Conditions: Relapsed Ovarian Cancer, BRCA Mutation, Platinum Sensitivity
Keywords: BRCA, ovarian, platinum, chemotherapy,
Allocation: RANDOMIZED | Intervention model: 
Enrollment: 266
Healthy volunteers: no

Brief summary:
Comparison of olaparib vs. physician's choice of single agent standard of care non-platinum based chemotherapy in patients with germline Breast Cancer susceptibility gene (gBRCA) mutated ovarian cancer who have progressed at least 6 months after the last platinum based chemotherapy. Patient should have received at least 2 prior lines of platinum based chemotherapy. The aim of the study is to assess the efficacy and safety of olaparib tablets.

Detailed description:
This open label, randomised, controlled, multi-centre study will assess the efficacy and safety of single agent olaparib vs. standard of care, based on physician's choice of single agent chemotherapy ( i.e paclitaxel, or topotecan, or pegylated liposomal doxorubicin, or gemcitabine) in platinum sensitive or partially platinum sensitive relapsed ovarian cancer patients who carry germline deleterious or suspected deleterious BRCA mutation and who have received at least 2 prior lines of platinum based chemotherapy. Patients are eligible to undergo BRCA testing even if they have not yet had recurrence or progression of disease \>6 months (\>/=183 days) after completion of their last platinum therapy.

Arms:
arm 1: olaparib 300mg oral tablets; twice daily arm 2: Physician's choice single agent chemotherapy

Interventions: intervention 1: OLAPARIB intervention 2: Single agent chemotherapy
Intervention descriptions: intervention 1: 300 mg olaparib tablets taken orally twice daily. All patients should continue to receive study treatment until objective radiological disease progression as per RECIST 1.1 as assessed by the investigator or the patient experiences unacceptable toxicity or they meet any other discontinuation criteria. intervention 2: Treatment of relapsed disease with single agent chemotherapy based on physician's choice of weekly paclitaxel, topotecan, pegylated liposomal doxorubicin, or gemcitabine. All patients should continue to receive study treatment until objective radiological disease progression as per RECIST 1.1 as assessed by the investigator or the patient experiences unacceptable toxicity or they meet any other discontinuation criteria

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
Drug Substance
AZD2281
Study Code
D0816C00010
Version
4.0
Date
20 December 2017 
A Phase III, Open Label, Randomised, Controlled, Multi-centre Study to 
assess the efficacy and safety of Olaparib Monotherapy versus Physician’s 
Choice Single Agent Chemotherapy in the Treatment of Platinum Sensitive 
Relapsed Ovarian Cancer in Patients carrying germline BRCA1/2 Mutations
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden


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VERSION HISTORY
Version 4.0, 29 September 2017
Rationale for the change: PARP inhibitors now being available as part of clinical practice 
create significant recruitment challenge for SOLO3 trial. Therefore, recruitment will close 
once a minimum of 250 patients are randomized instead of 411 as initially planned. 
The primary endpoint is objective response rate (ORR). This protocol assumes a response rate 
of 25% on the chemotherapy arm and a response rate of at least 45% on the Olaparib arm for 
subjects with measurable disease at baseline according to BICR. The data cut-off for the 
primary analysis will occur in January 2019 or at a minimum of 6 months after LSI, 
whichever is sooner, to ensure sufficient patient follow-up to characterize duration of response 
(DoR) and satisfy a regulatory commitment. The study will retain >80% power to detect a 
statistically significant difference in ORR at the two-sided 5% level.
The following changes were incorporated into version 4.0 of the protocol:

Primary objective and endpoint changed from PFS to ORR

Number of randomized patients changed from 411 to 250

The data cut-off for the primary analysis will occur in January 2019 or at a minimum
of 6 months after LSI, whichever is sooner.

Figure 1 was updated to reflect current number of patients

Section 1.1.4 updated based on IB v 14.0 section 6.2

Section 3.3 added wording regarding randomization timelines after screening closure

Section 3.10 death was added as criterion for withdrawal

Figure 2 study flow chart was updated

Based on IB v 14.0 regular pregnancy testing was added

Sections 5.4.1 and 10.4.3 were updated regarding PK sample analysis

Section 6.7 dose reduction scheme was corrected to be in line with section 6.8

Section 9.2 dispensation of IP was updated

Section 9.7.1.1 updated based on IB v 14 new data


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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
Section 10 and page 12 “statistical methods” were updated to reflect changes in
number of randomized patients and analyses based on new primary objective and
endpoint

Section 11.4 change of AZ Drug Dictionary to WHODRUG

Spelling mistake corrected “Friedlander”
Version 3.0, 03 August 2016
The following changes were incorporated into version 3.0 of the protocol:

Modification made to comments ‘a’ and ‘b’ to Table 2.

Removal of footnote “a” from  Tumour assessment visits every 8 or 12 weeks in the
header of Table 2

Addition of “or 12 weeks” to “Subsequent on treatment visits every 4 weeks” in the
header of Table 2

Changes to Sections 6.8.1 and 6.8.2 to align with the current guidelines for
haematological toxicity management
Version 2.0, 27 June 2016
The following changes were incorporated into version 2.0 of the protocol:

Note that when Version 2.0 of the protocol was prepared, the content of the protocol
and appendices were incorporated into the new AstraZeneca protocol template
resulting in modifications of cover page (tracking version history), removal of
Appendix A (signatures) and changes to Appendix numbering.

Minor editorial changes of a typographical nature were made throughout the protocol
for consistency and clarity.  Several references to sections were updated for accuracy.

Changes made to inclusion criteria 3, 6, 7 and 8 in order to allow BRCA mutation
testing to be carried out during second platinum line.

Rewording of inclusion criterion 12 for clarity.


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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
Update regarding new AZ randomization system in Section 3.5.

Changes to Section 3.8.1 Contraception and Appendix D to align with AstraZeneca’s
acceptable birth control methods for clinical trial purposes.

Removal of ‘death’ from list of situations for IP discontinuation in Section 3.9 and
from criteria for withdrawal and discontinuation in Section 3.10.

Modification made to comments ‘f’ and ‘g’ to Table 1.

Change in Discontinuation of Study Treatment visit window in Table 2 as it should not
be performed at -7 days before the subject discontinues IP.

Visit window of ±3 days added to Visit 2 in Table 2.

Alignment of tumour assessment visits to the on treatment visits added in comment
“b” to Table 2.

Clarification added to conditions for BP measurement in Section 5.2.4.1.

Clarification added to PRO information collection process in Section 5.3.1.5.

Window of ± 5 min added to PK sampling time of 1h post dose at Day 1 (Visit 2) in
Table 5 and Section 5.4.2 as well as in comment ‘g’ to Table 2.

Information added on data collected in CRF for BRCA testing in Section 5.6.1.1.

Clarification added to the collection of samples for BRCA testing in Section 5.6.2.

Clarification added to sample storage and destruction in Section 5.7.2.

Modification made to Section 6.4 describing SAE reporting process when WBDC is
not available.

Comments added regarding operational aspect of comparator drug supply in Section
9.1.

Information has been added regarding the effects of other drugs on olaparib and the
effects of olaparib on other drugs, to align the information in the protocol with the
updated olaparib Investigator’s Brochure dated 29 June 2015  (Sections affected:
exclusion criterion 11, Section 9.7.1.1 Olaparib drug-drug interactions).

Updated Section 9.7.1.5 regarding the start of corticosteroids to ensure consistency
with exclusion criterion 14.


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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
Change in source of definition for data validation in Data Management Section 11.4.
Edition number 1, 20 October 2014
Initial creation
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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PROTOCOL SYNOPSIS
A Phase III, Open Label, Randomised, Controlled, Multi-centre Study to 
assess the efficacy and safety of Olaparib Monotherapy versus Physician’s 
Choice Single Agent Chemotherapy in the Treatment of Platinum Sensitive 
Relapsed Ovarian Cancer in Patients carrying germline BRCA1/2 Mutations
International Co-ordinating Investigator
 
 
Study site(s) and number of patients planned
The study will be conducted in approximately 15 countries worldwide. Approximately 100 
centres will be initiated to randomise at least 250 patients. Additional sites may be added 
dependent on recruitment rates.
Study period
Phase of development
Estimated date of first patient enrolled
Q4 2014
III
Estimated date of last patient enrolled
Q2 2018
III
Study design
This open label, randomised, controlled, multi-centre study will assess the efficacy and safety 
of single agent olaparib vs. standard of care, based on physician’s choice of single agent 
chemotherapy (i.e weekly paclitaxel, topotecan, pegylated liposomal doxorubicin, or 
gemcitabine) in relapsed ovarian cancer patients who have received at least 2 prior lines of 
platinum based chemotherapy, who have progressed at least 6 months after their last platinum 
based chemotherapy and who carry a germline deleterious or suspected deleterious BRCA
mutation. Non-platinum based chemotherapy in this setting can be given to prolong the 
platinum free interval and can be followed by further platinum treatment at a later relapse or 
can be considered for patients who are not warranted for further platinum treatment. Due to 
different routes and schedules of administration of the study treatments and different toxicity 
profiles, the study is not feasible to be blinded. Given the open label design of the study, 
rigorous methodology will be employed to ensure robustness of the primary endpoint 
assessment with a primary analysis of objective response rate (ORR) based on blinded 
independent central review (BICR) of all patient scans using RECIST 1.1 criteria. Secondary 


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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endpoints will include progression free survival (PFS) by BICR using RECIST 1.1 criteria; 
time from randomisation to second progression (PFS2); overall survival (OS); CA-125 
response; safety assessments and health related quality of life. Full details provided below. 
A minimum of 250 patients will be randomised 2:1 (olaparib: chemotherapy) into the trial. 
The treatment groups include olaparib 300 mg po twice daily tablet continuously, or 
physician’s choice of chemotherapy. The investigator must declare prior to randomisation 
their choice of chemotherapy i.e. weekly paclitaxel, topotecan, pegylated liposomal 
doxorubicin, or gemcitabine.
The randomisation scheme will be stratified based on:

Selected chemotherapy (weekly paclitaxel vs. topotecan vs. pegylated 
liposomal doxorubicin vs. gemcitabine)

Received prior chemotherapy regimens for ovarian cancer (2 or 3 prior 
lines of chemotherapy vs. 4 or more)

Time to disease progression after the end of the last platinum based 
chemotherapy (6-12 mo vs. > 12 mo)
Objectives 
Primary Objective:
Outcome Measure:
To determine the efficacy of olaparib vs. 
physician’s choice single agent 
chemotherapy by assessment of Objective 
Response Rate (ORR) using blinded 
independent central review (BICR) 
Objective Response Rate (ORR) by BICR using 
RECIST 1.1 criteria
Secondary Objective:
Outcome Measure:
To compare the efficacy of single agent 
olaparib versus physician’s choice single 
agent chemotherapy

Progression Free Survival (PFS) by BICR using 
RECIST 1.1 criteria

Time from randomisation to second progression 
(PFS2) by investigator assessment of radiological, 
clinical or CA-125 progression

Overall survival (OS)

Time to earliest progression by RECIST 1.1 or 
CA-125 or death

Time from randomisation to first subsequent 
therapy or death (TFST)

Time from randomisation to second subsequent 
therapy or death (TSST)


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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Secondary Objective:
Outcome Measure:

Time from randomisation to study treatment 
discontinuation or death (TDT)

Duration of response (DoR) by BICR using 
RECIST 1.1 criteria for evaluable patients

Time to response (TTR) by BICR using RECIST 
1.1 criteria for evaluable patients
To compare the efficacy of single agent 
olaparib versus physician’s choice single 
agent chemotherapy on the Health-related 
Quality of Life (HRQoL) as measured by the 
trial outcome index (TOI) of the Functional 
Assessment of Cancer Therapy – Ovarian
(FACT-O)

Mean change from baseline in TOI score

Proportion improved (in the absence of 
subsequent cancer therapy) in TOI score
To assess efficacy of olaparib in patients 
identified as having a deleterious or 
suspected deleterious variant in either of the 
BRCA genes using variants identified with 
current and future BRCA mutation assays 
(e.g. gene sequencing and large 
rearrangement analysis)

ORR (by BICR), PFS (by BICR), PFS2, OS, 
TDT, TFST and TSST, analyses will be 
performed in those patients whose gBRCAm 
status is confirmed by the central Myriad test 
(only required if populations differ from the 
MDAS (for ORR) or FAS (for PFS) populations)

Development and delivery of a BRCA mutation 
companion diagnostic
To determine exposure to olaparib following 
dosing at the 300 mg bd tablet dose and 
explore exposure-response relationships
Safety Objective:
Outcome Measure:
To assess the safety and tolerability of single 
agent olaparib vs. physician’s choice single 
agent chemotherapy 
Adverse Events (AE), physical examination, vital 
signs including blood pressure (BP), pulse, 
electrocardiogram (ECG) and laboratory findings 
including clinical chemistry and haematology
Exploratory Objective:
Outcome Measure:
To assess the effect on patient self-reported 
feelings about side-effects of single agent 
olaparib versus physician’s choice of single 
agent chemotherapy using the ‘Feelings 
about side-effects’ domain of the Cancer 
Therapy Satisfaction Questionnaire (CTSQ-
16)

Treatment satisfaction score (as measured by the 
Satisfaction with Therapy scale of the CTSQ-16)

Patient-reported feelings  measured by the 
‘feelings about side-effects’ domain of the Cancer 
Therapy Satisfaction Questionnaire (CTSQ-16)


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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Exploratory Objective:
Outcome Measure:
To investigate the health economic impact of 
treatment and the disease on hospital related 
resource use and health state utility

Number, type and reason of hospitalisations and 
hospital attendances, procedures undertaken and 
hospital length of stay

Health state utility derived from the HRQL 
instrument, the EuroQoL EQ5D-5L
To explore methods of estimating overall 
survival (OS) adjusting for the impact of the 
control arm receiving subsequent 
Polyadenosine 5’diphosphoribose [poly 
(ADP ribose)] polymerise (PARP) inhibitors 
or imbalances between the treatment arms for 
other potentially active agents

Overall survival adjusted for impact of subsequent 
PARP inhibitors (or other potentially active 
investigational agents (if appropriate, to support 
reimbursement appraisals)
To determine the frequency of and describe
the nature of BRCA mutation/s in tumour 
samples and to compare this with germline 
BRCA mutation status

BRCA1 and/or BRCA2 mutation status in tumour
To explore whether resistance mechanisms to 
olaparib can be identified through analysis of 
tumour and blood samples – archival tumour 
(mandatory), blood samples at baseline and 
on disease progression (mandated) and serial 
biopsies at baseline and disease progression 
(optional)
Future exploratory research into factors that 
may influence development of cancer and/or 
response to treatment (where response is 
defined broadly to include efficacy, 
tolerability or safety) may be performed on 
the collected and stored archival tumour 
samples (mandatory), blood samples at 
baseline and on disease progression 
(mandated) and serial biopsies at baseline 
and disease progression (optional)
To collect and store DNA according to each 
country’s local and ethical procedures for 
future exploratory research into genes/genetic 
variation that may influence response (i.e. 
distribution, safety, tolerability and efficacy) 
to study treatments and/or susceptibility to 
disease (optional)

Potential retrospective tissue biomarker research
The exploratory analyses may not be reported in the clinical study report (CSR).  If not, they 
will be reported separately.


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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Target patient population
All patients randomised in the study will be selected based on the following 3 principles: 
Genetic selection: Documented germline mutation in BRCA1 or BRCA2 gene that is predicted 
to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of 
function).  Patients with BRCA1 and/or BRCA2 mutations that are considered to be non-
detrimental (eg, “Variants of uncertain clinical significance” or “Variant of unknown 
significance” or “Variant, favor polymorphism” or “benign polymorphism,” etc) will not be 
eligible for the study. BRCA status which is known, for patients determined by a local test will 
be accepted, however a confirmatory Myriad gBRCA test post randomisation will still be 
required.  Genetic counselling should be arranged as per local requirements.
Treatment setting: All patients should have relapsed high grade epithelial ovarian cancer 
(serous or endometrioid), primary peritoneal or fallopian-tube cancer and should have 
received at least 2 prior platinum based lines of chemotherapy for ovarian cancer. Patients 
should be suitable for treatment of relapsed disease with single agent chemotherapy based on 
physician’s choice of weekly paclitaxel, topotecan, pegylated liposomal doxorubicin, or 
gemcitabine. Patients should not have been previously exposed to the selected chemotherapy 
as a single agent. 
Platinum sensitivity: Patients can be either partially platinum sensitive (defined as 
progression 6 -12 months after the end of the last platinum based chemotherapy) or platinum 
sensitive (defined as progression >12 months after the end of the last platinum based 
chemotherapy). Patients who have platinum resistant or refractory disease will not be eligible 
for the study.  
Patients known to have a germline BRCA deleterious or suspected deleterious mutation 
(gBRCAm) (i.e. blood) prior to randomisation can enter the study based on this result. The 
result must be made available to AstraZeneca. In addition the patients must consent to provide 
2 blood samples. One sample will be used for a confirmatory gBRCA test post randomisation 
using the current commercial Myriad Integrated BRACAnalysis test (gene sequencing and 
large rearrangement analysis).  The second is required for a bridging study to develop and 
validate the BRCA companion diagnostic test for olaparib.
Patients with unknown BRCA status must consent to provide 2 blood samples for germline 
BRCA testing by Myriad and comply with all local ethical procedures for such genetic testing.  
One sample will be used to test for BRCA mutations using the current commercial Myriad 
Integrated BRACAnalysis test prior to study entry. When the result from the Myriad test 
indicates the patient does have a deleterious or suspected deleterious BRCA mutation, the 
patient can be randomised into the study (providing they have fulfilled all other screening 
requirements).  The second blood sample is required for a bridging study to develop and 
validate the BRCA companion diagnostic test for olaparib.  These samples will be required for 
the study even if the patients are found not to have a deleterious or suspected deleterious 
BRCA mutation.  


