Conditions: Non-Germline BRCA Mutated Ovarian Cancer
Keywords: Ovarian cancer non-gBRCA Platinum Chemotherapy
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 279
Healthy volunteers: no

Brief summary:
The purpose of the study is to assess the efficacy and safety of single-agent olaparib as a maintenance treatment in patients with relapsed High Grade Serous Ovarian Cancer (including patients with primary peritoneal and/or fallopian tube cancer) or high grade endometrioid cancer who do not have known deleterious or suspected deleterious germline BRCA mutations (non-gBRCAm) and who had responded following platinum based chemotherapy

Detailed description:
Maintenance monotherapy with the potent polyadenosine 5'diphosphoribose \[Poly (ADP-ribose)\] polymerisation (PARP) inhibitor (PARPi) olaparib will significantly prolong progression-free survival (PFS) in platinum sensitive relapsed non-germline breast cancer susceptibility gene (BRCA) mutated ovarian cancer patients who are in complete or partial response following platinum based chemotherapy.

Olaparib is a potent PARPi (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 anticancer agents. PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). Inhibiting PARP enzymes 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 (HR) repair. Tumours with HR deficiencies (HRDs), such as ovarian cancers in patients with BRCA1/2 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.

While multiple randomized controlled trials (RCTs) have demonstrated that platinum sensitive BRCAm patients have profound response to maintenance treatment with PARP inhibitors, PARP inhibitors target cells with homologous recombination deficiency (HRD), of which BRCA mutation is only one type. Consistent with the mechanism of action of PARP inhibition, response has also been seen in multiple RCTs in patients who are platinum sensitive but whose tumours do not harbor BRCA mutations. Presumably these responders have defects in other components of HRR pathways, though currently available diagnostic technology is not adequate to reliably identify the full spectrum of HRR deficiencies. Instead, these data support the hypothesis that platinum sensitivity itself is a clinical selection factor for HRD.

Arms:
arm 1: Olaparib will be supplied as film-coated tablets containing 150 mg or 100 mg of olaparib.

Patients will be administered olaparib orally twice daily (bid) at 300 mg.

Interventions: intervention 1: Olaparib
Intervention descriptions: intervention 1: 300 mg twice daily - oral

Protocol document:
Prot_002.pdf: 
Clinical Study Protocol 
Drug Substance
Olaparib, AZD2281, KU 0059436
Study Code
D0816C00020
Version
3.0
Date
26 October 2018
OPINION - A Phase IIIb, Single-arm, Open-label Multicentre Study of 
Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed non-
Germline BRCA Mutated Ovarian Cancer Patients who are in Complete or 
Partial Response Following Platinum based Chemotherapy
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
EudraCT number: 2017-002767-17






Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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3. Section 1.2 Rationale for Study Design, Doses and Control Groups: updated text 
summarizing previous study findings. Add m to gBRCAm in title of section on 
rational for patient selection.
4. Section 1.4 Study Design: text updated for clarity.
5. Figure 1: Protocol Schedule: Revised to clarify that patients must be negative for 
gBRCA.
6. Section 2.2 Secondary objectives: Moved measurement of OS from Exploratory 
Objectives (Section 2.4) to Secondary Objectives section per CHMP request.
Clarification of Myriad tests to be used. Ensure consistenct of wording with 
sysnopsis.
7. Section 2.4 Exploratory objectives: OS objective moved to Section 2.2; added 
analysis of OS by TP53 disruption status per CHMP request. Other minor text 
changes for clarity and to ensure consistency with synopsis.
8. Section 3.1 Inclusion Criteria: Text on special requirements for Japanese subjects 
removed (IC 2);text on gBRCA testing revised for clarity; oxaliplatin added as an 
acceptable platinum agent (IC 5); 24-hour urine added as alternative measure of 
Creatinine Clearance (IC 7) in line with new AZ standard guidance.
9. Section 3.2 Exclusion Criteria: Hormonal therapy added as an excluded therapy 
(EC4); revised AZ standard wording for EC 7 in line with new guidance.
10. Section 3.8 Restrictions: Subsection 3.8.1 Grapefruit juice - wording has been 
strengthened from saying ‘not recommended’ to ‘prohibited’ as per revised AZ 
standard guidance and grapefruit added.
11. Section 3.9.1 Procedures for discontinuation of a patient from investigational 
product: Removal of repeated sentence, “A patient that decides to discontinue IP 
will always be asked about the reason(s) for discontinuation and the presence of any 
adverse events. If possible they will be seen and assessed by an Investigator(s). AEs 
will be followed up(see Section 6)”. The sentence “At any time, patients are free to 
discontinue IP or withdraw from the study (i.e. IP and assessments; see Section 
3.10)” has been moved to the top of the section. Detail has been added to the 
penultimate sentence for clarification, with “up to the final analysis” being replaced 


Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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by “until 135 OS events (~54% maturity) have been recorded, estimated to be 
approximately 36 months after the first subject is enrolled.”
12. Section 3.10 Criteria for Withdrawal: Amended definition of “lost to follow up” in 
line with AZ Standard protocol.
13. Section 4 Table 1: Altered to show that confirmation of non-gBRCA status is 
required before screening. Clarification of when the tumour sample is to be 
obtained, both in the table and in the text of footnote g, replacing “All patients are 
required to submit an archival tumour sample for retrospective testing of their 
genetic status” with “All patients are required to submit either an archival tumour 
sample, or a fresh biopsy if an archival sample is not available, for retrospective 
testing of their genetic status. If archival tissue, the presence of adequate tissue 
needs to be confirmed prior to screening, but it will not be shipped to the central lab 
before Day1. If fresh, the biopsy should be taken after the baseline scan has been 
performed.”. Clarification of note e.
14. Section 4 Table 2: Add “blood” and delete “plasma” in describing samples to be 
taken for ctDNA and the retrospective gBRCA test. Add “all samples should be 
taken prior to first dose” to footnote d for clarity.
15. Section 4.1.1 Testing for gBRCA mutations for patients with unknown gBRCA
status: replaced “early” with “before screening”, “gBRCA mutation screening” with 
gBRCA mutation testing” and “lab” with “laboratory”, for clarity.
16. Section 4.2.3 Visit 4 (Day 57) and subsequent on-treatment tumour assessment 
visits: Added “until progression” at the end of the first pargraph, for clarity.
17. Section 4.3.2 Long-term follow up beyond 30 days after last dose of study 
medication: First sentence amended for clarity with addition of text shown in italics 
“Long-term follow up will be conducted until First Subsequent Treatment (or prior 
death), and for Overall Survival…”
18. Section 5: Deleted reference to Japan.
19. Section 5.2.1.2 Bone marrow or blood cytogenetic samples: The first sentence 
“Bone marrow or blood cytogenetic samples may be collected for patients with 
prolonged haematological toxicities as defined in Section 6.8.1” has been amended 


Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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to read. “In patients with prolonged haematological toxicities, bone marrow or blood 
cytogenetic samples may be indicated as defined in Section 6.8.1.3” for clarity.
20. Section 5.6 Genetics: Added “testing” and “(unless determined centrally at 
screening)” to the first sentence for clarity and consistency with Table 2. Deleted 
“compared with the broader population and historical controls”. Added additional 
sentence “The tumour samples will be analysed for deleterious or suspected 
deleterious mutations of TP53, and the effect of the presence of such mutations on 
PFS and OS explored” to reflect the new exploratory objective. Added text 
describing in detail which outcome measures will be explored (consistent with 
SAP).
21. Section 5.7 Biomarker Analysis: Blood sample size increased from 18mL to 
approximately 20mL to reflect change in standard collection tube size.
22. Section 6 Safety Reporting and Medical Management, subsection 6.1.1: Minor 
revisions in line with revised AZ standard guidance, and to clarify that the 
questionnaire information is not part of the study database.
23. Section 6.3 Recording of Adverse Events, subsections 6.3.1.1 and 6.3.10: Minor 
revisions in line with revised AZ standard guidance. Subsection 6.3.12 deletion of 
“post study” in the first sentence to avoid misunderstanding, as 30 day follow-up is 
part of study.
24. Section 6.8 Management of Investigational Product Related toxicities: Table 4 
Management of Anaemia: Inserted revised section on ‘action to be taken’taken in 
line with new AZ standard guidance.
25. Section 7.7 Concomitant and Other Treatments: Text on potential drug-drug 
interactions revised and updated in line with new AZ standard guidance.
26. Section 8.2 Sample Size Estimate: Addition of “A supplementary analysis of OS 
will be performed when 135 OS events (~54% maturity) have been recorded, 
estimated to be approximately 36 months after the first subject is enrolled” to the 
end of first paragraph, to align with other protocol sections.
27. Section 8.3 Definition of Analysis Sets:Deletion of sentence relating to Japan.


Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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28. Section 8.4.Outcome Measures for Analyses: 8.4.1. Amended definition of Time to 
Study Discontinuation or Death (TDT). Calculation or derivation of patient reported 
outcome variables (Health related quality of life): a new final sentence “In this study 
the 10-point minimum clinically important difference will be applied only to 
deterioration” has been added, consistent with analysis plan.
29. Section 8.5.1 Analysis of the primary variable (comparison to historical controls): 
Text shown in italics added to clarify status of this analysis “In a post-hoc
exploratory analysis, outcomes from this trial may be compared to historical data 
from published studies in a comparable patient population treated with placebo. 
Such an analysis does not form part of the formal study objectives”. Added “non-
BRCA mutated” to bullet 3 of subgroup analyses to be consistent with study 
objectives. Added “Histological subtype (HGSOC vs High grade endometrioid 
ovarian cancer)” as a further important clinical characteristic for PFS summaries.
30. Section 8.5.2: First sentence amended by addition of “..median and..” to reflect more 
accurately the intended analysis.
31. Section 8.5.3 Interim Analysis: Text “..for internal planning purposes, and to 
provide ongoing data to external bodies” added to clarify the purpose of the interim 
analysis.
32. Section 9.2.2 Direct access to source data in Japan: deleted.
33. Section 9.3 Study Timetable and End of Study: Text modifications to align with new 
study end date and explain that data will be added to the database after the primary 
analysis 
34. Appendix F: Pre study germline BRCA Testing: Clarification of instructions on 
gBRCA testing and alignment with Section 3.1
35. Appendix I: Summary of RECIST 1.1: updated to align better with study design and 
purpose.
This document contains confidential commercial information, disclosure of which is 
prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
8 (111)
CLINICAL STUDY PROTOCOL SYNOPSIS
OPINION - A Phase IIIb, Single-arm, Open-label Multicentre Study of 
Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed non-
Germline BRCA Mutated Ovarian Cancer Patients who are in Complete or 
Partial Response Following Platinum based Chemotherapy 
International Coordinating Investigator
INITIA ONCOLOGY
Hospital Quironsalud
Prof Severo Ochoa, 14 
Planta baja
46010 Valencia, Spain
Study sites and number of patients planned
The study will enrol approximately 250 patients with platinum sensitive high-grade serous 
ovarian cancer (HGSOC) (including patients with primary peritoneal and/or fallopian tube cancer) 
or high grade endometrioid ovarian cancer who are in complete or partial response following 
platinum based chemotherapy and who are germline BRCA1 and/or BRCA2 negative. The study will 
be conducted in approximately 19 countries worldwide, including Austria, Belgium, Bulgaria,
Canada, Czech Republic, Denmark, Finland, Israel, Italy, Netherlands, Norway, Poland,
Portugal, Romania, Slovenia, Spain, Sweden, Switzerland and the United Kingdom. 
Additional countries may be added depending on recruitment rates.
Study period (includes follow-up for OS)
Phase of development
Estimated date of first patient enrolled
Q1 2018
IIIb
Estimated date of last patient enrolled
Q1 2019
Estimated date of last patient completed1
Q1 2021
Estimated date of clinical study report2
Q1 2021
1including follow-up for survival (estimated at 36 months after first patient enrolled)
2based on primary analysis (estimated at 30 months after first patient enrolled)
PPD
PPD


Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
9 (111)
Study design
This is a Phase IIIb, single-arm, open-label, multicentre study to assess the efficacy and safety
of single-agent olaparib as a maintenance treatment in patients with relapsed HGSOC (including
patients with primary peritoneal and/or fallopian tube cancer) or high grade endometrioid ovarian 
cancer who do not have known deleterious or suspected deleterious germline BRCA mutations 
(non-gBRCAm) and who had responded following platinum based chemotherapy. Tumour 
assessments will be conducted every 8 weeks for the first 12 months, and thereafter every 12 
weeks up to disease progression.


Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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Objectives
Primary Objective:
Outcome Measure:
To determine the efficacy by progression-
free survival (PFS) (investigator-recorded 
assessments according to modified 
Response Evaluation Criteria In Solid 
Tumors [RECIST v1.1]) of olaparib 
maintenance monotherapy in non-
gBRCAm platinum sensitive relapsed 
(PSR) ovarian cancer
PFS: Time from date of first dose until the 
date of objective radiological disease 
progression according to modified RECIST 
1.1 or death (by any cause in the absence of 
progression)
Secondary Objectives:
Outcome Measures:
To determine the efficacy of olaparib 
maintenance monotherapy in non-
gBRCAm PSR ovarian cancer by 
assessment of time to first subsequent 
therapy or death (TFST) 

TFST: Time from date of first dose to date of 
first subsequent treatment commencement or 
death due to any cause if this occurs before 
commencement of first subsequent treatment 
To determine the efficacy of olaparib 
maintenance monotherapy in non-
gBRCAm PSR ovarian cancer by 
assessment of time to treatment 
discontinuation or death (TDT)

TDT: Time from date of first dose to date of 
study drug discontinuation or death due to 
any cause if this occurs before study drug 
discontinuation
To determine the efficacy by PFS 
(investigator-recorded assessments 
according to modified RECIST v1.1) of 
olaparib maintenance in non-gBRCAm 
PSR ovarian cancer according to tumour
homologous recombination deficiency 
(HRD) status using the Myriad myChoice
plus HRD test

PFS in the following subgroups: -
1. Somatic BRCA mutated and HRD scar 
positive; 
2. HRD scar positive, non-BRCA mutated; 
3. HRD scar negative, non-BRCA mutated
To determine the efficacy of olaparib 
maintenance monotherapy in non-
gBRCAm PSR ovarian cancer by 
assessment of chemotherapy-free interval 
(CT-FI)

CT-FI: Time from the date of the last dose of 
platinum chemotherapy prior to olaparib 
maintenance therapy until the date of 
initiation of the next anticancer therapy
To determine the overall survival (OS) of 
non-gBRCAm PSR ovarian cancer patients 
treated with olaparib maintenance 
monotherapy 

OS: Time from the date of first dose of 
olaparib to date of death from any cause


Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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To investigate the Health-related Quality 
of Life (HRQoL) of non-gBRCAm PSR 
ovarian cancer patients treated with 
olaparib maintenance monotherapy as 
assessed by the trial outcome index (TOI) 
of the Functional Assessment of Cancer 
Therapy – Ovarian (FACT-O) 

Proportion of patients with any improvement
from baseline in TOI score at any point 
during the treatment period

Proportion of patients with a 10 point 
deterioration from baseline in TOI score at 
any point during the treatment period
Safety Objective:
Outcome Measures:
To assess the safety and tolerability of
olaparib maintenance monotherapy in 
patients with non-gBRCAm PSR ovarian 
cancer

Adverse events/serious adverse events
     Collection of clinical chemistry/haematology 
parameters
Exploratory Objective
Outcome Measure
To explore the efficacy by PFS 
(investigator-recorded assessments 
according to modified RECIST v1.1) of 
olaparib maintenance monotherapy in non-
gBRCAm PSR ovarian cancer patients 
stratified into a range of molecular sub-
groups including mutations in Homologous 
recombination repair (HRR) genes,
microsatellite instability (MSI) status, and 
tumour mutation load score.  

PFS by molecular measures of HRR and 
genomic instability
To explore the impact of TP53 disruption 
status on both OS and PFS

OS and PFS by TP53 disruption status
To explore the impact of treatment and 
disease state on health state utility by 
EuroQoL five dimensions, five level (EQ-
5D-5L)

EQ-5D index score and the EQ-VAS score 
including the change from baseline for both 
scores
To explore the feasibility of reliably 
identifying mutations in homologous 
recombination genes from circulating 
tumour DNA (ctDNA) and to enable future 
diagnostic development.

Correlation between HRD status from tumour 
and ctDNA in matched patient samples


Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
12 (111)
Screening and follow-up
Patients must have an existing known and documented gBRCA test result. Patients with known 
deleterious or suspected deleterious gBRCA mutations will be excluded. All patients should 
additionally have a tumour sample available for the Myriad myChoice® HRD plus test, plus 
other molecular tests that measure homologous recombination repair competency and genomic 
instability. The gBRCA status of enrolled patients will be confirmed retrospectively using the 
Myriad BRCAnalysis CDx test.
Following screening assessments, all patients should have radiological (CT or MRI) tumour 
assessments at baseline (within 28 days of starting treatment), then every 8 weeks (±7 days) for 
the first 12 months, and then every 12 weeks (± 7 days) until documented evidence of objective 
radiological disease progression in accordance with modified RECIST 1.1, irrespective of 
treatment decisions (i.e. RECIST follow up until progression even if a patient discontinues study 
treatment prior to progression and/or receives subsequent therapy prior to progression). At 
baseline, eligible patients can have measurable disease (target lesions) or non-measurable 
disease (non-target lesions or no evidence of disease). 
Once a patient has progressed, the patient will be treated as per local clinical practice and will 
be followed to first subsequent treatment, and then approximately every 12 weeks for survival.  
Target patient population

Patients with platinum sensitive relapsed (PSR) high grade serous ovarian cancer (this 
includes any patients with primary peritoneal and / or fallopian tube cancer) or high grade 
endometrioid ovarian cancer without a gBRCA mutation. Patients will be in complete or 
partial response following completion (a minimum of 4 treatment cycles) of platinum-
based chemotherapy

Patients must have completed at least 2 previous lines of platinum-based therapy (e.g. 
containing carboplatin, cisplatin or oxaliplatin) before entry to the study and must be 
considered to have been platinum sensitive after the penultimate platinum-based 
chemotherapy - defined as disease progression greater than 6 months after completion (last 
dose) of the penultimate platinum chemotherapy

Patients must not have received bevacizumab during the chemotherapy course 
immediately prior to screening. Cytoreductive surgery is allowed before this course of 
chemotherapy.
Duration of treatment
Patients should continue to receive study treatment until objective disease progression as 
assessed by the investigator, or unacceptable toxicity or for as long as they do not meet any 
other discontinuation criteria. Patients should continue with therapy to RECIST progression 
despite rises in CA-125. Patients may continue to receive treatment beyond progression 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 study treatment, other treatment options will be at the discretion of the investigator.  


Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
13 (111)
Investigational product, dosage and mode of administration
Olaparib will be supplied to the investigator as film-coated tablets containing 150 mg or 100 
mg of olaparib.
Patients will be administered olaparib orally twice daily (bd) at 300 mg.  The planned dose of 
300 mg twice daily will be made up of two 150 mg tablets twice daily, with 100 mg tablets used 
to manage dose reductions which may be required in patients experiencing toxicities related to 
olaparib treatment, or because of concomitant medication.  Guidance on dose reductions are 
outlined in Sections 6.8 and 7.7
Olaparib tablets should be taken at the same times each morning and evening of each day, 
approximately 12 hours apart with a glass of water.  The olaparib tablets should be swallowed 
whole and not chewed, crushed, dissolved or divided.  Olaparib tablets can be taken with or 
without a meal.  
Statistical methods
The primary endpoint is investigator assessed PFS using modified RECIST criteria version 1.1.  
A sample size of approximately 250 patients is proposed for this study in order to provide an 
adequate level of precision around the primary endpoint in the whole population. The primary
analysis is planned to be undertaken after approximately 30 months with an interim analysis 
after approximately 18 months. Assessments for survival will continue to be performed every 
12 weeks following the primary analysis for PFS, until 135 OS events (~54% maturity) have 
been recorded, estimated to be approximately 36 months after the first subject is enrolled.
In two randomized placebo controlled studies (Study 19, Nova) where non-gBRCAm patients 
were treated with a Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), the median PFS 
for patients treated with a PARPi ranged from 8 to 9 months compared to 4 – 5.5 months for 
those treated with placebo.  Clinical trial simulations were performed assuming 250 patients 
enrolled over a 12 month period with 50% of patients enrolled after 8 months, a median PFS 
of 8.5 months and a piecewise exponential model for PFS.  Across 500 simulations it is 
estimated that the mean number of PFS events is approximately 135 at 18 months (54% 
maturity) and 180 at 30 months (72% maturity), with corresponding mean 95% confidence 
interval (CI) widths of 3.87 and 3.27 months respectively.   
All efficacy analyses will be based on the full analysis set (all enrolled patients assigned to 
olaparib) with safety data summarised from the safety-analyses set (all enrolled patients who 
have received at least one dose of olaparib).  Kaplan-Meier (KM) plots of PFS will be 
presented for all non-gBRCAm patients and for subgroups determined by the tumour HRD 
status. 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% CIs. 
Other time-to-events endpoints will be summarised in a similar manner. Data from patients 
treated with olaparib in the current study may be compared with historical data from published 
studies in a comparable patient population treated with placebo having adjusted for the 
prevalence of known prognostic factors.


Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
14 (111)
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
CLINICAL STUDY PROTOCOL SYNOPSIS ....................................................8
TABLE OF CONTENTS................................................................................... 14
1.
INTRODUCTION ............................................................................................. 23
1.1
Background and Rationale for Conducting This Study ....................................... 23
1.2
Rationale for Study Design, Doses and Control Groups...................................... 23
1.3
Benefit/Risk and Ethical Assessment ................................................................. 26
1.4
Study Design...................................................................................................... 26
1.5
Study Governance and Oversight ....................................................................... 27
2.
STUDY OBJECTIVES...................................................................................... 29
2.1
Primary Objective .............................................................................................. 29
2.2
Secondary Objectives......................................................................................... 29
2.3
Safety Objectives ............................................................................................... 30
2.4
Exploratory Objectives....................................................................................... 30
3.
PATIENT SELECTION, ENROLMENT, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL.................................................. 31
3.1
Inclusion Criteria ............................................................................................... 31
3.2
Exclusion Criteria .............................................................................................. 34
3.3
Patient Screening and Registration..................................................................... 36
3.4
Procedures for Handling Incorrectly Enrolled Patients ....................................... 37
3.5
Methods for Assigning Treatment Groups.......................................................... 37
3.6
Methods for Ensuring Blinding .......................................................................... 37
3.7
Methods for Unblinding..................................................................................... 37
3.8
Restrictions........................................................................................................ 37
Grapefruit juice.................................................................................................. 37
Contraception..................................................................................................... 37
3.9
Discontinuation of Investigational Product......................................................... 37
Procedures for discontinuation of a patient from investigational product ............ 38


Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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3.10
Criteria for Withdrawal ...................................................................................... 39
Screen failures ................................................................................................... 39
Withdrawal of the informed consent................................................................... 39
3.11
Discontinuation of the Study.............................................................................. 40
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 40
4.1
Screening/Enrolment Period............................................................................... 45
Testing for gBRCA mutations for patients with unknown gBRCA status............. 45
4.2
Treatment Period................................................................................................ 45
Visit 2 (Baseline Visit, Day 1)............................................................................ 45
Visit 3 (Day 29) ................................................................................................. 45
Visit 4 (Day 57) and subsequent on-treatment tumour assessment visits............. 45
Visits 5 and Subsequent safety test visits............................................................ 45
Study treatment discontinued ............................................................................. 46
4.3
Follow-up Period ............................................................................................... 46
Follow up 30 days after last dose of study medication ........................................ 46
Long-term follow up beyond 30 days after last dose of study medication ........... 46
5.
STUDY ASSESSMENTS.................................................................................. 46
5.1
Efficacy Assessments......................................................................................... 46
Tumour evaluation............................................................................................. 46
5.2
Safety Assessments............................................................................................ 47
Laboratory safety assessments............................................................................ 47
5.2.1.1
Coagulation........................................................................................................ 47
5.2.1.2
Bone marrow or blood cytogenetic samples ....................................................... 48
Physical examination and ECOG ....................................................................... 48
5.2.2.1
Vital signs and weight........................................................................................ 48
5.2.2.2
Pulse and blood pressure.................................................................................... 48
5.2.2.3
Body temperature............................................................................................... 48
Other safety assessments.................................................................................... 49
5.2.3.1
Serum or urine pregnancy test ............................................................................ 49
5.3
Other Assessments............................................................................................. 49
Patient Reported Outcomes (PRO: FACT-O) ..................................................... 49
EQ-5D-5L.......................................................................................................... 49
5.4
Pharmacokinetics ............................................................................................... 49
5.5
Pharmacodynamics ............................................................................................ 49
5.6
Genetics............................................................................................................. 50
5.7
Biomarker Analysis............................................................................................ 50
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 50
6.1
Definition of Adverse Events ............................................................................. 50
Olaparib adverse events of special interest ......................................................... 51


Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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6.2
Definitions of Serious Adverse Event................................................................. 51
6.3
Recording of Adverse Events............................................................................. 51
Time period for collection of adverse events ...................................................... 51
6.3.1.1
Adverse events after the 30-day follow-up period............................................... 52
Follow up of unresolved adverse events ............................................................. 52
Variables............................................................................................................ 52
Causality collection............................................................................................ 54
Adverse events based on signs and symptoms .................................................... 54
Adverse events based on examinations and tests ................................................ 54
Hy’s Law ........................................................................................................... 55
Disease progression............................................................................................ 55
Disease under study ........................................................................................... 55
New cancers....................................................................................................... 55
Lack of efficacy ................................................................................................. 55
Deaths................................................................................................................ 55
6.4
Reporting of Serious Adverse Events ................................................................. 56
6.5
Overdose............................................................................................................ 56
6.6
Pregnancy .......................................................................................................... 57
Maternal exposure.............................................................................................. 57
6.7
Medication Error................................................................................................ 57
6.8
Management of Investigational Product Related Toxicities ................................ 58
Management of haematological toxicity ............................................................. 59
6.8.1.1
Management of anaemia .................................................................................... 59
6.8.1.2
Management of neutropenia, leukopenia and thrombocytopenia......................... 60
6.8.1.3
Management of prolonged haematological toxicities while on study 
treatment............................................................................................................ 60
Management of non-haematological toxicity...................................................... 61
6.8.2.1
Management of new or worsening pulmonary symptoms ................................... 61
6.8.2.2
Management of nausea and vomiting ................................................................. 61
6.8.2.3
Interruptions for intercurrent non-toxicity related events .................................... 61
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 62
7.1
Identity of Investigational Product...................................................................... 62
7.2
Dose and Treatment Regimens........................................................................... 62
7.3
Labelling............................................................................................................ 63
7.4
Storage............................................................................................................... 64
7.5
Compliance........................................................................................................ 64
7.6
Accountability.................................................................................................... 64
7.7
Concomitant and Other Treatments.................................................................... 65
Other concomitant treatment .............................................................................. 67


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Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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7.8
Post Study Access to Study Treatment – Not Applicable.................................... 67
8.
STATISTICAL ANALYSES BY ASTRAZENECA.......................................... 67
8.1
Statistical Considerations ................................................................................... 67
8.2
Sample Size Estimate......................................................................................... 67
8.3
Definitions of Analysis Sets ............................................................................... 67
8.4
Outcome Measures for Analyses ........................................................................ 68
Calculation or derivation of efficacy variables.................................................... 68
Calculation or derivation of safety variables....................................................... 69
Calculation or derivation of patient reported outcome variables.......................... 70
8.5
Methods for Statistical Analyses ........................................................................ 71
Analysis of the primary variable......................................................................... 71
Analysis of the secondary/exploratory variables................................................. 72
9.
STUDY AND DATA MANAGEMENT............................................................ 73
9.1
Training of Study Site Staff................................................................................ 73
9.2
Monitoring of the Study..................................................................................... 73
Source data ........................................................................................................ 73
Study agreements............................................................................................... 73
Archiving of study documents............................................................................ 74
Deviation from the clinical study protocol.......................................................... 74
9.3
Study Timetable and End of Study..................................................................... 75
9.4
Data Management by Designated Clinical Research Organisation ...................... 76
10.
ETHICAL AND REGULATORY REQUIREMENTS....................................... 76
10.1
Ethical Conduct of the Study.............................................................................. 76
10.2
Patient Data Protection....................................................................................... 76
10.3
Ethics and Regulatory Review............................................................................ 77
10.4
Informed Consent............................................................................................... 78
10.5
Changes to the Clinical Study Protocol and Informed Consent Form.................. 78
10.6
Audits and Inspections ....................................................................................... 79
11.
LIST OF REFERENCES ................................................................................... 80
LIST OF TABLES
Table 1
Study Schedule – Screening (Visit 1) ....................................................40
Table 2
Study Plan Detailing the Procedures......................................................42


