all patients. Follow-up chest CT will be performed in patients with thoracic 
lesions or upper abdomen lymphadenopathy identified at baseline assessment.  Any other sites at which new disease is suspected should also be 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
51(96) 
appropriately imaged.  Patients will be followed until disease progression as per RECIST 1.1 guidelines.  If an unscheduled assessment was performed 
and the patient has not progressed, every attempt should be made to perform the subsequent assessments at their scheduled visits.  
b 
All anti-cancer treatments (including, but not limited to, chemotherapy and targeted agents), and the investigators opinion of response to them, 
significant patient toxicity arising from their use plus the date of progression, post discontinuation of olaparib need to be recorded 
c 
The status of ongoing, withdrawn (from the study) and “lost to follow-up” patients at the time of an overall survival analysis should be obtained by the 
site personnel by checking the patients notes, hospital records, contacting the patients general practitioner and checking publicly available death 
registries. In the event that the patient has actively withdrawn consent to the processing of their personal data the vital status of the patient can be 
obtained by site personnel from publicly available resources where it is possible to do so under applicable local laws. 
d 
In addition to their regular 12 weekly contact, patients will be contacted in the 7 days following a specified date (data cut-off date) for each survival 
analysis.  
e 
See section 6.4.3 for reporting of adverse events after the 30 day follow up period. 
f 
QoL questionnaires will be collected every 12 weeks (+/- 7 days) for 24 months or the data cut off for the primary analysis, whichever comes first. 
Patients who had disease progression will complete the questionnaires during the 12 weekly survival follow ups either in person or over the phone. 
g 
Assessment of CA-125 will be at the discretion of the investigator, according to the local clinical practice. 
 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
52(96) 
4.1 
Enrolment/screening period 
Procedures will be performed according to the Study Plan in Table 1. Each potential patient 
will provide written informed consent prior to any study specific procedures and undergo 
assessments applicable for the visit. 
Patients with unknown germline BRCA mutation status, or patients found to carry gBRCAwt 
disease, or patients previously identified as having BRCAm disease based on a tumour test 
(with unknown gBRCA mutation status or with previously identified gBRCAwt status) will be 
considered for screening.  
Patients previously diagnosed with gBRCAm disease will not be included in this study. 
Patients with unknown BRCA mutation status who are considered for inclusion in this study 
may start the screening procedure from the end of cycle 3 of their current chemotherapy, if 
they are responding to treatment in the opinion of the investigator. 
All patients who wish to participate in the study will have to consent to undergo tumour and 
germline BRCA testing as required as part of the screening procedures, depending on the 
sequence of testing and results from each test. BRCA mutation status will be determined or 
confirmed through central blood and tumour testing as outlined in Figure 2 (see also 
Section 5.7.6). Tumour BRCA mutation status will be determined by central laboratory test on 
tumour samples. An archival tumour sample should be provided for central determination of 
BRCA status. If an archival tumour sample is not available, a fresh biopsy should be provided 
(see section 5.7.1 for further details). Blood samples for central determination of gBRCA 
status will be collected from all patients who are found to carry a tumour BRCA mutation 
based on the central tumour test. This result will be used to confirm patients’ germline or 
somatic BRCA mutated disease (the latter with mutation present only in the tumour), and the 
test should be completed prior to study enrolment.  
Patients with unknown BRCA status and patients with prior assessment of gBRCAwt status 
will be screened for tumour BRCA mutation as described above and will start the study from 
screening Part 1 and continue to Part 2, if applicable. Patients who have been previously 
identified as having BRCA mutations in the tumour, determined in a local test (with unknown 
germline status or previously confirmed gBRCAwt status) can start the study from screening 
Part 2. However, confirmatory central test from tumour sample should be completed prior to 
enrolment. They can be enrolled in the study after central confirmation of the tumour BRCA 
mutation, and blood sample collection for central confirmation of the germline or somatic 
BRCA mutated disease.  
All patients will be asked to consent to and provide an adequate archival tumour sample, if 
available, for tissue-based HRR gene panel mutation testing using the investigational 
Lynparza HRR Assay from 
  Patients previously identified as carrying BRCAm ovarian 
cancer based on a tumour test will not be asked to consent to and provide a tumour sample for 
HRR testing. HRR tumour testing will be performed in parallel to the central BRCA tumour 
testing. Patients with BRCAwt tumour status who carry one or more BRCA-independent 
CCI


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Drug Substance Olaparib  
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Edition Number 3 
Date 22 July 2016 
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qualifying HRR gene alterations (as defined in Section 1.1.4) will be assigned to the 
exploratory HRRm study cohort (see Section 5.7.2).  
Additionally, all patients will be also asked to provide consent to supply optional tumour 
samples for exploratory analysis, and optional blood samples (collected only for patients with 
sBRCAm or HRRm disease). This consent is included in the main patient informed consent 
form.  However, consent for providing these samples is optional and will not prevent patients 
from enrolment into the study.  
4.2 
Treatment period 
Descriptions of the procedures for this period are included in the Study Plan, Table 2 and 
Table 3.  
4.3 
Follow-up period 
Patients should be discontinued from olaparib if any discontinuation criteria are fulfilled (see 
Section 3.9).  The assessments to be carried out at the visit are detailed in the study schedule 
(Table 2 and Table 3).  
4.3.1 
Follow-up 30 days after last dose of investigational product (IP) 
A follow-up visit should be conducted 30 days after the last dose of olaparib.  Any serious 
and/or non-serious AEs ongoing at the time of the Discontinuation Visit or which have 
occurred during the defined 30-day follow-up period must be followed-up.  Appropriate safety 
evaluations should be repeated and/or additional tests performed at any time when clinically 
indicated, or at the discretion of the investigator, until resolution, unless, in the investigator’s 
opinion, the condition is unlikely to resolve due to the patient’s underlying disease.  If the 
patient is lost to follow-up, then this should be noted in the eCRF.  The assessments to be 
carried out at the 30-day follow up visit are detailed in the study schedule (Table 2 and 
Table 3).  
4.3.2 
Survival 
Assessments for survival should be made every 12 weeks following disease progression.  
Survival information may be obtained via telephone contact with the patient, patient’s family 
or by contact with the patient’s current physician.  Survival data will be collected up to the 
time of the final overall survival (OS) analysis.  In addition, patients should be contacted in 
the week following the data cut-off for the primary PFS and final survival analyses to provide 
complete survival data. 
Patients will be followed up as per Table 3 to the point of the final analysis.  At this point 
investigators will be notified that no further data collection for the study is required.  
Monitoring and recording of SAEs will continue as per Section 6.4.3. 
The status of ongoing, withdrawn (from the study) and “lost to follow-up” patients at the time 
of an overall survival analysis should be obtained by the site personnel by checking the 
patients notes, hospital records, contacting the patients general practitioner and checking 


Clinical Study Protocol 
Drug Substance Olaparib  
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Edition Number 3 
Date 22 July 2016 
54(96) 
publicly available death registries. In the event that the patient has actively withdrawn consent 
to the processing of their personal data the vital status of the patient can be obtained by site 
personnel from publicly available resources where it is possible to do so under applicable 
local laws.  
4.3.3 
Second progression (PFS2) 
Patients should be assessed every 12 weeks for a second progression (using the 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 any 
of objective radiological, CA-125, clinical progression or death.  The date of PFS2 assessment 
and investigator opinion of progression status (progressed or non-progressed) at each 
assessment will be recorded in the eCRF. 
4.3.4 
Patient management post primary analysis 
The data cut-off for the statistical analysis for the primary objective in the patients enrolled 
with BRCAm will be at 60% maturity for PFS analysis. 
Patients on olaparib at the time of the data cut-off will continue to receive olaparib until they 
meet any discontinuation criteria as per Section 3.9.  
Patients on olaparib will be followed for routine safety assessments as per protocol and as per 
EU olaparib Prescribing Information or per IB as appropriate depending on country specific 
marketing authorisation status. These patients should be followed for disease progression 
according to routine clinical practice but visits are recommended to take place at least every 
12 weeks. 
All patients (patients still on olaparib and patients withdrawn from olaparib) will be followed 
for survival and disease progression. 
4.3.5 
Patient management post final analysis 
The data cut-off for the final statistical analysis of the study will be at approximately 60% OS 
maturity or a time point defined based on event rate and study closing timelines, whichever 
occurs first.  
At this time point, the clinical study database will close to new data.  Patients who are 
receiving olaparib can either choose to discontinue from the study or where the investigator 
believes patients are gaining clinical benefit, patients may continue to receive olaparib.  All 
patients will receive follow-up care in accordance with standard local clinical practice. 
AstraZeneca will continue to supply olaparib to patients after completion of this study if 
patients are considered to continue to benefit of olaparib treatment and no other 
discontinuation criteria are met.  
SAEs will continue to be reported to AstraZeneca Patient Safety Department, for any patients 
who continue on olaparib until 30 days after olaparib is discontinued, in accordance with 


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Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
55(96) 
Section 6.4.3.  Additionally as stated, any SAE or non-serious adverse event that is ongoing at 
the end of the study must be followed up to resolution unless the event is considered by the 
investigator to be unlikely to resolve, or the patient is lost to follow-up.  If an investigator 
learns of any SAEs, including death, at any time after a patient has completed the study, and 
he/she considers there is a reasonable possibility that the event is causally related to the 
investigational product, the investigator should notify AstraZeneca, Patient Safety. 
Investigators should also report MDS, AML or new primary cancer cases, as well as 
pneumonitis. 
Drug accountability should continue to be performed until the patient stops olaparib 
completely. 
5. 
STUDY ASSESSMENTS   
The 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 eCRF 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. The 
investigator will sign the completed eCRF.  A copy of the completed eCRF will be archived at 
the study site. 
5.1 
Efficacy assessments 
5.1.1 
CT and MRI scans tumour assessments  
It is required that all patients will have clinical and objective radiological tumour assessments 
performed according to RECIST 1.1 guidelines at baseline and every 12 weeks relative to date 
of enrolment, until objective radiological disease progression as determined by the 
investigator. All treatment decisions will be based on investigator’s assessment of the scans 
according to RECIST 1.1 guidelines. It is expected that a minimum of 50 patients with 
sBRCAm disease will have efficacy assessments performed according to RECIST guidelines. 
All patients should have assessments until documented evidence of objective radiological 
progression according to RECIST 1.1 guidelines, irrespective of treatment decisions (i.e., 
radiological follow up until progression even if a patient discontinues olaparib prior to 
progression and/or receives a subsequent therapy prior to progression). CT examination with 
intravenous (i.v.) contrast media administration is the preferred imaging modality. MRI 
should only be used where CT is not feasible or it is medically contra-indicated. For brain 
lesion assessment, MRI is the preferred method. In addition, FDG-PET, bone scintigraphy and 
ultrasound may also be used for identifications of new lesions only. 
At baseline, the imaging modalities used for assessment should be performed by contrast 
enhanced CT (MRI where CT is contraindicated) scans of the chest, abdomen and pelvis with 
other regions as clinically indicated for the assessment of disease. Follow-up CT or MRI 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
56(96) 
assessments will cover chest (in those patients with disease in the chest or upper abdomen 
lymphadenopathy at baseline), abdomen and pelvis with any other regions imaged at baseline 
where disease was present.  Any other sites at which new disease is suspected should also be 
appropriately imaged.   
Sites should use the same modality and acquisition parameters to assess a patient at baseline 
and at subsequent follow-up, in order to ensure longitudinal consistency.  
Radiological examinations performed in the conduct of this study should be retained at site as 
source data. 
There will be no central review of CT and MRI scans in this study. Radiological reading will 
be performed at the site level only. All treatment decisions will be based on site assessment of 
scans.     
5.1.2 
Tumour Evaluation 
RECIST 1.1 guidelines are mandated to be used to assess patient response to treatment by 
determining progression free survival (PFS) times, objective response rates (ORR) and 
duration of response (DoR).  The RECIST 1.1 guidelines for measurable, non-measurable, 
target and non-target lesions and the objective tumour response criteria (complete response, 
partial response, stable disease or progression of disease) are presented in Appendix F. 
CA-125 should not be directly used for assessing objective response or progression and 
patients should be continued on treatment until objective radiological disease progression. 
Categorisation of objective tumour response assessment should be guided by RECIST 1.1 
guidelines: complete response (CR), partial response (PR), stable disease (SD), progression of 
disease (PD), and not evaluable (NE).  Target lesion (TL) progression will be calculated in 
comparison to when the tumour burden was at a minimum (i.e., smallest sum of diameters 
previously recorded on study).  In the absence of a response of progression, tumour response 
(CR, PR, SD or NE) will be calculated in comparison to the baseline tumour measurements 
obtained before enrolment. 
For patients with non-measurable disease only at baseline, categorisation of objective tumour 
response assessment should be based on the RECIST 1.1 guidelines: CR, PD, Non CR/Non 
PD or NE (not evaluable).  
If the investigator is in doubt as to whether progression has occurred, particularly with 
response to non-target lesion (NTL) or the appearance of a new lesion, it is advisable to 
continue treatment until the next scheduled assessment or sooner if clinically indicated and 
reassess the patient’s status.  If repeat scans confirm progression, then the date of the initial 
scan should be declared as the date of progression.  
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumour burden has increased sufficiently to merit 


Clinical Study Protocol 
Drug Substance Olaparib  
Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
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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. Additionally, if in the 
investigator’s opinion, the patient would continue to derive benefit from treatment with study 
drug beyond progression and no other discontinuation criteria are met, treatment with olaparib 
could be continued to a point as judged clinically by the treating physician. 
Following progression, patients should continue to be followed up for survival every 12 weeks 
as outlined in the study plan (Table 2 and Table 3). It is important to follow the assessment 
schedules as closely as possible. 
5.2 
Safety assessments 
5.2.1 
Laboratory safety assessments 
Blood samples for determination of clinical chemistry and haematology will be taken at the 
times indicated in the Study Plan. 
Any clinical chemistry, haematology and urinalysis required as per prescribing information, 
where applicable, should be performed at a local laboratory at or near to the investigational 
site.  Sample tubes and sample sizes may vary depending on laboratory method used and 
routine practice at the site. 
The following laboratory variable listed in Table 4 will be measured. 
NB. In case a patient shows an AST or ALT [8/1RUWRWDOELOLUXELQ[8/1SOHDVHUHIHU
to Appendix D ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions. 
Table 4 
Laboratory Safety Variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Haemoglobin (Hb) 
S/P-Creatinine 
B-Leukocyte count 
S/P-Bilirubin, total 
Mean Cell Volume (MCV) 
S/P-Alkaline Phosphatase (ALP) 
B- Neutrophil count (absolute count) 
S/P-Aspartate Transaminase (AST) 
B-Platelet count  
S/P-Alanine Transaminase (ALT) 
 
S/P urea or Blood Urea Nitrogen (BUN) 
 
5.2.1.1 
Disease specific tumour marker samples (CA-125) 
It is important to follow the assessment schedule as closely as possible. If CA-125 assessment 
is performed, patients should be evaluated based on progressive serial elevation of serum CA-
125 according to the GCIG criteria (Rustin et al 2011) at the discretion of the investigator 
according to local clinical practice. 


Clinical Study Protocol 
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Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
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5.2.2 
Vital signs 
Vital signs will be performed at screening Part 2 and as clinically indicated thereafter. 
Height will be assessed at screening only.  Weight will be assessed at screening and as 
clinically indicated at any other time.  
Any changes in vital signs should be recorded as an AE, if applicable. 
5.2.2.1 
Pulse and blood pressure 
Blood pressure and pulse will be measured at baseline and as clinically indicated afterwards. 
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 Outcomes (PROs), an umbrella term referring to all outcomes and 
symptoms, are directly reported by the patient. PROs have become a significant endpoint 
when evaluating effectiveness of treatments in clinical trials. The following PROs will be 
administered in this study: Functional Assessment of Cancer Therapy-Ovarian (FACT-O), 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, the ORZORA QoL 
Additional Items Questionnaire (a set of newly developed ovarian cancer items) and 
Functional Living Index-Emesis (FLIE). Each is described below. 
5.3.2 
Administration of PRO questionnaires FACT-O and FACIT-Fatigue 
Paper questionnaires will be given to the patient at baseline, at Day 29, then every 12 weeks 
(+/- 7 days) for 24 months or the data cut off for the primary analysis, whichever comes first. 
In addition, QoL questionnaires will be collected at the discontinuation of study treatment 
visit and 30 days post last dose. Patients who had disease progression will complete the 
questionnaires during the 12 weekly survival follow ups either in person or over the phone 
(Table 3).  Following collection of the paper questionnaire (in person or over the phone), the 
site staff should enter the information directly into the WBDC electronic database system. 
Each centre must allocate the responsibility for the administration of the questionnaires to a 
specific individual (e.g., a research nurse, study coordinator) and if possible assign a back-up 
person to cover if that individual is absent.  The AstraZenaca Study Delivery Team (or 
delegate) will provide relevant training in administration of the questionnaires.  The 
significance and relevance of the data need to be explained carefully to participating patients 
so that they are motivated to comply with data collection. 
The instructions for completion of the PRO questionnaires are as follows: 
x 
Questionnaires must be completed prior to any other study procedures (following 
informed consent) and before discussion of disease progress to avoid biasing the 
patient’s responses to the questions; 


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x 
Questionnaires must be completed in private by the patient, where a visit to the 
clinic is not planned, i.e., for patients followed up for survival with no scheduled 
clinic visits, the site staff will administer questionnaires via telephone; 
x 
The patient should be given sufficient time to complete at their own speed; 
x 
The patient should not receive help from relatives, friends or clinic staff to answer 
the questionnaire.  However, if the patient is unable to read the questionnaires (e.g., 
is blind or illiterate) the questionnaires may be read out loud by trained clinic staff 
and the patient’s verbal responses recorded; 
x 
On completion of the questionnaire it should be handed back to the person 
responsible for questionnaires who should check for completeness; 
x 
Only one answer should be recorded for each question. 
5.3.3 
Functional Assessment of Cancer Therapy-Ovarian (FACT-O)  
Patient-reported health-related quality of life (HRQoL) will be assessed using the FACT-O 
questionnaire (Appendix H).  The FACT-O is composed of the following sub-scales: physical, 
social/family, emotional, and functional well-being as well as the additional concerns scales 
consisting of specific ovarian cancer symptoms. The main end point for health-related quality 
of life analysis will be the Trial Outcome Index (TOI), an established single targeted index 
derived from the FACT-O questionnaire and it is considered to target the most relevant 
symptoms together with function and physical well-being and can be directly related to signs 
and symptoms and AEs.  The TOI is composed of the following scales of the FACT-O: 
physical and functional well-being and additional concerns. 
5.3.4 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) 
Subjects in the study will complete the FACIT-Fatigue (Appendix H). The FACIT-Fatigue is 
a 13-item subject-completed questionnaire to assess subjects’ fatigue experience and its 
impact on their daily lives over the past 7 days. Sample items include “I feel fatigued,” “I feel 
weak all over,” and “I feel listless (washed out).” Responses range from 0 (= not at all) to 4 (= 
very much). By scoring convention, after appropriate reverse scoring of 11 items, lower scores 
on the FACIT-Fatigue subscale indicate greater levels of fatigue. Final scores are the sum of 
the responses (0-52) where higher scores indicate better HRQoL (Yellen et al 1997). Changes 
in scores SRLQWVDUHFRQVLGHred to be clinically meaningful (Cella et al 2002). 
5.3.5 
ORZORA QoL Additional Items Questionnaire  
In addition to FACT-O and FACIT-Fatigue, subjects will also complete the following set of 
newly developed ovarian cancer items: “I feel ill with low energy,” “I am able to enjoy life 
and I am still interested in my hobbies and interests,” “I am satisfied that my family 
understands my disease,” “I feel I am able to meet the needs of my family,” “I understand the 
need to take my medication and my treatment regimen,” “My treatment has had significantly 
negative effects on my QoL,” and “I feel like a normal woman” with the same recall period (7 


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60(96) 
days) and response options as in FACT-O. Finally, on a free text response scale, subjects will 
be asked to respond to the following question: “What are the 3 most significant issues you are 
struggling with, please list them starting with your worst first?” 
5.3.6 
Functional Living Index-Emesis (FLIE) 
The Functional Living Index-Emesis (FLIE) tool (Lindley et al 1992) will be used to assess 
study treatment-induced nausea and vomiting and will be assessed at the time points detailed 
in Table 2 and Table 3 of the study schedule. Further details will be provided in the SAP.  
5.4 
Pharmacokinetics 
5.4.1 
Collection of samples 
Pharmacokinetic (PK) samples will not be taken during the study.  
5.4.2 
Determination of drug concentration 
Not applicable. 
5.4.3 
Storage and destruction of pharmacokinetic samples 
Not applicable. 
5.5 
Pharmacodynamics 
5.5.1 
Collection of samples 
Pharmacodynamic samples will not be taken during the study. 
5.5.2 
Storage, re-use and destruction of pharmacodynamic samples 
Not applicable. 
5.6 
Pharmacogenetics 
Pharmacogenetic samples will not be taken during the study. 
5.6.1 
Collection of pharmacogenetic samples 
Not applicable. 
5.6.2 
Storage, re-use and destruction of pharmacogenetic samples 
Not applicable. 
5.7 
Biomarker analysis  
The patient’s consent before the use of donated biological samples for any biomarker analyses 
is mandatory.   


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Biological samples (e.g., archived tumour samples) will be collected and may be analysed for 
exploratory biomarkers to assess correlations with disease activity, effects of study drug, 
clinical outcomes and toxicity. 
5.7.1 
Collection of tumour sample for BRCA testing at screening (mandatory) 
All patients will be asked to provide a tumour sample for BRCA testing as part of the study 
screening procedures. The consent for this will be obtained prior to retrieving the archival 
tumour sample or obtaining the tumour tissue. In patients who have been previously identified 
as having BRCA mutations in the tumour, determined in a local test, collection of an archival 
tumour sample is performed to allow the central confirmation of the tumour BRCA mutation 
(see Section 5.7.6).  
Further exploratory work to elucidate the mechanism of response, understand the mode of 
action of study treatment, or improve the understanding of disease progression may be 
performed on surplus tumour tissue. The consent for this exploratory analysis is optional and 
has been included in the main consent form.  
Historical tumour tissue paraffin block from resection or a core biopsy from the primary 
tumour or metastases should be provided. The portion of tumour within the block should be 
20% at a minimum. This sample will have been collected anytime since the time of original 
diagnosis but prior to study entry.  Alternatively, sections mounted on glass slides prepared 
from the block can be provided.  
Please refer to the Myriad Instructions For Use for further details of archival tissue collection, 
shipping and storage.  
5.7.2 
Collection of tumour sample for HRR testing 
All patients with adequate archival tissue, with the exception of patients previously identified 
as carrying BRCAm ovarian cancer based on a tumour test, will be asked to provide a 
formalin fixed and paraffin embedded (FFPE) tumour sample for tissue-based HRR gene 
panel mutation testing using the investigational Lynparza HRR Assay from 
  
The exploratory cohort of HRRm patients will be defined by having BRCAwt tumour status by 
the test performed by Myriad, and one or more BRCA-independent qualifying LOF mutations 
in any of 13 HRR genes identified by the Lynparza HRR Assay on an archival tumour sample.  
The Lynparza HRR Assay is an investigational NGS-based assay that will be performed as a 
single laboratory testing service using DNA extracted from the provided tissue sample.  
The tumour sample will be tested for the following mutation in 15 biomarkers simultaneously: 
ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, 
PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L.  
For each patient that passes tissue sample quality control, 
 will generate a report to 
investigators; results concerning BRCA1 and BRCA2 will not be reported. A patient is 
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classified “positive” if one or more qualifying genetic alterations are found in any of the 13 
HRR genes (the 15 abovementioned excluding BRCA1 and BRCA2). Patients that do not meet 
such criteria are labelled as biomarker “negative”.  
Patients who do not have an adequate tumour tissue sample for HRR testing will continue 
screening as described in Sections 5.7.1, 5.7.4, 5.7.6 and 5.7.7. They remain eligible for the 
study if they are found to carry a germline or somatic BRCA mutation by the test performed by 
Myriad.  
Tumour samples for HRR testing must meet the following criteria: 
x An unstained, archival FFPE tumour tissue sample of sufficient quantity and quality 
(as specified in the 
 Central Laboratory Services Manual) to allow for central 
analysis of HRR gene mutation. Archival tissue samples may be from primary or 
metastatic tumour deposits. Archival bone metastases are not accepted. Provision of 
blocks is encouraged wherever possible. 
x If a tumour block is not available pre-cut 5 ȝPWKLFNXQVWDLQHGVHFWLRQVIURPFFPE 
tissue block may be provided. The number of sections to be supplied are detailed in the 
 Central Laboratory Services Manual.  
Any residual samples will be used for exploratory research by AstraZeneca, only in cases 
where optional consent has been provided. Residual tissue may be returned to site upon 
individual request. 
5.7.3 
Collection of tumour sample for exploratory analysis at screening and at 
disease progression (optional) 
All patients enrolled will be asked at screening to provide consent for optional most recent 
archival tumour tissue sample for exploratory analysis. Date that this sample was taken from 
the patient should after that of the mandated archival sample used to determine or confirm the 
tumour BRCA mutation. The consent for this is optional and has been included in the main 
consent form. Additionally, wherever possible, and also subject to optional informed consent, 
an on-study tumour biopsy sample obtained either from the progressed lesion or from a new 
lesion may be collected at disease progression, in order to perform exploratory testing. 
Biopsies may be particularly valuable where there is a marked phenotypic change in a 
particular lesion.  
Tumour tissue collected during the study should be immediately fixed and processed to a 
FFPE block. Alternatively, sections mounted on glass slides prepared from the block can be 
provided. 
In both cases, material will be used for additional exploratory work, which may be conducted 
to elucidate the mechanism of response, understand the mode of action of study treatment, or 
improve the understanding of disease progression.  
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Please refer to the 
 Central Laboratory Services Manual for further details regarding 
tissue collection, shipping and storage. 
5.7.4 
Exploratory use of data generated from 
 Central 
testing of tumor sample (Optional) 
The designated, investigational Lynparza HRR Assay involves the analysis of 13 HRR genes 
for the presence of qualifying mutations in this study. The gene panel used in this 
investigational test is based on the clinical-grade 
 test platform that generates 
results for 324 cancer-related genes. A full list of all 324 genes is available in the 
 