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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Duration of treatment
Patients will be randomised (using an IVRS/IWRS) in a 2:1 ratio to the treatments as specified 
below:

Olaparib tablets orally 300 mg twice daily (given as two 150mg tablets 
twice daily); total daily dose of 600 mg

Physician’s choice of chemotherapy (weekly paclitaxel, topotecan, 
pegylated liposomal doxorubicin, or gemcitabine)
All patients should continue to receive study treatment until objective radiological disease 
progression as per RECIST 1.1 as assessed by the investigator or the patient experiences 
unacceptable toxicity or they meet any other discontinuation criteria. 
All patients should have RECIST assessments until documented evidence of objective 
radiological progression in accordance with RECIST 1.1, irrespective of treatment decisions 
(i.e. RECIST follow up until progression even if a patient discontinues study treatment prior 
to progression and/or receives a subsequent therapy prior to progression). Patients who are 
determined to have progressed according to RECIST 1.1 criteria by the investigator will have 
one final RECIST assessment at the next scheduled RECIST visit in order to minimise bias in 
the BICR assessment in the event the investigator declares objective progression earlier than 
the BICR. After the primary ORR analysis, central review of scans will no longer be required 
and investigators will be advised when to stop sending copies of the scans to the CRO 
conducting the central review. 
RECIST assessments will be scheduled every 8 weeks (+/- 1 week) from randomisation for 48 
weeks and every 12 weeks (+/- 1 week) thereafter.  All CT/MRI scans will be sent to an 
AstraZeneca appointed Clinical Research Organisation (CRO) for blinded independent central 
review.  All treatment decision will be based on investigator’s assessment of the scans.  Once 
patients have been discontinued from study treatment, the investigator will be at liberty to 
define further the most appropriate anti-cancer treatment.  Information on all subsequent 
anticancer treatments will be collected in the eCRF. Within this study, patients on 
chemotherapy will not be provided olaparib post discontinuation of study treatment.
Following objective disease progression, patients may be allowed to continue study treatment 
if the investigator believes that the patient continues to receive benefit, the patient is not 
experiencing serious toxicity and there is no available better alternative treatment that could 
benefit the patient.
Investigational product, dosage and mode of administration
AstraZeneca’s Pharmaceutical Development, R&D Supply Chain will supply olaparib to the 
investigator as film-coated tablets.


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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Patients will be administered olaparib tablets orally twice daily (bd) at a dose of 300 mg.  Two 
(2) x 150 mg olaparib tablets should be taken at the same times each morning and evening of 
each day, approximately 12 hours apart with approximately 240 mL of water.  
The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or 
divided.  Dose reductions will be managed with 100 mg tablets. 
Comparator, dosage and mode of administration
Investigators will declare prior to randomisation in the IVRS their choice of one of the 
following regimens for each patient:

Weekly paclitaxel 80 mg/m2 iv on day 1, 8, 15, 22 every 4 weeks

Pegylated liposomal doxorubicin (PLD) 50 mg/m2 iv day 1 every 4 
weeks

Topotecan 4 mg/m2 iv on day 1, 8, 15 every 4 weeks

Gemcitabine 1000 mg/m2 iv on day 1, 8, 15 every 4 weeks 
Investigators should administer all the chemotherapies as per standard practice guidelines. 
Within this study there is no provision for patients on the control arm to receive olaparib post 
discontinuation of their study treatment.
Statistical methods 
A minimum of 250 patients will be randomised (2:1 ratio of olaparib:chemotherapy) and the 
data cut-off for the primary analysis will occur in January 2019 or at a minimum of 6 months 
after the last subject is randomised whichever is sooner. This is to ensure sufficient patient 
follow-up to characterize duration of response (DoR) and satisfy a regulatory committment.
With at least 223 subjects, the study will have >80% power to show a statistically significant 
difference in ORR at the two-sided 5% level, assuming a response rate of 25% on the 
chemotherapy arm and a response rate of at least 45% on the olaparib arm for subjects with 
measurable disease at baseline according to BICR. It is anticipated that approximately 90% of 
subjects will have measurable disease at baseline according to BICR and therefore to ensure 
adequate power, the sample size will have at least 250 subjects.
The statistical analysis of the efficacy of olaparib will include all randomised patients (Full 
Analysis Set, FAS), except for the primary endpoint, ORR, which will only include patients 
with Measurable Disease at baseline as confirmed by BICR (Measurable Disease Analysis 
Set, MDAS). Treatment groups will be compared on the basis of randomised treatment, 
regardless of the treatment actually received. When assessing safety and tolerability, 
summaries will be produced based on the Safety Analysis Set. This will include all patients 
who receive at least one dose of randomised treatment (olaparib or chemotherapy). The safety 
data will be summarised descriptively and will not be formally analysed.


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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ORR will be analysed using logistic regression adjusted by the stratification factors. If the 
number of responses in the individual stratum are too small for a meaningful analysis (less 
than 5 responses per stratum), a pre-specified strategy to account for such a situation, will be 
applied. Further details will be documented in the Statistical Analysis Plan. The odds ratio 
(OR) together with its 95% confidence interval (CI) and p-value will be presented (a OR less 
than 1 will favour olaparib). The primary analysis will be based on a blinded independent 
central review (BICR) of objective response by RECIST 1.1, however, a sensitivity analysis 
will be performed using the investigator-recorded assessment.
Subgroup analyses will 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 
patients in a subgroup).
An analysis of PFS, PFS2 and OS will be performed at the same time as the primary analysis 
of ORR. They will be analysed using a log rank test stratified by the stratification factors. The 
HR together with its 95% confidence interval (CI) and p-value will be presented (a HR less 
than 1 will favour olaparib).
A hierarchical testing strategy will be employed where ORR is tested first and key secondary 
endpoints of PFS, PFS2 and OS will then be tested using a multiple testing procedure with a 
recycling strategy. PFS will only be tested if the null hypothesis (of no difference) for ORR is 
rejected. PFS2 will only be tested if the null hypothesis (of no difference) is rejected for both 
ORR and PFS. OS will only be tested if the null hypothesis (of no difference) is rejected for 
ORR, PFS and PFS2.
An additional PFS2 and OS analysis will only be conducted with further follow up (~60% OS 
events) if both ORR and PFS are statistically significant based on the primary analysis and the 
null hypotheses for PFS2 and/or OS are not rejected at the time of the primary analysis.
Supportive analyses of time to first subsequent therapy (TFST), time to second subsequent 
therapy (TSST), time to earliest progression by RECIST 1.1 or CA-125 or death and time to 
discontinuation of study treatment or death (TDT) will be provided, using the same 
methodology as specified for the analysis of PFS, however no multiple adjustment will be 
applied as these are viewed as supportive endpoints.
CA-125 response rates and the percentage of patients who had a RECIST response and/or a 
CA-125 response will be summarised by treatment arm.
The analysis population for HRQoL data will be the FAS. Change from baseline in TOI score 
will be regarded as the primary analysis of the FACT-O questionnaire and will be analysed 
using a mixed model for repeated measures (MMRM) analysis of the change from baseline in 
TOI score for each visit. TOI improvement rate will be based on evaluable QoL data collected 
from randomisation up to the earliest of starting any subsequent cancer therapy or death. It 
will be analysed using a logistic regression model using the same covariates as used in the 


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Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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PFS analyses. Supportive analyses will be performed for the individual TOI domains for both 
change from baseline score and improvement rates. P-values will not be calculated for these 
supportive analyses. 
Appropriate summaries of exploratory outcome variables and data listings will be produced 
and compared across the two treatment arms. Graphical methods will be widely used in 
exploring the characteristics and relationships of outcome variables.


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
PROTOCOL SYNOPSIS.....................................................................................6
TABLE OF CONTENTS................................................................................... 15
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................... 23
1
INTRODUCTION ............................................................................................. 28
1.1
Ovarian cancer and its treatment ........................................................................ 28
1.1.1
PARP inhibition as a target for BRCA mutated ovarian cancer ........................... 29
1.1.2
Pre-clinical experience ....................................................................................... 30
1.1.3
Toxicology and safety pharmacology summary.................................................. 31
1.1.4
Clinical experience............................................................................................. 31
1.2
Research hypothesis........................................................................................... 32
1.3
Rationale for study design, doses and control groups.......................................... 32
1.3.1
Rationale for study treatment dose ..................................................................... 33
1.4
Benefit/risk and ethical assessment .................................................................... 33
1.4.1
Unmet need........................................................................................................ 33
1.4.2
Clinical benefit of olaparib monotherapy in patients with PSR gBRCA 
mutated ovarian cancer....................................................................................... 34
1.4.3
Safety and tolerability of olaparib ...................................................................... 35
1.4.4
Myelodysplastic syndrome/acute myeloid leukaemia(t-AML)............................ 35
1.4.5
New Primary Malignancies................................................................................ 36
1.5
Study Design...................................................................................................... 37
2
STUDY OBJECTIVES...................................................................................... 39
2.1
Primary objective............................................................................................... 39
2.2
Secondary objectives.......................................................................................... 39
2.3
Safety objectives................................................................................................ 40
2.4
Exploratory objectives ....................................................................................... 40
3
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 41
3.1
Inclusion criteria ................................................................................................ 41
3.2
Exclusion criteria ............................................................................................... 44
3.3
Patient enrolment and randomisation.................................................................. 46


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3.4
Procedures for handling incorrectly enrolled or randomised patients .................. 46
3.5
Methods for assigning treatment groups............................................................. 47
3.6
Methods for ensuring blinding ........................................................................... 47
3.7
Methods for unblinding...................................................................................... 47
3.8
Restrictions........................................................................................................ 47
3.8.1
Contraception..................................................................................................... 47
3.9
Discontinuation of investigational product ......................................................... 48
3.9.1
Procedures for discontinuation of a patient from investigational product 
(IP) .................................................................................................................... 48
3.10
Criteria for withdrawal....................................................................................... 49
3.10.1
Screen failures ................................................................................................... 49
3.10.2
Withdrawal of the informed consent................................................................... 49
3.10.3
Lost to follow-up ............................................................................................... 50
3.11
Discontinuation of the study............................................................................... 50
4
STUDY PLAN AND TIMING OF PROCEDURES........................................... 51
4.1
Enrolment/screening period................................................................................ 62
4.2
Treatment period................................................................................................ 62
4.3
Follow-up period................................................................................................ 62
4.3.1
Patients who have objective radiological disease progression but continue 
on study treatment.............................................................................................. 62
4.3.2
Follow-up 30 day after last dose of investigational product (IP) (follow-up 
visit) .................................................................................................................. 62
4.3.3
Survival ............................................................................................................. 63
4.3.4
Second progression ............................................................................................ 63
4.3.5
Patient management post primary analysis ......................................................... 63
4.3.6
Patient management post final analysis .............................................................. 64
5
STUDY ASSESSMENTS.................................................................................. 65
5.1
Efficacy assessments.......................................................................................... 65
5.1.1
CT and MRI scans tumour assessments (RECIST 1.1) ....................................... 65
5.1.2
Tumour Evaluation ............................................................................................ 66
5.1.3
Central reading of scans ..................................................................................... 67
5.2
Safety assessments............................................................................................. 67
5.2.1
Laboratory safety assessments............................................................................ 67
5.2.1.1
Disease specific tumour marker samples (CA-125) ............................................ 68
5.2.1.2
Bone marrow or blood cytogenetic samples ....................................................... 69
5.2.2
Physical examination ......................................................................................... 69
5.2.3
ECG................................................................................................................... 69
5.2.4
Vital signs.......................................................................................................... 70
5.2.4.1
Pulse and blood pressure.................................................................................... 70


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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5.2.4.2
Body temperature............................................................................................... 70
5.2.5
Other safety assessments.................................................................................... 70
5.2.5.1
Serum or urine pregnancy test............................................................................ 70
5.3
Other assessments.............................................................................................. 70
5.3.1
Patient reported outcomes .................................................................................. 70
5.3.1.1
FACT-O ............................................................................................................ 71
5.3.1.2
CTSQ-16 ........................................................................................................... 71
5.3.1.3
EQ-5D-5L.......................................................................................................... 71
5.3.1.4
PGIC.................................................................................................................. 71
5.3.1.5
Administration of PRO questionnaires ............................................................... 72
5.3.2
Health economics............................................................................................... 72
5.4
Pharmacokinetics ............................................................................................... 73
5.4.1
Pharmacokinetic samples (subset of patients)..................................................... 73
5.4.2
Collection of samples......................................................................................... 73
5.4.3
Determination of drug concentration.................................................................. 74
5.4.4
Storage and destruction of pharmacokinetic samples.......................................... 74
5.5
Pharmacodynamics ............................................................................................ 74
5.5.1
Collection of samples......................................................................................... 74
5.5.2
Storage, re-use and destruction of pharmacodynamic samples............................ 74
5.6
Biomarker analysis............................................................................................. 74
5.6.1
Collection of blood sample for Myriad germline BRCA1 and BRCA2
testing ................................................................................................................ 74
5.6.1.1
Guidance for BRCA testing of patients with unknown BRCA status.................... 75
5.6.2
Collection of sample for assessment of current and future BRCA assay(s) ..........75
5.6.3
Collection of biomarkers biological samples ...................................................... 76
5.6.4
Storage, re-use and destruction of biomarkers biological samples....................... 76
5.7
Pharmacogenetics .............................................................................................. 77
5.7.1
Collection of pharmacogenetics ......................................................................... 77
5.7.2
Storage, re-use and destruction of pharmacogenetics.......................................... 77
5.8
Labelling and shipment of biological samples .................................................... 77
5.8.1
Chain of custody of biological samples .............................................................. 78
5.8.2
Withdrawal of Informed Consent for donated biological samples....................... 78
5.9
Blood Volume.................................................................................................... 79
6
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 81
6.1
Definition of adverse events............................................................................... 81
6.2
Definitions of serious adverse event ................................................................... 81
6.3
Recording of adverse events............................................................................... 81
6.3.1
Time period for collection of adverse events ...................................................... 81
6.3.2
Follow-up of unresolved adverse events............................................................. 82
6.3.3
Adverse events after the 30 day follow-up period............................................... 82


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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6.3.4
Variables............................................................................................................ 82
6.3.5
Causality collection............................................................................................ 84
6.3.6
Adverse events based on signs and symptoms.................................................... 84
6.3.7
Adverse events based on examinations and tests ................................................ 84
6.3.8
Hy’s Law ........................................................................................................... 85
6.3.9
Disease progression............................................................................................ 85
6.3.10
New cancers....................................................................................................... 85
6.3.11
Lack of efficacy ................................................................................................. 85
6.3.12
Deaths................................................................................................................ 86
6.4
Reporting of serious adverse events ................................................................... 86
6.5
Overdose............................................................................................................ 87
6.6
Pregnancy .......................................................................................................... 87
6.6.1
Maternal exposure.............................................................................................. 88
6.6.2
Paternal exposure............................................................................................... 88
6.7
Management of IP related toxicities ................................................................... 88
6.8
Management of haematological toxicity............................................................. 89
6.8.1
Management of anaemia .................................................................................... 89
6.8.2
Management of neutropenia, leukopenia and thrombocytopenia......................... 89
6.8.3
Management of prolonged haematological toxicities while on study 
treatment............................................................................................................ 90
6.9
Management of non-haematological toxicity...................................................... 90
6.9.1
Management of new or worsening pulmonary symptoms ................................... 91
6.9.2
Management of nausea and vomiting ................................................................. 91
6.9.3
Interruptions for intercurrent non-toxicity related events .................................... 91
7
MANAGEMENT OF TOXICITY OF CHEMOTHERAPY ............................... 92
8
STUDY GOVERNANCE AND OVERSIGHT.................................................. 92
8.1
Data Monitoring Committee............................................................................... 92
9
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 92
9.1
Identity of investigational product(s).................................................................. 92
9.2
Dose and treatment regimens ............................................................................. 93
9.3
Labelling............................................................................................................ 93
9.4
Storage............................................................................................................... 94
9.5
Compliance........................................................................................................ 94
9.6
Accountability.................................................................................................... 94
9.7
Concomitant and other treatments ...................................................................... 94
9.7.1
Medications that may NOT be administered....................................................... 95
9.7.1.1
Olaparib and drug-drug interaction..................................................................... 95


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Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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9.7.1.2
Anticoagulant Therapy....................................................................................... 97
9.7.1.3
Anti-emetics/Anti-diarrhoeals ............................................................................ 97
9.7.1.4
Palliative radiotherapy ....................................................................................... 97
9.7.1.5
Administration of other anti-cancer agents ......................................................... 97
9.7.1.6
Subsequent therapies for cancer ......................................................................... 97
9.8
Post Study Access to Study Treatment ............................................................... 98
10
STATISTICAL ANALYSES............................................................................. 98
10.1
Statistical considerations .................................................................................... 98
10.2
Sample size estimate .......................................................................................... 98
10.3
Definitions of analysis sets................................................................................. 98
10.3.1
Full analysis set.................................................................................................. 98
10.3.2
Measurable disease analysis set (MDAS) ........................................................... 98
10.3.3
Safety analysis set.............................................................................................. 99
10.4
Outcome measures for analyses.......................................................................... 99
10.4.1
Calculation or derivation of efficacy variable(s)................................................. 99
10.4.1.1
Primary endpoint.............................................................................................. 100
10.4.1.2
Secondary endpoints ....................................................................................... 101
10.4.2
Calculation or derivation of safety variable(s) .................................................. 106
10.4.2.1
Other significant adverse events (OAE)............................................................ 106
10.4.3
Calculation or derivation of pharmacokinetic variables .................................... 107
10.4.4
Calculation or derivation of pharmacodynamic variable(s)............................... 107
10.4.5
Calculation or derivation of pharmacogenetic variables.................................... 107
10.4.6
Calculation or derivation of health economic variables..................................... 107
10.4.6.1
Resource Utilisation......................................................................................... 107
10.4.6.2
EQ-5D-5L........................................................................................................ 107
10.5
Methods for statistical analyses........................................................................ 108
10.5.1
Multiplicity strategy for primary and key secondary endpoints......................... 111
10.5.2
Analysis of the primary variable(s)................................................................... 112
10.5.2.1
Objective Response Rate (ORR) ...................................................................... 112
10.5.2.2
Subgroup analysis for the primary endpoint (ORR).......................................... 112
10.5.2.3
Sensitivity analyses for the primary endpoint (ORR)........................................ 113
10.5.3
Analysis of the secondary variable(s) ............................................................... 114
10.5.3.1
PFS analysis..................................................................................................... 114
10.5.3.2
Analysis of PFS2 endpoint............................................................................... 119
10.5.3.3
Analysis of OS endpoint .................................................................................. 119
10.5.3.4
Time to earliest progression by RECIST 1.1 or CA-125 or death...................... 119
10.5.3.5
Time to first subsequent chemotherapy or death (TFST) .................................. 120
10.5.3.6
Time to study treatment discontinuation (TDT)................................................ 120
10.5.3.7
Time to second subsequent chemotherapy or death (TSST).............................. 120
10.5.3.8
Duration of Response (DoR) and CA-125 response.......................................... 120
10.5.3.9
Time to response (TTR)................................................................................... 121
10.5.3.10 FACT-O .......................................................................................................... 121