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Study Code D0816C00020
Version 3.0
Date 26 October 2018
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Table 3
Laboratory Safety Variables..................................................................47
Table 4
Management of Anaemia ......................................................................59
Table 5
Management of Neutropenia, Leukopenia and Thrombocytopenia ........60
Table 6
Dose Reductions for Study Treatment ...................................................62
LIST OF FIGURES
Figure 1
Protocol Schedule .................................................................................28
LIST OF APPENDICES
Appendix A
Additional Safety Information...............................................................81
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document..............................................................................83
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ........................................................................84
Appendix D
Acceptable Birth Control Methods ........................................................89
Appendix E
ECOG Performance Status....................................................................91
Appendix F
Pre study germline BRCA Testing .........................................................92
Appendix I
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 (Response Evaluation Criteria in Solid Tumours)..............99
Appendix J
Signatures ........................................................................................... 108
CCI


Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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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
ADP
AE
Adenosine diphosphate
Adverse event
AESI
Adverse events of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AML
Acute myeloid leukaemia
ANC
Absolute neutrophil count
APTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
BRCA1, BRCA2
Breast cancer susceptibility genes
BUN
CA
Blood urea nitrogen
Cancer antigen
CI
Confidence interval
CrCl
CR
Creatinine clearance
Complete response
CRF
Case report form (electronic/paper)
CRO
Clinical research organisation
CSP
Clinical study protocol
CT
CT-FI
Computed tomography
Chemotherapy free interval
CTC(AE)
Common terminology criteria (for adverse event)
CYP
Cytochrome P450
DCIS
DCO
Ductal carcinoma in situ
Data cut off
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid 
DSB
Double strand break
dUCBT
Double umbilical cord blood transplantation
E-code
eCRF
Enrolment code
Electronic Case Report Form


Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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Abbreviation or 
special term
Explanation
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group; a performance status using scales 
and criteria to assess how a subject’s disease is progressing
EQ-5D-5L
ESMO
EWB
EuroQoL five dimensions, five level
European Society for Medical Oncology
Emotional well-being
FACT-O
FACIT
FOSI
FSH
FWB
gBRCAm
Functional Assessment of Cancer Therapy – Ovarian
Functional Assessment of Chronic Illness Therapy
FACT/NCCN Ovarian Symptom Index
Follicle-stimulating hormone
Functional well-being
Germline BRCA1/2 mutation
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GMP
Good Manufacturing Practice
Hb
Haemoglobin
HGSOC
High-grade serous ovarian cancer 
HIV
Human immunodeficiency virus
HL
Hy’s Law
HR
HR
HRCT
Homologous recombination
Hazard ratio
High resolution computed tomography
HRD
HRQoL
Homologous recombination deficiency
Health related quality of life
HRR
Homologous recombination repair 
IATA
International Airline Transportation Association
IB
ICF
Investigator brochure
Informed consent form
ICH
International Council for Harmonisation
International 
Coordinating 
Investigator
If a study is conducted in several countries the International Coordinating 
Investigator is the Investigator coordinating the Investigators and/or 
activities internationally.  
INR
International normalised ratio
IMP
Investigational medicinal product


Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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Abbreviation or 
special term
Explanation
IP
IRB
IVRS
IWRS
Investigational product 
Institutional Review Board synonymous to ethics committee
Interactive Voice Response System
Interactive Web Response System
KM
LH
Kaplan-Meier
Luteinizing hormone
MATE
Multidrug and toxin extrusion (MATE1, MATE2K)
MCV
Mean cell volume
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MRI
MSI
Magnetic resonance imaging
Micro satellite instability
NCCN
National Comprehensive Cancer Network
NCI
NE
National Cancer Institute
Not evaluable
OAE
Other significant adverse event
OAT
Organic anion transporter (OAT1, OAT2, OAT3)
OATP1B1
Organic anion transporting polypeptide 1B1
OCT
Organic cation transporter (OCT1, OCT2)
OS
Overall survival
PARP
PARPi
PD
Polyadenosine 5’diphosphoribose [poly (ADP ribose)] polymerase
Polyadenosine 5’diphosphoribose [poly (ADP ribose)] polymerase inhibitor
Progressive disease
PFS
Progression-free survival
P-gp
P-glycoprotein
PHL
PR
PRO
PSR
PWB
QoL
Potential Hy’s Law
Partial response
Patient reported outcomes
Platinum sensitive relapsed
Physical well-being
Quality of life
QT(c)
(Corrected) QT interval
RCT
Randomized controlled trial
RECIST
Response Evaluation Criteria in Solid Tumours 


Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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Abbreviation or 
special term
Explanation
SAE
Serious adverse event 
SAP
sBRCAm
SD
Statistical analysis plan
Somatic BRCA mutation
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvate transaminase
SSB
SWB
Single strand breaks
Social well-being
TBL
Total bilirubin
TFST
TSST
Time from first dose to first subsequent treatment or death 
Time to second subsequent therapy
TDT
Time to study treatment discontinuation or death
TOI
UCBT
Trial outcome index
Umbilical cord blood transplantation
ULN
Upper limit of normal
VAS
VUS
Visual analogue scale
Variants of uncertain clinical significance or Variant of unknown 
significance
WBDC
Web based data capture
WHO
wt
World Health Organization
Wild-type


Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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1.
INTRODUCTION
1.1
Background and Rationale for Conducting This Study
Research Hypothesis
Maintenance monotherapy with the potent polyadenosine 5’diphosphoribose [Poly (ADP-
ribose)] polymerisation (PARP) inhibitor (PARPi) olaparib will significantly prolong 
progression-free survival (PFS) in platinum sensitive relapsed non-germline breast cancer 
susceptibility gene (BRCA) mutated ovarian cancer patients who are in complete or partial 
response following platinum based chemotherapy 
Olaparib Mechanism of Action
Investigators should be familiar with the current olaparib (AZD2281, KU-0059436) 
Investigator brochure (IB).
Olaparib is a potent PARPi (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 
anticancer agents.
PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair 
mechanisms.  PARP enzymes are essential for repairing DNA single strand breaks (SSBs).  
Inhibiting PARP enzymes 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 (HR) repair.  Tumours with HR deficiencies (HRDs), such as ovarian cancers in 
patients with BRCA1/2 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 (Rottenberg et 
al 2008). The mechanism of action for olaparib results from the trapping of inactive PARP onto 
the SSBs 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 HR repair.  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.
AstraZeneca considers that the relapsed ovarian cancer patient population involved in this study 
falls under the advanced cancer, limited life expectancy definition outlined in International 
Conference on Harmonisation (ICH) S9 guideline "Non-clinical Evaluation for Anticancer 
Pharmaceuticals" and meets the requirements outlined in the guideline.
1.2
Rationale for Study Design, Doses and Control Groups
In patients with platinum sensitive relapsed (PSR) disease, platinum based chemotherapy is 
recommended for 6 cycles with no clear benefit of extending the chemotherapy cycles beyond 
6 and risk of accumulating unacceptable toxicity (NCCN Clinical Practice Guidelines in 
Oncology 2016). There is therefore a window of opportunity to introduce a maintenance 


Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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treatment with a drug suitable for long term use that can prolong the benefit achieved with the 
chemotherapy and continue to provide active anti-tumour control after chemotherapy has been 
completed to significantly and meaningfully delay the next recurrence for patients, extending 
PFS and delaying the time until further chemotherapy treatment is required.
Platinum sensitivity and response to platinum-containing therapy are clinical selection factors 
that can be used to identify patients that are likely to benefit from olaparib treatment. Olaparib 
is a highly specific PARPi that is generally well tolerated, and as maintenance therapy can fulfil 
a high unmet medical need and provide patients with PSR ovarian cancer an opportunity for 
prolonged disease control, meaningfully extended PFS and a longer chemotherapy-free interval. 
Clinical evidence to support olaparib as a maintenance treatment was first shown in a Phase II 
randomized, double-blind, placebo-controlled, multicentre study (D0810C00019 [Study 19]) in 
patients with PSR ovarian cancer. A second study, a Phase III randomized, double-blind, 
placebo-controlled, multicentre study, D0816C00002 (SOLO2), investigated olaparib 300 mg 
bd (2 x 150 mg bd) tablet formulation as a maintenance treatment in gBRCAm PSR ovarian 
cancer patients. In both SOLO2 and Study 19, patients with platinum-sensitive relapsed disease 
who were in response (complete or partial) to their final platinum regimen and who had received 
at least two previous lines of platinum-based therapy were randomized to receive either olaparib 
or placebo. The primary endpoint in both SOLO2 and Study 19 was PFS.
The SOLO2 data confirm that maintenance treatment with olaparib 300 mg bd (tablet 
formulation) offers a substantial efficacy improvement by prolonging PFS by 13.6 months 
compared to placebo and delaying the requirement for further anticancer treatment in patients 
with gBRCAm PSR ovarian cancer who are in response to platinum-based chemotherapy. Safety 
data from SOLO2 confirm that olaparib tablets are suitable for long-term use in a maintenance 
setting. The clinical benefit observed in SOLO2, along with the acceptable safety and 
tolerability profile and the convenience of an oral administration are critical factors in the 
consideration of an optimal maintenance regimen. Data from Study 19 provide evidence for the 
clinical activity of olaparib in the broader PSR ovarian cancer patients irrespective of their 
gBRCA status in the maintenance treatment setting, together with an acceptable safety and 
tolerability profile.
The totality of the data from SOLO2 and Study 19 demonstrates that olaparib maintenance 
therapy has a positive benefit-risk profile in the treatment of PSR ovarian cancer.
Clinical experience with olaparib is fully described in the current version of the olaparib IB.
Rationale for non-gBRCAm patient selection
While multiple randomized controlled trials (RCTs) have demonstrated that platinum-sensitive 
BRCAm patients have profound response to maintenance treatment with PARP inhibitors, 
PARP inhibitors target cells with homologous recombination deficiency (HRD), of which 
BRCA mutation is only one type.  Consistent with the mechanism of action of PARP inhibition, 
response has also been seen in multiple RCTs in patients who are platinum-sensitive but whose 
tumours do not harbor BRCA mutations (Study 19 and NOVA).  Presumably these responders 
have defects in other components of HRR pathways, though currently available diagnostic 
technology is not adequate to reliably identify the full spectrum of HRR deficiencies.  Instead, 
these data support the hypothesis that platinum sensitivity itself is a clinical selection factor for 
HRD.


Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
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Experience with Olaparib in Gynaecological Cancer
The results from two clinical studies (Study 19 and NOVA) have demonstrated the potential 
benefit of two different PARPi (olaparib and niraparib) as maintenance therapy in platinum-
sensitive ovarian cancer patients who do not have BRCA mutations.
Study D0810C00019 (NCT no. NCT00753545; EudraCT no. 2008-003439-18)
This was a Phase II study (D0810C00019/Study 19) in PSR ovarian cancer patients.
The study compared the efficacy of olaparib maintenance treatment of a capsule formulation 
[400 mg (8 x 50 mg capsules) twice daily] taken to progression with no maintenance treatment 
in 265 (136 olaparib and 129 placebo) PSR patients who were in response (complete or partial) 
following completion of platinum containing chemotherapy. The primary endpoint was PFS 
based on investigator assessment using RECIST 1.0. Secondary efficacy endpoints included 
overall survival (OS), disease control rate (DCR), Health Related Quality of Life (HRQoL), and 
disease related symptoms. Exploratory analyses of Time to first subsequent therapy or death
(TFST) and Time to second subsequent therapy or death (TSST) were also performed.
The study met its primary objective of demonstrating a statistically significant and clinically 
relevant improvement in PFS for olaparib compared with placebo: Hazard Ratio (HR) 0.35; 
95% confidence interval (CI) 0.25-0.49; p<0.00001; median 8.4 months olaparib vs 4.8 months 
placebo. Final OS (data cut off [DCO] 09 May 2016; 79% maturity) with a median duration of 
follow-up for OS of 6.5 years, showed favourable prolongation of OS for olaparib treated 
patients compared to placebo-treated patients.  The reduced risk of death in the olaparib treated 
patients is reflected by a clinically meaningful although not statistically significant HR of 0.73 
(95% CI 0.55 to 0.95, nominal p=0.02138) with a 2.0 month longer median OS for olaparib 
treated patients compared to placebo treated patients (29.8 months vs 27.8 months, 
respectively).  Similar OS HRs favouring olaparib were observed irrespective of patients’ 
gBRCA mutation status.
Preplanned subgroup analysis identified patients with BRCAm ovarian cancer (n=136, 51.3%) 
as the subgroup that derived the greatest clinical benefit from olaparib maintenance 
monotherapy. In BRCAm patients the median PFS improvement was 6.9 months over placebo 
(HR 0.18; 95% CI 0. 10-0.31; p<0.00001; median 11.2 months olaparib vs 4.3 months placebo). 
However, clinical benefit was also observed in the BRCA wild type (wt) patient population (7·4 
months [95% CI 5·5-10·3] median PFS in the olaparib group vs 5·5 months [95% CI 3·7-5·6]
in the placebo group; HR 0·54 [95% CI 0·34-0·85]; p=0·0075).
Long term benefit has been observed in PSR ovarian cancer patients, with olaparib maintenance 
therapy providing unprecedented periods of remission in some patients:
•
In the overall population, substantially more patients received olaparib vs placebo for 
≥2 years (24% vs 4%, respectively) and ≥6 years (11% vs 1%, respectively).  With the 
caveat of small numbers of patients, at least a third of the patients deriving long term 
(≥6 years) benefit from olaparib did not carry a gBRCA mutation.
•
In the overall population at the 09 May 2016 DCO analysis, 14 patients (including 5 
patients without a gBRCA mutation) were still receiving olaparib therapy compared to 


Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU 0059436
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Version 3.0
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only one placebo treated patient. The duration of olaparib therapy in these patients 
ranged between 6.3 and 7.1 years.
No statistically significant or clinically relevant differences in HRQoL were 
olaparib and placebo, as measured by the FACT/NCCN Ovarian Symptom 
total Functional Assessment of Cancer Therapy–Ovarian FACT-O scores
C
C


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Version 3.0
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Study PR-30-5011-C/ NOVA (NCT no. NCT01847274; EudraCT no. 2013-000685-11)
Study PR-30-5011-C was a randomized, double-blind, phase 3 trial to evaluate the efficacy of 
niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, 
recurrent ovarian cancer (niraparib 300 mg or placebo once daily). Of 553 enrolled patients, 
203 were in the gBRCA cohort (niraparib [n=138] , placebo[n=65]) and 350 patients were in the 
non-gBRCA cohort (niraparib [n=234] , placebo [n=116]). All the patients had shown sensitivity 
to platinum-based treatment and had received at least two such regimens. For the penultimate 
platinum-based chemotherapy before study enrolment, a patient must have had platinum-
sensitive disease after this treatment which was defined as having a complete or partial response 
and disease progression more than 6 months after completion of the last round of platinum 
therapy. Patients in the niraparib group had a significantly longer median duration of PFS
(primary endpoint) than did those in the placebo group, including 21.0 vs. 5.5 months in the 
gBRCA cohort as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for 
patients who had tumours with homologous recombination deficiency and 9.3 months vs. 3.9 
months in the overall non-gBRCA cohort. Among patients with platinum-sensitive, recurrent 
ovarian cancer, the median duration of PFS was significantly longer among those receiving 
niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA
mutations or HRD status, with moderate bone marrow toxicity. Grade 3 or 4 treatment-emergent 
events in the niraparib group (74.1%) were managed with dose modifications. (Mirza et al 
2016).
1.3
Benefit/Risk and Ethical Assessment
Olaparib has been well tolerated across various cancer entities.  The proposed study will be 
limited to patients with advanced ovarian cancer who are relapsed, non-gBRCA mutated, for 
whom clinical activity can be expected based on the results of the studies discussed in section 
1.2.  Therefore, a positive benefit/risk profile is expected and no ethical issues are identified 
from exposing patient to olaparib within the planned clinical study. 
Please see the current edition of the IB for the most recent summary of the risks of olaparib.
1.4
Study Design 
A Phase IIIb, single-arm, open-label multicentre study. to assess the efficacy and safety of 
single-agent olaparib as a maintenance treatment in patients with relapsed HGSOC (including 
patients with primary peritoneal and/or fallopian tube cancer) or high grade endometrioid 
ovarian cancer who do not have known deleterious or suspected deleterious germline BRCA
mutations (non-gBRCAm) and who had responded following platinum based chemotherapy. 
Olaparib will be administered to all patients in this single-arm study (see Figure 1).
Tumour assessments will be conducted every 8 weeks for the first 12 months, and thereafter 
every 12 weeks up to disease progression. 
1.5
Study Governance and Oversight
Not applicable 
CCI


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Version 3.0
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Figure 1
Protocol Schedule
(a) Patients will continue to receive treatment until objective radiological disease progression (according to RECIST 1.1), or for as long as they 
are receiving clinical benefit in the opinion of the investigator, unless any of the criteria for discontinuation are met first
If patients discontinue olaparib treatment in the absence of progression, they should continue to be followed for progression every 8 weeks 
for 12 months after first dose ,and every 12 weeks therafter.
HGSOC, High Grade Serous Ovarian Cancer; PR, Partial Response; CR Complete Response


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2.
STUDY OBJECTIVES
2.1
Primary Objective
Primary Objective:
Outcome Measure:
To determine the efficacy by progression-
free survival (PFS) (investigator-recorded 
assessments according to modified 
Response Evaluation Criteria In Solid 
Tumors [RECIST v1.1]) of olaparib 
maintenance monotherapy in non-
gBRCAm platinum sensitive relapsed 
(PSR) ovarian cancer

PFS: Time from date of first dose until the 
date of objective radiological disease 
progression according to modified RECIST 
1.1 or death (by any cause in the absence of 
progression)
2.2
Secondary Objectives
Secondary Objectives:
Outcome Measures:
To determine the efficacy of olaparib 
maintenance monotherapy in non gBRCAm 
PSR ovarian cancer by assessment of time 
to first subsequent therapy or death (TFST) 

TFST: Time from date of first dose to date of 
first subsequent treatment commencement or 
death due to any cause if this occurs before 
commencement of first subsequent treatment
To determine the efficacy of olaparib 
maintenance monotherapy in non gBRCAm 
PSR ovarian cancer by assessment of time 
to treatment discontinuation or death 
(TDT)

TDT: Time from date of first dose to date of 
study drug discontinuation or death due to 
any cause if this occurs before study drug 
discontinuation
To determine the efficacy by PFS 
(investigator-recorded assessments 
according to modified RECIST v1.1) of 
olaparib maintenance in non-gBRCAm 
PSR ovarian cancer according to tumour
homologous recombination deficiency
(HRD) status using the Myriad myChoice 
HRD plus test

PFS in the following subgroups: -
1. Somatic BRCA mutated and HRD scar 
positive; 
2. HRD scar positive, non-BRCA mutated; 
3. HRD scar negative, non-BRCA mutated
To determine the efficacy of olaparib 
maintenance monotherapy in non-
gBRCAm PSR ovarian cancer by 
assessment of chemotherapy-free interval 
(CT-FI)

CT-FI: Time from the date of the last dose of 
platinum chemotherapy prior to olaparib 
maintenance therapy  until the date of 
initiation of the next anticancer therapy


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To determine the overall survival (OS) of 
non-gBRCAm PSR ovarian cancer patients 
treated with olaparib maintenance 
monotherapy 

OS: Time from the date of first dose of 
olaparib to the date of death from any cause.
To investigate the Health-related Quality 
of Life (HRQoL) of non-gBRCAm PSR 
ovarian cancer patients treated with 
olaparib maintenance monotherapy as 
assessed by the trial outcome index (TOI) 
of the Functional Assessment of Cancer 
Therapy – Ovarian (FACT-O) 

Proportion of patients with any improvement 
from baseline in TOI score at any point 
during the treatment period

Proportion of patients with a 10 point 
deterioration from baseline in TOI score at 
any point during the treatment period
2.3
Safety Objectives
Safety Objective:
Outcome Measures:
To assess the safety and tolerability of 
olaparib maintenance monotherapy in 
patients with non-gBRCAm PSR ovarian 
cancer

Adverse events/serious adverse events
     Collection of clinical chemistry/haematology 
parameters
2.4
Exploratory Objectives 
Exploratory Objective
Outcome Measure
To explore the efficacy by PFS 
(investigator-recorded assessments 
according to modified RECIST v1.1) of 
olaparib maintenance monotherapy in non-
gBRCAm PSR ovarian cancer patients 
stratified into a range of molecular sub-
groups including mutations in Homologous 
recombination repair (HRR) genes, 
microsatellite instability (MSI) status, and 
tumour mutation load score.  

PFS by molecular measures of HRR and 
genomic instability: 
To explore the impact of TP53 disruption 
status on both OS and PFS

OS and PFS by TP53 disruption status
To explore the impact of treatment and 
disease state on health state utility by 
EuroQoL five dimensions, five level (EQ-
5D-5L)

EQ-5D index score and the EQ-VAS score 
including the change from baseline for both 
scores


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Exploratory Objective
Outcome Measure
To explore the feasibility of reliably 
identifying mutations in homologous 
recombination genes from circulating 
tumour DNA (ctDNA) and to enable future 
diagnostic development.

Correlation between HRD status from tumour 
and ctDNA in matched patient samples
3.
PATIENT SELECTION, ENROLMENT, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.  
3.1
Inclusion Criteria
Patients without deleterious or suspected deleterious gBRCA mutations will be included. The 
gBRCA status of enrolled patients will be confirmed retrospectively using a central laboratory 
gBRCA test (Myriad BRCAnalysis CDx).
Testing of gBRCA status should normally have been performed as part of national or 
institutional practice guidelines for the management of ovarian cancer, such as in the assessment 
of treatment options after chemotherapy. Under exceptional circumstances, gBRCA testing of 
potentially eligible patients whose gBRCA status is not yet known can be considered (by 
agreement with the Sponsor). In these cases the gBRCA test must be completed prior to other 
screening procedures. To ensure this, patients may be consented from the end of cycle 3 of their 
current chemotherapy if, in the opinion of the investigator, they are responding to treatment, 
and if it appears that the patient is likely to meet other eligibility requirements. The 28-day 
screening period will be considered to have started only after the availability of the gBRCA
status report at the site, at the start of the screening procedures listed in Table 1, column 2. 
Please refer to Appendix F for further details about the procedure and to the Laboratory Manual 
for further details of the test. Study sites should also offer access to a genetic counsellor (given 
that this is a genetic test which may have familial implications in the case of a positive result).
For inclusion in the study patients should fulfil all of the following criteria:
1.
Provision of informed consent prior to any study specific procedures 
2.
Patients must be ≥18 years of age 
3.
Female patients with histologically diagnosed relapsed HGSOC (including primary 
peritoneal and / or fallopian tube cancer) or high grade endometrioid ovarian cancer
4.
Documented gBRCA1/2 mutation status
Evidence that the patients do not have a gBRCA mutation that is predicted to be 
deleterious or suspected deleterious (known or predicted to be detrimental / lead to loss 


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of function). gBRCA1 and/or gBRCA2 variants that are classified as “Variants of 
uncertain clinical significance” or “Variant of unknown significance (VUS)” are 
eligible, as well as “Variant, favor polymorphism” or “benign polymorphism”. 
Evidence of the absence of a somatic BRCA mutation is not required. Patients with a 
tumour BRCA test result only must undergo a gBRCA test to determine whether the 
BRCA aberration is germline or somatic in origin.  If this analysis identifies the 
aberration as germline the patient is not eligible  
5.
Patients must have completed at least 2 previous courses of platinum containing 
therapy:
(a) For the penultimate chemotherapy course prior to enrolment on the study:

Treatment must have contained a platinum agent (e.g. carboplatin, cisplatin or oxaliplatin 
per standard clinical practice; there are no other specific requirements)

Patient was platinum sensitive after this treatment; defined as disease progression greater 
than 6 months after completion of their last dose of platinum chemotherapy

Maintenance treatment is allowed at the end of the penultimate platinum regimen, 
including bevacizumab
(b) 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), or may have no evidence of disease (if optimal cytoreductive 
surgery was conducted prior to chemotherapy), and no evidence of a rising CA-125, as 
defined below, following completion of this chemotherapy course

Patient must have received a platinum based chemotherapy regimen (e.g. carboplatin, 
cisplatin or oxaliplatin) and have received at least 4 cycles of treatment

Patients must not have received bevacizumab during this course of treatment

Patients must not have received any investigational agent during this course of treatment

Patients must initiate treatment within 8 weeks of their last dose of chemotherapy (last 
dose is the day of the last infusion)
6.
Pre-treatment CA-125 measurements must meet criterion specified below:

If the first value is within upper limit of normal (ULN) the patient is eligible to be 
enrolled and a second sample is not required


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
If the first value is greater than ULN a second assessment must be performed at least 7 
days after the 1st. If the second assessment is ≥ 15% more than the first, the patient is 
not eligible
7.
Patients must have normal organ and bone marrow function measured within 28 days of 
starting study treatment, as defined below. In the event of minor deviations from these 
values which would lead to screen failure, repeat testing within the 28-day screening 
period (limited to the tests listed below) is allowed before the patient is declared a screen 
failure.

Haemoglobin ≥10.0 g/dL with no blood transfusion in the past 28 days

Absolute neutrophil count (ANC) ≥1.5 X 109/L

Platelet count ≥100 X 109/L 

Total bilirubin (TBL) ≤1.5 X ULN

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 ≤5 X ULN

Patients must have creatinine clearance, estimated using the Cockcroft-Gault 
equation (below), or based on a 24 hour urine test, of ≥51 mL/min:
Estimated creatinine clearance (females) =
(140-age [years]) x weight (kg) x 0.85
                serum creatinine (mg/dL) x 72
8.
ECOG performance status 0-1 (see Appendix E)
9.
Patients must have a life expectancy ≥16 weeks
10.
Postmenopausal or evidence of non-childbearing status for women of childbearing 
potential: negative urine or serum pregnancy test within 28 days of study treatment and 
confirmed prior to treatment on day 1
Postmenopausal is defined as any of the following:

Amenorrhoeic for 1 year or more following cessation of exogenous hormonal 
treatments


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
For women under 50 years old, luteinizing hormone (LH) and follicle stimulating 
hormone (FSH) levels in the post-menopausal range 

Radiation-induced oophorectomy with interval of 1 year or more since last 
menses

Chemotherapy-induced menopause with >1 year interval since last menses

Surgical sterilisation (bilateral oophorectomy or hysterectomy).
11.
Patient is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations
12.
At least one lesion (measurable and/or non-measurable) that can be accurately assessed 
at baseline with computed tomography (CT) or magnetic resonance imaging (MRI) and 
is suitable for repeated assessment 
OR
No evidence of disease following a complete response to chemotherapy (with or without 
cytoreductive surgery)
13.
An appropriately prepared tumour sample from the cancer, of sufficient quantity and 
quality (as specified in the Central Laboratory Services Manual) must be available for 
future central testing of tumour genetic status. If a recent biopsied sample is provided, 
the biopsied tumour should not be assessed as target lesions as part of the RECIST 
assessments if there are other lesions available, and the biopsy should be taken after the 
baseline scan has been performed. Archival tissue samples may be from the primary 
tumour or metastatic tumour deposits. Archival bone metastases are not acceptable. 
Provision of blocks is usually preferred. Any exceptions to these conditions should be 
discussed with the Sponsor before enrollment of the patient. 
3.2
Exclusion Criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled.  
Those asterisked* should be excluded before a request can be considered to perform a gBRCA
test prior to full screening. Investigator judgement of patient’s potential eligibility to the study 
should be assessed as per Table 1 and by reviewing the below exclusion criteria.
1.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site)*
2.
Previous enrolment in the present study*
3.
Participation in another clinical study with an investigational product (IP) during 
the most recent chemotherapy course*
4.
Patients receiving any systemic hormonal therapy, chemotherapy or radiotherapy 
(except for palliative reasons) within 3 weeks prior to start of study treatment 


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5.
Any previous treatment with PARP inhibitor, including olaparib*
6.
Patients with a germline BRCA mutation that is predicted to be deleterious or 
suspected deleterious (known or predicted to be detrimental / lead to loss of 
function).
7.
Other malignancy unless curatively treated with no evidence of disease for ≥5 years  
except: adequately treated non-melanoma skin cancer, curatively treated in situ 
cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial 
carcinoma.  
8.
Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, 
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or 
cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate 
CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, 
verapamil).  The required washout period prior to starting olaparib is 2 weeks*. 
9.
Concomitant use of known strong (e.g., phenobarbital, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate 
CYP3A inducers (e.g., bosentan, efavirenz, modafinil).  The required washout 
period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other 
agents*
10.
Persistent toxicities (≥Grade 2 Common Terminology Criteria for Adverse Event 
(CTCAE) adverse event) caused by previous cancer therapy, excluding alopecia
11.
Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or 
with features suggestive of MDS/AML*
12.
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*  
13.
Major surgery within 3 weeks of starting study treatment and patients must have 
recovered from any effects of any major surgery
14.
Patients considered a poor medical risk due to a serious, uncontrolled medical 
disorder, non-malignant systemic disease or active, uncontrolled infection.  
15.
Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study 
medication*


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16.
Currently pregnant (confirmed with a positive pregnancy test) or breastfeeding 
women*
17.
Immuno-compromised patients e.g., Human Immunodeficiency Virus (HIV) 
requiring treatment or active Hepatitis B or C*
18.
Patients with a known hypersensitivity to olaparib or any of the excipients of the 
product*
19.
Patients with known active hepatitis (i.e., hepatitis B or C) due to risk of 
transmitting the infection through blood or other body fluids*
20.
Previous allogenic bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT)*
21.
Patients having gBRCA testing should not have had whole blood transfusions in the 
last 30 days prior to entry to the study (packed red blood cells and platelet 
transfusions are acceptable)
22.
Judgement by the Investigator that the patient should not participate in the study if 
the patient is unlikely or unable to comply with study procedures, restrictions and 
requirements.
For procedures for withdrawal of incorrectly enrolled Patients see Section 3.4.
3.3
Patient Screening and Registration
Investigators should keep a record, the Patient Screening Log, of patients who entered 
screening.The Investigators will:
1.
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed that are not part of routine medical care
2.
Obtain a unique patient reference number through the Interactive Voice Response 
System (IVRS)/Interactive Web Response System (IWRS). This number is the
patient’s unique identifier and will be maintained throughout the study
3.
Determine Patient eligibility (see Section 3.1 and 3.2)
If a patient does not meet eligibility criteria or withdraws from participation in the study, then 
their number cannot be reused. Re-screening for patients who fail screening and were NOT 
exposed to olaparib may be allowed, but a new number must be used. Patients who fail screening 
for minor abnormalities of haematology or biochemistry may be retested within the screening 
period and, if the value has returned to the range allowed by the protocol, they may be included.