Central Laboratory Services Manual. Patients will be asked to give optional consent to the use 
of this additional gene data by AstraZeneca for exploratory research, biomarker analysis in 
relation to olaparib, the study of ovarian cancer and development of future diagnostic tests. 
5.7.5 
Collection of blood sample for germline BRCA1 and BRCA2 testing  
For patients who are confirmed as having a tumour BRCAm status a 7 mL blood sample will 
be requested to test for germline BRCA mutations using the current commercial Myriad 
BRACAnalysis® test. Blood samples should not be collected and shipped until a tumour BRCA 
result has been received from Myriad.  
Please refer to the Myriad Instructions For Use for further details of blood collection, shipping 
and storage. 
5.7.6 
 Collection of blood sample for ctDNA analysis  
For patients who have confirmed sBRCAm or HRRm disease, three 10 mL blood samples for 
collection of plasma will be taken on visit 3 (day 29) for the purpose of exploring the potential 
of determining sBRCAm and HRRm status via analysis of ctDNA. The consent for this is 
optional and has been included in the main consent form. If sBRCAm status is not known at 
Day 29, these samples can be taken at a later study visit.  
Please refer to the 
 Central Laboratory Services Manual for further details regarding 
blood sample collection, shipping and storage. 
5.7.7 
Guidance for BRCA and HRR testing  
Patients previously diagnosed with gBRCAm disease will not be included in this study. 
Patients with unknown germline BRCA mutation status or patients found to carry gBRCAwt 
disease or patients previously identified as having BRCAm disease based on a tumour test 
(with unknown gBRCA mutation status or with previously identified gBRCAwt status) will be 
considered for screening.  
All patients who wish to participate in the study will have to consent to undergo tumour and 
germline BRCA testing as required as part of the screening procedures  
All patients considered for screening will provide an archival tumour sample to allow central 
tumour BRCAm testing.  
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For patients with unknown BRCA mutation status and patients with gBRCAwt disease (based 
on a previous blood test), tumour BRCA mutation status will be determined by central testing 
on the archival tumour sample.  
For patients who have been previously identified as having BRCA mutations in the tumour, on 
the basis of a local tumour test, central testing will be used to confirm the tumour BRCA 
mutation status.   
All patients found or confirmed to carry a deleterious or suspected deleterious BRCA mutation 
in the tumour based on the central tumour test are eligible to enter the study, providing that 
they meet the other eligibility criteria.  
A blood sample for central determination of the germline BRCA status will be collected as part 
of the screening procedures from all patients who are found to carry a BRCA mutation in the 
tumour based on the central tumour test. Central germline testing will also be performed for 
patients previously identified as having gBRCAwt disease based on a local test. 
The result of this blood test will be used to confirm the patient’s germline or somatic BRCA 
mutated disease, the latter by the absence of the same specific BRCA mutation that has been 
found in the patient’s tumour. Patients will need to have met the local ethical requirements for 
such genetic tests (e.g., genetic counselling) prior to the test procedure. Although all women 
with ovarian cancer would be supported to be tested as part of the screening for inclusion in 
the study, the following clinical and pathological features are known to play a role in 
association with an increased probability of BRCA mutations:  
1. Family history of breast or ovarian cancer, ethnicity and age 
2. High grade epithelial ovarian cancer. 
Patients who have no BRCA mutation in the tumour may be eligible for the study if they carry 
one or more BRCA-independent qualifying mutations in any of 13 HRR genes identified by 
the Lynparza HRR Assay (HRRm exploratory cohort).  
To enable the completion of the screening procedure within an 8-week window after the last 
dose of platinum-based therapy, HRR tumour testing will be performed in parallel to BRCA 
tumour testing, on two different tumour samples. Patients who have only one available tumour 
block will be tested only for BRCA mutated disease.  
5.7.8 
Storage, re-use and destruction of biological samples 
Samples will be stored for a maximum of 15 years from the date of the Last Patient’s Last 
Visit, 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. 


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5.7.9 
Labelling and shipment of biological samples 
The PI ensures that samples are labelled and shipped in accordance with the Laboratory 
Manual and the Biological Substance, Category B Regulations (materials containing or 
suspected to contain infectious substances that do not meet Category A criteria ), see 
Appendix C ‘IATA 6.2 Guidance Document’. 
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved. 
5.7.10 
Chain of custody of biological samples  
A full chain of custody is maintained for all samples throughout their lifecycle. 
The PI at each centre keeps full traceability of collected biological samples from the patients 
while in storage at the centre until shipment or disposal (where appropriate). 
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 lifecycle 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 lifecycle. 
5.7.11 
Withdrawal of Informed Consent for donated biological samples  
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed, 
AstraZeneca is not obliged to destroy the results of this research. 
Tumour sample for tumour BRCA testing and blood sample for germline BRCA testing: As 
collection of these biological materials is an integral part of the study, then the patient is 
withdrawn from further study participation. 
Tumour sample for central HRR testing using the Lynparza HRR Assay:  
x 
If the central BRCA test identifies the patient as carrying BRCAm disease, 
then the patient will remain in the study. The sample provided for HRR 
testing will be disposed of/destroyed, and the action documented.  If 
samples are already analysed, AstraZeneca is not obliged to destroy the 
results of this research.  
x 
If the central BRCA test identifies the patient as carrying BRCAwt 
disease, as collection of this biological material is an integral part of the 
study, then the patient is withdrawn from further study participation.  


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Exploratory analysis samples: archival tumour/ tumour tissue sample (biopsy samples) for 
exploratory analysis and blood samples for ctDNA analysis: As collection of these biological 
materials is an optional part of the study, then the patient may continue in the study. 
The PI: 
x 
Ensures patients’ withdrawal of informed consent to the use of donated 
samples is notified immediately to AstraZeneca or designated Contract 
Research Organisation (CRO) 
x 
Ensures that biological samples from that patient, if stored at the study 
site, are immediately identified, disposed of /destroyed, and the action 
documented 
x 
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 
x 
Ensures that the patient 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. 
5.8 
Blood volume 
The volume of blood that will be drawn from each patient will vary, dependent upon the 
length of time that the patient remains in the trial and on treatment.  However the volume of 
blood to be drawn from each patient during screening and up to Day 29 should not exceed 
50 mL. 
The total volume of blood to be drawn from each patient in the study, assuming they complete 
screening, 6 months of treatment, a treatment discontinuation visit and the 30-day follow-up 
visit, should not exceed 139 mL. 
Safety laboratory assessments will be performed locally at the discretion of the investigator 
according to routine local clinical practice and in line with the prescribing information or the 
IB as applicable based on country specific marketing authorisation status, where olaparib is 
approved, at each centre’s laboratory by means of their established methods.  The number of 
samples/blood volumes is therefore patient to site-specific change and the above is for 
guidance only.  
Extra blood samples may also be collected if, for example, additional samples are required for 
repeat safety assessments. 


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The estimated total volume of blood that will be drawn from each patient in this study is 
shown in Table 5. 
Table 5 
Estimated maximum volume of blood to be drawn from each patient 
based on 6 months of treatment 
Assessment 
Sample 
volume 
(mL) 
Screening  
No. of 
samples 
Month 1 
(Including 
day 29) 
No. of 
samples  
Months  
2-6 
No. of 
samples 
Treatment 
discontinuation 
visit and 30 day 
follow-up visit  
No. of samples 
Total 
vol. 
(mL) 
 
 
 
 
 
 
 
Safety 
Clinical 
chemistry 
(locally 
considered and 
assessed) 
5 
1 
2 
5 
2 
50 
Haematology 
(locally 
considered and 
assessed) 
5 
1 
2 
5 
2 
50 
Whole Blood sample: 
Prospective 
BRACAnalysis® test for 
patients with tumour 
BRCAm status  
7 
1 
 
 
 
7 
Serum pregnancy test 
Site 
dependent 
Site may 
use urine 
Site may 
use urine 
 
 
 
Blood sample for CA-
125 (locally considered 
and assessed) 
2 
1 
 
 
 
2 
Blood sample for plasma 
/ ctDNA analysis* 
10 
 
3 
 
 
 
Total volume (mL) 
 
19 
50 
50 
20 
139 
*: Optional and subject to specific informed consent. Only for patients with sBRCAm and HRRm ovarian cancer. 
If sBRCAm status is not known at Day 29, these samples can be taken at a later study visit.  
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, 


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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. 
6.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
x 
Results in death 
x 
Is immediately life-threatening 
x 
Requires in-patient hospitalisation or prolongation of existing hospitalisation  
x 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
x 
Is a congenital abnormality or birth defect 
x 
Is an important medical event that may jeopardise the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
For further guidance on the definition of a SAE, see Appendix B ‘Additional Safety 
Information’ to the Clinical Study Protocol. 
6.3 
Adverse events of special interest 
Adverse events of special interest (AESI) for olaparib 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 malignancies (other than MDS/AML) and 
pneumonitis type events.   
Any event of MDS/AML, new primary malignancy (other than MDS/AML), or pneumonitis 
should be reported to AstraZeneca Patient Safety whether it is considered a non-serious AE 
(e.g. non-melanoma skin cancer) or SAE, and regardless of investigator’s assessment of 
causality. These adverse events must be reported according to the timelines for reporting an 
SAE (see Section 6.4) to allow timely safety monitoring. 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 


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questionnaire to help characterise the event and gain a better understanding regarding the 
relationship between the event and study treatment. 
6.4 
Recording of adverse events 
6.4.1 
Time period for collection of adverse events 
Adverse Events, including Serious Adverse Events, will be collected from time of signature of 
informed consent, throughout the treatment period and 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 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. 
In cases where any transfusions to manage anaemia and or thrombocytopenia are needed, 
these should be recorded with date, type and units given.  
6.4.2 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the time of the 30 day follow-up, must be 
followed up by the investigator through to resolution, and whilst the database is 
open should be recorded on the database.  
AstraZeneca retains the right to request additional information for any patient 
with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
6.4.3 
Adverse events after the 30 day follow-up period 
For Pharmacovigilance purposes and characterisation of events of special interest, any case of 
MDS/AML or new primary malignancy, as well as pneumonitis occurring after the 30 day 
follow up period should be reported as SAE (or AE for non-melanoma skin cancers, if at least 
one of the criteria for SAE is not met, see Section 6.2) to AstraZeneca Patient Safety 
regardless of investigator’s assessment of causality.  A Questionnaire will be sent to any 
investigator reporting MDS/AML or new primary malignancy or pneumonitis as an aid to 
provide detailed information on the case.   
At any time after a patient has completed the study, if an investigator learns of any SAE 
including death, 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.  
If patients 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 Astra Zeneca Patient Safety within the usual timeframe. 


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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 patients.  This includes new AEs/SAEs in patients still being 
followed up for survival but who have completed the post treatment follow-up period (30 
days). 
6.4.4 
Variables  
The following variables will be collect for each AE: 
x 
AE (verbatim) 
x 
The date and time when the AE started and stopped 
x 
Max CTCAE grade and changes in CTCAE grade 
x 
Whether the AE is serious or not 
x 
Investigator causality rating against the IP (yes or no) 
x 
Action taken with regard to IP 
x 
AE caused patient’s withdrawal from study (yes or no)>> 
x 
Outcome. 
In addition, the following variables will be collected for SAEs: 
x 
Date AE met criteria for serious AE 
x 
Date Investigator became aware of serious AE 
x 
AE is serious due to (provide all seriousness criteria applicable) 
x 
Date of hospitalisation (if applicable) 
x 
Date of discharge (if applicable) 
x 
Probable cause of death (if applicable) 
x 
Date of death (if applicable) 
x 
Autopsy performed (yes or no; if yes provide report) (if applicable) 
x 
Causality assessment in relation to study procedure(s) 
x 
Description of serious AE. 
For each episode on an adverse event, all changes to the CTCAE grade attained as well as the 
highest attained CTCAE 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 6.1. An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE 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 a SAE when it satisfies the criteria 
shown in Section 6.2. 


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The grading scales found in the National Cancer Institute (NCI) CTCAE version 4.0 will be 
utilised 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). 
6.4.5 
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?’ 
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 B ‘Additional 
Safety Information’ to the Clinical Study Protocol. 
6.4.6 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or care provider 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 recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms.  However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately. 
6.4.7 
Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT [8/1WRJHWKHUZLWKWRWDOELOLUXELQ[8/1PD\QHHGWR
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. 
6.4.8 
Disease progression 
Disease progression can be considered as a worsening of a patient’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 (DUS) 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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6.4.9 
New cancers 
The development of a new primary cancer (including skin cancer) should be regarded as an 
AE and will generally meet at least one of the serious criteria (see Section 6.2).  New primary 
cancers are those that are not the primary reason for the administration of the study treatment 
and have developed after the inclusion of the patient into the study.  They do not include 
metastases of the original cancer.  Symptoms of metastasis or the metastasis itself should not 
be reported as an AE/SAE, as they are considered to be disease progression. 
6.4.10 
Lack of efficacy 
When there is deterioration in the ovarian 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. 
6.4.11 
Deaths 
All deaths that occur in screening Part 1 related to study procedures should be reported as a 
SAE. 
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: 
x 
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 eCRF but should not be reported as an SAE. 
x 
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 6.2 for further details).  
The report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign main and 
contributory causes of death.  This information can be captured in the 
‘Death eCRF’. 
x 
Deaths with an unknown cause should always be reported as a SAE.  A 
post mortem maybe 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. 
6.5 
Reporting of serious adverse events 
In screening Part 1, only SAEs related to study procedures must be reported.  From screening 
Part 2 onwards, all SAEs have to 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. 


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If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives 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 information is provided to the AstraZeneca Patient Safety data entry site within 1 
calendar day of initial receipt for fatal and life threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
designated 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 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 designated AstraZeneca representative by telephone. 
The designated AstraZeneca representative will advise the investigator/study site personnel 
how to proceed. 
The reference document for definition of expectedness/listedness is the IB or the Prescribing 
Information (Appendix G) as applicable based on country specific marketing authorisation 
status for the AstraZeneca drug. 
6.6 
Overdose 
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established.  
Olaparib 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.   
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately: 
x 
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. 
x 
An overdose without associated symptoms is only reported on the 
Overdose CRF module. 


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Date 22 July 2016 
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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 6.5.  
For other overdoses, reporting must occur within 30 days. 
6.7 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. 
6.7.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study olaparib should be discontinued 
immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the patient was discontinued from the study. 
If any pregnancy occurs during 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 provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.5) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy. 
6.7.2 
Paternal exposure  
Not applicable. 


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6.8 
Management of IP related toxicities, dose interruptions and dose 
reductions 
Study treatment may be temporarily interrupted to manage adverse reactions such as nausea, 
vomiting, diarrhoea, and anaemia and dose reduction can be considered. The recommended 
dose reduction is to 200 mg twice daily (equivalent to a total daily dose of 400 mg). If a 
further final dose reduction is required, then reduction to 100 mg twice daily (equivalent to a 
total daily dose of 200 mg) could be considered. In cases where any transfusions to manage 
anaemia and or thrombocytopenia are needed, these should be recorded with date, type and 
units given.  
6.9 
Study governance and oversight 
Not applicable. 
6.9.1 
Steering Committee 
Not applicable. 
6.9.2 
Data Monitoring Committee 
Not applicable. 
6.9.3 
Scientific Advisory Committee  
A scientific advisory committee will be established as part of the study to provide guidance on 
study conduct and interpretation, chaired by the PI and including key investigators and 
optional external experts as needed. This committee will be facilitated by AstraZeneca. 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational product(s) 
AstraZeneca’s Pharmaceutical Development, R&D Supply Chain will supply olaparib to the 
Investigator as white, size 0 capsules (Appendix G ‘Prescribing Information’).  
Investigational product 
Dosage form and strength 
 
Olaparib 
Capsule – 50 mg 
 
a 
Descriptive information for olaparib can be found in the Investigator’s Brochure or the Prescribing 
Information as applicable based on country specific marketing authorisation status 
 
7.2 
Dose and treatment regimens 
Olaparib capsules will be packed in high-density polyethylene (HDPE) bottles with child-
resistant closures.  Each bottle will contain 120 capsules and 4 bottles will be dispenses for a 4 
weekly visit, with a 2-day overage.  


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Patients will be administered olaparib capsules orally at a dose of 400 mg twice daily. 
Eight 50 mg olaparib capsules should be taken at the same time each day approximately 12 
hours apart with approximately 240 mL of water.   
The olaparib capsules should be swallowed whole and not chewed, crushed, dissolved or 
divided.  Olaparib capsules can be taken with a light meal/snack (e.g., 2 pieces of toast or a 
couple of biscuits). 
If vomiting occurs shortly after the olaparib capsules are swallowed, the dose should only be 
replaced if all of the intact capsules can be seen and counted.  Should any patient enrolled on 
the study miss a scheduled dose for whatever reason (e.g., as a result of forgetting to take the 
capsules or vomiting), the patient will be allowed to take the scheduled dose up to a maximum 
of 2 hours after that scheduled dose time.  If greater than 2 hours after the scheduled dose 
time, the missed dose is not to be taken and the patient should take their allotted dose at the 
next scheduled time. 
There is no maximum duration for taking olaparib.  Patients should continue to receive 
olaparib until disease progression as assessed by the investigator or as long as in the 
investigator’s opinion they are benefiting from treatment and they do not meet any other 
discontinuation criteria as outlined in Section 3.9. 
7.3 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language.  
Specific dosing instructions will not be included on the label, the site must complete the 
“Patient Dispensing Card” with the details of the dosing instructions at the time of dispensing.   
The patient emergency contact details will not be on the label, but can be found in the 
informed consent and the ‘Patient Dispensing Card’.  For emergency purposes the patient 
must be in possession of the emergency contact details at all times. 
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 investigational product should be recorded in the appropriate sections of 
the Case Report Form. 
Patients should be given clear instructions on how and when to take olaparib.  Patients will 
self-administer olaparib.  Study site staff will make capsule counts at regular intervals during 
treatment.  Compliance will be assessed by the capsule count and the information will be 


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recorded in the appropriate section of the eCRF.  After the capsule count has been performed, 
the remaining capsules will not be returned to the patient but will be retained by the 
investigative site until reconciliation is completed by the study monitor.  All patients must 
return their bottle(s) of olaparib at the appropriate scheduled visit, when a new bottle will be 
dispensed.  Patients will be instructed to notify study site personnel of missed (forgotten) 
doses.  Dates of missed or held doses will be recorded by the patient on their patient diary and 
by the site staff on the eCRF. 
Patients must return all containers and any remaining IP capsules at the end of the study. 
7.6 
Accountability 
The IP provided for this study will be used only as directed in the study protocol. 
The study personnel will account for all IP dispensed to and returned from the patient. 
Study site personnel or the study monitor will account for IP received at the site, unused study 
drugs and for appropriate destruction.  Certificates of delivery, destruction or return should be 
signed. 
7.7 
Concomitant and other treatments  
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy, 
radiotherapy, biological therapy or other novel agent) is to be permitted while the patient is 
receiving study medication.  Hormone replacement therapy (HRT) is acceptable. 
Live virus and bacterial vaccines should not be administered whilst the patient 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.  
The use of any natural/herbal products or other “folk remedies” should be discouraged and use 
of these products, as well as use of all vitamins, nutritional supplements and all other 
concomitant medications must be recorded. 
Any medications (with the detailed exceptions) which are considered necessary for the 
patient's welfare, and which it is believed will not interfere with the study medication, may be 
given at the discretion of the investigator and according to olaparib prescribing information 
where approved and applicable, providing the medications, the doses, dates and reasons for 
administration are recorded. 
In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the 
study period must be recorded.  This includes any blood transfusions. 
The reasons for the use, doses and dates of treatment should be recorded in the patient’s 
medical records and appropriate sections of the eCRF. 


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All medications (prescriptions or over the counter medications) continued at the start of study 
or started during the study or until 30 days from the end of the last IP dose and different from 
the study medication must be documented. 
Combination of olaparib with vaccines or immunosuppressant agents has not been studied. 
Therefore, caution should be taken if these drugs are co-administered with olaparib and 
patients should be closely monitored. 
Clinical studies to evaluate the impact of known CYP3A inhibitors and inducers have not 
been conducted and it is therefore recommended that known strong inhibitors (e.g., 
itraconazole, telithromycin, clarithromycin, boosted protease inhibitors, indinavir, saquinavir, 
nelfinavir, boceprevir, telaprevir) or inducers (e.g., phenobarbital, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) of these isozymes 
should be avoided with olaparib.  
Olaparib can inhibit CYP3A4 and UGT1A1 in vitro. These findings suggest that olaparib has 
the potential to cause clinically significant interactions with other CYP3A4 substrates or 
UGT1A1 substrates in the liver or gastrointestinal tract. Therefore, caution should be 
exercised when substrates of CYP3A4 are combined with olaparib, in particular those with a 
narrow therapeutic margin (e.g., simvastatin, cisapride, cyclosporine, ergot alkaloids, fentanyl, 
pimozide, sirolimus, tacrolimus and quetiapine). Substrates of UGT1A1 should also be given 
with caution in combination with olaparib (e.g., irinotecan, nintedanib, ezetimibe, raltegravir 
or buprenorphine). 
In vitro olaparib is a substrate for the efflux transporter P-gp. Clinical studies to evaluate the 
impact of known P-gp inhibitors and inducers have not been conducted. 
The potential for olaparib to induce CYP3A, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and 
P-gp is unknown and it cannot be excluded that olaparib upon co-administration may reduce 
the exposure to substrates of these metabolic enzymes and transport protein. The efficacy of 
hormonal contraceptives may be reduced if co-administered with olaparib. 
In vitro olaparib may be an inhibitor of P-gp and is an inhibitor of BRCP, OATP1B1, OCT1 
and OCT2. It cannot be excluded that olaparib may increase the exposure to substrates of P-gp 
(e.g., statins, digoxin, dabigatran, colchicine), BRCP (e.g., methotrexate, rosuvastatin and 
sulfasalazine), OATP1B1 (e.g., bosentan, glibenclamide, repaglinide, statins, and valsartan), 
OCT1 (e.g., metformin) and OCT2 (e.g., serum creatinine). In particular, caution should be 
exercised if olaparib is administered in combination with any statin.  
Patients who are taking warfarin or acenocoumarol may participate in this trial; however, it is 
recommended that prothrombin time (international normalised ratio [INR] and activated 
partial thromboplastin time [APTT]) be monitored at baseline if patients are on 
anticoagulation at enrolment and repeat as per local guidelines for the anticoagulation 
treatment after start of olaparib and when clinically indicated. For AEs of haemorrhage 
coagulation status and relevant monitoring of laboratory results is recommended.  


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From screening Part 2 onwards, should a patient develop nausea, vomiting and / or diarrhoea, 
then these symptoms should be reported as AEs and appropriate treatment of the event given. 
7.7.1 
Surgery and palliative radiotherapy 
Study treatment should be stopped at least 3 days prior to planned surgery. After surgery study 
treatment can be restarted when the wound has healed. No stoppage of study treatment is 
required for any biopsy procedure. 
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 patient undergoes therapeutic palliative radiation treatment.  
Olaparib should be restarted within 2 weeks as long as any bone marrow toxicity has 
recovered. 
7.7.2 
Administration of other anti-cancer agents 
Patients must not receive any other concurrent anti-cancer therapy, including investigational 
agents, while on olaparib. Patients may continue the use of bisphosphonates or denosumab for 
bone disease and corticosteroids for the symptomatic control of brain metastases provided the 
dose is stable before and during the study and they were started at least 2 weeks prior to 
beginning olaparib or if disease progression is recorded, then olaparib could be continued 
alongside bisphosphonates, denosumab or corticosteroids as above if the in the investigator’s 
assessment the patient would continue to benefit from further olaparib therapy . 
7.7.3 
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. 
7.7.4 
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the Case Report Form. 
7.8 
Post Study Access to Olaparib  
After the end of the study, patients still on study therapy at that time will continue to receive 
olaparib outside the study until they continue to derive clinical benefit from treatment in the 
view of the investigator and no other criteria for treatment discontinuation are met. 
8. 
STATISTICAL CONSIDERATIONS 
Analyses will be performed by AstraZeneca or its representatives.     


