A Phase IIIb, Randomised, Double-blind, Placebo-controlled, Multicentre Study of Olaparib Maintenance Retreatment in Patients With Epithelial Ovarian Cancer Previously Treated With a PARPi and Responding to Repeat Platinum Chemotherapy
Phase: PHASE3
Conditions: Epithelial Ovarian Cancer
Sponsor: AstraZeneca

 
 
 
 
 
 
 
 
 
 
 
 
A Phase IIIb, Randomised, Double-blind, Placebo-controlled, 
Multicentre Study of Olaparib Maintenance Retreatment in 
Patients with Epithelial Ovarian Cancer Previously Treated 
With a PARPi and Responding to Repeat Platinum 
Chemotherapy (OReO) 
 
 
 
 
ClinicalTrials.gov Identifier: NCT03106987 
 
 
 
 
 
Protocol Amendment No. 3: Final 4.0, 15 Oct 2020 

1 (150)
This submission/document contains trade secrets and confidential commercial information, disclosure of which is 
prohibited without providing advance notice to AstraZeneca and opportunity to object.
The following Amendment(s) and Administrative Changes have been made to this protocol 
since the date of preparation:
Amendment No.
Date of Amendment
Local Amendment No.
Date of Local Amendment
1
11 December 2017
2
04 January 2019
3
15 October 2020
Administrative 
Change No.
Date of Administrative 
Change
Local Administrative 
Change No.
Date of Local 
Administrative Change
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 
Drug Substance
Olaparib, AZD2281, 
KU-0059436
Study Code
D0816C00014
ENGOT Number
ENGOT-ov38/OReO
Version
4.0
Date
15 October 2020
A Phase IIIb, Randomised, Double-blind, Placebo-controlled, Multicentre Study of 
Olaparib Maintenance Retreatment in Patients with Epithelial Ovarian Cancer 
Previously Treated With a PARPi and Responding to Repeat Platinum Chemotherapy 
(OReO)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
3 (150)
• deletion of exclusion criteria “Previous allogeneic bone marrow transplant or double 
umbilical cord blood transplantation (dUCBT)” as this is not used in Ovarian Cancer and 
no treatment leading to total ablation of the bone marrow is ever given.
• Restrict eligibility for patients who have received a whole blood transfusion within 30 
days prior to screening tests instead of 90 days prior to randomization as only 30 days is 
required to perform gBRCA testing therefore no interference in testing
Section 4.10 (Screen Failures) This section was updated to clarify re-screening is 
permitted and process to perform re-screening
Table 3 (Scheduled Assessments for on Study Treatment and Study Discontinuation): 
This section was updated to
• Add requirement that pregnancy testing for females of childbearing potential should be 
conducted at during each on site treatment visit
• Remove requirements to complete additional eCRF for when an AE for nausea or 
vomiting occurs
• Clarify that if a patient discontinues treatment (and/or receives a subsequent cancer 
therapy) prior to progression then the patient should still continue to be followed until 
objective disease progression as defined by RECIST 1.1.  
Section 8.5.4 (Interim Analysis): This section was updated to include a pre-specified 
interim analysis for futility, ensuring that exposure of patients to an ineffective treatment 
is excluded. IDMC unblinded interim (or ongoing) efficacy and safety review to pick out 
a major risk:benefit discrepancy. Results from the planned interim analyses will be shared 
with the IDMC who will make a recommendation on continuing or stopping a cohort.
Appendix D (Acceptable Birth Control Methods): This section was updated to add 
clarification when abstinence is in line with the preferred and usual lifestyle of the 
subject.
Appendix F (Guidelines for Evaluation of Objective Tumour Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumours): This section was updated to 
clarify that 
• Chest x-ray, Ultrasound, Bone Scan and FDG-PET are not mandatory but can be used if 
clinically indicated and are acceptable methods for New lesion identification.
• CT examinations of the Chest, abdomen and pelvis, will be used to assess tumour 
burden at baseline and follow-up visits. 
• Follow-up assessments will be performed every 12 weeks

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
4 (150)
•
There will be no independent central review for this study
Version 3.0, 
Changes to the protocol are summarised below.
Protocol Synopsis: Number of patients reduced to 228; Oxaliplatin added as acceptable 
platinum chemotherapy; inclusion criterion related to continued platinum sensitivity 
modified to allow patients who have no measurable disease following debulking surgery 
and a CA-125 which is not rising; changed assumptions about expected median PFS in 
placebo treated patients (4.5 months) based on prior data; calculations of sample size 
adjusted to support detection of a 0.5 Hazard Ratio in both cohorts; SOLO2 data added to 
Table 1; Text justifying sample size modified to explain the choice of 4.5 months, and the 
selection of a HR = 0.5 in both cohorts; Text on statistical assumptions of the study 
revised, with altered recruitment targets; Text added to indicate that the assumptions on 
sample size will be reviewed at the time of the interim analysis; Statistical assumptions 
for the interim analysis revised
Introduction: Section 1.1. Research Hypothesis: text altered to reflect change in inclusion 
criterion #5. Olaparib Mechanism of Action: text updated. Section 1.2 Rationale for Study 
Design, Doses and Control Doses: text revised, updated and new data added to improved 
rationale. Section 1.3: Benefit/Risk and Ethical Assessment: text moved to Section 1.4. 
Section 1.4 Study Design: Text changes consistent with the modification of Inclusion 
Criterion #5. Text relating to blinding and unblinding moved from Section 1.3
Inclusion Criteria: Section 3.1. Inclusion Criterion #5 modified to allow patients with no 
measurable disease following optimal debulking surgery, and CA-125 level that is normal 
or not rising to enter the study
Study Plan and Timing of Procedures: Section 4, Table 2. Removal of footnote requiring 
additional CRF for nausea and vomiting. Table 3. Footnote (a) enhanced to clarify that 
randomization can take place prior to Day 1 for operational reasons. Section 4.1 
Clarification that screening should be done within 28 days of first dose (not 
randomisation). Section 4.2 Clarification that randomisation can be performed before 
before Day 1, that certain tests do not have to be repeated if performed within 7 days of 
Day 1 (not randomisation), and that ECOG status should be performed pre-dosing on Day 
1. Section 4.5 Revised instructions (simplification) for completion of long term follow up.
Statistical Analyses by Astrazeneca Vendor: Section 8.2 Sample Size Estimate. 
Adjustment of assumptions for mPFS of placebo control, and recalculation of sample size. 
Section 8.5.1: Adjustment of the number of progression events for the primary analysis of 
PFS. Section 8.5.4: Adjustment in the statistical basis for and timing of the interim 
analysis

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
5 (150)
Version 4.0, 15 October 2020
Changes to the protocol are summarised below.
Protocol Synopsis, Front page. Change of address for International Coordinating 
Investigator
Protocol Synopsis, Study Design. Addition of “and analysed” into the sentence “The 
BRCA1/2 (+ve) and BRCA1/2 (-ve) cohorts will be randomised and analysed separately”.
Protocol Synopsis, Statistical Methods. Added “Data cut off and subsequent database lock 
for the Primary Analysis will occur after the later of the two cohorts reaches the defined 
number of progression or death events” for clarification.
Section 1.4, Study Design. Minor corrections to ensure consistency with study schedule
Section 3.8.2 Acceptable Birth Control Methods: change in requirement that women of 
childbearing potential and their partners, who are sexually active, must agree to the use of 
one highly effective forms of contraception and their partners must use a male condom
Section 3.11, Discontinuation of the Study. Added “The study, or one cohort, may also be 
stopped at any time after the Primary Analysis if in the judgment of AstraZeneca, the 
ENGOT Principal Investigator and the Trial Steering Committee, there is insufficient 
clinical benefit from re-treatment.” 
Table 4, New Table: Scheduled Assessments: Patients Remaining on Study Treatment 
Post Primary Analysis
Section 4.5, Patients on Study Treatment Post Primary Analysis. New Section to detail 
assessments required in patients still on study treatment after Primary Analysis
Section 6.1.1: Update to AESI section to change MDS/AML from important potential risk 
to important identified risk
Section 8.1, Statistical Considerations. Added  “Data cut off and subsequent database lock 
for the Primary Analysis will occur after the later of the two cohorts reaches the defined 
number of progression or death events”
Section 8.5.1, Analysis of the Primary Variable(s). Clarify requirements for Primary 
Analysis “The primary analysis for PFS for each cohort will be performed when both 85 
progression or death events have occurred in the BRCA1/2 (+ve) cohort and 74 
progression or death events in the BRCA1/2 (-ve) cohort (whichever occurs later).”

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
6 (150)
Section 8.5.2.1, Overall Survival. Amend defined timings for analyses of overall survival 
to “OS will be analysed at the time of the primary analysis for PFS, and again after 50% 
death events in either cohort, or 60 months after FSI, whichever is the earlier”
Section 9.3 Study Timetable and End of Study. Clarify timing of final DCO “The final 
DCO will take place after 50% death events in either cohort, or 60 months after FSI, 
whichever is the earlier”. Added “The study, or one cohort, may also be stopped at any 
time after the Primary Analysis if in the judgment of AstraZeneca, the ENGOT Principal 
Investigator and the Trial Steering Committee, there is insufficient clinical benefit from 
re-treatment.” to be consistent with Section 3.11
Appendix H Acceptable Birth Control Methods: change in requirement that women of 
childbearing potential and their partners, who are sexually active, must agree to the use of 
one highly effective forms of contraception and their partners must use a male condom

7 (150)
ENGOT Number
ENGOT-ov38/OReO
PROTOCOL SYNOPSIS
A Phase IIIb, Randomised, Double-blind, Placebo-controlled, Multicentre 
Study of Olaparib Maintenance Retreatment in Patients with Epithelial 
Ovarian Cancer  Previously Treated With a PARPi and Responding to 
Repeat Platinum Chemotherapy (OReO)
International Coordinating Investigator
75008 Paris
France
Study Site(s) and Number of Patients Planned
The study will be conducted in approximately 11 countries worldwide.  Approximately 
110 centres will be initiated to randomise approximately 228 patients.  
Additional sites may be added dependent on recruitment rates.
Study Period
Phase of Development
Estimated date of first patient enrolled
Q2 2017
IIIb
Estimated date of last patient completed
Q2 2022
Study Design
This is a Phase IIIb, randomised, double-blind, placebo-controlled, multicentre study to assess 
the efficacy and tolerability of Olaparib retreatment, versus matching placebo, in non-
mucinous epithelial ovarian cancer (EOC) patients (including patients with primary peritoneal 
and/or fallopian tube cancer). To be eligible, patients must have received maintenance therapy 
with a polyadenosine 5’diphosphoribose [poly (ADP ribose)] polymerisation inhibitor 
PPD

Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
8 (150)
(PARPi) for a defined period (see Target Patient Population), and remain sensitive to 
platinum-based chemotherapy, based on their radiological or CA-125 response to their most 
recent course of platinum-based chemotherapy (carboplatin, cisplatin or oxaliplatin). Patients 
will be enrolled on the basis of their breast cancer susceptibility gene (BRCA1, BRCA2) status 
into one of two cohorts (BRCA1/2 (+ve) and BRCA1/2 (-ve)).
The BRCA1/2 (+ve) and BRCA1/2 (-ve) cohorts will be randomised and analysed separately. 
Within each cohort, patients will be randomised by prospective allocation in a 2:1 ratio 
(Olaparib:matching placebo) to the treatments as specified below:
!
Olaparib tablets (oral [p.o.]), 300 mg twice daily (bd; except where this dose 
and formulation was previously not tolerated; Section 6.7)
!
placebo tablets to match, p.o. bd
Randomisation will be stratified by:
∀
Use of prior bevacizumab (yes versus no)
∀
Number of prior regimens of platinum-containing chemotherapy (≤3 
regimens versus ≥4 regimens)
Investigators will be required to provide tumour assessment information using the Response 
Evaluation Criteria In Solid Tumours (RECIST) version 1.1 at baseline (a maximum of 28 
days prior to randomisation).  Following randomisation, patients in all study arms must have 
tumour assessments every 12 weeks (±7 days) until objective disease progression.  More 
information is provided in Section 5.1.
Patients should continue to receive study treatment until objective radiological disease 
progression as per RECIST 1.1 or as long as in the Investigator’s opinion they are benefiting 
from treatment and they do not meet any other discontinuation criteria.
Once a patient has stopped treatment, a 30 days post last study drug visit will be performed 
during which adverse events (AEs), concomitant medications and the completed health-related 
quality of life (HRQoL) questionnaire will be collected.  Thereafter, data on subsequent 
therapies according to routine clinical practice, adverse events of special interest (AESI) and 
survival will be collected until the data cut-off date for the final analysis.

Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
9 (150)
Objectives
The following objectives apply to both BRCA1/2 (+ve) and BRCA1/2 (-ve) cohorts. 
Primary Objective
Outcome Measure
To determine the efficacy of Olaparib
maintenance retreatment
compared to 
matching 
placebo 
by 
assessment 
of 
progression-free survival (PFS)
Time from randomisation to Investigator-assessed 
disease progression (according to RECIST 
version 1.1 guidelines) or death (by any cause in 
the absence of progression)
Secondary Objective
Outcome Measure
To determine the efficacy of Olaparib 
maintenance retreatment compared to 
matching placebo by assessment of overall 
survival (OS)
Time from randomisation to death from any cause
To determine the efficacy of Olaparib 
maintenance retreatment compared to 
matching placebo by assessment of time to 
progression
by 
Gynecologic 
Cancer 
Intergroup (GCIG) criteria
Time from randomisation to the earliest of 
Investigator-assessed disease progression by 
RECIST or cancer antigen 125 (CA-125), or death
(by any cause in the absence of progression)
To determine the efficacy of Olaparib 
maintenance retreatment compared to 
matching placebo by assessment of the use 
of subsequent therapies and study treatment 
discontinuation
∀
Time from randomisation to first subsequent 
treatment commencement or death if this 
occurs 
before 
commencement 
of 
first 
subsequent treatment (TFST)
∀
Time 
from 
randomisation 
to 
second 
subsequent treatment commencement or death 
if this occurs before commencement of second 
subsequent treatment (TSST)
∀
Time from randomisation to study treatment 
discontinuation or death if this occurs before 
discontinuation of study treatment (TDT)
To determine the HRQoL of Olaparib 
maintenance retreatment compared to 
matching placebo as measured by the 
Functional Assessment of Cancer Therapy 
– Ovarian (FACT-O) Trial Outcome Index 
(TOI)
Change from baseline, time to deterioration and 
proportion improved

Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
11 (150)
∀
The first cohort will enrol patients with confirmed BRCA1/2 (+ve) status 
(somatic, sBRCA1/2, or germline, gBRCA1/2) 
∀
The second cohort will enrol patients who are known gBRCA1/2 (-ve) 
and may include some patients who have an undetected sBRCA1/2 
mutation.
The minimum periods for which patients must have taken maintenance PARPi without 
progression to be eligible for this retreatment study are:
∀
For the BRCA1/2 (+ve) cohort, the duration of exposure must have been 
≥18 months following a first line of chemotherapy or ≥12 months 
following a second line or subsequent line of chemotherapy 
∀
For the BRCA1/2 (-ve) cohort, the duration of exposure must have been 
≥12 months following a first line of chemotherapy or ≥6 months 
following a second line or subsequent line of chemotherapy.
A month is defined as being from the start date to the same date in the next month (e.g. 01 
January to 01 July is 6 months).  These periods are of continuous PARPi administration and 
are measured from the date of the first dose to the date of the last dose of PARPi. During this 
period no new anticancer treatment for disease progression can have been administered, but 
patients may have had short breaks (maximum 14 days on any occasion) for holidays, control 
of toxicity or non-cancer treatments, for example. Unblinding of patients who received 
blinded treatment with a PARPi as an experimental arm should be medically justified
Patients may have, but do not need to have, a specific confirmatory homologous 
recombination repair (HRR) or homologous recombination deficiency (HRD) test. Patients 
with BRCA variants of unknown significance will be regarded as BRCA1/2 (-ve) for the 
purposes of this study. 
Patients should also have received subsequent platinum-based chemotherapy, excluding 
bevacizumab, following progression during or following prior PARPi therapy and have 
achieved, in the opinion of the Investigator, at least a partial radiological response, or not have 
a rising CA-125 following optimal debulking surgery with no measurable disease. In addition, 
patients must be randomised into the OReO study within 8 weeks of their last dose of 
platinum-based chemotherapy (last dose is the day of the last infusion).
Duration of Treatment
Unless patients experience unacceptable toxicity or withdraw from the study treatment or 
from the protocol, patients should continue to receive study treatment until there is objective 
radiological disease progression as assessed by RECIST 1.1 or as long as in the Investigator’s 
opinion they are benefiting from treatment.  

Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
12 (150)
Once patients have been discontinued from study treatment, other treatment options will be at 
the discretion of the Investigator.  
Study Treatment, Dosage, and Mode of Administration
Olaparib is available as a film-coated tablet containing 150 mg or 100 mg of Olaparib.  
Patients will be administered study treatment orally at a dose of 300 mg bd.  The planned dose 
of 300 mg bd will be made up of two 150 mg tablets bd with 100 mg tablets used to manage 
dose reductions (except where this dose and formulation was previously not tolerated; Section 
7.2).
The comparator in the OReO study is placebo to match Olaparib 150 mg or 100 mg tablets.  
Statistical Methods
All personnel involved with the analysis of the study will remain blinded to study treatment 
until database lock and protocol violators are identified. Data cut off and subsequent database 
lock for the Primary Analysis will occur after the later of the two cohorts reaches the defined 
number of progression or death events.
Efficacy data will be summarised for both cohorts using the full analysis set (FAS), including 
all randomised patients.  The primary outcome, PFS, will be analysed using a stratified log-
rank test and the effect of Olaparib retreatment will be estimated by the hazard ratio (HR) and 
associated 95% confidence interval and P-value.  Kaplan-Meier plots will be presented by 
treatment arm.  The analysis of other time-to-event endpoints will use the same methodology 
as for PFS (see Section 8).
HRQoL using the FACT-O tool will be analysed using a mixed model for repeated measures 
(MMRM) analysis of the change from baseline in TOI score for each scheduled post-baseline 
visit, based upon a subset of the FAS.
HRQoL mean scores will be analysed accounting for baseline scores and the stratification 
factors.  Time to deterioration will be analysed using survival analysis methodology as per the 
PFS endpoint.
Sensitivity analysis and subgroup analysis of PFS and other time-to-event endpoints will be 
performed as appropriate and as described in the statistical analysis plan (SAP). 
A comprehensive SAP will be prepared, and any subsequent amendments will be documented, 
with final amendments completed prior to un-blinding of the data.  Analyses will be 
performed in collaboration between AstraZeneca or its representatives and representatives of 
GINECO-ENGOT (Groupe d’Investigateurs Nationaux pour l’Étude des Cancers Ovariens et 
du sein [GINECO]; European Network for Gynaecological Oncological Trial [ENGOT]).
The analyses to be performed for the purpose of generating the clinical study report will be 
included in the study SAP that is prepared by the clinical research organisation (CRO), which 

Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
13 (150)
will be reviewed and agreed by AstraZeneca and GINECO-ENGOT.  All analyses in the SAP 
will then be generated by the CRO.
Sample Size
The benefit of Olaparib retreatment over matching placebo will be evaluated in both cohorts 
through the primary endpoint of PFS. 
Recently published data (Study 19, NOVA, SOLO2) of PARPi therapy following a second or 
subsequent line of platinum based chemotherapy indicated that a median PFS which does not 
exceed 5.5 months can be expected in the placebo-treated patients (Table 1).
Table 1
Median PFS of Study 19, SOLO2 (Olaparib) and NOVA (Niraparib) 
Patients According to BRCA Status and Treatment Arm, and 
Selection of Patients in OReO According to Previous Exposure to 
PARPi
BRCAm
placebo arm
late relapse
BRCAm
Olaparib arm
late relapse
BRCAwt
placebo arm
late relapse
BRCAwt
Olaparib arm
late relapse
Median PFS (months)
Study 19
4.3
11.2
5.5
7.4
NOVA
5.5
21.0
3.9
9.3
SOLO2
5.5
19.1
n/a
n/a
                                            
Selection in OReO 
according to previous 
PARPi exposure for 
relapse patients
> 12 
> 6
Selection in OReO 
according to previous 
PARPi exposure for first 
line patients
> 18
> 12
BRCAm = BRCA1/2 mutated; BRCAwt = BRCA1/2 wild type; n/a = not applicable
This study tests the hypothesis that patients judged to have received benefit from an initial 
maintenance course of PARPi, based on a duration of prior exposure specified according to 
their BRCA status, and number of prior courses of platinum-based chemotherapy, and who 
retain sensitivity to platinum-based chemotherapy, will benefit from repeat exposure to 
olaparib. The data above indicates that in platinum sensitive patients, regardless of BRCA
status, placebo maintenance following second-line chemotherapy results in a median PFS of 

Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
14 (150)
less than 5.5 months. Patients entering OreO may do so after a second or subsequent line of 
platinum based chemotherapy, and despite being selected for benefit from prior PARPi, are 
considered unlikely to demonstrate a longer median PFS on placebo than the similar patient 
populations tested in Study 19, SOLO2, and NOVA. Finally, the benefit from PARPi 
maintenance retreatment is assumed to be less than obtained on first treatment. So the 
expected median PFS for both the BRCA1/2 (+ve) and BRCA1/2 (-ve) cohorts has been 
estimated to be approximately 4.5 months for patients receiving placebo. Sample sizes have 
then been calculated based on an expectation of a clinically meaningful duration of benefit 
(HR 0.5 for both cohorts).
In the BRCA1/2 (+ve) cohort it is assumed that the median PFS from randomisation for
patients in the placebo arm will be approximately 4.5 months. In total, 85 progression or death
events from 120 patients will have 85% power to demonstrate significant PFS benefit at the 2-
sided 5% level if the assumed true treatment effect resulted in a HR of 0.5; this translates to a
4.5 month (100%) increase in median PFS beyond the 4.5 months expected for patients on
placebo, if PFS is exponentially distributed and allowing a 10% drop-out rate. An observed 
HR of 0.63 or less will be required to achieve this level of significance. Assuming 34
months of non-linear recruitment, 85 events are expected to occur approximately 41 months
after the first patient in (FSI) is enrolled into this cohort of the study.
In the BRCA1/2 (-ve) cohort it is assumed that the median PFS from randomisation for
patients in the placebo arm will be approximately 4.5 months. In total, 74 progression or death
events from 108 patients will have 80% power to demonstrate significant PFS benefit at the 2-
sided 5% level if the assumed true treatment effect resulted in a HR of 0.5; this translates to a
4.5 month (100%) increase in median PFS beyond the 4.5 months expected for patients on
placebo, if PFS is exponentially distributed and allowing a 10% drop-out rate. An observed 
HR of 0.61 or less will be required to achieve this level of significance. Assuming 36
months of non-linear recruitment, 74 events are expected to occur approximately 42 months
after the FSI is enrolled into this cohort of the study.
Considering both cohorts it is expected that approximately 228 patients in total will be 
enrolled into the study. The assumptions made in calculating the sample size will be evaluated 
at the time of the planned interim analysis.
FAS (Intent-to-Treat Principle)
The intent-to-treat (ITT) population will include all randomised patients and will compare the 
treatment groups on the basis of randomised treatment, regardless of the treatment actually 
received.  Patients who were randomised but did not subsequently go on to receive study 
treatment are included in the FAS.  Therefore, all efficacy data will be summarised and 
analysed using the FAS on an ITT basis as the primary analysis set.  Demographic and 
baseline characteristics will also be analysed using the FAS on an ITT basis. 
Safety Analysis Set

Clinical Study Protocol Synopsis
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
15 (150)
All patients who received at least one dose of randomised study treatment, Olaparib or 
placebo, will be included in the safety analysis set.  If a patient receives at least one dose of 
Olaparib study treatment they will be summarised in the Olaparib arm for safety summaries 
(e.g., Olaparib arm will include patients randomised to Olaparib who receive at least one dose 
of Olaparib or placebo patients who receive at least one dose of Olaparib study treatment in 
error at any time).  If a patient randomised to Olaparib receives only placebo treatment then 
the patient will be summarised as a part of the placebo arm. All safety data will be 
summarised and analysed using the safety analysis set.
Interim Analysis
In the BRCA1/2 (+ve) cohort an interim analysis for futility will be performed after 50% of the 
target PFS events (i.e. after 43 events). Based upon the assumed accrual and event rate it is 
estimated that this will occur after approximately 29 months. Using a conditional power non-
binding futility analysis the cohort may stop for futility if the hazard ratio > 1.056. Under the 
null hypothesis the probability of stopping for futility is 0.433 and under the alternative 
hypothesis it is 0.01.
In the BRCA1/2 (-ve) cohort an interim analysis for futility will be performed after 50% of the 
target PFS events (i.e. after 37 events). Based upon the assumed accrual and event rate it is 
estimated that this will occur after approximately 30 months. Using a conditional power non 
binding futility analysis the cohort may stop for futility if the hazard ratio > 1.02. Under the 
null hypothesis the probability of stopping for futility is 0.477 and under the alternative 
hypothesis it is 0.02.
Results from the planned interim analyses will be shared with the Independent data 
monitoring committee who will make a recommendation on continuing or stopping a cohort.

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
16 (150)
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
PROTOCOL SYNOPSIS.....................................................................................7
TABLE OF CONTENTS................................................................................... 16
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................... 23
1
INTRODUCTION ............................................................................................. 26
1.1
Background and Rationale for Conducting This Study ....................................... 26
1.2
Rationale for Study Design, Doses, and Control Groups..................................... 27
1.3
Benefit/Risk and Ethical Assessment ................................................................. 30
1.4
Study Design...................................................................................................... 30
2
STUDY OBJECTIVES...................................................................................... 34
2.1
Primary Objective .............................................................................................. 34
2.2
Secondary Objectives......................................................................................... 34
2.3
Safety Objectives ............................................................................................... 35
2.4
Exploratory Objectives....................................................................................... 35
3
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 36
3.1
Inclusion Criteria ............................................................................................... 36
3.2
Exclusion Criteria .............................................................................................. 39
3.3
Patient Enrolment and Randomisation................................................................ 42
3.4
Procedures for Handling Incorrectly Enrolled or Randomised Patients............... 43
3.5
Methods for Assigning Treatment Groups.......................................................... 43
3.6
Methods for Ensuring Blinding .......................................................................... 43
3.7
Methods for Un-blinding.................................................................................... 44
3.8
Restrictions........................................................................................................ 44
3.8.1
Grapefruit Juice..................................................................................................44
3.8.2
Contraception..................................................................................................... 44
3.9
Discontinuation of Study Treatment................................................................... 44

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
17 (150)
3.9.1
Procedures for Discontinuation of a Patient from Study Treatment Product........45
3.10
Criteria for Withdrawal......................................................................................46
3.10.1
Screen Failures...................................................................................................46
3.10.2
Withdrawal of the Informed Consent.................................................................. 46
3.11
Discontinuation of the Study.............................................................................. 47
4
STUDY PLAN AND TIMING OF PROCEDURES........................................... 47
4.1
Enrolment/Screening Period...............................................................................55
4.2
Treatment Period................................................................................................ 56
4.3
Study Treatment Discontinuation .......................................................................59
4.4
Follow-up Period ............................................................................................... 59
4.5
Long-Term Follow-up (12-Weekly Beyond 30 Days After Last Dose of 
Study Medication).............................................................................................. 60
4.6
Patients on Study Treatment Post Primary Analysis ...........................................60
5
STUDY ASSESSMENTS..................................................................................61
5.1
Efficacy Assessments......................................................................................... 61
5.1.1
CT and MRI Scans Assessments (RECIST 1.1).................................................. 61
5.1.2
Tumour Evaluation ............................................................................................62
5.1.3
CA-125 Measurements....................................................................................... 63
5.2
Safety Assessments............................................................................................ 64
5.2.1
Physical Examination and ECOG....................................................................... 64
5.2.2
Vital Signs and Weight ......................................................................................64
5.2.2.1
Pulse and Blood Pressure ................................................................................... 64
5.2.2.2
Body Temperature ............................................................................................. 64
5.2.3
Laboratory Safety Assessments.......................................................................... 64
5.2.3.1
Coagulation........................................................................................................ 66
5.2.3.2
Bone Marrow or Blood Cytogenetic Samples..................................................... 66
5.2.4
ECG................................................................................................................... 67
5.2.4.1
Resting 12-lead ECG .........................................................................................67
5.2.5
Other Safety Assessments .................................................................................. 67
5.2.5.1
Serum or Urine Pregnancy Test..........................................................................67
5.3
Other Assessments............................................................................................. 67

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
18 (150)
5.3.1
Patient Reported Outcomes (HRQoL: FACT-O) ................................................ 67
5.4
Biomarker Analysis............................................................................................ 68
5.4.1
Collection of Samples ........................................................................................68
5.4.1.1
CA-125.............................................................................................................. 68
5.4.1.2
Archival or Fresh Tumour Sample .....................................................................68
5.4.1.3
Blood Sample for Confirmation of gBRCA......................................................... 69
5.4.1.4
Blood Samples for Biomarker Analysis..............................................................69
5.4.1.5
Optional Tumour Samples..................................................................................69
5.5
Biomarker Analysis............................................................................................ 70
5.5.1
Storage, Re-use and Destruction of Biological Samples ..................................... 70
5.5.2
Labelling and Shipment of Biological Samples .................................................. 70
5.5.3
Chain of Custody of Biological Samples ............................................................ 70
5.5.4
Withdrawal of Informed Consent for Donated Biological Samples..................... 70
6
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 71
6.1
Definition of AEs...............................................................................................71
6.1.1
Olaparib AEs of Special Interest ........................................................................ 71
6.2
Definitions of SAE............................................................................................. 72
6.3
Recording of AEs............................................................................................... 72
6.3.1
Time Period for Collection of AEs ..................................................................... 72
6.3.1.1
AEs After the 30 day Follow-up Period.............................................................. 73
6.3.2
Follow-up of Unresolved AEs............................................................................ 73
6.3.3
Variables............................................................................................................ 73
6.3.4
Causality Collection........................................................................................... 75
6.3.5
AEs Based on Signs and Symptoms ...................................................................75
6.3.6
AEs Based on Examinations and Tests............................................................... 75
6.3.7
Hy’s Law ...........................................................................................................76
6.3.8
Disease Progression ........................................................................................... 76
6.3.9
New Cancers......................................................................................................76
6.3.10
Lack of Efficacy.................................................................................................76
6.3.11
Deaths................................................................................................................ 77
6.4
Reporting of Serious AEs................................................................................... 77

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
19 (150)
6.5
Overdose............................................................................................................ 78
6.6
Pregnancy .......................................................................................................... 79
6.6.1
Maternal Exposure............................................................................................. 79
6.6.2
Paternal Exposure .............................................................................................. 79
6.7
Management of Study Treatment Related Toxicities (Dose Reductions)............. 79
6.7.1
Management of Haematological Toxicity........................................................... 80
6.7.1.1
Management of Anaemia ...................................................................................80
6.7.1.2
Management of Neutropenia, Leukopenia and Thrombocytopenia ..................... 80
6.7.1.3
Management of Prolonged Haematological Toxicities While on Study 
Treatment........................................................................................................... 81
6.7.2
Management of Non-haematological Toxicity.................................................... 81
6.7.2.1
Management of New or Worsening Pulmonary Symptoms................................. 82
6.7.2.2
Management of Nausea and Vomiting................................................................ 82
6.7.2.3
Interruptions for Intercurrent Non-Toxicity Related Events................................ 82
6.8
Study Governance and Oversight ....................................................................... 83
6.8.1
Steering Committee............................................................................................83
6.8.2
Data Monitoring Committee...............................................................................83
6.8.3
Scientific Advisory Committee .......................................................................... 83
7
STUDY TREATMENT AND OTHER TREATMENTS.................................... 84
7.1
Identity of Study Treatment(s)............................................................................ 84
7.2
Dose and Treatment Regimens...........................................................................84
7.3
Labelling............................................................................................................ 85
7.4
Storage............................................................................................................... 85
7.5
Compliance........................................................................................................ 86
7.6
Accountability.................................................................................................... 86
7.7
Concomitant and Other Treatments.................................................................... 87
7.7.1
Other Concomitant Treatment............................................................................ 90
7.8
Post Study Access to Study Treatment ............................................................... 90
8
STATISTICAL ANALYSES BY ASTRAZENECA VENDOR......................... 90
8.1
Statistical Considerations ................................................................................... 90
8.2
Sample Size Estimate......................................................................................... 90

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
20 (150)
8.3
Definitions of Analysis Sets ............................................................................... 91
8.3.1
Full Analysis Set (Intent-to-Treat Principle)....................................................... 91
8.3.2
Safety Analysis Set ............................................................................................ 91
8.3.3
Pharmacokinetic Analysis Set ............................................................................ 91
8.3.4
PRO Analysis Set............................................................................................... 92
8.4
Outcome Measures for Analyses ........................................................................ 93
8.4.1
Progression-free Survival................................................................................... 93
8.4.2
Overall Survival.................................................................................................94
8.4.3
Time to Subsequent Therapies............................................................................ 94
8.4.4
Time to Study Treatment Discontinuation..........................................................94
8.4.5
Time to Earliest Progression (RECIST or CA-125) or Death.............................. 95
8.4.6
Calculation or Derivation of HRQoL Endpoints................................................. 95
8.4.7
Calculation or Derivation of Safety Variables .................................................... 97
8.4.8
Calculation or Derivation of Exploratory Variables............................................ 98
8.5
Methods for Statistical Analyses ........................................................................ 98
8.5.1
Analysis of the Primary Variable(s) ................................................................... 98
8.5.2
Analysis of the Secondary Variable(s)................................................................ 98
8.5.2.1
Overall Survival.................................................................................................98
8.5.2.2
Time to Subsequent Therapies or Death ............................................................. 99
8.5.2.3
Time to Study Treatment Discontinuation or Death............................................99
8.5.2.4
Time to Earliest Progression by RECIST or CA-125 or Death............................99
8.5.2.5
HRQoL Index Score........................................................................................... 99
8.5.2.6
Safety and Tolerability..................................................................................... 100
8.5.3
Subgroup Analysis........................................................................................... 101
8.5.4
Interim Analysis............................................................................................... 101
8.5.5
Sensitivity Analysis.......................................................................................... 102
8.5.6
Exploratory Analysis........................................................................................ 102
9
STUDY AND DATA MANAGEMENT BY ASTRAZENECA VENDOR...... 102
9.1
Training of Study Site Personnel...................................................................... 102
9.2
Monitoring of the Study................................................................................... 102
9.2.1
Source Data ..................................................................................................... 103

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
21 (150)
9.2.2
Study Agreements............................................................................................ 103
9.2.3
Archiving of Study Documents ........................................................................ 103
9.3
Study Timetable and End of Study................................................................... 103
9.4
Data Management by AstraZeneca Designated Clinical Research 
Organisation..................................................................................................... 104
10
ETHICAL AND REGULATORY REQUIREMENTS..................................... 105
10.1
Ethical Conduct of the Study............................................................................ 105
10.2
Patient Data Protection..................................................................................... 105
10.3
Ethics and Regulatory Review.......................................................................... 106
10.4
Informed Consent............................................................................................. 106
10.5
Changes to the Protocol and Informed Consent Form....................................... 107
10.6
Audits and Inspections ..................................................................................... 108
11
LIST OF REFERENCES ................................................................................. 108
LIST OF TABLES
Table 1
Median PFS of Study 19, SOLO2 (Olaparib) and NOVA 
(Niraparib) Patients According to BRCA Status and Treatment 
Arm, and Selection of Patients in OReO According to Previous 
Exposure to PARPi .....................................................................................13
Table 2
Screening (Visit 1) Study Schedule for OReO Patients (Locally 
Confirmed BRCA1/2 Mutation Status).........................................................48
Table 3
Scheduled Assessments for on Study Treatment and Study 
Discontinuation...........................................................................................50
Table 4
Scheduled Assessments for Patients Remaining on Study 
Treatment Post Primary Analysis ................................................................54
Table 5
Laboratory Safety Variables........................................................................66
Table 6
Management of Anaemia.............................................................................80
Table 7
Management of Neutropenia, Leukopenia and 
Thrombocytopenia ......................................................................................80
Table 8
Dose Reductions for Study Treatment .........................................................83
Table 9
HRQoL: Best Overall Score ........................................................................97
App. Table 1 Summary of Methods of Assessment......................................................... 134
App. Table 2 Evaluation of target lesions ....................................................................... 138

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
22 (150)
App. Table 3 Evaluation of Non-Target Lesions............................................................. 139
App. Table 4 Overall Visit Response.............................................................................. 140
LIST OF FIGURES
Figure 1
OReO Study Flow Chart .............................................................................33
Figure 2
OReO Study Screening and Eligibility Flow Chart......................................41
Figure 3
Overview of Treatments Before Study Randomisation ................................42
LIST OF APPENDICES
Appendix A
Additional Safety Information................................................................... 111
Appendix B
International Airline Transportation Association 6.2 Guidance 
Document..................................................................................................115
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law ......................................................................118
Appendix D
Acceptable Birth Control Methods ............................................................ 125
Appendix E
ECOG Performance Criteria...................................................................... 128
Appendix F
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid 
Tumours) .................................................................................................. 130
Appendix G
FACT-O QoL Questionnaire .....................................................................142
Appendix H
GCIG Criteria............................................................................................144
Appendix I
Signatures .................................................................................................146

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
23 (150)
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or special term
Explanation
AE
Adverse event
AESI
Adverse event 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
bd
Twice a day
BP
Blood pressure
BRCA1 and BRCA2
Breast cancer susceptibility genes
BRCAm
BRCA1/2 mutated
BUN
Blood urea nitrogen
CA-125
Cancer antigen 125
CI
Confidence interval
CR
Complete response
CrCl
Creatinine clearance
CRF
Case report form (electronic/paper)
CRO
Clinical research organisation
CSA
Clinical study agreement
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
CYP
Cytochrome P450
DCIS
Ductal carcinoma in situ
DCO
Data cut-off
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid 
DSB
DNA double strand breaks
dUCBT
Double umbilical cord blood transplantation
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EE
Ethinyl estradiol
ENGOT
European Network for Gynaecological Oncological Trial
EOC 
Epithelial ovarian cancer 
ESMO
European Society for Medical Oncology
CCI

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
24 (150)
Abbreviation or special term
Explanation
Ethics committee
Synonymous with institutional review board (IRB) and 
independent ethics committee (IEC)
EWB
Emotional well-being
FACIT
Functional Assessment of Chronic Illness Therapy
FACT-G
Functional Assessment of Cancer Therapy – General
FACT-O
Functional Assessment of Cancer Therapy – Ovarian
FAS
Full analysis set
FFPE
Formalin fixed, paraffin embedded
FSI
First patient in
FWB
Functional well-being
gBRCAm
Germline BRCAm
GCIG
Gynecologic Cancer InterGroup
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GINECO
Groupe d’Investigateurs Nationaux pour l’Étude des 
Cancers Ovariens et du sein
GMP
Good Manufacturing Practice
Hb
Haemoglobin
HGSOC
High grade serous ovarian cancer
HIV
Human immunodeficiency virus
HL
Hy’s Law
HR
Hazard ratio
HRCT
High resolution computed tomography
HRD
Homologous recombination deficiency
HRQoL
Health-related quality of life
HRR
Homologous recombination repair
IATA
International Airline Transportation Association
IB
Investigator brochure
ICH
International Conference on Harmonisation
IDMC
Independent data monitoring committee
IEC
Independent ethics committee
IMP
Investigational medicinal product
INR
International normalised ratio
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
IRB
Institutional review board
ITT
Intent-to-treat
IUS
Intrauterine system
IVRS
Interactive voice response system
IWRS
Interactive web response system
K-M
Kaplan-Meier
MAR
(Data being) missing at random

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
25 (150)
Abbreviation or special term
Explanation
MATE
Multidrug and toxin extrusion (MATE1, MATE2K)
MCV
Mean corpuscular/cell volume
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MID
Minimally important difference
MMRM
Mixed model for repeated measures
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
OAT3
Organic anion transporter 3
OATP1B1
Organic anion transporting polypeptide 1B1
OCS
Ovarian cancer subscale
OCT
Organic cation transporter (OCT1, OCT2)
OS
Overall survival
PARP
Polyadenosine 5’diphosphoribose [poly (ADP ribose)] 
polymerisation
PARPi
Polyadenosine 5’diphosphoribose [poly (ADP ribose)] 
polymerisation inhibitor
PD
Progression of disease
PFS
Progression-free survival
P-gp
P-glycoprotein
PHL
Potential Hy’s Law
p.o.
Oral 
PR
Partial response
PRO
Patient reported outcome
PWB
Physical well-being
QoL
Quality of life
QTc
Corrected QT interval
RECIST
Response Evaluation Criteria In Solid Tumours
SAE
Serious adverse event 
SAP
Statistical analysis plan
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
SmPC
Serum glutamic pyruvate transaminase
Summary of product characteristics 
SSB
DNA single strand break
SWB
Social/family well-being
TBL
Total bilirubin
TDT
Time to study treatment discontinuation or death 
TEAE
Treatment-emergent adverse event
TFST
Time to first subsequent treatment commencement or death
TL
Target lesion
TOI
Trial outcome index

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
26 (150)
Abbreviation or special term
Explanation
TSST
Time to second subsequent treatment commencement or 
death
ULN
Upper limit of normal
VEGFRi
Vascular endothelial growth factor receptor inhibitor
WBDC
Web-based data capture
1
INTRODUCTION
1.1
Background and Rationale for Conducting This Study
Research Hypothesis
Within the maintenance setting of relapsed breast cancer susceptibility gene mutated 
(BRCA1/2 mutated or BRCAm), non-mucinous epithelial ovarian cancer (EOC), maintenance 
retreatment with Olaparib leads to significantly increased PFS compared with matching 
placebo, amongst patients who had previously benefitted from polyadenosine 
5’diphosphoribose [poly (ADP ribose)] polymerisation inhibitor (PARPi) maintenance 
therapy.  
Patients must have received a platinum-based chemotherapy regimen (carboplatin, cisplatin or 
oxaliplatin) and must have had, in the opinion of the Investigator, at least a partial radiological 
response, or not have a rising CA-125 following optimal debulking surgery with no 
measurable disease. The prior period of exposure to PARPi will be used as a measure of 
benefit from previous PARPi therapy.
Olaparib Mechanism of Action
Investigators should be familiar with the current Olaparib (AZD2281) Investigator brochure 
(IB).  Olaparib (AZD2281, KU-0059436) is a potent PARPi that is being developed as an oral 
therapy, both as a monotherapy (including maintenance) and for combination with other anti-
cancer agents in several tumour types.  Olaparib tablets are currently approved for the 
maintenance treatment of patients with platinum sensitive relapsed EOC both in the European 
Union and the United States of America.
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 PARPs leads to the persistence of SSBs, which are then converted to the more 
serious DNA double strand breaks (DSBs) during the process of DNA replication. During the 
process of cell division, DSBs can be efficiently repaired in normal cells by homologous 
recombination repair (HRR).  Tumours with homologous recombination deficiencies (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, 

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
27 (150)
Olaparib may offer a potentially efficacious and less toxic cancer treatment compared with 
currently available chemotherapy regimens. 
BRCA1 and BRCA2 defective tumours are intrinsically sensitive to PARP inhibitors, both in 
tumour models in vivo (Rottenberg et al. 2008, Hay et al. 2009) and in the clinic (Fong et al. 
2009). The mechanism of action for Olaparib results from the trapping of inactive PARP onto 
the single-strand breaks preventing their repair (Murai et al. 2012, Helleday 2011).  
Persistence of SSBs during DNA replication results in their conversion into the more serious 
DNA DSBs that would normally be repaired by HRR.  Olaparib has been shown to inhibit 
selected tumour cell lines in vitro and in xenograft and primary explant models as well as in 
genetic BRCA1/2 knock-out models, either as a stand-alone treatment or in combination with 
established chemotherapies. 
AstraZeneca considers that the 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
Experience with Olaparib BRCAm Ovarian Cancer
The results of a pivotal Phase II trial (D0810C00019; Study 19), showed the benefit of 
Olaparib as maintenance monotherapy in patients with platinum sensitive relapsed High Grade
Serous Ovarian Cancer (HGSOC) especially in BRCAm1 tumours.
Study 19 was a randomised, double-blind, placebo-controlled study to evaluate `maintenance 
treatment with Olaparib (capsule formulation) in patients with platinum sensitive relapsed
HGSOC (including patients with primary peritoneal and/or fallopian tube cancer) who had 
received ≥2 previous platinum regimens and were in partial or complete response following 
their last platinum-containing regimen.  
The primary endpoint in Study 19 was Investigator-assessed PFS.  In total, 265 patients were 
randomised to Olaparib 400 mg twice daily (bd; 136 patients) or placebo (129 patients).  The 
primary analysis was carried out following 154 PFS events and demonstrated that 
maintenance treatment with Olaparib led to a significant PFS improvement versus placebo 
                                               
1 BRCAm status is defined as a mutation in BRCA1 or BRCA2 classified as "deleterious" or "suspected 
deleterious" in accordance with the American College of Medical Genetics and Genomics recommendations for 
standards for interpretation and reporting of sequence variants (Richards et al. 2008).  The OReO study will recruit 
patients with BRCA1/2 mutations that are either germline (gBRCAm) or somatic (sBRCAm; i.e., occurring in the 
tumour only).