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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10.5.4
Analysis of Exploratory Endpoints................................................................... 122
10.5.4.1
Cancer Therapy Satisfaction Questionnaire (CTSQ-16).................................... 122
10.5.4.2
Analysis of Healthcare Resource Use............................................................... 122
10.5.4.3
Health State Utility – EQ-5D-5L...................................................................... 122
10.5.4.4
Patient Global Impression of Change – PGIC................................................... 122
10.5.4.5
Impact of switching to PARP inhibitors (or other potentially active 
investigational agents) on Overall Survival Analyses ....................................... 122
10.5.4.6
Exploratory translational science endpoints...................................................... 123
10.5.5
Interim analysis................................................................................................ 123
11
STUDY AND DATA MANAGEMENT.......................................................... 124
11.1
Training of study site personnel ....................................................................... 124
11.2
Monitoring of the study.................................................................................... 124
11.2.1
Source data ...................................................................................................... 125
11.2.2
Study agreements............................................................................................. 125
11.2.3
Archiving of study documents.......................................................................... 125
11.3
Study timetable and end of study...................................................................... 125
11.4
Data management............................................................................................. 127
12
ETHICAL AND REGULATORY REQUIREMENTS..................................... 128
12.1
Ethical conduct of the study ............................................................................. 128
12.2
Patient data protection...................................................................................... 128
12.3
Ethics and regulatory review ............................................................................ 128
12.4
Informed consent ............................................................................................. 129
12.5
Changes to the protocol and informed consent form......................................... 130
12.6
Audits and inspections ..................................................................................... 130
13
LIST OF REFERENCES ................................................................................. 131
1
ACCEPTABLE BIRTH CONTROL METHODS ............................................ 144
1
PERFORMANCE STATUS (ECOG/KARNOFSKY SCALE)......................... 154
1.1
Example of Performance Status (ECOG/KARNOFSKY SCALE).................... 154
1
BACKGROUND AND RATIONALE............................................................. 164
2
GENETIC RESEARCH OBJECTIVES ........................................................... 164
3
GENETIC RESEARCH PLAN AND PROCEDURES..................................... 165
3.1
Selection of genetic research population........................................................... 165
3.1.1
Study selection record...................................................................................... 165
3.1.2
Inclusion criteria .............................................................................................. 165
3.1.3
Exclusion criteria ............................................................................................. 165
3.1.4
Discontinuation of subjects from this genetic research...................................... 165


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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3.2
Collection of samples for genetic research........................................................ 165
3.3
Coding and storage of DNA samples................................................................ 165
4
ETHICAL AND REGULATORY REQUIREMENTS..................................... 166
4.1
Informed consent ............................................................................................. 166
4.2
Subject data protection..................................................................................... 166
5
DATA MANAGEMENT................................................................................. 167
6
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE ................................................................................................................ 167
7
LIST OF REFERENCES ................................................................................. 167
LIST OF TABLES
Table 1
Study Schedule – Screening ..................................................................53
Table 2
Study Schedule – On Study Treatment and Discontinuation ..................55
Table 3
Study Schedule – Follow-up Post Discontinuation of Study 
Treatment..............................................................................................59
Table 4
Laboratory Safety Variables..................................................................68
Table 5
Pharmacokinetic samples ......................................................................73
Table 6
Estimated maximum volume of blood to be drawn from each 
patient based on 6 months of treatment..................................................80
Table 7
Dose reductions for study treatment ......................................................92
Table 8
Identity of investigational product.........................................................92
Table 9
Summary of Outcome Variables and Analysis Populations....................99
Table 10
Health Related QoL Visit Response .................................................... 106
Table 11
Health Related Quality of Life: Change rates - overall score ............... 106
Table 12
Formal Statistical Analyses to be Conducted and Pre-Planned 
Sensitivity Analyses............................................................................ 109
LIST OF FIGURES
Figure 1
Study Diagram......................................................................................38
Figure 2
Study Flow Chart ..................................................................................51


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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Figure 3
Multiple Testing Procedure................................................................. 111
LIST OF APPENDICES
Appendix A
Additional Safety Information.............................................................
Appendix B
International Airline Transportation Association (IATA) 6.2   
Guidance Document............................................................................
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ......................................................................
Appendix D
Acceptable Birth Control Methods ......................................................
Appendix E
Guidance for Evaluation of Objective Tumour Response Using 
Modified RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumours) ...................................................................................
Appendix F
Performance Status (ECOG/Karnofsky Scale).....................................
Appendix G
Patient Reported Outcomes – FACT-O, EQ-5D-5L and CTSQ-16 ......
Appendix H
Guidance on Grading of Serous Ovarian Carcinomas ..........................
Appendix I
Pharmacogenetic Research..................................................................


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse event 
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AML
Acute Myeloid Leukaemia
ANC
Absolute neutrophil count
APTT
Activated partial thromboblastin time
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve 
Baseline
Refers to the most recent assessment of any variable prior to dosing with 
study treatment
BICR
Blinded Independent Central Review
Bd
Bis in die (twice daily)
BoR
Best Overall RECIST Response
BP
Blood pressure
BRCA
Breast Cancer susceptibility gene
Integrated 
BRACAnalysis
Gene sequencing and large rearrangement analysis
BRCA mutation or 
BRCAm
Breast Cancer susceptibility gene mutation (see gBRCA mutation or 
gBRCAm)
CA-125
Cancer Antigen – 125
CDM
Clinical Development Manager
CI
Confidence Interval 
Cmax
The maximum or “peak” concentration of a drug observed after its 
administration
Cmin
The minimum or “trough” concentration of a drug observed after its 
administration 
CR
Complete response
CRF / eCRF
Case Report Form / electronic Case Report Form
CRO
Clinical Research Organisation
CSR
Clinical Study Report


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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Abbreviation or 
special term
Explanation
CT
Computed tomography
CTC / CTCAE
Common Terminology Criteria for Adverse Event
CTSQ-16
Cancer Therapy Satisfaction Questionnaire
CYP450
Cytochrome P450 (enzyme)
DCO
Data Cut-Off
DCR
Disease control rate
DNA
Deoxyribonucleic acid 
DoR
Duration of response
dUCBT
double Umbilical Cord Blood Transplantation
ECG
Electrocardiogram 
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
E-code
Enrolment code (allocated by IVRS/IWRS)
ECOG
Eastern Cooperative Oncology Group: A performance status using scales 
and criteria to assess how a patient’s disease is progressing
EQ-5D-5L
EuroQoL five dimensions, five level (EQ-5D-5L) health state utility index
EWB
Emotional well being
FACT-O
Functional Assessment of Cancer Therapy – Ovarian: A multidimensional 
questionnaire for patients with ovarian cancer
FAS
Full Analysis Set
FFPE
Formalin Fixed Paraffin Embedded
FWB
Functional well being 
gBRCA
Germline BRCA
gBRCA mutation or 
gBRCAm
The term "gBRCA mutation" is used to refer to a germline BRCA1 or 
BRCA2 mutation 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
gBRCA wt
gBRCA wildtype
GCIG
Gynecologic Cancer Intergroup 
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor 
GGT
Gamma glutamyl transferase


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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Abbreviation or 
special term
Explanation
GMP
Good Manufacturing Practice
Hb
Haemoglobin 
HCT
Haematocrit 
HR
Hazard Ratio
HRD
Homologous recombination repair deficiencies
HRQoL
Health-related Quality of Life
IATA
International Air Transport Association 
IB
Investigator’s brochure
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
International 
Co-ordinating 
Investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the Investigators and/or 
activities internationally. 
INR
International Normalised Ratio
IP
Investigational Product 
IRB
Institutional Review Board
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
KM
Kaplan-Meier
LIMS
Laboratory Information Management System
LPLV
Last Patient Last Visit
MCH
Mean cell haemoglobin
MCHC
Mean cell haemoglobin concentration
MCV
MDAS
Mean cell volume
Measurable disease analysis set
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MRI
Magnetic resonance imaging
MTP
Multiple Testing Procedure
NCI
National Cancer Institute


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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Abbreviation or 
special term
Explanation
NE
Not evaluable
OR
ORR
Odds ratio
Objective response rates
OS
Overall survival
PARP
Polyadenosine 5’diphosphoribose [poly (ADP ribose)] polymerisation
PD
Progressive disease
PFS / PFS1
Progression Free Survival
PFS2
Time from randomisation to second progression
PGIC
Patient Global Impression of Change
PI
Principal Investigator
PLD
Pegylated Liposomal Doxorubicin
PK
Pharmacokinetics
p.o.
Per os (by mouth, orally)
PSR
Platinum Sensitive Relapsed
PR
Partial response
PRO
Patient Reported Outcomes
PWB
Physical well being
QoL
Quality of Life
R&D
Research and Development
RBC
Red blood cell
RECIST
Response Evaluation Criteria In Solid Tumours.  This study will use 
RECIST version 1.1
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SD
Stable disease
SSB
Single strand break
SWB
Social well being 
Study treatment
Olaparib 
TDT
Time from randomisation to study treatment discontinuation or death
TFST
Time from randomisation to first subsequent therapy or death
tmax
Time at which maximum or “peak” concentration (Cmax) of a drug is 
observed after its administration


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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Abbreviation or 
special term
Explanation
TOI
Trial Outcome Index
TSST
Time from randomisation to second subsequent therapy or death
ULN
Upper limit of normal
WBC
White blood cells
WBDC
Web Based Data Capture


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
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1
INTRODUCTION
1.1
Ovarian cancer and its treatment
Ovarian cancer is the fifth most common cause of death from cancer in women (Colombo et al 
2010; NCCN Clinical Practice Guidelines in Oncology).  In the United States there were 
22,240 new cases and 14,030 deaths estimated in 2013 (Siegel et al 2013). In the European 
Community, approximately 28,000 new cases of ovarian cancer and approximately 17,000 
deaths are reported annually, ranking ovarian cancer as the leading cause of death from 
gynaecological cancer. Ovarian cancer is diagnosed predominantly in postmenopausal women 
with the majority of cases being diagnosed in women over 50 years of age.  More than 70% of 
the patients are diagnosed with advanced disease and less than 40% of women with ovarian 
cancer are cured (Fleming et al 2009, Jemal et al 2010). 
The standard therapy for advanced ovarian cancer consists of radical debulking surgery 
followed by post-operative platinum-based first-line chemotherapy.  Although 70% to 80% of 
patients respond to such initial treatment, the majority subsequently relapse (Ledermann and 
Kristleit 2010). Once relapsed, disease is no longer considered curable. The progression free 
interval after the last platinum based chemotherapy has prognostic value. Based on it the 
GCIG Consensus defined 4 categories of patients: ‘platinum sensitive’ progressing more than 
12 months after the last chemotherapy; ‘partially-platinum sensitive’ progressing between 6 
and 12 months after the last chemotherapy; ‘platinum resistant’ progressing within 6 months 
of the last chemotherapy and ’platinum refractory’ progressing during or within 4 weeks of 
the last dose of chemotherapy (Friedlander et al 2011).  Most patients with platinum-sensitive 
disease will respond further to platinum based chemotherapy and many will receive multiple 
lines of treatment over time but ultimately accumulate toxicities that limit the administration 
of further platinum or develop platinum resistance. The role of platinum based chemotherapy 
in ‘partially platinum sensitive’ patients remains controversial and platinum break with single 
agent chemotherapy presents another treatment option (Colombo et al 2013). Patients with 
platinum resistant or refractory disease have generally poor prognosis and treatment options 
consist of non-platinum monotherapy including weekly paclitaxel, topotecan, pegylated 
liposomal doxorubicin, gemcitabine (Ledermann et al 2014). Following each subsequent 
relapse, patients experience progressively shorter progression-free intervals and ultimately 
succumb to their disease (Colombo et al 2010).
Recently, the European Medicine Agency has approved the use of the angiogenesis inhibitor 
bevacizumab in combination with platinum based chemotherapy in first line and relapsed 
setting in platinum sensitive patients and in combination with non-platinum-based 
chemotherapy in platinum resistant patients, presenting another treatment option. No targeted 
treatment is currently licensed for ovarian cancer patients with germline BRCA mutation 
(gBRCAm). 


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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BRCA mutated ovarian cancer
The BRCA1 and BRCA2 genes were identified in the early 1990’s as genetic elements 
underlying inherited breast and ovarian cancer. BRCA mutations are particularly prevalent in 
people of Jewish descent (Roa et al 1996) and often associated with high-grade serous ovarian 
cancer, where the germline BRCA1 and BRCA2 (gBRCA) frequency in unselected patients is 
as high as 17% (Alsop et al 2012a; Alsop et al 2012b) and up to 38% in patients with 
platinum-sensitive recurrent high-grade serous ovarian cancer (Dann et al 2012).  Women 
inheriting a mutated copy of BRCA1 or BRCA2 have a 39% and 11% risk, respectively, of 
developing ovarian cancer by the age of 70 (Antoniou et al 2003).  Germline BRCA1 mutation 
confers a higher risk of developing ovarian cancer than germline BRCA2 mutation (Antoniou 
et al 2003) and ovarian tumours in BRCA1 mutation carriers generally arise several years, and 
in some cases up to a decade, earlier compared with those in BRCA2 (Alsop et al 2012a). 
Thus, BRCA1 mutations are more commonly identified in ovarian cancer patients than BRCA2 
mutations, with mutation frequencies of 62% vs. 38%, respectively (Alsop et al 2012a; Alsop 
et al 2012b).  Deficiency in BRCA ultimately leads to the accumulation of genetic alterations 
as a result of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, 
resulting in tumorigenesis.  
Consistent with this biology, patients with BRCA mutations often have platinum-sensitive 
epithelial ovarian cancer (Dann et al 2012; Hennessy et al 2010), associated with improved 
PFS outcomes (Tan et al 2008, Hennessy et al 2010). The largest series to date of 1,213 
patients with BRCA mutations (Bolton et al 2012) demonstrates that BRCA1- and BRCA2-
associated ovarian cancers have a better prognosis compared with sporadic ovarian cancers 
(Hyman and Spriggs 2012). However, the overall pattern of disease remains similar, with 
disease recurrence after each line of chemotherapy and patients ultimately dying from their 
disease.
Patients with BRCA-mutated ovarian cancer currently have identical treatment options as 
sporadic ovarian cancer patients.  They seem to have a better prognosis compared with the 
overall relapsed ovarian cancer patient population but the pattern of disease is similar, with 
patients eventually dying from their disease.  Ovarian cancer patients with BRCA mutation 
represent a small, well defined and medically recognised subpopulation for whom despite the 
potential for personalised healthcare, no targeted treatment currently exists.
1.1.1
PARP inhibition as a target for BRCA mutated ovarian cancer
Investigators should be familiar with the current olaparib (AZD2281) Investigator Brochure 
(IB).
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP 
ribose)] polymerisation (PARP) inhibitor (PARP-1, -2 and -3) that is being developed as an 
oral therapy, both as a monotherapy (including maintenance) and for combination with 
chemotherapy and other anti-cancer agents. PARP inhibition is a novel approach to targeting 
tumours with deficiencies in DNA repair mechanisms.  


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Numerous DNA single stranded breaks (SSBs) occur naturally as the result of normal 
metabolic activities and environmental factors, including UV light and radiation. PARP plays 
an important role in identifying and repairing SSBs. Olaparib, through direct PARP enzyme 
inhibition and trapping of PARP with the DNA in an open configuration, prevents repair of 
SSBs. As cells undergo replication, SSBs are converted to harmful double-strand breaks 
(DSBs). In normal cells, DSBs are repaired by a DNA repair mechanism called homologous 
recombination repair. Cells with homologous recombination repair deficiency (HRD), resort 
to the more error prone repair mechanism called non-homologous end joining (NHEJ). In cells 
with HRD, DNA damage accumulates and leads to high genomic instability and eventual cell 
death. Cancer with HRD would thus be more sensitive to induction of cell death by PARP 
inhibitors. 
To date, there is no well-established and available-for-testing single genetic/genomic signature 
which defines HRD. The most common function-altering mutations associated with HRD are 
a mutation in the breast cancer susceptibility gene (BRCA) BRCA1 or BRCA2 genes, which 
code for two of the critical proteins in homologous recombination repair. BRCA1 and BRCA2 
mutations that are defined as deleterious and suspected deleterious mutations are associated 
with loss of function of the protein. 
Consistent with the DNA repair biology, individuals with hereditary gBRCA mutations have 
an increased risk of breast, ovarian, pancreatic and other cancers. The cancer cells in such 
individuals have lost the second normal copy of the BRCA gene (loss of the wildtype allele), 
whereas their normal cells still have one normal allele as well as one mutated allele. Normal 
cells in patients who carry a gBRCA mutation can therefore repair DSBs with the functioning 
wildtype BRCA allele. In cancer cells, the loss of heterozygosity leaves the non-functional 
gBRCA allele as the sole copy. PARP inhibition takes advantage of this difference and 
preferentially kills the cancer cells with minimal toxicity to normal cells (Rottenberg et al 
2008; Hay et al 2009).
Deficiencies in other known homologous recombination repair pathway proteins (eg ATM, 
RAD51B, RRAD51C, RAD54L, RAD51D, FANCL J/BRIP1, FANCI, FANCL, FANCN 
(PALB2), BARD1, CHEK1, CHEK2, CDK12 and PPP2R2A1) may confer sensitivity to 
PARP inhibitors (McCabe et al 2006). However, these occur less commonly than BRCA 
mutations in ovarian cancer (Pennington et al 2014) and currently there is no simple assay to 
define an ‘HRD phenotype’.
HRD increases sensitivity to platinum-based chemotherapy, as the deficiency impairs the 
ability of cancer cells to repair the direct platinum-induced double strand DNA breaks. Thus, 
platinum sensitivity is often associated with an HRD tumour type.
1.1.2
Pre-clinical experience
The pre-clinical experience is fully described in the current version of the olaparib IB.  