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3.4
Procedures for Handling Incorrectly Enrolled Patients
Patients are considered enrolled once (i) it is confirmed that they meet all eligibility criteria 
(including gBRCA status) and (ii) the request has been made by the Investigator for the provision 
of study treatment for that patient.
Patients who fail to meet the eligibility criteria should not, under any circumstances, be enrolled 
or receive study medication.  There can be no exceptions to this rule.  Patients who are enrolled, 
but subsequently found not to meet all the eligibility criteria must not be initiated on treatment, 
and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is enrolled in error, or incorrectly 
started on treatment, the Investigator should inform the AstraZeneca Study Physician
immediately, and a discussion should occur between the AstraZeneca Study Physician and the 
Investigator regarding whether to continue or discontinue the 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
Grapefruit juice
Consumption of grapefruit or grapefruit juice while on olaparib therapy is prohibited.
Contraception
Women of childbearing potential and their partners, who are sexually active, must agree to the 
use of TWO highly effective forms of contraception in combination (as described in Appendix 
D).  This should be started from the signing of the informed consent and continue throughout 
the period of taking study treatment and for at least 1 month after last dose of study drug(s), or 
they must totally/truly abstain from any form of sexual intercourse (as described in Appendix 
D). For details of acceptable methods of contraception refer to Appendix D.
3.9
Discontinuation of Investigational Product
Patients may be discontinued from IP in the following situations:

Patient decision; the patient is at any time free to discontinue treatment, without 
prejudice to further treatment

Disease progression as assessed by the investigator 

Unacceptable toxicity (patients can temporarily discontinue IP due to toxicity; IP 
can be re-started provided the disease has not progressed since discontinuation)


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
Adverse Event

Severe non-compliance with the Clinical Study Protocol 

Bone marrow findings consistent with MDS/AML

Positive pregnancy test
Patients may continue to receive olaparib beyond Investigator-assessed progression as long as, 
in the Investigator's opinion, they are benefiting from treatment and they do not meet any other 
discontinuation criteria.
Procedures for discontinuation of a patient from investigational product 
At any time, patients are free to discontinue IP or withdraw from the study (i.e., IP and 
assessments; see Section 3.10), without prejudice to further treatment.  If possible, they will be 
seen and assessed by an Investigator(s).  A patient who discontinues will always be asked about 
the reason(s) for discontinuation and the presence of any adverse events. The Principal 
Investigator/Investigator will perform the best possible observation(s), test(s) and evaluation(s) 
as well as give appropriate medication and all possible measures for the safety of the patient. 
They will also immediately inform AstraZeneca of the withdrawal. Adverse events (AEs) will 
be followed up (See Section 6); all unused study drug should be returned by the patient.
By discontinuing from study treatment, the patient is not withdrawing from the study.  Patients 
should continue to be followed for progression (if discontinuation in the absence of 
progression), TFST and OS following treatment discontinuation as per the protocol schedule.  
Any patient discontinuing IP should be seen at 30 days post discontinuation for the evaluations 
outlined in the study schedule.  The patient’s tumour status should be assessed clinically and, if 
appropriate, disease progression should be confirmed by radiological assessment.  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. Patients will be required to 
attend the treatment discontinuation visit.
After discontinuation of the study medication at any point in the study, all ongoing AEs or SAEs 
must be followed until resolution unless, in the Investigator’s opinion the condition is unlikely 
to resolve due to the patient underlying disease, or the patient is lost to follow up (see Section 
6.3.2).  All new AEs and SAEs occurring during the 30 calendar days after the last dose of study 
medication must be reported (if SAEs, they must be reported to the AstraZeneca representative
within 24 hours as described in Section 6.4) and followed to resolution as above.  Patients should 
be seen at least 30 days after discontinuing study medication to collect and / or complete AE 
information.  For guidance on reporting AEs after the 30-day follow-up period, see Section 
6.3.1.1.
All patients must be followed for survival, until 135 OS events (~54% maturity) have been 
recorded, estimated to be approximately 36 months after the first subject is enrolled.
If a patient is withdrawn from study, see Section 3.10.


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3.10
Criteria for Withdrawal 
Reasons for withdrawal from the study:

Voluntary withdrawal by the patient who is at any time free to discontinue their 
participation in the study, without prejudice to further treatment.

Incorrectly enrolled patients who do not meet the required inclusion/exclusion 
criteria for the study and do not receive any dose of IP.

Patients lost to follow up. A patient unreachable at the end of the study should be 
considered to be lost to follow up with unknown vital status at end of study and 
censored at latest follow up contact.

Death.
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 ‘Screen failure’ (the potential patient who does not meet one or more criteria 
required for participation in the trial; this reason for study withdrawal is only valid for patients
who were not enrolled).
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (IP 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 AEs.  The Investigator will follow up AEs outside of the clinical study. 
If a patient withdraws from participation in the study, then his/her enrolment code cannot be 
reused.  Withdrawn patients will not be replaced. 
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent 
to:

further participation in the study including any further follow up (e.g., survival 
calls) 

the use of their study generated data

the use of any samples
The status of ongoing, withdrawn (from the study) and “lost to follow up” patients at the time 
of an OS analysis should be obtained by the site personnel by checking the patient notes, 
hospital records, contacting the patient’s general practitioner and checking publicly available 
death registries.  In the event that the patient has actively withdrawn consent to the processing 
of their personal data, the vital status of the patient can be obtained by site personnel from 
publicly available resources where it is possible to do so under applicable local laws.


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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:

meet individual stopping criteria or are otherwise considered significant 

are assessed as causally related to study drug

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 CRF.  All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.
4.
STUDY PLAN AND TIMING OF PROCEDURES 
The schedule of assessments for the screening visit is shown in Table 1.  On-study 
assessments are shown in Table 2.
Table 1
Study Schedule – Screening (Visit 1)
Day
Before 
screening 
period
-28 to -1
Informed consent
X
IVRS/IWRS unique patient number obtained
X
Demographics
X
Medical and surgical history
X
Prior cancer therapies including radiotherapy, best response to prior 
chemotherapy regimen
X
History of blood transfusions a
X
Inclusion/exclusion criteria
X
ECOG performance status
X
Physical examination
X
Vital signs (includes blood pressure, pulse and temperature), body weight
X
Haematology / clinical chemistry b,f
X
Urinalysis
X
Pregnancy test for women of childbearing potential c
X
Confirmed as having non-Germline BRCA Mutated ovarian cancer d
X


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Day
Before 
screening 
period
-28 to -1
Tumour assessment e
X
AEs (from time of consent)
X
Concomitant medications
X
Archival or fresh tumour biopsy sample for post treatment analysis 
confirmation of HRD status g
X
X
a
Include history of blood transfusion within previous 120 days from start of study treatment and the reasons, 
e.g., bleeding or myelosuppression.
b
Coagulation test should be performed if clinically indicated.  For a list of all required laboratory tests please 
refer to Section 5.2.1.
c
Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior 
to starting treatment and a confirmatory test before treatment on Day 1.  If results are positive, the patient is 
ineligible/must be discontinued from the study.
d
Patients must be non-germline BRCA mutated to be enrolled into the study. Patients for whom their gBRCA
status is already known should be consented to the study within 28 days prior to Day 1 of study treatment. 
Patients who do not know their mutation status will need BRCA1/2 mutation screening (see Section 4.1.1 
and Appendix F).  
e
Includes CA-125 measurement where required (Refer to Inclusion Criterion 6). RECIST assessment should 
be performed no more than 28 days before the start of study treatment, and ideally should be performed as 
close as possible to the start of study treatment.
Note: MRI/ CT scan more than 28 days prior to Day 1 may be acceptable, please consult with AstraZeneca. 
f
These measurements may be repeated within the screening period if abnormalities are found which are the 
only reason for screen failing the patient and which can reasonably be expected to have return to the 
acceptable range
g
All patients are required to submit either an archival tumour sample, or a fresh biopsy if an archival sample 
is not available, for retrospective testing of their genetic status. If archival tissue, the presence of adequate 
tissue needs to be confirmed prior to screening, but it will not be shipped to the central lab before Day1. If 
fresh, the biopsy should be taken after the baseline scan has been performed. Samples should be submitted 
as paraffin blocks, alternatively, sections mounted on glass slides prepared from the block can be provided. 
Please refer to the laboratory manual for further details regarding tissue collection, shipping and storage.


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Table 2
Study Plan Detailing the Procedures
Visit Number or type
2
3
Visit No. 4 and subsequent 
tumour assessment visits 
Visit No. 5 and 
subsequent safety visitsa  
(For the first 12 
months only)
Study treatment 
discontinued
Follow up 30 days 
after last dose of 
study medication
Long-term 
follow up
Day
1
29
On the first day of next visit 
period
(V4 = Day 57 and thereafter 
every 8 weeks for the first 
12 months; every 12 weeks 
thereaftera)
On the first day of next 
visit period
(V5=Day 85) and 
thereafter every 8
weeks)
Visit Window
0
±3d
±7d
±3d
±7d
+7d
Physical examination c
X b
Vital signs, body weight 
(includes blood pressure, pulse 
and temperature) c
X b
ECOG performance status
X
X
X
Haematology / clinical 
chemistry d
X b
X
X
X
X
X
Urinalysis c
X b
Pregnancy test e
X
X
X 
X 
X
Tumour assessment f
X
Blood sample for ctDNA
X
X
Blood sample for restrospective 
gBRCA testg
X
AEs h
X
X
X
X
X
X
FACT-O and EQ-5D-5L 
questionnaires 
X
X
X
X
                X


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Visit Number or type
2
3
Visit No. 4 and subsequent 
tumour assessment visits 
Visit No. 5 and 
subsequent safety visitsa  
(For the first 12 
months only)
Study treatment 
discontinued
Follow up 30 days 
after last dose of 
study medication
Long-term 
follow up
Day
1
29
On the first day of next visit 
period
(V4 = Day 57 and thereafter 
every 8 weeks for the first 
12 months; every 12 weeks 
thereaftera)
On the first day of next 
visit period
(V5=Day 85) and 
thereafter every 8
weeks)
Visit Window
0
±3d
±7d
±3d
±7d
+7d
Concomitant medications 
including blood transfusions 
X
X
X
X
X
X
Olaparib dispensed/returned 
X
X j
X j
X
Subsequent cancer therapy 
following discontinuation of 
study treatment k
X
X
Time to subsequent therapy and 
Survivall
X
a
From Visit 3 onwards, visits will take place on the first day of each 4-week visit period, relative to the date of the first olaparib dose (if the patient has 
not progressed and is still on treatment).  Where the visit does not coincide with tumour assessment visits, these safety visits will only be for laboratory 
and pregnancy testing and recording of ECOG status, AEs and concomitant medication including transfusions. Where these visits coincide with tumour 
assessments, the assessment visit schedule will be performed
b
If assessed within 7 days before first dose and meets the stated eligibility criteria (if applicable), it does not need to be repeated on Day 1 of study 
treatment unless Investigator believes that it is likely to have changed significantly. 
c
To be additionally performed if clinically indicated at any other time. 
d
All samples should be taken prior to first dose. Coagulation test should be performed if clinically indicated.  For a list of all required laboratory tests 
please refer to Section 5.2.1.
e
Pregnancy tests on blood or urine samples will be performed for women of childbearing potential within 28 days prior to the start of study treatment, on 
Day 1 of the study prior to commencing treatment, at the time points shown in Table 2 during study treatment and at the 30-day follow-up visit.  If 
results are positive the patient is ineligible/must be discontinued from study treatment immediately.
f      Visit 4 onwards: Subsequent tumour assessments will be conducted every 8 weeks (±7 days) for the first 12 months and then every 12 weeks (± 7 days) 
until documented disease progression.


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g
Unless patient was tested at Myriad as part of screening. All patients are required to provide a 9 ml blood sample for confirmation of gBRCA status.   
Please refer to the laboratory manual for further details regarding blood sample collection,shipping and storage.
h
All ongoing 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.
j
+/- 2 days visit window allowed for the dispensing.  Sufficient study treatment should be dispensed for at least each treatment period plus overage; 
however, additional treatment can be dispensed to patients to last longer if required.
k
Start date of the first anticancer treatments (including, but not limited to, chemotherapy and targeted agents), following discontinuation from study 
treatment must be recorded.
l
Patient will be followed (can be by phone or email) regularly until start of subsequent therapy; survival will be followed at approximately 12 weekly 
intervals thereafter.


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4.1
Screening/Enrolment Period
At screening, consenting patients are assessed to ensure that they meet eligibility criteria.  
Patients who do not meet these criteria must not be enrolled in the study. 
Procedures will be performed according to Table 1 within 28 days prior to Day 1. 
Testing for gBRCA mutations for patients with unknown gBRCA status 
Under exceptional circumstances, gBRCA testing of potentially eligible patients whose 
gBRCA status is not yet known can be considered, but permission must be sought from the 
sponsor. Patients who do not know their mutation status, and who are being considered for 
this trial should be identified before screening so that the appropriate gBRCA mutation testing 
procedures can be put in place in a timely manner (Section 3.1).  gBRCA testing will be 
conducted at a central laboratory (Myriad). Please refer to Appendix F for full instructions.
Turnaround times at this laboratory should be no longer than 4 weeks. 
4.2
Treatment Period
Descriptions of the procedures for this period are included in Table 2.
Visit 2 (Baseline Visit, Day 1)
Study procedures will be conducted on the scheduled day.  
Visit 3 (Day 29)
Study procedures will be conducted on the scheduled day +/- 3 days (unless otherwise 
specified).
All subsequent visits in the Treatment Period should be planned on the first day of each 
4 week period relative to the date of the first olaparib dose. Visit 4 will therefore be on 
Day 57
Visit 4 (Day 57) and subsequent on-treatment tumour assessment visits 
Visit 4, (Day 57) is the first tumour assessment visit. Subsequent tumour assessment visits 
will take place on the first day of each 8 week visit period, relative to the date of the first 
olaparib dose, for the first 12 months, and subsequently each 12-week visit period, relative to 
the date of the first olaparib dose, until progression. 
Study procedures will be conducted on the scheduled day +/- 3day, but radiological 
assessments can be conducted on the scheduled day ±7 days.
Visits 5 and Subsequent safety test visits  
Visit 5 (Day 85) and subsequent 8 weekly visits which fall between on-treatment assessment 
visits will be for haematology, biochemistry and pregnancy testing, AEs and concomitant 
medication including transfusions.  These safety-specific test visits will cease after the first 12 
months and safety tests will then be conducted at the tumour assessment visits only.
Study procedures will be conducted on the scheduled day +/- 3days.


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Study treatment discontinued
Unused study treatment should be returned and study procedures for this visit should be 
conducted within 7 days of treatment discontinuation as shown in Table 2.
4.3
Follow-up Period
The start date of the subsequent anticancer treatment after discontinuation of study treatment 
needs to be recorded (including, but not limited to, chemotherapy and targeted agents).
Follow up 30 days after last dose of study medication
30 days after last dose of study medication (+/- 7 days), study procedures should be conducted 
as shown in Table 2. All ongoing AEs/SAEs and any new AEs/SAEs identified during the 30-
day follow-up period after last dose of study medication must be followed to resolution.
Long-term follow up beyond 30 days after last dose of study medication
Long-term follow up will be conducted until First Subsequent Treatment (or prior death), and
for Overall Survival (by approximately 12 weekly contact with the patient after the 30 day visit 
described in 4.3.1). These assessments can be undertaken by phone or e-mail or mail, and do 
not require the patient to visit the Site.
Patients who discontinue study treatment in the absence of disease progression should continue 
to be followed for progression, after treatment discontinuation, as per the protocol schedule
regardless of whether they start a subsequent therapy.
5.
STUDY ASSESSMENTS
A Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The Investigator will ensure that data are recorded on the eCRFs as specified in the 
Clinical 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 eCRFs.  A copy of the completed electronic CRFs will be 
archived at the study site.
The Principal Investigator/Investigator will record data on the observations, tests and 
assessments specified in the protocol on the eCRFs provided for this study. The CRF will be 
accompanied with ‘Instructions for the Investigator’, which should be followed. These 
instructions provide guidance for the recording of study data in the CRF including how to 
change data incorrectly recorded
5.1
Efficacy Assessments
Tumour evaluation
Following the screening assessment, subsequent tumour assessments will be conducted as per 
schedule up to disease progression regardless of whether study treatment is discontinued or 
delayed, protocol violations, or if the patient receives another anti-cancer therapy prior to 
progression, unless the patient withdraws consent.


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5.2
Safety Assessments
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis 
will be taken at the times indicated in Table 1 and Table 2.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
The clinical chemistry, haematology and urinalysis will be performed at a local laboratory at 
or near to the Investigator site.  Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site.The following laboratory variables will 
be measured:
Table 3
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
B-Absolute neutrophil count
S/P-Alkaline phosphatase (ALP)
B-Absolute lymphocyte count
S/P-Aspartate transaminase (AST)
B-Platelet count
S/P-Alanine transaminase (ALT)
B-Mean cell volume (MCV)
S/P-Albumin
S/P- Calcium
S/P-Potassium
Urinalysis (dipstick)
S/P-Sodium
U-Hb/Erythrocytes/Blood 
S/P-Urea or Blood Urea Nitrogen (BUN)
U-Protein/Albumin 
S/P-Total Protein
U-Glucose 
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables.  For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.3.
NB. In case a patient shows an AST or ALT ≥3 x ULN or total bilirubin ≥2 x ULN please 
refer to Appendix C, for further instructions.
5.2.1.1
Coagulation 

Activated partial thromboplastin time (APTT) will be performed if clinically 
indicated  


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
Prothrombin time will be assessed and the international normalised ratio (INR) 
recorded at screening if clinically indicated.  Patients taking warfarin may 
participate in this study; however, it is recommended that the INR be monitored 
carefully at least once per week for the first month, then monthly if the INR is 
stable.
Each coagulation test result will be recorded in the eCRF.
5.2.1.2
Bone marrow or blood cytogenetic samples 
In patients with prolonged haematological toxicities, bone marrow or blood cytogenetic 
samples may be indicated as defined in Section 6.8.1.3
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity.  If it is not 
possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to carry out the tests on a blood sample.  Full reports must be 
provided by the Investigator for documentation on the Patient Safety database.  These data are 
not required to be entered into the eCRF.
Physical examination and ECOG
ECOG status is performed at screening, baseline, at the start of each tumour assessment visit, 
and at the 30 day follow up. Physical examination, vital signs are performed at screening, 
baseline and as clinically indicated thereafter (see Table 1 and Table 2).  ECOG performance 
status: refer to Appendix E.
5.2.2.1
Vital signs and weight
Weight will be assessed at screening and baseline according to the Study Schedule (see Table 
1 and Table 2) and as clinically indicated at any other time. 
Any changes in vital signs should be recorded as an AE, if applicable.  For information on 
how AEs based on changes in vital signs should be recorded and reported, see Section 6.3.
5.2.2.2
Pulse and blood pressure
Blood pressure and pulse will be assessed at screening and baseline according to the Study 
Schedule (see Table 1 and Table 2) and as clinically indicated at any other time.
Blood pressure and pulse rate will be measured preferably using a semi-automatic BP 
recording device with an appropriate cuff size after 10 minutes rest.  
The date of collection and measurement will be recorded on the appropriate eCRF.
5.2.2.3
Body temperature
Body temperature will be measured in degrees Celsius according to local practice at 
screening, baseline and as clinically indicated (see Table 1 and Table 2).
The date of collection and measurement will be recorded on the appropriate eCRF.


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Other safety assessments
5.2.3.1
Serum or urine pregnancy test
Pregnancy tests on blood or urine samples will be performed for women of childbearing 
potential within 28 days prior to the start of study treatment, on Day 1 of the study prior to 
commencing treatment, at the time points shown in Table 2 during study treatment and at the 
30-day follow-up visit.  Tests will be performed by the hospital’s local laboratory.  If results 
are positive the patient is ineligible/must be discontinued from study treatment immediately.
5.3
Other Assessments 
Patient Reported Outcomes (PRO: FACT-O)
The FACT-O (version 4) is a valid and reliable assessment of the quality of life (QoL) of women 
with ovarian cancer (Basen-Engquist et al. 2001). The FACT-O will be self-reported through 
patient questionnaires according to the study plan.  No proxy reporting will be permitted as the 
equivalence of patient-completed versus proxy FACT-O reports has not been established.  The 
questionnaire covers a 7-day recall period.  All patients will be asked to complete the FACT-O.  
The FACT-O questionnaire will be administered prior to dosing at baseline, at Day 29, Visit 4 
(week 8), and then at every tumour assessment visit until progression. In addition, QoL 
questionnaires will be collected at the discontinuation of study treatment visit, and at 30 days 
post last dose.  The timing of assessments coincide with other clinical assessments (when the 
patient will be attending clinic) in order to minimise patient burden while maximizing both 
compliance and the association of the PRO with the clinical outcomes.  The reason for any 
missing assessment will be collected in the CRF.
Subscales will be derived from the FACT-O according to the Functional Assessment of Chronic 
Illness Therapy (FACIT) Administration and Scoring Guidelines. The endpoint for HRQoL 
analysis will be the FACT-O Trial Outcome Index (TOI). Other subscales will be considered as 
exploratory endpoints
EQ-5D-5L
EuroQol five dimensions questionnaire (EQ-5D-5L) is a standardized instrument for 
measuring generic health status. The EQ-5D questionnaire is made up of two components; 
health state description and evaluation. In the description part, health status is measured in 
terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Patients will self-rate their level of severity for each dimension using a 
five-level scale (5L). In the evaluation part, the respondents evaluate their overall health status 
using the visual analogue scale (EQ-VAS).  The EQ-5D-5L questionnaire will be administered 
at the same time points as the FACT-O (5.3.1)
.
5.4
Pharmacokinetics
Not applicable
5.5
Pharmacodynamics
Not applicable 
CCI
CCI


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5.6
Genetics
A blood sample for retrospective gBRCA testing (unless determined centrally at screening) 
and archival tumour sample for genetic analysis will be taken as per Table 1 and 2. 
The effect of the following identifiable genetic subtypes will be examined through the impact 
of treatment on PFS in each group: -
1. somatic BRCA mutated and HRD scar positive; 
2. HRD scar positive, non-BRCA mutated; 
3. HRD scar negative, non-BRCA mutated
The tumour samples will be analysed for molecular sub-groups including mutations in 
Homologous recombination repair (HRR) genes, microsatellite instability (MSI) status, and 
tumour mutation load score. The following outcome measures will be explored:-

PFS by molecular measures of HRR and genomic instability including:
o
MSI (positive vs negative)
o
HRR deleterious or suspected deleterious mutation (yes vs no)
o
TP53 deleterious or suspected deleterious mutation (yes vs no)
o
Tumour mutation load score
o
Loss of heterozygosity (yes vs no) for patients with a HRR mutation

OS by TP53 mutation status (yes vs no).
5.7
Biomarker Analysis
Samples (about 20 mL whole blood to provide plasma) will be taken at Visit 2 and at 
treatment discontinuation to explore the feasibility of reliably identifying mutations in 
homologous recombination genes from circulating tumour DNA (ctDNA) by matching with 
results from tumour testing, and to enable future diagnostic development.
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.
Medical management of patient according to local practice is acceptable for AEs that are not 
SAEs and not adverse events of special interest (AESI), and that are grade 1 or 2 in severity.
6.1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
patient administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (e.g., an abnormal laboratory finding), symptom (e.g., nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product. 


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The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
Olaparib adverse events of special interest
Adverse events of special interest [AESI] are events of scientific and medical interest specific 
to the further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. AESIs for olaparib are the important 
potential risks of MDS/AML, new primary malignancy (other than MDS/AML) and 
pneumonitis.  
AZ Safety will send a questionnaire to any investigator reporting an AESI, as an aid to 
provide further detailed information on the event.  This information is separate from the 
eCRF. During the study there may be other events identified as AESIs that require the use of a 
questionnaire to help characterise the event and gain a better understanding regarding the 
relationship between the event and study treatment.
6.2
Definitions of Serious Adverse Event
A SAE 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:

Results in death

Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol.
6.3
Recording of Adverse Events
Time period for collection of adverse events
AEs/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 IP except for 
AEs described in Section 6.3.1.1).
After any interim analysis, any ongoing AEs/SAEs need to be unlocked and followed for 
resolution.


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6.3.1.1
Adverse events after the 30-day follow-up period 
For Pharmacovigilance purposes and characterisation, any SAE of MDS/AML or new primary 
malignancy occurring after the 30 day follow up period should be reported to AstraZeneca 
Patient Safety regardless of the investigator’s assessment of causality or knowledge of the 
treatment.  Investigators will ask, during the regular follow up for overall survival, if the 
patient has developed MDS/AML or a new primary malignancy and must report any such 
cases.  
At any time after a patient has completed the study, if an Investigator learns of any SAE 
including sudden death of unknown cause, 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 Patient Safety within the usual timeframe.
Otherwise, after study treatment completion (i.e. after any scheduled post treatment follow-up 
period has ended) there is no obligation to actively report information on new AEs or SAEs 
occurring in former study 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).
Follow up of unresolved adverse events
Any SAE or non-SAE that is ongoing at the time of the 30-day follow up must be 
followed up to resolution unless the event is considered by the Investigator to be 
unlikely to resolve, or the patient is lost to follow up.  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.
Variables 
The following variables will be collect for each AE:

AE (verbatim)

The date when the AE started and stopped

Maximum intensity / intensity / changes in intensity will all be recorded for the 
following AE: nausea, vomiting, fatigue and anaemia. For all other AE, only 
intensity is required

CTCAE grade and changes in CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the IP (yes or no)

Action taken with regard to IP


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
Outcome of the AE

AE caused patient’s withdrawal from study (yes or no)
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date Investigator became aware of SAE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication

Description of AE
Severity of adverse event
For each episode of an AE, all changes to the CTCAE grade attained as well as the highest 
attained CTC grade should be reported.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not 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.
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 web site (http://ctep.cancer.gov).


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Causality collection
The Investigator will assess the causal relationship between IP and each AE, and answer ‘yes’ 
or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event 
may have been caused by the IP?’
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol.
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: e.g., ‘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.
Adverse events based on examinations and tests
The results from the Clinical Study Protocol-mandated laboratory tests and vital signs will be 
summarised in the clinical study report.  Deterioration as compared to baseline in protocol-
mandated laboratory values, vital signs and ECG abnormalities should therefore only be 
reported as AEs if one of the following is met:

Any criterion for an SAE is fulfilled

Causes study treatment discontinuation

Causes study treatment interruption

Causes study treatment dose reduction

The Investigator believes that the abnormality should be reported as an AE
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin 
value).  In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.