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
28 (150)
giving a hazard ratio (HR) of 0.35 with a 95% confidence interval (CI) of 0.25 to 0.49 
(P<0.00001) (Ledermann et al. 2012). 
A subgroup analysis (pre-specified in the statistical analysis plan [SAP]) showed that Olaparib
led to a greater clinical benefit in patients with a known gBRCAm; gBRCAm status was 
determined retrospectively for all consenting patients (n=166) using blood samples taken 
before randomisation.  Somatic (i.e., tumour only) BRCA1/2 status was determined from 
archival tumour samples from 196 patients.  The results showed an increased PFS benefit for 
BRCAm patients (HR, 0.18; 95% CI 0.10-0.31; median: 11.2 versus 4.3 months; P<0.00001)
compared with non-BRCAm (HR,0.54; CI 0.34-0.85; median:7·4 months vs 5·5 months; 
P=0·0075)
In the latest analysis of overall survival (OS; 70% maturity), data for BRCAm patients resulted 
in an OS HR of 0.62 (95% CI 0.41-0.94; median: 34.9 months versus 30.2 months)
(Ledermann et al. 2016).
Olaparib tolerability was similar in BRCAm patients and the overall population.  The findings 
from Study 19 are supported by clinical data from over 350 additional patients with BRCAm
ovarian cancer in 6 other Olaparib trials demonstrating consistent response rates. Results from 
the Phase III confirmatory trial (Study D0816C00002; the SOLO2 study) conducted with the
tablet formulation (300 mg bd), in BRCAm patients showed a median PFS for the Olaparib
treated patients of 19.1 months, compared with 5.5 months for the placebo group (HR of 0.3; 
95% CI 0.22-0.41; P<0.0001).  
The tablet dose was chosen based on data from Study D0810C00024 (Study 24).  Study 24 
explored the tablet formulation in terms of bioavailability, tolerability, and activity and 
selected the 300 mg bd dose for further development on the basis that this dose was 
considered to have similar efficacy in terms of tumour shrinkage in BRCAm ovarian cancer 
patients compared with the 400 mg bd capsule dose.  In the Study 24 ovarian cancer 
population, comparison of the change in tumour size data for 300 mg Olaparib tablets bd with 
400 mg Olaparib capsules bd showed the two treatments had similar effects on efficacy (Week 
8 difference=1.8%, 95% CI: -22.8%, 26.4%; P=0.881).  
Both capsule and tablet formulations have a similar tolerability profile.  Toxicities considered 
to be associated with administration of Olaparib include haematological effects (anaemia, 
neutropenia, lymphopenia, thrombocytopenia, mean corpuscular volume [MCV] elevation), 
decreased appetite, nausea and vomiting, diarrhoea, dyspepsia, stomatitis, upper abdominal 
pain, dysgeusia, fatigue (including asthenia), increase in blood creatinine, headache and 
dizziness.  Further information is provided in the summary of product characteristics (SmPC).  
Patients who have received platinum-based chemotherapy followed by PARPi as maintenance 
monotherapy to progression, and thereafter treated with a further line of platinum-based 
chemotherapy receive no further treatment until progression, according to current treatment 
paradigms.

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
29 (150)
EOC patients often show responses to multiple lines of platinum therapy (i.e., retreatment
with platinum-based chemotherapy agents following initial progression).  There is a potential 
that such patients could also respond to a retreatment with PARPi therapy, particularly those 
with BRCA1/2 mutations, since genomic instability in BRCA1 and BRCA2 can be enhanced by 
chemotherapy agents affecting DNA repair, potentially making them more susceptible to 
PARP inhibition following a platinum therapy response. At present, it is not known whether 
retreatment with a PARPi therapy after a response to retreatment with platinum-based
chemotherapy agents may work in a similar manner, but there is agreement amongst clinicians 
that exploring retreatment is an unmet need.  
Niraparib Experience in gBRCA1/2 Ovarian Cancer 
ENGOT-OV16/NOVA was a Phase III, randomised, double-blind placebo-controlled trial of 
niraparib, a PARPi, as maintenance therapy in patients with platinum-sensitive, relapsed 
ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with predominantly high-
grade serous histologic features (Mirza et al. 2016). Patients were grouped according to the 
presence or absence of a germline BRCA1/2 (gBRCA1/2) mutation (203 patients in the 
gBRCA1/2 cohort and 350 patients in the non-gBRCA1/2 cohort). They were randomised in a 
2:1 ratio to receive niraparib (300 mg) or placebo once daily.
Patients who received niraparib had a significantly longer median PFS duration than those 
who received the placebo: 21.0 versus 5.5 months in the gBRCA1/2 cohort (HR, 0.27; 95% CI, 
0.17 to 0.41) and 12.9 months versus 3.8 months in the non-gBRCA1/2 cohort for patients 
who had tumours with HRD (HR, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months versus 3.9 
months in the overall non-gBRCA1/2 cohort (HR, 0.45; 95% CI, 0.34 to 0.61). Therefore, 
compared to placebo, niraparib improved PFS (primary endpoint) regardless of BRCA1/2
mutation or HRD tumour status (P was <0.001 in all three primary efficacy populations).
In the niraparib group, the most commonly reported grade 3 or 4 adverse events (AEs) were 
thrombocytopenia (in 33.8%), anaemia (in 25.3%) and neutropenia (in 19.6%), which were 
managed with dose modifications.
Rationale for the OReO study
Prior experience has demonstrated that PARPi therapy improves median PFS when used in 
patients who are at least partially platinum sensitive. Following progression on PARPi
maintenance therapy many of these patients are found to retain sensitivity to platinum-based 
chemotherapy. It is not known whether these patients will benefit from an additional period of 
PARPi maintenance therapy. The OReO study will investigate the efficacy and safety of 
Olaparib maintenance retreatment in patients with relapsed non-mucinous EOC, who have had 
disease progression following maintenance therapy with a PARPi and who remain sensitive 
to platinum-based chemotherapy.
Multiple studies of patients given no maintenance therapy following first line platinum-based 
chemotherapy show that they can expect a median PFS of between 12 and 18 months, with the 

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
30 (150)
longer periods being more common in patients with BRCA mutations (13.8 months in the 
recent SOLO1 study). This has provided the rationale for requiring patients who received 
PARPi initially after first line therapy to have been exposed for 18 months (BRCA1/2+ve) and 
12 months (BRCA1/2-ve), in an attempt to select those patients benefiting from a PARPi. A 
similar approach has been adopted for those receiving their initial PARPi after later lines of 
chemotherapy, with the 12 months required for BRCA1/2+ve being consistent with the PFS 
seen in Study 19, and the 6 months for BRCA1/2-ve
1.3
Benefit/Risk and Ethical Assessment
Please see current edition of the SmPC for the most recent summary of the risks of Olaparib.
1.4
Study Design 
This is a Phase IIIb, randomised, double-blind, placebo-controlled, multicentre study to assess 
the efficacy and tolerability of Olaparib retreatment, versus matching placebo, in non-
mucinous EOC patients (including patients with primary peritoneal and/or fallopian tube 
cancer). To be eligible, patients must have received maintenance therapy with a PARPi, and 
must have had at least a partial radiological response to their most recent course of platinum-
based chemotherapy, or may have no evidence of disease (if optimal cytoreductive surgery 
was conducted prior to chemotherapy), and no evidence of a rising CA-125. All patients must 
have a confirmed genetic status for BRCA1/2. 
Patients will be randomised into one of two cohorts depending on their known BRCA1/2 status
(see Figure 1):
∀
The first cohort will enrol patients with confirmed BRCA1/2 (+ve) status 
(somatic, sBRCA1/2, or germline, gBRCA1/2) 
∀
The second cohort will enrol patients who are known gBRCA1/2 (-ve) 
and may include some patients who have an undetected sBRCA1/2 
mutation.
Within each cohort, patients will be randomised by prospective allocation in a 2:1 ratio 
(Olaparib:matching placebo) to the treatments as specified below:
∀
Olaparib tablets (oral [p.o.]), 300 mg bd (except where this dose and 
formulation was previously not tolerated; Section 6.7)
∀
placebo tablets to match, p.o. bd
Randomisation will be stratified by:
∀
Use of prior bevacizumab (yes versus no)

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
31 (150)
∀
Number of prior regimens of platinum-containing chemotherapy (≤3 
regimens versus ≥4 regimens)
The minimum periods for which patients must have taken maintenance PARPi without 
progression to be eligible for this retreatment study are:
∀
For the BRCA1/2 (+ve) cohort, the duration of exposure must have been 
≥18 months following a first line of chemotherapy or ≥12 months 
following a second line or subsequent line of chemotherapy 
∀
For the BRCA1/2 (-ve) cohort, the duration of exposure must have been 
≥12 months following a first line of chemotherapy or ≥6 months 
following a second line or subsequent line of chemotherapy
A month is defined as being from the start date to the same date in the next month (e.g. 01 
January to 01 July is 6 months).  These periods are of continuous PARPi administration and 
are measured from the date of the first dose to the date of the last dose of PARPi. During this 
period no new anticancer treatment for disease progression can have been administered, but 
patients may have had short breaks (maximum 14 days on any occasion) for holidays, control 
of toxicity or non-cancer treatments, for example.
Patients may have, but do not need to have, a specific confirmatory HRR or HRD test. 
Patients with BRCA variants of unknown significance will be regarded as BRCA1/2 (-ve) for 
the purposes of this study. 
Patients should also have received subsequent platinum-based chemotherapy, excluding 
bevacizumab, following progression during or after prior PARPi therapy and remain platinum 
sensitive. For the purposes of this study, platinum sensitivity means that the patient had a 
Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 partial or complete 
response (as determined by the Investigator) to the most recent line of platinum-based 
chemotherapy, or may have no evidence of disease (if optimal cytoreductive surgery was 
conducted prior to chemotherapy), and no evidence of a rising CA-125.
In addition, patients must be randomised into the OReO study within 8 weeks of their last 
dose of platinum-based chemotherapy (last dose is the day of the last infusion).
Investigators will be required to provide tumour assessment information using RECIST 1.1 
and health-related quality of life (HRQoL) questionnaires at baseline (a maximum of 28 days 
prior to randomisation).  Following randomisation, patients in all study arms must have 
tumour assessments every 12 weeks (±7 days) until objective disease progression.  More 
information is provided in Section 5.1.
Patients should continue to receive study treatment until objective radiological disease 
progression as per RECIST 1.1 or as long as in the Investigator’s opinion they are benefiting 
from treatment and they do not meet any other discontinuation criteria. Such patients should 
additionally:

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
32 (150)
∀
Not have symptoms and signs (including worsening of laboratory values) 
indicating unequivocal progression of disease
∀
Not have a decline in Eastern Cooperative Oncology Group (ECOG) 
performance status that can be attributed to disease progression
∀
Not have tumour progression at critical anatomical sites that cannot be 
readily managed and stabilised by protocol allowed medical interventions
∀
Be provided information deferring any standard treatment options that 
may exist in favour of continuing investigational product treatment at the 
time of initial progression.
Once a patient has stopped treatment, a 30 days post last study drug visit will be performed 
during which AEs, concomitant medications and the completed HRQoL questionnaire will be 
collected.  Thereafter, data on subsequent therapies according to routine clinical practice, 
adverse events of special interest (AESI), FACT-O (up to 2 years post randomisation) and 
survival will be collected until the data cut-off date for the final analysis (see Section 4.6).
The methods for ensuring blinding are addressed in Section 3.6; methods for un-blinding are 
addressed in Section 3.7.   

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
34 (150)
2
STUDY OBJECTIVES
The following objectives apply to both BRCA1/2 (+ve) and BRCA1/2 (-ve) cohorts.
2.1
Primary Objective
Primary Objective
Outcome Measure
To determine the efficacy of Olaparib
maintenance retreatment
compared to 
matching 
placebo 
by 
assessment 
of 
progression-free survival (PFS)
Time from randomisation to Investigator-assessed 
disease progression (according to RECIST 
version 1.1 guidelines) or death (by any cause in 
the absence of progression)
2.2
Secondary Objectives
Secondary Objective
Outcome Measure
To determine the efficacy of Olaparib 
maintenance retreatment compared to 
matching placebo by assessment of overall 
survival (OS)
Time from randomisation to death from any cause
To determine the efficacy of Olaparib 
maintenance retreatment compared to 
matching placebo by assessment of time to 
progression
by 
Gynecologic 
Cancer 
Intergroup (GCIG) criteria
Time from randomisation to the earliest of 
Investigator-assessed disease progression by 
RECIST or cancer antigen 125 (CA-125), or death
(by any cause in the absence of progression)
To determine the efficacy of Olaparib 
maintenance retreatment compared to 
matching placebo by assessment of the use 
of subsequent therapies and study treatment 
discontinuation
∀
Time from randomisation to first subsequent 
treatment commencement or death if this 
occurs 
before 
commencement 
of 
first 
subsequent treatment (TFST)
∀
Time 
from 
randomisation 
to 
second 
subsequent treatment commencement or death 
if this occurs before commencement of second 
subsequent treatment (TSST)
∀
Time from randomisation to study treatment 
discontinuation or death if this occurs before 
discontinuation of study treatment (TDT)

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
36 (150)
3
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study (see Figure 2 and Figure 3).  Under no circumstances can there be exceptions to this 
rule. Patients who fail screening for issues such as correctable laboratory abnormalities may 
be resubmitted for screening (see section 3.10.1)
3.1
Inclusion Criteria
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 non-mucinous EOC (including 
primary peritoneal and/or fallopian tube cancer). (Non-mucinous EOC includes patients 
with serous, endometrioid, and transitional cell tumours, and those with mixed histology 
where one of these subtypes is predominant (>50%). Inclusion of other subtypes should 
first be discussed with the Medical Monitor).
4.
Documented BRCA1/2 status
!
To be regarded as BRCA1/2 (+ve), the patient must have a mutation that is 
predicted to be deleterious or suspected deleterious (known or predicted to be 
detrimental / lead to loss of function)
5.
Patients must have received one prior PARPi therapy
!
PARPi therapy includes any agent (including Olaparib) used in a maintenance 
setting
!
For the BRCA1/2 (+ve) cohort, the duration of first PARPi exposure must have 
been ≥18 months following a first line of chemotherapy or ≥12 months following 
a second or subsequent line of chemotherapy 
!
For the BRCA1/2 (-ve) cohort, the duration of first PARPi exposure must have 
been ≥12 months following a first line of chemotherapy or ≥6 months following 
a second or subsequent line of chemotherapy
For the last chemotherapy course immediately prior to randomisation on the study
!
Patients must have received a platinum-based
chemotherapy regimen 
(carboplatin, cisplatin or oxaliplatin) and have received at least 4 cycles of 
treatment

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
37 (150)
!
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
!
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 randomised and a second sample is not required
!
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.
!
Patients must not have received bevacizumab during this course of treatment.  
Bevacizumab use as part of an earlier line of chemotherapy is permitted
!
Patients must not have received any investigational agent during this course of 
treatment
!
Patients must be randomised within 8 weeks of their last dose of chemotherapy 
(last dose is the day of the last infusion)
6.
Patients must have normal organ and bone marrow function measured within 28 days of 
randomisation, 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 with no platelet transfusion in the last 14 days
!
Total bilirubin (TBL) ≤1.5 X institutional 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 (CrCl) estimated using the Cockcroft-
Gault equation of  ≥51 mL/min or based on a 24 hour urine test:
Estimated CrCl = 
(140-age [years]) X weight (kg)    (X F)a
serum creatinine (mg/dL) X 72
awhere F=0.85 for females

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
38 (150)
7.
ECOG performance status 0-1 (see Appendix E)
8.
Patients must have a life expectancy ≥16 weeks
9.
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:
!
Amenorrhoeic for 1 year or more following cessation of exogenous hormonal 
treatments
!
Luteinizing hormone and follicle stimulating hormone levels in the post-
menopausal range for women under 50
!
Radiation-induced oophorectomy with last menses >1 year ago
!
Chemotherapy-induced menopause with >1 year interval since last menses
!
Surgical sterilisation (bilateral oophorectomy or hysterectomy).
10.
Patient is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations
11.
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 measurable disease following a complete response to most recent chemotherapy (+/-
surgery)
12.
A formalin fixed, paraffin embedded (FFPE) tumour sample from the cancer of 
sufficient quantity and quality (as specified in the Covance 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 preferred. Alternatively pre-cut 5μm thick, 
unstained sections from the FFPE block may be provided. Any exceptions to these 
conditions should be discussed with the Sponsor before randomisation of the patient.
13.
For inclusion in the optional biomarker research, patients must fulfil the following 
criteria:
!
Provision of informed consent for biomarker research.

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
39 (150)
If a patient declines to participate in the optional biomarker research, there will be no penalty 
or loss of benefit to the patient.  The patient will not be excluded from other aspects of the study.
3.2
Exclusion Criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site)
2.
Previous randomisation in the present study
3.
Participation in another clinical study with an investigational product during the 
chemotherapy course immediately prior to randomisation.
4.
Other malignancy within the last 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, or other solid tumours including lymphomas 
(without bone marrow involvement) curatively treated with no evidence of disease for 
≥5 years.  Patients with history of primary breast cancer may be eligible provided they 
completed their definitive anticancer treatment more than 3 years ago and they remain 
breast cancer disease free prior to start of study treatment
5.
Resting electrocardiogram (ECG) with corrected QT interval (QTc) >470 msec on 2 or 
more time points within a 24 hour period or family history of long QT syndrome
6.
Patients receiving any systemic chemotherapy or radiotherapy (except for palliative 
radiotherapy) within 3 weeks prior to study treatment
7.
Concomitant use of known strong cytochrome P450 (CYP) subfamily 3A (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 study treatment is 2 weeks
8.
Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or 
moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil).  The required washout 
period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 
3 weeks for other agents
9.
Persistent toxicities (Common Terminology Criteria for Adverse Event [CTCAE]
grade2 or higher) caused by previous cancer therapy, excluding alopecia and stable 
Grade 2 peripheral neuropathy

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
40 (150)
10.
Patients with current or previous myelodysplastic syndrome (MDS)/acute myeloid 
leukaemia (AML) or with features suggestive of MDS/AML
11.
Patients with symptomatic uncontrolled brain metastases.  A scan to confirm the absence 
of brain metastases is not required.  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 for 28 days
12.
Major surgery within 2 weeks of starting study treatment and patients must have 
recovered from any effects of any major surgery
13.
Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, 
non-malignant systemic disease or active, uncontrolled infection.  Examples include, 
but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) 
myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord 
compression, superior vena cava syndrome, extensive interstitial bilateral lung disease 
on high resolution computed tomography (HRCT) scan or any psychiatric disorder that 
prohibits obtaining informed consent
14.
Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication
15.
Breast feeding women
16.
Immunocompromised patients, e.g., patients who are known to be serologically positive 
for human immunodeficiency virus (HIV)
17.
Patients with a known hypersensitivity to Olaparib or any of the excipients of the product
18.
Patients with known active hepatitis (i.e., Hepatitis B or C) 
19.
Patient who have received a whole blood transfusion within 30 days prior to screening 
tests (packed red blood cells and platelet transfusions are acceptable).
For procedures for withdrawal of incorrectly enrolled patients see Section 3.4.