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1.1.3
Toxicology and safety pharmacology summary
Olaparib has been tested in a standard range of safety pharmacology studies e.g. dog 
cardiovascular and respiratory function tests, and the rat Irwin test.  There were no noticeable 
effects on the cardiovascular or respiratory parameters in the anaesthetized dog or any 
behavioural, autonomic or motor effects in the rat at the doses studied.
Rodent and dog toxicology studies have indicated that the primary target organ of toxicity is 
the bone marrow with recovery seen following withdrawal of olaparib. Ex-vivo studies have 
confirmed that olaparib is cytotoxic to human bone marrow cells. 
Olaparib was not mutagenic in the Ames test but was clastogenic in the Chinese hamster 
ovary (CHO) chromosome aberration test in vitro.  When dosed orally, olaparib also induced 
micronuclei in the bone marrow of rats. This profile is consistent with the potential for 
genotoxicity in man. 
Reproductive toxicology data indicate that olaparib can have adverse effects on embryofoetal 
survival and development at dose levels that do not induce significant maternal toxicity.
Further information can be found in the current version of the olaparib IB.
1.1.4
Clinical experience
Clinical experience with olaparib is fully described in the current version of the olaparib IB.  
The olaparib capsule formulation was registered for use in the EU and US in December 2014.  
The recommended olaparib monotherapy capsule dose is 400 mg bd.  The Phase III 
registration studies and most new clinical studies are investigating the tablet formulation 
which delivers the therapeutic dose of olaparib in fewer dose units than the capsule. The 
recommended olaparib monotherapy tablet dose under investigation is 300 mg bd.  As of 
15 December 2016, approximately 6558 patients are estimated to have received olaparib in the 
clinial programme including AstraZeneca-sponsored studies (3923 patients), a MAP (676 
patients), ISSs and collaborative group studies (1959 patients). An estimated 4475 patients 
with ovarian, breast, pancreatic, gastric and a variety of other solid tumours are estimated to 
have received treatment with olaparib in AstraZeneca-sponsored, interventional studies (3799 
patients) and the MAP (676 patients). Since 2012/2013, most new clinical studies have 
utilised the tablet formulation which was designed to deliver the therapeutic dose of olaparib 
in fewer dose units than the capsule. Of the 4475 patients, 2109 received the capsule 
formulation, 2341 received the tablet formulation, and 25 received both capsule and tablet. In 
the AstraZeneca-sponsored, interventional studies, olaparib was given either as monotherapy 
(2618 patients) or in combination with chemotherapy or other anti-cancer agents, including 
studies where patients received monotherapy and combination therapy sequentially (n=1181).  
Data from the available pre-clinical studies and subsequent clinical development programme
demonstrate that olaparib appears to be active and generally well tolerated in patients with
solid tumours including those with BRCA mutated cancers. In ovarian cancer, responses have
been seen in all patient groups, including platinum resistant and refractory cancer.  From the 


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available data to date in patients with advanced cancer, there is no evidence of any unexpected
toxicity following long-term olaparib (capsule) monotherapy exposure.
Adverse laboratory findings and/or clinical diagnoses considered to be associated with
administration of olaparib monotherapy include haematological effects (anaemia, neutropenia,
lymphopenia, thrombocytopenia, MCV elevation and increase in blood creatinine), nausea and
vomiting, decreased appetite, diarrhoea, dyspepsia, stomatitis, upper abdominal pain,
dysgeusia, fatigue (including asthenia), headache and dizziness. Most of these events were
generally mild or moderate in intensity.  In a relatively small number of patients, pneumonitis, 
MDS/AML and new primary
malignancies have been observed. Evidence from across the development programme for
olaparib does not support a conclusion that there is a causal relationship between olaparib and
these events. These are important potential risks for olaparib and are being kept under close
surveillance.
1.2
Research hypothesis
Olaparib, administered as monotherapy improves objective response rates (ORR) compared to 
physician’s choice of single agent standard of care chemotherapy (weekly paclitaxel, 
topotecan, pegylated liposomal doxorubicin (PLD), or gemcitabine) in patients with relapsed 
platinum sensitive ovarian cancer who have received at least 2 prior platinum based lines of 
chemotherapy and carry gBRCA mutation.
1.3
Rationale for study design, doses and control groups
The proposed phase III trial is designed to confirm the benefit of olaparib by assessing the 
efficacy and safety of olaparib monotherapy vs. physician’s choice of single agent standard of 
care non-platinum based chemotherapy in patients with gBRCA mutated relapsed platinum 
sensitive ovarian cancer who had received at least 2 prior lines of platinum based 
chemotherapy.  Treatment of platinum sensitive relapse usually involves re-treatment with 
platinum regimen. However, non-platinum based chemotherapy can be given in this setting to 
prolong the platinum free interval and can be followed by further platinum treatment at a later 
relapse or can be considered for patients who are not warranted for further platinum treatment.  
Weekly paclitaxel, topotecan, PLD and gemcitabine are the most commonly used non 
platinum agents in relapsed ovarian cancer with no agent proven to be superior to the others.  
Therefore, physician’s choice of chemotherapy is provided for the control arm of the study. 
Due to different routes and schedules of administration of the chemotherapies on the control 
arm as well as their different tolerability profiles, the study is not feasible to be blinded. Given 
the open label design of the study, rigorous methodology will be employed to ensure 
robustness of the primary endpoint assessment with a primary analysis of ORR based on 
blinded independent central review (BICR) of all patients’ scans. 
A number of secondary endpoints will provide further support for the clinical benefit of 
olaparib in this patient population including progression free survivial (PFS) by BICR, time 


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from randomisation to second progression (PFS2), overall survival (OS), CA-125 response, 
safety assessments and health related quality of life. 
1.3.1
Rationale for study treatment dose
The safety and efficacy of olaparib has been demonstrated in the clinical programs using 
predominantly the capsule formulation (400 mg [8 capsules] twice daily). However, an 
improved tablet formulation (2 tablets twice daily) has been developed and will be used in this 
study. The recommended tablet formulation of olaparib as monotherapy is 300 mg twice daily 
which is considered similar in terms of efficacy and safety to the capsule 400 mg twice daily 
dose. However, the capsule and the tablet formulations are not bioequivalent, as observed in 
Study 24 where 300 mg twice daily tablet dose matched or exceeded the exposure of the 400 
mg capsule in terms of AUC, Cmaxss, and Cminss. The tolerability profile of the 300 mg bd tablet 
dose in Study 24 was considered similar to the 400 mg bd capsule formulation. The most 
common AEs were consistent with the known safety profile of olaparib, namely low grade 
nausea, vomiting, fatigue, and anaemia. Tablet formulation is used across the olaparib 
Phase III programme. 
Olaparib, when given via the tablet formulation has a tmax typically between 0.5 and 2 hours 
and mean terminal half-life of approximately 12 to 15 hours. Based on the average single dose 
t½, it would be expected that steady state exposure would be achieved within approximately 3 
days of commencing dosing with olaparib. It is metabolized primarily by the CYP3A4 
enzyme and is excreted through the urine (35% to 50%) and feces (12% to 60%).
Further information is provided in the olaparib Investigator’s Brochure.
1.4
Benefit/risk and ethical assessment
1.4.1
Unmet need
Ovarian cancer is a serious, life-threatening disease for which new medicines are needed.  The 
current mainstay of therapy consists of multiple lines of chemotherapy, where a platinum 
agent is routinely employed.  However, despite good initial responses in many platinum 
sensitive patients, the toxicity burden of platinum agents, including carboplatin is significant, 
with cumulative toxicity limiting the duration of treatment possible at each line of therapy.  
There is a large unmet need for a therapy that is well tolerated and can provide an alternative 
to chemotherapy for a well-defined patient population who have already received at least 2 
prior platinum based chemotherapy lines and will be next treated with non-platinum single 
agent chemotherapy. 
PARP inhibitors are the first targeted agents to be used in selected ovarian cancer patients.  
The biology of PARP predicts for benefit in BRCAm patients, regardless of whether their 
mutation is detected by blood (germline) or tumour testing (Ledermann et al 2014).  The 
selection of patients in this trial will be based on a blood test (the Myriad Integrated 
BRACAnalysistest) for the detection of germline BRCA mutations.  Therefore the risk 


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benefit focuses on findings in the gBRCAm subgroup in accordance with the selected study 
population.
1.4.2
Clinical benefit of olaparib monotherapy in patients with PSR gBRCA mutated 
ovarian cancer
The pooled analysis from 6 olaparib (Phase I and II) monotherapy clinical studies consisting 
of 300 patients with gBRCA mutated relapsed ovarian cancer (including fallopian tube and 
primary peritoneal), of whom 273 had measurable disease and were evaluable for response, 
demonstrated response rate with olaparib in the overall group of 36% (97/273) and 7.4 months 
duration of response.  The majority of the patients (n=223) had received 3 or more prior lines 
of therapy and of these, 205 patients had measurable disease.  In these patients the response 
rate was 31% (64/205) and duration of response was 7.8 months. Nineteen percent (n=51) of 
the 273 patients with measurable disease were classified as platinum sensitive.  The response 
rate in the platinum sensitive patients was 53% (27/51) and the duration of response was 8.2 
months. 
The majority of the patients in the pooled analysis (n=193) were enrolled in study 42, a Phase 
II, open-label, non-randomised, non-comparative, multicentre study to assess the efficacy and 
safety of olaparib (400 mg capsules) given orally bd in patients with advanced cancers, which 
were refractory to standard therapy or for whom no suitable, effective/curative therapy 
existed, and who had a confirmed genetic BRCA1 and/or BRCA2 mutation.  In Study 42, there 
were 193 patients with relapsed ovarian cancer (including fallopian tube and primary 
peritoneal), of whom 167 had measurable disease.  In this overall group the response rate was 
36% (60/167) and duration of response was 7.4 months (Kaufman et al 2013).  Patients were 
also analysed by their platinum sensitivity status, if their last treatment was platinum based, 
and in the group of patients who were classed as platinum sensitive but ineligible to receive 
further platinum, the response rate with olaparib was higher than in the group of patients with 
platinum resistant disease (60% [15/25] vs. 15% [6/40]) respectively (AZ data on file).
Furthermore, 97 patients in the pooled analysis were included from Study 12, a randomised, 
open-label phase II dose-finding study of olaparib monotherapy (200 mg bd and 400 mg bd 
capsule) vs. pegylated liposomal doxorubicin (PLD) in gBRCAm ovarian cancer patients who 
had failed previous platinum therapy and were not considered candidates for further platinum 
treatment.  The primary analysis of PFS (Investigator assessment) comparing both doses of 
olaparib to PLD did not demonstrate a statistically significant difference (n=81, HR=0.88 95% 
CI (0.51, 1.56)), median PFS 6.5 months, 8.8 months and 7.1 months for the olaparib 200 mg, 
olaparib 400 mg and PLD groups (Kaye S et al 2012).  Objective response rates were 25%, 
31% and 18% for the olaparib 200 mg, 400 mg and PLD groups respectively.  However, a 
pre-specified subgroup analysis in the platinum sensitive patients in the trial (n=48), showed 
HR for PFS numerically higher for olaparib 400mg group vs. PLD (n=34, HR 0.61 95% CI 
(0.24,1.50) ) with median PFS 9.2 months in the olaparib 400 mg group and 7.4 months in the 
PLD group and response rates 47% and 26% respectively. 


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Finally, a recently reported investigator-sponsored, randomised, open label, phase II clinical 
trial, not included in the pooled analysis, compared olaparib single agent (400mg bd capsule) 
vs. olaparib (200 mg bd capsule) in combination with cediranib (30 mg daily) in platinum 
sensitive relapsed ovarian cancer patients who had failed at least one prior chemotherapy (Liu 
J et al 2014).  Fifty two percent of the patients in the trial had known gBRCA mutation (47/90) 
and in this pre-defined subgroup, olaparib single agent showed median PFS of 16.5 months 
and response rate of 63%.  Phase III trials for the combination of olaparib and cediranib are 
planned to better characterise the efficacy and safety of the combination.   
1.4.3
Safety and tolerability of olaparib
The tolerability profile of olaparib is well characterised and suitable for long-term dosing until 
disease progression in patients with relapsed platinum sensitive ovarian cancer who carry 
gBRCAm.  The common AEs of olaparib include nausea, vomiting, fatigue and anemia. The 
low grade and intermittent nature of these events means that nausea and vomiting can be 
treated empirically and anti-emetic prophylaxis is not required.  Hematological changes 
including anemia should be monitored routinely using standard assessments of hematological 
laboratory parameters, as is routine for patients receiving anti-cancer therapies.  Where 
necessary, AEs can be managed by interrupting or reducing the olaparib dose, treating 
symptomatically with standard procedures (eg, antiemetics for nausea and vomiting, 
occasional blood transfusions for anemia) or in rare cases by permanently discontinuing 
olaparib treatment.
Long-term tolerability to olaparib maintenance therapy has been demonstrated, with 45%, 
25% and 17% of the patients in the gBRCA subgroup in study 19 in the olaparib arm 
remaining on treatment at 1 year, 2 years and 3 years, respectively.  Most patients remained on 
treatment until disease progression, with only a small number of patients permanently 
discontinuing study treatment due to AEs (9.4% with olaparib vs. 0% with placebo in the 
gBRCA subgroup).  MDS/AML are considered AEs of special interest as they may be related 
to agents that affect DNA repair, including chemotherapy.  These events have been seen in 
less than 1% of patients who received olaparib.  These events will be actively monitored in the 
ongoing phase III studies, including prompted follow-up.
1.4.4
Myelodysplastic syndrome/acute myeloid leukaemia(t-AML)
Development of secondary myelodysplastic syndrome (MDS)/therapy-related acute myeloid 
leukemia (t-AML) is an AE of interest, as it may be related to products that affect DNA repair 
mechanisms.  As of 20 August 2014, 21 reports of MDS/AML have been received out of 
2,866 olaparib treated patients, giving a cumulative reporting rate of 0.7%.  Across the clinical 
study program, MDS has also been reported for 2 patients who did not receive olaparib: one 
patient that received placebo in Study 19 (0.8% [1/128]) and one patient treated with 
pegylated liposomal doxorubicin as the comparator in Study 12 (3.1% [1/32]), giving a similar 
reporting rate.  Of the 21 cases reported across the development program, 14 have been 
reported in monotherapy studies and 7 in combination studies. Sixteen of the patients had a 
gBRCA mutation.  In 13 cases, the diagnosis was MDS without a report of AML.  There were 
8 cases of AML.  The median age of onset was 63 years and all but 3 patients had ovarian 


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cancer.  Eight patients had a history of previous cancer.  The mean time from diagnosis of 
current cancer to onset of MDS or AML was 62 months.  All patients had associated history 
features that may have contributed to the development of MDS/AML.  All had received 
chemotherapy with DNA damaging agents, including platinum, taxanes and anthracyclines.  
Many patients received multiple treatment regimens over multiple years and 7 patients had 
also received radiotherapy.  Four patients were treated with olaparib for less than 6 months, 5 
patients were treated for between 6 months and 1 year, 4 patients were treated for between 1 
and 2 years, and 8 patients were treated for more than 2 years. In the majority of cases, MDS 
occurred while on treatment with olaparib but in 4 cases the onset of MDS was more than 5 
months after olaparib was discontinued.
Epidemiological studies from the literature have indicated a higher risk of therapy related 
AML in ovarian cancer populations, particularly those receiving alkylating agents and pelvic 
irradiation with a wide range of incidence rates.  In two recent studies using the US SEER 
database, Vey et al identified 98 cases of t-AML among 63,359 epithelial ovarian cancer 
cases, with an overall incidence of 0.15% (Vay et al 2011), while another SEER-based study 
in registries representing 9.5% of the US population for years 1975-2008 reported 72 t-AML 
cases among 23,180 ovarian cancer patients (incidence of 0.31%) (Morton et al 2013).  The 
SEER data need to be reviewed with caution because MDS is not collected in cancer registries 
as it is considered pre-malignant and the data from the early episodes are confounded by a 
higher contemporaneous use of Melphalan, which is no longer prescribed. While non-clinical 
data suggest bone marrow progenitor cell populations are reduced temporarily following 
olaparib treatment, there is no evidence to date linking olaparib treatment to the generation of 
abnormal bone marrow precursors.  Moreover, preclinical data suggest potential benefit with 
PARP inhibitors in MDS/AML and clinical trials are now underway to assess this effect 
(Gaymes et al 2008). 
To ensure robust safety monitoring, additional safety measures are incorporated into the phase 
III protocol: normal hematological values are required before inclusion into the studies; 
regular blood tests are required while on treatment to detect hematological abnormalities early 
and in case of prolonged cytopenias patients are to be referred to a hematologist and bone 
marrow analysis should be considered.  If a diagnosis of MDS is confirmed, study treatment 
must be discontinued and the event, treatment, course and outcome must be reported as an 
SAE.  Furthermore, any cases of MDS/AML will be collected in the long term survival follow 
up and an Independent Data Monitoring Committee (IDMC) will review the emerging safety 
data from the trial. 
1.4.5
New Primary Malignancies
Similar to MDS/AML, the development of new primary malignancies is an adverse event of 
interest that may be related to products that affect DNA repair mechanisms, and of relevance 
to patients with germline BRCA mutations, who are at risk of developing other cancers.  As of 
20 August 2014, 21 of the 2,866 patients who had received olaparib had reported 23 events of 
a new primary malignancy (other than MDS/AML), giving a cumulative incidence of 0.73% 
for new primary malignancies.  Ten of the events were non-melanoma skin cancers.  The 


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remaining events were: breast cancer (n=3), intraductal proliferative breast lesion, lung cancer 
(n=2), gastric cancer, plasma cell myeloma, malignant melanoma, precursor T-lymphoblastic 
lymphoma/leukemia, colon cancer, tongue neoplasm and malignant muscle neoplasm (pre-
existing before olaparib treatment).  In addition, one patient in the placebo arm of the double 
blind Study 19 reported a new primary malignancy event of bladder cancer (1/128, [0.78%]).  
All patients had already previously received various chemotherapy agents including multiple 
cycles of DNA damaging platinum containing chemotherapies, taxanes, anthracyclines and 
other alkylating and DNA damaging agents.  Four patients were reported to have had prior 
radiotherapy. Nineteen patients had a documented breast cancer gene mutation (BRCA 1 or 2).  
Seven patients had an earlier diagnosis of a previous cancer (ovarian, cervix, breast, 
peritoneal) prior to their cancer under investigation in the olaparib study.  New primary 
malignancies are monitored actively in the phase III trial both during study treatment and 
during the long term survival follow up. 
In summary, this trial is designed to confirm the benefit and assess the safety of olaparib 
monotherapy vs. single agent standard of care non-platinum based chemotherapy in patients 
with gBRCA mutated relapsed platinum sensitive ovarian cancer who have received at least 2 
prior platinum based lines of chemotherapy.  Based on the results presented above and data 
from the full clinical program to date, olaparib is considered to have a positive benefit risk 
profile for the treatment of this small well-defined population.  Moreover, another 
confirmatory phase III study (SOLO2) designed to establish the clinical benefit of olaparib 
maintenance therapy in relapsed platinum sensitive BRCA mutated ovarian cancer patients is 
ongoing and expected to be fully enrolled with 264 patients in Q1 2015. 
1.5
Study Design
This open label, randomised, controlled, multi-centre study will assess the efficacy and safety
of single agent olaparib vs. standard of care, based on physician’s choice of single agent 
chemotherapy (i.e weekly paclitaxel, topotecan, pegylated liposomal doxorubicin, or 
gemcitabine) in relapsed ovarian cancer patients who have received at least 2 prior lines of 
platinum based chemotherapy, who have progressed at least 6 months after their last platinum 
based chemotherapy and who carry a germline deleterious or suspected deleterious BRCA
mutation. Non-platinum based chemotherapy in this setting can be given to prolong the 
platinum free interval and can be followed by further platinum treatment at a later relapse or 
can be considered for patients who are not warranted for further platinum treatment. Due to 
different routes and schedules of administration of the study treatments and different toxicity 
profiles, the study is not feasible to be blinded. Given the open label design of the study, 
rigorous methodology will be employed to ensure robustness of the primary endpoint 
assessment with a primary analysis of ORR based on blinded independent central review 
(BICR) of all patient scans. Secondary endpoints will include progression free survival (PFS) 
by BICR; time from randomisation to second progression (PFS2); overall survival (OS); CA-
125 response; safety assessments and health related quality of life. Full details provided 
below. 