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A comprehensive SAP will be prepared and any subsequent amendments will be documented, 
with final amendments completed prior to the start of the first patients on the study. Data will 
be summarised for all patients who have received at least one dose of olaparib and will be 
presented separately for patients with BRCAm and BRCA-independent HRRm ovarian cancer.  
8.1 
Sample size estimate 
Patients with sBRCAm disease 
Based on the expected proportion of sBRCAm disease among all patients with BRCA mutated 
disease, as outlined in section 1.1.2, the study is aiming to recruit at least 50 patients with 
sBRCAm disease.  
Assuming a median PFS value of 11.2 months (as observed in the phase 2 maintenance study), 
and a data cut off at 60% maturity, 30 progression or death events are expected from 50 
patients with sBRCAm disease.  Assuming 23 months non-linear recruitment, in the sBRCAm 
cohort these 30 progression or death events are expected to occur approximately 32 months 
after first subject is enrolled in the study (FSI).   
All patients with BRCAm disease 
The sample size of approximately 250 patients is driven by the need to understand patterns of 
olaparib use across multiple countries with the capsule formulation and across various 
subgroups and the primary analysis will be performed after the accumulation of 150 
progression or death events which corresponds to 60% maturity. Assuming a median PFS 
value of 11.2 months and a data cut off at 60% maturity with approximately 23 months of 
non-linear recruitment 150 progression or death events are expected to occur approximately 
32 months after first subject is enrolled in the study (FSI). 
HRRm exploratory cohort 
It is expected that approximately 450 patients with BRCAwt status will be screened using the 
Lynparza HRR Assay. Assuming that approximately 5% of patients with BRCAwt disease 
screened in the study will carry a qualifying genetic alteration in any of the 13 genes involved 
in the HRR pathway (excluding BRCA1 and BRCA2), it is estimated that approximately 25 
patients will be included in the HRRm cohort before the target number of 250 patients with 
BRCAm disease is reached.  
8.2 
Definitions of analysis sets 
Table 6 gives a summary of outcome variables and analysis populations. 
Table 6 
Summary of Outcome Variables and Analysis Populations 
Outcome Variable 
Populations 
Efficacy Data 
 
- Primary: PFS 
Full 


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Outcome Variable 
Populations 
- Secondary: OS, PFS2, TFST, TSST, TDT, symptom/QoL endpoints Full 
Demography 
Full 
Safety Data 
 
- Adverse Events 
Safety 
- Lab measurements 
Safety 
- Vital Signs 
Safety 
Note: TFST: time to first subsequent therapy or death; TSST:  time to second subsequent therapy or death; TDT:  
time to olaparib discontinuation or death; PFS2: Investigator assessed second progression; OS: Overall 
Survival. 
8.2.1 
Full analysis set 
The full analysis set (FAS) includes all patients who have been assigned olaparib (all enrolled 
patients as an intention to treat analysis set). All efficacy analyses will be based on the FAS. 
8.2.2 
Safety analysis set 
The safety analysis set comprises all patients who received at least 1 dose of olaparib. All 
safety analyses will be based on the safety analysis set. 
8.2.3 
PK analysis set 
Not applicable. 
8.2.4 
PRO analysis set 
PRO analyses will be based on the FAS, with additional exclusion criteria, excluding: 
x Patients who do not have any evaluable baseline data 
x 
Patients who do not have any evaluable post-baseline data. 
8.3 
Outcome measures for analyses 
8.3.1 
Calculation or derivation of efficacy variable(s) 
At each visit patients will be programmatically assigned a visit response of CR, PR, SD, PD, 
NE based on RECIST 1.1 guidelines or other methods depending on the status of their disease 
compared to baseline and previous assessments, based on the investigator assessment. 
8.3.2 
Primary endpoint 
PFS is defined as the time from enrolment until the date of objective radiological disease 
progression (assessed via RECIST 1.1) or death (by any cause in the absence of disease 
progression) regardless of whether the patient withdraws from therapy or receives another 
anticancer therapy prior to disease progression.  Patients who have not progressed or died at 
the time of analysis will be censored at the time of the latest date of assessment from their last 


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evaluable efficacy assessment.  However, if the patient progresses or dies after two or more 
missed visits, the patient will be censored at the time of the latest evaluable assessment.  
Given the scheduled visit assessment scheme, two missing visits will equate to more than 26 
weeks since the previous RECIST 1.1 assessment, allowing for early and late visits. If the 
patient has no evaluable visits or does not have a baseline assessment they will be censored at 
day 1 unless they die within two visits of baseline (25 weeks allowing for visit window).  
The PFS time will always be derived based on scan/assessment dates not visit dates. 
Assessments/scans contributing towards a particular visit may be performed on different 
dates. The following rules will be applied: 
x 
Date of progression will be determined based on the earliest of the 
assessment/scan dates of the component that triggered the progression.   
x 
When censoring a patient for PFS the patient will be censored at the latest 
of the assessment/scan dates contributing to a particular overall visit 
assessment. 
Overall visit assessments will be determined for each assessment (scheduled or unscheduled) 
and will contribute to the derivation of PFS. 
Objective radiological progression is defined as at least a 20% increase in the sum of the 
diameters of the target lesions (compared to previous minimum sum) and an absolute increase 
of > 5 mm, or an overall non-target lesion assessment of progression or a new lesion.  
8.3.3 
Secondary endpoints  
Overall Survival 
Overall survival is defined as the time from the date of enrolment in the study until death due 
to any cause.  Any patient not known to have died at the time of analysis will be censored 
based on the last recorded date on which the patient was known to be alive. 
Note: Survival calls will be made in the week following the DCO for the analysis, and if 
patients are confirmed to be alive or if the death date is post the DCO date these patients will 
be censored at the date of DCO. 
Time from enrolment to second progression (PFS2) 
Time from enrolment to second progression is defined as the time from the date of enrolment 
to the earliest of the progression event subsequent to that used for the primary variable PFS or 
death.  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, CA-125 progression or death. Second progression status will be reviewed every 
12 weeks following the progression event used for the primary variable PFS (the first 
progression) and status recorded.  Patients alive and for whom a second disease progression 
has not been observed should be censored at the last time known to be alive and without a 


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second disease progression, i.e., censored at the last assessment for progression date if the 
patient has not had a second progression or death. 
Time to first subsequent anti-cancer therapy or death (TFST) 
As a supportive summary to PFS, time to start of first subsequent anti-cancer therapy or death 
will be assessed.  Time to first subsequent therapy or death is defined as the time from the date 
of enrolment to the earlier of first subsequent therapy start date, or death date.  Any patient not 
known to have had a further subsequent therapy or death will be censored at the last known 
time to have not received subsequent anti-cancer therapy.  
Time to study treatment discontinuation or death (TDT) 
Time to study treatment discontinuation or death (TDT) will be assessed.  TDT is defined as 
the time from the date of enrolment to the earlier of the date of study treatment 
discontinuation or death.  Any patient not known to have died at the time of analysis and not 
known to have discontinued study treatment will be censored based on the last recorded date 
on which the patient was known to be alive. 
Time to second subsequent chemotherapy or death (TSST) 
As a supportive summary to PFS2, time to start of second subsequent chemotherapy or death 
(TSST) will be assessed.  Time to second subsequent chemotherapy or death is defined as the 
time from the date of enrolment to the earlier of the date of second subsequent chemotherapy 
start date, or death date.  Any patient not known to have had a further second subsequent 
therapy or death will be censored at the last known time to have not received second 
subsequent chemotherapy. 
8.3.4 
Calculation or derivation of health-related quality of life variables 
FACT-O 
Patient-reported health-related quality of life (HRQoL) will be assessed using the FACT-O 
questionnaire (Appendix H). The FACT-O is composed of the following sub-scales: physical, 
social/family, emotional, and functional well-being as well as the additional concerns scales 
consisting of specific ovarian cancer symptoms.  
The main end point for health-related quality of life analysis will be the Trial Outcome Index 
(TOI), an established single targeted index derived from the FACT-O questionnaire and it is 
considered to target the most relevant symptoms together with function and physical well-
being and can be directly related to signs and symptoms and AEs. The TOI is composed of the 
following scales of the FACT-O: physical and functional well-being and additional concerns. 
Data relating to the FACT-O will be self-reported through patient questionnaires according to 
the study plan. Patients will be asked to report their health-related quality of life over the 
course of the previous 7 days.  All patients will be asked to complete the FACT-O.  The 
FACT-O questionnaire will be administered per study schedule (Table 2 and Table 3). In 


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addition, Quality of Life questionnaire will be collected at the discontinuation of study 
treatment visit 8 and 30 days post last dose. Patients who had disease progression according to 
RECIST 1.1 will complete the questionnaires during the 12 weekly survival follow up either 
in person or over the phone. 
The Trial Outcome Index (TOI) score will be derived from the sum of the scores of the 25 
items included in the physical well-being (7 items), functional well-being (7 items), and 
ovarian cancer subscale (11 items) of the FACT-O questionnaire version 4. The total FACT-O 
score will also be calculated which is made up of the sum of the individual subscale scores: 
physical well-being (PWB), social well-being (SWB), emotional well-being (EWB) and 
functional well-being (FWB), and the ovarian cancer subscale (Additional Concerns). 
The scores will be derived in accordance with the FACT-O scoring manual. A number of 
items are negatively stated and need to be reversed by subtracting the response from “4”. The 
scoring manual identifies that the following items need to be reversed prior to summarizing: 
GP1-7, GE1, GE3-6, O1-3, C2, and B5. After reversing proper items, scores are summarised 
and multiplied by the number of items in the domain. For each subscale, if less than 50% of 
the subscale items are missing, the subscale score will be divided by the number of non-
missing items and multiplied by the total number of items on the subscale. If at least 50% of 
the items are missing, that subscale also will be treated as missing. The reason for any missing 
assessment will be identified. If data are missing at random, the above techniques will be 
used. If there is evidence that the missing data are systematic, missing values will be handled 
to ensure that any possible bias is minimised.  The TOI score ranges from 0-100 and the 
FACT-O from 0-152.  For all Functional Assessment of Chronic Illness Therapy (FACIT) 
scales and symptom indices, a higher score indicates a higher HRQoL.   
The actual change from baseline in TOI score will be derived for each visit where there is 
available data. For example; at visit X, the calculation will be (TOI score at visit X- baseline 
TOI score). Actual change from baseline for the individual domain scores will be calculated in 
a similar way. 
A change of at least 10 points in TOI score will be considered as a clinically relevant or a 
minimally important difference.  
The threshold for a clinically important deterioration is outlined below (Table 7): 
Table 7 
Health-Related QoL 
Score 
Change from baseline 
Visit response 
TOI 
 
Improved 
 
-10 
Worsened 
 
Otherwise 
No change 
 


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Best Overall TOI improvement (in absence of starting any subsequent cancer therapy) will be 
defined as a change from baseline in the TOI of + 10 points or more  sustained for at least 28 
days, the denominator consisting of a subset of the efficacy population who have baseline 
TOI. It will be derived as the best symptom improvement response the patient achieved, based 
on evaluable QoL data collected from enrolment up to the earliest of starting any subsequent 
cancer therapy or death. Therefore, at the conclusion of the trial, the following criteria, will be 
used to assign a best overall score response based on the individual visit responses (Table 8). 
Table 8 
Health-Related Quality of Life: Change rates - overall score. 
Best Overall TOI score response 
Criteria 
Improved 
Two visit responses of “improved” a 
minimum of 28 days apart without an 
intervening visit response of “worsened” 
No change 
Does not qualify for overall score response of 
“improved”. Two visit responses of either “no 
change” or “improved and “no change” a 
minimum of 28 days apart without an 
intervening visit response of “worsened” 
Worsened 
Does not qualify for overall score response of 
“improved” A visit response of “worsened” 
without a response of “improved” or “no 
change” within 28 days. 
Other 
Does not qualify for one of the above. 
 
A TOI improvement rate (in the absence of subsequent cancer therapy) will be calculated as 
the proportion of all analysed patients with a best overall score response of improved. In the 
calculation of the proportion of patients that have a response of Improved, No Change or 
Worsened, the denominator used in the calculation will use the number evaluable for that 
individual TOI domain score at baseline. 
FACIT-Fatigue 
The scores will be derived in accordance with the FACIT-Fatigue Scoring Guidelines.  A 
number of items are negatively stated and need to be reversed by subtracting the response 
from “4”. The scoring manual identifies that the following items need to be reversed prior to 
summarising: HI7, HI12, An1, An2, An3, An4, An8, An12, An14, An15 and An16. After 
reversing proper items, scores are summarised and multiplied by the number of items in the 
domain (x13) and divided by number of items answered to obtain the Fatigue subscale score.  
ORZORA QoL Additional Items Questionnaire 


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As no scoring guidelines exist for these new questions, the number and percentage of patients 
giving each response (“Not at all”, “A little bit”, “Somewhat”, “Quite a bit”, “Very much”) 
will be summarised.   
FLIE 
The Functional Living Index-Emesis (FLIE) scores will be derived. - Full details will be 
provided in the Statistical Analysis Plan. 
8.3.5 
Calculation or derivation of safety variable(s) 
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, and vital 
signs.  These will be collected for all patients. The number of patients experiencing each AE 
(based on Medical Dictionary for Regulatory Activities [MedDRA] preferred term) will be 
summarised by CTCAE grade. 
8.3.6 
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 and discontinuation of investigational product 
due to adverse events (DAEs).  Based on the expert’s judgement, significant adverse events of 
particular clinical importance may, after consultation with the Global Patient 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 haematological and other laboratory abnormalities, and certain events that 
lead to intervention (other than those already classified as serious), dose reduction or 
significant additional treatment. 
8.3.7 
Exploratory endpoints  
Descriptive analyses will be performed for exploratory endpoints. Specific analyses will be 
described in the Statistical Analysis Plan.  
8.4 
Methods for statistical analyses 
Data will be summarised for all patients who have received at least one dose of olaparib and 
will be presented separately for the BRCAm and HRRm patients. 
The primary analysis will be performed at 60% maturity, that is, at the time of accrual of 150 
progression or death events in the 250 BRCAm patients, with assessment of progression based 
on RECIST 1.1guidelines. It is expected that the cohort of patients with sBRCAm disease will 
comprise at least 50 patients at the time of this analysis, and that 30 progression/death events 
will have occurred in this cohort. 
Subgroup analyses will be performed on the gBRCAm group separately. 


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8.4.1 
Analysis of the primary variable  
PFS will be analysed when approximately 150 progression events among patients with BRCA 
mutated ovarian cancer have occurred in the study (60% maturity). At this point, it is expected 
that 30 progression events (60% maturity) would have occurred in the cohort of at least 50 
patients with sBRCAm disease. PFS analyses will be performed in the cohort of patients with 
sBRCAm disease and all BRCAm patients, both assessed according to RECIST 1.1 guidelines, 
to address the co-primary objectives of the study.  
Kaplan-Meier (KM) plots of PFS will be presented for the cohort of patients with sBRCAm 
disease and for all patients with BRCAm disease. Summaries of the number and percentage of 
patients experiencing a PFS event, and the type of event (progression or death) will be 
provided along with median PFS and 95% confidence intervals. 
The analyses on PFS will be based on investigator assessments according to RECIST 1.1 
guidelines, and using all scans regardless of whether they were scheduled or not. The 
estimated PFS rates at 6 months, 12 months and 24 months will be summarised (using the KM 
curves) for the cohort of patients with sBRCAm disease and for all patients with BRCAm 
disease. 
The number of patients prematurely censored will be summarised together with baseline 
prognostic factors of the prematurely censored patients.  A patient is defined as prematurely 
censored if they had not progressed and the latest scan prior to DCO was more than 1 
scheduled tumour assessment interval (+ 2 weeks) prior to the DCO date. 
The analyses of PFS will be repeated on the exploratory HRRm cohort. 
8.4.2 
Analysis of the secondary variable(s) 
All time to event endpoints (OS, PFS2, TFST, TSST, and TDT) will be described as for PFS 
in the subset of patients with sBRCAm disease, and for all patients with BRCAm disease. A 
summary of PFS2 and OS will be produced at the time of the PFS data cut off. Descriptive 
analyses will be performed on all QoL endpoints, using frequency distribution for categorical 
endpoints and means and corresponding 95% confidence intervals for continuous endpoints. 
The analyses of OS will be repeated on the exploratory HRRm cohort. Further details will be 
provided in the Statistical Analysis Plan.   
Safety data will be summarised and reported for all patients with BRCAm, patients with 
sBRCAm and patients with HRRm ovarian cancer. 
8.4.3 
Subgroup analysis  
Among patients with BRCAm disease, subgroup analyses will be presented, as described for 
the primary analysis of PFS, to assess the consistency of olaparib effect across potential or 
expected prognostic factors.  
The following subgroups of the FAS may be summarised. 


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x Response to previous platinum chemotherapy (CR vs PR) 
x Time to disease progression on last platinum based chemotherapy received prior to 
first dose of olaparib (6 – 12 months / > 12 months) 
x Measurable versus non-measurable disease at baseline 
x BRCA mutation type, e.g. gBRCA; BRCA1, BRCA2 or BRCA1/2 (both)  
x Age at enrolment (<65 vs  years old)  
x Region  
x Prior PARP inhibitor use  
x Family history 
x Prior bevacizumab use. 
Other baseline variables may also be assessed if there is clinical justification. Further 
explorations will be undertaken for patient characteristics within germline and somatic BRCA 
mutated disease groups. Details will be provided in the Statistical Analysis Plan.   
8.4.4 
Interim analysis 
No formal statistical interim analyses for PFS are planned for this trial. 
8.4.5 
Exploratory analysis (if applicable) 
Exploratory translational science endpoints 
Full statistical methods for biomarker exploratory endpoints will be defined in a separate 
translation science analysis plan.  Biomarker data will be summarised descriptively using 
tables and plots.  If the data is available at the time of developing the CSR then the biomarker 
data will be included in the CSR.  Otherwise the biomarker data will be reported in a separate 
addendum to the CSR (if applicable).  Further details on the data summaries and plots for the 
biomarker data for the CSR will be provided in the SAP. 
8.5 
Training of study site personnel 
Before the first patient is entered into the study, a designated 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 
WBDC and/or any electronic PROs system(s) utilised. 
The PI will ensure that appropriate training relevant to the study is given to all of these staff, 
and that any new information relevant to the performance of this study is forwarded to the 
staff involved. 
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff). 


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8.6 
Monitoring of the study 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 
x 
Provide information and support to the Investigator(s) 
x 
Confirm that facilities remain acceptable 
x 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed 
x 
Perform source data verification (a comparison of the data in the CRFs with the patient’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating patients. This will require 
direct access to all original records for each patient (e.g., clinic charts) 
x 
Ensure withdrawal of informed consent to the use of the patient’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the patient. 
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 
8.6.1 
Source data 
Refer to the Clinical Study Agreement for location of source data. 
8.6.2 
Study agreements 
The PI at each/the centre should comply with all the terms, conditions, and obligations of the 
Clinical Study Agreement, or equivalent, for this study.  In the event of any inconsistency 
between this Clinical Study Protocol and the Clinical Study Agreement, the terms of Clinical 
Study Protocol shall prevail with respect to the conduct of the study and the treatment of 
patients and in all other respects, not relating to study conduct or treatment of patients, the 
terms of the Clinical Study Agreement shall prevail. 
Agreements between AstraZeneca and the PI should be in place before any study-related 
procedures can take place, or patients are enrolled. 
8.6.3 
Archiving of study documents 
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA). 
8.7 
Study timetable and end of study 
The end of the study is defined as ‘the last visit of the last patient undergoing the study’. 


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The study is expected to start in Q3 2015 and to end by Q2 2018. 
The study may be terminated at individual centres if the study procedures are not being 
performed according to Good Clinical Practice (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. 
8.8 
Data management by AstraZeneca  
Data management will be performed by an AstraZeneca representative, according to the Data 
Management Plan.   
The data collected through third party sources will be obtained and reconciled against study 
data. 
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the AstraZeneca Drug Dictionary.  All entries to the study 
database will be available in an audit trail. 
The data will be validated as defined in the Clinical Informatics Plan and Data Quality 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 Plans 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, 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 Patient Safety database 
and/or the investigational site.  
Data management of genotype data 
Exploratory genotype data generated in this study will be stored in the AstraZeneca 
genotyping LIMS database, or other appropriate secure system within AstraZeneca and/or 
third party contracted to work with AstraZeneca to analyse samples.  The results from this 
exploratory genetic research may be reported in the CSR. 
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. 
Data associated with human biological samples 


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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. 
9. 
ETHICAL AND REGULATORY REQUIREMENTS 
9.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca 
policy on Bioethics and Human Biological Samples. 
9.2 
Patient data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
9.3 
Ethics and regulatory review 
An Ethics Committee (EC) should approve the final study protocol, including the final version 
of the Informed Consent Form and any other written information and/or materials to be 
provided to the patients.  The Informed Consent Form will address the donation of tissue and 
blood samples for BRCA testing, tissue sample for HRR testing, as well as optional tissue 
samples for exploratory analysis and optional blood samples for ctDNA analysis. 
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 enrolment of any patient into the study.  
The Ethics Committee should approve all advertising used to recruit patients for the study. 
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements. 


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Study Code D0816C00012 
Edition Number 3 
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If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually. 
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations. 
AstraZeneca 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. 
For the US and Canada, may also be applicable to other countries: 
Each PI is responsible for providing the Ethics Committees/IRB with reports of any serious 
and unexpected adverse drug reactions from any other study conducted with the 
investigational product.  AstraZeneca will provide this information to the PI so that he/she can 
meet these reporting requirements. 
9.4 
Informed consent 
The Principal Investigator(s) at each centre will: 
x 
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study 
x 
Ensure each patient is notified that they are free to discontinue from the study at any 
time 
x 
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided 
x 
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study 
x 
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File 
x 
Ensure a copy of the signed Informed Consent Form is given to the patient 
x 
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the informed consent form that is approved by an Ethics Committee. 


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9.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator, the Principal Investigator and AstraZeneca or designated CRO. 
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 or designated CRO will distribute any subsequent amendments and new versions 
of the protocol to each Principal Investigator(s). For distribution to Ethics Committee see 
Section 9.6. 
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. 
9.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements.  The Investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the centre. 
10. 
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Study Code D0816C00012 
Edition Number 3 
Date 22 July 2016 
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Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AOH, 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. 
Rustin et al 2011 
Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, et al. Definitions for response and 
progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by 
the gynecological Cancer Intergroup (CGIG). Int J Gynecol Cancer 2011;21:419-423. 
Sant et al 2009 
Sant M, Allemani C, Santaquilani M, et al. EUROCARE-4. Survival of cancer patients 
diagnosed in 1995-1999. Results and commentary. Eur J Cancer. 2009;45(6):931-91. 
Siegel et al 2014 
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64(1):9-29. 
Yellen et al 1997 
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other 
anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) 
measurement system. J Pain Symptom Manage. 1997;13(2):63-74. 
Zhang et al 2011 
Zhang S, Royer R, Li S, et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 
unselected patients with invasive ovarian cancer. Gynecol Oncol 2011;121(2):353-7. 
 
 


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Clinical Study Protocol Appendix B
Drug Substance
Olaparib
Study Code
D0816C00012
Edition Number
1
Date
26 February 2015
Appendix B
Additional Safety Information


Clinical Study Protocol Appendix B
Drug Substance Olaparib
Study Code D0816C00012
Edition Number 1
Date 26 February 2015
2(3)
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE)
Life threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the adverse 
event (AE) as it occurred or it is suspected that use or continued use of the product would 
result in the patient’s death. ‘Life-threatening’ does not mean that had an AE occurred in a 
more severe form it might have caused death (eg, hepatitis that resolved without hepatic 
failure).
Hospitalisation
Out-patient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the patient 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 should be used.
Examples of such events are:
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse.


Clinical Study Protocol Appendix B
Drug Substance Olaparib
Study Code D0816C00012
Edition Number 1
Date 26 February 2015
3(3)
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug.
!
Time Course.  Exposure to suspect drug. Has the patient actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?
!
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
Dechallenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Rechallenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped?  AstraZeneca would not normally recommend or support 
a rechallenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship?
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist.
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE.
In difficult cases, other factors could be considered such as:
!
Is this a recognised feature of overdose of the drug?
!
Is there a known mechanism?
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility.



Clinical Study Protocol Appendix C
Drug Substance
Olaparib
Study Code
D0816C00012
Edition Number
1
Date
26 February 2015
Appendix C
International Airline Transportation Association (IATA) 6.2 Guidance 
Document


Clinical Study Protocol Appendix C
Drug Substance Olaparib
Study Code D0816C00012
Edition Number 1
Date 26 February 2015
2(3)
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm). For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg. Ebola, Lassa fever virus
!
are to be packed and shipped in accordance with IATA Instruction 602
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg. Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations.
!
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm).
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content.
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable.


Clinical Study Protocol Appendix C
Drug Substance Olaparib
Study Code D0816C00012
Edition Number 1
Date 26 February 2015
3(3)
!
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used.