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Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 x ULN together with total bilirubin ≥ 2 x ULN may need 
to be reported as SAEs.  Please refer to Appendix C for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law.
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the 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.
Disease under study 
Symptoms of the disease under study are those which might be expected to occur as a direct 
result of metastatic ovarian cancer or procedures to diagnose or treat it.  Events, which are 
unequivocally due to disease under study, should not be reported as an AE during the study 
unless they meet SAE criteria or lead to discontinuation of the IP.
New cancers
The development of a new primary cancer should be reported as an AE (see Section 6.1.1  
Olaparib Adverse Events of Special Interest) and would in most cases meet seriousness 
criteria (with the exception of some non-melanoma skin cancers). New primary malignancies 
are those that are not the primary reason for the administration of the study treatment and have 
developed after the inclusion of the patient into the study.  They do not include metastases of 
the original cancer.  Symptoms of metastasis or the metastasis itself should not be reported as 
an AE/SAE, as they are considered to be disease progression.
Lack of efficacy
When there is deterioration in the 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.
Deaths
All deaths that occur during the study, or within the protocol-defined 30-day follow-up period 
after the administration of the last dose of study treatment, must be reported as follows:

Death clearly the result of disease progression should be reported to the study 
monitor at the next monitoring visit and should be documented in the DEATH 
eCRF but should not be reported as an SAE.


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
Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to the study monitor as a SAE 
within 24 hours (see Section 6.4 for further details).  The report should contain a 
comment regarding the co-involvement of progression of disease, if appropriate, 
and should assign main and contributory causes of death.  This information can be 
captured in the ‘death eCRF’.

Deaths with an unknown cause should always be reported as a SAE.  A post-
mortem may be helpful in the assessment of the cause of death, and if performed a 
copy of the post-mortem results should be forwarded to AstraZeneca within the 
usual timeframes.
6.4
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
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 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 AEs where important or relevant information is missing, active 
follow up is undertaken immediately.  Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, i.e., immediately but no later than 24 hours of when he or she becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated e-mail alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site staff reports a 
SAE to the appropriate AstraZeneca representative by SAE paper form. The AstraZeneca 
representative will advise the Investigator/study site staff on how to proceed. Investigators or 
other site personnel send relevant CRF modules by fax to the designated AstraZeneca 
representative.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug.
6.5
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.


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
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply (see Section 6.4).  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the AstraZeneca 
representative except iif the pregnancy is discovered before the study patient has received any 
study drug
Maternal exposure
If a patient becomes pregnant during the course of the study, IP should be discontinued 
immediately.
The outcomes of any conception occurring from the date of the first dose of study medication 
until 1 month after the last dose of study medication must be followed up and documented.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP 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 in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
6.7
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in
the treatment process for an AstraZeneca study drug that either causes harm to the patient or 
has the potential to cause harm to the patient. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or patient.


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Medication error includes situations where an error

occurred

was identified and intercepted before the patient received the drug

did not occur, but circumstances were recognise that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error, e.g., medication prepared incorrectly, even if it was not actually 
given to the patient

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated, e.g., tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed, e.g., kept in the fridge when it should be at room 
temperature 

Wrong patient received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to patient (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS, including those which lead to one of 
the above listed events that would otherwise have been a medication error 

Patient accidentally missed drug dose(s), e.g., forgot to take medication

Accidental overdose (will be captured as an overdose)

Patient failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.  
If an medication error occurs  in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors.
6.8
Management of Investigational Product Related Toxicities
Any toxicity observed during the course of the study could be managed by interruption of the 
dose of study treatment or dose reductions.  Repeat dose interruptions are allowed as required, 
for a maximum of 4 weeks on each occasion.  If the interruption is any longer, the study team 
must be informed.  Study treatment can be dose reduced to 250 mg twice daily as a first step 


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and to 200 mg twice daily as a second step.  If the reduced dose of 200 mg twice daily is not 
tolerable, no further dose reduction is allowed and study treatment should be discontinued. 
Once dose is reduced, escalation is not permitted.
Management of haematological toxicity
6.8.1.1
Management of anaemia
Table 4
Management of Anaemia
Haemoglobin (Hb)
Action to be taken
Hb < 10 but ≥ 8 g/dL 
(CTCAE grade 2)
First occurrence:
Give appropriate supportive treatment and investigate causality. 
Investigator judgement to continue olaparib with supportive treatment (eg 
transfusion) or interrupt dose for a maximum of 4 weeks. Study treatment 
can be restarted if Hb has recovered to > 9g/dl.
Subsequent occurrences:
If  Hb < 10 but ≥ 9 g/dl investigator judgement to continue olaparib with 
supportive treatment (eg transfusion) or dose interrupt (for max of 4 
weeks) and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second step).
If  Hb < 9 but ≥ 8 g/dl, dose interrupt (for max of 4 weeks) until Hb ≥ 9 
g/dl and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second step).
Hb < 8 g/dL
(CTCAE grade 3)
Give appropriate supportive treatment (e.g., transfusion) and investigate 
causality. 
Interrupt olaparib for a maximum of 4 weeks until improved to Hb ≥ 9
g/dL.
Upon recovery dose reduce to 250 mg twice daily as a first step and to 
200 mg twice daily as a second step in the case of repeat Hb decrease.
Common treatable causes of anaemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  In some cases 
management of anaemia may require blood transfusions.  For cases where patients develop 
prolonged haematological toxicity (≥2-week interruption/delay in study treatment due to CTC 
grade 3 or worse anaemia and/or development of blood transfusion dependence), refer to 
Section 6.8.1.3 for the management of this.


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6.8.1.2
Management of neutropenia, leukopenia and thrombocytopenia
Table 5
Management of Neutropenia, Leukopenia and Thrombocytopenia
Toxicity
Study treatment dose adjustment
CTCAE grade 1-2
Investigator judgement to continue treatment or if dose interruption, this 
should be for a maximum of 4 weeks; appropriate supportive treatment 
and causality investigation
CTCAE grade 3-4
Dose interruption until recovered to CTCAE grade 1 or better for a 
maximum of 4 weeks.  If repeat CTCAE grade 3-4 occurrence, dose 
reduce study treatment to 250 mg twice daily as a first step and 200 mg
twice daily as a second step
AE of neutropenia and leukopenia should be managed as deemed appropriate by the 
Investigator with close follow up and interruption of study drug if CTC grade 3 or worse 
neutropenia occurs.
Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is not 
recommended; however, if a patient develops febrile neutropenia, study treatment should be 
stopped and appropriate management including G-CSF should be given according to local 
hospital guidelines.  Please note that G-CSF should not be used within at least 24 hours (7 
days for pegylated G-CSF) of the last dose of study treatment unless absolutely necessary.
Platelet transfusions, if indicated, should be done according to local hospital guidelines.
For cases where patients develop prolonged haematological toxicity (≥2-week 
interruption/delay in study treatment due to CTC grade 3 or worse), refer to Section 6.8.1.3. 
6.8.1.3
Management of prolonged haematological toxicities while on study treatment
If a patient develops prolonged haematological toxicity such as:

≥2-week interruption/delay in study treatment due to CTC grade 3 or worse 
anaemia and/or development of blood transfusion dependence

≥2-week interruption/delay in study treatment due to CTC grade 3 or worse 
neutropenia (ANC < 1 x 109/L)

≥2-week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (platelets 
< 50 x 109/L)
Check weekly differential blood counts including reticulocytes and peripheral blood smear.  If 
any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the patient
should be referred to haematologist for further investigations.  Bone marrow analysis and/or 
blood cytogenetic analysis should be considered at this stage according to standard 
haematological practice.  Study treatment should be discontinued if blood counts do not recover 
to CTC grade 1 or better within 4 weeks of dose interruption.
Development of a confirmed MDS or other clonal blood disorder should be reported as a SAE 
and full reports must be provided by the Investigator to the AstraZeneca representative.  


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Olaparib treatment should be discontinued if patient’s diagnosis of MDS and/or AML is 
confirmed.
Management of non-haematological toxicity
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion.  
If the interruption is any longer than this the study monitor must be informed.  Where toxicity 
reoccurs following re-challenge with study treatment, and where further dose interruptions are 
considered inadequate for management of toxicity, then the patient should be considered for 
dose reduction or must permanently discontinue study treatment.
Study treatment can be dose reduced to 250 mg twice daily as a first step and to 200 mg twice 
daily as a second step.  Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 AE 
occurs which the Investigator considers to be related to administration of study treatment.
6.8.2.1
Management of new or worsening pulmonary symptoms 
If new or worsening pulmonary symptoms (e.g., dyspnoea) or radiological abnormalities 
occur in the absence of a clear diagnosis, an interruption in study treatment dosing is 
recommended and further diagnostic workup (including a HRCT scan) should be performed to 
exclude pneumonitis.
Following investigation, if no evidence of abnormality is observed on computed tomography 
(CT) imaging and symptoms resolve, then study treatment can be restarted, if deemed 
appropriate by the Investigator.  If significant pulmonary abnormalities are identified, these 
need to be discussed with the Study Physician.
6.8.2.2
Management of nausea and vomiting
Events of nausea and vomiting are known to be associated with olaparib treatment.  In SOLO-
2, nausea was reported in 78% of the olaparib treated patients and 33% of the placebo treated 
patients and vomiting was reported in 37% of the olaparib treated patients and 19% of the 
placebo treated patients.  These events are generally mild to moderate (CTCAE grade 1 or 2) 
severity, intermittent and manageable on continued treatment. The first onset of nausea and 
vomiting was reported in the first 3 months for 71 and 25% of patients respectively. 
No routine prophylactic antiemetic treatment is required at the start of study treatment;
however, patients should receive appropriate antiemetic treatment at the first onset of nausea 
or vomiting and as required thereafter, in accordance with local treatment practice guidelines.  
Alternatively, olaparib tablets can be taken with a light meal/snack (i.e., two pieces of toast or 
a couple of biscuits).
As per international guidance on antiemetic use in cancer patients (European Society for 
Medical Oncology [ESMO], National Comprehensive Cancer Network [NCCN]), generally a 
single agent antiemetic should be considered, e.g., dopamine receptor antagonist, 
antihistamines or dexamethasone.
6.8.2.3
Interruptions for intercurrent non-toxicity related events
Study treatment dose interruption for conditions other than toxicity resolution should be kept 
as short as possible.  If a patient cannot restart study treatment within 4 weeks for resolution 
of intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with the AZ Study Physician.


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All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF. 
Study treatment should be stopped at least 3 days prior to planned surgery.  After surgery,
study treatment can be restarted when the wound has healed.  No stoppage of study treatment 
is required for any needle biopsy procedure.
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment.  Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered.
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, patients 
should be advised to use caution while driving or using machinery if these symptoms occur.
Table 6
Dose Reductions for Study Treatment
Initial Dose
Following re-challenge post 
interruption: Dose reduction 1
Dose reduction 2
300 mg twice daily
250 mg twice daily
200 mg twice daily
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of Investigational Product
Investigational product a
Dosage form and strength
Olaparib
100 mg and 150 mg tablet
a
Descriptive information for olaparib can be found in the olaparib IB. Manufacturer will also be included in 
the Quality section of the Investigational Medicinal Product Dossier.
7.2
Dose and Treatment Regimens
For all centres, olaparib tablets will be packed in high-density polyethylene bottles with child-
resistant closures.  Each dosing container will contain sufficient medication for at least 28 
days plus overage.  Olaparib will be dispensed to patients as detailed in Table 2 until the 
patient completes the study, withdraws from the study or closure of the study.
Study treatment is available as film-coated tablets containing 100 mg or 150 mg of olaparib.
Patients will be administered olaparib orally twice daily (300 mg twice daily) continually.  
Two x 150 mg olaparib tablets should be taken at the same times each day, approximately 12 
hours apart with one glass of water.  The tablets should be swallowed whole and not chewed, 
crushed, dissolved or divided.  Olaparib tablets can be taken with or without food. 
Dose reduction may be necessary to manage toxicity (doses down to 200mg twice daily, see 
Section 6.8), or because of the requirement to co-administer with CYP3A4  inhibitors (doses 
down to 100mg twice daily, see Section 7.7). Dose reductions can be managed in 50mg 
increments by combination of 150mg and 100mg tablets
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted.  Should any patient enrolled on the 
study miss a scheduled dose for whatever reason (e.g., as a result of forgetting to take the 


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tablets or vomiting), the patient will be allowed to take the scheduled dose up to a maximum 
of 2 hours after that scheduled dose time.  If greater than 2 hours after the scheduled dose 
time, the missed dose is not to be taken and the patient should take their allotted dose at the 
next scheduled time.
Patients will continue with olaparib until documented disease progression as assessed by the 
Investigator or unacceptable toxicity or for as long as they do not meet any other 
discontinuation criteria. Patients may continue to receive treatment beyond progression 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 study treatment, other treatment options will be at 
the discretion of the Investigator. 
Dose reductions 
For guidance on dose reductions for management of AEs refer to Section 6.8.
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors 
cannot be avoided see Section 7.7.
Renal impairment   
If subsequent to study entry and while still on study therapy, a patient’s estimated creatinine 
clearance (CrCl) falls below the threshold for study inclusion (≥51 mL/min), retesting should 
be performed promptly. 
A dose reduction is recommended for patients who develop moderate renal impairment 
(calculated CrCl by Cockcroft-Gault equation of between 31 and 50 mL/min) for any reason 
during the course of the study: the dose of olaparib should be reduced to 200 mg twice daily.
Because the CrCl determination is only an estimate of renal function, in instances where the 
CrCl falls to between 31 and 50 mL/min, the Investigator should use his or her discretion in 
determining whether a dose change or discontinuation of therapy is warranted.
Olaparib has not been studied in patients with severe renal impairment (CrCl ≤ 30 mL/min) or 
end-stage renal disease; if patients develop severe impairment or end-stage disease, it is 
recommended that olaparib be discontinued.
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language.
Each bottle/pack of investigational medicinal product (IMP) will have an IP label permanently 
affixed to the outside stating that the material is for clinical study/investigational use only and 
should be kept out of reach of children.  The label will include a space for the enrolment code 
(E-code) to be completed at the time of dispensing.
Specific dosing instructions will not be included on the label; the site must complete the 
‘Patient Dispensing Card’ with the details of the dosing instructions at the time of dispensing.
The patient’s 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 
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7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The IP 
label on the bottle specifies the appropriate storage.
7.5
Compliance
The administration of all study drugs (including IPs) should be recorded in the appropriate 
sections of the CRF.
Patients should be given clear instructions on how and when to take their study treatment.  
Patients will self-administer olaparib.  Study site staff will make tablet counts at regular 
intervals during treatment.  Compliance will be assessed by the tablet count and the 
information will be recorded in the appropriate section of the eCRF.  After the tablet count has 
been performed, the remaining tablets will not be returned to the patient but will be retained 
by the investigative site until reconciliation is completed by the study monitor.  All patients 
must return their 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 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 tablets at the end of the study.
7.6
Accountability
The study drug provided for this study will be used only as directed in the Clinical Study 
Protocol.  It is the Investigator/institution’s responsibility to establish a system for handling 
study treatments, including IPs, so as to ensure that:

Deliveries of such products from AstraZeneca or its representative are correctly 
received by a responsible person

Such deliveries are recorded

Study treatments are handled and stored safely and properly as stated on the label

Study treatments are only dispensed to patients in accordance with the protocol
The study site staff will account for all study drugs dispensed to and returned from the patient.
At the end of the study, it must be possible to reconcile delivery records with records of usage 
and destroyed/returned stock.  Records of usage should include the identification of the person 
to whom the study treatment was dispensed, the quantity and date of dispensing and unused 
study treatment returned to the Investigator.  This record is in addition to any drug accountability 
information recorded on the eCRF.  Any discrepancies must be accounted for on the appropriate 
forms.  Certificates of delivery and return must be signed, preferably by the Investigator or a 
pharmacist, and copies retained in the Investigator site file.  Dispensing and accountability 
records will continue to be collected for as long as patients continue to receive study treatment, 
although they will not be entered on the database after the database has closed.  Study site staff, 
if applicable, or the Clinical Research Organization (CRO) Monitor will account for all study 
drugs received at the site, unused study drugs and for appropriate destruction.  Certificates of 
delivery and destruction should be signed.


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7.7
Concomitant and Other Treatments 
The use of any natural/herbal products or other traditional remedies should be discouraged, 
but use of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the CRF.  
Medications that may NOT be administered
No other anticancer therapy (chemotherapy, immunotherapy, hormonal therapy [hormone 
replacement therapy is acceptable], radiotherapy, biological therapy or other novel agent) is to 
be permitted while the patient is receiving study medication.
Live virus and live 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.
Restricted concomitant medications
Strong or Moderate CYP3A inhibitors 
Known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, boosted 
protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate 
CYP3A inhibitors (ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) should not 
be taken with study treatment.
If there is no suitable alternative concomitant medication, then the dose of study treatment 
should be reduced for the period of concomitant administration.  The dose reduction of study 
treatment should be recorded in the CRF with the reason documented as concomitant CYP3A 
inhibitor use. 

Strong CYP3A inhibitors – reduce the dose of olaparib to 100 mg twice daily for 
the duration of concomitant therapy with the strong inhibitor and for 5 half-lives 
afterwards

Moderate CYP3A inhibitors – reduce the dose of olaparib to 150 mg twice daily for 
the duration of concomitant therapy with the moderate inhibitor and for 3 half-lives 
afterwards

After the washout of the inhibitor is complete, the olaparib dose can be re-escalated.
Strong or moderate CYP3A inducers
Strong (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide and St John’s Wort) and moderate CYP3A inducers (e.g., bosentan, 
efavirenz, modafinil) should not be taken with study treatment.
If the use of any strong or moderate CYP3A inducers are considered necessary for the 
patient’s safety and welfare this could diminish the clinical efficacy of olaparib.
If a patient requires use of a strong or moderate CYP3A inducer, then they must be monitored 
carefully for any obvious change in the efficacy of study treatment.
P-glycoprotein inhibitors
It is possible that co-administration of P-glycoprotein (P-gp) inhibitors (e.g., amiodarone, 
azithromycin) may increase exposure to olaparib.  Caution should therefore be observed.


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Effect of olaparib on other drugs
Based on limited in vitro data, olaparib may increase the exposure to substrates of CYP3A4, 
P-gp, organic anion transporting polypeptide 1B1 (OATP1B1), organic cation transporters 
(OCT1, OCT2), organic anion transporter 3 (OAT3), and multidrug and toxin extrusion 
proteins (MATE1, MATE2K.).
Based on limited in vitro data, olaparib may reduce the exposure to substrates of 2B6. 
Caution should therefore be observed if substrates of these isoenzymes or transporter proteins 
are co-administered.
Examples of substrates include:

CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine

CYP2B6 – bupropion, efavirenz

OATP1B1 – bosentan, glibenclamide, repaglinide, statins and valsartan

OCT1, MATE1, MATE2K – metformin

OCT2 – serum creatinine

OAT3 – furosemide, methotrexate
The efficacy of hormonal contraceptives may be reduced if co-administered with olaparib.   
Anticoagulant therapy
Patients who are taking warfarin may participate in this trial; however, it is recommended that 
prothrombin time, INR be monitored carefully at least once per week for the first month, then 
monthly if the INR is stable.  Subcutaneous heparin and low molecular weight heparin are 
permitted.
Antiemetic/anti-diarrhoeal drugs
From screening onwards, should a patient develop nausea, vomiting, and/or diarrhoea, then 
these symptoms should be reported as AEs (see Section 6.3) and appropriate treatment of the 
event given.
Palliative radiotherapy 
Palliative radiotherapy may be used for the treatment of pain at the site of bony metastases 
that were present at baseline, provided the Investigator does not feel that these are indicative 
of clinical disease progression during the study period.  Study treatment should be 
discontinued for a minimum of 3 days before a patient undergoes therapeutic palliative 
radiation treatment.  Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered.  
Administration of other anticancer agents
Patient must not receive any other concurrent anticancer therapy, including investigational 
agents, while on study treatment.  Patients may continue the use of bisphosphonates or 


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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 4 weeks prior to beginning study treatment. 
Subsequent therapies for cancer 
Details of first therapy for cancer  after discontinuation of treatment will be collected. 
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the CRF.
In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the 
study period must be recorded in the eCRF.
7.8
Post Study Access to Study Treatment – Not Applicable
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical Considerations
A comprehensive statistical analysis plan (SAP) will be prepared and finalised prior to the 
first analysis.  All analyses will be performed by AstraZeneca or its representatives.
8.2
Sample Size Estimate
The primary endpoint is investigator assessed PFS using modified RECIST criteria version 1.1.  
A sample size of approximately 250 patients is proposed for this study in order to provide an 
adequate level of precision around the primary endpoint in the whole population.  The primary
analysis is planned at approximately 30 months after the first patient is enrolled, with an interim 
analysis after approximately 18 months. A supplementary analysis of OS will be performed 
when 135 OS events (~54% maturity) have been recorded, estimated to be approximately 36 
months after the first subject is enrolled.
From published data (Study 19, Nova study) on non-gBRCA patients treated with a PARPi the 
median PFS ranges from 8 to 9 months compared to 4–5.5 months for those treated with 
placebo. Clinical trial simulations were performed assuming 250 patients enrolled over a 12 
month period with 50% of patients enrolled after 8 months, a median PFS of 8.5 months and a 
piecewise exponential model for PFS.  Across 500 simulations it is estimated that the mean 
number of PFS events is approximately 135 at 18 months (54% maturity) and 180 at 30 months 
(72% maturity), with corresponding mean 95% confidence interval (CI) widths of 3.87 and 3.27 
months respectively.   
8.3
Definitions of Analysis Sets
All efficacy analyses will be based on the full analysis set (all enrolled patients assigned to 
olaparib) with safety data summarised from the safety-analysis set (all enrolled patients who 
have received at least one dose of olaparib).  The PRO analysis set will consist of the FAS 


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patients with at least a baseline and one other post-baseline assessment (excluding end of 
treatment and 30-day follow up assessments).  
8.4
Outcome Measures for Analyses
Calculation or derivation of efficacy variables
Investigator RECIST based assessments
From the investigator’s review of the imaging scans, the RECIST tumour response data will
be used to determine each patient’s visit response according to RECIST version 1.1.  At each 
visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, PR, SD 
or PD depending on the status of their disease compared with baseline and previous 
assessments.  If a patient has had a tumour assessment which cannot be evaluated, then the
patient will be assigned a visit response of not evaluable (NE) (unless there is evidence of
progression in which case the response will be assigned as PD).
A visit response of PD is defined as at least a 20% increase in the sum of the diameters of the 
target lesions (compared to previous minimum sum) or an overall non-target lesion 
assessment of progression or a new lesion.  For patients who are in complete response 
following chemotherapy or are enrolled with no evidence of disease, progression will be based 
on the presence of a new lesion.  The earliest visit response of PD will be used to determine 
the date of disease progression.  
Please refer to Appendix I for the definitions of Complete Response, Partial Response, Stable 
Disease and Progressive Disease by modified RECIST 1.1.
Progression-free survival (PFS)
PFS is defined as the time from the date of first dose until the earliest date of disease 
progression or death (by any cause in the absence of progression) regardless of whether the 
patient withdraws from therapy, receives another anticancer therapy prior to progression or 
has notable increases in CA-125.  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 
progression 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 progression assessment 
prior to the two missed visits.  If the patient has no evaluable visits they will be censored at 1 
day unless they die within two visits (17 weeks allowing for visit window) from baseline. 
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:

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 
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Overall survival (OS)
OS is defined as the time from the date of the first dose of olaparib to the date of death from 
any cause with patients censored on the last recorded date on which the patient was known to 
be alive.
Time to first subsequent treatment or death (TFST)
TFST is defined as the time from the date of the first dose of olaparib to the earliest of the date 
of death or commencement of first subsequent anticancer treatment.  Patients who are alive 
and have not been recorded as taking a subsequent anticancer treatment will be censored at the 
last date their treatment status was recorded.
Time to study treatment discontinuation or death (TDT)
TDT is defined as the time from the date of the first dose olaparib to the earliest of the date of 
death or discontinuation of olaparib.  Patients who are alive and are still receiving olaparib 
will be censored at the last date they are known to be alive.
Chemotherapy Free Interval (CT-FI)
CT-FI is defined as the time from the date of the last dose of platinum chemotherapy in the 
course immediately prior to enrolment in the study until the date of commencement of the first 
subsequent anticancer treatment (whether or not this is chemotherapy). Patients who are alive 
and have not been recorded as taking a subsequent anticancer treatment will be censored at the 
last date their treatment status was recorded. Patients who have died prior to the start of a 
subsequent anticancer treatment will be censored at their date of death.
Calculation or derivation of safety variables
Safety and tolerability will be assessed in terms of AEs, deaths and laboratory data.  These 
will be collected for all patients.
Adverse events
AEs (both in terms of the Medical Dictionary for Regulatory Activities [MedDRA] preferred 
terms and CTCAE grade) will be listed individually by patient.
Any AE occurring before treatment with olaparib will be included in the data listings but will 
not be included in the summary tables of AEs.
Any AE occurring within 30 days of discontinuation of olaparib will be included in the AE 
summaries.  Any events in this period that occur after a patient has received further therapy 
for cancer (following discontinuation of olaparib) will be flagged in the data listings. 
Other significant adverse events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and AEs leading to discontinuation.  Based on 
the expert’s judgement, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant adverse 
events (OAEs) and reported as such in the clinical study report.  A similar review of 


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laboratory/vital signs (pulse and blood pressure) data will be performed for identification of 
OAEs.
Examples of these could be 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.
Calculation or derivation of patient reported outcome variables
Health-Related Quality of Life
Patient-reported health-related quality of life (HRQoL) will be assessed using the FACT-O 
questionnaire (Basen-Enquist K et al 2001).  The FACT-O is composed of the following 
subscales: physical, social/family, emotional, and functional well-being as well as the 
additional concerns scales consisting of specific ovarian cancer symptoms.  The endpoint for 
health-related quality of life analysis will be the Trial Outcome Index (TOI), (Cella D et al 
1993).   Patients will be asked to report their health-related quality of life over the course of 
the previous 7 days. 
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).
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 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 TOI score ranges from 0-100 and 
the FACT-O from 0-152.  A higher score indicates a higher HRQoL.
The change from baseline in TOI score will be derived for each visit where there is available 
data. A change of at least 10 points in TOI score is considered as a clinically relevant or a 
minimally important difference (Osoba et al 2005). In this study the 10-point minimum 
clinically important difference will be applied only to deterioration.
EQ-5D-5L
The EQ-5D-5L index comprises five dimensions of health (mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression). For each dimension, respondents select 
which statement best describes their health on that day from a possible five options of 
increasing levels of severity (no problems, slight problems, moderate problems, severe 
problems and unable to/extreme problems). 
A unique EQ-5D health state is referred to by a five digit code allowing for a total of 3125 
health states. For example, state 11111 indicates no problems on any of the five dimensions. 
This data will be converted into a weighted health state index by applying scores from EQ5D 
value sets elicited from general population samples (the base case will be the UK valuation 


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set, with other country value sets applied in scenario analyses).  Where values sets are not 
available, the EQ-5D-5L to EQ-5D-3L crosswalk will be applied.  In addition to the 
descriptive system, respondents also assess their health today on a visual analogue scale
(VAS), ranging from 0 (worst imaginable health) to 100 (best imaginable health).  This score 
is reported separately.
The change from baseline in EQ-5D-5L index score and VAS score will be calculated at each 
visit.
8.5
Methods for Statistical Analyses
The precision of all estimates will be presented using a 95% CI noting that the coverage of 
these intervals assume the patients recruited are a random sample of patients with the disease.
Analysis of the primary variable
PFS will be summarised using the Kaplan-Meier (KM) method, which will include a graph 
depicting the proportion of patients alive and without progression and estimates of median 
PFS and associated 95% CI.  In addition, progression rates and 95% CIs at clinically 
important landmarks (such as 1 year and 18 months) will be estimated using the KM method.   
The standard error of the natural log of survival time will be used to calculate CIs. The CI for 
the median will be calculated by determining the earliest and latest survival times whose 95% 
CIs contain 0.5.  If the 95% CI for survival at the largest event time contains 0.5 then the 
upper confidence limit will be described as Not Calculated. 
Sensitivity analyses
A sensitivity analysis may be performed on PFS excluding any patients who did not have a 
negative gBRCA mutation status confirmed by the central Myriad test. Further details on any 
sensitivity analyses will be provided in the SAP.
Comparison to historical controls
In a post-hoc exploratory analysis, outcomes from this trial may be compared to historical data 
from published studies in a comparable patient population treated with placebo. Such an 
analysis does not form part of the formal study objectives. 
Subgroup analysis
The primary endpoint will be summarised by HRD status in the following subgroups:

HRD scar positive and somatic BRCA mutated

HRD scar positive, non-BRCA mutated

HRD scar negative, non-BRCA mutated
In exploratory analysis, PFS will also be summarised according to a range of molecular sub-
groups including mutations in homologous recombination repair (HRR) genes, microsatellite 
instability (MSI) status, and tumour mutation load score (see Section 5.6).
In addition, PFS will be summarised according to important clinical characteristics, which will 
include:

Best response to the last platinum regimen (CR or PR)


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
Prior use of bevacizumab in combination with penultimate platinum regimen

Number of prior platinum regimens (two vs. greater than two)

Degree of sensitivity to the penultimate platinum chemotherapy: partial (6-12 
months PFS) vs fully (≥12 months PFS) sensitive

Histological subtype (HGSOC vs. high grade endometrioid ovarian cancer)
Pre-specified subgroup analyses will be further described in the SAP.
Analysis of the secondary/exploratory variables
Overall Survival
OS will be summarised using a KM plot to estimate the median and proportion of patients 
alive at clinically relevant time points such as 12, 24 and 30 months
Other Time-to-event endpoints
TFST, TDT and CT-FI will be summarised using a KM plot to estimate the median and event 
rates from clinically important landmarks such as 1 and 2 years. 
FACT-O 
Descriptive summary statistics and graphs will be reported for the TOI by visit as well as the 
change in TOI score from baseline. 
The proportion of patients with any improvement from baseline in TOI score and the 
proportion of patients with at least a 10 point deterioration from baseline in TOI score will be 
estimated together with the exact 95% CI. 
Additional analyses may be performed and will be described in the SAP.
EQ-5D-5L
Descriptive statistics will be calculated for each scheduled visit/time point in the study. 
Additionally summary statistics will be reported for the EQ-5D index score and the EQ-VAS 
score, and the change from baseline for the EQ-5D index score and the EQ-VAS score.
Graphical plots of the mean EQ-5D index score and EQ-VAS score, including change from 
baseline, and associated 95% CI by scheduled visits/time points in the study will be produced.
Additional analyses may be performed and will be described in the SAP.
8.5.3
Interim Analysis
An interim analysis of PFS will be performed approximately 18 months after the first patient 
is enrolled into the study, for internal planning purposes, and to provide ongoing data to 
external bodies. Based upon simulations (see Section 8.2) it is estimated that approximately 
135 events will have occurred at the time of the interim analysis, equating to approximately 
54% data maturity. Further details on the interim analysis will be provided in the SAP.