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
43 (150)
If a patient withdraws from participation in the study, then her enrolment/randomisation code 
cannot be reused.
Randomisation codes will be assigned strictly sequentially as patients become eligible for 
randomisation.
3.4
Procedures for Handling Incorrectly Enrolled or Randomised Patients
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 
randomised or initiated on treatment and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomised 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 patient’s circumstances should be discussed with the ENGOT trial Principal 
Investigator before the decision to withdraw is made. The AstraZeneca study physician must 
ensure all decisions are appropriately documented.
3.5
Methods for Assigning Treatment Groups
Eligible patients from both cohorts will be randomised separately in a 2:1 ratio 
(Olaparib:matching placebo).  The actual treatment given to individual patients will be 
determined by a randomisation scheme that has been loaded into the Interactive Voice Response 
System / Interactive Web Response System (IVRS/IWRS) database.  A blocked randomisation 
will be generated for all centres.  The randomisation scheme will be stratified based on the 
following: 
∀
Use of prior bevacizumab (yes versus no) and
∀
Number of prior regimens of platinum-containing chemotherapy (≤3 
versus ≥4 regimens).
Specific information concerning the use of IVRS/IWRS will be provided in a separate manual.  
It is recommended that patients commence study treatment on the day of randomisation if 
possible, and if not, then ideally within 3 days.
3.6
Methods for Ensuring Blinding
Olaparib and matched placebo treatment will be blinded.  The study medication will be 
labelled using a unique MedID number, which is linked to the randomisation scheme.  The 
active and placebo tablets and their packaging will look identical to ensure blinding of the
study medication.

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
44 (150)
3.7
Methods for Un-blinding 
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the Investigator(s) or pharmacists from the IVRS/IWRS.  Routines 
for this will be described in the IVRS/IWRS user manual that will be provided to each centre.
The treatment code must not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation.  The 
Investigator documents and reports the action to AstraZeneca or its agent, without revealing 
the treatment given to patient.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to study treatment and that potentially require expedited 
reporting to regulatory authorities.  Investigators and patients will not be un-blinded to study 
treatment for the planned analyses of data until all decisions on the evaluability of the data 
from each individual patient have been made and documented.  After the final data cut-off 
(DCO), all patients will be un-blinded to study treatment.
3.8
Restrictions
3.8.1 Grapefruit Juice
It is not recommended to consume grapefruit juice while on study therapy.
3.8.2 Contraception
Female patients of child bearing potential, who are sexually active, must agree to the use of 
one highly effective forms of contraception and their partners must use a male condom
throughout the period of taking study treatment and for 1 month (female patients) after last 
dose of study drug. For details refer to Appendix D (Acceptable Birth Control Methods).
3.9
Discontinuation of Study Treatment 
Patients may be discontinued from study treatment in the following situations:
∀
Patient decision.  The patient is at any time free to discontinue treatment, 
without prejudice to further treatment
∀
AE
∀
Severe non-compliance with the study protocol as judged by the 
Investigator and/or AstraZeneca
∀
Bone marrow findings consistent with MDS/AML

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
45 (150)
∀
Objective progression according to the RECIST criteria as assessed by 
the Investigator (unless in the Investigator’s opinion the patient is 
benefiting from the treatment and does not meet any other 
discontinuation criteria as outlined in Section 3.11).
3.9.1 Procedures for Discontinuation of a Patient from Study Treatment 
Product 
At any time, patients are free to discontinue study treatment or withdraw from the study (i.e., 
study treatment and assessments – see Section 3.10), without prejudice to further treatment.  
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.  AEs 
will be followed up (see Section 6), completed questionnaires (e.g., for patient reported 
outcomes [PROs]) and all unused study treatment should be returned by the patient. 
By discontinuing from study treatment, the patient is not withdrawing from the study.  
Patients should be followed for progression (if discontinuation in the absence of progression) 
and overall survival following treatment discontinuation as per the protocol schedule. 
Any patient discontinuing study treatment 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. After discontinuation of study medication, 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. In addition, they 
will record on the electronic case report form (eCRF) the date of discontinuation, the reasons, 
manifestation, and treatment at the time of discontinuation. If patients discontinue study 
treatment, the site monitor must be informed immediately. Patients will be required to attend 
the treatment discontinuation visit. The patient should return all study medication.
After discontinuation of the study medication at any point in the study, all ongoing AEs or 
SAEs must be followed until resolution unless, in the Investigator’s opinion the condition is 
unlikely to resolve due to the patients 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 AstraZeneca 
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.
Any patient who has not yet shown objective radiological disease progression at withdrawal 
from investigational product should continue to be followed as per RECIST as detailed in 
Section 5.1. All patients must be followed for AESIs, survival and subsequent therapies, up to 
the final analysis. If a patient is withdrawn from study, see Section 3.10.

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
46 (150)
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; i.e., the patient does not meet the required 
inclusion/exclusion criteria for the study. The patient’s circumstances 
should be discussed with the ENGOT trial Principal Investigator and the 
sponsor AstraZeneca before the decision to withdraw is made.
∀
Patient lost to follow-up
∀
Death.
3.10.1Screen Failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised.  These patients should have the reason for study withdrawal 
recorded as ‘Incorrect Enrolment’ (i.e., patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screen failures (not randomised 
patients).
RE-SCREEN: subjects that initially failed the screening process for minor, potentially 
correctable abnormalities, such as laboratory testing, are allowed to be resubmitted to the 
screening process.
Re-screened subjects will be re-consented and given a new subject number, as if they have not 
previously undergone the screening process. The site would follow the same procedures as 
they would with a new subject. The patient must still be randomised within 8 weeks from the 
last dose of chemotherapy.
3.10.2Withdrawal of the Informed Consent
Patients are free to withdraw from the study at any time (study treatment 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 her enrolment/randomisation code 
cannot be reused.  Withdrawn patients will not be replaced. 

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
47 (150)
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) 
∀
Withdrawal of consent to the use of their study generated data
∀
Withdrawal to the use of any samples (see Section 5.5.4).
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.
3.11 Discontinuation of the Study
The study may be stopped if, in the judgment of AstraZeneca, together with that of the 
ENGOT Principal Investigator and after the recommendation of the independent data 
monitoring committee (IDMC), the 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 eCRF.  All reasons for discontinuation of 
treatment must be documented.
The study, or one cohort, may also be stopped at any time after the Primary Analysis if in the 
judgment of AstraZeneca, the ENGOT Principal Investigator and the Trial Steering 
Committee, there is insufficient clinical benefit from re-treatment.
In terminating the study, AstraZeneca will ensure that adequate consideration is given to the 
protection of the patients’ interests.
4
STUDY PLAN AND TIMING OF PROCEDURES 
The scheduled screening assessments are summarised in Table 2.

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
48 (150)
The scheduled assessments for on study treatment and study discontinuation are summarised 
in Table 3.
Table 2
Screening (Visit 1) Study Schedule for OReO Patients (Locally 
Confirmed BRCA1/2 Mutation Status)
Day
Day -27 to Day 0
Informed consent and inclusion / exclusion criteria review
X
Demographics including date of birth, gender, and where permitted race 
and/or ethnicity
X
Standard medical, medication and surgical history a
X
Prior cancer therapies including radiotherapy
X
History of blood transfusions b
X
Physical examination and ECOG 
X
Vital signs (includes blood pressure [BP], pulse and temperature), body 
weight 
X
ECG c
X
Haematology/clinical chemistry d
X
Urinalysis
X
Pregnancy test e
X
Blood sample for disease specific marker (CA-125)
X
BRCA1/2 status f
X
Tumour assessment (CT or MRI according to RECIST 1.1) g
X
AEs (from time of consent)
X
Concomitant medications
X
Archival or fresh tumour sample (mandatory) h
X
Response to current chemotherapy regimen
X
a
Medical history can be limited to relevant history of ovarian cancer (surgery, prior treatments), other 
conditions requiring ongoing treatment and any conditions potentially impacting trial participation.
b
Include history of blood transfusion within previous 30 days prior to screening tests and the reasons e.g., 
bleeding or myelosuppression.
c
ECG should be performed once the patient has been in the supine position for at least 5 minutes.
d
International normalised ratio (INR) and activated partial thromboplastin time (APTT) should be performed 
at screening and if clinically indicated.  Platelet count will be performed as part of haematology testing and 
fibrinogen only as clinically indicated. For a list of all required laboratory tests please refer to Section 5.2.3.
e
Pre-menopausal women of child-bearing 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.  
f
Patients must have a documented BRCA1/2 status to be randomised in the study. A BRCA1/2 test should be 
performed as soon as a potentially eligible patient is identified who does not already have confirmed BRCA1/2 
status as part of the screening assessments. Patients for whom their gBRCA1/2 status is already known should 
be consented to the study within 28 days prior to day 1 of study treatment.

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
49 (150)
g
RECIST assessments will be performed using CT or MRI scans of chest, abdomen, and pelvis.  Any other 
areas of disease involvement should be additionally imaged based on the signs and symptoms of individual 
patients.  Baseline assessments 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.
h
All patients will need to submit either an archival sample or, if preferred, a recent tumour sample, for post-
analysis testing of their 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.

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
50 (150)
Table 3
Scheduled Assessments for on Study Treatment and Study Discontinuation 
Visit number
2
3
4 onwards (subsequent on-treatment visits:
every 4 weeks for 12 weeks, then every 12 
weeks) a
Study 
treatment 
discontinue
d
Follow-up 30 
days after last 
dose of study 
medication
Long-term follow-up 
(12-weekly beyond 
30 days after last 
dose of study 
treatment)
Day
1
29
Day 1 of next visit period
(Visit 4 equals day 57, Visit 5 equals day 85, 
etc.)
Visit window
±3d
±3d
±3d
±7d
±14d
Randomisation
Xa
Physical exam (prior 
to dosing) c
X b
X
X
X
Vital signs (includes 
BP, pulse and 
temperature), body 
weight c
X b
X
X
X
X
ECOG performance 
status
X
X
X
ECG c
X b
Haematology / 
clinical chemistry
X d
X
X
X
X
X e
Study treatment 
dispensed / returned f
X
X
X
X (Returned)
X (Returned)
Urinalysis (if 
indicated)
X
Pregnancy test g
X
X
X

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
51 (150)
Table 3
Scheduled Assessments for on Study Treatment and Study Discontinuation 
Visit number
2
3
4 onwards (subsequent on-treatment visits:
every 4 weeks for 12 weeks, then every 12 
weeks) a
Study 
treatment 
discontinue
d
Follow-up 30 
days after last 
dose of study 
medication
Long-term follow-up 
(12-weekly beyond 
30 days after last 
dose of study 
treatment)
Day
1
29
Day 1 of next visit period
(Visit 4 equals day 57, Visit 5 equals day 85, 
etc.)
Visit window
±3d
±3d
±3d
±7d
±14d
Blood sample for 
disease specific 
marker (CA-125) h
X
[Every 12 weeks (±7d)]
Blood sample for  
biomarker analysis p
X
X (At 
progression)
Blood sample for 
confirmation of 
gBRCA1/2 i
X
Tumour biopsy 
(optional) j
X (At 
progression)
Tumour assessment 
(CT or MRI 
according to 
RECIST 1.1) k
X
[Every 12 weeks (±7d)]
AEs l
X
X
X
X
X
X

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
52 (150)
Table 3
Scheduled Assessments for on Study Treatment and Study Discontinuation 
Visit number
2
3
4 onwards (subsequent on-treatment visits:
every 4 weeks for 12 weeks, then every 12 
weeks) a
Study 
treatment 
discontinue
d
Follow-up 30 
days after last 
dose of study 
medication
Long-term follow-up 
(12-weekly beyond 
30 days after last 
dose of study 
treatment)
Day
1
29
Day 1 of next visit period
(Visit 4 equals day 57, Visit 5 equals day 85, 
etc.)
Visit window
±3d
±3d
±3d
±7d
±14d
Concomitant 
medications 
including blood 
transfusions m
X
X
X
X
X
FACT-O n
X
X
X
X
X
X
Survival
X
X
X
Subsequent cancer 
therapy following 
discontinuation of 
study treatment o
X
X
a
Randomisation can occur prior to Day 1 for operational reasons, provided the patient has completed screening and meets all inclusion/exclusion criteria. 
Subsequent visits take place relative to the date of first dose (Day 1). Visits occur on Day 1 of a 4-week (28-day) visit period for the first 12 weeks and 
then 12 weekly on Day 1 of a 12-week visit period .
b
If assessed within 7 days before randomisation 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
Safety blood samples do not need to be repeated on Day 1 of study treatment if assessed at least 3 weeks after the last dose of chemotherapy but within 7 
days before starting study treatment, unless the Investigator believes that it is likely to have changed significantly.  Coagulation test should be performed 
at screening and if clinically indicated.  For a list of all required laboratory tests please refer to Section 5.2.3.
e
Haematology tests, but no clinical chemistry tests. Coagulation tests will only be performed if clinically indicated.

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
53 (150)
f
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 in accordance with local practice.
g
Pre-menopausal women of child-bearing 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.  In the event of suspected pregnancy during the study, the test should be repeated and, if positive, the patient 
discontinued from study treatment immediately.
h
CA-125 to be measured at the same time points as CT/MRI scans. Repeat measurements should be taken ≥1 week after a value suggesting progression. 
i
All patients should have a blood sample taken and stored for subsequent confirmation of gBRCA1/2 status, although the test will not be performed unless 
required to further analyse the treatment response at the end of the study.
j
Optional tumour sample at progression of disease.
k
Follow-up assessments will be performed every 12 weeks (±7d) after randomisation until objective disease progression as defined by RECIST 1.1.  If a 
patient discontinues treatment (and/or receives a subsequent cancer therapy) prior to progression then the patient should still continue to be followed until 
objective disease progression as defined by RECIST 1.1.  Any other sites at which new disease is suspected should also be appropriately imaged.  If an 
unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent assessments at their 
scheduled visits.
l
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. Only AESIs will be collected during long-term follow-up.
m
All concomitant medications will be collected at screening. At subsequent visits, only antibiotics, anti-emetics, transfusions, erythropoietin, granulocyte 
colony-stimulating factor (G-CSF) and concomitant medications associated with an AE will be collected.
n
FACT-O to be completed at baseline (pre dose) and 4, 8, 12, 24, 36, and 48 week visits, then 12-weekly (±14 days) up to 2 years post patient randomisation.
o
All anti-cancer treatments (including, but not limited to, chemotherapy and targeted agents), start and stop dates, reason(s) for stopping and the 
Investigator’s opinion of response to them plus the date of progression post discontinuation of study treatment need to be recorded.
p
Optional in countries that do not permit this approach
NB. Bone marrow or blood cytogenetic samples may be collected for patients with prolonged haematological toxicities as defined in Section 6.7.1.

Clinical Study Protocol
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
54 (150)
Table 4
Scheduled Assessments for Patients Remaining on Study Treatment Post Primary Analysis
Subsequent on-treatment 
visits every 12 weeks
Study treatment 
discontinued
Follow-up 30 days after last 
dose of study medicationc
Adverse Events (includes SAE and AESI)a
X
X
X
Haematology/Clinical Chemistryb
X
Pregnancy
X
Concomitant Medication
X
X
X
FACT-O
X
X
X
Study Treatment Dispensed/Returned
X
X (Returned)
Subsequent Cancer Treatment
X
Tumour Biopsy on Progression (optional)
X
Blood Sample for Biomarker Analysis
X
Survival
X
X
a
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  Only AESIs will be collected during long-term follow-up
b
Other laboratory analyses, such as urinalysis, and physical examination, ECG and EGOG status may be performed as part of SOC but this data is not required post Primary Analysis
c
Post 30-day follow up, patients will enter long term follow up per Table 3

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
55 (150)
4.1
Enrolment/Screening Period
Procedures will be performed according to the Study Plan. 
At screening, consenting patients are assessed to ensure that they meet the eligibility criteria.  
Patients who do not meet these criteria must not be enrolled in the study.
Prior to Randomisation:
∀
BRCA1/2 test to be performed as soon as a potentially eligible patient is 
identified who does not already have confirmed BRCA1/2 status
Within 4 Weeks (28 Days) Prior to First Dose:
∀
Demographics data and other characteristics will be recorded as will date 
of birth, gender and, where permitted, race and/or ethnicity
∀
A standard medical, medication and surgical history will be obtained with 
review of the selection criteria with the patient. A medical history can be 
limited to relevant history of ovarian cancer (surgery, prior treatments), 
other conditions requiring ongoing treatment and any conditions 
potentially impacting trial participation.
∀
Prior cancer therapies including radiotherapy will be recorded
∀
History of blood transfusions within the previous 30 days prior to 
screening tests and the reasons for transfusion, e.g., bleeding or 
myelosuppression
∀
Physical examination, ECOG performance status assessment, collection 
of vital signs, body weight
∀
ECG, which should be performed once the patient has been in the supine 
position for at least 5 minutes in each case 
∀
Haematology and clinical chemistry tests.  Coagulation tests will only be 
performed if clinically indicated
∀
Urinalysis
∀
Patients must be postmenopausal, or have evidence of non-childbearing 
status. 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

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
56 (150)
∀
Blood sample for disease specific marker (CA-125)
∀
Baseline RECIST 1.1 assessments will be performed using CT or MRI 
scans of the chest, abdomen and pelvis (no more than 28 days before 
randomisation, and as close as possible to start of study treatment.
∀
Recording of concomitant medications
∀
Recording of AEs (from time of consent)
∀
Provision of archival or fresh tumour sample (mandated for all patients)
for post-analysis testing of genetic status
∀
Recording of response to current chemotherapy regimen.
4.2
Treatment Period
One cycle is 28 days.  Unless otherwise specified, procedures should be conducted on the 
scheduled day (±3 days).  This excludes Study Visit 2.
Study Visit 2 (Day 1 of Study Treatment):
∀
Randomisation (2:1, Olaparib:matching placebo) is allowed before study 
Day 1 for operational reasons if the patient has completed screening and 
met all inclusion and exclusion criteria
∀
Physical examination (does not need to be repeated if assessed within 7 
days of Day 1 and eligibility requirements were met, unless Investigator
believes patient status is likely to have changed significantly)
∀
Vital signs (includes BP, pulse and temperature), body weight (does not 
need to be repeated if assessed within 7 days of Day 1 and eligibility 
requirements were met, unless Investigator believes they are likely to 
have changed significantly)
∀
HRQoL baseline assessment with FACT-O questionnaires pre-dosing
∀
ECOG performance status pre-dosing
∀
Haematology/clinical chemistry (blood samples do not need to be 
repeated on Day 1 if assessed at least 3 weeks after last dose of 
chemotherapy but within 7 days before starting study treatment unless 
Investigator believes they are likely to have changed significantly.  
Coagulation tests only required if clinically indicated)

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
57 (150)
∀
Urinalysis (to be repeated only if clinically indicated)
∀
Patients must be postmenopausal or have evidence of non-childbearing 
status. Women of childbearing potential must have a confirmatory 
negative urine or serum pregnancy test before treatment on Day 1.  In the 
event of suspected pregnancy during the study, the test should be 
repeated and, if positive, the patient discontinued from study treatment 
immediately)
∀
Recording of AEs
∀
Recording of concomitant medications, including blood transfusions 
∀
Study treatment dispensed - 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 in
accordance with local practice
∀
Blood samples for biomarker analysis (optional in countries that do not 
permit this approach)
∀
Blood sample taken and stored for subsequent confirmation of gBRCA1/2
status (test will be performed at end of treatment only if required to 
further analyse the treatment response at the end of the study)
∀
ECG - if assessed within 7 days before Day 1 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. 
Study Visit 3 (Day 29): 
∀
Physical examination 
∀
Vital signs (includes BP, pulse and temperature), body weight 
∀
HRQoL assessment with FACT-O questionnaire
∀
Haematology/clinical chemistry 
∀
Recording of AEs
∀
Recording of concomitant medications (only antibiotics, anti-emetics, 
transfusions, erythropoietin, G-CSF and concomitant medications 
associated with an AE will be collected)