Clinical Study Protocol Appendix D
Drug Substance
Olaparib
Study Code
D0816C00012
Edition Number
1
Date
26 February 2015
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law


Clinical Study Protocol Appendix D
Drug Substance Olaparib
Study Code D0816C00012
Edition Number 1
Date 26 February 2015
2(7)
TABLE OF CONTENTS
PAGE
TITLE PAGE............................................................................................................................1
TABLE OF CONTENTS .........................................................................................................2
1.
INTRODUCTION ...................................................................................................3
2.
DEFINITIONS.........................................................................................................3
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES...................................4
4.
FOLLOW-UP ..........................................................................................................4
4.1
Potential Hy’s Law Criteria not met ........................................................................4
4.2
Potential Hy’s Law Criteria met ..............................................................................4
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES...............5
6.
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW CRITERIA 
ARE MET BEFORE AND AFTER STARTING STUDY TREATMENT ............6
7.
REFERENCES ........................................................................................................7


Clinical Study Protocol Appendix D
Drug Substance Olaparib
Study Code D0816C00012
Edition Number 1
Date 26 February 2015
3(7)
1.
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.  
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
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.
2.
DEFINITIONS
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication  irrespective of an increase in Alkaline Phosphatase 
(ALP).


Clinical Study Protocol Appendix D
Drug Substance Olaparib
Study Code D0816C00012
Edition Number 1
Date 26 February 2015
4(7)
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, eg, 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.
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
!
ALT ≥ 3xULN
!
AST ≥ 3xULN
!
TBL ≥ 2xULN
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix 
for definition) by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory CRF
4.
FOLLOW-UP
4.1
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
4.2
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
!
Notify the AstraZeneca representative who will then inform the central Study Team 


Clinical Study Protocol Appendix D
Drug Substance Olaparib
Study Code D0816C00012
Edition Number 1
Date 26 February 2015
5(7)
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:
!
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 
!
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. 
!
Complete the three Liver CRF Modules as information becomes available 
!
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
5.
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. 


Clinical Study Protocol Appendix D
Drug Substance Olaparib
Study Code D0816C00012
Edition Number 1
Date 26 February 2015
6(7)
∀
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
!
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
6.
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW
CRITERIA ARE MET BEFORE AND AFTER STARTING 
STUDY TREATMENT 
This section is applicable to patients who meet PHL criteria on study treatment having 
previously met PHL criteria at a study visit prior to starting study treatment.
At the first on study treatment occurrence of PHL criteria being met the Investigator will:
!
Determine if there has been a significant change in the patients’ condition#
compared with the last visit where PHL criteria were met#
∀
If there is no significant change no action is required
∀
If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described is 
Section 4.2 of this Appendix
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or 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.


Clinical Study Protocol Appendix D
Drug Substance Olaparib
Study Code D0816C00012
Edition Number 1
Date 26 February 2015
7(7)
7.
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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Clinical Study Protocol Appendix F 
Drug Substance 
Olaparib 
Study Code 
D0816C00012 
Edition Number 
2 
Date 
30 April 2015 
 
 
 
 
 
 
 
 
 
Appendix F 
Guidance of Evaluation of Objective Tumour Response Using Modified 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumours) 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib 
Study Code D0816C00012  
Edition Number 2 
Date 30 April 2015 
2(10) 
ϭ͘ 
INTRODUCTION
This appendix details the implementation of modified RECIST 1.1 Guidelines (Eisenhauer et 
al 2009) for the 
 study with regards to Investigator assessment of tumour 
burden including protocol-specific requirements for this study. 
1.     DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET 
AND NON-TARGET LESIONS 
Patients with measurable disease and/or non measurable and/or no evidence of disease 
assessed at baseline by CT/MRI will be entered in this study. RECIST 1.1. has been modified 
to allow the assessment of progression due to new lesions in patients with no evidence of 
disease at base-line. 
Measurable: 
A lesion, not previously irradiated, that can be accurately PHDVXUHGDWEDVHOLQHDVPPLQ
WKHORQJHVWGLDPHWHUH[FHSWO\PSKQRGHVZKLFKPXVWKDYHVKRUWD[LVPPZLWK
computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for 
accurate repeated measurements. 
Non-measurable: 
x 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
O\PSKQRGHVZLWKWRPPVKRUWD[LVDWEDVHOLQH 
x 
Truly non-measurable lesions include the following: bone lesions, 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. 
x 
Previously irradiated lesions** 
x 
Skin lesions assessed by clinical examination 
x 
Brain metastasis 
* Nodes with <10mm short axis are considered non-pathological and should not be recorded 
or followed as NTL. 
**Localised 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. 
Special Cases: 
CCI


Clinical Study Protocol Appendix F 
Drug Substance Olaparib 
Study Code D0816C00012  
Edition Number 2 
Date 30 April 2015 
3(10) 
x 
Lytic bone lesions or mixed lytic±blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. Blastic lesions are considered non-measurable. 
x 
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present 
in the same patient; these 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. 
2.     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 tumour assessments for this study are highlighted, with the rationale provided. 
Table 1 
Summary of Methods of Assessment 
Target Lesions  
Non-Target Lesions 
New Lesions 
CT (preferred) 
MRI 
CT (preferred) 
MRI 
Clinical examination  
X-ray, Chest x-ray 
CT (preferred) 
MRI 
Clinical examination  
X-ray, Chest x-ray 
Ultrasound 
Bone Scan 
FDG-PET 
 
3.1 
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.  


Clinical Study Protocol Appendix F 
Drug Substance Olaparib 
Study Code D0816C00012  
Edition Number 2 
Date 30 April 2015 
4(10) 
In the D0816C00012 study it is recommended that CT examinations of the chest*, abdomen 
and pelvis will be used to assess tumour 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. 
x 
*Chest, abdomen and pelvis CT/MRI scans should be performed at baseline.  
x 
*In those patients with thoracic lesions or upper abdomen lymphadenopathy 
identified at baseline assessment, chest, abdomen and pelvis should be performed at 
follow-up.  
x 
*In those patient with no disease present in the chest and no upper abdomen 
lymphadenopathy then follow-up is by abdomen and pelvis only. 
3.2 
Clinical examination  
In the D0816C00012 study, clinical examination will not be used for assessment of TL.  
Clinically detected lesions can be selected as target lesions if they are assessed by CT or MRI 
scans.  Clinical examination can be used to assess NTL and to identify the presence of new 
lesions. 
3.3 
X-ray 
3.3.1 Chest X-ray 
In the D0816C00012 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. 
3.3.2 Plain X-ray  
In the D0816C00012 study plain x-ray may be used as a method of assessment for bone NTL 
and to identify the presence of new bone lesions.  
3.4 
Ultrasound  
In the D0816C00012 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 tumour 
size and it is subjective and operator dependent.  Ultrasound examination can, however, be 
used to identify the presence of new lesions.  If new clinical symptoms occur and an 
ultrasound is performed then new lesions should be confirmed by CT or MRI examination. 
3.5 
Endoscopy and laparoscopy  


Clinical Study Protocol Appendix F 
Drug Substance Olaparib 
Study Code D0816C00012  
Edition Number 2 
Date 30 April 2015 
5(10) 
In the D0816C00012 study, endoscopy and laparoscopy will not be used for tumour 
assessments as they are not validated in the context of tumour assessment. 
3.6 
Tumour markers  
In the D0816C00012 study tumour markers will not be used for tumour response assessments 
as per RECIST 1.1. 
In this study the following marker(s) CA-125 are being collected for separate analysis.  
However, the results will not contribute to tumour response based on RECIST 1.1 assessment. 
3.7 
Cytology and histology  
In the D0816C00012 study histology will not be used as part of the tumour response 
assessment as per RECIST 1.1.  
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease.  In such circumstances, the cytology is necessary to differentiate between 
response / stable disease (an effusion may be a side effect of the treatment) and progressive 
disease (if the neoplastic origin of the fluid is confirmed).  Where cytology findings are not 
available, any effusion that significantly worsens (from trace to large) or appearance of 
clinically significant effusion (requiring change in drug therapy) during the study treatment 
will be considered to be progression of NTL, or disease progression due to new lesions.  
3.8 
Isotopic bone scan  
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or X-
ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment.   
In the D0816C00012 study isotopic bone scans may 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 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.  Confirmation by CT, MRI and 
x-ray is recommended where bone scan findings are equivocal. 
3.9 
FDG-PET scan  
In the D0816C00012 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 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib 
Study Code D0816C00012  
Edition Number 2 
Date 30 April 2015 
6(10) 
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. 
3.     TUMOUR 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 patients and should be performed no more than 28 days 
before randomisation, and ideally should be performed as close as possible to the start of 
study treatment.  Follow-up assessments will be performed every 12 weeks (±1 week), up to 
72 weeks, then every 24 weeks (±1 week) relative to date of randomisation, until objective 
disease progression as defined by modified RECIST 1.1. See Table 3: Study Schedule from 
Study Protocol for further information.  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 patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.  This 
schedule is to be followed in order to minimise any unintentional bias caused by some patients 
being assessed at a different frequency than other patients. 
4.2 
Target lesions (TL) 
4.2.1 Documentation of target lesions 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved should be identified as 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: 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib 
Study Code D0816C00012  
Edition Number 2 
Date 30 April 2015 
7(10) 
x 
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.  
x 
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. 
x 
If a lesion has completely disappeared, the longest diameter should be recorded as 
0 mm. 
x 
If a TL splits into two or more parts, then record the sum of the diameters of those 
parts.  
x 
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).   
x 
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. 
x 
If a TL cannot be measured accurately due to it being too large, provide an estimate 
of the size of the lesion.  
x 
When a TL has had any intervention e.g. radiotherapy, embolisation, surgery etc., 
during the study, the size of the TL should still be provided where possible. 
4.2.2 Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumour visit 
response for TL. 
Table 2 
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. 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib 
Study Code D0816C00012  
Edition Number 2 
Date 30 April 2015 
8(10) 
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 
4.3 
Non-target lesions (NTL) 
4.3.1 Evaluation of non-target lesions 
All other lesions (or sites of disease) 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 3 
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. 
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 patients 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. 
7RDFKLHYHµXQHTXLYRFDOSURJUHVVLRQ¶RQWKHEDVLVRIQRQ-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 tumour burden has increased sufficiently to merit 
GLVFRQWLQXDWLRQRIWKHUDS\$PRGHVWµLQFUHDVH¶LQWKHVL]HRIRQHRUPRUHQRQ-target lesions 
is usually not sufficient to qualify for unequivocal progression status. 
4.4 
New Lesions 
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. 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib 
Study Code D0816C00012  
Edition Number 2 
Date 30 April 2015 
9(10) 
The finding of a new lesion should be unequivocal: i.e. not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour. 
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan. 
4.5 
Symptomatic deterioration 
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy. 
PatLHQWVZLWKµV\PSWRPDWLFGHWHULRUDWLRQ¶UHTXLULQJGLVFRQWLQXDWLRQRIWUHDWPHQWZLWKRXW
objective evidence of disease progression at that time should continue to undergo tumour 
assessments where possible until objective disease progression is observed. 
4.6 
Evaluation of Overall Visit Response 
The overall visit response will be derived using the algorithm shown in Table 4. 
Table 4 
Overall Visit Response 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
NA 
CR 
No 
CR 
CR 
Non CR/Non PD  
No 
PR 
CR 
NE 
No  
PR 
PR 
Non PD or NE 
No 
PR 
SD  
Non PD or NE 
No 
SD 
NA 
Non CR/Non PD 
No 
SD (Non CR/Non PD) 
NE 
Non PD or NE 
No 
NE 
NA 
NE 
No  
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
NA 
NA 
No 
NED 


Clinical Study Protocol Appendix F 
Drug Substance Olaparib 
Study Code D0816C00012  
Edition Number 2 
Date 30 April 2015 
10(10) 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease, NE = not evaluable, NED = no evidence of disease, NA = not applicable (only 
relevant if there were no TL/NTL at baseline). 
4.     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 


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Clinical Study Protocol Appendix H 
Drug Substance Olaparib 
Study Code D0816C00012  
Edition Number 2 
Date 01 September 2015 
1(1) 
 
Clinical Study Protocol Appendix H 
 
Drug Substance 
Olaparib 
 
Study Code 
D0816C00012 
 
Edition Number 
2 
 
Date 
01 September 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix H 
Patient Reported Outcomes - FACT-O, ORZORA QoL Additional Items 
Questionnaire, FACIT Fatigue Scale and Functional Living Index Emesis 
(FLIE) 
 
 


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FACIT Fatigue Scale (Version 4) 
English (Universal) 
 
16 November 2007 
Copyright 1987, 1997 
 
Page 1 of 1 
 
 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
HI7 
I feel fatigued ...................................................................
0 
1 
2 
3 
4 
HI12 
I feel weak all over...........................................................
0 
1 
2 
3 
4 
An1 
I feel listless (“washed out”).............................................
0 
1 
2 
3 
4 
An2 
I feel tired.........................................................................
0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am tired................
0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am tired .............
0 
1 
2 
3 
4 
An5 
I have energy....................................................................
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities....................................
0 
1 
2 
3 
4 
An8 
I need to sleep during the day ...........................................
0 
1 
2 
3 
4 
An12 
I am too tired to eat...........................................................
0 
1 
2 
3 
4 
An14 
I need help doing my usual activities ................................
0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the things I want 
to do.................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
An16 
I have to limit my social activity because I am tired..........
0 
1 
2 
3 
4 
 
 









 
Page 1 of 2  
Clinical Study Protocol Errata List 
Drug Substance 
Olaparib 
Study Code 
D0816C00012 
Edition Number 
3  
Date 
15 November  2016 
 
An Open Label, Single Arm, Multicentre Study to Assess the Clinical 
Effectiveness and Safety of Lynparza (Olaparib) Capsules Maintenance 
Monotherapy in Platinum Sensitive Relapsed somatic or germline BRCA 
Mutated Ovarian Cancer Patients who are in Complete or Partial Response 
Following Platinum based Chemotherapy (ORZORA) 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden.   
This submission /document contains trade secrets and confidential commercial information, disclosure of 
which is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
 
 
 


 
Page 2 of 2  
 
Section/Document 
Page 
Reads  
Should read 
Section 4 Table 2 last 
row 
47-48-
49 
Optional tumour sample on 
progression j 
Optional tumour sample on progression k 
Section 4 Table 2 last 
footnote 
47-48-
49 
h 
Optional and subject to 
specific informed consent.  
 
k 
Optional and subject to specific 
informed consent.  
 
 
 

SAP_001.pdf: 
CONFIDENTIAL AND PROPRIETARY
1 of 82
Statistical Analysis Plan
Study Code
D0816C00012
Edition Number
5.0
Date
19 February 2020
An Open Label, Single Arm, Multicentre Study to Assess the Clinical 
Effectiveness and Safety of Lynparza (Olaparib) Capsules Maintenance 
Monotherapy in Platinum Sensitive Relapsed somatic or germline BRCA
Mutated Ovarian Cancer Patients who are in Complete or Partial Response 
Following Platinum-based Chemotherapy (ORZORA)


PPD


PPD


PPD


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
5 of 82
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE 
..........................................................2
SIGNATURE 
..................................3
SIGNATURE 
........................................................4
TABLE OF CONTENTS.....................................................................................5
LIST OF ABBREVIATIONS ..............................................................................9
AMENDMENT HISTORY................................................................................ 12
1.
STUDY DETAILS.............................................................................................14
1.1
Study Objectives................................................................................................14
1.1.1
Primary Objectives.............................................................................................14
1.1.2
Secondary Objectives.........................................................................................14
1.1.3
Safety Objective.................................................................................................15
1.1.4
Exploratory Objectives.......................................................................................15
1.2
Study design ...................................................................................................... 16
1.3
Number of patients.............................................................................................18
2.
ANALYSIS SETS .............................................................................................18
2.1
Definition of analysis sets .................................................................................. 18
2.1.1
Full analysis set..................................................................................................21
2.1.2
Safety analysis set..............................................................................................21
2.2
Violations and deviations ................................................................................... 21
3.
PRIMARY AND SECONDARY ENDPOINTS.................................................22
3.1
Derivation of RECIST visit response..................................................................22
3.1.1
Target lesions (TLs)........................................................................................... 22
3.1.2
Non-target lesions (NTLs) and new lesions ........................................................27
3.1.3
Overall visit response.........................................................................................27
3.2
Primary endpoint................................................................................................28
3.2.1
Progression Free Survival (PFS) ........................................................................28
3.3
Secondary endpoints .......................................................................................... 29
3.3.1
Overall Survival (OS) ........................................................................................29
3.3.2
Time to second progression or death (PFS2) ......................................................30
3.3.3
Time to first subsequent anti-cancer therapy or death (TFST).............................31
3.3.4
Time to second subsequent anti-cancer therapy or death (TSST)........................31
PPD
PPD
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Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
6 of 82
3.3.5
Time to study treatment discontinuation or death (TDT) ....................................31
3.3.6
QoL endpoints ...................................................................................................31
3.3.6.1
Patient Reported Outcomes (PROs).................................................................... 31
3.3.6.2
Functional Living Index-Emesis (FLIE)............................................................. 33
3.3.6.3
Functional Assessment of Cancer Therapy-Ovarian (FACT-O)..........................34
3.3.6.4
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)..............36
3.3.6.5
ORZORA QoL Additional Items Questionnaire .................................................37
3.4
Exploratory endpoints ........................................................................................ 37
3.4.1
MDS/AML and New primary malignancies ....................................................... 37
3.4.2
Side effects and Comorbidities...........................................................................37
3.4.3
Progression Free Interval (PFI) with olaparib.....................................................37
3.4.4
Progression Free Interval (PFI) for penultimate platinum ...................................38
3.4.5
CA-125 progression........................................................................................... 39
3.5
Safety endpoints.................................................................................................39
3.5.1
Adverse Events ..................................................................................................39
3.5.2
Adverse Events of Special Interest (AESI)......................................................... 40
3.5.3
Other Significant Adverse Events (OAEs).......................................................... 40
3.5.4
Laboratory safety assessments............................................................................40
3.5.5
Vital sign safety assessments..............................................................................40
3.5.6
Calculation or derivation of safety variables....................................................... 41
3.5.6.1
Exposure............................................................................................................41
3.5.6.2
Compliance........................................................................................................ 41
3.5.6.3
Dose intensity ....................................................................................................41
3.5.6.4
Dose interruption ...............................................................................................42
3.5.6.5
AEs, SAEs, AESI and OAEs.............................................................................. 42
3.5.6.6
Laboratory assessments...................................................................................... 42
3.5.6.7
Vital signs assessment........................................................................................42
4.
ANALYSIS METHODS....................................................................................43
4.1
General Principles.............................................................................................. 43
4.1.1
Rules for Reporting Statistics.............................................................................43
4.1.2
Rules for Handling Missing Data .......................................................................43
4.1.3
Data cut-off........................................................................................................ 45
4.1.4
Visit windows....................................................................................................45
4.2
Descriptive Analysis .......................................................................................... 47
4.2.1
Patient Disposition.............................................................................................47
4.2.2
Protocol deviations.............................................................................................48
4.2.3
Demographics and Baseline Characteristics .......................................................48
4.2.4
Medical History .................................................................................................48
4.2.5
Medication.........................................................................................................48
4.3
Primary Analysis: PFS ....................................................................................... 49
4.3.1
Real-world clinical effectiveness of olaparib by investigator assessed PFS 
in patients with BRCAm ovarian cancer using RECIST criteria ..........................49


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
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4.3.2
Subgroups analysis of PFS in patients with BRCAm ovarian cancer using 
RECIST criteria .................................................................................................49
4.3.3
Sensitivity analysis of PFS in patients with BRCAm ovarian cancer ...................50
4.3.4
Real-world clinical effectiveness of olaparib by investigator assessed PFS 
in patients with sBRCAm using RECIST criteria ................................................50
4.4
Secondary Analysis............................................................................................51
4.4.1
Real-world clinical effectiveness of olaparib by assessment of OS .....................51
4.4.2
Real-world clinical effectiveness of olaparib by assessment of PFS2..................51
4.4.3
Real-world clinical effectiveness of olaparib by assessment of TFST.................51
4.4.4
Real-world clinical effectiveness of olaparib by assessment of TSST.................51
4.4.5
Real-world clinical effectiveness of olaparib by assessment of TDT...................51
4.4.6
Nature and patterns of AEs of nausea and vomiting and their impact on 
QoL and toxicity management patterns used in routine clinical practice .............51
4.4.7
QoL of patients .................................................................................................. 52
4.4.7.1
Functional Living Index Emesis (FLIE) .............................................................52
4.4.7.2
Functional Assessment of Cancer Therapy-Ovarian (FACT-O)..........................52
4.4.7.3
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)..............52
4.4.7.4
ORZORA QoL Additional Items Questionnaire .................................................53
4.5
Exploratory Analysis.......................................................................................... 57
4.5.1
The long-term safety of olaparib, including follow up for MDS/AML, New 
primary malignancies and pneumonitis ..............................................................57
4.5.2
Incidence of side effects and QoL according to age and the presence of 
comorbidities .....................................................................................................57
4.5.3
Clinical effectiveness of (response to) subsequent line of treatment and 
correlating it with the PFI (artificial prolongation of PFI through olaparib) ........58
4.5.4
Efficacy of olaparib according to the previous therapy, with or without 
bevacizumab, and according to the PFI (recurrence during or after the end 
of bevacizumab maintenance) ............................................................................58
4.5.5
Activity of olaparib according to the germline mutational status (BRCA1 vs 
2), and to the presence of family history of ovarian/breast cancer (yes vs 
no) .....................................................................................................................58
4.5.6
Kinetic of Ca125 progression according to GCIG criteria and its 
correlation with disease progression by RECIST during olaparib therapy...........58
4.5.7
Real-world clinical effectiveness of olaparib by assessment of PFS in 
patients with HRRm^ ovarian cancer ................................................................. 58
4.5.8
Real-world clinical effectiveness of olaparib by assessment of OS in 
patients with HRRm^ ovarian cancer ................................................................. 59
4.6
Safety Analysis ..................................................................................................59
4.6.1
Exposure............................................................................................................59
4.6.2
Compliance........................................................................................................ 59
4.6.3
Dose intensity ....................................................................................................59
4.6.4
Dose interruptions/Reductions ...........................................................................59
4.6.5
Adverse Events (AEs)........................................................................................59
4.6.6
Adverse Events Special Interest (AESIs)............................................................ 61


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
8 of 82
4.6.7
Laboratory Results............................................................................................. 61
4.6.8
Vital Signs .........................................................................................................62
5.
INTERIM ANALYSES .....................................................................................62
6.
CHANGES OF ANALYSIS FROM PROTOCOL .............................................62
7.
REFERENCES ..................................................................................................63
8.
APPENDIX .......................................................................................................64
LIST OF TABLES
Table 1
Summary of Endpoints, Analysis Populations and Patient Groups.........19
Table 2
TL visit responses .................................................................................23
Table 3
Overall Visit Response..........................................................................28
Table 4
Health Related QoL ..............................................................................35
Table 5
Health Related Quality of Life: Change rates - overall score .................36
Table 6
Laboratory Safety Variables..................................................................40
Table 7
Visit Windows ......................................................................................46
Table 8
Table of efficacy and Qol analyses and pre-planned sensitivity, 
subgroup analyses .................................................................................54
LIST OF FIGURES
Figure 1
Study Flow Chart ..................................................................................17
Figure 2
PFI Flow Chart......................................................................................37


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
9 of 82
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AC
Additional Concerns
AE
Adverse event 
AML
Acute Myeloid Leukaemia 
AESI
Adverse Event of Special Interest
ATC
Anatomical Therapeutic Chemical 
BP
Blood Pressure
BRCA
Breast cancer susceptibility gene (in accordance with scientific convention, 
gene and mutation is italicised whereas protein is not italicised)
BRCAm
gBRCA and/or sBRCA mutated
CA-125
Cancer antigen 125
CI
Confidence Interval
CR
Complete Response
CSP
Clinical Study Protocol
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
Circulating Tumour DNA
DCO
Date Cut-Off
DNA
Deoxyribonucleic Acid 
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EU
European Union
EWB
Emotional well-being 
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy-Fatigue 
FACT-O
Functional Assessment of Cancer Therapy-Ovarian
FAS
Full Analysis Set
FLIE
Functional Living Index-Emesis
FWB
Functional well-being 
gBRCA
germline BRCA
CCI


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
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Abbreviation or 
special term
Explanation
gBRCAm
germline BRCA mutated
GCIG
Gynaecological Cancer Inter Group
HRQoL
Health-Related Quality of Life
HRR
Homologous Recombination Repair
HRRm
Qualifying mutation in the tumour of any of 15 genes involved in DNA
homologous recombination repair 
IP
Investigational Product 
KM
Kaplan-Meir
LOF
Loss of Function
LOH
Loss of Heterozygosity
MedDRA
Medical Dictionary for Regulatory Activities
MDS
Myelodysplastic Syndrome 
MRI
Magnetic Resonance Imaging
NE
Not evaluable
NED
No evidence of disease
NTL
Non-target Lesion
OAEs
Other Significant Adverse Events
OS
Overall Survival
PARP
Poly-adenosine 5’diphosphoribose (ADP) Polymerase
PD
Progression of Disease
PFI
Progression Free Interval
PFS
Progression Free Survival 
PFS2
Second Progression Free Survival 
p.o.
Administered by mouth 
PR
Partial Response
PRO
Patient Reported Outcome
PT
Preferred Term
PWB
Physical well-being
QoL
Quality of Life
RECIST
Response Evaluation Criteria In Solid Tumours
SAE
Serious adverse event 


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
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Abbreviation or 
special term
Explanation
sBRCAm
Somatic tumour BRCA mutated (mutation detected in the tumour but not in 
the germline)
SD
Stable Disease
SOC
System Organ Class
SWB
Social/family well-being 
TDT
Time to Discontinuation of Treatment
TFST
Time to First Subsequent Treatment
TL
Target Lesion
TOI
Trial Outcome Index
TSST
Time to Second Subsequent Treatment
ULN
Upper Limit of Normal
ULRR
Upper Limit of Response Range
WBDC
Web Based Data Capture
WHODrug
World Health Organization Drug 


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
12 of 82
AMENDMENT HISTORY
Category: 
Change refers 
to
Date
Brief description of change
In line with CSP?
Y (version) /
No /NA
Rationale
Other
23 March 2016
(V2.0)
Updated in accordance with protocol 
edition 2, 22 December 2015. Key 
changes in the CSP were a 
clarification of the populations of
interest; a reduction in sample size 
required; and additional secondary 
endpoints related to QoL and safety.
Y (Ed 2)
To limit the enrolment of patients 
previously diagnosed with germline 
BRCA mutated disease and ensure that 
at least 50 patients with somatic BRCA
mutated disease will be enrolled. To 
specify that, following consultancy 
with the Committee for Human 
Medicines Products (CHMP): The 
assessment of effectiveness of olaparib 
in the cohort of patients with somatic 
BRCA mutated disease, based on 
progression-free survival, has become a 
primary endpoint.  Quality of life 
objectives have become secondary 
objectives. 
Other
3 November 
2016 (V3.0)
Updated in accordance with protocol 
edition 3, 22 July 2016; addition of an 
HRR exploratory cohort
Y (Ed 3)
The real world
clinical effectiveness and safety of 
olaparib maintenance therapy will 
be described for this exploratory 
HRRm cohort.
Other
31 May 2019
(V4.0)
Updated in preparation for protocol, 
edition 4, 22 March 2019, which was 
not subsequently approved.
Y (Ed 4)
Protocol V4 was intended to allow the
study to stop after primary analysis.