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9.
STUDY AND DATA MANAGEMENT 
9.1
Training of Study Site Staff
Before the first patient is entered into the study, the CRO will review and discuss the 
requirements of the Clinical Study Protocol and related documents with the investigational 
staff and train them in any study-specific procedures and any system(s) utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the Study
During the study, the CRO will have regular contacts with the study site, including visits to:

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the Clinical Study 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

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)

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 CRO will be available between visits if the Investigator(s) or other staff at the centre 
needs information and advice about the study conduct.
Source data
Refer to the Clinical Study Agreement for location of source data.
Study agreements
The Principal Investigator at each centre should comply with all the terms, conditions, and 
obligations of the Study Agreement with the Principal Investigator, or equivalent, for this 
study. In the event of any inconsistency between this clinical study protocol (CSP) and the 
Study Agreement with Principal Investigator, the terms of CSP shall prevail with respect to the 
conduct of the study and the treatment of patients and in all other respects, not relating to study 


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conduct or treatment of patients, the terms of the Study Agreement with Principal Investigator 
shall prevail. Agreements between AstraZeneca and the Principal Investigator should be in 
place before any study-related procedures can take place, or any patients are enrolled.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.
Archiving of study documents
Study files.  AstraZeneca will provide the Principal Investigator with a file in which to organise 
and retain all study-related documents.  All study documents (including letters from 
AstraZeneca) should be retained in this file by the Principal Investigator.  The monitor will 
regularly check the file to ensure that all relevant documents are retained.  The contents of the 
file may be audited/inspected by AstraZeneca’s auditor, regulatory authorities, or IRB.
Period of record retention.  The study site (and the Principal Investigator) will retain the 
essential documents specified in the ICH GCP (e.g., source document such as medical records, 
contract, signed consent form).  Essential documents should be retained at the study site for at 
least 15 years following completion of the study, or per regulatory obligations if longer, and 
thereafter destroyed only after agreement with AstraZeneca. However, this is not always applied 
to those that are not preservable such as blood samples. In the event of any inconsistency 
between the above-mentioned contents and the contract with the study site, the contract shall 
prevail. These documents should be retained for a longer period however if needed by 
AstraZeneca, and the specific period and method of retention will be separately discussed 
between the study site and AstraZeneca. AstraZeneca should notify the head of the study site in 
writing when the study related records are no longer needed.  The records should be managed 
by a responsible person appointed by the head of the study site. The Investigator follows the 
principles outlined in the Clinical Study Agreement or the equivalent (e.g., site contract with 
CRO).
Deviation from the clinical study protocol
The Investigator(s) must not deviate from or make any changes to the protocol without 
documented agreement between the Principal Investigator and AstraZeneca or the IRB 
approval based on its deliberations. However, this shall not apply to cases where the deviation 
or change is necessary to avoid an immediate hazard to the patients or for other compelling 
medical reasons, or where the changes involve only logistical or administrative aspects of the 
clinical study (e.g., changes to the organisation/structure of  AstraZeneca, the 
name/department name of the study site, the address or phone number of the study site or 
AstraZeneca, the job title of the Investigator, and monitors).
The Investigator(s) should document any deviation from the protocol regardless of their 
reasons. Only when the protocol was not followed in order to avoid an immediate hazard to 
the patients or for other medically compelling reason, the Investigator should prepare and 
submit the records explaining the reasons thereof to AstraZeneca and the head of study site, 
and retain a copy of the records.
The Investigator(s) may deviate from or make a change to the protocol without documented 
agreement between the Principal Investigator and AstraZeneca or the IRB approval, only in 
the event of a medical emergency, e.g., it is only way to avoid an immediate hazard to the 
patients. In such case, the Principal Investigator must notify details of the deviation or 


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change, the reason, and a proposed revision in the protocol if required, to AstraZeneca and the 
head of the study site and IRB via the head of the study site as soon as possible, in order to 
obtain their approval. A certificate of approval by the head of the study site as well as 
AstraZeneca should be obtained via the head of the study site.
9.3
Study Timetable and End of Study
Planned duration of the study:
Study period: from Q1 2018 (first patient enrolled) to Q1 2021 (last patient completes follow 
up). 
Discontinuation or suspension of the whole study programme
If AstraZeneca decides to prematurely terminate or suspend the study, the Principal 
Investigator/Investigator, the head of the study site, and regulatory authorities should receive 
written notification of the reasons for the premature termination or suspension.
The Principal Investigator/Investigator will immediately notify the decision to the patients, 
give appropriate medical treatment; take necessary measures, and record treatment or 
measures provided on the source documents.
Completion of the study
Upon terminating the study, the Principal Investigator/Investigator will report in writing the 
completion of the study as well as the summary of the results to the head of the study site in 
accordance with the study site’s rules.  The head of the study site, who is informed of the 
termination by the Investigator, will provide a written notification of the results to the IRB and 
AstraZeneca.
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
The data cut-off for the primary analysis will be when all patients receiving olaparib have been 
followed for a minimum period of 18 months since the start of treatment.  New data will be 
added to the clinical database after this time point to provide additional data maturity for the OS 
analysis.  Patients are permitted to continue to receive study treatment beyond the closure of the 
database if, in the opinion of the Investigator, they are continuing to receive benefit from 
treatment with olaparib.  For patients who do continue to receive treatment beyond the time of 
this data cut-off, Investigators will continue to report all SAEs to the AstraZeneca representative
until 30 days after study treatment is discontinued, in accordance with Section 6.4 (Reporting 
of Serious Adverse Events).  If an Investigator learns of any SAEs, including death, at any time 
after a patient has completed the study, and he/she considers there is a reasonable possibility 
that the event is causally related to the IP, the Investigator should notify the AstraZeneca 
representative. Additionally as stated in Section 6.3 (Recording of Adverse Events), any SAE 
or non-SAE that is ongoing at the time of this data cut-off, must be followed up to resolution 
unless the event is considered by the Investigator to be unlikely to resolve, or the patient is lost 
to follow up.
The study is expected to start in Q1 2018 and to end by Q1 2021
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.


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9.4
Data Management by Designated Clinical Research Organisation
Data management will be performed by a CRO according to the Data Management Plan.
If applicable, the data collected through third party sources will be obtained and reconciled 
against study data.
AEs and medical/surgical history will be classified according to the terminology of the latest 
version of the MedDRA.  Medications will be classified according to the World Health 
Organization (WHO) Drug Dictionary.  All coding will be performed by the CRO.
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the study 
database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control procedures 
will be applied to each stage of data handling to ensure that all data are reliable and have been 
processed correctly.  The Data Management Plan will also clarify the roles and responsibilities 
of the various functions and personnel involved in the data management process.
When all data have been coded, validated, signed and locked, a clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.
Serious Adverse Event Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database and/or 
the investigational site. 
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical Conduct of the Study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements 
and the AstraZeneca policy on Bioethics and Human Biological Samples.
10.2
Patient Data Protection
The Master Informed Consent Form will explain that:

Study data will be stored in a computer database, maintaining confidentiality in 
accordance with national data legislation

Patient data will be maintaining confidentiality in accordance with national data 
legislation

For data verification purposes, authorised representatives of AstraZeneca, a 
regulatory authority, an IRB may require direct access to parts of the hospital or 
practice source records relevant to the study, including patients’ medical history
All data computer processed by AstraZeneca will be identified by study code and enrolment 
code (E-code).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.


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10.3
Ethics and Regulatory Review
An Ethics Committee should approve the final Clinical 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 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.
If required by local regulations, the Clinical Study Protocol should be re-approved by the 
Ethics Committee annually.
Before enrolment of any patient into the study, the final Clinical 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.
Each Principal Investigator is responsible for providing the Ethics Committees/Institutional 
Review Board (IRB) with reports of any serious and unexpected adverse drug reactions from 
any other study conducted with the IP.  AstraZeneca will provide this information to the 
Principal Investigator so that he/she can meet these reporting requirements. An IRB should 
approve the final study protocol, including the final version of the Informed Consent Form 
and any other written information and/or materials to be provided to the patients. The head of 
the study site will ensure the distribution of these documents to the applicable IRB, and the 
Principal Investigator to the Investigator and study site staff.
The opinion of the IRB should be given in writing. The head of the study site should submit a 
notification of direction/determination as well as a copy of the IRB written approval to 
AstraZeneca and the Principal Investigator before enrolment of any patient should into the 
study.
The IRB 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.
A valid contract between the study site and AstraZeneca should be signed before the 
Investigator can enrol any patient into the study. The protocol should be re-approved by the 
IRB annually.
The head of the study site should seek the opinion of the IRB with respect to the 
appropriateness of continuing the study at the study site at least once a year when the duration 
of the study exceeds one year. The Principal Investigator should submit progress reports to the 
IRB via the head of the study site at the time of the protocol re-approval.
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the ICF, should be approved by the national regulatory authority with notification 
provided, according to local regulations.  AstraZeneca will handle the distribution of any of 
these documents to the national regulatory authorities.


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AstraZeneca will provide Regulatory Authorities, IRB, the head of the study site and the 
Principal Investigator with safety updates/reports according to local requirements.
The head of the study site should submit a written report to the IRB providing the details of all 
safety relative information reported by AstraZeneca.
10.4
Informed Consent
The Principal Investigator(s) at each centre will:

Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study

Ensure each patient is notified that they are free to discontinue from the study at any 
time

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided

Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study

Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File

Ensure a copy of the signed Informed Consent Form is given to the patient

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the Informed Consent Form that is approved by an Ethics Committee.
If any new information on the study medication becomes available which may influence the 
decision of the patient to continue the study, the Investigator(s) should inform the patient of 
such information immediately, record this in a written form, and confirm with the patient if he 
or she wishes to continue the participation in the study.  In addition, if the Investigator(s) deem 
it necessary to revise the Informed Consent Form, they should revise it immediately (Refer to 
Section 10.5).  The Investigator(s) should re-explain to the patients using updated Informed 
Consent Form even if although the patients have already been informed of the new information 
verbally.  Written informed consent to continue participation in the study should be provided 
separately.
10.5
Changes to the Clinical Study Protocol and Informed Consent 
Form
Study procedures will not be changed without the mutual agreement of the International 
Coordinating Investigator, National Coordinating Investigator, and the Principal Investigator 
and AstraZeneca.
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a new version of the study protocol.


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The new version of the Clinical Study Protocol 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 new versions of Clinical Study 
Protocols.
AstraZeneca will distribute any new versions of the Clinical Study Protocol to each Principal 
Investigator(s).  For distribution to Ethics Committee, see Section 10.3.
If a change to a Clinical Study Protocol 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. Study procedures will not be changed without the mutual 
agreement of the Principal Investigator and AstraZeneca.  If it is necessary for the study protocol 
to be amended, the amendment should be submitted to the Head of the Study Site and be 
approved by its IRB.  If applicable, AstraZeneca should submit a notification to the regulatory 
authority before it is implemented.  If a protocol amendment requires a change to a particular 
centre's Informed Consent Form, then AstraZeneca and the centre's IRB should be notified.  
Approval of the revised Informed Consent Form by AstraZeneca and by the IRB is required 
before the revised form is used.  If an administrative change is required, such a change should 
be notified to or approved by each IRB according to local requirements.
10.6
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 Clinical Study 
Protocol, GCP, guidelines of the ICH, and any applicable regulatory requirements.  The 
Investigator will contact AstraZeneca immediately if contacted by a regulatory agency about 
an inspection at the centre.
All study data may undergo a reliability review and onsite-GCP inspection by the regulatory 
authorities.


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11.
LIST OF REFERENCES
Fong et al 2009
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-
ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123-
34.
Hay et al 2009
Hay T1, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, Douglas-Jones A, Smith GC, 
Martin NM, O'Connor M, Clarke AR. Poly(ADP-ribose) polymerase-1 inhibitor treatment 
regresses autochthonous BRCA2/p53-mutant mammary tumors in vivo and delays tumor relapse 
in combination with carboplatin. Author information Cancer Res. 2009 May 1;69(9):3850-5. 
doi: 10.1158/0008-5472.CAN-08-2388. Epub 2009 Apr 21.
[PubMed PMC2579381]
Helleday 2011
The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the 
misunderstandings. Mol Oncol. 2011 Aug;5(4):387-93. doi: 10.1016/j.molonc.2011.07.001. 
Epub 2011 Jul 22. Review. [PubMed 21821475]
Mirza et al 2016
Mirza M, Monk B, Herrstedt J, et al.  Niraparib Maintenance Therapy in Platinum-Sensitive, 
Recurrent Ovarian Cancer. NEJM. 2016  Oct 8; N Engl J Med 2016;375:2154-64.
DOI: 10.1056/NEJMoa1611310
Murai et al 2012
Junko Murai, Shar-yin N. Huang, Benu Brata Das, Amelie Renaud, Yiping Zhang, James H. 
Doroshow, Jiuping Ji, Shunichi Takeda, Yves Pommier. Differential trapping of PARP1 and 
PARP2 by clinical PARP inhibitors. Cancer Res. Author manuscript; available in PMC 2013 
Nov 1. Published in final edited form as: Cancer Res. 2012 Nov 1; 72(21): 5588–5599. doi: 
10.1158/0008-5472.CAN-12-2753. [PubMed PMC3528345]
Rottenberg et al 2008
Rottenberg S1, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen 
PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O'Connor MJ, Martin NM, 
Borst P, Jonkers J. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor 
AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008 Nov 
4;105(44):17079-84. doi: 10.1073/pnas.0806092105. Epub 2008 Oct 29. [PubMed 
PMC2579381]


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Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event
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 (e.g., hepatitis that resolved without hepatic 
failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious adverse event (SAE), 
although the reasons for it may be (e.g., 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 must be used.

Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality, consider the following factors when deciding if 
there is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course.  Exposure to suspect drug.  Has the patient actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?


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
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class?  Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience.  Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped?  AstraZeneca would not normally 
recommend or support a re-challenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship.
In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if, following a review of the relevant data, there is evidence for 
a ‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


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Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labelling and Shipment of Biohazard Samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 
three categories.  For transport purposes the classification of infectious substances according 
to risk groups was removed from the Dangerous Goods Regulations in the 46th edition (2005).  
Infectious substances are now classified either as Category A, Category B or Exempt.  There 
is no direct relationship between risk groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are, e.g., Ebola, Lassa fever 
virus:

Are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are, e.g., hepatitis A, B, C, D, and E viruses, 
human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:

UN 3373 – Biological Substance, Category B

Are to be packed in accordance with UN3373 and IATA 650
Exempt – all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging 

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

Samples routinely transported by road or rail are patient to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.


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Appendix C
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
1. Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law (HL).  It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries.  Specific guidance on managing liver 
abnormalities can be found in Section 6.3.7 of the Clinical Study Protocol.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a 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 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 (AEs) and serious adverse events (SAEs) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
2. Definitions
Potential Hy’s Law
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 x upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥ 2 x ULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline phosphatase
(ALP).
Hy’s Law
AST or ALT ≥ 3 x ULN  together with TBL ≥ 2 x ULN, where no other reason, other than 
the IMP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e., on 
the same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
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 ≥ 3 x ULN

AST ≥ 3 x ULN

TBL ≥ 2 x ULN


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The Investigator will remain vigilant for any local laboratory reports where the identification 
criteria are met; where this is the case, the Investigator will:

Notify the AstraZeneca representative

Request a repeat of the test (new blood draw) by the local laboratory

Complete the appropriate unscheduled laboratory case report form (CRF) module(s) 
with the original local laboratory test result
When the identification criteria are met from local laboratory results, the Investigator will 
without delay:

Determine whether the patient meets PHL criteria (see Section 2 within this appendix 
for definition) by reviewing laboratory reports from all previous visits (local laboratory 
results)
The Investigator will without delay review each new laboratory report and if the identification
criteria are met will:

Notify the AstraZeneca representative

Determine whether the patient meets PHL criteria (see Section 2 within 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:

Inform the AstraZeneca representative that the patient has not met PHL criteria.

Perform follow up on subsequent laboratory results according to the guidance provided 
in the Clinical Study Protocol.
4.2 Potential Hy’s Law Criteria Met
If the patient does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (see Section 6)

Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow up and the continuous review of data.  Subsequent to 
this contact the Investigator will:


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
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 aetiology 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 Global Clinical Lead or equivalent and Global Safety Physician will 
also be involved in this review together with other patient 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 AstraZeneca 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 a SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above


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
Continue follow up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined.
6. Actions Required When Potential Hy’s Law Criteria Are Met Before and After 
Starting Study Treatment 
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment.
At the first on study treatment occurrence of PHL criteria being met the Investigator will:

Determine if there has been a significant change in the patient’ condition# compared 
with the last visit where PHL criteria were met#

If there is no significant change, no action is required

If there is a significant change, notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Section 4.2 of this appendix
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
7. Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:

Was the alternative cause for the previous occurrence of PHL criteria being met found 
to be the disease under study, e.g., chronic or progressing malignant disease, severe 
infection or liver disease, or did the patient meet PHL criteria prior to starting study 
treatment and at their first on study treatment visit as described in Section 6 ?
If No: follow the process described in Section 4.2
If Yes:
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met

If there is no significant change, no action is required

If there is a significant change, follow the process described in Section 4.2


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# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf


Clinical Study Protocol Appendix D
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Appendix D
Acceptable Birth Control Methods
Olaparib is regarded as a compound with medium/high foetal risk.
Women of childbearing potential and their partners, who are sexually active, must agree to the 
use of TWO highly effective forms of contraception in combination (as listed below).  This 
should be started from the signing of the informed consent and continue throughout the period 
of taking study treatment and for at least 1 month after last dose of study drug(s), or they must 
totally/truly abstain from any form of sexual intercourse (see below).
Male subjects must use a condom during treatment and for 3 months after the last dose of 
olaparib when having sexual intercourse with a pregnant woman or with a woman of 
childbearing potential.  Female partners of male subjects should also use a highly effective 
form of contraception if they are of childbearing potential (as listed below).  Male subjects 
should not donate sperm throughout the period of taking olaparib and for 3 months following 
the last dose of olaparib. 
Acceptable Non-hormonal birth control methods include:

Total/True abstinence: When the subject refrains from any form of sexual 
intercourse and this is in line with their usual and/or preferred lifestyle; this must 
continue for the total duration of the trial and for at least 1 month after the last dose 
of study drug (for 3 months after last dose for male subjects).  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods or declaration of 
abstinence solely for the duration of a trial) and withdrawal are not acceptable 
methods of contraception.

Vasectomised sexual partner PLUS male condom.  With participant assurance that 
partner received post-vasectomy confirmation of azoospermia.

Tubal occlusion PLUS male condom

Intrauterine device PLUS male condom.  Provided coils are copper-banded
Acceptable hormonal methods:

Normal and low dose combined oral pills PLUS male condom 

Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only highly 
efficacious progesterone based pill.

Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom

Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom 

Norelgestromin / ethinyl estradiol transdermal system PLUS male condom 


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
Intrauterine system (IUS) device (e.g., levonorgestrel releasing IUS -Mirena®) 
PLUS male condom 

Intravaginal device (e.g., ethinyl estradiol and etonogestrel) PLUS male condom 


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Appendix E
ECOG Performance Status
GRADE
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655.


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Appendix F
Pre study germline BRCA Testing
Germline BRCA testing of potentially eligible patients whose gBRCA status is not yet known 
can be considered. Prior agreement of the sponsor is required.
In these cases the gBRCA test must be completed prior to patient enrolment, and before other 
screening procedures are undertaken. To ensure this, patients may be consented from the end 
of cycle 3 of their current chemotherapy if, in the opinion of the investigator, they are 
responding to treatment, and if it appears that the patient is likely to meet other eligibility 
requirements (see below).
In these cases, 28-day screening period will be considered to have started only after the 
availability of the gBRCA status report at the site, at the start of the screening procedures 
listed in Table 1, column 2.
Patients with unknown gBRCA status must consent to provide a blood sample for gBRCA
testing and follow all local ethical procedures for genetic testing. The sample will be used to 
test for BRCA mutations using the current commercial Myriad BRACAnalysis® test prior to 
study entry. When the result from the Myriad test indicates the patient does NOT have a 
deleterious or suspected deleterious gBRCA mutation, the patient can be enrolled into the 
study (providing they have fulfilled all other screening requirements). 
Prior to considering the patient for gBRCA testing, the following inclusion criteria must be 
met:
2.
Patients must be ≥18 years of age 
3.
Female patients with histologically diagnosed relapsed HGSOC (including primary 
peritoneal and / or fallopian tube cancer) or high grade endometrioid ovarian cancer
5.
Patients must have completed at least 2 previous courses of platinum containing 
therapy
Additionally the patient should not fall in any of the exclusion criteria marked with an asterisk 
in Section 3.2
If the patient enters the study, this test fulfils the requirement for a sample to be held for 
retrospective confirmation of gBRCA status, and an additional sample does not need to be sent
Patients found to be BRCA positive should have appropriate counselling according to local or 
institutional guidelines
The sample must be sent to Myriad Genetic Laboratories, 320 Wakara Way, Salt Lake City, 
UT 84108. Please refer to laboratory manual for further instructions.


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Clinical Study Protocol Appendix I
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Appendix I
Guidelines for Evaluation of Objective Tumour Response 
Using RECIST 1.1 (Response Evaluation Criteria in Solid Tumours)
Introduction
This appendix details the implementation of RECIST (Response Evaluation Criteria in Solid 
Tumours) 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.
Definition of Measurable, Non-measurable, Target and Non-target Lesions
Patients with at least one lesion (measurable and/or non-measurable) that can be accurately 
assessed at baseline by computerised tomography (CT), or magnetic resonance imaging 
(MRI), or with no measureable disease, may be included in this study.
Measurable lesions
A lesion, not previously irradiated, that can be measured accurately at baseline as ≥ 10 mm in 
the longest diameter (except lymph nodes which must have a short axis ≥ 15 mm with CT or 
MRI) and which is suitable for accurate repeated measurements. CT slice thickness should be 
no greater than 5mm.
Non-measurable lesions

All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 mm to < 15 mm short axis at baseline).  Nodes with < 10 
mm short axis are considered non-pathological and should not be recorded as non-
target lesions (NTLs)

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 are not measurable by CT or 
MRI

Previously irradiated lesions as localised post-radiation changes, which affect lesion 
sizes, may occur.  Therefore, lesions that have been previously irradiated will not be 
considered measurable and should be selected as NTLs at baseline and followed up 
as part of the NTL assessment

Skin lesions assessed by clinical examination

Brain metastases
Special cases

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.

Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present 
in the same patient, these non-cystic lesions should be selected as the target lesions 
(TLs).


Clinical Study Protocol Appendix I
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Study Code D0816C00020
Version 3.0
Date 26 October 2018
100 (111)
Target lesions
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline.  
Non-target lesions
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline.  
Methods of Measurement
The same method of assessment and the same technique should be used to characterise 
each identified and reported lesion at baseline and during follow-up.
The methods to be used for RECIST assessment are summarised in Table 7 and those 
excluded for tumour assessments in this study are discussed below, with the rationale 
provided.
Table 7
Summary of Methods of Assessment
Target Lesions
Non target lesions
New Lesions
CT (preferred)
MRI
CT (preferred)
MRI
Plain X-ray (includes chest X-
ray)
Clinical examination 
CT (preferred)
MRI
Plain X-ray (includes chest X-
ray)
Clinical examination
Ultrasound
FDG-PET
CT and MRI 
CT and MRI are generally considered to be the best currently available and reproducible
methods to measure TLs selected for response assessment and to assess NTLs and 
identification of new lesions.
In this study it is recommended that CT examinations will be used to assess tumour burden at 
baseline and follow-up visits.  CT examination with intravenous contrast media administration 
is the preferred method.  MRI should be used where CT is not feasible or it is medically 
contra-indicated.  For assessment of brain lesions MRI is the preferred method.
Clinical examination 
Clinical examination will not be used for assessment of TLs.  Clinically detected lesions can 
be selected as TLs if they are then assessed by CT or MRI scans.  Clinical examination can be 
used to assess NTLs in patients that also have other lesions assessable by CT, MRI and to 
identify the presence of new lesions.


Clinical Study Protocol Appendix I
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
101 (111)
X-rays
Plain X-ray
Plain X-rays may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions. 
Chest X-ray
Chest X-rays will not be used for assessment of TLs as they will be assessed by CT or MRI 
examination.  Chest X-rays can, however, be used to assess NTLs and to identify the presence 
of new lesions.
Ultrasound 
Ultrasound examination will not be used for assessment of TLs and NTLs as it is not a 
reproducible method, does not provide an accurate assessment of tumour size and it is 
subjective and operator dependent. Ultrasound examination can, however, be used to identify 
the presence of new lesions.  If new clinical symptoms occur and an ultrasound is performed 
then new lesions should be confirmed by CT or MRI examination.
Endoscopy and laparoscopy
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour measurements.
Tumour markers 
Tumour markers will not be used for tumour response assessments per RECIST 1.1.
Cytology and histology 
Histology will not be used as part of the tumour response assessment 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 the appearance of a 
clinically significant effusion (requiring change in drug therapy) during the study treatment 
will be considered to be progression of NTLs or disease progression due to new lesions.
FDG-PET scan 
FDG-PET (fluorodeoxyglucose positron emission tomography) 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 (defined as when an uptake greater than twice 
that of the surrounding tissue is observed) not present on baseline FDG-PET scan or in a 
location corresponding to a new lesion on CT/MRI at the same follow-up visit.  If there is no 
baseline FDG-PET scan available, and no evidence of new lesions on CT/MRI scans then 
follow-up CT/MRI assessments should be continued, scheduled as per protocol or clinical 
indicated, in order to confirm new lesions.


Clinical Study Protocol Appendix I
Drug Substance Olaparib, AZD2281, KU 0059436
Study Code D0816C00020
Version 3.0
Date 26 October 2018
102 (111)
Tumour response evaluation 
Schedule of evaluation
Baseline tumour assessments should encompass all areas of known predilection for metastases 
in the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual patients and should be performed no more than 28 
days before the start of study treatment.  Follow-up assessments should be performed 
according to the study schedule (Table 2) after the start of treatment until discontinuation of 
study treatment or withdrawal of consent.  Any other sites at which new disease is suspected 
should also be adequately imaged at follow-up.
Target lesions
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved, should be identified as TLs at baseline.  
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions) but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimetres.  At baseline, the sum of the diameters for all TLs will be calculated and reported 
as the baseline sum of diameters.  At follow-up visits the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters.  
Special cases:

For TLs measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short 
axis. 

If the CT/MRI slice thickness used is > 5mm, the minimum size of measurable 
disease at baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the longest diameter should be recorded as 
0 mm.