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A minimum of 250 patients will be randomised 2:1 (olaparib: chemotherapy) into the trial. 
The treatment groups include olaparib 300 mg po twice daily tablet continuously, or 
physician’s choice of chemotherapy. The investigator must declare prior to randomisation 
their choice of chemotherapy i.e. weekly paclitaxel, topotecan, pegylated liposomal 
doxorubicin, or gemcitabine. The investigator should administer all the chemotherapies as per 
standard practice guidelines.
The randomisation scheme will be stratified based on:

Selected chemotherapy (weekly paclitaxel vs. topotecan vs. pegylated 
liposomal doxorubicin vs. gemcitabine)

Received prior chemotherapy regimens for ovarian cancer (2 or 3 prior 
lines of chemotherapy vs. 4 or more)

Time to disease progression after the end of the last platinum based 
chemotherapy (6-12 months vs. > 12 months)
Figure 1
Study Diagram


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2
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To determine the efficacy of olaparib vs. 
physician’s choice single agent 
chemotherapy by assessment of Objective 
Response Rate (ORR) using blinded 
independent central review (BICR)

Objective Response Rate (ORR) by BICR using 
RECIST 1.1
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To compare the efficacy of single agent 
olaparib versus physician’s choice single 
agent chemotherapy

Progression Free Survival (PFS) by BICR
using RECIST 1.1

Time from randomisation to second progression 
(PFS2) by investigator assessment of radiological, 
clinical or CA-125 progression

Overall survival (OS)

Time to earliest progression by RECIST 1.1 or 
CA-125 or death

Time from randomisation to first subsequent 
therapy or death (TFST)

Time from randomisation to second subsequent 
therapy or death (TSST)

Time from randomisation to study treatment 
discontinuation or death (TDT)

Duration of response (DoR) by BICR using 
RECIST 1.1 criteria for evaluable patients

Time to response (TTR) by BICR using RECIST 
1.1 criteria for evaluable patients
To compare the efficacy of single agent 
olaparib versus physician’s choice single 
agent chemotherapy on the Health-related 
Quality of Life (HRQoL) as measured by the 
trial outcome index (TOI) of the Functional 
Assessment of Cancer Therapy – Ovarian 
(FACT-O)

Mean change from baseline in TOI score

Proportion improved (in the absence of 
subsequent cancer therapy) in TOI score
To assess efficacy of olaparib in patients 
identified as having a deleterious or 

ORR (by BICR), PFS (by BICR), PFS2, OS, 
TDT, TFST and TSST, analyses will be 


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Secondary Objective:
Outcome Measure:
suspected deleterious variant in either of the 
BRCA genes using variants identified with 
current and future BRCA mutation assays 
(e.g. gene sequencing and large 
rearrangement analysis)
performed in those patients whose gBRCAm 
status is confirmed by the central Myriad test 
(only required if populations differ from the 
MDAS (for ORR) or FAS (for PFS) populations)

Development and delivery of a BRCA mutation 
companion diagnostic
To determine exposure to olaparib following 
dosing at the 300 mg bd tablet dose and 
explore exposure-response relationships
2.3
Safety objectives
Safety Objective:
Outcome Measure:
To assess the safety and tolerability of single 
agent olaparib vs. physician’s choice single 
agent chemotherapy 
Adverse Events (AE), physical examination, vital 
signs including blood pressure (BP), pulse, 
electrocardiogram (ECG) and laboratory findings 
including clinical chemistry and haematology
2.4
Exploratory objectives 
Exploratory Objective:
Outcome Measure:
To assess the effect on patient self-reported 
feelings about side-effects of single agent 
olaparib versus physician’s choice of single 
agent chemotherapy using the ‘Feelings 
about side-effects’ domain of the Cancer 
Therapy Satisfaction Questionnaire (CTSQ-
16)

Treatment satisfaction score (as measured by the 
Satisfaction with Therapy scale of the CTSQ-16)

Patient-reported feelings  measured by the 
‘feelings about side-effects’ domain of the Cancer 
Therapy Satisfaction Questionnaire (CTSQ-16)
To investigate the health economic impact of 
treatment and the disease on hospital related 
resource use and health state utility

Number, type and reason of hospitalisations and 
hospital attendances, procedures undertaken and 
hospital length of stay

Health state utility derived from the HRQL 
instrument, the EuroQoL EQ5D-5L
To explore methods of estimating overall 
survival (OS) adjusting for the impact of the 
control arm receiving subsequent 
Polyadenosine 5’diphosphoribose [poly 
(ADP ribose)] polymerise (PARP) inhibitors 
or imbalances between the treatment arms for 
other potentially active agents

Overall survival adjusted for impact of subsequent 
PARP inhibitors (or other potentially active 
investigational agents (if appropriate, to support 
reimbursement appraisals)
To determine the frequency of and describe 
the nature of BRCA mutation/s in tumour 
samples and to compare this with germline 

BRCA1 and/or BRCA2 mutation status in tumour


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Edition Number 4.0
Date 20 December 2017
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Exploratory Objective:
Outcome Measure:
BRCA mutation status
To explore whether resistance mechanisms to
olaparib can be identified through analysis of 
tumour and blood samples – archival tumour 
(mandatory), blood samples at baseline and 
on disease progression (mandated) and serial 
biopsies at baseline and disease progression 
(optional)
Future exploratory research into factors that 
may influence development of cancer and/or 
response to treatment (where response is 
defined broadly to include efficacy, 
tolerability or safety) may be performed on 
the collected and stored archival tumour 
samples (mandatory), blood samples at 
baseline and on disease progression 
(mandated) and serial biopsies at baseline 
and disease progression (optional)
To collect and store DNA according to each 
country’s local and ethical procedures for 
future exploratory research into genes/genetic 
variation that may influence response (i.e. 
distribution, safety, tolerability and efficacy) 
to study treatments and/or susceptibility to 
disease (optional)

Potential retrospective tissue biomarker research
The exploratory analyses may not be reported in the clinical study report (CSR).  If not, they 
will be reported separately.
3
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
The patient population should be selected without bias.
Investigator(s) should keep a record of the patient screening log and of patients who entered 
pre-study screening.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
Patients who already know they have a mutation in the BRCA1 or BRCA2 gene that is 
predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead 
to loss of function) must fulfil all of the criteria below.  Patients that do not know their 


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Edition Number 4.0
Date 20 December 2017
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mutation status, and who are being considered for this trial must fulfil all of the criteria 
marked with an asterisk (*) below prior to BRCA mutation testing being carried out.  To 
perform the BRCA testing investigator judgement of patient’s potential eligibility to the study 
should be assessed as per Table 1 and by reviewing the inclusion/exclusion criteria.   All 
inclusion criteria will then be assessed following confirmation that patient carry an 
appropriate BRCA mutation.  
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 high grade serous ovarian 
cancer (including primary peritoneal and/or fallopian tube cancer) or high grade 
endometrioid cancer (please refer to Appendix H). Patients are eligible to undergo 
BRCA testing even if they have not yet had recurrence or progression of disease 
>6 months (>/=183 days) after completion of their last platinum therapy.
4.
Documented germline mutation in BRCA1 and/or BRCA2 that is predicted to be 
deleterious or suspected deleterious (known or predicted to be detrimental/lead to 
loss of function)
5.
At least one lesion (measurable and/or non-measurable) that can be accurately 
assessed at baseline by CT/MRI and is suitable for repeated assessment
6.
Patients must have received at least 2 prior platinum based lines of chemotherapy 
for ovarian cancer 
7.
Patients must be partially platinum sensitive (defined as progression 6 -12 months 
after the end of the last platinum based chemotherapy) or platinum sensitive 
(defined as progression > 12 months after the end of the last platinum based 
chemotherapy)
8.
Patients must be suitable to start treatment with single agent chemotherapy based on 
physician’s choice of weekly paclitaxel or topotecan or pegylated liposomal 
doxorubicin (PLD), or gemcitabine
9.
Patients must have normal organ and bone marrow function measured within 
28 days of randomisation, as defined below:

Haemoglobin ≥ 10.0 g/dL with no packed red cells transfusions in the 
past 28 days

Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

Platelet count ≥ 100 x 109/L


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Edition Number 4.0
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
Total bilirubin ≤ 1.5 x institutional upper limit of normal 

Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic 
Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum 
Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper 
limit of normal unless liver metastases are present in which case they 
must be ≤ 5x ULN

Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN)
10.
*Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see 
Appendix F)
11.
*Patients must have a life expectancy ≥ 16 weeks
12.
*Patient must show evidence of non-childbearing status: negative urine or serum 
pregnancy test within 7 days before first study drug dose (for women of 
childbearing potential) or must be postmenopausal. Postmenopausal is defined as: 

Age ≥ 60 yrs,

Age < 60 and any one of the conditions below:

Amenorrheic for 1 year or more in the absence of chemotherapy and/or 
hormonal treatments;

Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) and 
oestradiol levels in the post menopausal range for women under 60;

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)  
13.
*Patient is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations
14.
*Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary or 
recurrent cancer must be available for central testing. If there is not written 
confirmation of the availability of an archived tumour sample prior to enrolment the 
patient is not eligible for the study 
For inclusion in the optional exploratory genetic research and/or the optional biomarker 
research, patients must fulfil the relevant criteria below:


Clinical Study Protocol
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Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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
Provision of informed consent for genetic research 

Provision of informed consent for biomarker research
If a patient declines to participate in the optional exploratory genetic research or 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.
BRCA 1 and/or BRCA2 mutations that are considered to be non detrimental (e.g., 
“Variants of uncertain clinical significance” or “Variant of unknown significance” 
or “Variant, favor polymorphism” or “benign polymorphism” etc.)
3.
*Previous randomisation in the present study
4.
Exposure to any investigational product within 30 days or 5 half lives (whichever is 
longer) prior to randomisation
5.
*Any previous treatment with a PARP inhibitor, including olaparib
6.
*Patients who have platinum resistant or refractory disease defined as progression 
during or within 6 months of their last platinum based chemotherapy 
7.
*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 primary triple negative breast cancer may be 
eligible provided they completed their definitive treatment more than 3 years ago 
and they remain breast cancer disease free prior to randomization
8.
Resting ECG with clinically abnormal findings  
9.
Patients receiving any systemic chemotherapy within 3 weeks prior to first dose of 
study treatment (or a longer period depending on the defined characteristics of the 
agents used) or radiotherapy within 2 weeks prior to first dose of study treatment  
10.
Previous single agent exposure to the selected chemotherapy regimen (e.g. 
investigator cannot choose weekly paclitaxel for a patient who has previously  
received single agent weekly paclitaxel)


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Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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11.
*Concomitant use of known potent CYP3A4/5 inhibitors such as ketoconazole, 
itraconazole, boosted protease inhibitors (ritonavir, indinavir, saquinavir, 
telithromycin, nelfinavir, boceprevir, telaprevir) and clarithromycin 
12.
*Persistent toxicities (> Common Terminology Criteria for Adverse Event
(CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia and 
CTCAE grade 2 peripheral neuropathy
13.
*Patients with myelodysplastic syndrome/treatment related acute myeloid 
leukaemia (t-AML) or with features suggestive of MDS/AML
14.
*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 randomisation.  Patients with spinal cord compression unless 
considered to have received definitive treatment for this and evidence of clinically 
stable disease for 28 days prior to randomisation
15.
Major surgery within 2 weeks of starting study treatment and patients must have 
recovered from any effects of any major surgery
16.
*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 would limit ability to comply with 
study procedures, and any other medical condition that in the opinion of the
investigator places the patient at unacceptable risk of toxicity 
17.
*Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication
18.
*Breastfeeding women
19.
*Patients with a known hypersensitivity to olaparib or any of the excipients of the 
product
20.
*Patients with known active hepatitis B or C or HIV 
21.
*Previous allogeneic bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT)


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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22.
*Whole blood transfusions in the last 120 days prior to central BRCA testing 
(packed red blood cells transfusions are acceptable, for timing refer to inclusion 
criteria no.9)
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrolment and randomisation
Investigator(s) should keep a record of the patient screening log and of patients who entered 
pre-study screening.
The investigator(s) will:
1.
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed.  For patients with unknown BRCA status, specific 
informed consent for BRCA testing must be given by the patient prior to any study 
procedures for the Screening Part 1 visit. 
2.
Assign potential patient a unique enrolment number, beginning with ‘E#’ (This 
number will be obtained through Interactive Voice/Web Response System 
[IVRS/IWRS]).
3.
Determine patient eligibility. See Section 3.
4.
Obtain the randomisation code (patient number) through IVRS/IWRS.
If a patient discontinues or withdraws from participation in the study, then her 
enrolment/randomisation codes cannot be reused.
Screening will be closed when sufficient patients have been enrolled to reach the 
required number of randomised patients. Any patients who remain in screening at this 
time will be eligible for randomization up to 2 months after screening is closed. If after 2 
months the patient is not yet eligible for randomization, randomization into the study 
will be closed and these patients will be considered screen failures.
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 Study Physician 
immediately, and a discussion should occur between the Study Physician and the investigator 


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Edition Number 4.0
Date 20 December 2017
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regarding whether to continue or discontinue the patient from treatment. The Study Physician 
must ensure all decisions are appropriately documented.
3.5
Methods for assigning treatment groups
Eligible patients will be randomised in a 2:1 ratio. 
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.  The randomisation scheme will be produced by a 
computer software program called AZRand (AZ Randomisation system). A blocked 
randomisation will be generated for all centres.  
The randomisation scheme will be stratified based on the following:

Selected chemotherapy (weekly paclitaxel vs. topotecan vs. pegylated 
liposomal doxorubicin vs. gemcitabine)

Received prior chemotherapy regimens for ovarian cancer (2 or 3 prior 
lines of chemotherapy vs. 4 or more)

Time to disease progression after the end of the last platinum based 
chemotherapy ( 6-12 mo vs. > 12 mo)
Specific information concerning the use of IVRS/IWRS will be provided in 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
Not applicable. 
3.7
Methods for unblinding 
Not applicable.
3.8
Restrictions
3.8.1
Contraception
Patients and their partners, who are sexually active and of childbearing potential, must agree 
to the use of TWO highly effective forms of contraception in combination, throughout the 
period of taking study treatment and for 1 month after last dose of study drug(s), or they must 
totally/truly abstain from any form of sexual intercourse when this is in line with their 
preferred and usual lifestyle. For details refer to Appendix D Acceptable Birth Control 
Methods.


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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3.9
Discontinuation of investigational product
Patients may be discontinued from investigational product (IP) in the following situations:

Patient’s decision.  The patient is at any time free to discontinue 
treatment, without prejudice to further treatment

Adverse Event

Bone marrow findings consistent with myelodysplastic syndrome 
(MDS)/acute myeloid leukaemia (AML)

Severe non-compliance with the study protocol 

Objective progression according to RECIST 1.1 criteria (unless in the 
investigator’s opinion the patient is benefiting from the treatment and 
does not meet any other discontinuation criteria)
3.9.1
Procedures for discontinuation of a patient from investigational product (IP) 
By discontinuing from IP, the patient is not withdrawn from the study.  If a patient is 
withdrawn from study, see Section 3.10.
At any time, patients are free to discontinue investigational product or withdraw from the 
study, without prejudice to further treatment.  A patient that decides to discontinue IP will 
always be asked about the reason(s) and the presence of any adverse events.  If possible, they 
will be seen and assessed by an investigator(s).  Any patient discontinuing IP should be seen 
at 30 days post last dose of IP for the evaluations outlined in the study schedule. After 
discontinuation of IP, the Principal Investigator/Sub-Investigator will perform the best 
possible observation(s), test(s) and evaluation(s) as well as give appropriate medication and all 
possible measures for the safety of the patient. Patients who discontinue treatment prior to 
documented RECIST progression should continue to be followed for progression as per the 
protocol schedule.  Once progressed, all patients should be followed for PFS2 and OS as per 
the protocol schedule.  In addition, they will record on the eCRF the date of discontinuation, 
the reasons, manifestation and treatment at the time of discontinuation. If patients discontinue 
study treatment, the study monitor must be informed immediately. Patients will be required to 
attend the treatment discontinuation visit. The patient should return all IP.
After discontinuation of the study treatment 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 3.10.3). All new AEs and SAEs occurring during the 30 calendar days after the 
last dose of study treatment 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 the last IP dose to collect and / or complete 
AE information. Any untoward event occurring subsequent to the 30-day follow-up AE 


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Edition Number 4.0
Date 20 December 2017
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reporting period that the investigator assesses as possibly related to the study medication 
should also be reported as an AE.
Any patient who has not yet shown objective radiological disease progression at withdrawal 
from IP should continue to be followed as per RECIST 1.1 as detailed in Table 3.
All patients must be followed for survival, up to the final analysis.
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. This option is only applicable to 
patients not randomised into the study (ie screen failures identified prior 
to randomisation).