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
58 (150)
∀
Study treatment dispensed - 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 in 
accordance with local practice
∀
Unused study treatment returned
∀
Pregnancy test if required.
Subsequent On-treatment Visits: Every 4 Weeks Then Every 12 Weeks
Every 4 weeks in the first 12 weeks, and thereafter every 12 weeks to coincide with the 
radiographic assessments (if not progressed and still on treatment). The visit day is Day 1 of 
the visit period, i.e., Visit 4=Treatment Day 57, Visit 5=Treatment Day 85, etc.
∀
Physical examination 
∀
Vital signs (includes BP, pulse and temperature), body weight 
∀
HRQoL assessment with FACT-O questionnaire
∀
ECOG performance status
∀
Haematology/clinical chemistry 
∀
Blood sample for disease specific marker (CA-125) every 12 weeks (±7 
days). Repeat measurements should be taken ≥1 week after a value 
suggesting progression.
∀
Tumour assessment (by RECIST 1.1) as assessed by the Investigator
every 12 weeks  (±7 days)
∀
Recording of AEs
∀
Recording of concomitant medications (only antibiotics, anti-emetics, 
transfusions, erythropoietin, G-CSF and concomitant medications 
associated with an AE will be collected)
∀
Study treatment dispensed - 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 in 
accordance with local practice
∀
Unused study treatment returned

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
59 (150)
∀
Pregnancy test if required.
4.3
Study Treatment Discontinuation
∀
Physical examination 
∀
Vital signs (includes BP, pulse and temperature), body weight 
∀
HRQoL assessment with FACT-O questionnaire
∀
ECOG performance status
∀
Haematology/clinical chemistry 
∀
Recording of AEs
∀
Recording of concomitant medications (only antibiotics, anti-emetics, 
transfusions, erythropoietin, G-CSF and concomitant medications 
associated with an AE will be collected)
∀
Unused study treatment returned
∀
Tumour biopsy on progression (optional)
∀
Blood samples for biomarker analysis on progression (optional in 
countries that do not permit this approach)
∀
Survival status. 
4.4
Follow-up Period
Unless otherwise specified, procedures should be conducted on the scheduled day (±7 days).
30 Days After Last Dose of Study Treatment:
∀
Vital signs (includes BP, pulse and temperature), body weight 
∀
Recording of AEs
∀
HRQoL assessment with FACT-O questionnaire
∀
Haematology / clinical chemistry 
∀
Recording of concomitant medications (only antibiotics, anti-emetics, 
transfusions, erythropoietin, G-CSF and concomitant medications 
associated with an AE will be collected)

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
60 (150)
∀
Recording of subsequent cancer therapy following discontinuation of 
study treatment; all anti-cancer treatments (including, but not limited to, 
chemotherapy and targeted agents), start and stop dates, reason(s) for 
stopping and the Investigator’s opinion of response to them plus the date 
of progression post discontinuation of study treatment need to be 
recorded
∀
Unused study treatment returned
∀
Pregnancy test
∀
Blood samples for biomarker analysis on progression
∀
Survival status.
4.5
Long-Term Follow-up (12-Weekly Beyond 30 Days After Last Dose of 
Study Medication)
Unless otherwise specified, procedures should be conducted every 12 weeks (±14 days). If 
haematology testing is not indicated, long-term follow up, including FACT-O, can be 
conducted by phone.
∀
Recording of AESIs
∀
FACT-O (up to 2 years post randomisation)
∀
Recording of subsequent cancer therapy following discontinuation of 
study treatment; all anti-cancer treatments (including, but not limited to, 
chemotherapy and targeted agents), start and stop dates, reason(s) for 
stopping and the Investigator’s opinion of response to them plus the date 
of progression post discontinuation of study treatment need to be 
recorded
∀
Survival status
∀
For patients with unresolved haematological toxicity only: haematology 
or coagulation tests as judged clinically necessary 
4.6
Patients on Study Treatment Post Primary Analysis
Patients remaining on study treatment following the Data Cut Off for the Primary Analysis 
will follow a reduced data collection schedule (Table 4) on a 12 weekly basis until either 
progression or the decision to stop study treatment (see sections 4.3 and 4.4)
∀
Recording of Adverse Events (including AESI and SAE)

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
61 (150)
∀
Haematology and Clinical Chemistry
∀
Pregnancy Test
∀
HRQoL assessment with FACT-O questionnaire
∀
Recording of concomitant medications (only antibiotics, anti-emetics, 
transfusions, erythropoietin, G-CSF and concomitant medications 
associated with an AE will be collected)
∀
Survival
∀
Study treatment dispensed - 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 in 
accordance with local practice
∀
Unused study treatment returned
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 case report forms (CRFs)
as specified in the study protocol and in accordance with the instructions provided.
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the clinical study agreement (CSA).  
The Investigator will sign the completed CRFs.  A copy of the completed 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 CRFs provided.  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
5.1.1 CT and MRI Scans Assessments (RECIST 1.1)
Following the baseline assessment, subsequent tumour assessments according to RECIST 1.1 
should be performed every 12 weeks (±7 days) relative to the date of randomisation, up to 
objective disease progression by RECIST 1.1. 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
62 (150)
For those patients with no evidence of disease at baseline, following a clinical complete 
response to chemotherapy, progression is defined by the detection of new lesions on follow up 
radiological assessments (RECIST 1.1).
The imaging modalities used for RECIST assessment will be CT or MRI scans of the chest, 
abdomen, and pelvis with other regions as clinically indicated for the assessment of disease.  
Any other sites at which new disease is suspected should also be appropriately imaged.  The 
methods of assessment of tumour burden used at baseline must be used at each subsequent 
follow-up assessment.
Radiological examinations performed in the conduct of this study should be retained at site as 
source data.
All treatment decisions will be based on site assessment of scans.  
It is important to follow the assessment schedule as closely as possible.  If scans are 
performed outside of scheduled visit ±7 day window interval and the patient has not 
progressed, every attempt should be made to perform the subsequent scans at their time points 
as originally scheduled.  Patients will be evaluated until objective radiological disease 
progression by RECIST 1.1 as per the study schedule (see Table 2 and Table 3)regardless of 
whether study treatment is discontinued or delayed and/or protocol violations, unless they 
withdraw consent.
5.1.2 Tumour Evaluation
RECIST 1.1 criteria will be used to assess patient response to treatment for determining PFS 
times. The RECIST 1.1 guidelines for measurable, non-measurable, target and non-target 
lesions and the objective tumour response criteria (complete response [CR], partial response 
[PR], stable disease [SD], or progression of disease [PD]) are presented in Appendix F.
The methods of assessment of tumour burden used at baseline - CT or MRI scans of chest, 
abdomen, pelvis, must be used at each subsequent follow-up assessment.  Any other areas of 
disease involvement should be additionally imaged based on the signs and symptoms of 
individual patients.
Following the baseline assessment, efficacy for all patients will be assessed by objective 
tumour assessments every 12 weeks #7 days after randomisation, until objective disease 
progression as defined by RECIST 1.1.  Any other sites at which new disease is suspected 
should also be appropriately imaged. 
If a patient discontinues treatment (and/or receives a subsequent cancer therapy) prior to 
progression then the patient should still continue to be followed until objective disease 
progression as defined by RECIST 1.1.  
Categorisation of objective tumour response assessment will be based on the RECIST 1.1 
criteria of response: CR, PR, SD, and PD.  Target lesion (TL) progression will be calculated in 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
63 (150)
comparison to when the tumour burden was at a minimum (i.e. smallest sum of diameters 
previously recorded on study).  In the absence of progression, tumour response (CR, PR, and 
SD) will be calculated in comparison to the baseline tumour measurements obtained before 
starting treatment.  
For patients with non-measurable disease only at baseline, categorisation of objective tumour 
response assessment will be based on the RECIST 1.1 criteria of response: CR, PD, and non 
CR/non PD.
If the Investigator is in doubt as to whether progression has occurred, particularly with 
response to non-target lesion or the appearance of a new lesion, it is advisable to continue 
treatment until the next scheduled assessment or sooner if clinically indicated and reassess the 
patient’s status.  If repeat scans confirm progression, then the date of the initial scan should be 
declared as the date of progression.
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more non-target lesions 
is usually not sufficient to quality for unequivocal progression status.
Following progression, patients should continue to be followed up for survival according to 
the institution’s local practice as outlined in the study plan.
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
study plan in Table 2 and Table 3.
5.1.3
CA-125 Measurements
At the same time as the CT or MRI scans, CA-125 measurements will be taken, and used in 
conjunction with the (RECIST 1.1) radiological data using the GCIG criteria (see Appendix 
H) as a measure of tumour progression. The outcomes according to GCIG criteria will be 
assessed as a secondary objective.
It is important to follow the assessment schedule as closely as possible.  If CA-125 assessment 
is performed outside of the scheduled visit ±7 day window interval, every attempt should be 
made to assess the next CA-125 at the scheduled time points.  Repeat measurements should be 
taken ≥1 week after a value suggesting progression.
Patients will be evaluated until objective disease progression, based on progressive serial 
elevation of serum CA-125 according to the GCIG criteria, or until discontinuation for other 
reasons.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
64 (150)
5.2
Safety Assessments
5.2.1 Physical Examination and ECOG
A complete physical examination with weight will be performed and include an assessment of 
the following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal (including spine 
and extremities) and neurological systems.
Physical examinations will be performed at screening, prior to dosing on Day 1, Day 29, and 
Day 1 of each successive visit period, and at study discontinuation.
5.2.2 Vital Signs and Weight
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.
Weight will be assessed according to the Study Schedule (see Table 2 and Table 3) and as 
clinically indicated at any other time. (Height will be assessed only when relevant for 
additional study treatments.)
5.2.2.1
Pulse and Blood Pressure
Pulse and BP (systolic and diastolic) will be assessed at screening (Visit 1, within 28 days 
prior to start of study treatment), Visit 2 (Day 1 of the treatment period), Visit 3 (Day 29), Day 
1 of each successive visit period, at treatment discontinuation, and at the follow-up visit (30 
days after last dose of study medication). 
5.2.2.2
Body Temperature
Body temperature will be assessed at screening (Visit 1, within 28 days prior to start of study 
treatment), Visit 2 (Day 1 of the treatment period), Visit 3 (Day 29), Day 1 of each successive 
visit period, at treatment discontinuation, and at the follow-up visit (30 days after last dose of 
study medication).
5.2.3 Laboratory Safety Assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation 
(only if clinically indicated), and urinalysis will be taken at the times indicated in the study 
plan (see Section 4).
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 the

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
65 (150)
laboratory method used and routine practice at the site. Every effort should be made to ensure 
that the same local laboratory is used for all tests.
The following laboratory variables will be measured:

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
66 (150)
Table 5
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- ALT
B-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 TBL ≥2 X ULN please refer to 
Appendix C (Actions Required in Cases of Increases in Liver Biochemistry and Evaluation of 
Hy’s Law) for further instructions.
5.2.3.1
Coagulation
APTT will be performed at screening and if clinically indicated  
INR will be performed at screening and if clinically indicated.  Patients taking warfarin may 
participate in this study; however, it is recommended that INR be monitored carefully at least 
once per week for the first month, then monthly if the INR is stable.
Platelet count will be performed as part of haematology testing and fibrinogen only as 
clinically indicated.
Each coagulation test result will be recorded in eCRF.
5.2.3.2
Bone Marrow or Blood Cytogenetic Samples 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
haematological toxicities as defined in Section 6.7.1.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
67 (150)
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 eCRF.
5.2.4 ECG
5.2.4.1
Resting 12-lead ECG
ECGs are required within 7 days prior to starting study treatment and when clinically 
indicated.
12-lead ECGs will be obtained after the patient has been rested in a supine position for at least 
5 minutes in each case.  The Investigator or designated physician will review the paper copies 
of each of the timed 12-lead ECGs on each of the study days when they are collected.
ECGs will be recorded at 25 mm/sec.  All ECGs should be assessed by the Investigator as to 
whether they are clinically significantly abnormal / not clinically significantly abnormal.  If 
there is a clinically significant abnormal finding, the Investigator will record it as an AE on 
the eCRF.  The original ECG traces must be stored in the patient medical record as source 
data.
5.2.5 Other Safety Assessments
5.2.5.1
Serum or Urine Pregnancy Test
Pregnancy tests on blood or urine samples will be performed for pre-menopausal women of 
child-bearing potential, one within 28 days prior to the start of study treatment and the other 
on Day 1 of the study prior to commencing treatment.  Tests will be performed by the 
hospital’s local laboratory.  If results are positive the patient is ineligible/must be discontinued 
from the study.  In the event of a suspected pregnancy during the study, the test should be 
repeated.
At 30 day follow-up a repeat pregnancy test should be performed.
5.3
Other Assessments
5.3.1 Patient Reported Outcomes (HRQoL: 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 paper-based 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 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
68 (150)
dosing at baseline, at Day 29, then every 4 weeks (±7 days) for the first 12 weeks, and then 
every 12 weeks until 2 years from the date of randomisation.  In addition, QoL questionnaires 
will be collected at the discontinuation of study treatment visit, 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.  Patients who had RECIST 1.1 disease 
progression will complete the questionnaires during the 12-weekly survival follow-ups for up 
to a period of 2 years from patient randomisation.  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 (See Section 8.4.5 for full
details).  The endpoint for HRQoL analysis will be the FACT-O Trial Outcome Index (TOI).  
Other subscales will be considered as exploratory endpoints.
5.4
Biomarker Analysis
5.4.1 Collection of Samples
Blood samples for biomarker analysis will be taken during the study.
5.4.1.1
CA-125
Blood samples for the disease specific marker, CA-125, will be collected at screening (Visit 1)
and every 12 weeks (±7 days), at the same time as the CT or MRI scans, until objective 
disease progression, based on progressive serial elevation of serum CA-125 according to the 
GCIG criteria, or until discontinuation for other reasons.
5.4.1.2
Archival or Fresh Tumour Sample
All patients are required to submit an archival tumour sample or, if preferred, a recent tumour 
sample, for post-analysis testing of their genetic status. Confirmation is required in clinical 
notes regarding availability of sample during the screening period; however, samples are only 
required to be submitted once the patient has been randomised.
Samples should be submitted as paraffin blocks, alternatively, sections mounted on glass 
slides prepared from the block can be provided. 
Material provided will be used for additional exploratory work, which may be conducted to 
elucidate the mechanism of response, understand the mode of action of study treatment, or 
improve the understanding of disease progression.
Please refer to the laboratory manual for further details regarding tissue collection, shipping 
and storage.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
69 (150)
5.4.1.3
Blood Sample for Confirmation of gBRCA
All patients are required to provide a 9 ml blood sample at Visit 2 for subsequent confirmation 
of gBRCA status. BRCA testing will not be performed unless required to further analyse the 
treatment response at the end of the study.
Samples may be used for additional 
 work, which may be conducted to elucidate
the mechanism of response, understand the mode of action of study treatment, or improve the 
understanding of disease progression.
Please refer to the laboratory manual for further details regarding blood sample collection, 
shipping and storage.
5.4.1.4
Blood Samples for Biomarker Analysis 
The following blood sample will be taken at Visit 2 and at disease progression:
1 X 20 mL whole blood to provide plasma
Samples may be used for additional 
 work, which may be conducted to elucidate 
the mechanism of response, understand the mode of action of study treatment, or improve the 
understanding of disease progression.
Please refer to the laboratory manual for further details regarding blood sample collection, 
shipping, and storage.
5.4.1.5
Optional Tumour Samples 
Wherever possible, and also subject to optional informed consent, an on-study tumour biopsy 
sample obtained either from the progressed lesion or from a new lesion may be collected at 
disease progression, 
.  Biopsies may be particularly 
valuable where there is a marked phenotypic change in a particular lesion.
Tumour tissue collected during the study should be immediately fixed and processed to a 
FFPE block.  Alternatively, sections mounted on glass slides prepared from the block can be 
provided.
In both cases, material will be used for additional 
 work, which may be conducted 
to elucidate the mechanism of response, understand the mode of action of study treatment, or 
improve the understanding of disease progression.
Please refer to the laboratory manual for further details regarding tissue collection, shipping, 
and storage.
CCI
CCI
CCI
CCI

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
70 (150)
5.5
Biomarker Analysis 
The patient’s consent to the use of optional donated biological samples is mandatory (optional 
in countries that do not permit this approach).  
Biological samples (e.g., archived tumour samples) will be collected and may be analysed for 
 biomarkers to assess correlations with disease activity, effects of study drug, 
clinical outcomes, and toxicity.
5.5.1 Storage, Re-use and Destruction of Biological Samples
Samples will be stored for a maximum of 15 years from the date of the Last Patient’s Last 
Visit, after which they will be destroyed.  The results of this biomarker research will be 
reported either in the clinical study report (CSR) itself or as an addendum, or separately in a 
scientific report or publication.  The results of this biomarker research may be pooled with 
biomarker data from other studies with the study drug to generate hypotheses to be tested in 
future research.
5.5.2 Labelling and Shipment of Biological Samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual. 
5.5.3 Chain of Custody of Biological Samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the patients while in storage at the centre until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca Biobank during the entire 
life cycle.
5.5.4 Withdrawal of Informed Consent for Donated Biological Samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological samples is an optional part of the study, then the patient may 
continue in the study.
CCI

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
71 (150)
The Principal Investigator:
∀
Ensures patients’ withdrawal of informed consent to the use of donated 
samples is notified immediately to AstraZeneca
∀
Ensures that biological samples from that patient, if stored at the study 
site, are immediately identified, disposed of /destroyed, and the action 
documented
∀
Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed 
of/destroyed, the action documented and the signed document returned to 
the study site
∀
Ensures that the patient and AstraZeneca are informed about the sample 
disposal.
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
6
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this Section.
6.1
Definition of AEs
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product.  An undesirable medical condition can be 
symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver), or the abnormal 
results of an investigation (e.g., laboratory findings, ECG).  In clinical studies, an AE can 
include an undesirable medical condition occurring at any time, including run-in or washout 
periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.1.1 Olaparib AEs of Special Interest
AESIs are events of scientific and medical interest specific to the further understanding of 
Olaparib’s safety profile and require close monitoring and rapid communication by the 
Investigators to AstraZeneca.  An AESI may be serious or non-serious.  AESIs for Olaparib
are the important identified risks of MDS/AMLand the important potential risks of new 
primary malignancy (other than MDS/AML) and pneumonitis.  

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
72 (150)
ANY event of MDS/AML, new primary malignancy, or pneumonitis should be reported to 
AstraZeneca Patient Safety whether it is considered a non-serious AE (e.g., non-melanoma 
skin cancer) or SAE, and regardless of Investigator’s assessment of causality or knowledge of 
the treatment arm.
A questionnaire will be sent to any Investigator reporting an AESI, as an aid to provide further 
detailed information on the event.  During the study there may be other events identified as 
AESIs that require the use of a questionnaire to help characterise the event and gain a better 
understanding regarding the relationship between the event and study treatment.
6.2
Definitions of SAE
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/incapacity or substantial 
disruption of the ability to conduct normal life functions
∀
Is a congenital abnormality or birth defect
∀
Is an important medical event that may jeopardise the patient or may 
require medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol.
6.3
Recording of AEs
6.3.1 Time Period for Collection of AEs
AEs will be collected from time of signature of informed consent, throughout the treatment 
period and including the 30-day follow-up period after the last dose of treatment. Only AESIs 
will be collected during long-term follow-up.
SAEs will be recorded from the time of informed consent.
After any interim analysis, any ongoing AEs/SAEs need to be unlocked and followed for 
resolution.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
73 (150)
6.3.1.1
AEs After the 30 day Follow-up Period 
For Pharmacovigilance purposes and characterisation, any case of MDS/AML or new primary 
malignancy occurring after the 30 day follow up period should be reported to AstraZeneca 
Patient Safety whether it is considered a non-serious AE [e.g., non-melanoma skin cancer] or 
SAE, and regardless of Investigator’s assessment of causality or knowledge of the treatment 
arm.  Investigators will be asked during the regular follow up for overall survival if the patient 
has developed MDS/AML or a new primary malignancy and prompted to 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 DCO
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).
6.3.2 Follow-up of Unresolved AEs
Any SAE or non-serious AE 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.
6.3.3 Variables 
The following variables will be collect for each AE:
∀
AE (verbatim)
∀
The date and time when the AE started and stopped
∀
CTCAE grade and changes in CTCAE grade
∀
Whether the AE is serious or not
∀
Investigator causality rating against the study treatment (yes or no)

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
74 (150)
∀
Action taken with regard to study treatment
∀
Treatment administered with the following as a result of the AE: 
antibiotics oral, antibiotics I.V., red blood cell transfusion, platelet 
transfusion, granulocyte-macrophage colony-stimulating factor or G-
CSF, erythropoietin, anticoagulant p.o., parenteral anticoagulant  
∀
AE caused patient’s withdrawal from study (yes or no)
∀
Outcome.
In addition, the following variables will be collected for SAEs:
∀
Date AE met criteria for serious AE
∀
Date Investigator became aware of serious AE
∀
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 in relation to Other medication
∀
Description of AE.
Severity of AE
For each episode of an AE, all changes to the CTCAE grade attained as well as the highest 
attained CTCAE grade should be reported.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  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 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
75 (150)
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 will be 
utilised for all events with an assigned CTCAE grading.  For those events without assigned 
CTCAE grades the recommendation is that the CTCAE criteria that convert mild, moderate, 
and severe events into CTCAE grades should be used.
A copy of the CTCAE version can be downloaded from the Cancer Therapy Evaluation 
program website (http://ctep.cancer.gov).
6.3.4 Causality Collection
The Investigator will assess causal relationship between study treatment 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 study treatment product?’
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol.
6.3.5 AEs Based on Signs and Symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’ , or revealed by observation will be collected and recorded in the CRF.  
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
6.3.6 AEs Based on Examinations and Tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
CSR.  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