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
13 of 82
Category: 
Change refers 
to
Date
Brief description of change
In line with CSP?
Y (version) /
No /NA
Rationale
Other
19 February
2020 (V5.0)
Updated to bring text in line with
current Oncology standards; updated 
text around protocol deviations to be 
more specific; clarification that the 
exploratory endpoint around Loss of 
Heterozygosity will be reported as an 
addendum to the primary CSR; 
addition of summary tables for 
common Olaparib AEs based on
grouped preferred terms; clarification 
of subgroup on penultimate platinum
chemotherapy; the primary objective 
is no longer referenced as co-
primary to avoid confusion with 
the interpretation of study 
outcomes. The study does not test 
formal statistical hypotheses. As 
such, the study does not require the
implementation of formal 
statistical procedures to protect
from reporting false positive 
results
Y (Ed 3)
To clarify text around analysis 
procedures.


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
14 of 82
1.
STUDY DETAILS
1.1
Study Objectives
1.1.1
Primary Objectives
The primary objectives are listed below:
!
To assess the real-world clinical effectiveness of olaparib maintenance 
monotherapy by investigator assessed progression free survival (PFS) according to 
modified Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 in patients
with somatic BRCA mutated (sBRCAm) ovarian cancer.
!
To assess the real-world clinical effectiveness of olaparib maintenance 
monotherapy by investigator assessed PFS according to RECIST 1.1 in patients 
with BRCA mutated (BRCAm) ovarian cancer.
1.1.2
Secondary Objectives
The secondary objectives are listed below:
!
To assess the real-world clinical effectiveness of olaparib maintenance 
monotherapy in patients with BRCAm ovarian cancer and patients with sBRCAm 
ovarian cancer, by assessment of:
(a) Overall survival (OS)
(b) Time to investigator-assessed second progression (PFS2), or death
!
To assess the real-world clinical effectiveness of olaparib maintenance 
monotherapy in patients with BRCAm ovarian cancer and patients with sBRCAm 
ovarian cancer, by assessment of
(a) Time to first subsequent therapy or death (TFST)
(b) Time to second subsequent therapy or death (TSST)
(c) Time to olaparib discontinuation or death (TDT)
!
To assess and describe the quality of life (QoL) of patients with BRCAm ovarian 
cancer and patients with sBRCAm ovarian cancer.
!
To describe the nature and patterns of adverse events (AEs) of nausea and vomiting 
and their impact on QoL in patients with BRCAm ovarian cancer and patients with 
sBRCAm ovarian cancer. To describe nausea/vomiting toxicity management 
patterns used in routine clinical practice.


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
15 of 82
1.1.3
Safety Objective
!
To assess the safety and tolerability of olaparib maintenance monotherapy in 
patients with BRCAm ovarian cancer and patients with sBRCAm ovarian cancer.
1.1.4
Exploratory Objectives
!
To describe the longer-term safety of olaparib monotherapy, including follow up for 
Myelodysplastic Syndrome (MDS)/ Acute Myeloid Leukaemia (AML)/ and New 
primary malignancies (other than MDS/AML).
!
To correlate the incidence of side effects and QoL according to age and the 
presence of comorbidities.
!
To describe the clinical effectiveness of (response to) subsequent line of treatment
and correlating it with the progression-free interval (PFI) (artificial prolongation of 
PFI through olaparib).
!
To describe the efficacy of olaparib according to the previous therapy, with or 
without bevacizumab, and according to the PFI (recurrence during or after the end
of bevacizumab maintenance).
!
To describe the activity of olaparib according to the germline mutational status 
(BRCA1 vs BRCA2), and to the presence of family history (yes vs no).
!
To describe the kinetic of CA-125 progression according to Gynaecological Cancer 
Inter Group (GCIG) criteria and its correlation with disease progression by RECIST 
1.1 guidelines during olaparib therapy.
!
To measure loss of heterozygosity (LOH) for the BRCA1 and BRCA2 genes in 
tumour samples and explore any potential association with efficacy*.
!
To describe the real-world clinical effectiveness and safety of olaparib maintenance
monotherapy in patients with BRCA-independent homologous recombination repair 
gene mutated (HRRm) ovarian cancer, by the following (for definition of HRRm 
cohort, please refer to Section 1.2):
(a) Investigator assessed PFS according to RECIST 1.1
(b) OS
(c) Safety and tolerability.
!
Potential exploratory research into frequency, nature and predictive value of HRR 
gene mutations, including BRCA1 and BRCA2, may be performed on the optional 
collected and stored tumour samples available at study entry or tumour biopsy
samples collected during the course of the study. These could include studying 


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
16 of 82
resistance mechanisms to olaparib, future exploratory research into factors that may 
influence development of cancer and/or response to study treatment. 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 to 
study treatment and/or susceptibility to disease (optional)*.
!
To explore the feasibility of reliably measuring sBRCAm and HRRm from 
circulating tumour DNA (ctDNA)**
*This exploratory analysis will be reported as an addendum to the primary clinical
study report (CSR).
**This exploratory analysis will not be reported in the (CSR). They will be reported 
separately.
1.2
Study design
This is a prospective, open-label, single arm, multi-centre study to assess the real-world 
clinical effectiveness and safety of olaparib maintenance monotherapy will be conducted in 
patients with platinum-sensitive relapsed BRCAm (germline and/or somatic) high grade 
epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete 
response [CR] or partial response [PR]) to platinum-based chemotherapy.
BRCA mutations are documented germline or somatic mutations in BRCA1 or BRCA2 that are 
predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead
to loss of function).
An additional, exploratory cohort of patients with BRCA-independent qualifying alterations in 
genes involved in the HRR pathway will be enrolled into the study (HRRm cohort). 
Qualifying genetic alterations are loss of function (LOF) mutations in any of the 13 genes 
other than BRCA1 and BRCA2 involved in the HRR pathway that are predicted to be 
deleterious or suspected deleterious. These 13 genes are: ATM, BARD1, BRIP1, CDK12, 
CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L.  
The investigational clinical trial assay known as the Lynparza HRR Assay from 
 
will be used for this testing. 
The study flow chart is presented in Figure 1.
CCI


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Figure 1
Study Flow Chart
Patients will be assigned to olaparib capsules administered by mouth [p.o.] 400 mg twice 
daily. They should initiate olaparib treatment within 8 weeks after their last dose of platinum-
containing chemotherapy (last dose is the day of the last infusion).
All patients will have clinical and objective radiological tumour assessments according to 
modified Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 criteria at baseline 
and every 12 weeks relative to date of enrolment, until objective radiological disease 
progression as determined by the investigator. Patients could continue to receive olaparib for
as long as determined by the investigator, until objective radiological disease progression or as
long as in the investigator’s opinion they are benefiting from treatment in relation to other 
clinical assessments and they do not meet any other discontinuation criteria. The study will 
recruit at least 50 patients with sBRCAm disease. Once a patient has discontinued olaparib she 
will be managed as per local clinical practice but will remain in the study. Data will be 
collected on subsequent treatments, progression, overall survival and safety.
The schedule of assessments is found in Tables 1, 2, and 3 of the clinical study protocol.


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1.3
Number of patients
Patients enrolled with sBRCAm disease
The study will recruit at least 50 patients with sBRCAm disease. Assuming a median PFS 
value of 11.2 months (as observed in the phase 2 maintenance study), and a data cut off at 
approximately 60% maturity, ~30 progression or death events would be expected from 50 
patients with sBRCAm disease. Assuming 23 months non-linear recruitment in the sBRCAm
cohort, approximately 30 progression or death events are expected to occur approximately 32 
months after the first subject is enrolled in the study (FSI).  
All BRCAm patients
The sample size of approximately 250 patients is driven by the need to have at least 50 
patients with sBRCAm disease, and to help understand patterns of olaparib use in routine
clinical practice with the capsule formulation and across various subgroups. Assuming a
median PFS value of 11.2 months and a data cut off at approximately 60% maturity then with 
approximately 23 months of non-linear recruitment, ~60% maturity is expected to occur 
approximately 32 months after FSI.
Patients enrolled with HRRm disease
Assuming that approximately 5% of patients with BRCAwt disease screened in the study will 
carry a qualifying genetic alteration in any of the 13 genes involved in the HRR pathway
(excluding BRCA1 and BRCA2), it is estimated that approximately 25 patients will be 
included in the HRRm cohort before the target number of 250 patients with BRCAm disease is 
reached. 
2.
ANALYSIS SETS
2.1
Definition of analysis sets
Table 1 gives a summary of outcome variables and analysis populations.


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Table 1
Summary of Endpoints, Analysis Populations and Patient Groups
Endpoints
Populations
Patient Groups
Primary endpoints
PFS in patients with BRCAm disease
Full Analysis Set
BRCAm*
PFS in patients with sBRCAm disease
Full Analysis Set
sBRCA
Secondary endpoints
OS, PFS2, TFST, TSST, TDT
Full Analysis Set
BRCAm* and
sBRCAm 
QoL: FLIE, FACT-O, FACIT-F, ORZORA Qol (additional 
ovarian cancer items)
Full Analysis Set
BRCAm* and 
sBRCAm 
Safety endpoints
AEs, SAEs, Lab results, vital signs.
Safety Analysis Set
BRCAm*, 
sBRCAm, and 
HRRm^
Exploratory endpoints
Incidences of MDS/AML, new primary malignancies, 
pneumonitis.
Safety Analysis Set
BRCAm*, 
sBRCAm, and 
HRRm^
PFI with olaparib.
Full Analysis Set
BRCAm
PFI for penultimate platinum therapy.
Full Analysis Set
BRCAm
CA-125 progression.
Full Analysis Set
BRCAm
PFS and OS in patients with BRCAm independent HRRm
disease
Full Analysis Set
HRRm^
Demographics and Baseline characteristics
Full Analysis Set
BRCAm*, sBRCAm
and HRRm^
*gBRCAm patient group will also be presented for completeness
HRRm^=HRRm excluding BRCA1 and BRCA2
TFST: time to first subsequent therapy or death; TSST:  time to second subsequent therapy or death; TDT:  time 
to olaparib discontinuation or death; PFS2: Investigator assessed second progression; OS: Overall survival; PFI: 
Progression-free interval.
BRCAm, gBRCAm, sBRCA, and HRRm^ subgroups will be calculated based on:


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Mutation 
Conditions
gBRCAm
!
gBRCAm=”Yes” for patients with BLOOD mutation:
o
If patient is from protocol edition = 1, the patient should show all these 3 characteristics 
Loss of function mutation = “Yes” AND
BRCA mutation type = “BRCA1” or “BRCA2” or “both” AND
BRCA mutation category = “Deleterious mutation” or “Genetic variant, suspected 
deleterious” 
o
If patient is from protocol edition > 1, the patient should show all these 5 characteristics
BRCA Tested = “current (central)” AND
BRCA Laboratory = “Myriad Genetics Lab” AND
Loss of function mutation = “Yes” AND
BRCA mutation type = “BRCA1” or “BRCA2” or “both” AND
BRCA mutation category = “Deleterious mutation” or “Genetic variant, suspected 
deleterious” 
!
Otherwise gBRCAm=”No”
sBRCAm
!
sBRCAm=”Yes” for patient with TUMOR mutation: 
o
If patient is from protocol edition = 1, the patient should show all these 5 characteristics 
gBRCA ≠(“Not tested” and missing) AND
gBRCAm=”No” AND
Loss of function mutation = “Yes” AND
BRCA mutation type = “BRCA1” or “BRCA2” or “both” AND
BRCA mutation category = “Deleterious mutation” or “Genetic variant, suspected 
deleterious” 
o
If patient is from protocol edition > 1, the patient should show all these 7 characteristics
gBRCA ≠(“Not tested” and missing) AND
gBRCAm=”No” AND
BRCA Tested = “current (central)” AND
BRCA Laboratory = “Myriad Genetics Lab” AND
Loss of function mutation = “Yes” AND
BRCA mutation type = “BRCA1” or “BRCA2” or “both” AND
BRCA mutation category = “Deleterious mutation” or “Genetic variant, suspected 
deleterious” 
!
Otherwise sBRCAm=”No”
BRCAm
!
BRCAm=”Yes” for patient with gBRCAm=”Yes” OR sBRCAm=”Yes” 
!
Otherwise BRCAm=”No”
HRRm^
!
HRRm^=”Yes” for patients with HRRm status= “mutated” AND gBRCAm=”No” AND
sBRCAm=”No”
!
Otherwise HRRm^=”No”


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2.1.1
Full analysis set
The full analysis set includes all patients who have been assigned olaparib (all enrolled 
patients as an intention to treat analysis set). Patients are considered enrolled once it is 
confirmed that they meet all eligibility criteria and the request has been made by the 
Investigator for the provision of study treatment for that patient. Where a patient does not 
meet all the eligibility criteria but is enrolled in error, she will still be a part of the FAS. All 
efficacy analyses will be based on the Full Analysis Set (FAS).
Patient Reported Outcomes (PRO) (FLIE, HRQoL (FACT-O, FACIT-Fatigue, and a set of 
new ovarian cancer items) will be based on the FAS with additional exclusion criteria for each 
PRO analysis independently, excluding:
!
Subjects who do not have any evaluable baseline data
!
Subjects who do not have any evaluable post-baseline data.
2.1.2
Safety analysis set
The safety analysis set comprises all patients who received at least one dose of olaparib. All 
safety analyses will be based on the safety analysis set.
2.2
Violations and deviations
The following general categories will be considered important protocol deviations to be 
included in the CSR. These will be listed and discussed in the CSR as appropriate:
!
Patients entered but who did not receive study treatment (Deviation 1).
!
Patients who deviate from key entry criteria per the Clinical Study Protocol (CSP)
(inclusion criteria 3, 4 and 5, exclusion criteria 4, 5, 6, 7 and 8) (Deviation 2).  
!
Baseline RECIST scan > 42 days before first dose of study treatment (Deviation 3). 
!
No baseline RECIST 1.1 assessment on or before date of first dose of study
treatment (Deviation 4).
!
Received prohibited concomitant medications (including other anti-cancer agents) 
(Deviation 5).  Please refer to the CSP section 7.7 for those medications that are 
detailed as being ‘excluded’ from permitted use during the study.  This will be used 
as a guiding principle for the physician review of all medications prior to database 
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The important protocol deviations will be listed and summarised using the FAS group.  
Deviation 1 will lead to exclusion from the safety analysis set.  None of the other deviations 
will lead to patients being excluded from the analysis sets described in section 2.1.  
The final classification of deviations will be made based on regular meetings with 
AstraZeneca.
3.
PRIMARY AND SECONDARY ENDPOINTS
3.1
Derivation of RECIST visit response
The primary PFS endpoint will be based on investigator-assessment according to RECIST 1.1 
guidelines.
Where it is available, the RECIST tumour response data will be used to determine each
subject’s visit response according to RECIST version 1.1 (Eisenhauer et al 2009).  It will also 
be used to determine if and when a subject has progressed in accordance with RECIST 1.1 and 
also their best objective response.
Baseline radiological tumour assessments are to be performed no more than 28 days prior to 
starting olaparib and as close as possible to the start of olaparib. Tumour assessments are then 
performed every 12 weeks (±1 week) relative to date of enrolment, until disease progression 
as determined by the investigator.
At each visit, an overall visit response will be determined programmatically - using the 
information from target lesions (TL), non-target lesions (NTL) and new lesions. RECIST 1.1 
outcomes will be calculated using a computer program.
3.1.1
Target lesions (TLs)
Measurable disease is defined as having at least one measurable lesion which is ≥ 10 mm in 
the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with 
computed tomography (CT) or magnetic resonance imaging (MRI). A subject can have a 
maximum of 5 measurable lesions recorded at baseline 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 to enrolment will be used to define the baseline sum of TLs.
Note: For patients who do not have measurable disease at entry (i.e. no TLs), 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).


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Table 2
TL visit responses
Visit Reponses
Description
Complete response (CR)
Disappearance of all target lesions. Any pathological lymph nodes 
selected as target lesions must have a reduction in short axis to 
<10mm.
Partial response (PR)
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters as long as 
criteria for PD are not met.
Progressive disease (PD)
A ≥ 20% increase in the sum of diameters of target lesions and an 
absolute increase of ≥5mm, taking as reference the smallest sum 
of diameters since treatment started including the baseline sum of 
diameters.
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD.
Not evaluable (NE)
Only relevant in certain situations (i.e. if any of the target lesions 
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 
target lesion response.
Not applicable (NA)
No target lesions 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 1 decimal place before assigning a target lesion 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 target lesion 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 
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Lymph nodes
For lymph nodes, if the size reduces to < 10mm then these are considered non-pathological. 
However, a size will still be given and this size should still be used to determine the TL visit 
response as normal.  In the special case where all lymph nodes are < 10mm and all other TLs 
are 0mm then although the sum may be >0mm the calculation of TL response should be over-
written as a CR.
TL Visit responses subsequent to CR
A CR response can only be followed by CR, PD or NE.  If a CR has occurred, then the 
following rules at the subsequent visits must be applied:
!
Step 1:  If all lesions meet the CR criteria (i.e. 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 is 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 target lesion 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 target lesion response would not give an overall visit response of PD, 
then this will be flagged and reviewed by the study team. It is expected that a visit response of 
PD will remain in the vast majority of cases.
TL too small to measure
If a target lesion becomes too small to measure a value of 5mm will be entered into the 
database and used in TL calculations, unless the radiologist has indicated and entered a 
smaller value that can be reliably measured.  If a target lesion response of PD results (at a 
subsequent visit), then this will be reviewed by the study team.


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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 
once a lesion has had intervention then it should be treated as having intervention for the 
remainder of the study noting that an intervention will most likely shrink the size of tumours:
!
Step 1: the diameters of the TLs (including the lesions that have had intervention) 
will be summed and the calculation will be performed in the usual manner. If the 
visit response is PD this will remain as a valid response category. 
!
Step 2: If there was no evidence of progression after step 1, treat the lesion diameter 
(for those lesions with intervention) as missing and scale up as described below as 
long as there remain ∀1/3 of the TLs with missing measurements.  If the scaling 
results in a visit response of PD then the subject would be assigned a TL response 
of PD.
!
Step 3: If after both steps PD has not been assigned, then a scaled sum of diameters 
will be calculated (as long as ≤1/3 TLs have missing measurements), treating the 
lesion with intervention as missing, 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 also has a value of 0 recorded. If scaling up is not 
appropriate due to too few non-missing measurements, then the visit response will 
be set to NE.
At subsequent visits the above steps will be repeated to determine the TL and overall visit 
response. When calculating the previous minimum, 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 the target lesion measurements are missing (because of an 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.


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Example of scaling
Lesion
Longest diameter at nadir 
visit
Longest diameter at follow-up 
visit
1
2
3
4
5
7.2
6.7
4.3
8.6
2.5
7.1
6.4
4.0
8.5
Intervention
Sum
29.3
26
Lesion 5 is missing at the follow-up visit.
The sum of lesions 1-4 at the follow-up is 26 cm.  The sum of the corresponding lesions at 
nadir visit is 26.8 cm.
Scale up as follows to give an estimated TL sum of 28.4cm:
cm
4.
28
3.
29
8.
26
26
#
∃
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 target lesions merge, then the LD of the merged lesion should be recorded for one of 
the TL sizes and the other TL size should be recorded as 0cm.
Change in method of assessment of target lesions
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 (see study protocol for more information of tumour assessment of this study). 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.


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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
Non-target lesion response will be derived based on the Investigator’s overall assessment of 
NTLs as follows:
Progressive disease:
Unequivocal progression of existing NTLs, which may be due to an 
important progression in one lesion only or in several lesions
Complete response:
Disappearance of all NTLs present at baseline with all lymph nodes 
non-pathological in size (<10mm short axis).
Non-CR/Non-PD:
Persistence of one or more NTLs with no evidence of progression.
Not evaluable:
Only relevant when one or some of the NTLs have not been assessed 
and in the Investigator’s opinion they are not able to provide an 
evaluable overall NTL assessment at this visit.
Not applicable:
Only relevant if there are no NTLs at baseline
New lesions will be identified via a Yes/No tick box. 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’ 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 and should 
be treated as NE in the derivation of overall visit response.
3.1.3
Overall visit response
Table 3 defines how the previously defined TL and NTL visit responses will be combined 
with new lesion information to give an overall visit response.


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Table 3
Overall Visit Response
Target lesions
Non-Target lesions
New Lesions
Overall visit response
CR
CR (or NA)
No (or NE)
CR
CR
Non-CR/Non-PD or NE
No (or NE)
PR
PR
Non-PD or NE or NA
No (or NE)
PR
SD
Non-PD or NE or NA
No (or NE)
SD
PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Yes
PD
NE
Non-PD or NE or NA
No (or NE)
NE
NA
CR
No (or NE)
CR
NA
Non-CR/Non-PD
No (or NE)
SD
NA
NE
No (or NE)
NE
NA
NA
No (or NE)
NED
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/NTL at baseline), NED = no evidence of 
disease.
For patients with no disease at baseline (i.e. no TLs and no NTLs), evaluation of overall visit 
responses will be based on absence/presence of new lesions. If no TLs and no NTLs are 
recorded at a visit, both the TL and NTL visit response will be recorded as NA and the overall 
visit response will be no evidence of disease (NED). If a new lesion is observed, then the 
overall visit response will be PD.
3.2
Primary endpoint
3.2.1
Progression Free Survival (PFS)
PFS is defined as the time from the date of enrolment until the date of objective radiological 
disease progression (assessed via RECIST 1.1), or death (by any cause in absence of disease 
progression) regardless of whether the patient withdraws from therapy or receives another 
anticancer therapy prior to disease progression (i.e. date of PFS event or censoring – date of 
enrolment + 1). Patients who have not progressed or died at the time of analysis will be
censored at the time of the latest date of assessment from their last evaluable efficacy
assessment. However, if the patient progresses or dies immediately after two or more missed 
visits, the patient will be censored at the time of the latest evaluable assessment prior to the 
two missed visits (Note: NE visit is not considered as missed visit).
Given the scheduled visit assessment scheme (tumour assessment every 12 weeks), two 
missing visits will equate to 26 weeks since the previous RECIST 1.1 assessment, allowing
for early and late visits. If the patient has no evaluable visits or does not have a baseline 


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assessment, they will be censored at day 1 unless they die within two visits of baseline (25 
weeks allowing for visit window).
The date of the first progression will be programmatically determined from investigator 
assessed data. The PFS time will always be derived based on scan/assessment dates, not visit 
dates.
RECIST assessments/scans contributing towards a particular visit may be performed on
different dates. The following rules will be applied:
!
Date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression.  
!
When censoring a patient for PFS the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment.
Overall visit assessments will be determined for each assessment (scheduled or unscheduled) 
and will contribute to the derivation of PFS.
3.3
Secondary endpoints
All time to event endpoints (OS, PFS2, TFST, TSST, and TDT) will be described as for PFS 
in the subset of patients with sBRCAm disease, and for all patients with BRCAm disease.
3.3.1
Overall Survival (OS)
OS is defined as the time from the date of enrolment until death due to any cause regardless of 
whether the patient withdraws from therapy or receives another anti-cancer therapy (i.e. date 
of death or censoring – date of enrolment + 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 (SUR_DAT, recorded within the SURVIVE module of the electronic case report form 
(eCRF)).
Assessments for survival should be made every 12 weeks following disease progression.  
Survival information may be obtained via telephone contact with the patient, patient’s family 
or by contact with the patient’s current physician. Survival data will be collected up to the 
time of the final analysis. Survival calls will be performed in the week following the date of 
data cut off (DCO) for the analysis and if patients are confirmed to be alive or if the death date 
is post the DCO date these patients will be censored at the date of DCO.
For the ongoing, withdrawn (from the study) and “lost to follow-up” patients at the time of the 
analysis, survival information should be obtained by the site personnel by contacting the 
patient, checking the patients notes, hospital records, contacting the patients’ general 
practitioner and checking publicly available death registries. In the event that the patient has 
actively withdrawn consent to the processing of their personal data the vital status of the 
patient can be obtained by site personnel from publicly available resources where it is possible 
to do so under applicable local laws.