Patient lost to follow-up (section 3.10.3).

Death.
* If a patient withdraws consent, they will be specifically asked if they are withdrawing 
consent to:

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 5.8.2).
3.10.1 Screen 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 in eCRF.  This reason for study withdrawal is only valid for screen failures (not 
randomised patients).
3.10.2 Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.


Clinical Study Protocol
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Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The investigator will follow up AEs outside of the clinical study.  
The status of ongoing, withdrawn (from the study), and “lost to follow-up” patients at the time 
of an overall survival analysis should be obtained by the site personnel by checking the 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.
3.10.3 Lost to follow-up
Patient is considered lost to follow up when any of the following attempts of contact are 
failed: 

3 attempts of either phone calls, faxes or emails

Having sent 1 registered letter/certified mail

One unsuccessful effort to check the vital status of the patient using 
publicly available sources, if allowed by local regulations
3.11 Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings that are not considered to be consistent 
with continuation of the study.
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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4
STUDY PLAN AND TIMING OF PROCEDURES 
Figure 2
Study Flow Chart


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Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
53(167)
Table 1
Study Schedule – Screening  
Day
Part 1
Patient with unknown 
gBRCA status only
Part 2
Patients with known 
gBRCAmutation
Part 3
if patient is still 
eligible after Part 2
Day
-28 to –1
-7 to –1
Informed consent
Xa
Xl
Demographics
X
X
Medical and surgical 
history
X
Prior cancer therapies 
including radiotherapy
X
Inclusion/exclusion criteria
Xb (all * inclusion/exclusion 
criteria)
X
ECOG Performance Status 
(0-2)
X
Physical examination
X
Vital signs, body weight, 
height (Includes BP, pulse 
and temperature)
X
ECGc
X
Haematology / clinical 
chemistryd
X
Urinalysis
X
Pregnancy teste
X
Blood sample for disease 
specific marker (CA-125)
X
Blood sample for 
determination of BRCA
status via Myriad
Xf
Xg
Tumour Assessment (CT 
or MRI according to 
RECIST v1.1)h
X
Adverse Events (from time 
of consent)
Xi
X
X
Concomitant medications
X
X
Archival tumour sample 
(mandatory)j
X


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
54(167)
Table 1
Study Schedule – Screening  
Day
Part 1
Patient with unknown 
gBRCA status only
Part 2
Patients with known 
gBRCAmutation
Part 3
if patient is still 
eligible after Part 2
Baseline tumour sample 
(optional)k
X
a
Informed consent for central Myriad germline BRCA testing.
b
See section 3 for specific eligibility criteria for having the gBRCA status Myriad assessment sample.
c
ECG should be performed once the patient has been in the supine position for at least 5 minutes in each 
case.
d
Coagulation tests will only be required if clinically indicated.  
e
Pre-menopausal women of child-bearing potential must have a negative urine or serum pregnancy test 
within 7days prior to starting treatment. In the event of suspected pregnancy during the study, the test 
should be repeated and, if positive, the patient discontinued from study treatment immediately.
f
Patients with an unknown gBRCA status must provide a blood sample at Screening Part 1 for Myriad  
gBRCA testing. Any patient who consents to study related Myriad gBRCA status testing must also provide a 
second  blood sample taken at the same time for the purpose of developing and validating future diagnostic 
test(s) for BRCA mutations, if allowed by local regulations
g
Patients with known gBRCA status from local lab result must provide a blood sample at Screening Part 2 for 
confirmatory purposes.  Their involvement in the study will not be affected by the result of the Myriad test. 
Any patient who consents to study related Myriad gBRCA status testing must also provide a second blood 
sample taken at the same time for the purpose of developing and validating future diagnostic test(s) for 
BRCA mutations, if allowed by local regulations.
h
CT/MRI of the chest, abdomen and pelvis not more than 28 days prior to study treatment start and as close 
as possible to the start of study treatment.
i
Only SAE’s related to blood sampling for the Myriad gBRCA test will be collected at this visit.
j
Mandatory sample for all randomised patients only.  Confirmation required in clinical notes regarding 
availability of sample during the screening period, however, sample will only be submitted once the patient 
has been randomised.
k
The biopsied tumour should not be assessed as a target lesion as part of the RECIST assessments if there 
are other lesions available.  The biopsy should be taken after the baseline scan has been performed.
l
Informed consent for participation in the main study.


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Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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Table 2
Study Schedule – On Study Treatment and Discontinuation 
Visit Number
2
3
4
5
6
Visit No. 7 onwards 
Subsequent on treatment visits every 4 
or 12  weeksa
Tumour assessment visits every 8 or 12 
weeksb
Discontinuation 
of study 
treatment 
Safety Follow-up 
30 days after last 
dose of IP
Day
1
8
15
22
29
Day 1of next visit period
(Visit 7 equals day 57 (week 8) then 
visit 8 equals day 85 (week 12) etc)
Visit Window
±3d
±3d
±3d
±3d
±3d
±3d
+7d
±7d
Randomisation
X
Physical examc
X
X
X
X
Vital signs, body weightc
(Includes BP, pulse and 
temperature) and ECG
As clinically indicated
ECOG performance status
X
X
X
Haematology / clinical 
chemistryf
X
X
X
X
X
X
X
X
Pregnancy test n
X
X
X (Pregnancy testing for females of 
childbearing potential must be 
conducted at regular intervals (e.g. 
monthly, but ideally aligned with the 
on site visit schedule )
Blood sample for disease 
specific marker (CA-125)
X
X
X
X
Blood sample for PK 
analysis (Subset of 
patients)g
X
X


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Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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Table 2
Study Schedule – On Study Treatment and Discontinuation 
Visit Number
2
3
4
5
6
Visit No. 7 onwards 
Subsequent on treatment visits every 4 
or 12  weeksa
Tumour assessment visits every 8 or 12 
weeksb
Discontinuation 
of study 
treatment 
Safety Follow-up 
30 days after last 
dose of IP
Day
1
8
15
22
29
Day 1of next visit period
(Visit 7 equals day 57 (week 8) then 
visit 8 equals day 85 (week 12) etc)
Visit Window
±3d
±3d
±3d
±3d
±3d
±3d
+7d
±7d
Tumour Assessment (CT or 
MRI according to RECIST 
v1.1)b
Every 8 weeks for 48 weeks and every 
12 weeks thereafter until PD, one 
additional RECIST assessment required
after PD declared by the investigator
Adverse Eventsh
X
X
X
X
X
X
X
X
Concomitant medications 
including blood transfusions
X
X
X
X
X
X
X
X
EQ-5D-5Li
X
X
X
X
FACT-Oi
X
X
X
X
CTSQ-16
X (week 24 only)
X
PGIC
X (week 24 only)
X
Resource use
X
X
X
X
X
Olaparib  
dispensed/returnedj
X
Xi
Xi
X
Subsequent cancer therapy 
following discontinuation of 
study treatment k
X


Clinical Study Protocol
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Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
57(167)
Table 2
Study Schedule – On Study Treatment and Discontinuation 
Visit Number
2
3
4
5
6
Visit No. 7 onwards 
Subsequent on treatment visits every 4 
or 12  weeksa
Tumour assessment visits every 8 or 12 
weeksb
Discontinuation 
of study 
treatment 
Safety Follow-up 
30 days after last 
dose of IP
Day
1
8
15
22
29
Day 1of next visit period
(Visit 7 equals day 57 (week 8) then 
visit 8 equals day 85 (week 12) etc)
Visit Window
±3d
±3d
±3d
±3d
±3d
±3d
+7d
±7d
Blood sample for 
pharmacogenetics (optional 
patient consent required)
X
Tumour biopsy on 
progression (optional)l
X
Blood samples for 
biomarker analysism
X
X
a
Visit to take place on Day 1 of a 4 week (28 day) visit period up to  48   weeks (if not progressed and still on treatment), then on day 1 of a 12 week visit 
period relative to date of randomisation. Visits for patients who remain on treatment post progression should take place every 12 weeks.
b
Follow-up assessments will be performed every 8 weeks (±1 week) up to 48 weeks, then every 12 weeks (±1 week) relative to date of randomisation. 
Follow-up CT or MRI assessments will cover chest (in those patients with disease in the chest or upper abdomen lymphadenopathy at baseline), 
abdomen and pelvis. Any other sites at which new disease is suspected should also be appropriately imaged. Patients must be followed until RECIST
disease progression. 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. Patients who are determined to have progressed according to RECIST 1.1 criteria by the investigator 
will have one final RECIST assessment at the next scheduled RECIST visit.
c
Vital signs if clinically indicated during study treatment.  Physical examination should be performed according to the schedule, after the baseline 
assessment it is not necessary to record the details on an eCRF. Any clinically significant changes should be recorded as adverse events.
d
Temperature and weight only required if clinically indicated.
e
ECG will only be performed if clinically indicated. ECG should be performed once the patient has been in the supine position for at least 5 minutes in 
each case.
f
Safety blood samples do not need to be repeated on Day 1 of study treatment if assessed at least 3 weeks after the last dose of chemotherapy but within 7 
days before starting study treatment, unless the investigator believes that it is likely to have changed significantly.  Coagulation tests only required if 


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clinically indicated.  For a list of all required laboratory tests please refer to section 5.2.1.  Safety bloods for the patients randomised to single agent 
chemotherapy should be performed as per standard practice. All randomised patients will have safety bloods taken weekly during the 1st month on 
treatment followed by 4 weekly assessments until discontinuation of study treatment. Safety bloods will be taken at the 30-day FU visit as well. CA-125 
will be tested at baseline and every month thereafter until serological disease progression as per GCIG CA-125 criteria.
g
PK sampling to be performed in a subset of patients. Sampling times: Day 1 pre-dose & 1 hour ± 5 min post-dose; Day 29 pre-dose, 0.5-1 hour, 1-3 
hours 3-6 hours and 6-12 hours (see section 5.4). NOTE: the post-dose samples are timed from the first dose of the day.
h
When an AE for nausea and vomiting occurs, an additional eCRF will require completion.  All ongoing adverse events/serious adverse events 
(AEs/SAEs) and any new AEs/SAEs identified during the 30 calendar days follow up period after last dose of study medication must be followed to 
resolution.
i
FACT-O and EQ5D will be collected at baseline, day 29, week 8, 16, 24, 32, 40 and 48 (+/- 1 week) from start of study treatment regardless of treatment 
discontinuation or disease progression. Patients who have progressed as per RECIST 1.1 and attend visits on 12 weekly basis should continue to 
complete the questionnaires on 8 weekly basis until week 48. Assessments can be done in person or over the phone.   
j
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.
k
All anti-cancer treatments (including, but not limited to, chemotherapy and targeted agents), and the investigator’s opinion of response to them plus the 
date of progression, post discontinuation of study treatment need to be recorded.
l
Optional tumour biopsy to be taken at objective radiological disease progression (so not at every treatment visit).
m
Blood sample for biomarker analysis to be taken at randomisation and at objective radiological disease progression (so not at every treatment visit).
n
Pregnancy tests on blood or urine samples will be performed for women of childbearing potential within 7 days prior to the start of study treatment, on 
Day 1 of the study prior to commencing treatment, at the time points shown in Table 2 during study treatment and at the 30 day follow up visit If results 
are positive the patient is ineligible/must be discontinued from study treatment immediately. The pregnancy test results need to be recorded in the 
patients’ notes.


Clinical Study Protocol
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Edition Number 4.0
Date 20 December 2017
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Table 3
Study Schedule – Follow-up Post Discontinuation of Study Treatment
Visit Number
Off treatment follow-up 
Study treatment discontinued due to 
reasons other than disease 
progression
2nd progression (PFS2) and Survival follow-up for patients 
who have discontinued study treatment due to disease progression:

Objective Radiological progression

Clinical progression

CA-125 progression
Follow up for 1st progression
Tumour assessment visits every 8 weeks or 
12 weeksa
Visits to occur every 12 weeks from the date of first progression
Visit Window
±7d
±7d
Blood sample for disease 
specific marker (CA-125)
X
Tumour Assessment (CT 
or MRI according to 
RECIST v1.1) a
Every 8 weeks for 48 weeks and every 
12 weeks thereafter until PD, one 
additional RECIST assessment required 
after PD declared by the investigator
Adverse Events
Xi
Xi
ECOG performance status
X
X
EQ-5D-5Lb
X
Xb
FACT-Ob
X
Xb
Resource usef
X
Subsequent cancer therapy 
following discontinuation 
of study treatmentc
X
X
Tumour biopsy on 
progression (optional)g
X


Clinical Study Protocol
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Edition Number 4.0
Date 20 December 2017
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Table 3
Study Schedule – Follow-up Post Discontinuation of Study Treatment
Visit Number
Off treatment follow-up 
Study treatment discontinued due to 
reasons other than disease 
progression
2nd progression (PFS2) and Survival follow-up for patients 
who have discontinued study treatment due to disease progression:

Objective Radiological progression

Clinical progression

CA-125 progression
Follow up for 1st progression
Tumour assessment visits every 8 weeks or 
12 weeksa
Visits to occur every 12 weeks from the date of first progression
Blood samples for
biomarker analysis on
progressionh
X
Time to second 
progression
X
Survivald,e
X
X
a
RECIST follow-up assessments will be performed as per the original schedule every 8 weeks (±1 week) during the first 48 weeks and every 12 weeks 
(±1 week) thereafter relative to date of randomisation. Patients who are determined to have progressed according to RECIST 1.1 criteria by the 
investigator will have one final RECIST assessment at the next scheduled RECIST visit in order to minimise bias in the BICR assessment in the event 
the investigator declares objective progression earlier than the BICR. Follow-up assessment will include CT or MRI assessments of abdomen and pelvis 
for all patients. Follow-up chest CT will be performed in patients with thoracic lesions or upper abdomen lymphadenopathy identified at baseline 
assessment.  Any other sites at which new disease is suspected should also be appropriately imaged. Patients must be followed until RECIST disease 
progression.  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. Patients who are determined to have progressed according to RECIST 1.1 criteria by the investigator will have one 
final RECIST assessment at the next scheduled RECIST visit.
b
FACT-O and EQ-5D will be collected at baseline, day 29, week 8, 16, 24, 32, 40 and 48 (+/- 1 week) from start of study treatment regardless of 
treatment discontinuation or disease progression. Patients, who have progressed as per RECIST1.1 and attend visits on 12 weekly basis, should continue 
to complete the questionnaires on 8 weekly basis until week 48. Assessments can be done in person or over the phone.   
c
All anti-cancer treatments (including, but not limited to, chemotherapy and targeted agents), and the investigators opinion of response to them, 
significant patient toxicity arising from their use plus the date of progression, post discontinuation of study treatment need to be recorded
d
The status of ongoing, withdrawn (from the study) and “lost to follow-up” patients at the time of an overall survival analysis should be obtained by the 
site personnel by checking the patients notes, hospital records, contacting the patients general practitioner and checking publicly available death 
registries. In the event that the patient has actively withdrawn consent to the processing of their personal data the vital status of the patient can be 
obtained by site personnel from publicly available resources where it is possible to do so under applicable local laws.


Clinical Study Protocol
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e
In addition to their regular 12 weekly contact, patients will be contacted in the 7 days following a specified date (data cut-off date) for each survival 
analysis
f
In line with the RECIST assessments (every 8 or 12 weeks) until objective radiological disease progression, at discontinuation of study treatment visit 
and then 30 days post last dose
g
Optional tumour biopsy to be taken at objective radiological disease progression (so not at every off-treatment follow up visit)
h
Blood sample for biomarker analysis to be taken at objective radiological disease progression ( not at every off-treatment follow-up visit).
i
Please refer to section 6.3.3


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4.1
Enrolment/screening period
Procedures will be performed according to the Study Plan in Table 1.
Each potential patient will provide written informed consent prior to any study specific 
procedures and undergo assessments applicable for the visit.
Patients with unknown gBRCA status will be screened for BRCA mutation and will start the 
study from screening Part1 and continue with Part 2 and Part 3, if applicable.
Patients with known gBRCA mutation (by central or local BRCA test) will start study from 
screening Part 2 and continue to Part 3.  
All patients will be required to provide consent to supply a sample of their biological sample 
for entry into this study. This consent is included in the main patient informed consent form. 
4.2
Treatment period
Descriptions of the procedures for this period are included in the Study Plan, Table 2 and 
Table 3. 
4.3
Follow-up period
Patients should be discontinued from study treatment if any discontinuation criteria are 
fulfilled (see Section 3.9).  The assessments to be carried out at the visit are detailed in the 
study schedule (Table 2 and Table 3). 
4.3.1
Patients who have objective radiological disease progression but continue on 
study treatment
Patients should be discontinued from study treatment if they have objective radiological 
disease progression according to RECIST (see Appendix E), unless in the investigator’s 
opinion they are benefiting from treatment and they do not meet any other discontinuation 
criteria (as outlined in Section 3.9).  These patients will continue on treatment following 
procedures as per the second column of Table 3 and will be followed for PFS2 and OS. Safety 
assessments can occur with the same frequency as the visits unless more frequent testing is 
clinically indicated.
4.3.2
Follow-up 30 day after last dose of investigational product (IP) (follow-up visit)
A follow-up visit should be conducted 30 days after the last dose of study treatment.  Any 
serious and/or non-serious AEs ongoing at the time of the Discontinuation Visit or which have 
occurred during the defined 30-day follow-up period must be followed-up.  Appropriate safety 
evaluations should be repeated and/or additional tests performed at any time when clinically 
indicated, or at the discretion of the investigator, until resolution, unless, in the investigator’s 
opinion, the condition is unlikely to resolve due to the patient’s underlying disease.  If the 
patient is lost to follow-up, then this should be noted in the eCRF.  The assessments to be 