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
76 (150)
!
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.
6.3.7 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 TBL ≥2 X ULN may need to be 
reported as SAEs.  Please refer to Appendix C: Actions Required in Cases of Increases in 
Liver Biochemistry and Evaluation of Hy’s Law.
6.3.8 Disease Progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the study treatment is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  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.
6.3.9 New Cancers
The development of a new primary cancer (including skin cancer) should be regarded as an 
AE (see Section 6.1.1).  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.
6.3.10Lack 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 
AstraZeneca or the reporting physician considers that the study treatment contributed to the 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
77 (150)
deterioration of the condition, or local regulations state to the contrary, the deterioration 
should be considered to be a lack of efficacy and not an AE.
6.3.11Deaths
All deaths that occur during the study, or within the protocol-defined 30-day post-study 
follow-up period after the administration of the last dose of study treatment, must be reported 
as follows:
∀
Death clearly the result of disease progression should be reported to the 
study monitor at the next monitoring visit and should be documented in 
the DEATH eCRF but should not be reported as an SAE.
∀
Where death is not due (or not clearly due) to progression of the disease 
under study, the AE causing the death must be reported to the study 
monitor as a SAE within 24 hours (see Section 6.4 for further details).  
The report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign main and 
contributory causes of death.  This information can be captured in the 
‘death eCRF’.
∀
Deaths with an unknown cause should always be reported as a SAE.  A 
post mortem maybe helpful in the assessment of the cause of death, and if 
performed a copy of the post-mortem results should be forwarded to 
AstraZeneca within the usual timeframes.
6.4
Reporting of Serious AEs
All SAEs have to be reported, whether or not considered causally related to the study 
treatment, 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 one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary 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 one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
78 (150)
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed. 
Investigators or other site personnel send relevant CRF modules by fax to the designated 
AstraZeneca representative. 
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug. 
6.5
Overdose
There is currently no specific treatment in the event of overdose with Olaparib and possible 
symptoms of overdose are not established. 
Study treatment must only be used in accordance with the dosing recommendations in this 
protocol.  Any dose or frequency of dosing that exceeds the dosing regimen specified in this 
protocol should be reported as an overdose. 
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately.
∀
An overdose with associated AEs is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the CRF and on the 
Overdose CRF module.
∀
An overdose without associated symptoms is only reported on the 
Overdose CRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
79 (150)
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1 Maternal Exposure
If a patient becomes pregnant during the course of the study, study treatment 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 study treatment 
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.
6.6.2 Paternal Exposure 
Not applicable.
6.7
Management of Study Treatment Related Toxicities (Dose Reductions)
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 bd as a first step and to 
200 mg bd as a second step.  If the reduced dose of 200 mg bd is not tolerable, no further dose 
reduction is allowed and study treatment should be discontinued. 
Patients known to be intolerant of the standard dose of the tablet formulation, based on 
previous use, may start on a dose of 250 mg Olaparib/placebo bd.  They may then step down 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
80 (150)
to 200 mg bd if required.  Patients who are known to be intolerant of 200 mg bd of the tablet 
formulation should not enter the study. 
Once dose is reduced, escalation is not permitted.
6.7.1 Management of Haematological Toxicity
6.7.1.1
Management of Anaemia
Table6
Management of Anaemia
Haemoglobin
Action to be taken
Hb <10 but ≥8 g/dL 
(CTCAE Grade 2)
Give appropriate supportive treatment and investigate causality. 
Investigator judgement to continue study treatment with supportive treatment 
(e.g., transfusion) or interrupt dose for a maximum of 4 weeks. 
If repeat Hb <10 but ≥8 g/dL, dose interrupt (for max of 4 weeks) until Hb 
≥10 g/dL and upon recovery dose reduction to 250 mg bd as a first step and 
to 200 mg bd as a second step may be considered.
Hb <8 g/dL
(CTCAE Grade 3)
Give appropriate supportive treatment (e.g., transfusion) and investigate 
causality. 
Interrupt study treatment for a maximum of 4 weeks until improved to Hb 
≥10 g/dL.
Upon recovery dose reduce to 250 mg bd as a first step and to 200 mg bd 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 
CTCAE grade 3 or worse anaemia and/or development of blood transfusion dependence), 
refer to Section 6.7.1.3 for the management of this. 
6.7.1.2
Management of Neutropenia, Leukopenia and Thrombocytopenia
Table7
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 bd as a first step and 200 mg bd as a second step

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
81 (150)
AE of neutropenia and leukopenia should be managed as deemed appropriate by the 
Investigator with close follow up and interruption of study drug if CTCAE grade 3 or worse 
neutropenia occurs.
Primary prophylaxis with G-CSF is not recommended, however, if 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 h (7 days for pegylated G-CSF) of the last dose of study treatment 
unless absolutely necessary.
Platelet transfusions, if indicated, should be done according to local hospital guidelines.
For cases where patients develop prolonged haematological toxicity (≥2 week 
interruption/delay in study treatment due to CTCAE grade 3 or worse), refer to Section 
6.7.1.3.
6.7.1.3
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 CTCAE grade 3 or 
worse anaemia and/or development of blood transfusion dependence
∀
≥2 week interruption/delay in study treatment due to CTCAE grade 3 or 
worse neutropenia (ANC <1 X 109/L)
∀
≥2 week interruption/delay in study treatment due to CTCAE grade 3 or 
worse thrombocytopenia 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 CTCAE grade 1 or better within 4 weeks of dose interruption.
Development of a confirmed MDS or other clonal blood disorder should be reported as an 
SAE and full reports must be provided by the Investigator to AstraZeneca Patient Safety.  
Study treatment should be discontinued if patient’s diagnosis of MDS and/or AML is 
confirmed.
6.7.2 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.  

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
82 (150)
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 bd as a first step and to 200 mg bd as a second 
step.  Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 AE occurs which the 
Investigator considers to be related to administration of study treatment.
6.7.2.1
Management of New or Worsening Pulmonary Symptoms 
If new or worsening pulmonary symptoms (e.g., 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 high resolution CT scan) should be 
performed to exclude pneumonitis.
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then study treatment can be restarted, if deemed appropriate by the 
Investigator.  If significant pulmonary abnormalities are identified, these need to be discussed 
with the Study Physician.
6.7.2.2
Management of Nausea and Vomiting
Events of nausea and vomiting are known to be associated with Olaparib treatment.  In study 
D0810C00019 nausea was reported in 71% of the Olaparib treated patients and in 36% of the 
placebo treated patients, and vomiting was reported in 34% of the Olaparib treated patients 
and in 14% 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 generally occurs in the first month of treatment for nausea and within the first 6 
months of treatment for vomiting.  For nausea, the incidence generally plateaus at around 9 
months, and for vomiting at around 6 to 7 months.
No routine prophylactic anti-emetic treatment is required at the start of study treatment; 
however, patients should receive appropriate anti-emetic treatment at the first onset of nausea 
or vomiting and as required thereafter, in accordance with local treatment practice guidelines.  
Alternatively, study treatment tablets can be taken with a light meal/snack (e.g., 2 pieces of 
toast or a couple of biscuits).
As per international guidance on anti-emetic 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.
6.7.2.3
Interruptions for Intercurrent Non-Toxicity Related Events
Study treatment dose interruption for conditions other than toxicity resolution should be kept 
as short as possible.  If a patient cannot restart study treatment within 4 weeks for resolution 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
83 (150)
of intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with AstraZeneca study physician.
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF. 
Study treatment should be stopped at least 3 days prior to planned surgery.  After surgery 
study treatment can be restarted when the wound has healed.  No stoppage of study treatment 
is required for any needle biopsy procedure.
Study treatment should be discontinued for a minimum of 3 days before a 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. 
Table8
Dose Reductions for Study Treatment
Initial dose
Following re-challenge post interruption: Dose 
reduction 1
Dose reduction 2
300 mg bd
250 mg bd
200 mg bd
6.8
Study Governance and Oversight
6.8.1 Steering Committee
This will consist of the Global Principal Investigator, a representative from each participating 
group of GINECO-ENGOT (Groupe d’Investigateurs Nationaux pour l’Étude des Cancers 
Ovariens et du sein [GINECO]; European Network for Gynaecological Oncological Trial 
[ENGOT]), AstraZeneca and GINECO-ENGOT Statisticians, AstraZeneca Medical 
Representative, an operational representative (observer) and/or research representative 
(agenda driven).
6.8.2 Data Monitoring Committee
An IDMC will be involved in this study. The committee will be consulted as described in the 
data monitoring committee charter.
6.8.3 Scientific Advisory Committee
A scientific advisory committee will not be involved in this study.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
84 (150)
7
STUDY TREATMENT AND OTHER TREATMENTS
7.1
Identity of Study Treatment(s)
Study treatmentsa
Dosage form and strength
Olaparib/Placebo
150 mg tablet
Olaparib/Placebo
100 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, study treatment tablets will be packed in high-density polyethylene bottles 
with child-resistant closures.  Each container will contain sufficient medication for at least 28 
days plus overage.  Study treatment will be dispensed to patients on Day 1 and every 28 days 
for the first 12 weeks, and then 12 weekly thereafter until the patient completes the study, 
withdraws from the study or closure of the study.  
Study treatment is available as a film-coated tablet containing 150 mg or 100 mg of Olaparib, 
or placebo.
Patients will be administered study treatment orally bd at 300 mg bd continually, or lower if 
300 mg is not tolerated on initial PARPi treatment.  Two x 150 mg Olaparib (or placebo) 
study treatment tablets should be taken at the same time each day, approximately 12 hours 
apart with one glass of water.  The tablets should be swallowed whole and not chewed, 
crushed, dissolved or divided.  Study treatment tablets can be taken with or without food.
If vomiting occurs shortly after the study treatment 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 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.
Unless patients experience unacceptable toxicity or withdraw from the study treatment or 
from the protocol, patients should continue to receive study treatment until there is objective 
radiological disease progression as assessed by RECIST 1.1 or as long as in the Investigator’s 
opinion they are benefiting from treatment and they do not meet any other discontinuation 
criteria.
Once patients have been discontinued from study treatment, other treatment options will be at 
the discretion of the Investigator.  Patients and Investigators will not be routinely un-blinded 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
85 (150)
to study treatment prior to the final analysis. No cross-over to Olaparib is permitted for 
patients who have progressed on the placebo treatment arm.
Dose Reductions 
For guidance on dose reductions for management of AEs refer to Section 6.7.
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 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 study treatment should be reduced to 200 mg bd.
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 is it 
recommended that study treatment 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.
Specific dosing instructions will not be included on the label; the site must complete the 
“Patient Dispensing Card” with the details of the dosing instructions at the time of dispensing.
The patient emergency contact details will not be on the label, but can be found in the 
informed consent and the “Patient Dispensing Card”.  For emergency purposes the patient 
must be in possession of the emergency contact details at all times.
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
study treatment label on the bottle specifies the appropriate storage.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
86 (150)
7.5
Compliance
The administration of all medication (including study treatments) must be recorded in the 
appropriate sections of the CRFs.
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the Case Report Form.
Patients should be given clear instructions on how and when to take their study treatment.  
Patients will self-administer study treatment.  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 study treatment 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 is for use only as directed in the study protocol. It is the 
Investigator/institution’s responsibility to establish a system for handling study treatments, 
including IPs, so as to ensure that:
∀
Deliveries of such products from AstraZeneca or its representative are 
correctly received by a responsible person
∀
Such deliveries are recorded
∀
Study treatments are handled and stored safely and properly as stated on 
the label
∀
Study treatments are only dispensed to patients in accordance with the 
protocol.
The study personnel 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 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
87 (150)
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 personnel, if applicable, or the AZ monitor will account for all study drugs 
received at the site, unused study drugs and for appropriate destruction. Certificates of 
delivery, and destruction should be signed.
7.7
Concomitant and Other Treatments 
The use of any natural/herbal products or other traditional remedies should be discouraged, 
but use of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the CRF. All concomitant medications will be 
collected at screening. At subsequent visits, only antibiotics, anti-emetics, transfusions, 
erythropoietin, G-CSF and concomitant medications associated with an AE will be collected.
Medications That May NOT Be Administered
No other anti-cancer 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 study treatment to 100 mg 
bd for the duration of concomitant therapy with the strong inhibitor and 
for 5 half lives afterwards.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
88 (150)
∀
Moderate CYP3A inhibitors - reduce the dose of study treatment to 
150 mg bd 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 study treatment dose 
can be re-escalated.
Strong or moderate CYP3A inducers
Strong (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide, and St John’s Wort) and moderate CYP3A inducers (e.g., bosentan, 
efavirenz, modafinil) of CYP3A should not be taken with 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 change in efficacy of study treatment.
P-glycoprotein (P-gp) inhibitors
It is possible that co-administration of P-gp inhibitors (e.g., amiodarone, azithromycin) may 
increase exposure to Olaparib.  Caution should therefore be observed.
Effect of Olaparib on other drugs
Based on limited in vitro data, Olaparib may increase the exposure to substrates of CYP3A4, 
P-gp, 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 CYP3A4, 
2B6, 2C9, 2C19 and P-gp. 
The efficacy of hormonal contraceptives may be reduced if co-administered with Olaparib. 
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

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
89 (150)
∀
CYP2C9 – warfarin 
∀
CYP2C19 – lansoprazole, omeprazole, S-mephenytoin
∀
P-gp – simvastatin, pravastatin, digoxin, dabigatran, colchicine
∀
OATP1B1 – bosentan, glibenclamide, repaglinide, statins and valsartan
∀
OCT1, MATE1, MATE2K – metformin
∀
OCT2 – serum creatinine
∀
OAT3 – furosemide, methotrexate.
Anticoagulant Therapy
Patients who are taking warfarin may participate in this trial; however, it is recommended that
prothrombin time, INR and APTT be monitored carefully at least once per week for the first 
month, then monthly if the INR is stable.  Subcutaneous heparin is permitted.
Anti-emetics/Anti-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 Anti-Cancer Agents
Patients must not receive any other concurrent anti-cancer therapy, including investigational 
agents, while on study treatment.  Patients may continue the use of bisphosphonates or 
denosumab for bone disease and corticosteroids for the symptomatic control of brain 
metastases provided the dose is stable before and during the study and they were started at 
least 4 weeks prior to beginning study treatment. 
Subsequent Therapies for Cancer 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
90 (150)
Details of first and subsequent therapies for cancer and/or details of surgery for the treatment 
of the cancer, after discontinuation of treatment, will be collected.  Reasons for starting 
subsequent anti-cancer therapies including access to other PARP inhibitors or investigational 
drugs will be collected and included in the 
 analysis of overall survival.
7.7.1 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 CRF.
7.8
Post Study Access to Study Treatment
Not applicable.
8
STATISTICAL ANALYSES BY ASTRAZENECA VENDOR
8.1
Statistical Considerations
All personnel involved with the analysis of the study will remain blinded to study treatment 
until database lock and protocol violators are identified. Data cut off and subsequent database 
lock for the Primary Analysis will occur after the later of the two cohorts reaches the defined 
number of progression or death events. Analyses will be performed by AstraZeneca or its 
representatives.
A comprehensive SAP will be prepared and any subsequent amendments will be documented, 
with final amendments completed prior to un-blinding of the data.  Further details of the 
analyses will be provided in the SAP.
8.2
Sample Size Estimate
The benefit of Olaparib maintenance retreatment over matching placebo will be evaluated 
through the primary endpoint of PFS and supporting secondary endpoints.  Recently published 
data (Study 19, NOVA, SOLO2) of PARPi therapy following a second or subsequent line of 
platinum based chemotherapy indicated a median PFS of less than 5.5 months can be expected 
in the placebo treated patients (see Table 1), irrespective of whether they are BRCA1/2 (+ve) 
or BRCA1/2 (-ve). 
In the BRCA1/2 (+ve) cohort it is assumed that the median PFS from randomisation for 
patients in the placebo arm will be approximately 4.5 months. In total, 85 progression or death 
events from 120 patients will have 85% power to demonstrate significant PFS benefit at the 2-
CCI

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
91 (150)
sided 5% level if the assumed true treatment effect resulted in a HR of 0.5; this translates to a 
4.5 month (100%) increase in median PFS beyond the 4.5 months expected for patients on 
placebo, if PFS is exponentially distributed and allowing for a 10% drop-out rate. An 
observed HR of 0.63 or less will be required to achieve this level of significance. Assuming 
34 months of non-linear recruitment, 85 events are expected to occur approximately 41
months after the first patient in (FSI) is enrolled into this cohort of the study.
In the BRCA1/2 (-ve) cohort it is assumed that the median PFS from randomisation for 
patients in the placebo arm will be approximately 4.5 months. In total, 74 progression or death 
events from 108 patients will have 80% power to demonstrate significant PFS benefit at the 2-
sided 5% level if the assumed true treatment effect resulted in a HR of 0.5; this translates to a 
4.5 month (100%) increase in median PFS beyond the 4.5 months expected for patients on 
placebo, if PFS is exponentially distributed and allowing for a 10% drop-out rate. An 
observed HR of 0.61 or less will be required to achieve this level of significance.. Assuming 
36 months of non-linear recruitment, 74 events are expected to occur approximately 42
months after the FSI is enrolled into this cohort of the study.
Considering both cohorts it is expected that approximately 228 patients in total will be 
enrolled into the study.
8.3
Definitions of Analysis Sets
8.3.1 Full Analysis Set (Intent-to-Treat Principle)
The intent-to-treat (ITT) population will include all randomised patients and will compare the 
treatment groups on the basis of randomised treatment, regardless of the treatment actually 
received.  Patients who were randomised but did not subsequently go on to receive study 
treatment are included in the full analysis set (FAS).  Therefore, all efficacy and HRQoL data 
will be summarised and analysed using the FAS on an ITT basis as the primary analysis set.  
Demographic and baseline characteristics will also be analysed using the FAS on an ITT 
basis. 
8.3.2 Safety Analysis Set
All patients who received at least one dose of randomised study treatment, Olaparib or 
placebo, will be included in the safety analysis set.  If a patient receives at least one dose of 
Olaparib study treatment they will be summarised in the Olaparib arm for safety summaries 
(e.g., Olaparib arm will include patients randomised to Olaparib who receive at least one dose 
of Olaparib or placebo patients who receive at least one dose of Olaparib study treatment in 
error at any time).  If a patient randomised to Olaparib receives only placebo treatment then 
the patient will be summarised as a part of the placebo arm.
8.3.3 Pharmacokinetic Analysis Set
Not applicable.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
92 (150)
8.3.4 PRO Analysis Set
The PRO analysis set will consist of the FAS patients with at least a baseline and one other 
post-baseline assessment (excluding end of treatment and post-progression follow up 
assessments).