If a TL splits into two or more parts, then record the sum of the diameters of those 
parts

If two or more TLs merge then the sum of the diameters of the combined lesion 
should be recorded for one of the lesions and 0 mm recorded for the other lesion(s)

If a TL is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned.  If an accurate measure can be given, this 
should be recorded, even if it is below 5mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate 
of the size of the lesion

When a TL has had any intervention eg, radiotherapy, embolisation, surgery etc, 
during the study, the size of the TL should still be provided where possible


Clinical Study Protocol Appendix I
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Study Code D0816C00020
Version 3.0
Date 26 October 2018
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Evaluation of target lesions
Table 8 provides the definitions of the criteria used to determine objective tumour visit 
response for TLs.
Table 8
Overall Visit Response for Target Lesions
Complete Response (CR)
Disappearance of all TLs since baseline.  Any pathological 
lymph nodes selected as TLs must have a reduction in short axis 
to < 10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of diameters of TLs, taking as 
reference the baseline sum of diameters.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD.
Progressive Disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5mm.
Not Evaluable (NE)
Only relevant if any of the TLs were not assessed or not 
evaluable or had a lesion intervention at this visit.
Note: If the sum of diameters meets the progressive disease 
criteria, progressive disease overrides not evaluable as a TL 
response
Non-Target lesions
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline.  Measurements are not required for these lesions but their status should be followed 
at subsequent visits.  At each visit, an overall assessment of the NTL response should be 
recorded by the investigator.  Table 9 provides the definitions of the criteria used to determine 
and record overall response for NTLs at the investigational site at each visit.
Table 9
Overall Visit Response for Non-Target Lesions
Complete Response (CR)
Disappearance of all NTLs since baseline.  All lymph nodes must 
be non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD
Persistence of one or more NTLs.
Progressive Disease (PD)
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions.  In all cases the progression MUST 
clinically significant for the physician to consider changing or 
stopping therapy


Clinical Study Protocol Appendix I
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Not Evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and in the investigator’s opinion they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: For patients without TLs at baseline, this is relevant if any 
of the NTLs were not assessed at this visit and the progression 
criteria have not been met.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumour burden has increased sufficiently to merit discontinuation of therapy.  A 
modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for 
unequivocal progression status.
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.
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.
Patients with ‘symptomatic deterioration’ requiring discontinuation of study treatment without 
objective evidence of disease progression at that time will undergo no further tumour 
assessments in this study.  Tumour response data for such patients will be censored at the date 
of their last RECIST assessment.
Evaluation of Overall Visit Response and Best Overall Response
The overall visit response will be derived using the algorithm shown in Table 10
Table 10
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


Clinical Study Protocol Appendix I
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Version 3.0
Date 26 October 2018
105 (111)
Table 10
Overall Visit Response
Target lesions
Non-Target lesions
New Lesions
Overall response
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
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease
IR = incomplete response, NE = not evaluable, NA = not applicable (relevant when no TLs/NTLs at baseline)
Specifications for Radiological Imaging
These notes are recommendations for use in clinical studies.  The use of standardised 
protocols for CT and MRI allows comparability both within and between different studies, 
irrespective of where the examination has been undertaken.
CT Scan
CT scans of the chest, abdomen, and pelvis should be contiguous throughout all the 
anatomical regions of interest.  
The most critical CT image acquisition parameters for optimal tumour evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval.
Anatomic coverage
Optimal anatomic coverage for most solid tumours is the chest, abdomen and pelvis.  
Coverage should encompass all areas of known predilection for metastases in the disease 
under evaluation and should additionally investigate areas that may be involved based on 
signs and symptoms of individual patients.  Because a lesion later identified in a body part not 
scanned at baseline would be considered as a new lesion representing disease progression, 
careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points.  This will enable better consistency not only of tumour 
measurements but also identification of new disease.
Intravenous contrast administration
Optimal visualisation and measurement of metastases in solid tumours requires consistent 
administration (dose and rate) of intravenous contrast as well as timing of scanning.  
Typically, most abdominal imaging is performed during the portal venous phase and 
(optimally) about the same time frame after injection on each examination.  An adequate 
volume of a suitable contrast agent should be given so that the metastases are demonstrated to 
best effect and a consistent method is used on subsequent examinations for any given patient.  


Clinical Study Protocol Appendix I
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Study Code D0816C00020
Version 3.0
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106 (111)
It is very important that the same technique be used at baseline and on follow- up 
examinations for a given patient.  For patients who develop contraindications to contrast after 
baseline contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or 
non-enhanced) should be performed should also be based on the tumour type, anatomic 
location of the disease and should be optimised to allow for comparison to the prior studies if 
possible.  Each case should be discussed with the radiologist to determine if substitution of 
these other approaches is possible and, if not, the patient should be considered not evaluable 
from that point forward.  Care must be taken in measurement of TLs on a different modality 
and interpretation of non-target disease or new lesions, since the same lesion may appear to 
have a different size using a new modality.  Oral contrast is recommended to help visualise 
and differentiate structures in the abdomen.
If iodine contrast media is medically contraindicated at baseline or at any time during the 
course of the study then the recommended methods are: CT thoracic examination without 
contrast and abdominal and pelvic MRI with contrast.  If MRI cannot be performed then CT 
without intravenous contrast is an option for the thorax, abdomen and pelvic examinations.  
Slice thickness and reconstruction material
It is recommended that CT scans be performed at 5mm contiguous slice thickness and this 
guideline presumes a minimum 5 mm thickness in recommendations for the measurable lesion 
definition.  Exceptionally, particular institutions may perform medically acceptable scans at 
slice thicknesses greater than 5 mm.  If this occurs, the minimum size of measurable lesions at 
baseline should be twice the slice thickness of the baseline scans.
All window settings should be included in the assessment, particularly in the thorax where 
lung and soft tissue windows should be considered.  When measuring lesions, the TLs should 
be measured on the same window setting for repeated examinations throughout the study.  All 
images from each examination should be included in the assessment and not “selected” 
images of the apparent lesion.
MRI Scan
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity 
and measurement.  Furthermore, the availability of MRI is variable globally.  The modality 
used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  Generally, axial imaging of the abdomen and 
pelvis with T1 and T2 weighted imaging along with gadolinium-enhanced imaging should be 
performed.  The field of view, matrix, number of excitations, phase encode steps, use of fat 
suppression and fast sequences should be optimised for the specific body part being imaged as 
well as the scanner utilised.  It is beyond the scope of this appendix to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts and diseases.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques if possible.
For these reasons, CT is the imaging modality of choice.


Clinical Study Protocol Appendix I
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Study Code D0816C00020
Version 3.0
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107 (111)
FDG-PET scans
FDG-PET has gained acceptance as a valuable tool for detecting, staging and restaging several 
malignancies.  If  FDG-PET scans are included in a protocol, an FDG uptake period of 60 min 
prior to imaging has been decided as the most appropriate for imaging of  patients with 
malignancy. Whole-body acquisition is important since this allows for sampling of all areas 
of interest and can assess if new lesions have appeared thus determining the possibility of 
interval progression of disease. Images from the base of the skull to the level of the mid-thigh 
should be obtained 60 min post injection.  PET camera specifications are variable and 
manufacturer specific, so every attempt should be made to use the same scanner, or the same 
model scanner, for serial scans on the same patient.  Whole-body acquisitions can be 
performed in either 2- or 3-dimensional mode with attenuation correction, but the method 
chosen should be consistent across all patients and serial scans in the clinical trial.
PET/CT scans
At present, low dose or attenuation correction CT portions of a combined PET–CT are of 
limited use in anatomically based efficacy assessments and it is therefore suggested that they 
should not be substituted for dedicated diagnostic contrast enhanced CT scans for tumour 
measurements by RECIST 1.1.  In exceptional situations, if a site can document that the CT 
performed as part of a PET–CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast) then the CT portion of the PET–CT can be used for RECIST measurements.  
However, this is not recommended because the PET portion of the CT introduces additional 
data that may bias an investigator if it is not routinely or serially performed.
REFERENCES
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij 
J.  New response evaluation criteria in solid tumours: Revised RECIST guideline (version 
1.1). European Journal of Cancer.  45 (2009) 228-247.


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SAP_003.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Statistical Analysis Plan 
Drug Substance  
Olaparib, AZD2281, KU 
Study Code 
D0816C00020 
Edition Number 
2.0 
Date 
09/December/2019 
OPINION - A Phase IIIb, Single-arm, Open-label Multicentre Study of 
Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed non-
Germline BRCA Mutated Ovarian Cancer Patients who are in Complete or 
Partial Response Following Platinum based Chemotherapy 
 
 
 
 


PPD
PPD


PPD


Statistical Analysis Plan 
Drug Substance Olaparib, AZD2281, KU 0059436  
Study Code D0816C00020 
Edition Number 2.0 
Date 09/Dec/2019 
4 
TABLE OF CONTENTS 
PAGE 
TABLE OF CONTENTS ......................................................................................................... 4 
LIST OF TABLES ................................................................................................................... 7 
LIST OF FIGURES .................................................................................................................. 7 
LIST OF ABBREVIATIONS .................................................................................................. 8 
AMENDMENT HISTORY .................................................................................................... 11 
1. 
STUDY DETAILS ................................................................................................. 17 
1.1 
Study objectives ..................................................................................................... 17 
1.2 
Study design ........................................................................................................... 19 
1.3 
Number of subjects ................................................................................................ 20 
2. 
ANALYSIS SETS ................................................................................................. 21 
2.1 
Definition of analysis sets ...................................................................................... 21 
2.2 
Violations and deviations ....................................................................................... 22 
3. 
PRIMARY AND SECONDARY VARIABLES ................................................... 23 
3.1 
Derivation of RECIST responses ........................................................................... 23 
3.1.1 
Evaluation of target lesions .................................................................................... 23 
3.1.2 
Evaluation of non-target lesions ............................................................................ 31 
3.1.3 
New lesions ............................................................................................................ 31 
3.1.4 
Overall response ..................................................................................................... 32 
3.2 
Primary variable ..................................................................................................... 32 
3.2.1 
Progression-free survival ....................................................................................... 32 
3.3 
Secondary variables ............................................................................................... 33 
3.3.1 
Time to first subsequent therapy or death .............................................................. 33 
3.3.2 
Time to treatment discontinuation or death ........................................................... 34 
3.3.3 
Progression-free survival by HRD subgroups ....................................................... 34 
3.3.4 
Chemotherapy-free interval ................................................................................... 35 
3.3.5 
Overall survival ...................................................................................................... 35 
3.3.6 
Functional assessment of cancer therapy – ovarian (trial outcome index) ............ 36 
3.4 
Safety variables ...................................................................................................... 37 
3.4.1 
Exposure ................................................................................................................ 37 
3.4.1.1 
Drug exposure ........................................................................................................ 37 
3.4.1.2 
Dose intensity ......................................................................................................... 37 
3.4.2 
Adverse events ....................................................................................................... 38 
3.4.2.1 
Adverse events of special interest .......................................................................... 38 
3.4.2.2 
Other significant adverse events ............................................................................ 38 
3.4.3 
Laboratory results .................................................................................................. 39 
3.4.3.1 
Clinical chemistry, hematology and urinalysis ...................................................... 39 


Statistical Analysis Plan 
Drug Substance Olaparib, AZD2281, KU 0059436  
Study Code D0816C00020 
Edition Number 2.0 
Date 09/Dec/2019 
5 
3.4.4 
ECOG ..................................................................................................................... 40 
3.4.5 
Vital signs .............................................................................................................. 40 
3.5 
Exploratory variables ............................................................................................. 40 
3.5.1 
Progression-free survival by important characteristics .......................................... 40 
3.5.2 
Overall survival by TP53 disruption status ............................................................ 41 
3.5.3 
Functional assessment of cancer therapy – ovarian (subscales and total 
scores) .................................................................................................................... 41 
3.5.4 
Plasma and red cell folate, and plasma B12 .......................................................... 42 
3.5.5 
EuroQol five dimensions, five levels ..................................................................... 42 
3.5.6 
Correlation between HRD status and ctDNA ........................................................ 43 
4. 
ANALYSIS METHODS ....................................................................................... 43 
4.1 
General principles .................................................................................................. 43 
4.1.1 
Baseline definition ................................................................................................. 43 
4.1.2 
General descriptive statistics .................................................................................. 43 
4.1.3 
Rules for handling missing data ............................................................................. 44 
4.1.4 
Data cut-off ............................................................................................................ 45 
4.1.5 
Visit windows ........................................................................................................ 46 
4.2 
Analysis methods ................................................................................................... 48 
4.2.1 
Baseline descriptive analysis ................................................................................. 48 
4.2.1.1 
Patient disposition .................................................................................................. 48 
4.2.1.2 
Protocol deviations ................................................................................................. 48 
4.2.1.3 
Demographics and baseline characteristics............................................................ 48 
4.2.2 
Medical/surgical history and blood transfusion ..................................................... 49 
4.2.3 
Medication and prior cancer therapy/radiotherapy ................................................ 50 
4.2.4 
Primary variable ..................................................................................................... 50 
4.2.4.1 
Sensitivity analyses of the primary variable .......................................................... 51 
4.2.5 
Secondary variables ............................................................................................... 51 
4.2.5.1 
Time to first subsequent therapy or death .............................................................. 51 
4.2.5.2 
Time to study treatment discontinuation or death .................................................. 51 
4.2.5.3 
Progression-free survival by HRD subgroups ....................................................... 52 
4.2.5.4 
Chemotherapy-free interval ................................................................................... 52 
4.2.5.5 
Overall survival ...................................................................................................... 52 
4.2.5.6 
Functional assessment of cancer therapy – ovarian ............................................... 52 
4.2.6 
Exploratory variables ............................................................................................. 54 
4.2.6.1 
Progression-free survival by important clinical characteristics ............................. 54 
4.2.6.2 
Overall survival by TP53 disruption status ............................................................ 54 
4.2.6.3 
Functional assessment of cancer therapy – ovarian ............................................... 55 
4.2.6.4 
EuroQol five dimensions, five levels ..................................................................... 55 
4.2.7 
Safety variables ...................................................................................................... 55 
4.2.7.1 
Drug exposure ........................................................................................................ 55 
4.2.7.2 
Adverse events ....................................................................................................... 56 
4.2.7.3 
Laboratory assessments ......................................................................................... 57 
4.2.7.4 
Vital signs .............................................................................................................. 58 
4.2.7.5 
ECOG performance status ..................................................................................... 58 


Statistical Analysis Plan 
Drug Substance Olaparib, AZD2281, KU 0059436  
Study Code D0816C00020 
Edition Number 2.0 
Date 09/Dec/2019 
6 
5. 
INTERIM ANALYSES ......................................................................................... 59 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL ............................................... 59 
7. 
REFERENCES ...................................................................................................... 60 
8. 
APPENDICES ....................................................................................................... 61 
8.1 
Examples of dose intensity calculations ................................................................ 61 
 
 
 
 
CCI


Statistical Analysis Plan 
Drug Substance Olaparib, AZD2281, KU 0059436  
Study Code D0816C00020 
Edition Number 2.0 
Date 09/Dec/2019 
7 
LIST OF TABLES 
Table 1: Study Outcome Measures and Analysis Sets ........................................................... 21 
Table 2: Target Lesion (TL) Visit Responses ........................................................................ 26 
Table 3: Non-Target Lesion (NTL) Visit Responses ............................................................. 31 
Table 4: Overall Visit Responses ........................................................................................... 32 
Table 5: Classification of TOI Change from Baseline ........................................................... 37 
Table 6: Laboratory Safety Variables ..................................................................................... 39 
Table 7: ECOG Performance Status ....................................................................................... 40 
Table 8: Visit Windows .......................................................................................................... 47 
Table 9: Example of Olaparib Dosing .................................................................................... 61 
 
LIST OF FIGURES 
Figure 1: Protocol Schedule ................................................................................................... 20 
 


Statistical Analysis Plan 
Drug Substance Olaparib, AZD2281, KU 0059436  
Study Code D0816C00020 
Edition Number 2.0 
Date 09/Dec/2019 
8 
LIST OF ABBREVIATIONS 
Abbreviation or special term 
Explanation 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase/transaminase 
AML 
acute myeloid leukemia 
AST 
aspartate aminotransferase/transaminase 
ATC 
Anatomical Therapeutic Chemical 
BRCA  
breast cancer susceptibility gene  
CI 
confidence interval 
CM 
concomitant medication 
CR 
complete response 
CSR 
clinical study report 
CT 
computed tomography 
ctDNA 
circulating tumor deoxyribonucleic acid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT-FI 
chemotherapy-free interval 
CTMS 
clinical trial management system 
DCO 
data cut-off 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EQ-5D-5L 
EuroQol five dimensions, five levels 
EWB 
emotional well-being 
FACT-O 
Functional Assessment of Cancer Therapy – Ovarian 
FAS 
full analysis set 
FWB 
functional well-being 
gBRCA 
germline BRCA 
gBRCAm 
germline BRCA mutation (or mutated) 
HGSOC 
high-grade serous ovarian cancer 
HRD 
homologous recombination deficiency 


Statistical Analysis Plan 
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Abbreviation or special term 
Explanation 
HRQoL 
health-related quality of life 
HRR 
homologous recombination repair  
IMP 
Investigational medical product 
KM 
Kaplan-Meier 
LD 
longest diameter 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
NA 
not applicable 
NTL 
non-target lesion 
OAE 
other significant adverse event 
OCS 
ovarian cancer subscale 
OS 
overall survival 
PFS 
progression-free survival 
PID 
percentage intended dose 
PR 
partial response 
PRO 
patient-reported outcome 
PSR 
platinum sensitive relapsed 
PT 
preferred term 
PWB 
physical well-being 
Q1 
first quartile 
Q3 
third quartile 
RDI 
relative dose intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
REML 
restricted maximum likelihood 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


Statistical Analysis Plan 
Drug Substance Olaparib, AZD2281, KU 0059436  
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Edition Number 2.0 
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Abbreviation or special term 
Explanation 
SAS 
safety analysis set 
sBRCA 
somatic BRCA 
SD 
stable disease 
SOC 
System Organ Class 
SWB 
social/family well-being 
TBL 
total bilirubin 
tBRCA 
tumor BRCA 
TDT 
time to treatment discontinuation or death 
TFST 
time to first subsequent therapy or death  
TL 
target lesion 
TOI 
trial outcome index 
TP53 
tumor protein p53 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WHODrug 
World Health Organization Drug Dictionary 
 
 


Statistical Analysis Plan 
Drug Substance Olaparib, AZD2281, KU 0059436  
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AMENDMENT HISTORY 


Statistical Analysis Plan 
Drug Substance Olaparib, AZD2281, KU 0059436  
Study Code D0816C00020 
Edition Number 2.0 
Date 09/Dec/2019 
12 
Category: 
Change refers to 
Date 
Description of change 
In line with 
CSP?  
Y (version) / 
N / NA 
Rationale 
Primary or secondary 
endpoints 
09 December 
2019 
Redefined the HRD 
subgroups for the 
progression-free survival 
analysis (sections 3.3.3 
and 4.2.5.3). 
N 
Based on evolving 
science and to generate 
olaparib efficacy data in 
sBRCAm population. 
Primary or secondary 
endpoints 
09 December 
2019 
Included a sensitivity 
analysis of the primary 
endpoint should there be a 
significant number of 
important protocol 
deviations reported 
(section 4.2.4.1).  
NA 
In order to assess impact 
of important protocol 
deviations on the primary 
endpoint. 
Primary or secondary 
endpoints 
09 December 
2019 
The interim analysis will 
also include the reporting 
of secondary endpoints 
(section 5). 
NA 
Updated based on 
regulatory feedback. 
Derivation of primary 
or secondary endpoints 
09 December 
2019 
Refined rules for patients 
with no evidence of 
disease at baseline 
(section 3.1.1) and 
updated the overall visit 
response definition of 
patients without any 
target lesions, non-target 
lesions at baseline and no 
new lesions post baseline 
(section 3.1.4; Table 4).  
NA 
In order to further 
clarify/correct derivations. 


Statistical Analysis Plan 
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Derivation of primary 
or secondary endpoints 
09 December 
2019 
Removed the derivation 
column (section 3.1.1; 
Table 2 and Table3).  
NA 
Removed as more 
appropriate for 
programming 
documentation. 
Derivation of primary 
or secondary endpoints 
09 December 
2019 
Updated the text for 
censoring for the 
endpoints time to first 
subsequent therapy or 
death and time to 
chemotherapy-free 
interval (sections 3.3.1 
and 3.3.4). 
NA 
In order to further clarify 
censoring rules and 
ensure alignment across 
outcome variables. 
Derivation of primary 
or secondary endpoints 
09 December 
2019 
Added details to 
determine the last 
recorded date on which 
the patient was known to 
be alive (section 3.3.5). 
NA 
Undertaken to clarify 
where to censor patients 
who are alive and not in 
overall survival follow-
up. 
Data presentations 
09 December 
2019 
Removed a sentence 
regarding the calculation 
of percentages with 
respect to missing values 
(section 4.1.2). 
NA 
Removed as this sentence 
is not applicable to all 
summary tables i.e. 
demographic summaries 
Data presentations 
09 December 
2019 
Tables presented by visit 
will also include study 
treatment discontinuation 
and follow-up after 
treatment discontinuation 
visits (sections 4.2.5.6 and 
4.2.6.3). The time 
window definition for 
those visits has been 
added (section 4.1.5). 
NA 
Clarified in order to 
match with the 
requirements of the table 
shell. 


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Data presentations 
09 December 
2019 
Patients 
ongoing/discontinuing 
study treatment categories 
included in the disposition 
summary table (section 
4.2.1.1). 
NA 
In order to present the full 
list of disposition contents 
as per the table shell. 
Data presentations 
09 December 
2019 
Updated format of 
demographic and 
exposure summaries 
(section 4.2.1.3 and 
section 4.2.7.1). 
NA 
In order to match the 
requirements of the table 
shells and clarify 
derivations. 
Data presentations 
09 December 
2019 
Updated the format of 
event and censored 
categories (sections 
4.2.5.1, 4.2.5.2, 4.2.5.4 
and 4.2.5.5). 
NA 
Clarified in order to 
match the requirements of 
the table shell. 
Data presentations 
09 December 
2019 
Removed reference to the 
presentation of p-values 
(section 4.2.5.6). 
NA 
Since no statistical test is 
planned in this single arm 
study. 
Other 
09 December 
2019 
Updated the definition of 
the important protocol 
deviations (section 2.2). 
NA 
Updated the list to key 
criteria aligned with the 
AZ Oncology SAP 
guidance.  
Other 
09 December 
2019 
Included the definition of 
time on study (section 
3.4.1.1).  
NA 
In order to clarify the 
derivation of this variable. 
Other 
09 December 
2019 
Updated the adverse 
events of special interest 
definition (section 
3.4.2.1) and included 
summary tables for the 
common olaparib AEs 
(section 4.2.7.2)  
NA 
Updated to align with the 
standard project safety 
reporting 
rules/summaries. 


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Other 
09 December 
2019 
Removed the reporting of 
PFS stratified into a range 
of molecular subgroups 
including microsatellite 
instability status and 
tumor mutation load score 
(sections 3.5.1 and 
4.2.1.3). 
N 
Removed since such an 
analysis when split by 
such groups is unlikely to 
be meaningful i.e., 
microsatellite instability-
H prevalence is very low 
in ovarian cancer; tumor 
mutation burden cut off of 
high vs low has not been 
established in ovarian 
cancer. 
Other 
09 December 
2019 
Included death as an event 
in time to PRO-
deterioration (section 
3.5.3) 
NA 
Included since death is 
standardly included as an 
event. 
Other 
09 December 
2019 
Added details of the 
components of the EQ-5D 
questionnaire (section 
3.5.5) 
NA 
In order to aid 
understanding. 
Other 
09 December 
2019 
Imputation rules for 
missing stop dates 
updated (section 4.1.3). 
NA 
In order to provide more 
accurate data handling 
rules of missing stop 
dates compared to dose 
dates. 
Other 
09 December 
2019 
Clarified the text for the 
data cut-off definitions 
(section 4.1.4). 
NA 
In order to clarify the data 
cut-off principles for the 
interim and primary PFS 
analyses as well as OS. 


Statistical Analysis Plan 
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Study Code D0816C00020 
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Other 
09 December 
2019 
Amended the percentages 
for relative dose intensity 
and percentage intended 
dose examples (section 
8.1). 
NA 
In order to correct errors 
noted. 
 
 
 


Statistical Analysis Plan 
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1. 
STUDY DETAILS 
1.1 
Study objectives 
The study objectives are as follows: 
Primary Objective:  
Outcome Measure: 
To determine the efficacy by progression-free 
survival (PFS) (investigator-recorded assessments 
according to modified Response Evaluation 
Criteria In Solid Tumors [RECIST v1.1]) of 
olaparib maintenance monotherapy in non-
germline breast cancer susceptibility gene (BRCA) 
mutated (non-gBRCAm) platinum sensitive 
relapsed (PSR) ovarian cancer. 
• PFS: Time from date of first dose until the 
date of objective radiological disease 
progression according to modified RECIST 
1.1 or death (by any cause in the absence of 
progression) 
Secondary Objectives:  
Outcome Measures: 
To determine the efficacy of olaparib maintenance 
monotherapy in non-gBRCAm PSR ovarian 
cancer by assessment of time to first subsequent 
therapy or death (TFST) 
• TFST: Time from date of first dose to date of 
first subsequent treatment commencement or 
death due to any cause if this occurs before 
commencement of first subsequent treatment 
To determine the efficacy of olaparib maintenance 
monotherapy in non-gBRCAm PSR ovarian 
cancer by assessment of time to treatment 
discontinuation or death (TDT) 
• TDT: Time from date of first dose to date of 
study drug discontinuation or death due to any 
cause if this occurs before study drug 
discontinuation 
To determine the efficacy by PFS (investigator-
recorded assessments according to modified 
RECIST v1.1) of olaparib maintenance in non-
gBRCAm PSR ovarian cancer according to tumor 
homologous recombination deficiency (HRD) 
status using the Myriad myChoice plus 
HRD test 
• PFS in the following subgroups: 
1. Somatic BRCA (sBRCA) mutated and HRD 
scar positive; 
2. HRD scar positive, non-BRCA mutated; 
3. HRD scar negative, non-BRCA mutated 
 


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To determine the efficacy of olaparib maintenance 
monotherapy in non-gBRCAm PSR ovarian 
cancer by assessment of chemotherapy-free 
interval (CT-FI) 
• CT-FI: Time from the date of the last dose of 
platinum chemotherapy prior to olaparib 
maintenance therapy until the date of initiation 
of the next anticancer therapy 
To determine the overall survival (OS) of non-
gBRCAm PSR ovarian cancer patients treated 
with olaparib maintenance monotherapy 
• OS: Time from the date of first dose of 
olaparib to the date of death from any cause 
To investigate the Health-related Quality of Life 
(HRQoL) of non-gBRCAm PSR ovarian cancer 
patients treated with olaparib maintenance 
monotherapy as assessed by the trial outcome 
index (TOI) of the Functional Assessment of 
Cancer Therapy – Ovarian (FACT-O) 
• Proportion of patients with any improvement 
from baseline in TOI score at any point during 
the treatment period 
• Proportion of patients with a 10 point 
deterioration from baseline in TOI score at 
any point during the treatment period 
Safety Objective:  
Outcome Measures: 
To assess the safety and tolerability of olaparib 
maintenance monotherapy in patients with non-
gBRCAm PSR ovarian cancer 
• Adverse events (AEs)/serious adverse events 
(SAEs) 
• Collection of clinical chemistry/hematology 
parameters 
Exploratory Objectives:  
Outcome Measures: 
To explore the efficacy by PFS (investigator-
recorded assessments according to modified 
RECIST v1.1) of olaparib maintenance 
monotherapy in non-gBRCAm PSR ovarian 
cancer patients stratified into a range of molecular 
sub-groups including mutations in Homologous 
recombination repair (HRR) genes, microsatellite 
instability (MSI) status, and tumour mutation load 
score.   
• PFS by molecular measures of HRR and 
genomic instability 
To explore the impact of tumor protein p53 
(TP53) disruption status on both OS and PFS 
• OS and PFS by TP53 disruption status 


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To explore the impact of treatment and disease 
state on health state utility by EuroQoL five 
dimensions, five levels (EQ-5D-5L) 
• EQ-5D index score and the EQ-visual analog 
scale (VAS) score including the change from 
baseline for both scores 
To explore the feasibility of reliably identifying 
mutations in homologous recombination genes 
from circulating tumor deoxyribonucleic acid 
(ctDNA) and to enable future diagnostic 
development 
• Correlation between HRD status from tumor 
and ctDNA in matched patient samples 
 
1.2 
Study design 
This is a Phase IIIb, single-arm, open-label multicenter study to assess the efficacy and safety 
of single-agent olaparib as a maintenance treatment in patients with relapsed high-grade 
serous ovarian cancer (HGSOC) (including patients with primary peritoneal and/or fallopian 
tube cancer) or high grade endometrioid cancer who do not have known deleterious or 
suspected deleterious germline BRCA mutations (gBRCAm) and who had responded following 
platinum-based chemotherapy.  
Olaparib will be administered to all patients in this single-arm study (see Figure 1) at a 
starting dose of 300 mg twice daily. Dose reductions may be required in patients experiencing 
toxicities related to olaparib treatment or due to concomitant medication (CM).  
Tumor assessments will be conducted every 8 weeks (± 7 days) in the first 12 months of 
follow-up, and thereafter every 12 weeks up to documented evidence of radiological disease 
progression in accordance to modified RECIST v1.1. The first tumor assessment visit will be 
conducted 8 weeks after the baseline visit (Day 57). Safety assessments will be conducted 
every 8 weeks (± 3 days) starting 4 weeks after the baseline visit (Day 29). Laboratory data 
and pregnancy tests are assessed at each visit. Eastern Cooperative Oncology Group (ECOG) 
will be performed at each tumor assessment visit. Safety-specific visits will cease after the 
first 12 months and safety tests will then be conducted at the tumor assessment visits only. 