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carried out at the 30 day follow up visit are detailed in the study schedule (Table 3 and Table 
2).
4.3.3
Survival
Assessments for survival should be made every 12 weeks following objective radiological 
disease progression according to RECIST 1.1. Survival information may be obtained via 
telephone contact with the patient, patient’s family or by contact with the patient’s current 
physician. Survival data will be collected up to the time of the final overall survival (OS) 
analysis. In addition, patients should be contacted in the week following the data cut-off for 
the primary and final survival analyses to provide complete survival data.
Patients will be followed up as per Table 3 to the point of the final analysis.  At this point 
investigators will be notified that no further data collection for the study is required.  
Monitoring and recording of SAEs will continue as per Section 6.3.3.
The status of ongoing, withdrawn (from the study) and “lost to follow-up” patients at the time 
of an overall survival analysis should be obtained by the site personnel by checking the 
patients notes, hospital records, contacting the patients general practitioner and checking 
publicly available death registries. In the event that the patient has actively withdrawn consent 
to the processing of their personal data the vital status of the patient can be obtained by site 
personnel from publicly available resources where it is possible to do so under applicable 
local laws. 
4.3.4
Second progression
Following objective progression, copies of the patient’s radiological scans are no longer 
required to be sent for blinded independent central review.  Patients will be assessed every 12 
weeks for a second progression (using the patient’s status at first progression as the reference 
for assessment of second progression).  A patient’s progression status is defined according to 
local standard clinical practice and may involve any of; objective radiological, CA-125, 
clinical progression or death.  RECIST measurements will not be collected for assessment of 
PFS2.  The date of PFS2 assessment and investigator opinion of progression status 
(progressed or non-progressed) at each assessment will be recorded in the eCRF.
4.3.5
Patient management post primary analysis
The data cut-off for the primary analysis will occur in January 2019 or at a minimum of 
6 months after LSI, whichever is sooner.
Patients on study treatment at the time of the data cut-off will continue to receive study 
treatment until they meet any discontinuation criteria as per Section 3.9. 
Patients on study treatment will be followed for core safety assessments and disease 
progression (haematology, clinical chemistry, AEs/SAEs and concomitant medications 
(including any subsequent cancer therapy), study treatment dosing details, objective 
radiological disease progression according to RECIST1.1, and as per Table 2).  These patients 


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Date 20 December 2017
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should be followed according to routine clinical practice but visits should take place at least 
every 12 weeks.
All patients (patients still on study treatment and patients withdrawn from study treatment) 
will be followed for survival and disease progression.
After the primary analysis, central review of scans will no longer be required and investigators 
will be advised when to stop sending copies of the scans to the CRO conducting the central 
review.
HRQoL data will not be collected post primary analysis.
4.3.6
Patient management post final analysis
An additional PFS2 and OS analysis will only be conducted with further follow up if both 
ORR and PFS are statistically significant based on the primary analysis and the null 
hypotheses for PFS2 and/or OS are not rejected at the time of the primary analysis. The data-
cut off for this additional analysis will be established when the OS data approximately 60% 
mature.
At this time point, the clinical study database will close to new data.  Patients who are 
receiving active treatment can either choose to discontinue from the study, or if the 
investigator believes patients are gaining clinical benefit, patients may continue to receive 
study treatment. All patients will receive follow-up care in accordance with standard local 
clinical practice.
AstraZeneca will continue to supply olaparib after completion of this study until either 
olaparib is licenced in that country, or it is determined that the benefit to risk profile does not 
support continued development of olaparib, or the national health authority has deemed the 
drug not approvable.  In all these scenarios, AstraZeneca will work with investigators on the 
proper transition of patients to alternative therapies if possible.
SAEs will continue to be reported to AstraZeneca Patient Safety Department, for any patients 
who continue on olaparib until 30 days after study treatment is discontinued, in accordance 
with Section 6.3.3.  Additionally as stated any SAE or non-serious adverse event, that is 
ongoing at the end of the study, must be followed up to resolution unless the event is 
considered by the investigator to be unlikely to resolve, or the patient is lost to follow-up.  If 
an investigator learns of any SAEs, including death, at any time after a patient has completed 
the study, and he/she considers there is a reasonable possibility that the event is causally 
related to the investigational product, the investigator should notify AstraZeneca, Patient 
Safety.
Drug accountability should continue to be performed until the patient stops study treatment 
completely.


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Date 20 December 2017
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5
STUDY ASSESSMENTS
The Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The investigator will ensure that data are recorded on the electronic Case Report 
Forms (eCRF) as specified in the study protocol and in accordance with the instructions 
provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRF.  A copy of the completed eCRF will be archived at 
the study site.
5.1
Efficacy assessments
5.1.1
CT and MRI scans tumour assessments (RECIST 1.1)
Baseline assessment will be performed no more than 28 days prior to study treatment start and 
as close as possible to study treatment start.  Following the baseline assessment, subsequent 
tumour assessments according to RECIST 1.1 should be performed at the end of every 8 
weeks (+/- 1 week) from randomisation for 48 weeks and every 12 weeks (+/- 1 week) 
thereafter. All CT/MRI scans will be sent to an AstraZeneca appointed Clinical Research 
Organisation (CRO) for blinded independent central review. All treatment decision will be 
based on investigator’s assessment of the scans. 
All patients should have RECIST assessments until documented evidence of objective 
radiological progression in accordance with RECIST 1.1, irrespective of treatment decisions 
(i.e., RECIST follow up until progression even if a patient discontinues study treatment prior 
to progression and/or receives a subsequent therapy prior to progression). Patients who are 
determined to have progressed according to RECIST 1.1 criteria by the investigator will have 
one final study RECIST assessment at the next scheduled RECIST visit in order to minimise 
bias in the BICR assessment in the event the investigator declares objective progression earlier 
than the BICR. 
At baseline, the imaging modalities used for RECIST assessment will be CT (MRI where CT 
is contraindicated) scans of the chest, abdomen and pelvis with other regions as clinically 
indicated for the assessment of disease. Follow-up CT or MRI assessments will cover chest (in 
those patients with disease in the chest or upper abdomen lymphadenopathy at baseline), 
abdomen and pelvis with any other regions imaged at baseline where disease was present.  
Any other sites at which new disease is suspected should also be appropriately imaged.  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.


Clinical Study Protocol
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Anonymised copies of the scans are to be sent to an AstraZeneca appointed CRO for blinded 
independent central review.
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 ± 1 week window interval and the patient has not progressed, every 
attempt should be made to perform the subsequent scans at their scheduled time points.  
Patients will be evaluated until objective radiological disease progression by RECIST 1.1 as 
per the study schedule and then followed for second progression and survival, 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 by determining 
progression free survival (PFS) times, objective response rates (ORR) and duration of 
response (DoR).  The RECIST 1.1 guidelines for measurable, non-measurable, target and non-
target lesions and the objective tumour response criteria (complete response, partial response, 
stable disease or progression of disease) are presented in Appendix E.
Although CA-125 is measured in this study it will not be directly used for assessing objective 
response or progression and patients should be continued on treatment until objective 
radiological 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: complete response (CR), partial response (PR), stable disease (SD), 
progression of disease (PD), and not evaluable (NE).  Target lesion (TL) progression will be 
calculated in comparison to when the tumour burden was at a minimum (i.e., smallest sum of 
diameters previously recorded on study).  In the absence of a response of progression, tumour 
response (CR, PR, SD or NE) will be calculated in comparison to the baseline tumour 
measurements obtained before randomisation.
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 (complete 
response), PD (progression of disease), Non CR/Non PD or NE (not evaluable). A response of 
CR or PR will not require confirmation due to the randomized controlled study design as per 
the RECIST guidelines. However, a sensitivity analysis of confirmed CR or PR will be 
conducted.
If the investigator is in doubt as to whether progression has occurred, particularly with 
response to NTL (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. 


Clinical Study Protocol
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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 qualify for unequivocal progression status.
Following progression, patients should continue to be followed up for survival every 12 weeks 
as outlined in the study plan (Table 2 and Table 3). It is important to follow the assessment 
schedules as closely as possible.
5.1.3
Central reading of scans
An independent review of all scans used in the assessment of tumours using RECIST 1.1 will 
be conducted.  All imaging assessments including unscheduled visit scans will be collected on 
an ongoing basis and sent to an AstraZeneca appointed CRO for central analysis.  Results of 
this independent review will not be communicated to investigators, and the management of 
patients will be based solely upon the results of the RECIST assessment conducted by the 
investigator. Please note that patients who are determined to have progressed according to 
RECIST 1.1 criteria by the investigator will have one final RECIST assessment at the next 
scheduled RECIST visit (8 or 12 weeks) in order to minimise bias in the BICR assessment in 
the event the investigator declares objective progression earlier than the BICR. 
After the primary PFS analysis, central review of scans will no longer be required and 
investigators will be advised when to stop sending copies of the scans to the CRO conducting 
the central review.  
The primary analysis for this study will be based on the blinded independent central review 
(BICR) of the radiological scans.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation,
and urinalysis will be taken at the times indicated in the Study Plan.
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 investigational site.  Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site.
The following laboratory variable listed in Table 4 will be measured.


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NB. In case a patient shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer 
to Appendix C ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions.
Table 4
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
B- Red Blood Cells count (RBC)
S/P-Alkaline Phosphatase (ALP)
Mean Cell Haemoglobin Concentration (MCHC) 
S/P-Aspartate Transaminase (AST)
Mean Cell Volume (MCV)
S/P-Alanine Transaminase (ALT)
Mean Cell Haemoglobin (MCH) 
S/P-Albumin
B-Leukocyte differential count (absolute count)
S/P-Potassium
B-Platelet count
S/P-Calcium, total
White Blood Cells (WBC) with absolute 
differential white cell count1
S/P-Sodium
S/P GGT
Urinalysis (dipstick)
S/P urea or Blood Urea Nitrogen (BUN)
U-Hb/Erythrocytes/Blood 
S/P – Protein, total
U-Protein/Albumin 
Activated Partial Thromboblastin Time 
(APTT)2
U-Glucose 
International Normalised Ratio (INR)3
1
Neutrophils, lymphocytes, monocytes, eosinophils and basophils and absolute neutrophil count or 
segmented neutrophil count and Band forms should be performed at each visit and when clinically 
indicated. If absolute differentials are not available please provide % differentials.
2
Coagulation will be performed if clinically indicated  
3
INR will be performed if clinically indicated unless the patient is receiving warfarin or acenocoumarol. 
Patients taking warfarin or acenocoumarol may participate in this study; however, it is recommended that 
prothrombin time (INR and APTT) be monitored carefully at baseline and at least once per week for the 
first month, then monthly if the INR is stable.  This information must be recorded on the lab form of the 
eCRF.
5.2.1.1
Disease specific tumour marker samples (CA-125)
As part of the routine safety blood samples, all patients will supply blood sample for CA-125 
(2 mL) for assessment at each time point indicated in Table 1, Table 2 and Table 3. 


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It is important to follow the assessment schedule as closely as possible. If CA-125 assessment 
is performed outside of scheduled visit ± 1 week window interval, every attempt should be 
made to assess the CA-125 at the scheduled time points. Patients will be evaluated until 
objective disease progression, based on progressive serial elevation of serum CA-125 
according to the Gynecologic Cancer InterGroup criteria GCIG criteria (Further assessment of 
CA 125 post serological progression will be at the discretion of the investigator according to 
local clinical practice.
5.2.1.2
Bone marrow or blood cytogenetic samples 
Bone marrow or blood cytogenetic samples may be considered for patients with prolonged 
haematological toxicities as defined in Section 6.8.
At the discretion of a haematology consultant, 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.
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 5.2.1.
5.2.2
Physical examination
For timing of individual measurement refer to study schedule (see Table 1, Table 2, and Table 
3).
A complete physical examination 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, musculo-skeletal (including 
spine and extremities) and neurological systems.
5.2.3
ECG
ECGs are required within 7 days prior to starting study treatment and as clinically indicated 
afterwards.  No repeat ECG is required at screening or baseline if the first ECG shows no 
clinically significant abnormalities.
Twelve-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 


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
70(167)
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.
5.2.4
Vital signs
Vital signs will be performed during study treatment if clinically indicated.
Height will be assessed at screening only.  Weight will be assessed at screening and as 
clinically indicated at any other time. 
Any changes in vital signs should be recorded as an AE, if applicable.
5.2.4.1
Pulse and blood pressure
Blood pressure and pulse rate will be measured preferably using a semiautomatic BP 
recording device with an appropriate cuff size after 10 minutes rest on a bed or seated on a 
chair.  Blood pressure and pulse will be measured at baseline and as clinically indicated 
afterwards.
The date of collection and measurement will be recorded on the appropriate eCRF.
5.2.4.2
Body temperature
Body temperature will be measured in degrees Celsius using an automated thermometer at the 
times indicated in the Study Schedule (see Table 1, Table 2, and Table 3).
The date of collection and measurement will be recorded on the appropriate eCRF.
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 women of childbearing 
potential within 7 days prior to the start of study treatment, on Day 1 of the study prior to 
commencing treatment, at the time points shown in Table 2 during study treatment and at the 
30 day follow up visit. Tests will be performed by the hospital’s local laboratory. If results are 
positive the patient is ineligible/must be discontinued from study treatment immediately. 
5.3
Other assessments
5.3.1
Patient reported outcomes
Patient Reported Outcomes (PRO), an umbrella term referring to all outcomes and symptoms, 
are directly reported by the patient.  Patient Reported Outcomes have become a significant 
endpoint when evaluating effectiveness of treatments in clinical trials.  The following PROs 
will be administered in this study: FACT-O, CTSQ-16, EQ-5D-5L and PGIC. Each is 
described below.


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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5.3.1.1
FACT-O
Patient-reported health-related quality of life (HRQoL) will be assessed using the FACT-O 
questionnaire, see Appendix G.  The FACT-O is composed of the following sub-scales: 
physical, social/family, emotional, and functional well-being as well as the additional 
concerns scales consisting of specific ovarian cancer symptoms. The main endpoint for health-
related quality of life analysis will be the Trial Outcome Index (TOI), an established single 
targeted index derived from the FACT-O questionnaire and it is considered to target the most 
relevant symptoms together with function and physical well-being and can be directly related 
to signs and symptoms and AEs.  The TOI is composed of the following scales of the FACT-
O: physical and functional well-being and additional concerns.
5.3.1.2
CTSQ-16
The CTSQ-16 is a validated 16-item questionnaire measuring 3 domains related to patients’ 
satisfaction with cancer therapy: Expectations of Therapy (ET), Feelings about Side Effects 
(FSE), and Satisfaction with Therapy (SWT) (see Appendix G).  The CTSQ-16 was developed 
for use in a wide range of cancer types and stages, and is specific to adult patients receiving 
cancer therapy.  In particular, this instrument can be used for both intravenous (IV) and oral 
cancer therapy assessments.
5.3.1.3
EQ-5D-5L
The EQ-5D is a standardised measure of health status developed by the European Quality of 
Life (EuroQoL) Group in order to provide a simple, generic measure of health for clinical and 
economic appraisal (EuroQoL Group 1990), see Appendix G.  Applicable to a wide range of 
health conditions and treatments, it provides a simple descriptive profile and a single index 
value for health status that can be used in the clinical and economic evaluation of health care 
as well as in population health surveys. The questionnaire assesses 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression.  Each dimension has 5 
response options (no problems, slight problems, moderate problems, severe problems, and 
extreme problems) that reflect increasing levels of difficulty (EuroQoL Group 2013). Since 
2009, the EuroQoL group has been developing a more sensitive version of the EQ-5D (the 
EQ-5D-5L), which expands the range of responses to each dimension from 3 to 5 levels of 
increasing severity (Herdman et al 2011).  Preliminary studies indicate that the 5 level (5L)
version improves upon the properties of the 3 level (3L) measure in terms of reduced ceiling 
effect, increased reliability, and an improved ability to differentiate between different levels of 
health (Pickard et al 2007, Janssen et al 2008, Janssen et al 2008b). The patient will be asked 
to indicate his/her current health state by selecting the most appropriate level in each of the 5 
dimensions.  The questionnaire also includes a visual analogue scale (VAS), where the patient 
will be asked to rate current health status on a scale of 0 to 100, with zero being the worst 
imaginable health state.
5.3.1.4
PGIC
Patient Global Impression of Change is a one-item instrument asking patients at the end of 
treatment to assess on a 7-point scale to what extent they perceive that their main symptoms 


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
72(167)
under treatment have changed since the beginning of treatment, where -3 implies that 
symptoms are very much worse, 0 implies no change, and +3 that symptoms are very much 
improved.
5.3.1.5
Administration of PRO questionnaires
The PROs will be completed at given time points as described in the study schedule (Table 2, 
and Table 3). Paper questionnaires will be given to the patient at baseline, at Day 29, week 8, 
16, 24, 32, 40 and 48 relative to the day of randomisation.  For all PROs, patients are to 
complete the questionnaire during their clinic visit.  The site staff will enter the information 
directly into the eCRF. 
Each centre must allocate the responsibility for the administration of the questionnaires to a 
specific individual (e.g., a research nurse, study coordinator) and if possible assign a back-up 
person to cover if that individual is absent. The study monitor will provide relevant training in 
administration of the questionnaires. The significance and relevance of the data need to be 
explained carefully to participating patients so that they are motivated to comply with data 
collection.
The instructions for completion of the PRO questionnaires are as follows:

It must be completed prior to any other study procedures (following 
informed consent) and before discussion of disease progress to avoid 
biasing the patient’s responses to the questions

It must be completed in private by the patient

The patient should be given sufficient time to complete at their own 
speed

The patient should not receive help from relatives, friends or clinic staff 
to answer the questionnaire. However, if the patient is unable to read the 
questionnaire (e.g., is blind or illiterate) the questionnaire may be read 
out by trained clinic staff and responses recorded

On completion of the questionnaire it should be handed back to the 
person responsible for questionnaires who should check for completeness

Only 1 answer should be recorded for each question
5.3.2
Health economics
Resource use will be captured including inpatient admissions, Intensive Care Unit and length 
of stay in hospital.