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In the absence of survival calls being made, it may be necessary to use all relevant eCRF 
fields to determine the last recorded date on which the patient was known to be alive. The last 
date for each individual patient is defined as the latest among the following dates recorded on 
the eCRFs:
!
AE start and stop dates
!
Admission and discharge dates of hospitalization
!
Study treatment date
!
End of treatment date
!
Laboratory test dates
!
Date of vital signs
!
Disease assessment dates on RECIST eCRF
!
Start and stop dates of alternative anticancer treatment
!
Date last known alive on survival status eCRF
!
End of study date
3.3.2
Time to second progression or death (PFS2)
Time from enrolment to second progression is defined as the time from the date of enrolment
to the earliest of the progression event subsequent to that used for the primary variable PFS or 
death (by any cause in the absence of progression). Patients whose progression event for PFS 
was death will have this counted as a progression event for PFS2 also. The date of second 
progression will be recorded by the investigator and defined according to local standard 
clinical practice and may involve any of the following: objective radiological, symptomatic, 
CA-125 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 on the 
eCRF. 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 last assessment for progression date if the patient has not had a second 
progression or death.
Patients should be assessed every 12 weeks for a second progression (using the patient’s status 
at first progression as the reference for assessment of second progression).


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3.3.3
Time to first subsequent anti-cancer therapy or death (TFST)
As a supportive summary to PFS, time to start of first subsequent anti-cancer therapy or death 
(TFST) will be assessed. Time to first subsequent anti-cancer therapy or death is defined as 
the time from the date of enrolment to the earlier of first subsequent anti-cancer therapy start 
date, or death date (i.e. date of first subsequent cancer therapy/death or censoring – date of 
enrolment + 1). Any patient not known to have had a further subsequent therapy or death will
be censored at the last date that the patient was known not to have received a first subsequent 
anti-cancer therapy. If a patient terminated the study for reason other than death before first 
subsequent therapy, these patients will be censored at the earliest of their last known to be 
alive and termination dates (study discontinuation date).  
3.3.4
Time to second subsequent anti-cancer therapy or death (TSST)
As a supportive summary to PFS2, time to start of second subsequent anti-cancer therapy or 
death (TSST) will be assessed. Time to second subsequent anti-cancer therapy or death is 
defined as the time from the date of enrolment to the earlier of the date of second subsequent
anti-cancer therapy start date, or death date (i.e. date of second subsequent cancer 
therapy/death or censoring – date of enrolment + 1). Any patient not known to have had a 
second subsequent anti-cancer therapy or death will be censored at the last date the patient 
was known not to have received second subsequent anti-cancer therapy. If a patient terminated 
the study for reason other than death before second subsequent therapy, these patients will be 
censored at the earliest of their last known to be alive and termination dates (study 
discontinuation date).  
3.3.5
Time to study treatment discontinuation or death (TDT)
Time to olaparib discontinuation or death (TDT) is defined as the time from the date of 
enrolment to the earlier of the date of study treatment discontinuation or death (earliest of 
[date of death; date of discontinuation of olaparib] or date of censoring – date of enrolment + 
1). Any patient not known to have died at the time of analysis and not known to have 
discontinued study treatment will be censored based on the last recorded date on which the 
patient was known to be alive.
3.3.6
QoL endpoints
3.3.6.1
Patient Reported Outcomes (PROs)
The following Patient Reported Outcomes instruments (PROs) will be administered in this 
study: Functional Assessment of Cancer Therapy-Ovarian (FACT-O), Functional Assessment 
of Chronic Illness Therapy (FACIT)-Fatigue, the ORZORA QoL Additional Items
Questionnaire (a set of newly developed ovarian cancer items) and Functional Living Index-
Emesis (FLIE). Each is described below.
Administration of PRO questionnaires
Paper questionnaires were expected to be collected from the patient at baseline, at day 29, then 
every 12 weeks (+/- 7 days) for 24 months or up to the data cut off for the final analysis, 
whichever comes first. However, these were more frequently collected than expected, every 4 


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weeks, and the additional PRO questionnaires will also be presented in the tables. In addition, 
the FLIE questionnaire will be administered to the patient weekly in the first month from 
starting the study treatment in person or over the phone. In addition, PRO questionnaires will 
be collected at the discontinuation of study treatment visit and 30 days post last dose. Patients
who had disease progression will complete the questionnaires during the 12 weekly survival 
follow ups either in person or over the phone. PRO questionnaires will be provided to patients 
and they will complete them on paper and site staff will enter information directly into the
eCRF.
Evaluable patients for each PRO questionnaire
PRO analyses (FLIE, FACT-O. FACIT-Fatigue, ORZORA QoL Additional Items 
Questionnaire) will be based on the FAS. However, additional exclusion criteria will be 
considered for each PRO analysis separately:
!
The subject does not have any evaluable baseline data
!
The subject does not have any evaluable post-baseline data
Rules for Handling Missing Data of PRO questionnaires
Unless explicitly stated otherwise, missing data will not be imputed and data will be analysed
and presented according to the following rule: for each subscale, if less than 50% of the 
subscale items are missing, the subscale score will be divided by the number of non-missing 
items and multiplied by the total number of items on the subscale. If 50% or more of the items
are missing, that subscale also will be treated as missing. The reason (if available) for any 
missing assessment will be identified. If data are missing at random, the above techniques will 
be used. If there is evidence that the missing data are systematic, missing values will be 
handled to ensure that any possible bias is minimised using other techniques such as 
simple/multiple imputation methods or statistical models.
Compliance of PRO questionnaires
Summary measures of overall compliance and compliance over time will be derived for the 
FACT-O, FACIT-Fatigue, and FLIE respectively. These will be based upon:
!
Received questionnaire = a questionnaire that has been received and has a 
completion date and at least one individual item completed.
!
Expected questionnaire = a questionnaire that is expected to be completed at a 
scheduled assessment time e.g. a questionnaire 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 HRQoL follow-up at the specified assessment time. Date of study 


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discontinuation will be mapped to the nearest visit date to define the number of 
expected forms.
!
Evaluable questionnaire = a questionnaire with a completion date and at least one 
subscale that is non-missing.
!
Overall PRO compliance rate is defined as: Total number of evaluable 
questionnaires across all scheduled time points, divided by total number of 
questionnaires expected to be received across all scheduled time points multiplied 
by 100. Note: questionnaires completed at non-scheduled assessments will not 
contribute to this statistic.
!
Overall patient compliance rate is defined as: Total number of patients with an 
evaluable baseline and at least one evaluable follow-up questionnaire (as defined 
above), divided by the total number of patients expected to have completed at least 
a baseline questionnaire multiplied by 100.
Compliance over time will be calculated separately for each visit, including baseline, as the 
number of patients with an evaluable questionnaire at the time point (as defined above),
divided by number of patients still expected to complete questionnaires.
3.3.6.2
Functional Living Index-Emesis (FLIE)
The FLIE tool will be used to assess study treatment-induced nausea and vomiting. The FLIE 
consists of nine nausea-specific and nine vomiting-specific items that address the effect of 
nausea and vomiting on daily functioning following chemotherapy. The first item in each 
domain asks the patient to rate how much nausea and vomiting he or she has experienced in 
the past 3 days from day of FLIE completion. The remaining eight items covers different 
sections influencing the patient's quality of daily life (i.e., “recreation or leisure activities,” 
“make meal/do tasks,” “ability to enjoy meal,” “enjoy drinking fluids,” “see family/ friends,” 
“daily functioning,” “personal hardship,” “hardship on others”). For more details about FLIE 
questionnaire see Appendix 1.
!
To derive nausea total score
Nausea total score = [(8-Q1) + (8-Q2) + Q3 + (8-Q4) + (8-Q5) + Q6 + (8-Q7) + (8-Q8) + (8-
Q9)]*9/Number of items answered
Nausea total score range: 9-63
Nausea total score meaning: A higher score corresponds to a higher QoL or less impact on 
QoL


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!
To derive vomit total score
Vomit total score = [(8-Q10) + Q11 + (8-Q12) + (8-Q13) + (8-Q14) + Q15 + (8-Q16) + (8-
Q17) + Q18]*9/Number of items answered
Vomit total score range: 9-63
Vomit total score meaning: A higher score corresponds to a higher QoL or less impact on QoL
!
To derive FLIE total score
FLIE total score = Nausea total score + Vomit total score
FLIE total score range: 18-126
FLIE total score meaning: A higher score corresponds to a higher QoL or less impact on QoL
3.3.6.3
Functional Assessment of Cancer Therapy-Ovarian (FACT-O)
The FACT-O is composed of the following sub-scales: physical well-being (PWB), 
social/family well-being (SWB), emotional well-being (EWB), and functional well-being 
(FWB) as well as the additional concerns (AC) scales consisting of specific ovarian cancer
(OCS) symptoms. For more details about FACT-O Scoring Guidelines see Appendix 2.
!
To derive all subscales scores
Physical well-being (PWB) score = [(4-GP1) + (4-GP2) + (4- GP3) + (4- GP4) + (4- GP5) + 
(4- GP6) + (4- GP7)]*7/Number of items answered
PWB score range: 0-28
Social/family well-being (SWB) score = [GS1 + GS2 +GS3+ GS4 + GS5 + GS6 + 
GS7]*7/Number of items answered
SWB score range: 0-28
Emotional well-being (EWB) score = [(4-GE1) + GE2 + (4- GE3) + (4- GE4) + (4- GE5) + 
(4- GE6)]*6/Number of items answered
EWB score range: 0-24
Functional well-being (FWB) score = [GF1 + GF2 +GF3+ GF4 + GF5 + GF6 + 
GF7]*7/Number of items answered
FWB score range: 0-28


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Ovarian Cancer Subscale (OCS) score (or Additional Concerns (AC) score) = [(4-O1) + (4-
C2) + C3 + (4-O2) + (4-B5) + C6 + C7 + BMT5 + B9 + (4-O3) + BL4] * 11/Number of items 
answered
OCS score range: 0-44
OCS is a set of new ovarian cancer items added in FACT-O. Note that although the item 
BMT7 is included in the eCRF, this is not currently used to calculate OCS score (or AC 
score).
!
To derive FACT-O total score
FACT-O Total score = PWB score + SWB score + EWB score + FWB score + OCS score
FACT-O Total score range: 0-152.
!
To derive FACT-O Trial Outcome Index (TOI) score
FACT-O TOI score = PWB score + FWB score + OCS score
FACT-O TOI score range: 0-100.
The actual change from baseline in TOI score will be derived for each visit where there is 
available data. For example; at visit X, the calculation will be (TOI score at visit X- baseline 
TOI score). Actual change from baseline for the individual domain scores will be calculated in 
a similar way.
A change of at least 10 points in TOI score will be considered as a clinically relevant or a 
minimally important difference (Osoba et al 2005).
The threshold for a clinically important change is outlined below (Table 4):
Table 4
Health Related QoL
Score
Change from baseline*
Visit response
TOI
≥ +10
Improved(1)
≤ -10
Worsened(2)
Otherwise
No change(3)
(1): Patients with baseline score > 90 cannot show improvement and will not be included in the denominator to 
evaluate the proportion of patients that have a response of Improved
(2): Patients with baseline score < 10 cannot show worsening and will not be included in the denominator to 
evaluate the proportion of patients that have a response of Worsened
(3): All patients with baseline score will be included in the denominator to evaluate the proportion of patients that 
have a response of No Change


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Best Overall TOI improvement (in absence of starting any subsequent cancer therapy) will be 
defined as a change from baseline in the TOI of + 10 points or more sustained for at least 28 
days, the denominator consisting of a subset of the FAS who have baseline TOI. It will be 
derived as the best symptom improvement response the patient achieved, based on evaluable 
QoL data collected from first olaparib dose up to the earliest of starting any subsequent cancer 
therapy or death. Therefore, at the conclusion of the trial, the following criteria will be used to 
assign a best overall score response based on the individual visit responses (Table 5).
Table 5
Health Related Quality of Life: Change rates - overall score
Best Overall TOI score response
Criteria
Improved
Two visit responses of “improved” a minimum of 
28 days apart without an intervening visit 
response of “worsened”
No change
Does not qualify for overall score response of 
“improved”. Two visit responses of either “no 
change” or “improved and “no change” a 
minimum of 28 days apart without an intervening 
visit response of “worsened”
Worsened
Does not qualify for overall score response of 
“improved”. A visit response of “worsened” 
without a response of “improved” or “no change” 
within 28 days.
Other
Does not qualify for one of the above.
A TOI improvement rate (in the absence of subsequent cancer therapy) will be calculated as 
the proportion of all analysed patients with a best overall score response of improved. In the 
calculation of the proportion of patients that have a response of Improved, No Change or 
Worsened, the denominator used in the calculation will use the number evaluable for that 
individual TOI domain score at baseline (see notes of Table 4).
3.3.6.4
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
The scores will be derived in accordance with the FACIT-Fatigue Scoring Guidelines. Final 
scores are the sum of the responses (0-52) where higher scores indicate better HRQoL (Yellen 
et al 1997). Changes in scores ≥ 3 points are considered to be clinically meaningful (Cella et 
al 2002. For more details about FACIT-F questionnaire see Appendix 3.
The calculation of the Fatigue score is presented below:
FACIT-F total score = [(4-HI7) + (4-HI12) + (4- An1) + (4- An2) + (4- An3) + (4-
An4) + An5 + An7 + (4- An8) + (4- An12) + (4- An14) + (4- An15) + (4- An16)]*13 
/Number of items answered.


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3.3.6.5
ORZORA QoL Additional Items Questionnaire
In addition to FACT-O and FACIT-Fatigue, subjects will also complete the following set of 
newly developed ovarian cancer items: “I feel ill with low energy,” “I am able to enjoy life 
and I am still interested in my hobbies and interests,” “I am satisfied that my family 
understands my disease,” “I feel I am able to meet the needs of my family,” “I understand the 
need to take my medication and my treatment regimen,” “My treatment has had significantly 
negative effects on my QoL,” and “I feel like a normal woman” with the same recall period (7 
days) and response options as in FACT-O. Finally, on a free text response scale, subjects will 
be asked to respond to the following question: “What are the 3 most significant issues you are 
struggling with, please list them starting with your worst first?”. As no scoring guidelines 
exist for these new questions, the number and percentage of patients giving each response 
(“Not at all”, “A little bit”, “Somewhat”, “Quite a bit”, “Very much”) will be summarised. For 
more details about ORZORA QoL Additional Items Questionnaire, see Appendix 4.
3.4
Exploratory endpoints
3.4.1
MDS/AML and New primary malignancies
Long term safety data of olaparib monotherapy, including follow up for Myelodysplastic 
Syndrome (MDS)/Acute Myeloid Leukaemia (AML) and new primary malignancies, as well 
as pneumonitis, will be collected.
3.4.2
Side effects and Comorbidities
Side effects are recorded as AEs and comorbidities will be collected in medical history.
3.4.3
Progression Free Interval (PFI) with olaparib
The progression free interval (PFI) flow chart for penultimate platinum and for previous 
platinum therapy with olaparib is presented in Figure 2 below:
Figure 2
PFI Flow Chart


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The analysis will be based on the investigator progression assessment. It is required that 
patients have clinical and objective radiological tumour assessments according to RECIST 
criteria.
PFI with olaparib is defined as the time from the last date of previous platinum chemotherapy 
dose until the date of progression on or after olaparib (PFS event date). Note that progression 
on or after olaparib will be date of objective radiological disease progression, regardless of 
whether the patient receives another anticancer therapy prior to disease progression. Patients 
who have died before progression on or after olaparib or have not progressed at the time of 
analysis will have their PFI measured up to the time of death (PFS event date) or PFS 
censoring date (see section 3.2.1 progression free survival (PFS) for more details of PFS
event).
Overall visit assessments will be determined for each assessment (scheduled or unscheduled) 
and will contribute to the derivation of PFI.
PFI with olaparib will be categorised as follows:
!
PFI ≤6 months
!
PFI between > 6 and ≤ 12 months
!
PFI >12 months
Response to a subsequent line of therapy is defined as the best response to the first line of
therapy post-olaparib. These data are collected in the eCRF as CR, PR, SD, PD, NE and not
applicable.
3.4.4
Progression Free Interval (PFI) for penultimate platinum
PFI for penultimate platinum is defined as the time from the last date of penultimate platinum 
therapy (platinum therapy before the platinum therapy discussed in previous exploratory aim; 
see Figure 2 for more details) to progression on that line of therapy. As date of progression of 
previous line therapies are not collected in the eCRF, start date of the following therapy will 
be used as the nearest surrogate.
PFI for penultimate platinum will be categorised as follows:
!
Patients with bevacizumab maintenance and PFI between >6 and ≤12 months 
!
Patients without bevacizumab maintenance and PFI between >6 and ≤12 months
!
Patients with bevacizumab maintenance and PFI >12 months
!
Patients without bevacizumab maintenance and PFI >12 months


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3.4.5
CA-125 progression
A blood sample for CA-125 will be taken at screening, starting treatment (day 1) and every 4 
weeks until discontinuation of olaparib. When CA-125 assessment is performed, patients 
should be evaluated based on progressive serial elevation of serum CA-125 according to the 
Gynaecologic Cancer Inter Group (GCIG) criteria at the discretion of the investigator and 
according to local clinical practice.
Progression or recurrence based on serum CA-125 levels will be defined on the basis of a 
progressive serial elevation of serum CA-125 according to the following criteria (Gordon et al
2011):
A. Patients with elevated CA-125 pre-treatment (greater than the upper limit of
normal (ULN) range) and normalization of CA-125 whilst on treatment (within 
normal range) must show evidence of CA-125 greater than, or equal to, 2 times the 
ULN range on 2 occasions at least 1 week apart or
B. Patients with elevated CA-125 before treatment (greater than the ULN range), 
which never normalizes whilst on treatment (never within normal range), must 
show evidence of CA-125 greater than, or equal to, 2 times the pre-treatment nadir 
value on 2 occasions at least 1 week apart or
C. Patients with CA-125 in the reference normal range before treatment must show 
evidence of CA- 125 greater than, or equal to, 2 times the ULN range on 2 
occasions at least 1 week apart.
CA-125 progression will be assigned to the date of the first measurement that meets the 
criteria as noted.
3.5
Safety endpoints
Safety and tolerability will be assessed in terms of adverse events (AEs), serious adverse 
events (SAEs), adverse events of special interest (AESI), other significant adverse events 
(OAEs), laboratory data, and vital signs.  These will be collected for all patients. In addition, 
safety analysis will also present treatment exposure, dose intensity and dose interruption.
3.5.1
Adverse Events
AEs and SAEs will be collected from time of signature of informed consent, throughout the 
treatment period and including the follow-up period (30 days after discontinuing olaparib 
except for AESIs). Investigators will report after the 30 day follow-up period if the patient has 
developed an AESI of Myelodysplastic syndrome (MDS) or Acute myeloid leukaemia (AML) 
or a new primary malignancy as well as pneumonitis.
Note, in screening part 1, only SAEs related to study procedures will be collected, see 
section 4 of the Clinical Study Protocol for more details. For AEs and SAEs definition, see 
section 6.1 to 6.2 of the Clinical Study Protocol.


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3.5.2
Adverse Events of Special Interest (AESI)
AESI for olaparib are the important potential risks of MDS/AML, new primary malignancies 
(other than MDS/AML) and pneumonitis. AESI will be defined on the basis of AstraZeneca 
standard list of AE preferred terms for Olaparib studies.
A summary table will be produced capturing these toxicities of interest from first dose of olaparib 
until the end of the study (i.e. not restricted to treatment emergent AEs). 
For more details of AESI, see section 6.3 of the Clinical Study Protocol.  
3.5.3
Other Significant Adverse Events (OAEs)
For OAEs definition, see section 8.3.6 of the Clinical Study Protocol.  
3.5.4
Laboratory safety assessments
Blood samples for determination of clinical chemistry and haematology will be taken within 7 
days before starting olaparib and every 4 weeks until the safety follow-up 30 days after last 
dose of olaparib.
The following laboratory variables listed in Table 6 will be measured.
Table 6
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
Mean Cell Volume (MCV)
S/P-Alkaline Phosphatase (ALP)
B- Neutrophil count (absolute count)
S/P-Aspartate Transaminase (AST)
B-Platelet count
S/P-Alanine Transaminase (ALT)
S/P urea or Blood Urea Nitrogen (BUN)
3.5.5
Vital sign safety assessments
Vital signs will be measured at screening part 2 (for more details, see section 4 of the Clinical 
Study Protocol) and as clinically indicated thereafter.
The date of collection and measurement will be recorded on the appropriate eCRF.
Any clinically significant changes in vital signs should be recorded as an AE.
The following vital signs will be measured:


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!
Weight
!
Blood Pressure (BP)
!
Pulse
3.5.6
Calculation or derivation of safety variables
3.5.6.1
Exposure
The total treatment duration will be derived by using the following formula:
Total treatment duration (months) = (last dose date - first dose date +1) / (365.25/12)
The actual treatment duration is equal to the total treatment duration, excluding dose 
interruptions.
3.5.6.2
Compliance
The compliance with the therapy will be derived by using the following formula:
Therapy compliance (%) = 100 * (total dose received / total dose planned)
where
Total dose received = (number of days on treatment excluding interruptions * dose received 
per day)
Total dose planned = (number of days on treatment including interruptions * dose prescribed 
per day)
Days on treatment = date of last dose – date of first dose + 1
3.5.6.3
Dose intensity
Dose intensity will be derived by the following two standard definitions: relative dose 
intensity (RDI) and percentage intended dose (PID).
RDI is the percentage of the actual dose intensity delivered relative to the intended dose 
intensity through treatment discontinuation and will be derived by using the following 
formula:
RDI = 100% * d/D
where d is the actual cumulative dose delivered up to the earlier of progression (or a
censoring event) or the actual last day of dosing and D is the intended cumulative dose up to 
the earlier of progression (or a censoring event) or the actual last day of dosing.


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PID is the percentage of the actual dose delivered relative to the intended dose through 
progression and will be derived using the following formula:
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.
Examples of dose intensity calculations can be found in appendix 5.
3.5.6.4
Dose interruption
Dose interruption will be captured on the eCRF as an action taken with the study drug.
3.5.6.5
AEs, SAEs, AESI and OAEs
All AEs, including SAEs, AESI and OAES, will be coded using MedDRA coding dictionary. 
The version of the MedDRA coding dictionary used will be specified in the data display 
footnote. All AEs will be tabulated by MedDRA System Organ Class (SOC) and Preferred 
Term (PT). SOC terms will be sorted alphabetically and then PT will be sorted in order of 
frequency of the total column within each SOC.
The grading scales found in the National Cancer Institute (NCI) CTCAE version 4.0 will be
utilised for all AEs reported in the eCRF.
For each episode on an AE, all changes to the CTCAE version 4.0 grade attained as well as 
the maximum CTC grade should be reported.
In the summary tables, patients may be counted under multiple SOCs and PTs, but for each 
SOC and PT, patients are only counted once. If a patient experiences the same AE more than 
once (based on MedDRA PT), the maximum CTCAE grade for the event will be presented.
3.5.6.6
Laboratory assessments
Several blood samples for haematology and clinical chemistry could be collected within 7 
days before starting olaparib. If a patient has more than one measurement, the latest 
measurement will be used in the summary table. All complete laboratory test results will be 
listed by patient and date.
3.5.6.7
Vital signs assessment
Height will be assessed at screening only. Weight will be assessed at screening and as 
clinically indicated at any other time. Body Mass Index (BMI) will be calculated at screening
and as clinically indicated at any other time and presented as vital sign using the equation 
below:


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BMI (kg/m2) = Weight (Kg) / [Height (m) * Height (m)]
Blood pressure and pulse will be measured at baseline and as clinically indicated afterwards.
As vital signs (weight, BMI, BP and pulse) will be assessed as clinically indicated after 
screening (these are not assessed at scheduled visits), vital sign measurements will be listed
only by patient and date.
4.
ANALYSIS METHODS
All statistical computations and construction of tables, listings and figures will be performed 
using Statistical Analysis System (SAS) Version 9.4.
4.1
General Principles
Patient listings of key data represented in the electronic case report form (eCRF) will be 
provided. Measurements from patients excluded from the pre-defined analysis populations or 
extra measurements (such as unscheduled or repeat assessments) will not be included in 
summary tables unless specified otherwise but will be included in the patient listings. This is 
not applicable for unscheduled tumour assessments that will be considered for PFS evaluation or
for the additional reported PRO questionnaires (every 4 weeks) that will be presented int the 
tables. In general, the patient listings will be sorted by patient number and assessment date
(and time), if applicable.
4.1.1
Rules for Reporting Statistics
Unless otherwise specified, continuous/quantitative variables will be summarized using 
descriptive statistics which will include the number of patients with data to be summarized 
(n), mean, standard deviation, median, minimum and maximum. The same number of decimal 
places as in the raw data will be presented when reporting minimum and maximum, one more 
decimal place than in the raw data will be presented when reporting mean and median, and 
two more decimal places than in the raw data will be presented when reporting standard 
deviation.
All categorical/qualitative data will be presented using frequency counts and percentage. 
Percentages equal to 100 will be presented as 100% and percentage will not be presented for 
0 frequencies. Percentages will be rounded to 1 decimal place.
4.1.2
Rules for Handling Missing Data
Every effort will be made to capture all available data. Unless explicitly stated otherwise, 
missing data will not be imputed, and data will be presented and summarized as it is recorded
in the database. However, if there is any date-related variable that is only partial, it will be 
imputed as follows to be used in the planned analysis.
The partial missing disease diagnosis dates will be imputed as per the following imputation 
rules.