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Figure 1: Protocol Schedule 
 
 
1.3 
Number of subjects 
The primary endpoint is the investigator assessed PFS using modified RECIST v1.1.   
A sample size of approximately 250 patients is proposed for this study in order to provide an 
adequate level of precision around the primary endpoint in the whole patient population. The 
primary analysis is planned at approximately 30 months after the first patient is enrolled, with 
an interim analysis after approximately 18 months. A supplementary analysis of OS will be 
performed when 135 OS events (~ 54% maturity) have been recorded, estimated to be 
approximately 36 months after the first patient is enrolled.  
In published data (Study D0810C00019, Study PR-30-5011-C/NOVA) on non-gBRCAm 
patients treated with a polyadenosine 5’diphosphoribos polymerisation inhibitor, the median 
PFS ranged from 8 to 9 months compared to 4–5.5 months for those treated with placebo. 
Clinical trial simulations were performed assuming 250 patients enrolled over a 12-month 
period with 50% of patients enrolled after 8 months, a median PFS of 8.5 months and a 
piecewise exponential model for PFS. Across 500 simulations, it was estimated that the 
expected number of PFS events would be approximately 135 at 18 months (54% maturity) and 


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180 at 30 months (72% maturity), with a corresponding mean 95% confidence interval (CI) 
width of 3.87 and 3.27 months, respectively. 
 
2. 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
Four main analysis sets are defined for this study.  
Full Analysis Sets: 
Full Analysis Set (FAS). The FAS consists of all patients enrolled during the target enrolment 
period and assigned to olaparib. Patients are considered enrolled once it is confirmed that they 
meet all eligibility criteria (including non-gBRCAm status) 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. 
 
Safety Analysis Sets: 
Safety Analysis Set (SAS). The SAS consists of all patients in the FAS who have received at 
least one dose of olaparib. 
 
Patient-reported outcomes (PRO) Analysis Sets: 
FACT-O Set. The FACT-O Set consists of all FAS patients with at least a baseline and a 
post-baseline assessment (excluding the end of treatment and 30-day follow-up assessments). 
EQ-5D-5L Set. The EQ-5D-5L Set consists of all FAS patients with at least a baseline and a 
post-baseline assessment (excluding the end of treatment and 30-day follow-up assessments). 
 
Table 1: Study Outcome Measures and Analysis Sets 
Study Outcome Measures 
Analysis Set(s) 
Demographics and baseline characteristics 
FAS 
Important protocol deviations 
FAS 
Primary 
Outcome 
PFS 
FAS 
TFST 
FAS 


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Study Outcome Measures 
Analysis Set(s) 
Secondary 
Outcomes 
TDT 
FAS 
PFS by HRD subgroups 
FAS  
CT-FI 
FAS 
OS 
FAS 
FACT-O TOI score  
FACT-O Set 
Safety 
Outcomes 
AE/SAE 
SAS 
Clinical chemistry/hematology parameters 
SAS 
Exploratory 
Outcomes 
PFS by molecular measures of HRR and genomic instability 
FAS 
PFS and OS by TP53 disruption status 
FAS 
FACT-O subscales and total score 
FACT-O Set 
EQ-5D-5L index  
EQ-5D-5L Set 
EQ-VAS score 
EQ-5D-5L Set 
 
2.2 
Violations and deviations 
The following general categories will be considered important protocol deviations and will be 
programmatically derived from the electronic case record form (eCRF) data.  These will be 
listed and discussed in the clinical study report (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 (inclusion 
criteria 3, 4, 5, 6, and 12, and exclusion criteria 4, 5, 8, 9, 11, 12, and 13) (Deviation 
2).   
• 
Baseline RECIST 1.1 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 Clinical Study Protocol 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 lock.  


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The important protocol deviations will be listed and summarised using the FAS.  Deviation 1 
will lead to exclusion from the SAS. None of the other deviations will lead to patients being 
excluded from the analysis sets described in section 2.1.   
3. 
PRIMARY AND SECONDARY VARIABLES 
3.1 
Derivation of RECIST responses 
Patients with measurable or non-measurable disease or no evidence of disease assessed at 
baseline by computed tomography (CT)/ magnetic resonance imaging (MRI) will be entered 
in this study.  RECIST 1.1 (Eisenhauer et al, 2009) has been modified to allow for the 
assessment of progression due to new lesions in patients with no evidence of disease at 
baseline. For all patients, the RECIST tumor response data will be used to determine each 
patient’s visit response according to modified RECIST version 1.1.  This tumor response data 
will also be used to determine if, and when, a patient has progressed in accordance with 
RECIST, and also to determine the patients’ best overall response.   
RECIST assessment should be performed no more than 28 days before the start of study 
treatment, and should be ideally performed as close as possible to the start of study treatment.  
Subsequent tumor assessments will be conducted every 8 weeks (±7 days) for the first 12 
months and then every 12 weeks (± 7 days) until documented disease progression. 
If an unscheduled assessment was performed and the patient had not progressed, every 
attempt should be made to perform the subsequent assessments at their scheduled visits. This 
schedule is to be followed, to minimize any unintentional bias caused by some patients being 
assessed at a different frequency than other patients. 
At each visit, an overall visit response will be determined using the information from target 
lesions (TLs), non-target lesions (NTLs) and new lesions. For the investigator assessments 
this will be done programmatically and the RECIST outcomes will be calculated using a 
computer program. Progression for patients with no evidence of disease at study enrollment 
will be assessed on the appearance of new lesions (see section 3.1.3 below). 
   
3.1.1 
Evaluation of target lesions 
Measurable disease is defined as having at least one measurable lesion, not previously 
irradiated, which is ≥ 10 mm in the longest diameter (LD) (except lymph nodes which must 


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have short axis ≥ 15 mm) with CT or MRI and which is suitable for accurate repeated 
measurements. A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ 
(including lymph nodes), representative of all lesions involved, should be identified as TLs at 
baseline. The site and location of each TL should be documented as well as the LD for non-
nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimeters. 
Note: For patients who do not have measurable disease at entry (i.e. no TLs) but have non-
measurable disease, evaluation of overall visit responses will be based on the overall NTL 
assessment and the absence/presence of new lesions.  If a patient does not have measurable 
disease at baseline then the TL visit response will be not applicable (NA).   
For patients with no evidence of 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 the baseline visit, both the TL and NTL visit response will be recorded 
as NA and the overall visit response will be no evidence of disease, unless progressive disease 
occurs due to presence of new lesions. 
At baseline, the sum of the diameters for all TLs will be calculated and reported as the 
baseline sum of diameters. At follow-up visits the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters: 
At each visit the sum of TLs LD will be calculated as: 
• Visit (i) total TLs diameter (mm) = Sum of visit (i) (TL1: TL5) LD; 
Where (i) is any visit where the tumor assessment is performed. 
 
The % change from baseline sum of TLs LD will be calculated as: 
• % Change from baseline total TLs diameter = 100*(Visit (j) total TLs diameter 
(mm) – Baseline total TLs diameter)/(Baseline total TLs diameter); 
Where (j) is any post-baseline visit where the tumor assessment is performed. 
 
The previous smallest sum of total TLs diameter on study at visit (i) will be calculated as: 
• Previous smallest total TLs diameter (mm) = min (Visit (1 to i-1) total TLs 
diameter); 


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This is to be repeated for each visit. 
 
At each visit, the difference from the previous smallest sum of total TLs diameter will be 
calculated as: 
• Change from previous smallest total TLs diameter (mm) = (Visit (i) total TLs 
diameter – previous smallest total TLs diameter at visit (i)) 
 
The % change from the previous smallest sum of total TLs diameter will be calculated (for 
each visit) only if the previous smallest total TLs diameter > 0 as: 
• % Change from previous smallest total TLs diameter = 100*(Change from 
previous smallest total TLs diameter) / (Previous smallest total TLs diameter); 
Table 2 provides the definitions of the criteria that are used to determine the objective tumor 
visit response for TLs. 
 


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Table 2: Target Lesion (TL) Visit Responses 
Visit 
Responses 
Description 
Complete 
Response (CR) 
Disappearance of all TLs since baseline. Any pathological lymph nodes selected 
as TLs must have a reduction in short axis to < 10 mm. 
Partial 
Response (PR) 
At least a 30% decrease in the sum of diameters of TLs, taking as reference the 
baseline sum of diameters. 
Progressive 
Disease (PD) 
At least a 20% increase in the sum of diameters of TLs, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5mm. 
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD. 
Not Evaluable 
(NE) 
Only relevant if any of the TLs were not assessed or not evaluable or had a lesion 
intervention at this visit. Note: If the sum of diameters meets the progressive 
disease criteria, progressive disease overrides not evaluable as a TL response 
Not applicable 
(NA) 
No TLs are recorded at baseline. 
 
Rounding of TL data: 
For calculation of PD and PR for TLs percentage changes from baseline and previous 
minimum should be rounded to 1 decimal place before assigning a TL response.  For example 
19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%. 
Missing TL data: 
For a visit to be evaluable then all TL measurements should be recorded.  However, a visit 
response of PD should still be assigned if any of the following occurred: 
• 
A new lesion is recorded 
• 
A NTL visit response of PD is recorded 


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• 
The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute 
increase of ≥ 5mm, from nadir even assuming the non-recorded TLs have 
disappeared 
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 and the sum of lesions meets the 
criteria for PD then response will be set to PD. 
• 
Step 4:  If after steps 1 – 3 a response can still not be determined the response will 
be set to remain as CR. 
TL too big to measure 


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If a TL becomes too big to measure this should be indicated in the database and a size (‘x’) 
above which it cannot be accurately measured should be recorded. If using a value of x in the 
calculation of TL response would not give an overall visit response of PD, then this will be 
flagged and reviewed by the study team. It is expected that a visit response of PD will remain 
in the vast majority of cases. 
TL too small to measure 
If a TL becomes too small to measure a value of 5mm will be entered into the database and 
used in TL calculations, unless the radiologist has indicated and entered a smaller value that 
can be reliably measured.  If a TL response of PD results then this will be reviewed by the 
study team. 
Irradiated lesions/lesion intervention 
Previously irradiated lesions (i.e. lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment. 
Any TL (including lymph nodes), which has had intervention during the study (for example, 
irradiation / palliative surgery / embolisation), should be handled in the following way and 
once a lesion has had intervention then it should be treated as having intervention for the 
remainder of the study noting that an intervention will most likely shrink the size of tumors: 
• 
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 patient would be assigned a TL response of 
PD. 


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• 
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 0mm (or <10mm for lymph nodes) and the lesions that have 
been subject to intervention also have a value of 0mm 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 TL 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). 
Example of scaling 
Lesion 
Longest diameter at nadir 
visit (cm) 
Longest diameter at follow-up 
visit (cm) 
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 
 


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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 28.4 cm: 
 
 
CR will not be allowed as a TL response for visits where there is missing data. Only PR, SD 
or PD (or NE) could be assigned as the TL visit response in these cases.  However, for visits 
with 1/3 lesion assessments not recorded, the scaled up sum of TLs diameters will be 
included when defining the nadir value for the assessment of progression. 
Lesions that split in two 
If a TL splits in two, then the LDs of the split lesions should be summed and reported as the 
LD for the lesion that split. 
Lesions that merge 
If two TLs merge, then the LD of the merged lesion should be recorded for one of the TL 
sizes and the other TL size should be recorded as 0cm. 
Change in method of assessment of target lesions 
CT, MRI and clinical examination are the only methods of assessment that can be used within 
the trial, with CT and MRI being the preferred methods and clinical examination only used in 
special cases (see study protocol for more information of tumor 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. 
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. 
cm
4.
28
3.
29
8.
26
26
=



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3.1.2 
Evaluation of non-target lesions 
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline.  Measurements are not required for these lesions but their status should be followed 
at subsequent visits.  At each visit, an overall assessment of the NTL response should be 
recorded by the investigator. Table 3  provides the definitions of the criteria used to determine 
and record the overall response for NTLs at the investigational site at each visit. 
Table 3: Non-Target Lesion (NTL) Visit Responses 
Visit 
Responses 
Description 
Complete 
Response 
(CR) 
Disappearance of all NTLs since baseline. All lymph nodes must be non-
pathological in size (< 10 mm short axis). 
Non-CR/Non-
PD 
Persistence of one or more NTLs. 
Progressive 
Disease (PD) 
Unequivocal progression of existing NTLs. Unequivocal progression may be due 
to an important progression in one lesion only, or in several lesions. In all cases the 
progression MUST be clinically significant for the physician to consider changing 
or stopping therapy. 
Not Evaluable 
(NE) 
Only relevant when one or some of the NTLs were not assessed and in the 
investigator’s opinion they are not able to provide an evaluable overall NTL 
assessment at this visit. Note: For patients without TLs at baseline, this is relevant 
if any of the NTLs were not assessed at this visit and the progression criteria have 
not been met. 
Not 
Applicable 
(NA) 
Only relevant if there are no NTLs at baseline 
 
3.1.3 
New lesions 
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. 
 


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3.1.4 
Overall response 
The overall visit response will be derived using the algorithm shown in Table 4: 
 
Table 4: Overall Visit Responses 
TLs 
NTLs 
New Lesions Overall Response 
NA 
NA 
No 
NED 
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  
NE 
Non-PD or NE 
No 
NE 
NA 
NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease,  
NA = not applicable, NE = not evaluable, NED = no evidence of disease. 
 
3.2 
Primary variable 
3.2.1 
Progression-free survival 
PFS is defined as the time from the date of the first dose of olaparib, until the date of objective 
radiological disease progression according to RECIST 1.1 or death (by any cause in the 
absence of progression), regardless of whether the patient withdraws from treatment or 
receives another anti-cancer therapy prior to progression (in months) and is calculated as 
follows:  
• PFS (months): ((earliest of [date of progression; date of death] or date of censoring) – start 
date of olaparib + 1) / 30.4375. 


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Patients who have not progressed or died at the date of data cut-off (DCO), will be censored at 
the time of the latest date of tumor assessment according to modified RECIST v1.1. 
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 tumor assessment prior to the two missed visits.  
Two missed visits will equate to more than 18 weeks follow-up since the previous RECIST 
assessment occurred during the first 12 months, or more than 26 weeks follow-up if the last 
evaluable assessment occurred on or after the ‘week-48’ visit (allowing for visit windows). If 
the patient has no evaluable visits they will be censored at Day 1, unless they die within two 
visits (17 weeks allowing for visit window) from baseline. 
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: 
• 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. 
Censored patients’ follow-up time (months) will be calculated as follows: 
• (date of censoring – start date of olaparib + 1) / 30.4375. 
3.3 
Secondary variables 
3.3.1 
Time to first subsequent therapy or death 
TFST is defined as the time from the date of the first dose of olaparib to the earliest of the 
dates of death or commencement of first subsequent anticancer treatment.  
• TFST (months): ((earliest of [date of death; start date of anticancer treatment post-
baseline] or date of censoring) – start date of olaparib + 1) / 30.4375. 
Patients who are alive and have not been recorded as taking a subsequent anticancer treatment, 
will be censored at the last date that the patient was known not to have received a first 
subsequent anti-cancer therapy i.e., these patients will be censored at the earliest of their last 
known to be alive and termination dates.  


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The subsequent anticancer therapies will be documented as follows: 
• Therapy Class (Platinum Chemotherapy, Taxane Chemotherapy, PARP 
Inhibitor, Immunotherapy, Hormonal Therapy, Cytotoxic Chemotherapy, 
Targeted Therapy, Antiangiogenic Therapy, Radiopharmaceuticals, Other) 
• Agent name (Anatomical Therapeutic Chemical [ATC] class and preferred 
name) 
3.3.2 
Time to treatment discontinuation or death 
TDT is defined as the time from the date of the first dose olaparib to the earliest of the dates of 
death or discontinuation of olaparib.  
• TDT (months): ((earliest of [date of death; date of discontinuation of olaparib] or date 
of censoring) – start date of olaparib + 1) / 30.4375. 
Patients who are alive and are still receiving olaparib will be censored at the last recorded date 
they are known to be alive.  
3.3.3 
Progression-free survival by HRD subgroups 
PFS as described in section 3.2.1 will be also performed in the following subgroups:  
- 
HRD scar positive and/or sBRCA mutated;  
- 
HRD scar positive, non-BRCA mutated;  
- 
HRD scar negative, non-BRCA mutated. 
- 
sBRCA mutated.  
The Myriad myChoice HRD plus test will return HRD scar results as a numerical value and 
will identify patients with a deleterious or suspected deleterious mutation in tumor BRCA 
(tBRCA). An HRD score ≥42 will be considered as HRD scar positive. The Myriad 
BRCAnalysis CDx test will identify patients with a deleterious or suspected deleterious 
mutation in germline BRCA (gBRCA). 
 
sBRCA mutated patients will be identified as those that have a deleterious or suspected 
deleterious mutation in tBRCA by the Myriad myChoice HRD plus assay and an absence of 
deleterious or suspected deleterious mutation in gBRCA by the Myriad BRCAnalysis CDx 
test. Non-BRCA mutated patients will be identified by having an absence of a deleterious or 
suspected deleterious mutation in both tBRCA and gBRCA as determined by the relevant test. 


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3.3.4 
Chemotherapy-free interval 
CT-FI is defined as the time from the date of the last dose of platinum chemotherapy in the 
course, immediately prior to enrolment in the study until the date of commencement of the 
first subsequent anticancer treatment (whether or not this is chemotherapy).  
• CT-FI (months): ((start date of anticancer treatment post-baseline or date of censoring) 
– last dose date of platinum chemotherapy + 1) / 30.4375. 
Patients who are alive and have not been recorded as taking a subsequent anticancer treatment, 
will be censored at the last date that the patient was known not to have received a first 
subsequent anti-cancer therapy i.e., these patients will be censored at the earliest of their last 
known to be alive and termination dates. Patients who have died prior to the start of a 
subsequent anticancer treatment will be censored at their date of death. 
3.3.5 
Overall survival 
OS is defined as the time from the date of the first dose of olaparib to the date of death from 
any cause, with patients alive at the data cut-off date censored on the last recorded date on 
which the patient was known to be alive. 
• OS (months): (date of death or date of censoring) – start date of olaparib + 1) / 
30.4375. 
For any OS analysis performed prior to the final OS analysis, in the absence of survival calls 
being made, it may be necessary to use all relevant CRF fields to determine the last recorded 
date on which the patient was known to be alive for those patients still on treatment (since the 
SURVIVE CRF page is only completed for patients off treatment if a survival sweep is not 
performed). The last date for each individual patient is defined as the latest among the 
following dates recorded on the CRFs: 
• 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 CRF 


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• Start and stop dates of alternative anticancer treatment 
• Date last known alive on survival status CRF 
• End of study date 
3.3.6 
Functional assessment of cancer therapy – ovarian (trial outcome index) 
The secondary endpoint for HRQoL analysis will be the TOI score. The FACT-O is composed 
of the following subscales: physical, social/family, emotional, and functional well-being 
(FWB) as well as the additional concerns scales consisting of specific ovarian cancer 
symptoms (see Appendix G in Clinical Study Protocol). The TOI score will be derived from 
the sum of the scores of the 25 items included in the physical well-being (PWB) (7 items), 
FWB (7 items), and ovarian cancer subscale (OCS) (11 items) of the FACT-O questionnaire 
version 4. 
 
For each patient the subscales and the TOI will be calculated as follows: 
• Physical well-being (PWB): 
o If the number of available items n(PWB) is ≥ 4 then: 
PWB=7*[(4-gp1)+(4-gp2)+(4-gp3)+(4-gp4)+(4-gp5)+(4-gp6)+(4-gp7)] / 
n(PWB); 
o If n(PWB) is <4 then set PWB to missing. 
• Functional well-being (FWB): 
o If the number of available items n(FWB) is ≥ 4 then: 
FWB=7*[gf1+ gf2+ gf3+ gf4+ gf5+ gf6+ gf7] / n(FWB); 
o If n(FWB) is <4 then set FWB to missing. 
• Ovarian cancer subscale (OCS): 
o If the number of available items n(OCS) is ≥ 6 then: 
OCS= 11*[(4-o1)+(4-c2)+c3+(4-o2)+c6+c7+bmt5+b9+(4-o3)+bl4+(4-b5)] / 
n(OCS); 
o If n(OCS) is <6 then set OCS to missing. 
Missing items will not concur to the calculation of the scores. 
• TOI = PWB + FWB + OCS. 
 
CCI


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TOI absolute values and change from baseline will be calculated for each patient at each visit. 
For each post-baseline visit a patient will be classified as in Table 5: 
Table 5: Classification of TOI Change from Baseline 
Category 
TOI change from baseline 
Improved 
>0 
Deteriorated* 
≤ -10 
No change 
[-9; 0] 
TOI = trial outcome index. 
* If a patient has a baseline TOI <10, she will not be included in the denominator to evaluate the 
proportion of patients that have deteriorated. 
 
3.4 
Safety variables 
Safety and tolerability will be assessed in terms of drug exposure, dose intensity, AEs, SAEs, 
adverse events of special interest (AESIs), other significant adverse events (OAEs), laboratory 
data (chemistry, hematology, and urinalysis), vital signs and the ECOG performance status. 
3.4.1 
Exposure 
3.4.1.1 
Drug exposure 
The total treatment duration will be derived irrespective of treatment interruptions, by using 
the following formula: 
• Total treatment exposure (months) = (last dose date - first dose date + 1) / 30.4375. 
The actual treatment exposure is equal to the total treatment exposure, excluding dose 
interruptions and cases when the patient forgot to take a dose (this calculation does not take 
dose reductions into account).  
The time on study will be derived using the following formula: 
• Time on study (months) = (earliest (date last known to be alive, date of termination) – 
first dose date + 1) / 30.4375. 
3.4.1.2 
Dose intensity 
Dose intensity will be derived by the following two standard definitions: relative dose 
intensity (RDI) and percentage intended dose (PID). 


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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. 
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 the Appendix (section 8.1). 
 
3.4.2 
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 during the regular follow-up for OS if the patient 
has developed an AESI of Myelodysplastic syndrome (MDS) or Acute myeloid leukemia 
(AML) or a new primary malignancy. 
 
3.4.2.1 
Adverse events of special interest 
AESIs for olaparib are MDS/AML, new primary malignancy (other than MDS/AML) and 
pneumonitis.  
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). 
3.4.2.2 
Other significant adverse events  
An AstraZeneca medically qualified expert will review the list of AEs extracted from the 
database, and identify AEs of particular interest that were not reported as SAEs or AEs 
leading to discontinuation. Examples of these could be marked as hematological and other 


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laboratory abnormalities, and certain events that lead to an intervention (other than those 
already classified as serious), dose reduction or significant additional treatment. These AEs 
will be indicated by the AstraZeneca expert as OAEs. The list of OAEs will then be integrated 
in the derived datasets to report them separately. 
3.4.3 
Laboratory results 
3.4.3.1 
Clinical chemistry, hematology and urinalysis 
Blood samples for the determination of clinical chemistry, hematology and urinalysis, will be 
taken at screening, baseline, visit 3 (Day 29), every 4 weeks thereafter during the first year of 
follow-up, every 12 weeks after 12 months follow-up, at study treatment discontinuation, and 
at follow-up 30 days after the last dose of the study treatment. Urine samples for the 
determination of urinalysis will be taken at screening, baseline and as clinically indicated 
thereafter. 
The following variables of clinical chemistry, hematology and urinalysis will be analyzed in 
this study (Table 6).  
Table 6: Laboratory Safety Variables 
Hematology/Hemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Hemoglobin (Hb) 
S/P-Creatinine 
B-Leukocyte count 
S/P-Bilirubin, total 
B-Absolute neutrophil count 
S/P-Alkaline phosphatase (ALP) 
B-Absolute lymphocyte count 
S/P-Aspartate aminotransferase/transaminase 
(AST) 
B-Platelet count 
S/P-Alanine aminotransferase/transaminase 
(ALT) 
 
B-Mean cell volume (MCV) 
S/P-Albumin 
S/P-Calcium 
S/P-Potassium 
Urinalysis (dipstick) 
S/P-Sodium 
U-Hb/Erythrocytes/Blood  
S/P-Urea or Blood Urea Nitrogen (BUN) 
U-Protein/Albumin  
S/P-Total Protein 
U-Glucose  
 


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3.4.4 
ECOG 
ECOG (Oken M et al, 1982) performance status (see Table 7) is performed at screening, 
baseline, at the start of each tumor assessment visit (Visit 4 and thereafter every 8 weeks for 
the first 12 months, every 12 weeks thereafter) and at the treatment discontinuation visit.  
Table 7: ECOG Performance Status 
 
 
3.4.5 
Vital signs 
Weight, pulse, blood pressure (systolic and diastolic), and body temperature will be assessed 
at screening, baseline and as clinically indicated thereafter.  
 
3.5 
Exploratory variables 
3.5.1 
Progression-free survival by important characteristics 
PFS as defined in section 3.2.1 of this SAP will be summarized according to subgroups based 
on important clinical characteristics, which will include Myriad myChoice HRD plus test 
parameters: 
- 
HRR deleterious or suspected deleterious mutation (yes vs. no) 
- 
Disruptive or non-disruptive mutation in TP53 (yes vs. no) 
and data collected in the electronic case report form (eCRF):  
- 
Best response to the last platinum regimen (CR or PR); 
- 
Prior use of bevacizumab in combination with the penultimate platinum regimen; 
- 
Number of prior platinum regimens (two vs. greater than two); 
- 
Degree of sensitivity to the penultimate platinum chemotherapy: partial (6-12 months 
PFS) vs. fully (≥12 months PFS) sensitive; 
GRADE 
ECOG performance status 
0 
Normal activity 
1 
Restricted activity 
2 
In bed less than or equal to 50% of the time 
3 
In bed more than 50% of the time 
4 
100% bedridden 
5 
Death 


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o Previous platinum chemotherapy PFS will be defined as the time from the date 
of the last dose of the penultimate platinum chemotherapy to the date of disease 
progression (in their penultimate platinum chemotherapy). 
- 
Histological subtype (HGSOC vs. high grade endometrioid cancer). 
o Serous vs. endometrioid. 
- 
Measurable disease vs. non-measurable disease vs. no evidence of disease at baseline 
o Measurable disease is defined as having at least one measurable lesion, not 
previously irradiated, which is ≥ 10 mm in LD (except lymph nodes which 
must have short axis ≥ 15 mm) with CT or MRI at the baseline visit. 
o Non-measurable disease is defined as patients with NTLs but no TLs at the 
baseline visit. 
o No disease at baseline is defined as no TLs and no NTLs at baseline. 
- 
Age (years) at enrolment (<65 vs. >=65). 
3.5.2 
Overall survival by TP53 disruption status 
- 
OS as defined in section 3.3.5 will be repeated by: Disruptive or non-disruptive 
mutation in TP53 (yes vs. no).  
3.5.3 
Functional assessment of cancer therapy – ovarian (subscales and total scores) 
FACT-O subscale and total scores will be included in exploratory analyses, PWB (7 items), 
social/family well-being (SWB) (7 items), emotional well-being (EWB) (6 items), FWB (7 
items), OCS (11 items). FACT-O total score (all 38 items), PRO-deterioration free (10-point 
TOI deterioration) survival will also be explored.  
For PWB, FWB and OCS subscales’ scoring refer to section 3.3.6. The other scores will be 
calculated as follows: 
• Social/family well-being (SWB): 
o If the number of available items n(SWB) is >=4 then: 
SWB =7*[gs1+gs2+gs3+gs4+gs5+gs6+gs7] / n(SWB); 
o If n(SWB) is <4 then set SWB to missing. 
• Emotional well-being (EWB): 
o If the number of available items n(EWB) is >=3 then: 
EWB=6*[(4-ge1)+ge2+(4-ge3)+(4-ge4)+(4-ge5)+(4-ge6)] / n(EWB); 


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o If n(EWB) is <3 then set EWB to missing. 
Missing items will not concur to the calculation of the scores. 
• FACT-O total score = PWB + FWB + OCS + SWB + EWB. 
PRO-deterioration free survival is defined as the time from the date of first dose of olaparib, 
until the earliest date a patient became ‘deteriorated’ as described in section 3.3.6. 
• PRO-deterioration (months): (earliest of [date of deterioration; date of death] or date of 
censoring – start date of olaparib + 1) / 30.4375. 
Patients who have not been classified as ‘deteriorated’ until the time of analysis will be 
censored at the time of the latest date of FACT-O assessment. 
3.5.4 
Plasma and red cell folate, and plasma B12  
It is possible that the macrocytic anaemia associated with olaparib administration in a 
proportion of patients is associated with reduced folate or B12 levels. To investigate whether 
levels are reduced during maintenance treatment with olaparib, plasma and red cell folate 
levels, and plasma B12 levels will be measured at baseline/Visit 2 and at the end of 
treatment/treatment discontinuation visit. Samples will be analyzed at a central laboratory. 
These analyses are outside of the scope of this SAP and will not be included in the CSR. 
These analyses will be described and reported elsewhere. 
3.5.5 
EuroQol five dimensions, five levels 
The EQ-5D questionnaire is made up of two components; health state description and 
evaluation. In the description part, health status is measured in terms of five dimensions; 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Patients will self-
rate their level of severity for each dimension using a five-level scale. In the evaluation part, 
the respondents evaluate their overall health status using the visual analogue scale (EQ-VAS) 
(see Appendix H in Clinical Study Protocol).  
EQ-5D index and the EQ-VAS score including the change from baseline for both scores will 
be summarized. The EQ-5D-5L profile will be converted into a weighted health state utility 
value, termed the EQ-5D index, by applying a country-specific equation to the profile that 
represents the comparative value of health states. This equation is based on national valuation 
sets elicited from the general population. Where a valuation set has not been published, the 


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EQ-5D-5L profile will be converted to the EQ-5D index using a crosswalk algorithm (van 
Hout et al 2012). The EQ-VAS will be reported separately.  
3.5.6 
Correlation between HRD status and ctDNA  
Biomarker analysis: Correlation between HRD score and ctDNA levels. 
ctDNA levels will be assessed at screening and treatment discontinuation visits. The HRD 
score will be performed using the Myriad’s myChoice HRD plus test. These analyses are 
outside of the scope of this SAP and will not be included in the CSR.  These analyses will be 
described and reported elsewhere.   
 