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
93 (150)
8.4
Outcome Measures for Analyses
Outcome variable 
Populations 
Efficacy Data
Primary: PFS
FAS (ITT)
Secondary: OS, TFST, TSST, TDT, Time to 
earliest progression by RECIST or CA-125,
or death
FAS (ITT) 
Secondary: HRQoL
PRO
Demography and baseline characteristics
FAS (ITT) 
Safety data
Exposure
Safety
AEs and AESIs
Safety
Laboratory measurements
Safety
Vital signs
Safety
8.4.1 Progression-free Survival
The primary endpoint of PFS is defined as the time from randomisation until the date of 
Investigator assessed objective radiological disease progression according to RECIST 1.1 or 
death (by any cause in the absence of disease progression) regardless of whether the patient 
withdraws from randomised therapy or receives another anticancer therapy prior to disease 
progression.  Patients who have not progressed or died at the time of analysis will be censored 
at the time of the latest date of assessment from their last evaluable RECIST 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 RECIST 1.1 assessment.  Given the scheduled visit 
assessment scheme two missing visits will equate to more than 26 weeks since the previous 
RECIST assessment, allowing for early and late visits.  If the patient has no evaluable visits or 
does not have a baseline assessment they will be censored at day 1 unless they die within two 
visits of baseline (25 weeks allowing for visit window). 
The PFS time will always be derived based on scan/assessment dates not visit dates. 
RECIST assessments/scans contributing towards a particular visit may be performed on 
different dates.  The following rules will be applied: 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
94 (150)
(a) Date of progression will be determined based on the earliest of the RECIST 
assessment/scan dates of the component that triggered the progression. 
(b) When censoring a patient for PFS the patient will be censored at the latest of the RECIST 
assessment/scan dates contributing to a particular overall visit assessment. 
Overall visit assessments will be determined for each assessment (scheduled or unscheduled) 
and will contribute to the derivation of PFS. 
Objective progression is defined as at least a 20% increase in the sum of the diameters of the 
target lesions (compared to previous minimum sum) and an absolute increase of >5 mm, or an 
overall non-target lesion assessment of progression or a new lesion.
8.4.2 Overall Survival
OS is defined as the time from the date of randomisation until death due to any cause.  Any 
patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive. 
Note: Survival calls will be made in the week following the DCO date for the analysis, and if 
patients are confirmed to be alive or if the death date is post the DCO date these patients will 
be censored at the date of DCO.
8.4.3 Time to Subsequent Therapies
As a supportive summary to PFS, time to start of first subsequent therapy or death will be 
assessed.  Time to first subsequent therapy or death is defined as the time from the date of 
randomisation to the earlier of first subsequent therapy start date, or death date.  Any patient 
not known to have had a further subsequent therapy or death will be censored at the last 
known time to have not received subsequent therapy.  If a patient terminated the study for 
reason other than death before first subsequent therapy, these patients will be censored at the 
earliest of their last known to be alive and termination dates.
Additionally, time to start of second subsequent therapy or death will be assessed.  Time to 
second subsequent therapy or death is defined as the time from the date of randomisation to 
the earlier of the date of second subsequent therapy start date, or death date.  Any patient not 
known to have had a further second subsequent therapy or death will be censored at the last 
known time to have not received second subsequent therapy.  If a patient terminated the study 
for reason other than death before second subsequent therapy, these patients will be censored 
at the earliest of their last known to be alive and termination dates.
8.4.4 Time to Study Treatment Discontinuation
Time to study treatment discontinuation is defined as the time from randomisation to study 
treatment discontinuation or death if this occurs before discontinuation of study treatment.  
Any patient not known to have died at the time of analysis and not known to have 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
95 (150)
discontinued study treatment will be censored based on the last recorded date on which the 
patient was known to be alive.
8.4.5 Time to Earliest Progression (RECIST or CA-125) or Death
Progression or recurrence based on serum CA-125 levels will be defined on the basis of a
progressive serial elevation of serum CA-125, according to the following GCIG criteria (note 
GCIG criteria is not validated for this trial population):
∀
For patients with elevated CA-125 on or before the date of randomisation 
(i.e. greater than the upper limit of normal (ULN)), 
(a)
If CA-125 does not fall to within the normal range post randomisation then there 
must be evidence of CA-125 greater than, or equal to, 2 times the nadir value in the 
28-day period before day 1 on two occasions at least 1 week apart 
(b)
Where CA-125 does fall to within the normal range post randomisation (and the 
patient has not already progressed by way of a) above), then there must be evidence 
of CA-125 greater than, or equal to, 2 times the ULN on two occasions at least 1 
week apart
∀
Patients with CA-125 in the normal range on or before the date of 
randomisation and no results greater than ULN on or before the date of 
randomisation must show evidence of CA- 125 greater than, or equal to, 
2 times the ULN on two occasions post randomisation at least 1 week 
apart.
∀
CA-125 progression will be assigned the date of the first measurement 
that meets the criteria as noted.
Time to progression by RECIST or CA-125 or death is defined as the time from 
randomisation to the earlier date of RECIST progression or CA-125 progression or death by 
any cause. Patients without a CA-125 progression or a RECIST progression who are still alive 
at the time of analysis will be censored at the time of their last evaluable RECIST assessment 
and/or their last available CA-125 measurement, whichever is the earliest at the time of 
analysis. Patients that do not have any evaluable RECIST assessments or any CA-125 results 
post randomisation will be censored at the date of randomisation.
8.4.6 Calculation or Derivation of HRQoL Endpoints 
The FACT-O consists of 39 questions: the 27 Functional Assessment of Cancer Therapy –
General (FACT-G) items and 12 Additional Concerns items consisting of specific ovarian 
cancer symptoms).  The questionnaire will be scored into subscales according to the FACIT 
scoring guidelines as follows:-
∀
Physical Well-Being (PWB): Score range 0-28

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
96 (150)
∀
Social/Family Well-Being (SWB): Score range 0-28
∀
Emotional Well-Being (EWB): Score range 0-24
∀
Functional Well-Being (FWB): Score range 0-28
∀
Ovarian Cancer Subscale (OCS): Score range 0-44
∀
FACT-O TOI, Score range 0-100.  Derived using PWB+FWB+OCS
∀
FACT-O total score, Score range 0-152, Derived using 
PWB+FWB+SWB+EWB+OCS
∀
FACT-G total score: Score range 0-108.  Derived using 
PWB+FWB+EWB+SWB.
The higher the score, the better the HRQoL for all subscales.  Missing items will be dealt with 
as described in the FACIT Administration and Scoring Guidelines.  If at least 50% of items in 
a subscale have been answered the subscale score will be prorated.  Subscale scores will be 
missing if less than 50% of items within that subscale have been answered.  Total scores will 
only be calculated if all component subscales have valid scores.  The reason for any missing 
assessment will be collected in the CRF.
The subscale of primary interest will be the TOI score.  Other subscales will be considered as 
exploratory.
Change from baseline scores will be calculated at each visit.
Four outcome measures will be calculated:
∀
Change from baseline score 
∀
The actual change from baseline score will be derived for each visit 
where there is available data.  For example; at visit X, the calculation will 
be (subscale score at visit X – Baseline subscale score).  Actual change 
from baseline for the individual subscale scores will be calculated in a 
similar way.  Subscale-specific minimally important differences (MID) 
will be used for interpretation where available (Yost and Eton 2005).
∀
Proportion of patients with a PRO response (improved PRO Score)
The proportion of patients with an improved score (≥MID points change from baseline), 
worsened (≤MID points change from baseline) or no change (changes of less than MID points 
in either direction) will be calculated at each visit.  The denominator will consist of the FAS 
population with a baseline PRO.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
97 (150)
∀
Best overall response  
Best overall improvement (improvement in the absence of subsequent cancer therapy) will be 
defined as a change from baseline of ≥MID sustained for at least 28 days, the denominator 
consisting of a subset of the FAS population who have a baseline score.  It will be derived as 
the best symptom improvement response the patient achieved, based on evaluable QoL data 
collected from randomisation up to the earliest of starting any subsequent cancer therapy or 
death.  Therefore, the following criteria will be used to assign a best overall score response for 
each patient based on the individual visit responses (Table ).
Table 9
HRQoL: Best Overall Score 
Best overall score response 
Criteria 
Improved 
Two visit responses of “improved” a minimum of 28 days apart 
without an intervening visit response of “worsened” 
No change 
Does not qualify for overall score response of “improved”.  Two 
visit responses of either “no change” or “improved and “no 
change” a minimum of 28 days apart without an intervening 
visit response of “worsened” 
Worsened 
Does not qualify for overall score response of “improved” A 
visit response of “worsened” without a response of “improved” 
or “no change” within 28 days.  
Other 
Does not qualify for one of the above.  
An improvement rate (in the absence of subsequent cancer therapy) will be calculated as the 
% of all analysed patients with a best overall score response of improved.  In the calculation 
of the proportion of patients that have a response of Improved, No Change or Worsened, the 
denominator used in the calculation will use the number evaluable for the subscale score at 
baseline.
∀
PRO deterioration-free survival
Time from randomisation to definitive deterioration of PRO subscale score (≤MID points 
change from baseline with no further improvement of ≥MID points or subsequent missing 
data) or PFS/death if these events occur prior to definitive deterioration in PRO subscale.
8.4.7 Calculation or Derivation of Safety Variables
Safety and tolerability will be assessed in terms of AEs, SAEs, AEs leading to discontinuation 
of study drug from randomisation to 30 days after last study treatment, AESIs, laboratory data 
including chemistry and haematology, and vital signs.  The latest NCI-CTCAE version will be 
used to grade toxicities.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
99 (150)
time points.  K-M curves will also be provided, with tick marks to identify censored 
observations.  
The HR and its 95% CI will be estimated (HR less than 1.0 favours Olaparib) from a Cox 
Proportional Hazards model (with ties = Efron and the stratification factors as covariates) and 
the CI will be calculated using a profile likelihood approach. OS will be analysed at the time 
of the primary analysis for PFS and after 50% death events in either cohort, or 60 months after 
FSI, whichever is the earlier.
8.5.2.2
Time to Subsequent Therapies or Death
Time to first subsequent treatment or death and time to second subsequent treatment or death 
for the two treatment groups will be compared using a 2-sided stratified log-rank test at the 
5% significance level, based on the two stratification factors at the time of randomisation: use 
of prior bevacizumab (yes versus no) and number of prior regimens of platinum-containing 
chemotherapy (≤3 versus ≥4 regimens).
The HR and its 95% CI will be estimated (HR less than 1.0 favours Olaparib) using the same 
methods as for PFS and OS. A K-M analysis will also be performed and K-M curves 
presented.
These endpoints will be analysed at the time of the primary analysis of PFS and again at the 
end of study follow-up.
8.5.2.3
Time to Study Treatment Discontinuation or Death
Time to study treatment discontinuation or death will be compared between the two treatment 
groups using a 2-sided stratified log-rank test as defined for the previous endpoints. The HR
and its 95% CI will be estimated (HR less than 1.0 favours Olaparib) using the same methods 
as described for PFS and OS.
A K-M analysis will also be performed and K-M curves presented.
This endpoint will be analysed at the time of the primary analysis of PFS and again at the end 
of study follow-up.
8.5.2.4
Time to Earliest Progression by RECIST or CA-125 or Death
Time to progression by RECIST 1.1, CA-125 or death will be performed at the same time as 
the primary analysis of PFS and will use the same methodology and model.
The number (%) of patients reporting a CA-125 progression, an objective RECIST 1.1 
progression and both a CA-125 and/or objective RECIST progression will be tabulated.
8.5.2.5
HRQoL Index Score
FACT-O completion rates will be calculated out of the number of randomised patients and 
also the number of patients expected to have a PRO assessment (alive and on-treatment).  

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
101 (150)
with AEs in different categories (e.g., causally related, CTCAE grade ≥3 etc.) will be 
summarised by treatment group, and events in each category will be further summarised by 
MedDRA system organ class and preferred term.  SAEs and deaths will be summarised and 
listed.  
Each AE event rate (per 1000 patient years) will also be summarised by preferred term within 
each system organ class. For each preferred term, the event rate will be presented and will be 
defined as the number of patients with that AE divided by the sum of the duration from the 
start of treatment to 30 days after the last treatment dose (for patients without the event) and 
the time to the AE (for patients with the event) in each group multiplied by 1000.
Haematology and clinical chemistry will be summarised by treatment group for change from 
baseline using descriptive statistics (mean, median, standard deviation, minimum, maximum 
and number of observations) and by worst grade during the treatment period using descriptive 
statistics (frequency and percent).  Shift tables for change in grade from baseline by treatment 
group may be presented.  For all laboratory variables which are included in the current version 
of CTCAE, the grade will be calculated.  
Vital signs will be summarised by treatment group using descriptive statistics (mean, median, 
standard deviation, minimum, maximum and number of patients).
8.5.3 Subgroup Analysis
In the final analysis of PFS and other time-to-event endpoints, subgroup analyses may be 
conducted to assess consistency of treatment effect across potential or expected prognostic 
factors.  An analysis will not be performed if there are too few events available for a 
meaningful analysis of a particular subgroup (i.e., if there are less than 20 events in a 
subgroup). Pre-specified subgroups will be described in the SAP.
8.5.4 Interim Analysis
In the BRCA1/2 (+ve) cohort an interim analysis for futility will be performed after 50% of the
target PFS events (i.e. after 43 events). Based upon the assumed accrual and event rate it is
estimated that this will occur after approximately 29 months. Using a conditional power non
binding futility analysis the cohort may stop for futility if the hazard ratio > 1.056. Under the
null hypothesis the probability of stopping for futility is 0.433 and under the alternative
hypothesis it is 0.01.
In the BRCA1/2 (-ve) cohort an interim analysis for futility will be performed after 50% of the
target PFS events (i.e. after 37 events). Based upon the assumed accrual and event rate it is
estimated that this will occur after approximately 30 months. Using a conditional power non
binding futility analysis the cohort may stop for futility if the hazard ratio > 1.02. Under the
null hypothesis the probability of stopping for futility is 0.477 and under the alternative
hypothesis it is 0.02.
Results from the planned interim analyses will be shared with the IDMC who will make a
recommendation on continuing or stopping a cohort.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
103 (150)
∀
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 AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1 Source Data
Refer to the CSA for location of source data.
9.2.2 Study Agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study.  In the event of any inconsistency 
between this Clinical Study Protocol and the CSA, the terms of Clinical Study Protocol shall 
prevail with respect to the conduct of the study and the treatment of patients and in all other 
respects, not relating to study conduct or treatment of patients, the terms of the CSA shall 
prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.
9.2.3 Archiving of Study Documents
The Investigator follows the principles outlined in the CSA.
9.3
Study Timetable and End of Study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
The final DCO will take place after 50% death events in either cohort, or 60 months after FSI, 
whichever is the earlier. At this time point, the clinical study database will close to new data.  
Patients are, however, permitted to continue to receive study treatment beyond the closure of 
the database if, in the opinion of the Investigator, they are continuing to receive benefit from 
treatment with study treatment.  For patients who do continue to receive treatment beyond the 
time of this DCO, Investigators will continue to report all AESIs and SAEs to AstraZeneca 
Patient Safety until 30 days after study treatment is discontinued, in accordance with Section 
6.4 (Reporting of Serious AEs).  If an Investigator learns of any SAEs, including death, at any 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
104 (150)
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 study treatment, the Investigator should 
notify AstraZeneca, Patient Safety.  Additionally as stated in Section 6.3 (Recording of AEs), 
any SAE or non-serious AE that is ongoing at the time of this DCO, 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 Q2 2017 and to end by Q2 2022.
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.
The study, or one cohort, may also be stopped at any time after the Primary Analysis if in the 
judgment of AstraZeneca, the ENGOT Principal Investigator and the Trial Steering 
Committee, there is insufficient clinical benefit from re-treatment.
9.4
Data Management by AstraZeneca Designated Clinical Research 
Organisation  
Data management will be performed by a clinical research organisation (CRO) according to 
the Data Management Plan.  AEs and medical/surgical history will be classified according to 
the terminology of the latest version the MedDRA.  Medications will be classified according 
to the WHO Drug Dictionary.  Classification coding will be performed by the CRO. 
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 the MedDRA.  Medications will be classified according to the 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, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
105 (150)
SAE Reconciliation
AE reconciliation reports are produced and reconciled with the Patient Safety database and/or 
the investigational site. 
Data Associated with Human Biological Samples
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca.
Management of External Data
The data collected through third party sources will be obtained and reconciled against study 
data.
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 institutional review board (IRB)/independent 
ethics committee (IEC) may require direct access to parts of the hospital 
or practice source records relevant to the study, including patients’
medical histories
∀
All data computer processed by AstraZeneca will be identified by study 
code and enrolment code (E-code).
If applicable, AstraZeneca will not provide individual genotype results to patients, any 
insurance company, any employer, their family members, general physician or any other third 
party, unless required to do so by law.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
106 (150)
If applicable, precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the patient.  In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a patient.  For 
example, in the case of a medical emergency, an AstraZeneca Physician or an Investigator 
might know a patient’s identity and also have access to his or her genetic data.  Also 
Regulatory authorities may require access to the relevant files, though the patient’s medical 
information and the genetic files would remain physically separate.
10.3 Ethics and Regulatory Review
An Ethics Committee should approve the final study protocol, including the final version of 
the Informed Consent Form and any other written information and/or materials to be provided 
to the 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 protocol should be re-approved by the Ethics Committee 
annually.
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees, and Principal 
Investigators with safety updates/reports according to local requirements.
Each Principal Investigator is responsible for providing the Ethics Committees with reports of 
any serious and unexpected adverse drug reactions from any other study conducted with the 
study treatment.  AstraZeneca will provide this information to the Principal Investigator so 
that he/she can meet these reporting requirements.
10.4 Informed Consent
The Principal Investigator(s) at each centre will:

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
107 (150)
∀
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.
10.5 Changes to the 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 study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s).  For distribution to Ethics Committee see Section 10.3.
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used. 

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
108 (150)
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
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 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.
11 LIST OF REFERENCES
Basen-Engquist et al. 2001
Basen-Engquist, K., D. Bodurka-Bevers, M. A. Fitzgerald, K. Webster, D. Cella, S. Hu & D. 
M. Gershenson (2001) Reliability and validity of the functional assessment of cancer therapy-
ovarian. J Clin Oncol, 19, 1809-17.
Bell and Fairclough 2014
Bell, M. L. & D. L. Fairclough (2014) Practical and statistical issues in missing data for 
longitudinal patient-reported outcomes. Stat Methods Med Res, 23, 440-59.
Cella et al. 1993
Cella, D. F., D. S. Tulsky, G. Gray, B. Sarafian, E. Linn, A. Bonomi, M. Silberman, S. B. 
Yellen, P. Winicour, J. Brannon & et al. (1993) The Functional Assessment of Cancer 
Therapy scale: development and validation of the general measure. J Clin Oncol, 11, 570-9.
Fong et al. 2009
Fong, P. C., D. S. Boss, T. A. Yap, A. Tutt, P. Wu, M. Mergui-Roelvink, P. Mortimer, H. 
Swaisland, A. Lau, M. J. O'Connor, A. Ashworth, J. Carmichael, S. B. Kaye, J. H. Schellens 
& J. S. de Bono (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA 
mutation carriers. N Engl J Med, 361, 123-34.
Hay et al. 2009
Hay, T., J. R. Matthews, L. Pietzka, A. Lau, A. Cranston, A. O. Nygren, A. Douglas-Jones, G. 
C. Smith, N. M. Martin, M. O'Connor & A. R. Clarke (2009) Poly(ADP-ribose) polymerase-1 
inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and 
delays tumor relapse in combination with carboplatin. Cancer Res, 69, 3850-5.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
109 (150)
Helleday 2011
Helleday, T. (2011) The underlying mechanism for the PARP and BRCA synthetic lethality: 
clearing up the misunderstandings. Mol Oncol, 5, 387-93.
Ledermann et al. 2012
Ledermann, J., P. Harter, C. Gourley, M. Friedlander, I. Vergote, G. Rustin, C. Scott, W. 
Meier, R. Shapira-Frommer, T. Safra, D. Matei, E. Macpherson, C. Watkins, J. Carmichael & 
U. Matulonis (2012) Olaparib maintenance therapy in platinum-sensitive relapsed ovarian 
cancer. N Engl J Med, 366, 1382-92.
Ledermann et al. 2016
Ledermann, J. A., P. Harter, C. Gourley, M. Friedlander, I. Vergote, G. Rustin, C. Scott, W. 
Meier, R. Shapira-Frommer, T. Safra, D. Matei, A. Fielding, S. Spencer, P. Rowe, E. Lowe, 
D. Hodgson, M. A. Sovak & U. Matulonis (2016) Overall survival in patients with platinum-
sensitive recurrent serous ovarian cancer receiving Olaparib maintenance monotherapy: an 
updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet 
Oncol.
Mirza et al. 2016
Mirza, M. R., B. J. Monk, J. Herrstedt, A. M. Oza, S. Mahner, A. Redondo, M. Fabbro, J. A. 
Ledermann, D. Lorusso, I. Vergote, N. E. Ben-Baruch, C. Marth, R. Madry, R. D. 
Christensen, J. S. Berek, A. Dorum, A. V. Tinker, A. du Bois, A. Gonzalez-Martin, P. Follana, 
B. Benigno, P. Rosenberg, L. Gilbert, B. J. Rimel, J. Buscema, J. P. Balser, S. Agarwal, U. A. 
Matulonis & E.-O. N. Investigators (2016) Niraparib Maintenance Therapy in Platinum-
Sensitive, Recurrent Ovarian Cancer. N Engl J Med.
Murai et al. 2012
Murai, J., S. Y. Huang, B. B. Das, A. Renaud, Y. Zhang, J. H. Doroshow, J. Ji, S. Takeda & 
Y. Pommier (2012) Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer 
Res, 72, 5588-99.
Richards et al. 2008
Richards, C. S., S. Bale, D. B. Bellissimo, S. Das, W. W. Grody, M. R. Hegde, E. Lyon, B. E. 
Ward & A. L. Q. A. C. Molecular Subcommittee of the (2008) ACMG recommendations for 
standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med,
10, 294-300.
Rottenberg et al. 2008
Rottenberg, S., J. E. Jaspers, A. Kersbergen, E. van der Burg, A. O. Nygren, S. A. Zander, P. 
W. Derksen, M. de Bruin, J. Zevenhoven, A. Lau, R. Boulter, A. Cranston, M. J. O'Connor, N. 
M. Martin, P. Borst & J. Jonkers (2008) 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, 105, 17079-84.

Clinical Study Protocol 
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date15 October 2020
110 (150)
Yost and Eton 2005
Yost, K. J. & D. T. Eton (2005) Combining distribution- and anchor-based approaches to 
determine minimally important differences: the FACIT experience. Eval Health Prof, 28, 172-
91.

ENGOT Number
ENGOT-ov38/OReO
111 (150)
Drug Substance
Olaparib, AZD2281, 
KU-0059436
Study Code
D0816C00014
Version
4.0
Date
15 October 2020
Appendix A
Additional Safety Information

Clinical Study Protocol Appendix A
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
112 (150)
Further Guidance on the Definition of a SAE
Life Threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 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 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 jeopardize 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 iv 
hydrocortisone treatment
∀
Hepatotoxicity caused by paracetamol (acetaminophen) overdose 
requiring treatment with N-acetylcysteine
∀
Intensive treatment in an emergency room or at home for allergic 
bronchospasm
∀
Blood dyscrasias (e.g., neutropenia or anaemia requiring blood 
transfusion, etc.) or convulsions that do not result in hospitalisation
∀
Development of drug dependency or drug abuse

Clinical Study Protocol Appendix A
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
113 (150)
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?
∀
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’.