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Variable
Imputation of missing date 
Disease diagnosis date
Month and year should be required in CRF.
If day is missing, it will be imputed to 1st of month 
The below partially missing dates of AEs and medications will be imputed as per the phUSE 
guidelines. Imputation rule is assuming the worst / make the most conservative judgment 
when imputing AEs and medications start/stop dates. Duration of AEs and medications will
not be derived using imputed dates. The purpose of imputing a start date is to help define 
whether the AEs and medications started while taking the study drug
For missing start date:
!
Missing day - Impute the 1st of the month unless month is 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 – impute first dose date unless the end date suggests it could 
have started prior to this, 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 i.e. is prior 
to the end date of the AE or medication.
For missing stop date: 
!
Missing day - Impute the last day of the month unless month is the same as month 
of last dose of study drug then impute last dose date. If last dose date occurs in a 
subsequent month then the last day of the month imputation will be kept.
!
Missing day and month – impute 31st December unless year is the same as last dose 
date then impute last dose date
!
Completely Missing – need to look at whether the AE/medication is still ongoing 
before imputing a date and also when it started in relation to study drug. If the 
ongoing flag is marked or the ongoing flag is missing, then assume that AE is still 
present / medication is still being taken (i.e. do not impute a date). If the 
AE/medication has stopped and start date is prior to first dose date then impute the 
1st dose date, if it started on or after the first dose date, then impute the last dose 
date.
When dates and times are imputed, a flag should be provided to show that this is an imputed 
rather than actual date. The Clinical Data Interchange Standards Consortium Analysis Data 
Model has some rules to follow for both date and time imputations. Date imputation flags 
should have the name suffix –DTF and contain “D” for day, “M” for month, or “Y” for year. 


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Note that “M” implies that both the day and month are imputed, and “Y” implies day, month, 
and year are all imputed.
For some of the key date variables which require a full date in the CRF, those are not included 
in this section as no imputation is necessary. However, in some date-cases “unknown” could
be provided for day; in that case, it will be imputed following the previous rules. For all other 
missing date-related variables, no imputation is envisioned since there is no planned analysis 
that requires an imputation.
4.1.3
Data cut-off
The data cut-off for the primary analysis of the study will occur after approximately 60%
maturity of PFS in the sBRCA and all BRCA patient populations.
A final analysis of OS will occur after approximately 60% maturity of OS in the sBRCA and 
all BRCA patient populations.
4.1.4
Visit windows
Due to the practicality of scheduling patient visits, not all patients will have visits on the same 
study day. To allow for any presentations that summarize values by visit, visit windows will 
be defined according to Table 7. 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). The half way point is 
assumed to be the midpoint of the number of days between the visits, excluding both visit 
days (for example there are assumed to be 56 days between Day 56 and Day 112). If an odd 
number of days exist between two consecutive visits, then the upper limit is taken as the 
midpoint value plus 0.5 day.


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Table 7
Visit Windows
Visit
Day
Laboratory/PRO assessments
Screening 
Up to Day 1 
(-28 : -1)
Day 1, Baseline
Day 1 
(1 : 1)
Week 4
Day 29 
(2 : 43)
Week 8 
Day 57
(44 : 70)
Week 12 
Day 85
(71 : 98)
Week 16
Day 113
(99 : 126)
Week 20
Day 141
(127: 154)
Week 24
Day 169
(155 : 182)
Week 28
Day 197
(183 : 210)
Week 32
Day 225
(211 : 238)
Week 36
Day 253
(239 : 266)
Week 40
Day 281
(267 : 294)
Week 44
Day 309
(295 : 322)
Week 48
Day 337
(323 : 350)
Week 52
Day 365
(351 : 378)
Week 56
Day 393
(379 : 406)
Week 60
Day 421
(407 : 434)
Week 64
Day 449
(435 : 462)
Week 68
Day 477
(463 : 490)
Week 72
Day 505
(491 :518)
Week 76
Day 533
(519 : 546)
Week 80
Day 561
(547 : 574)
Week 84
Day 589
(574 : 602)
Week 88
Day 617
(603 : 630)
Week 92
Day 645
(631 : 658)
Week 96
Day 673
(659 : 686)
Week 100
Day 701
(689 : 714)
Week 104
Day 729
(715 : 742)
Etc.
Visit window (min : max)
Analysis visits will be applied to laboratory and PRO questionnaires assessments and 
determined based upon assessments dates and not on nominal visits designated in the
database.
Note that PRO questionnaires were expected to be collected at baseline, at Day 29, then every 
12 weeks (+/- 7 days) for 24 months or the data cut off for the final analysis, whichever comes 
first. However, as investigators reported PRO questionnaires more frequently, every 4 weeks, 
and that extra data will be presented in the tables, visit windows are calculated every 4 weeks 
for PRO questionnaires,


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4.2
Descriptive Analysis
All descriptive analyses except ‘patient disposition’, which will be based on screened patients,
will be based on the FAS. All descriptive analyses will be performed on BRCAm, sBRCAm, 
gBRCAm and HRRm^ patients (separately).
4.2.1
Patient Disposition
The following frequencies (number and percent) will be displayed in the BRCAm, sBRCAm, 
and gBRCAm patient disposition table by clinical study protocol version (patients screened
before vs patients screened on or after protocol V2.0 22Dec2015), and HRRm^ patients:
!
Patients screened
%
Patients included in the FAS
%
Patients excluded from the FAS (and reasons)
%
Patients included in the safety analysis set
%
Patients excluded from the safety analysis set (and reasons)
The denominators for the percent calculations will be the number of patients screened, 
whether or not they are included in any of the analyses.
A summary of the number of patients who discontinued treatment and who terminated the
study will be presented. The following frequencies (number and percent) will be displayed in 
the patient disposition table:
!
Patients included in the FAS
%
Patients ongoing in the study
%
Patients terminated from the study (and reasons)
%
Patients ongoing study treatment
%
Patients who discontinued the treatment (and reasons)
The denominators for the percent calculations will be the number of patients enrolled in the 
study and are in the FAS.
Additionally, follow-up time will also be summarized. The follow-up time will be calculated 
as the median time from the date of enrolment to death or censoring in all patients. 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.
A listing of disposition will be provided for all patients.


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4.2.2
Protocol deviations
A listing of important protocol deviations will be provided for all patients in the FAS with 
important protocol deviations. The number of patients with at least one important protocol 
deviation and the corresponding count and percentage of patients in each important protocol 
deviation category will be summarized.
4.2.3
Demographics and Baseline Characteristics
Baseline is defined to be the last evaluable visit prior to starting treatment.
Demographics and baseline characteristics will be listed and summarized for all patients in the 
FAS. Demographic characteristics will include age, sex, race, ethnicity, height, and weight. 
Age will be calculated using the equation below:
Age = (date of informed consent – date of birth + 1) / 365.25 and truncated to complete years.
Baseline characteristics will include:
!
General pathology characteristics
!
Family history of cancer
!
Breast cancer gene status
!
Eastern Cooperative Oncology Group (ECOG) performance status
4.2.4
Medical History
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. The version of the coding dictionary used will be included in a 
footnote on the output. Coded medical history terms will be summarized for the full analysis 
set, by MedDRA System Organ Class (SOC) and Preferred Term (PT). SOC terms will be 
sorted alphabetically and then preferred term will be sorted in order of frequency of the total 
column within each SOC.
Patient listings of coded medical history terms will be provided.
4.2.5
Medication
A summary of the prior and concomitant medication received will be provided. Medications 
(prior, concomitant) will be coded using the World Health Organization Drug Dictionary 
(WHODrug). The WHODrug version used will be specified in the data display footnote. Prior 
and concomitant medications will be listed separately and sorted alphabetically by Anatomical 
Therapeutic Chemical (ATC) class (and preferred drug name).
Prior medications are defined as medications taken prior to date of first dose of olaparib (date 
of last medication dose or end medication before date of first dose of treatment) and


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concomitant medications are defined as medications that are taken on or after date of first dose 
of olaparib.
4.3
Primary Analysis: PFS
The primary analysis will be performed when approximately 60% maturity of PFS has been 
observed in sBRCAm patients, and when approximately 60% maturity of PFS has been 
observed in all BRCAm patients. For details about PFS definition based on investigator
assessment according to RECIST 1.1 see section 3.2.1.
4.3.1
Real-world clinical effectiveness of olaparib by investigator assessed PFS in 
patients with BRCAm ovarian cancer using RECIST criteria
This primary analysis will be performed on BRCAm patients based on the FAS using 
investigator assessment of PFS according to RECIST 1.1guidelines.
PFS will be summarized using the total number and percentage of subjects experiencing a PFS 
event, the type of event (RECIST progression or death in absence of progression), the number 
and percentage of censored patients, the number and percentage of progression-free subjects at 
time of the analysis, patients who are lost to follow-up and patients who withdrew consent. 
In addition, the PFS rate and associated 95% CI will be summarized at six-monthly intervals 
using the Kaplan-Meier (KM) method. The median PFS and corresponding 95% CI (whenever 
estimable) and the median follow-up time in censored patients (in months) will also be 
presented. A KM plot of PFS will be presented. 
4.3.2
Subgroups analysis of PFS in patients with BRCAm ovarian cancer using 
RECIST criteria
Subgroup analyses are considered exploratory analyses. These will be performed on BRCAm 
patients based on the FAS.
Subgroup analysis will be performed for the PFS endpoint to assess the consistency of 
olaparib effect across important clinical characteristics. The following subgroups will be 
summarised:
!
gBRCAm
!
Response to previous platinum chemotherapy (CR vs PR).
!
Time to disease progression on penultimate platinum chemotherapy (6 – 12 months 
vs > 12 months) (as disease progression on penultimate platinum chemotherapy is 
not reported in the eCRF, time to disease progression will be approximated using 
time from first dose of penultimate platinum chemotherapy to first dose of last 
platinum chemotherapy).
!
Measurable disease, non-measurable disease, and NED at baseline.


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!
BRCA mutation type: gBRCA: BRCA1, BRCA2, BRCA1-2 (both).
!
Age at enrolment (<65 vs. ≥65 years old).
!
Region (Eastern Europe vs Western Europe/Canada). Western Europe includes:
Italy, Spain, UK. Eastern Europe includes: Bulgaria, Czech Republic, Hungary, 
Poland.
!
Family history of ovarian/breast cancer (Yes/No).
!
Prior bevacizumab use (Yes/No).
!
Number of prior chemotherapy lines (≤3, ≥4).
For each subgroup analysis KM curves and median PFS and 95%CI will be presented.
4.3.3
Sensitivity analysis of PFS in patients with BRCAm ovarian cancer
Sensitivity analyses are considered exploratory analyses. These will be performed on BRCAm 
patients based on the FAS.
!
Sensitivity analysis for PFS in patients with BRCAm ovarian cancer will be 
performed to assess attrition bias. Patients who take subsequent anti-cancer therapy 
prior to progression or death will be censored at the last available tumour 
assessment date prior to the date of subsequent anti-cancer therapy and those who 
miss > 1 assessment visit will not be censored. 
!
Additionally, a descriptive analysis of demographic and baseline characteristics for 
patients prematurely censored and not prematurely censored for PFS in patients 
with BRCAm ovarian cancer will be performed. A patient is defined as prematurely 
censored if they had not progressed (or died in the absence of progression) and the 
latest scan prior to date cut-off (DCO) was more than one scheduled tumour 
assessment interval (+ 2 weeks) prior to the DCO date.
4.3.4
Real-world clinical effectiveness of olaparib by investigator assessed PFS in 
patients with sBRCAm using RECIST criteria
This primary analysis will be performed on sBRCAm patients based on the FAS using 
investigator assessment of PFS according to RECIST 1.1 guidelines.
PFS will be summarized in the same way as described in section 4.3.1. A KM curve of PFS 
for the sBRCAm group of patients will be presented. 


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4.4
Secondary Analysis
4.4.1
Real-world clinical effectiveness of olaparib by assessment of OS
OS will be analysed in BRCAm and sBRCAm as well as gBRCAm patients separately based 
on the FAS. OS will be summarized in the same way as PFS as described in section 4.3.1 with 
the exception that the only event considered is death. KM plots will be presented. In addition, 
the median follow-up time in censored (in months) will also be presented.
4.4.2
Real-world clinical effectiveness of olaparib by assessment of PFS2
PFS2 will be analysed in BRCAm and sBRCAm as well as gBRCAm patients separately based 
on the FAS. PFS2 will be summarized in the same way as PFS as described in section 4.3.1
with the exception that the number and % of patients with ‘second progression’ will replace 
RECIST progression events in the table. KM plots will also be presented. 
4.4.3
Real-world clinical effectiveness of olaparib by assessment of TFST
TFST will be analysed in BRCAm and sBRCAm as well as gBRCAm patients separately based 
on the FAS. TFST will be summarized in the same way as PFS as described in section 4.3.1
with the exception that the number and % of patients ‘commencing subsequent anti-cancer 
therapy’ will replace RECIST progression events in the table. KM plots will also be presented. 
4.4.4
Real-world clinical effectiveness of olaparib by assessment of TSST
TSST will be analysed in BRCAm and sBRCAm as well as gBRCAm patients separately based 
on the FAS. TSST will be summarized in the same way as PFS as described in section 4.3.1
with the exception that the number and % of patients ‘commencing second subsequent anti-
cancer therapy’ will replace RECIST progression events in the table. KM plots will also be 
presented. 
4.4.5
Real-world clinical effectiveness of olaparib by assessment of TDT
TDT will be analysed in BRCAm and sBRCAm as well as gBRCAm patients separately based 
on the FAS. TDT will be summarized in the same way as PFS as described in section 4.3.1
with the exception that the number and % of patients ‘discontinuing olaparib’ will replace 
RECIST progression events in the table. KM plots will also be presented.
4.4.6
Nature and patterns of AEs of nausea and vomiting and their impact on QoL
and toxicity management patterns used in routine clinical practice
The safety and tolerability analysis of olaparib maintenance therapy, including AEs of nausea 
and vomiting, are assessed and presented in section 4.6 (Safety analysis).
The impact of nausea and vomiting on Qol, using FLIE questionnaire, is assessed and 
presented in section 4.4.7.1 (Functional living index emesis).
A summary of concomitant medication received will be provided, see section 4.2.5 for further 
details.


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4.4.7
QoL of patients
4.4.7.1
Functional Living Index Emesis (FLIE) 
This exploratory analysis will be performed on BRCAm and sBRCAm as well as gBRCAm 
patients separately based on the FAS.
The total score of the FLIE questionnaire and change from baseline will be summarized using 
descriptive statistics and presented for each follow-up time point. Furthermore, overall 
compliance and compliance over time will be also summarized using frequency counts and 
percentages (for definition of compliance of PRO please see section 3.3.6.1).
4.4.7.2
Functional Assessment of Cancer Therapy-Ovarian (FACT-O)
This exploratory analysis will be performed on BRCAm and sBRCAm as well as gBRCAm 
patients separately based on the FAS.
To assess and describe the patient-reported health-related quality of life (HRQoL) the Trial 
Outcome Index (TOI) score and change from baseline will be summarized using descriptive 
statistics and presented for each follow-up time point including data post progression where 
available (up to 24 months collection). 
Visit response based on change from baseline of TOI score (improved, worsened, no change) 
will be summarized using frequency counts and percentages for each follow-up time point (for 
further information about visit response definitions please see section 3.3.6.3).
Best overall TOI score response (improved, worsened, no change, other) will be summarized 
using frequency counts and percentages (for further information about best overall TOI 
response definitions please see section 3.3.6.3).
FACT-O total score and changes from baseline will also be summarized using descriptive 
statistics and presented for each follow-up time point.
Furthermore, overall compliance and compliance over time will be also summarized using 
frequency counts and percentages (for definition of compliance of PRO please see section 
3.3.6.1).
4.4.7.3
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
This exploratory analysis will be performed on BRCAm and sBRCAm as well as gBRCAm 
patients separately based on the FAS.
FACIT-F total score and changes from baseline will also be summarized using descriptive 
statistics and presented for each follow-up time point (for further information about FACIT-F 
total score definition please see section 3.3.6.4). Furthermore, overall compliance and
compliance over time will be also summarized using frequency counts and percentages (for
definition of compliance of PRO please see section 3.3.6.1).


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4.4.7.4
ORZORA QoL Additional Items Questionnaire
This exploratory analysis will be performed on BRCAm and sBRCAm as well as gBRCAm 
patients separately based on the FAS.
The answers of the first 7 additional ovarian cancer items will be summarized using frequency 
and percentage at baseline and for each follow-up time point. The answers of the last free text
item will be listed (for further information about the newly developed ovarian cancer items
please see section 3.3.6.5). Furthermore, overall compliance and compliance over time will be 
also summarized using frequency counts and percentages (for definition of compliance of 
PRO please see section 3.3.6.1).
Table 8 below provides a summary of the efficacy and Qol analyses.


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Table 8
Table of efficacy and Qol analyses and pre-planned sensitivity, subgroup analyses
Study objectives
Analyses Notes
Primary objectives
To assess the real-world clinical effectiveness of 
olaparib maintenance monotherapy by 
investigator assessed progression free survival 
(PFS) according to RECIST 1.1 in patients with 
BRCAm ovarian cancer
Primary Analysis Endpoint: PFS
PFS Assessment: Investigator-assessed PFS according to RECIST 1.1
Population: Full Analysis Set
Patient Group: BRCAm
Analysis Method: KM plot , median PFS and 95%CI will be provided as 
well as the PFS rate and 95% CI at six-monthly intervals using KM
method.
Subgroups analyses and sensitivity analyses below are considered 
supportive
Subgroup Analyses: 
gBRCAm
Response to previous platinum chemotherapy (CR vs PR).
Time to PD on penultimate platinum chemotherapy (6 – 12 months / > 12 
months) (as disease progression on penultimate platinum chemotherapy is 
not reported in the eCRF, time to disease progression will be 
approximated using time from first dose of penultimate platinum
chemotherapy to first dose of last platinum chemotherapy).
Measurable disease, non-measurable disease, and NED at baseline.
BRCA mutation type: gBRCA (based on RECIST), BRCA1, BRCA2, 
BRCA1-2 (both).
Age at enrolment (<65 vs. ≥65 years old). 
Region (Eastern Europe vs Western Europe/Canada).
Family history of ovarian/breast cancer (Yes/No).
Prior bevacizumab use (Yes/No).
Number of prior chemotherapy lines (≤3, ≥4).
Median PFS and 95%CI, PFS rate and 95%CI at six-monthly intervals


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Study objectives
Analyses Notes
and KM plot will be provided
Sensitivity Analyses:  
PFS recalculation to assess attrition bias: BRCAm patients who take 
subsequent anti-cancer therapy prior to progression will be censored and 
those who miss > 1 assessment visit will not be censored. 
!
KM plot, median PFS and 95%CI will be provided.
PFS analysis of patients prematurely censored: BRCAm patients who have 
not progressed (or died in the absence of progression) and the latest scan 
prior to DCO was more than one scheduled tumour assessment interval (+ 
2 weeks) prior to the DCO date.
!
Descriptive summary only
To assess the real-world clinical effectiveness of 
olaparib maintenance monotherapy by 
investigator assessed progression free survival 
(PFS) according to modified Response Evaluation 
Criteria In Solid Tumours (RECIST) 1.1 in 
patients with sBRCAm ovarian cancer
Endpoint: PFS
PFS Assessment: Investigator-assessed PFS according to RECIST 1.1
Population: Full Analysis Set
Patient Group: sBRCAm
Analysis Method: Median PFS and 95%CI, PFS rate and 95%CI at six-
monthly intervals, and KM plot will be provided
Secondary objectives
To assess the real-world clinical effectiveness of 
olaparib maintenance monotherapy in patients 
with BRCAm ovarian cancer and patients with 
sBRCAm ovarian cancer, by assessment of: a) 
overall survival (OS), b) time to investigator-
assessed second progression (PFS2), or death, in 
patients with BRCAm ovarian cancer.
Endpoints: OS and PFS2
Population: Full Analysis Set
Patient Group: BRCAm, gBRCAm and sBRCAm (separately)
Analysis Method: Median PFS2/OS and 95%CI, OS/PFS2 rate and 
95%CI at six-monthly intervals, and KM plot will be provided
To assess the real-world clinical effectiveness of 
olaparib maintenance monotherapy in patients 
Endpoints: TFST, TSST and TDT
Population: Full Analysis Set


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Study objectives
Analyses Notes
with BRCAm ovarian cancer and patients with 
sBRCAm ovarian cancer, by assessment of a) 
time to first subsequent therapy or death (TFST), 
b) time to second subsequent therapy or death
(TSST) and c) time to olaparib discontinuation or 
death (TDT) in patients with BRCAm ovarian 
cancer
Patient Group: BRCAm, gBRCAm and sBRCAm (separately)
Analysis Method: Median TFST/TSST/TDT and 95%CI, 
TFST/TSST/TDT rate and 95%CI at six-monthly intervals, and KM plot
will be provided
To assess and describe the quality of life (QoL) of 
patients with BRCAm ovarian cancer and patients 
with sBRCAm ovarian cancer.
Endpoints: FLIE, FACT-O, FACIT-F, ORZORA Qol (additional ovarian 
cancer items)
Population: Full Analysis Set
Patient Group: BRCAm, gBRCAm and sBRCAm (separately)
Analysis Method of FLIE and FACIT-F: Total score and change from 
baseline will be summarize using descriptive statistics and presented for 
each follow-up time point
Analysis Method of FACT-O:
TOI score and change from baseline will be summarize using descriptive 
statistics and presented for each follow-up time point 
Visit response based on change from baseline of TOI score (improved, 
worsened, no change) will be summarized using frequency counts and 
percentages for each follow-up time point
Best overall TOI score response (improved, worsened, no change, other) 
will be summarized using frequency counts and percentages
FACT-O total score and change from baseline will be summarize using 
descriptive statistics and presented for each follow-up time point
Analysis Method of ORZORA Qol: Additional ovarian cancer items will 
be summarized using frequency and percentage at baseline and for each 
follow-up time point


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4.5
Exploratory Analysis
4.5.1
The long-term safety of olaparib, including follow up for MDS/AML, New 
primary malignancies and pneumonitis
This exploratory analysis will be performed on all patients based on the safety analysis set.
Patients with BRCA1 alone, BRCA2 alone or both mutations will be identified.
For pharmacovigilance purpose and characterisation of events of special interest, the number 
and proportions of patients who developed MDS/AML, new primary malignancies and 
pneumonitis will be summarized.
In the summary tables, frequencies and percentages of patients for each event separately 
(MDS/AML, new primary malignancies, and pneumonitis) will be presented in the form of 
absolute percentage and in terms of 100 patient years. Note that patients with multiple events 
(MDS/AML, new primary malignancies and pneumonitis) will be only counted once within 
each subtype and percentages will be calculated for all patients in the safety analysis set.
Incidence rates of each event separately (MDS/AML, new primary malignancies, and 
pneumonitis) per 100 patient years will also be presented, respectively. Incidence rate is 
calculated as follows:
Incidence rates = 100 * (number of events / total patient years at risk)
Total patient years at risk is calculated as a sum of the follow-up period for each patient:
! For patients with the event in question: time from first dose to the event in question.
!For patients without the event in question: time from first dose to earliest of date last
known to be alive or date of termination
Number of events is the count of each individual event (MDS/AML, new primary 
malignancies, and pneumonitis) including recurrent event per subject.
4.5.2
Incidence of side effects and QoL according to age and the presence of 
comorbidities
The incidence of side effects according to age and the presence of comorbidities (as collected 
in the medical history table in the CRF) are assessed and presented in section 4.6.5.
QoL according to age will be performed on BRCAm patients based on the FAS. The total
score of FLIE, FACT-O (including TOI score) and FACIT-F questionnaires and changes from 
baseline will be summarized by age group (< 65 years, ≥ 65 years) using descriptive statistics 
and presented for each follow-up time point.
Standard summaries of AEs, QoL and medical history (see sections 4.6.5, 3.3.6 and 4.2.4) will 
facilitate a descriptive exploration of this exploratory endpoint.