4. 
ANALYSIS METHODS 
Statistical analysis and generation of all tables, listings and figures will be performed using 
SAS® (SAS Institute, North Carolina), version 9.4 or higher. 
4.1 
General principles 
Patients’ listings of key data represented in the 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 
tumor assessments that will be considered for PFS evaluation. In general, the patient listings 
will be sorted by patient number and assessment date (and time), if applicable.  
4.1.1 
Baseline definition 
Baseline is defined to be the last evaluable measurement prior to starting treatment. Change 
from baseline will be derived for each visit where there is available data.  
4.1.2 
General descriptive statistics 
Categorical variables will be summarized as frequency counts and percentages (%) of patients 
in each category. As general rules, descriptive statistics will be drawn on patients with 
available data. Counts of missing data will be provided in all tables for information only. 
Percentages will be rounded up to one decimal place. 
Continuous variables will be presented as the number of observations (n), mean, standard 
deviation, median, first and third quartiles (Q1 and Q3; presented only for selected variables), 
minimum and maximum. The same number of decimal places as in the raw data will be 


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presented when reporting minimum and maximum, one more decimal place than in the raw 
data will be presented when reporting mean, median, Q1 and Q3, and two more decimal 
places than in the raw data will be presented when reporting standard deviation. 
4.1.3 
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 analyzed and presented as they are recorded 
in the database. The extent of missing data will be indicated for all variables in descriptive 
tables.  
 
The below partially missing dates will be imputed as per the phUSE guidelines. Imputation 
rule is assuming the worst / make the most conservative judgment when imputing AE and CM 
start/stop dates. Duration of AE/CM should not be derived using imputed dates. The purpose 
of imputing a start date is to help define whether the AE/CM 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 CM. 
 
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. 


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- 
Completely missing – need to look at whether the AE/CM is still ongoing before 
imputing a date and also when it started in relation to study drug. For CM if the 
ongoing flag is marked or the ongoing flag is missing then assume that the CM is still 
being taken (i.e. do not impute a date). If the AE/CM 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. 
Note that “M” implies that both the day and month are imputed, and “Y” implies day, month, 
and year are all imputed. 
 
4.1.4 
Data cut-off 
1. The DCO for the interim analysis will be approximately 18 months after the first patient 
is enrolled, when approximately 135 PFS events have occurred. Additional follow-up 
data will be collected after the DCO for the primary analysis approximately 30 months 
after first patient is enrolled (a minimum period of 18 months from last patient is 
enrolled), when approximately 180 PFS events have occurred. A supplementary analysis 
of OS is expected when approximately 135 death events have occurred, estimated to be 
approximately 36 months after the first patient is enrolled.    
2. Survival calls will be performed in the week following the date of DCO for the 
primary PFS analysis and supplementary analysis of OS, and if patients are confirmed 
to be alive or if the death date is past the DCO date these patients will be censored at 
the date of DCO.  
The status of ongoing, withdrawn (from the study) and “lost to follow-up” patients at 
the time of the primary PFS analysis (and final supplementary OS analysis) should be 
obtained by site personnel by checking the patient’s notes, hospital records, contacting 
the patient’s general practitioner and checking publicly available death registries. In 
the event that the patient has actively withdrawn consent for the processing of their 


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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. 
3. PRO questionnaires (FACT-O and EQ-5D-5L) will be collected from the patient at 
baseline, at day 29, at day 57 and every 8 weeks for the first 12 months, then every 12 
weeks (+/- 7 days), at study treatment discontinuation visit and at follow-up 30 days 
after the last dose of the study treatment. 
4.1.5 
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 8. 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 8: Visit Windows 
Visit 
Day 
Safety assessments 
(Laboratory) 
ECOG/Tumor 
assessments 
Questionnaire 
assessments  
 
 
Visit window (min : max) 
Screening 
Up to Day 1 
(-28 : -1) 
Day 1, Baseline 
Day 1 
(1 : 1) 
Day 29 
Day 29 
(2 : 43) 
 
(2 : 43) 
Week 8 
Day 56 
(44 : 70) 
(2 : 84) 
(44 : 98) 
Week 12 
Day 84 
(71 : 98) 
 
 
Week 16 
Day 112 
(99 : 126) 
(85 : 140)  
(99 : 140) 
Week 20 
Day 140 
(127 : 154) 
 
 
Week 24 
Day 168 
(155 : 182) 
(141 : 196) 
Week 28 
Day 196 
(183 : 210) 
 
 
Week 32 
Day 224 
(211 : 238) 
(197 : 252) 
Week 36 
Day 252 
(239 : 266) 
 
 
Week 40 
Day 280 
(267 : 294) 
(253 : 308) 
Week 44 
Day 308 
(295 : 322) 
 
 
Week 48 
Day 336 
(323 : 350) 
(309 : 378) 
Week 52 
Day 364 
(351 : 392) 
 
 
Week 60 
Day 420 
(393 : 462) 
(379 : 462) 
Week 72 
Day 504 
(463 : 546) 
Week 84 
Day 588 
(547 : 630) 
Week 96 
Day 672 
(631 : 700) 
Week 104 
Day 728 
(701 : 756) 
 
In addition, an End of Treatment visit will be identified as the visit occurring between 1 and 8 
days (inclusive) after the end of treatment. Similarly, a 30-day follow-up visit will be 
identified as the visit between 9 and 31 days (inclusive) following end of treatment. These 
additional points will allow summaries to be presented for these post-treatment visits. Values 
mapped both to scheduled and post-treatment visits will be assigned to both as per visit 
windows definition. 
If there is more than one value per patient within a time window then the closest value will be 
summarized, or the earlier value in the event the values are equidistant from the nominal visit 
day. For the End of Treatment and 30-day follow-up visits the earlier value will be 
summarized in case there is more than one per patient.  In case of multiple assessments within 
the same time window, if the closest/earlier assessment has missing values for one or more 
parameters then the missing records will be derived by the subsequent farther/later 
assessment.  


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Analysis visits will be determined based upon assessments dates and not on nominal visits 
designated in the database. 
4.2 
Analysis methods 
4.2.1 
Baseline descriptive analysis 
All baseline descriptive analyses except ‘patients disposition’ based on enrolled patients will 
be based on the FAS. 
4.2.1.1 
Patient disposition 
The following frequencies (number and percent) will be displayed for all patients.  
• Patients screened 
− 
Patients with screen failure and excluded from the study 
− 
Patients enrolled in the study. 
− 
Patients included in the FAS 
− 
Patients included in the SAS 
− 
Patients included in the FACT-O Set 
− 
Patients included in the EQ-5D-5L Set 
− 
Patients ongoing in the study 
− 
Patients discontinued 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 i.e. number of patients entered (including those who did not receive treatment but 
excludes screening failures), whether or not they are included in any of the analyses.  
4.2.1.2 
Protocol deviations 
A listing of important protocol deviations will be provided for all patients. 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.  
4.2.1.3 
Demographics and baseline characteristics 
Demographics and baseline characteristics will be listed and summarized for all patients in the 
FAS. Demographic characteristics include age, age group, race, ethnicity and country. Patient 


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baseline characteristics include heart rate (pulse), systolic and diastolic blood pressure, weight 
and body temperature. 
Age group is divided into four categories, i.e. <50, ≥50 - < 65, ≥ 65 - <75 and ≥ 75.  
Weight group is divided into three categories, i.e. < 70, ≥ 70 - ≤ 90, > 90. 
 
Baseline characteristics will also include: 
• General pathology characteristics at baseline, including Time from original diagnosis 
(years), primary tumor location, Federation of Gynecology and Obstetrics tumor stage, 
histology type, platinum sensitivity to the penultimate platinum chemotherapy, 
objective response to latest platinum-chemotherapy and overall disease classification.   
• Time from original diagnosis (years) = (date of informed consent – date of original 
diagnosis + 1) / 365.25. 
• BRCA testing performed at screening: local (blood, saliva/scraping or tumor) test or 
central (blood) test; absence of deleterious or suspected deleterious BRCA mutation 
(yes, no, unknown).    
• Tumor and blood central /Myriad tests: gBRCA status (BRCA1, BRCA2, both, 
negative, unknown); tBRCA status (BRCA1, BRCA2, both, negative, unknown), 
sBRCA status (positive, negative, unknown), HRD status (positive, negative, 
unknown), HRR mutation status (positive, negative, unknown), disruptive or non-
disruptive mutation TP53 mutation status according to tBRCA status (yes, no, 
unknown). 
• ECOG performance status at baseline (see Table 7 of section 3.4.4). 
• The extent of the disease at baseline (locally advanced or metastatic) and the 
corresponding sites.  
The frequency and % of the above baseline characteristics will be calculated. The descriptive 
summaries will be provided for time from original diagnosis (years). 
Categories will be summarized as they are collected in the eCRF. 
4.2.2 
Medical/surgical history and blood transfusion 
Medical and surgical history will be coded using the latest available version of MedDRA 
coding dictionary. The version of the coding dictionary used will be included in a footnote on 


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the output. Coded medical history terms will be summarized for the FAS, by MedDRA 
System Organ Class (SOC) and PT. SOC terms will be sorted alphabetically and then PTs will 
be sorted in order of frequency. 
Patient listings of coded medical and surgical history terms will be provided for the FAS. 
Blood products transfusions’ details (product type, units, volume, transfusion origin and date) 
will be listed for the FAS. 
4.2.3 
Medication and prior cancer therapy/radiotherapy 
A summary of the prior and CM received, prior cancer therapy and prior radiotherapy will be 
provided for the FAS. Medications (prior, concomitant) will be coded using the latest 
available version of World Health Organization Drug Dictionary (WHODrug). The 
WHODrug version used will be specified in the data display footnote. Prior and CMs will be 
presented in the same table and sorted alphabetically by ATC class (and preferred drug name). 
In addition a summary of previous disease-related treatment modalities (Platinum 
Chemotherapy, Taxane Chemotherapy, PARP Inhibitor, Immunotherapy, Hormonal Therapy, 
Cytotoxic Chemotherapy, Targeted Therapy, Antiangiogenic Therapy, Radiopharmaceuticals, 
Other). The count (%) of patients by number of previous platinum chemotherapy regimens 
received will be also presented. The summary of the number of previous regimens will be 
reported as well. Previous disease related-related chemotherapy treatments will also be 
presented by regimen order. 
All medications will be also listed for the FAS. 
4.2.4 
Primary variable 
PFS as defined in section 3.2.1 will be summarized using the total number and % of patients 
experiencing a PFS event and the type of event (RECIST progression or death in absence of 
progression). The number and % of censored patients will be presented including patients 
progression-free at the time of the analysis or discontinued the study.  
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 be also 
included.  


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PFS will be also presented in a KM graph that will include tick marks to identify censored 
observations and number at risk at baseline and at three-monthly intervals. The primary 
analysis will be based on the FAS. 
4.2.4.1 
Sensitivity analyses of the primary variable 
A sensitivity analysis may be performed on PFS excluding any patients from the FAS who did 
not have a negative gBRCAm status confirmed by the central Myriad test.  
Attrition bias will be assessed by repeating the PFS analysis using the actual PFS event times, 
rather than the censored times, of patients who progressed or died in the absence of 
progression immediately following two, or more, non-evaluable tumor assessments. In 
addition, and within the same sensitivity analysis, patients who take subsequent therapy prior 
to their last evaluable RECIST assessment or progression or death will be censored at their 
last evaluable assessment prior to taking the subsequent therapy. 
A ‘deviation bias’ sensitivity analysis may be performed on PFS excluding patients with 
important protocol deviations that may affect the efficacy of the trial therapy. The need for 
such a sensitivity analysis will be determined following review of the important protocol 
deviations ahead of database lock and will be documented prior to the primary analysis being 
conducted. 
 
4.2.5 
Secondary variables 
All the secondary analyses except PRO outcomes will be based on the FAS. 
4.2.5.1 
Time to first subsequent therapy or death 
TFST as defined in section 3.3.1 will be summarized in the same way as PFS as described in 
section 4.2.4.. The number and % of patients commencing subsequent anticancer treatment or 
died in the absence of subsequent anticancer treatment will be presented. The number and % 
of censored patients will be presented including patients who have not commenced subsequent 
anticancer treatment at time of the analysis or discontinued the study. 
The number and % of patients with any subsequent anticancer therapies and therapy class and 
agent names (coded as ATC) will be summarized. 
4.2.5.2 
Time to study treatment discontinuation or death 
TDT as defined in section 3.3.2 will be summarized in the same way as PFS as described in 
section 4.2.4. The number and % of patients who have discontinued treatment or died in the 


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absence of treatment discontinuation will be presented. The number and % of censored 
patients will be presented, these being patients who are still on treatment at the time of the 
analysis. 
4.2.5.3 
Progression-free survival by HRD subgroups 
PFS will be summarized in the same way as PFS as described in section 4.2.4 in the following 
subgroups as defined in section 3.3.3:  
- 
HRD scar positive and/or sBRCA mutated;  
- 
HRD scar positive, non-BRCA mutated;  
- 
HRD scar negative, non-BRCA mutated; 
- 
sBRCA mutated.  
Overlaid KM curves will be provided. 
4.2.5.4 
Chemotherapy-free interval 
CT-FI as defined in section 3.3.4 will be summarized in the same way as PFS as described in 
section 4.2.4. The number and % of patients who have commenced subsequent anticancer 
treatment will be presented. The number and % of censored patients will be presented 
including patients who have not commenced subsequent anticancer treatment at time of the 
analysis, discontinued the study or died prior to the start of a subsequent anticancer treatment. 
4.2.5.5 
Overall survival 
OS as defined in section 3.3.5 will be summarized in the same way as PFS as described in 
section 4.2.4. The number and % of patients who have died will be presented. The number and 
% of censored patients will be presented, these being patients who are still alive at the time of 
the analysis and those who discontinued the study prior to death. 
4.2.5.6 
Functional assessment of cancer therapy – ovarian 
Compliance 
Summary measures of overall compliance and compliance over time will be derived for the 
FACT-O questionnaire. These will be based upon: 
• 
Received forms = number of FACT-O forms received back plus the number not 
received back where the reason was patient ‘Too Affected by Symptoms of Disease 
Under Investigation’. 


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• 
Expected forms = number of patients still under HRQoL follow-up at the specified 
assessment time. 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 discontinuation will be 
mapped to the nearest visit date to define the number of expected forms. 
• 
Evaluable forms = subset of expected FACT-O forms with at least one subscale that 
can be determined; or where the reason the patient did not complete the form was 
‘Too Affected by Symptoms of Disease Under Investigation’. 
Thus the overall compliance rate is defined as the number of patients with an evaluable 
baseline and at least one evaluable follow-up form (as defined above), divided by the number 
of patients expected to have completed at least a baseline FACT-O form. 
Compliance over time will be calculated separately for each visit, including baseline, as the 
number of patients with an evaluable baseline form and a form at the time point (as defined 
above), divided by number of patients still expected to complete forms at that visit. Similarly, 
the evaluability rate over time will be calculated separately for each visit, including baseline, 
as the number of evaluable forms (per definition above), divided by the number of received 
forms. 
FACT-O trial outcome index 
The proportion of patients with any improvement from baseline in TOI score and the 
proportion of patients with at least a 10-point deterioration from baseline in TOI score (see 
definitions in section 3.3.6) will be estimated together with the exact 95% CI (i.e., Clopper-
Pearson CI).  
The TOI index score and the change from baseline will be summarized using descriptive 
statistics and presented for each follow-up time point including data post progression, where 
available.  
FACT-O TOI score will be also analyzed with a repeated measures analysis model. 
Change from baseline in TOI score will be analyzed using a mixed model for repeated 
measures (MMRM) analysis for each visit. The analysis will evaluate the visit effect from 
baseline to the last assessment (which will include visit data obtained at baseline, day 29 


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[week 4], weeks 8, 16, 24, 32, 40, 48, 60, 72, 84, 96, and 104. The treatment discontinuation 
and follow-up visits will not be included in the model.). 
The MMRM model will include patient and visit as explanatory variables, the baseline TOI 
score as a covariate along with the baseline TOI score by visit interaction. Visit will be the 
fixed effect in the model; patient will be included as a random effect. Restricted maximum 
likelihood (REML) estimation will be used. For each visit, the adjusted (least squares) mean 
estimates, corresponding 95% CIs, estimates of the visit difference, corresponding 95% CIs 
will be presented.   
An unstructured covariance matrix will be used to model the within-subject error and the 
Kenward-Roger approximation will be used to estimate the degrees of freedom. The following 
provides sample code for implementing the MMRM analysis:  
proc mixed data=TOI method = reml; 
   class VISIT SUBJECT; 
   model TOISC = VISIT TOIBL TOIBL*VISIT / s ddfm=kr; 
   repeated VISIT / type=UN subject=SUBJECT; 
   lsmeans VISIT / at means pdiff diff alpha=0.05 cl; 
where VISIT is the visit, TOISC is the change from baseline in the TOI score, and TOIBL is 
the baseline TOI score.  
If the fit of the unstructured covariance structure fails to converge, the following covariance 
structures will be tried until convergence is reached: toeplitz with heterogeneity, 
autoregressive with heterogeneity, toeplitz, and autoregressive. If there are still issues with the 
fit of the model or estimation of the effects, SUBJECT will be treated as a fixed effect. 
4.2.6 
Exploratory variables 
All the exploratory analyses except PRO outcomes will be based on the FAS. 
4.2.6.1 
Progression-free survival by important clinical characteristics 
Similar analyses will be performed as in section 4.2.4  for subgroups as defined in section 
3.5.1.  
4.2.6.2 
Overall survival by TP53 disruption status 
Similar analyses will be performed as in section 4.2.5.5 for subgroups as defined in section 
3.5.2.  


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4.2.6.3 
Functional assessment of cancer therapy – ovarian 
FACT-O total, PWB, FWB, OCS, SWB and EWB as described in sections 3.5.3 and 3.3.6 
absolute scores and change from baseline will be summarized using descriptive statistics and 
presented for each visit including data post progression, where available.  
4.2.6.4 
EuroQol five dimensions, five levels 
Summary measures of overall compliance and compliance over time will be derived for the 
EQ-5D-5L questionnaire using the same calculation described for the calculation of FACT-O 
compliance in section 4.2.5.6.  
The EQ-5D index and EQ-VAS absolute scores and change from baseline will be summarized 
using descriptive statistics and presented for each visit including data post progression, where 
available (excluding discontinuation and follow-up visits that will be only listed).  
The EQ-5D index and EQ-VAS will be also analyzed with repeated measures analyses model 
as described in section 4.2.5.6 for the FACT-O TOI. 
Graphical plots of the mean EQ-5D index and EQ-VAS absolute scores and change from 
baseline with associated 95% CI by scheduled visits will be produced. 
4.2.7 
Safety variables 
Safety and tolerability will be assessed in terms of drug exposure (see section 3.4.1), AEs, 
SAEs, AESIs and OAEs (see section 3.4.2), deaths (see section 6.3.12 of Clinical Study 
Protocol) and laboratory data (see section3.4.3), based on the SAS. 
4.2.7.1 
Drug exposure 
Duration of drug exposure (total and actual), time on study and dose intensity (RDI and PID) 
will be summarized using descriptive statistics (number of valid observations, mean, standard 
deviation, median, Q1, Q3, minimum and maximum). Cumulative sum will be presented for 
drug exposure and time on study only.  
In addition, the total number and % of patients with: 
• Any dose reduction / interruption / modification (i.e. either dose reduction and/or 
interruption); 
• 1 dose reduction / interruption / modification (i.e. either dose reduction and/or 
interruption); 


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• 2+ dose reductions / interruptions / modification (i.e. either dose reduction and/or 
interruption). 
The reasons for dose reduction, interruption and modification will also be included. 
4.2.7.2 
Adverse events 
The term AE is used to include both serious and non-serious AEs. AEs (both in terms of the 
MedDRA PTs and CTCAE grade) will be listed individually by patient and described by SOC 
and PT. Any AE occurring before treatment with olaparib will be included in the data listings 
but will not be included in the summary tables of AEs. Any AE occurring within 30 days of 
discontinuation of olaparib will be included in the AE summaries. Any events in this period 
that occur after a patient has received further therapy for cancer (following discontinuation of 
olaparib) will be flagged in the data listings. 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 by international order and then PT will be sorted in 
order of frequency 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 highest severity 
recorded based on CTCAE grade for the event will be presented.  
 
Two tables will summarize the following categories of AEs using (i) number and % of 
patients and (ii) number of events: 
• Any AE 
• Any AE by maximum reported CTCAE grade 
• Any AE causally related to study medication* 
• Any AE by maximum reported CTCAE grade 3 or higher 
• Any AE by maximum reported CTCAE grade 3 or higher causally related to study 
medication* 
• Any AE with outcome of death 
• Any AE with outcome of death causally related to study medication* 
• Any SAE (including events with outcome of death) 


Statistical Analysis Plan 
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• Any SAE (including events with outcome of death) causally related to study 
medication* 
• Any AE leading to olaparib discontinuation 
• Any AE leading to olaparib discontinuation causally related to study medication* 
• Any AE leading to olaparib interruption 
• Any AE leading to olaparib interruption causally related to study medication* 
• Any AE leading to olaparib reduction 
• Any AE leading to olaparib reduction causally related to study medication* 
• Any AE leading to olaparib modification 
• Any AE leading to olaparib modification causally related to study medication* 
* as assessed by the investigator. 
 
Summary tables will also be produced for the following common olaparib AEs, based on 
grouped preferred terms: 
• Anaemia 
• Neutropenia 
• Thrombocytopenia 
• Nausea 
• Vomiting 
• Fatigue/Asthenia 
 
All the AEs will be also listed by patient including: verbatim term, SOC, PT, AE start-stop 
dates, relative AE start day, AE occurred after receipt of further therapy for cancer (following 
discontinuation of olaparib), maximum CTCAE grade, SAE (Y/N), action taken with regard to 
olaparib, AE caused by olaparib, AE caused patient´s withdrawal from study (Y/N), outcome. 
4.2.7.3 
Laboratory assessments 
Blood and urine samples for determination of clinical chemistry, hematology and urinalysis 
will be taken at the times indicated in Table 1 and Table 2 of the Clinical Study Protocol, 
section 4. 
 


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Study Code D0816C00020 
Edition Number 2.0 
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All laboratory results and change from baseline in hematology and clinical chemistry will be 
summarized using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, min and 
max) and presented by visit. 
 
A shift table will be produced showing the number and % 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 and maximum value on treatment (classified as 
normal, abnormal and not done). 
 
For the evaluation of Hy’s law, a table will be produced showing the number of patients with 
maximum on-treatment alanine aminotransferase/transaminase (ALT) and aspartate 
aminotransferase/transaminase (AST) values greater than 3, 5 and 10 times the upper limit of 
normal (ULN) 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. 
 
A plot of ALT vs. TBL values will also be produced with reference lines at 3×ULN for ALT, 
and 2×ULN for TBL. A plot of AST vs. TBL values will also be produced with reference lines 
at 3×ULN for AST, and 2×ULN for TBL. In each plot, TBL will be in the vertical axis. 
Urinalysis results will be listed only. 
The complete clinical laboratory measurements will be listed by patient and date. 
4.2.7.4 
Vital signs 
Vital signs parameter values (weight, systolic blood pressure, diastolic blood pressure, pulse 
and body temperature) will be obtained at screening, baseline 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, these data will only be presented 
in a listing. 
4.2.7.5 
ECOG performance status 
The ECOG performance status will be summarized at baseline and by visit using frequency 
and %s for each category. The ECOG performance status shift table by visit will be provided 
as increased/worsened (change from baseline > 0), decreased/improved (change from baseline 


Statistical Analysis Plan 
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Study Code D0816C00020 
Edition Number 2.0 
Date 09/Dec/2019 
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< 0) and no change (change from baseline = 0) and the related frequency and % will be 
summarized.  
The complete ECOG performance status will be listed by patient and date. 
5. 
INTERIM ANALYSES 
An interim analysis of PFS will be performed approximately 18 months after the first patient 
is enrolled into the study. Based upon simulations (see section 8.2 in Clinical Study Protocol) 
it is estimated that approximately 135 events will have occurred at the time of the interim 
analysis, equating to approximately 54% data maturity. The primary focus of the interim 
analysis will be the primary and secondary endpoints and PFS by HRD status, the descriptive 
baseline characteristics and safety analyses.  
 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL 
The secondary objective concerning PFS according to tumor HRD status using the Myriad 
myChoice plus HRD test has been updated to include the following subgroups; (i) sBRCA 
mutated and/or HRD scar positive, (ii) HRD scar positive, non-BRCA mutated, (iii) HRD scar 
negative, non-BRCA mutated, and (iv) sBRCA mutated. 
 
The exploratory objective concerning PFS stratified into a range of molecular sub-groups 
including MSI status and tumor mutation load score will not be performed.  
 
 
 


Statistical Analysis Plan 
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Study Code D0816C00020 
Edition Number 2.0 
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7. 
REFERENCES 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij 
J.  New response evaluation criteria in solid tumours: Revised RECIST guideline (version 
1.1).  European Journal of Cancer.  45 (2009) 228-247. 
 
van Hout, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, Lloyd A, Scalone L, 
Kind P, Pickard AS. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L 
value sets. Value Health. 2012 Jul-Aug;15(5):708-15. 
 
 
 




Statistical Analysis Plan 
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Study Code D0816C00020 
Edition Number 2.0 
Date 09/Dec/2019 
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Patient 3: 
RDI = PID = (5 * 600 mg)/ 6000 mg = 50% 
Patient 4: 
RDI = PID = ((5 * 600 mg) + (4 * 400 mg))/ 6000 mg = 77% 
Patient 5: 
RDI = ((3 * 600 mg) + (2 * 400 mg))/ 4200 mg = 62% 
PID = ((3 * 600 mg) + (2 * 400 mg))/ 6000 mg = 43% 
 
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Study Code D0816C00020 
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Statistical Analysis Plan 
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Study Code D0816C00020 
Edition Number 2.0 
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Statistical Analysis Plan 
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Study Code D0816C00020 
Edition Number 2.0 
Date 09/Dec/2019 
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