Clinical Study Protocol Appendix A
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
114 (150)
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

ENGOT Number
ENGOT-ov38/OReO
115 (150)
Drug Substance
Olaparib, AZD2281, 
KU-0059436
Study Code
D0816C00014
Version
4.0
Date
15 October 2020
Appendix B
International Airline Transportation Association 6.2 
Guidance Document

Clinical Study Protocol Appendix B
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
116 (150)
Labelling and Shipment of Biohazard Samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations 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, 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, 
HIV types 1 and 2.  They are assigned the following UN number and proper shipping name:
∀
UN 3373 – Biological Substance, Category B
∀
They 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 

Clinical Study Protocol Appendix B
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
117 (150)
standards are encouraged wherever possible when road or rail transport is 
used.

ENGOT Number
ENGOT-ov38/OReO
118 (150)
Drug Substance
Olaparib, AZD2281, 
KU-0059436
Study Code
D0816C00014
Version
4.0
Date
15 October 2020
Appendix C
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law

Clinical Study Protocol Appendix C
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
119 (150)
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.  
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 AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
Definitions
Potential Hy’s Law
AST or ALT ≥3 X ULN together with TBL ≥2 X ULN at any point during the study 
following the start of study medication  irrespective of an increase in 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.
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:

Clinical Study Protocol Appendix C
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
120 (150)
∀
ALT ≥3 X ULN
∀
AST ≥3 X ULN
∀
TBL ≥2 X ULN
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:
∀
Notify the AstraZeneca representative
∀
Request a repeat of the test (new blood draw) by the local laboratory
∀
Complete the appropriate unscheduled laboratory 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 Definitions within this Appendix 
for definition) by reviewing laboratory reports from all previous visits.
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 Definitions within this Appendix 
for definition) by reviewing laboratory reports from all previous visits
∀
Promptly enter the laboratory data into the laboratory CRF.
Follow-up
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.
Potential Hy’s Law Criteria Met
If the patient does meet PHL criteria the Investigator will:

Clinical Study Protocol Appendix C
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
121 (150)
∀
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Actions Required When Potential Hy’s Law Criteria are Met Before and 
After Starting Study Treatment)
∀
Notify the AstraZeneca representative who will then inform the central Study Team. 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:
∀
Monitor the patient until liver biochemistry parameters and appropriate 
clinical symptoms and signs return to normal or baseline levels, or as 
long as medically indicated 
∀
Investigate the etiology of the event and perform diagnostic 
investigations as discussed with the Study Physician.  
∀
Complete the three Liver CRF Modules as information becomes available 
∀
If at any time (in consultation with the Study Physician) the PHL case 
meets serious criteria, report it as an SAE using standard reporting 
procedures.
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other 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

Clinical Study Protocol Appendix C
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
122 (150)
∀
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 an SAE (report term ‘Hy’s Law’) according to AstraZeneca 
standard processes. 
!
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
!
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:
∀
Report an SAE (report term ‘Potential Hy’s Law’) applying serious 
criteria and causality assessment as per above
∀
Continue follow-up and review according to agreed plan.  Once the 
necessary supplementary information is obtained, repeat the review and 
assessment to determine whether HL criteria are met.  Update the SAE 
report according to the outcome of the review.
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment 
This section is applicable to 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 patients’ 
condition# compared with the last visit where PHL criteria were met#
!
If there is no significant change no action is required
!
If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Potential Hy’s Law Criteria Met of this Appendix

Clinical Study Protocol Appendix C
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
123 (150)
# 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.
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 Actions Required When Potential 
Hy’s Law Criteria are Met Before and After Starting Study Treatment?
If No: follow the process described in Potential Hy’s Law Criteria Met of this Appendix
If Yes:
Determine if there has been a significant change in the 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 Actions Required 
When Potential Hy’s Law Criteria are Met Before and After Starting Study Treatment.
# 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.

Clinical Study Protocol Appendix C
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
124 (150)
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

ENGOT Number
ENGOT-ov38/OReO
125 (150)
Drug Substance
Olaparib, AZD2281, 
KU-0059436
Study Code
D0816C00014
Version
4.0
Date
15 October 2020
Appendix D
Acceptable Birth Control Methods

Clinical Study Protocol Appendix D
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
126 (150)
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 one highly effective forms of 
contraception and their partners must use a male condom (as listed 
below), 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).
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. [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 (EE) transdermal system PLUS male 
condom 
∀
Intrauterine system (IUS) device (e.g., levonorgestrel releasing IUS -
Mirena®) PLUS male condom 

Clinical Study Protocol Appendix D
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
127 (150)
∀
Intravaginal device (e.g., EE and etonogestrel) PLUS male condom.

ENGOT Number
ENGOT-ov38/OReO
128 (150)
Drug Substance
Olaparib, AZD2281, 
KU-0059436
Study Code
D0816C00014
Version
4.0
Date
15 October 2020
Appendix E
ECOG Performance Criteria

Clinical Study Protocol Appendix E
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
129 (150)
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.

ENGOT Number
ENGOT-ov38/OReO
130 (150)
Drug Substance
Olaparib, AZD2281, 
KU-0059436
Study Code
D0816C00014
Version
4.0
Date
15 October 2020
Appendix F
Guidelines for Evaluation of Objective Tumour Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumours)

Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
131 (150)
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION ........................................................................................... 132
2.
DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET 
AND NON-TARGET LESIONS...................................................................... 132
3.
METHODS OF ASSESSMENT ...................................................................... 133
3.1.
CT and MRI..................................................................................................... 134
3.2.
Clinical examination ........................................................................................ 134
3.3.
X-ray ............................................................................................................... 134
3.3.1.
Chest X-ray...................................................................................................... 134
3.3.2.
Plain X-ray....................................................................................................... 135
3.4.
Ultrasound ....................................................................................................... 135
3.5.
Endoscopy and laparoscopy ............................................................................. 135
3.6.
Tumour markers............................................................................................... 135
3.7.
Cytology and histology .................................................................................... 135
3.8.
Isotopic bone scan............................................................................................ 135
3.9.
FDG-PET scan................................................................................................. 136
4.
TUMOUR RESPONSE EVALUATION.......................................................... 136
4.1.
Schedule of evaluation ..................................................................................... 136
4.2.
Target lesions (TL) .......................................................................................... 136
4.2.1.
Documentation of target lesions ....................................................................... 136
4.2.2.
Evaluation of target lesions .............................................................................. 138
4.3.
Non-Target lesions (NTL)................................................................................ 138
4.3.1.
Evaluation of non-target lesions ....................................................................... 138
4.4.
New Lesions .................................................................................................... 139
4.5.
Symptomatic deterioration ............................................................................... 140
4.6.
Evaluation of Overall Visit Response............................................................... 140
5.
CENTRAL REVIEW....................................................................................... 140
6.
REFERENCES ................................................................................................ 141

Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
132 (150)
1.
INTRODUCTION
This appendix details the implementation of RECIST 1.1 Guidelines (Eisenhauer et al 2009) 
for the D0816C00014 study with regards to Investigator assessment of tumour burden 
including protocol-specific requirements for this study.
2.
DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET 
AND NON-TARGET LESIONS
Only patients with measurable disease at baseline should be included in the study.  
Measurable disease is defined by the presence of at least one measurable lesion which has not 
been previously irradiated and not chosen for biopsy during the screening period.
Measurable:
A lesion, not previously irradiated and not chosen for biopsy during the screening period, that 
can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph 
nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic 
resonance imaging (MRI) and which is suitable for accurate repeated measurements. If only 
one measurable lesion exists, it is acceptable to be used (as a target lesion) as long as it has not 
been previously irradiated and baseline tumour assessment scans are done at least 14 days 
after the screening biopsy is performed.
Non-measurable:
∀
All other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15mm short axis at baseline*).
∀
Truly non-measurable lesions include the following: bone lesions, 
leptomeningeal disease, ascites, pleural / pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical 
examination that is not measurable by CT or MRI.
∀
Previously irradiated lesions**
∀
Skin lesions assessed by clinical examination
∀
Brain metastasis

Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
133 (150)
∀
Lesions biopsied within the screening period (exception: If only one 
measurable lesion exists, it is acceptable to be used [as a target lesion] as 
long as it has not been previously irradiated and baseline tumour 
assessment scans are done at least 14 days after the screening biopsy is 
performed).
* Nodes with <10mm short axis are considered non-pathological and should not be recorded 
or followed as NTL.
**Localised post-radiation changes which affect lesion sizes may occur.  Therefore, lesions 
that have been previously irradiated will not be considered measurable and must be selected as 
Non-Target Lesions (NTL) at baseline and followed up as part of the NTL assessment.
Special Cases:
∀
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 should be selected as 
target lesions.
Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as 
target lesions (TL) at baseline.
Non-Target lesions:
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.
3.
METHODS OF ASSESSMENT
The same method of assessment and the same technique should be used to characterize 
each identified and recorded lesion at baseline and during follow-up visits.

Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
134 (150)
A summary of the methods to be used for RECIST assessment is provided below and those 
excluded from tumour assessments for this study are highlighted, with the rationale provided.
App. Table 1
Summary of Methods of Assessment
Target Lesions
Non-Target Lesions
New Lesions
CT (preferred)
MRI
CT (preferred)
MRI
Clinical examination 
X-ray, Chest x-ray*
CT (preferred)
MRI
Clinical examination 
X-ray, Chest x-ray*
Ultrasound*
Bone Scan*
FDG-PET*
*Not mandatory per D0816C00014 protocol; can be used if clinically indicated and are 
acceptable methods for New lesion identification.
3.1.
CT and MRI 
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and identification 
of any new lesions. 
In the D0816C00014 study it is recommended that CT examinations of the Chest, abdomen
and pelvis, will be used to assess tumour burden at baseline and follow-up visits.  CT 
examination with intravenous (i.v.) contrast media administration is the preferred method.  
MRI should be used where CT is not feasible or it is medically contra-indicated.  For brain 
lesion assessment, MRI is the preferred method although CT is acceptable.
3.2.
Clinical examination 
In the D0816C00014 study, clinical examination will not be used for assessment of TL.  
Clinically detected lesions can be selected as target lesions if they are assessed by CT or MRI 
scans.  Clinical examination can be used to assess NTL and to identify the presence of new 
lesions.
3.3.
X-ray
3.3.1. Chest X-ray
In the D0816C00014 study, chest x-ray assessment will not be used for assessment of TL as 
they will be assessed by CT examination or MRI examination.  Chest X-ray can, however, be 
used to assess NTL and to identify the presence of new lesions.

Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
135 (150)
3.3.2. Plain X-ray 
In the D0816C00014 study plain x-ray may be used as a method of assessment for bone NTL 
and to identify the presence of new bone lesions. 
3.4.
Ultrasound 
In the D0816C00014 study, ultrasound examination will not be used for assessment of TL and 
NTL as it is not a reproducible method, does not provide an accurate assessment of tumour 
size and it is subjective and operator dependent.  Ultrasound examination can, however, be 
used to identify the presence of new lesions.  If new clinical symptoms occur and an 
ultrasound is performed then new lesions should be confirmed by CT or MRI examination.
3.5.
Endoscopy and laparoscopy 
In the D0816C00014 study, endoscopy and laparoscopy will not be used for tumour 
assessments as they are not validated in the context of tumour assessment.
3.6.
Tumour markers 
In the D0816C00014 study tumour markers will not be used for tumour response assessments 
as per RECIST 1.1.
3.7.
Cytology and histology 
In the D0816C00014 study histology will not be used as part of the tumour response 
assessment as per RECIST 1.1. 
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease.  In such circumstances, the cytology is necessary to differentiate between 
response / stable disease (an effusion may be a side effect of the treatment) and progressive 
disease (if the neoplastic origin of the fluid is confirmed).  Where cytology findings are not 
available, any effusion that significantly worsens (from trace to large) or appearance of 
clinically significant effusion (requiring change in drug therapy) during the study treatment 
will be considered to be progression of NTL, or disease progression due to new lesions. 
3.8.
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or X-
ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment.  
In the D0816C00014 study isotopic bone scans may be used as a method of assessment to 
identify the presence of new bone lesions at follow-up visits.  New lesions will be recorded 

Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
136 (150)
where a positive hot-spot that was not present on the baseline bone scan assessment is 
identified on a bone scan performed at any time during the study.  The Investigator should 
consider the positive hot-spot to be a significant new site of malignant disease and represent 
true disease progression in order to record the new lesion.  Confirmation by CT, MRI and x-
ray is recommended where bone scan findings are equivocal.
3.9.
FDG-PET scan 
In the D0816C00014 study FDG-PET scans may be used as a method for identifying new 
lesions, according with the following algorithm:  New lesions will be recorded where there is 
positive FDG uptake* not present on baseline FDG-PET scan or in a location corresponding 
to a new lesion on CT/MRI at the same follow-up visit.  If there is no baseline FDG-PET scan 
available, and no evidence of new lesions on CT/MRI scans then follow-up CT/MRI 
assessments should be continued, scheduled as per protocol or clinical indicated, in order to 
confirm new lesions.
* A positive FDG-PET scan lesion should be reported only when an uptake greater than twice 
that of the surrounding tissue is observed.
4.
TUMOUR RESPONSE EVALUATION 
4.1.
Schedule of evaluation
Baseline assessments should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based 
on signs and symptoms of individual patients and should be performed no more than 28 days 
before the start of study treatment (refer to Study Plan and section 5.1 from the study 
protocol).  Follow-up assessments will be performed every 12 weeks (± 1 week) after 
randomisation until objective disease progression as defined by RECIST 1.1 even if a patient 
discontinues treatment prior to progression or receives other anti-cancer treatment.  Any other 
sites at which new disease is suspected should also be adequately imaged at follow-up.
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.  This 
schedule is to be followed in order to minimise any unintentional bias caused by some patients 
being assessed at a different frequency than other patients.
4.2.
Target lesions (TL)
4.2.1. Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved should be identified as TL at baseline.  

Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
137 (150)
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions), but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimeters.  At baseline the sum of the diameters for all TL will be calculated and reported as 
the baseline sum of diameters.  At follow-up visits the sum of diameters for all TL will be 
calculated and reported as the follow-up sum of diameters.
Special cases:
∀
For TL measurable in 2 or 3 dimensions, always report the longest 
diameter. For pathological lymph nodes measurable in 2 or 3 dimensions, 
always report the short axis. 
∀
If the CT/MRI slice thickness used is > 5mm, the minimum size of 
measurable disease at baseline should be twice the slice thickness of the 
baseline scan.
∀
If a lesion has completely disappeared, the longest diameter should be 
recorded as 0 mm.
∀
If a TL splits into two or more parts, then record the sum of the diameters 
of those parts. 
∀
If two or more TL merge then the sum of the diameters of the combined 
lesion should be recorded for one of the lesions and 0 mm recorded for 
the other lesion(s).  
∀
If a TL is believed to be present and is faintly seen but too small to 
measure, a default value of 5mm should be assigned.  If an accurate 
measure can be given, this should be recorded, even if it is below 5mm.
∀
If a TL cannot be measured accurately due to it being too large, provide 
an estimate of the size of the lesion. 
∀
When a TL has had any intervention e.g. radiotherapy, embolisation, 
surgery etc., during the study, the size of the TL should still be provided 
where possible.

Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
138 (150)
4.2.2. Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumour visit 
response for TL.
App. Table 2
Evaluation of target lesions
Complete Response (CR)
Disappearance of all target lesions since baseline.  
Any pathological lymph nodes selected as target 
lesions must have a reduction in short axis to < 10 
mm.
Partial Response (PR)
At least a 30% decrease in the sum of the 
diameters of TL, taking as reference the baseline 
sum of diameters
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD
Progressive Disease (PD)
At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the 
relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5mm.
Not Evaluable (NE)
Only relevant if any of the target lesions were not 
assessed or not evaluable or had a lesion 
intervention at this visit. Note:  If the sum of 
diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a 
target lesion response
4.3.
Non-Target lesions (NTL)
4.3.1. Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.  At each visit an overall assessment of the NTL response should be 
recorded by the Investigator.  This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit.

Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
139 (150)
App. Table 3
Evaluation of Non-Target Lesions
Complete Response 
(CR)
Disappearance of all non-target lesions since baseline. All lymph nodes 
must be non-pathological in size (< 10 mm short axis).
Non CR/Non PD
Persistence of one or more NTL
Progression (PD)
Unequivocal progression of existing non-target lesions.  Unequivocal 
progression may be due to an important progression in one lesion only or in 
several lesions.  In all cases the progression MUST be clinically significant 
for the physician to consider changing (or stopping) therapy.
Not Evaluable (NE)
Only relevant when one or some of the non-target lesions were not assessed 
and, in the Investigator's opinion, they are not able to provide an evaluable 
overall non-target lesion assessment at this visit.
Note:  For patients without target lesions at baseline, this is relevant if any 
of the non-target lesions were not assessed at this visit and the progression 
criteria have not been met.
To achieve ‘unequivocal progression’ on the basis of non-target lesions, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target lesions, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more non-target lesions 
is usually not sufficient to qualify for unequivocal progression status.
4.4.
New Lesions
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression. 
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: i.e. not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.

Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
140 (150)
4.5.
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumour 
assessments where possible until objective disease progression is observed.
4.6.
Evaluation of Overall Visit Response
The overall visit response will be derived using the algorithm shown in Table 4.
App. Table 4
Overall Visit Response
Target lesions
Non-Target lesions
New Lesions
Overall response
CR
CR
No
CR
CR
NA
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
NE
Non PD or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable, NA = not applicable (only relevant if there were no NTLs at baseline).
5.
CENTRAL REVIEW
No independent central review will be performed for this study.

Clinical Study Protocol Appendix F
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
141 (150)
6.
REFERENCES
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R.  New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer 
45 (2009) 228-247.

ENGOT Number
ENGOT-ov38/OReO
142 (150)
Drug Substance
Olaparib, AZD2281, 
KU-0059436
Study Code
D0816C00014
Version
4.0
Date
15 October 2020
Appendix G
FACT-O QoL Questionnaire

Clinical Study Protocol Appendix G
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
143 (150)
FACT-O (Version 4), English (Universal), Copyright 1987, 1997
http://www.facit.org/LiteratureRetrieve.aspx?ID=42283
NB: TOI is a targeted summary index of physical/functional outcomes and has been shown to 
be responsive to changes in the clinical trial setting (http://www.facit.org/FACITOrg/FAQ).  
The TOI is considered to target the most relevant symptoms together with function and 
physical well-being and can be directly related to signs and symptoms and AEs (Cella et al. 
1993).

ENGOT Number
ENGOT-ov38/OReO
144 (150)
Drug Substance
Olaparib, AZD2281, 
KU-0059436
Study Code
D0816C00014
Version
4.0
Date
15 October 2020
Appendix H
GCIG Criteria

Clinical Study Protocol Appendix H
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
145 (150)
Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, du Bois A, 
Kristensen G, Jakobsen A, Sagae S, Greven K, Parmar M, Friedlander M, Cervantes A, 
Vermorken J; Gynecological Cancer Intergroup. Definitions for response and progression in 
ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the 
Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 2011;21(2):419-23. 
Available for free at 
http://journals.lww.com/ijgc/Fulltext/2011/02000/Definitions_for_Response_and_Progression
_in.34.aspx

ENGOT Number
ENGOT-ov38/OReO
146 (150)
Drug Substance
Olaparib, AZD2281, 
KU-0059436
Study Code
D0816C00014
Version
4.0
Date
15 October 2020
Appendix I
Signatures

Clinical Study Protocol Appendix I
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
147 (150)
AstraZeneca Signature(s)
A Phase IIIb, Randomised, Double-blind, Placebo-controlled, Multicentre Study of Olaparib 
Maintenance Retreatment in Patients with Epithelial Ovarian Cancer  Previously Treated With 
a PARPi and Responding to Repeat Platinum Chemotherapy (OReO)
This Clinical Study Protocol has been subjected to an internal AstraZeneca review.
I agree to the terms of this study protocol.
AstraZeneca Representative
Cambridge, CB2 8PA, UK
Date
(Day Month Year)
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from AstraZeneca.  Investigators are cautioned 
that the information in this protocol may be subject to change and revision.
PPD

Clinical Study Protocol Appendix I
Drug Substance Olaparib, AZD2281, KU-0059436
Study Code D0816C00014
Version 4.0
Date 15 October 2020
ENGOT Number
ENGOT-ov38/OReO
150 (150)
SIGNATURE OF INTERNATIONAL COORDINATING INVESTIGATOR
A Phase IIIb, Randomised, Double-blind, Placebo-controlled, Multicentre Study of Olaparib 
Maintenance Retreatment in Patients with Epithelial Ovarian Cancer  Previously Treated With 
a PARPi and Responding to Repeat Platinum Chemotherapy (OReO)
This Clinical Study Protocol has been subjected to an internal AstraZeneca review.
I agree to the terms of this study protocol.
International Coordinating 
Investigator
75008 Paris
France
Date
(Day Month Year)
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from AstraZeneca. Investigators are cautioned 
that the information in this protocol may be subject to change and revision.
PPD
PPD

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d0816c00014-csp-v4
Document Title:
D0816C00014 Clinical Study Protocol version 4
Document ID:
Version Label:
4.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
26-Oct-2020 16:55 UTC
Management Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
CCI