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4.5.3
Clinical effectiveness of (response to) subsequent line of treatment and 
correlating it with the PFI (artificial prolongation of PFI through olaparib)
This exploratory analysis will be performed on BRCAm patients based on the FAS. However, 
patients who have died before progression on olaparib, have not progressed at the time of 
analysis or have not received a subsequent line of therapy for any other reason will not be
included in this exploratory analysis.
The best response to subsequent first line therapy post olaparib will be summarized using 
frequency and percentage of patients for each PFI with olaparib category and overall (see 
section 3.4.3 for PFI with olaparib category definitions).
4.5.4
Efficacy of olaparib according to the previous therapy, with or without
bevacizumab, and according to the PFI (recurrence during or after the end of 
bevacizumab maintenance)
This exploratory analysis will be performed on BRCAm patients based on the FAS.
The penultimate PFI will be used in this analysis. For each penultimate PFI category with and 
without bevacizumab, the number of patients and number of PFS events will be summarized 
(see section 3.4.4 for penultimate PFI category definition). KM curves and median PFS and 
95% CIs will be presented.
4.5.5
Activity of olaparib according to the germline mutational status (BRCA1 vs 2), 
and to the presence of family history of ovarian/breast cancer (yes vs no)
Consistency of Olaparib effect on PFS across germline mutational status (BRCA1 vs 2) and 
the presence of family history (yes/no) will be assessed. Subgroup analysis of PFS are 
presented for patients who had gBRCA, BRCA1, BRCA2 and BRCA1-2 (both) mutational 
status and by presence or non-presence of family history of ovarian/breast cancer in section 
4.3.2.
4.5.6
Kinetic of Ca125 progression according to GCIG criteria and its correlation 
with disease progression by RECIST during olaparib therapy
This exploratory analysis will be performed on BRCAm patients based on the FAS.
The number and percentage of patients who progressed and did not progress according to CA-
125 (as defined in section 3.4.5) versus progression or non-progression via RECIST during 
olaparib therapy will be summarized using a 2x2 contingency table.
4.5.7
Real-world clinical effectiveness of olaparib by assessment of PFS in patients 
with HRRm^ ovarian cancer
This exploratory analysis will be performed on HRRm^ patients based on the FAS using 
investigator assessment of PFS according to RECIST 1.1 guidelines.
PFS will be summarized in the same way as described in section 4.3.1. A KM plot of PFS will 
also be presented.


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4.5.8
Real-world clinical effectiveness of olaparib by assessment of OS in patients 
with HRRm^ ovarian cancer
OS will be analysed in HRRm^ patients based on the FAS. OS will be summarized in the 
same way as PFS as described in section 4.3.1 with the exception that the only event 
considered is death. KM plots will also be presented. 
4.6
Safety Analysis
All safety analyses will be based on the safety analysis set and will be performed on patients 
with BRCAm, sBRCAm, gBRCAm and HRRm^ ovarian cancer (separately).
4.6.1
Exposure
The duration of exposure will be summarized by presenting summary statistics of the total 
treatment duration and actual treatment duration (for more details of exposure definition 
please see section 3.5.6.1).
4.6.2
Compliance
Compliance will be summarized by presenting summary statistics of the percentage of therapy 
compliance (100*(total dose received / total dose planned)) (for more details of compliance 
definition please see section 3.5.6.2).
4.6.3
Dose intensity
Dose intensity will be summarized by presenting summary statistics of the RDI and PID (for 
more details of RDI and PDI definitions please see section 3.5.6.3).
4.6.4
Dose interruptions/Reductions
The total number of dose interruptions per patient will be summarized by presenting summary 
statistics (mean, standard deviation, median, minimum, maximum). Additionally, the number 
of patients with a dose interruption will be summarised using frequency and percentages for
the following categories: none, 1, 2, and 3 or more dose interruptions.
In addition, the number of patients with a dose reduction will be summarized using frequency
and percentages for the following categories: none, 1 dose reduction, and more than 1 dose 
reductions.
4.6.5
Adverse Events (AEs)
The term AE is used to include both serious and non-serious AEs (for more details of AE 
definition please see section 3.5).
All AEs will be tabulated by MedDRA SOC and PT. AEs occurring before treatment with 
olaparib will be included in the data listings but will not be included in the summary tables of 
AEs, except for AEs occurring before olaparib treatment with AE which worsen (by 
investigator report of a change in intensity) at or after start of the first dose of olaparib. Any 
AE occurring within 30 days of discontinuation of olaparib will be included in the AE 


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summaries. Any AE occurring 30 days after discontinuation of olaparib will be included in the 
data listings but will not be included in the summary tables of AEs.
All AEs and separately all AEs with outcome of death, all SAEs, all AEs leading to olaparib 
discontinuation will be tabulated by MedDRA SOC and PT. SOC terms will be sorted 
alphabetically and then PT will be sorted in order of frequency of the total column within each 
SOC. In the summary tables, patients may be counted under multiple SOCs and PTs, but for 
each SOC and PT, patients are only counted once. If a patient experiences the same AE more 
than once (based on MedDRA PT), the maximum CTCAE grade for the event will be 
presented. 
The following summary tables will be generated using number and percentage of patients and 
number of events:
!
All AEs 
!
All AEs with causality related to olaparib*
!
All SAEs
!
All SAEs with causality related to olaparib*
!
All OAEs
!
All AEs leading to olaparib interruption
!
All AEs leading to olaparib interruption and with causality related to olaparib*
!
All AEs with an outcome of death 
!
All AEs with an outcome of death and with causality related to olaparib*
!
All AEs with CTCAE grade 3 or higher
!
All AEs with CTCAE grade 3 or higher and with causality related to olaparib*
!
All AEs leading to olaparib discontinuation
!
All AEs with the maximum reported CTCAE grade
!
All AEs according to age group (< 65 years, ≥ 65 years)
!
All AEs according to the presence of comorbidities (presence/absence of additional 
disorders)
* as assessed by the investigator.
Summary tables will also be produced for the following common olaparib AEs, based on 
grouped preferred terms:
!
Anaemia
!
Neutropenia


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!
Thrombocytopenia
!
Nausea
!
Vomiting
!
Fatigue/Asthenia
The AEs will be listed by patient including: verbatim term, SOC, PT, AE start-stop dates, max
CTCAE grade, SAE (Y/N), causality olaparib (Y/N), action taken with regard to olaparib, AE 
caused patient´s withdrawal from study (Y/N), outcome.
4.6.6
Adverse Events Special Interest (AESIs)
The term AESI is used to include the important potential risks of MDS/AML, new primary 
malignancies (other than MDS/AML) and pneumonitis (for more details of AESI definition 
please see section 3.5.2).
All AESIs will be tabulated by MedDRA SOC and PT. AESIs occurring before treatment with 
olaparib will be included in the data listings but will not be included in the summary tables of 
AESIs, except for AESIs occurring before olaparib treatment with AESI which worsen (by 
investigator report of a change in intensity) at or after start of the first dose of olaparib.
A summary table will be produced capturing these toxicities.
4.6.7
Laboratory Results
Blood samples for haematology and clinical chemistry will be collected within 7 days before 
starting olaparib (if a patient shows more than one measurement, the latest measurement will 
be used), and every 4 weeks until the safety follow-up 30 days after last dose of olaparib.
All laboratory results and change from baseline in haematology and clinical chemistry will be 
summarized using descriptive statistics (n, mean, standard deviation, median, lower and upper 
quartile) and presented by visit.
A table will be produced showing the number of patients with maximum on-treatment ALT 
and AST values greater than 3, 5 and 10 times the upper limit of the local laboratory reference 
ranges. This summary will be produced overall and also split by maximum total bilirubin 
(TBL) values greater than 2 times the upper limit of the local laboratory reference range.
Plots of ALT vs TBL will also be produced with reference lines at 3×ULN for ALT, and 
2×ULN for TBL. Plots of AST vs TBL will also be produced with reference lines at 3×ULN 
for AST, and 2×ULN for TBL, where necessary. In each plot, TBL will be in the vertical axis.
A shift table will be produced showing the number and percentage of patients switching from 
normal, abnormal and not done laboratory results at baseline (the last lab result obtained prior 
to the start of olaparib treatment) to the maximum value on treatment (classified as normal, 
abnormal and not done).


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A shift table for haemoglobin, leukocytes, neutrophils, and platelets will be produced showing 
the number and percentage of patients switching from normal, abnormal and not done 
laboratory results at baseline (the last lab result obtained prior to the start of olaparib 
treatment) to the minimum value on treatment (classified as normal, abnormal and not done).
The complete laboratory test results will be listed by patient and date.
4.6.8
Vital Signs
Vital signs parameter values (weight, BMI, BP, and pulse) will be obtained at the screening
visit and clinically indicated thereafter (the date of collection and measurement will be 
recorded on the appropriate eCRF). As vital signs data are not collected at scheduled time 
points, vital sign measurements will be listed only by patient and date.
5.
INTERIM ANALYSES
No interim analysis is planned for this study.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
The following changes of analysis from protocol were applied.
Protocol
Analysis
Protocol section 4: QoL questionnaires will
be collected at baseline, at Day 29, then every 
12 weeks (+/- 7 days) for 24 months or the 
data cut off for the final analysis, whichever 
comes first.
SAP section 4.1.4: Visit windows for QoL
questionnaires were derived at baseline, at 
day 29, then every 4 weeks for 24 months or 
data cut off for the final analysis, whichever 
come last.
Reason: Investigators reported more 
frequently Qol questionnaires than expected 
initially in the protocol. As the data was 
collected, it was decided to report all the 
visits outputs.
Protocol section 8.4.3 Subgroup analysis:  
Time to disease progression on last platinum
based chemotherapy received prior to first 
dose of olaparib (6-12 months / >12 months)
SAP section 4.3.2: Time to disease 
progression on penultimate platinum
chemotherapy (6-12 months / > 12 months).
Reason: Clarification of the time period 
intended as the language was not clear


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7.
REFERENCES
Cella et al 2002
Cella DF, Eton DT, Lai JS, Peterman AH, Merkel DE. Combining anchor and distribution-
based methods to derive minimal clinically important differences on the functional assessment 
of cancer therapy (FACT) anaemia and fatigue scales. J Pain Symptom Manage. 2002;24:547-
61.
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
Gordon et al 2011
Gordon John, Sampson Rustin, Ignace Vergote, Elizabeth Eisenhauer, Eric Pujade-Lauraine, 
Michael Quinn, Tate Thigpen, Andreas du Bois, Gunnar Kristensen, Anders Jakobsen, Satoru 
Sagae, Kathryn Greven, Mahesh Parmar, Michael Friedlander, Andres Cervantes, Jan 
Vermorken. Definitions for Response and Progression in Ovarian Cancer Clinical Trials 
Incorporating RECIST 1.1 and CA 125 Agreed by the Gynecological Cancer Intergroup 
(GCIG). Int J Gynecol Cancer 2011;21: 419Y423
Osoba et al 2005
Osoba D, Bezjak A, Brundage M, et al: Analysis and interpretation of health-related quality-of 
life data from clinical trials: Basic approach of The National Cancer Institute of Canada 
Clinical Trials Group. Eur J Cancer 2005; 41:280-287
Yellen et al 1997
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other 
anaemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) 
measurement system. J Pain Symptom Manage. 1997;13:63-74.
http://www.phusewiki.org/wiki/index.php?title=Imputing_Partial_Dates


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8.
APPENDIX
Appendix 1: FLIE questionnaire from the eCRF
FLIE-Functional Living Index Emesis 
Date of completion
__ / __ / ____
1 How much nausea have you had in past 3 days?
○None
○ 2
○ 3
○ 4
○ 5
○ 6
○ A great deal
2 Has nausea affected your ability to maintain usual 
recreation or leisure activities in the past 3 days?
○ Not at all
○ 2
○ 3
○ 4
○ 5
○ 6
○ A great deal
3 Has nausea affected your ability to make a meal or do 
minor household repairs during the past 3 days?
○ A great deal
○ 2
○ 3
○ 4
○ 5
○ 6
○ Not at all
4 How much has nausea affected your ability to enjoy a 
meal in the past 3 days?
○ Not at all
○ 2
○ 3
○ 4
○ 5
○ 6
○ A great deal
5 How much has nausea affected your ability to enjoy 
liquid refreshment in the past 3 days?
○ Not at all
○ 2


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○ 3
○ 4
○ 5
○ 6
○ A great deal
6 How much has nausea affected your willingness to see 
and spend time with family and friends, in the past 3 
days?
○ A great deal
○ 2
○ 3
○ 4
○ 5
○6
○ Not at all
7 Has nausea affected your daily functioning in the past 3 
days?
○ Not at all
○ 2
○ 3
○ 4
○5
○6
○ A great deal
8 Rate the degree to which your nausea has imposed a 
hardship on you (personally) in the past 3 days.
○ Not at all
○ 2
○ 3
○ 4
○ 5
○ 6
○ A great deal
9 Rate the degree to which your nausea has imposed a 
hardship on those closest to you in the past 3 days
○Not at all
○ 2
○ 3
○ 4
○ 5
○ 6
○ A great deal
10 How much vomiting have you had in the past 3 days?
○ None
○ 2
○ 3
○ 4
○ 5
○ 6


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○ A great deal
11 Has vomiting affected your ability to maintain usual 
recreation or leisure activities during the past 3 days?
○ A great deal
○ 2
○ 3
○ 4
○ 5
○ 6
○ Not at all
12 Has vomiting affected your ability to complete your
usual household tasks during the past 3 days?
○ Not at all
○ 2
○ 3
○ 4
○ 5
○ 6
○ A great deal
13 How much has vomiting affected your ability to enjoy
a meal in the past 3 days?
○ Not at all
○ 2
○ 3
○4
○ 5
○ 6
○ A great deal
14 How much has vomiting affected your ability to enjoy 
liquid refreshment in the past 3 days?
○ Not at all
○ 2
○ 3
○ 4
○ 5
○ 6
○ A great deal
15 How much has vomiting affected your willingness to 
see and spend time with friends, in the past 3 days?
○ A great deal
○ 2
○ 3
○ 4
○ 5
○ 6
○ Not at all
16 Has vomiting affected your daily functioning during 
the past 3 days?
○ Not at all
○ 2
○ 3


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○ 4
○ 5
○ 6
○ A great deal
17 Rate the degree to which your vomiting has imposed a 
hardship on you (personally) in the past 3 days.
○ Not at all
○2
○ 3
○ 4
○5
○ 6
○ A great deal
18 Rate the degree to which your vomiting has imposed a 
hardship on those closest to you in the past 3 days.
○ A great deal
○ 2
○ 3
○ 4
○ 5
○ 6
○ Not at all


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Appendix 2: FACT-O questionnaire from the eCRF and scoring guidelines
Functional Assessment of Cancer Therapy-Ovarian (symptoms in past 7 days)
Date of completion
__ / __ / ____
Physical well-being (PWB)
1 I have a lack of energy (GP1)
○Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
2 I have nausea (GP2)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
3 Because of my physical condition, I have trouble
meeting the needs of my family (GP3)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
4 I have pain (GP4)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
5 I am bothered by side effects of treatment (GP5)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
6 I feel ill (GP6)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much


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7 I am forced to spend time in bed (GP7)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
Social/Family well-being (SWB)
8 I feel close to my friends (GS1)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
9 I get emotional support from my family (GS2)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
10 I get support from my friends (GS3)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
11 My family has accepted my illness (GS4)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
12 I am satisfied with family communication about my 
illness (GS5)
○Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
13 I feel close to my partner (or the person who is my 
main support) (GS6)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
14 Declined satisfied with sex life (GS7)
○ Declined to Answer
14 I am satisfied with my sex life (GS7)
○ Not At All


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○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
Emotional well-being (EWB)
15 I feel sad (GE1)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
16 I am satisfied with how I am coping with my illness
(GE2)
○ Not At All
○ A Little Bit
○Somewhat
○ Quite A Bit
○ Very Much
17 I am losing hope in the fight against my illness (GE3)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
18 I feel nervous (GE4)
○Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
19 I worry about dying (GE5)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
20 I worry that my condition will get worse (GE6)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
Functional well-being (FWB)
21 I am able to work (include work at home) (GF1)
○ Not At All
○ A Little Bit


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○ Somewhat
○ Quite A Bit
○ Very Much
22 My work (include work at home) is fulfilling (GF2)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
23 I am able to enjoy life (GF3)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
24 I have accepted my illness (GF4)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
25 I am sleeping well (GF5)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
26 I am enjoying the things I usually do for fun  (GF6)
○ Not At All
○A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
27 I am content with the quality of my life right now 
(GF7)
○Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○Very Much
Additional concerns (OCS)
28 I have swelling in my stomach area (O1)
○ Not At All
○A Little Bit
○ Somewhat
○ Quite A Bit


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○ Very Much
29 I am losing weight (C2)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
30 I have control of bowels (C3)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
31 I have been vomiting (O2)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
32 I am bothered by hair loss (B5)
○ Not At All
○A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
33 I have a good appetite (C6)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
34 I like the appearance of my body (C7)
○ Not At All
○ A Little Bit
○ Somewhat
○Quite A Bit
○ Very Much
35 I am able to get around by myself (BMT5)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
36 I am able to feel like a woman (B9)
○ Not At All
○ A Little Bit


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○ Somewhat
○ Quite A Bit
○ Very Much
37 I have cramps in my stomach area (O3)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
38 I am interested in sex (BL4)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
39 I have concerns about my ability to have children
(BMT7)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much


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FACT-O Scoring Guidelines (Version 4) – Page 1
Instructions:*
1. Record answers in "item response" column. If missing, mark with an X
   
2. Perform reversals as indicated, and sum individual items to obtain a score.
3. Multiply the sum of the item scores by the number of items in the subscale, then divide by 
the number of items answered. This produces the subscale score.
4. Add subscale scores to derive total scores (TOI, FACT-G & FACT-O). 
5. The higher the score, the better the QOL.
Subscale
Item Code
Reverse item? 
Item response
Item Score
PHYSICAL 
WELL-BEING (PWB)
Score range: 0-28
GP1
4        -
________
=________
GP2
4        -
________
=________
GP3
4        -
________
=________
GP4
4        -
________
=________
GP5
4        -
________
=________
GP6
4        -
________
=________
GP7
4        -
________
=________
Sum individual item scores: ________  
Multiply by 7: ________
Divide by number of items answered: ________= PWB subscale score
SOCIAL/FAMILY 
WELL-BEING (SWB)
Score range: 0-28
GS1
0        +
________
=________
GS2
0       +
________
=________
GS3
0        +
________
=________
GS4
0        +
________
=________
GS5
0        +
________
=________
GS6
0       +
________
=________
GS7
0        +
________
=________
Sum individual item scores: ________  
Multiply by 7: ________
Divide by number of items answered: ________= SWB subscale score
EMOTIONAL
WELL-BEING (EWB)
Score range: 0-24
GE1
4        -
________
=________
GE2
0        +
________
=________
GE3
4        -
________
=________
GE4
4        -
________
=________
GE5
4        -
________
=________
GE6
4        -
________
=________
Sum individual item scores: ________  
Multiply by 6: ________
Divide by number of items answered: ________= EWB subscale score


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FUNCTIONAL 
WELL-BEING (FWB)
Score range: 0-28
GF1
0        +
________
=________
GF2
0        +
________
=________
GF3
0        +
________
=________
GF4
0       +
________
=________
GF5
0        +
________
=________
GF6
0        +
________
=________
GF7
0        +
________
=________
Sum individual item scores: ________  
Multiply by 7: ________
Divide by number of items answered: ________= FWB subscale score
FACT-O Scoring Guidelines (Version 4) – Page 2
Subscale
Item Code
Reverse item? 
Item response
Item Score
OVARIAN CANCER 
SUBSCALE (OCS)
Score range: 0-44
O1
4        -
________
=________
C2
4        -
________
=________
C3
0        +
________
=________
O2
4        -
________
=________
B5
4        -
________
=________
C6
0        +
________
=________
C7
0        +
________
=________
BMT5
0        +
________
=________
B9
0        +
________
=________
O3
4        -
________
=________
BL4
0        +
________
=________
     BMT7               NOT CURRENTLY SCORED
Sum individual item scores: ________  
Multiply by 11: ________
Divide by number of items answered: ________= OC subscale score
To derive a FACT-O Trial Outcome Index (TOI): 
Score range: 0-100
__________
+ __________
+ __________
= __________
=FACT-O TOI
(PWB score)
(FWB score)
(OCS score)


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To derive a FACT-G total score: 
Score range: 0-108
__________
+ __________
+ __________
+ __________
= __________
=FACT-G Total
(PWB score)
(SWB score)
(EWB score)
(FWB score)
To derive a FACT-O total score: 
Score range: 0-152
__________
+ _________
+ _________
+ _________
+ _________
= _____
=FACT-O Total
(PWB score)
(SWB score)
(EWB score)
(FWB score)
(OCS score)
*For guidelines on handling missing data and scoring options, please refer to the Administration and Scoring 
Guidelines in the manual or on-line at www.facit.org.


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
77 of 82
Appendix 3: FACIT-Fatigue questionnaire from the eCRF and scoring 
guidelines
Functional Assessment of Chronic Illness Therapy-Fatigue (symptoms in past 7 days)
Date of completion
__ / __ / ____
1 I feel fatigued (HI7)
○Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
2 I feel weak all over (HI12)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
3 I feel listless (“washed out”) (AN1)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
4 I feel tired (AN2)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
5 I have trouble starting things because I am tired (AN3)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
6 I have trouble finishing things because I am tired (AN4)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
78 of 82
7 I have energy (AN5)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
8 I am able to do my usual activities (AN7)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
9 I need to sleep during the day (AN8)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
10 I am too tired to eat (AN12)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
11 I need help doing my usual activities (AN14)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
12 I am frustrated by being too tired to do the things I 
want (AN15)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
13 I have to limit my social activity because I am tired 
(AN16)
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
79 of 82
FACIT-Fatigue Scale (version 4) Scoring Guidelines
Items are scored as follows: 4=Not At All; 3=A Little Bit; 2=Somewhat; 1=Quite A Bit; 
0=Very Much, EXCEPT items #7 and #8 which are reversed scored. Score range 0-52. 
A score of less than 30 indicates severe fatigue. The higher the score, the better the quality of 
life.
Item Number
Reverse Item?
Item Response
Item Score
1
4
-
=
2
4
-
=
3
4
-
=
4
4
-
=
5
4
-
=
6
4
-
=
7
0
+
=
8
0
+
=
9
4
-
=
10
4
-
=
11
4
-
=
12
4
-
=
13
4
=
Sum individual item scores: ________
Multiply by 13: ________
Divide by number of items answered: ________
For guidelines on handling missing data and scoring options, please refer to the 
Administration and Scoring Guidelines on-line at www.facit.org.


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
80 of 82
Appendix 4: ORZORA Qol: Additional Ovarian Cancer Items from the 
eCRF
ORZORA QoL additional items questionnaire (symptoms in past 7 days)
Date of completion
__ / __ / ____
1 I feel ill with low energy
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
2 I am able to enjoy life and I am still interested in my 
hobbies and interests feel 
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
3 I am satisfied that my family understands my disease
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
4 I feel I am able to meet the needs of my family
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
5 I understand the need to take my medication and my 
treatment regimen
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
6 My treatment has had significantly negative effects on 
my QoL
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
81 of 82
7 I feel like a normal woman
○ Not At All
○ A Little Bit
○ Somewhat
○ Quite A Bit
○ Very Much
8 1st Significant Issue Struggling with
(Free text response)
9 2nd Significant Issue Struggling with
(Free text response)
10 3rd Significant Issue Struggling with
(Free text response)


Statistical Analysis Plan
Study Code D0816C00012
Edition Number 5.0
Date 19 Feb 2020
CONFIDENTIAL AND PROPRIETARY
82 of 82
Appendix 5: Examples of dose intensity calculations
Example Olaparib dosing
The planned dosing schedule was 400mg twice daily (a total daily dose of 800mg per day).
RDI
PID
Patient
Study Day
1
2
3
4
5
6
7
8
9
10
11
100%
100%
1
P
100%
50%
2
D
P
50%
50%
3
P
70%
70%
4
P
57%
40%
5
D
P
Received the total daily dose of 800mg
Dose reduction (less than 800mg; in this example 400mg)
Missed dose (0mg)
D
Discontinuation IP
P
Progression (or censoring event)
Patients 1-5 progressed on Day 11, so the intended dose through to progression was 10 * 800 
mg of olaparib = 8000 mg.
Patient 1 received a total dose of 8000mg of olaparib, whereas patients 2-5 received less 
treatment due to:
!
Early stopping (Patient 2)
!
Missed dose (Patient 3)
!
Dose reduction and missed dose (Patient 4)
!
Early stopping, missed doses and dose reductions (Patient 5)
Patient 1:
RDI = PID = (10 * 800mg)/ 8000 mg = 100%
Patient 2:
RDI = (5 * 800 mg)/ 4000 mg = 100%
PID = (5 * 800 mg)/ 8000 mg = 50%
Patient 3:
RDI = PID = (5 * 800 mg)/ 8000 mg = 50%
Patient 4:
RDI = PID = ((5 * 800 mg) + (4 * 400 mg))/ 8000 mg = 70%
Patient 5:
RDI = ((3 * 800 mg) + (2 * 400 mg))/ 5600 mg = 57%
PID = ((3 * 800 mg) + (2 * 400 mg))/ 8000 mg = 40%