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
73(167)
5.4
Pharmacokinetics
PK sampling is to be performed in a subset of patients from the olaparib treatment arm.  
5.4.1
Pharmacokinetic samples (subset of patients)
Approximately 65 evaluable patients (i.e., those that have been randomised to olaparib) 
randomised at pre-agreed sites will have PK assessment samples taken.
In order to assess the potential influence of ethnicity/race on olaparib, centres are requested to 
consider favouring Black American, Asian and Hispanic patients for this PK subset 
population.
Table 5
Pharmacokinetic samples
Visit Number
2
3
4
5
6
Day
1 
8
15 
22
29
Sampling time
Pre dose and 
1 hr ± 5 min 
post dose
Pre-dose; 
0.5-1 hour, 1-3 
hours 
3-6 hours, and 
6-12 hours 
post dose
Blood sample for PK analysis 
(Subset of patients)
X
X
5.4.2
Collection of samples
Blood samples for determination of olaparib concentrations in plasma will be taken at the 
times presented in Table 5.
To ensure that the assessments are carried out such that the PK sampling is performed within 
the required sampling windows, it will be necessary to arrange the assessment procedures so 
that the PK assessments fall at/around the correct timing.  The actual time of dosing and 
collection of all PK samples must be recorded as described below:
On Day 1 the times of the pre-dose and 1 hour ± 5 min post dose PK samples must be 
recorded along with the times of both the morning and evening study treatment doses.
On Day 29, the morning dose of study treatment should not be taken at home, but must be 
taken after the pre-dose PK sample has been taken. The times of the pre-dose and all of the 
post dose PK samples and the times of both the morning and evening doses of study treatment 


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
74(167)
must be recorded. In addition to the dosing times on the PK day, it is important to record the 
previous day’s morning and evening doses of study treatment (i.e. Day 28).
Samples will be collected, labelled stored and shipped as detailed in the Laboratory Manual.
NOTE: all post-dose samples are timed from the first dose of olaparib of the day. 
5.4.3
Determination of drug concentration
Samples for determination of olaparib concentration in plasma will be analysed by Covance 
on behalf of AstraZeneca, using an appropriate bioanalytical method.  Full details of the 
analytical method used will be described in a separate bioanalytical report.
5.4.4
Storage and destruction of pharmacokinetic samples
PK samples will be disposed of after the Bioanalytical Report finalization or six months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless requested for future 
analyses.
PK samples may be disposed of or destroyed and anonymised by pooling. Additional analyses 
may be conducted on the anonymised, pooled pharmacokinetic samples to further evaluate 
and validate the analytical method. Any results from such analyses may be reported 
separately from the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the Clinical Study 
Report but separately in a Bioanalytical Report.
5.5
Pharmacodynamics
5.5.1
Collection of samples
Pharmacodynamic samples will not be taken during the study.
5.5.2
Storage, re-use and destruction of pharmacodynamic samples
Not applicable.
5.6
Biomarker analysis
5.6.1
Collection of blood sample for Myriad germline BRCA1 and BRCA2 testing
All patients must have a known deleterious or suspected deleterious BRCA mutation to be 
randomised; this may have been determined prior to study entry or may be assessed as part of 
the enrolment procedure for the study (via Myriad). 
For patients that can be randomised to the study on the basis of a pre-existing known BRCA 
mutation test result, a blood sample for a confirmatory BRCA mutation test by Myriad must 
be taken once the patient has consented to the study.  Should the result from the Myriad test 


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
75(167)
indicate the patient does not have a deleterious or suspected deleterious BRCA mutation, the 
patient can continue in the study and can continue to receive their allocated study treatment. 
Residual blood (or its derivatives) may be used to develop and validate future BRCA 
companion diagnostic tests and for additional exploratory work, to elucidate the mechanism of 
response, understand the mode of action of study treatment, and improve the understanding of 
disease recurrence (including BRCA mutation status and its role in response).  
For patients who meet the trial eligibility criteria, but do not know their BRCA mutation 
status, a blood sample for the Myriad BRCA test can be taken once all local ethical procedures 
for such testing have been completed.  When the result from the Myriad test indicates the 
patient does have a deleterious or suspected deleterious BRCA mutation, the patient can be 
randomised into the study.  Residual blood (or its derivatives) may be used to develop and 
validate future BRCA companion diagnostic tests and for additional exploratory work, to 
elucidate the mechanism of response, understand the mode of action of study treatment, and 
improve the understanding of disease recurrence (including BRCA mutation status, its role in 
response and mutation status of other genes known/predicted to have a role in ovarian cancer).
For blood volume see Section 5.9.
5.6.1.1
Guidance for BRCA testing of patients with unknown BRCA status
Patients that do not know their BRCA status, but meet all other eligibility criteria must have a 
Myriad test prior to randomisation in to the study.  If the result shows that the patient has a 
deleterious/suspected deleterious gBRCA mutation, the patient can then be randomised to the 
study.  Patients will need to have met the local ethical requirements for such genetic tests 
(e.g., genetic counseling) prior to the test procedure.
The following clinicopathological features are known to be associated with an increased 
probability of BRCA mutations: 
1.
Family history of breast or ovarian cancer, ethnicity and age
2.
High grade serous ovarian cancer
The patient must meet all the eligibility criteria in Sections 3.1 and 3.2 with an asterisk prior 
to having the blood sample taken for the Myriad gBRCA status test.  The patient’s consent to 
the use of donated biological samples is mandatory. The aforementioned clinicopathological 
features (family history of cancer, ethnicity, age and grade of cancer) are collected in CRF. 
5.6.2
Collection of sample for assessment of current and future BRCA assay(s)
As part of the requirements for the development of a companion diagnostic for olaparib it will 
be necessary to collect a second blood specimen from all patients who submit samples for 
Myriad testing if allowed by local regulations.  These samples will be stored for subsequent 
analysis to enable development and validation of a companion diagnostic for olaparib. Where 
allowed this includes samples from those patients who were shown not to have a deleterious 


Clinical Study Protocol
Drug Substance AZD2281
Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
76(167)
or suspected deleterious BRCA1 or BRCA2 mutation.  Residual blood (or its derivatives) may 
be used to develop and validate future BRCA companion diagnostic tests and for additional 
exploratory work, to elucidate the mechanism of response, understand the mode of action of 
study treatment, and improve the understanding of disease recurrence (including BRCA 
mutation status, its role in response and mutation status of other genes known/predicted to 
have a role in ovarian cancer).
For blood volume see Section 5.9.
5.6.3
Collection of biomarkers biological samples
Biological samples (archived tumour samples and blood samples) will be collected and may 
be analysed for exploratory biomarkers to assess correlations with disease activity, effects of 
study drug, clinical outcomes and toxicity: 

Mandatory: Archived tumour sample 
Formalin fixed, paraffin embedded (FFPE) tumour sample from the 
primary or recurrent cancer must be available for central testing. If there 
is not written confirmation of the availability of an archived tumour 
sample prior to enrolment the patient is not eligible for the study. 

Optional: Tumour biopsy at baseline and/or disease progression
The baseline biopsied tumour should not be assessed as a target lesion as 
part of the RECIST assessments if there are other lesions available.  The 
biopsy should be taken after the baseline scan has been performed.

Mandatory: Blood sample for biomarker analysis
Two 6 mL blood samples (one plasma and one serum) will be collected 
from all patients at randomisation and at progression for exploratory 
biomarker work.
5.6.4
Storage, re-use and destruction of biomarkers biological samples
Samples will be stored for a maximum of 15 years from the date of the Last Patient’s Last 
Visit, after which they will be destroyed.  The results of this biomarker research will be 
reported either in the Clinical Study Report itself or as an addendum, or separately in a 
scientific report or publication. The results of this biomarker research may be pooled with 
biomarker data from other studies with the study drug to generate hypotheses to be tested in 
future research.


Clinical Study Protocol
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Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
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5.7
Pharmacogenetics
5.7.1
Collection of pharmacogenetics
The patient’s consent to participate in the pharmacogenetic research components of the study 
is mandatory.  
The blood sample for genetic research will be obtained from the patients at Visit 2.  Although 
genotype is a stable parameter, early sample collection is preferred to avoid introducing bias 
through excluding patients who may withdraw due to an adverse event (AE), such patients 
would be important to include in any genetic analysis.  If for any reason the sample is not 
drawn at Visit 2, it may be taken at any visit until the last study visit.  Only one sample should 
be collected per patient for genetics during the study.
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.
5.7.2
Storage, re-use and destruction of pharmacogenetics
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  If allowed by local regulations 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.  DNA is a finite resource that may be used up during analyses.  The 
results of any further analyses will be reported either in the Clinical Study Report itself or as 
an addendum, or separately in a scientific report or publication.
For all samples irrespective of the type of coding used the DNA will be extracted from the 
blood sample.  The DNA sample will be assigned a unique number replacing the information 
on the sample tube. Thereafter, the DNA sample will be identifiable by the unique DNA 
number only.  The DNA number is used to identify the sample and corresponding data at the 
AstraZeneca genetics laboratories, or at the designated contract laboratory.  No personal 
details identifying the individual will be available to any person (AstraZeneca employee or 
contract laboratory staff working with the DNA.)
The samples and data for genetic analysis in this study will be single coded.  The link between 
the patient enrolment/randomisation code and the DNA number will be maintained and stored 
in a secure environment, with restricted access within the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca.  The link will be used 
to identify the relevant DNA samples for analysis, facilitate correlation of genotypic results 
with clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent when the patient has requested disposal/destruction of collected 
samples not yet analysed.
5.8
Labelling and shipment of biological samples
The Principal Investigator at each centre ensures that samples are labelled and shipped in 
accordance with the Laboratory Manual and the Biological Substance, Category B 
Regulations (materials containing or suspected to contain infectious substances that do not 


Clinical Study Protocol
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Edition Number 4.0
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meet Category A criteria), see Appendix B International Air Transport Association (IATA) 
6.2 Guidance Document.
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved.
5.8.1
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 will keep full traceability of collected biological 
samples from the patients while in storage at the centre until shipment or disposal (where 
appropriate) and keeps documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca Biobank during the entire 
life cycle.
5.8.2
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.
Prospective Myriad BRCA sample for patients with unknown BRCA status: As collection of 
the biological sample is an integral part of the study, then the patient is withdrawn from 
further study participation.
Archival tumour sample: Although mandatory, the patient may continue in the study if the 
patient is already randomised.
Tumour biopsy samples: As collection of the biological samples is an optional part of the 
study, then the patient may continue in the study.
Blood samples for biomarker analysis: Although mandatory, the patient may continue in the 
study if the patient is already randomised.
The Principal Investigator:

Ensures patients’ withdrawal of informed consent to the use of donated 
samples is notified immediately to AstraZeneca or designated CRO


Clinical Study Protocol
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Date 20 December 2017
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
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.
5.9
Blood Volume
The volume of blood that will be drawn from each patient will vary, dependent upon the 
length of time that the patient remains in the trial and on treatment and if the patient is in the 
subset having PK samples taken.  However the volume of blood to be drawn from each patient 
(including for PK samples) during screening and up to Day 29 should not exceed 150 mL.
The total volume of blood to be drawn from each patient in the study, assuming they complete 
screening, 6 months of treatment, a treatment discontinuation visit and the 30-day follow-up 
visit, should not exceed 210 mL.
Safety laboratory assessments will be performed locally at each centre’s laboratory by means 
of their established methods.  The number of samples/blood volumes is therefore patient to 
site-specific change. 
Extra blood samples may also be collected if, for example, additional samples are required for 
repeat safety assessments.
The estimated total volume of blood that will be drawn from each patient in this study is 
shown in Table 6.


Clinical Study Protocol
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Study Code D0816C00010
Edition Number 4.0
Date 20 December 2017
80(167)
Table 6
Estimated maximum volume of blood to be drawn from each patient based on 6 months of treatment
Assessment
Sample 
volume 
(mL)
Screening 
No. of samples
Month 1 
(Including 
day 29)
No. of 
samples
Mths  2-6
No. of 
samples
Treatment 
Discontinuation 
visit and 30 day 
follow-up visit 
No. of samples
Objective 
radiological 
disease 
progression 
No. of samples
Total 
vol. (mL)
Safety
Clinical chemistry (locally 
assessed)
5
1
5
1(x4)
1(x2)
60
Haematology (locally 
assessed)
5
1
5
1(x4)
1(x2)
60
Whole Blood sample: Prospective 
Myriad BRCA test for patients with 
unknown BRCA status or for 
confirmation of BRCA status for those 
with previous results
10
1
10
Whole blood sample For assessment 
of current and future BRCA mutation 
assay(s)
10
1
10
Blood samples (plasma and serum) 
for biomarker analysis
12 
1
1
24
Serum pregnancy test
Site 
dependent
Site may use 
urine instead
Site may use 
urine instead
Blood sample for CA-125 
(locally assessed)
2
1
1(x2)
1(x4)
1(x1) (only treatment 
discontinuation visit)
16
Pharmacokinetic (Blood samples 
processed to plasma & frozen)
2
7
14
Optional exploratory 
Pharmacogenetics 
9
1
9
Total volume (ml)
32
89
48
22
12
203


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6
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

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 adverse events
6.3.1
Time period for collection of adverse events
Adverse Events, including Serious Adverse Events, will be collected from time of signature of 
informed consent, throughout the treatment period and up to and including the 30-day follow-
up period*.  All ongoing and any new AEs/SAEs identified during the 30 calendar days 


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follow up period after last dose of study medication must be followed to resolution.  After any 
interim analysis, any ongoing AEs/SAEs need to be unlocked and followed for resolution. 
*Exception: In screening part 1 only SAEs related to study procedures must be reported (AEs 
do not require reporting).  From screening part 2 onwards - all AEs/SAEs must be reported.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the time of the 30 day follow-up, must be followed up by the 
investigator through to resolution, and whilst the database is open should be recorded on the 
database. 
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Adverse events 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 [eg 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. A Questionnaire will be sent to any investigator reporting MDS/AML or new primary 
malignancy as an aid to provide detailed information on the case. 
At any time after a patient has completed the study, if an investigator learns of any SAE 
including death, and he/she considers there is a reasonable possibility that the event is causally 
related to the investigational product, the investigator should notify AstraZeneca, Patient 
Safety. 
If patients who are gaining clinical benefit are allowed to continue study treatment post data 
cut-off and/or post study completion then all SAEs must continue to be collected and reported 
to 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).
6.3.4
Variables 
The following variables will be collected for each AE:

AE (verbatim)

The date and time when the AE started and stopped


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
Max CTCAE grade and changes in CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the IP (yes or no)

Action taken with regard to IP

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 (provide all seriousness criteria applicable)

Date of hospitalisation (if applicable)

Date of discharge (if applicable)

Probable cause of death (if applicable)

Date of death (if applicable)

Autopsy performed (yes or no; if yes provide report) (if applicable)

Causality assessment in relation to Study procedure(s)

Description of AE
For each episode on an adverse event, all changes to the CTCAE grade attained as well as the 
highest attained CTC grade should be reported.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.1. An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
The grading scales found in the National Cancer Institute (NCI) CTCAE version 4.0 will be 
utilised for all events with an assigned CTCAE grading. For those events without assigned 


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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).
6.3.5
Causality collection
The investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol.
6.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study personnel: ‘Have you had any health problems since the 
previous visit/you were last asked?’, or revealed by observation will be collected and recorded 
in the CRF.  When collecting AEs the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms.  However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
6.3.7
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report.  Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs and ECG abnormalities should therefore only be reported as AEs if one of 
the following is met:

Any criterion for an SAE is fulfilled

Causes study treatment discontinuation

Causes study treatment interruption

Causes study treatment dose reduction

The investigator believes that the abnormality should be reported as an 
AE


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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.
6.3.8
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to 
be reported as SAEs. Please refer to Appendix C for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
6.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study (DUS) and/or increases in the signs and symptoms of the 
cancer.  The development of new, or progression of existing metastasis to the primary cancer 
under study should be considered as disease progression and not an AE.  Events, which are 
unequivocally due to disease progression, should not be reported as an AE during the study.
6.3.10 New cancers
The development of a new primary cancer (including skin cancer) should be regarded as an 
AE and will generally meet at least one of the serious criteria (see Section 6.2).  New primary 
cancers are those that are not the primary reason for the administration of the study treatment 
and have developed after the inclusion of the patient into the study.  They do not include 
metastases of the original cancer.  Symptoms of metastasis or the metastasis itself should not 
be reported as an AE/SAE, as they are considered to be disease progression.
6.3.11 Lack of efficacy
When there is deterioration in the ovarian cancer, for which the study treatment(s) is being 
used, there may be uncertainty as to whether this is lack of efficacy or an AE.  In such cases, 
unless the Sponsor or the reporting physician considers that the study treatment contributed to 
the deterioration of the condition, or local regulations state to the contrary, the deterioration 
should be considered to be a lack of efficacy and not an AE.


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6.3.12 Deaths
All deaths that occur in screening part 1 related to study procedures should be reported as a 
SAE.
All deaths that occur during the study, or within the protocol-defined 30-day post-study 
follow-up period after the administration of the last dose of study treatment, must be reported 
as follows:

Death clearly the result of disease progression should be reported to the 
study monitor at the next monitoring visit and should be documented in 
the eCRF but should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease 
under study, the AE causing the death must be reported to the study 
monitor as a SAE within 24 hours (see Section 6.2 for further details).  
The report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign main and 
contributory causes of death.  This information can be captured in the 
‘death eCRF’.

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 adverse events
In Screening part 1, only SAEs related to study procedures must be reported.  From Screening 
part 2 onwards, all SAEs have to be reported, whether or not considered causally related to the 
investigational product, or to the study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives immediately, but no later than 24 hours of when 
he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
designated AstraZeneca representatives of any follow-up information on a previously reported 
SAE within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.


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Once the investigators or other site personnel indicate an AE is serious in the WBDC system, 
an email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the investigator or other study site personnel 
reports a SAE to the appropriate designated AstraZeneca representative in a SAE Report 
Form.
The designated AstraZeneca representative will advise the investigator/study site personnel 
how to proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug.
6.5
Overdose
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established. 
Olaparib must only be used in accordance with the dosing recommendations in this protocol. 
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol 
should be reported as an overdose.  The recommended Phase III clinical trials dose for 
olaparib tablet is 300 mg twice daily.
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately.

An overdose with associated AEs is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the CRF and on the 
Overdose CRF module.

An overdose without associated symptoms is only reported on the 
Overdose CRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.


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6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study investigational product should be 
discontinued immediately.
The outcomes of any conception occurring from the date of the first dose of study medication 
until 3 months after the last dose of study medication must be followed up and documented.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the patient was discontinued from the study.
If any pregnancy occurs during the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1day 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.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
6.6.2
Paternal exposure 
Not applicable.
6.7
Management of IP related toxicities 
Any toxicity observed during the course of the study could be managed by interruption of the 
dose of study treatment or dose reductions. Repeat dose interruptions are allowed as required, 
for a maximum of 4 weeks on each occasion. If the interruption is any longer, the study team 
must be informed. Study treatment can be dose reduced to 250 mg twice daily as a first step 
and to 200 mg twice daily as a second step.. If the reduced dose of 200 mg twice daily is not 
tolerable, no further dose reduction is allowed and study treatment should be discontinued. 
Once dose is reduced, escalation is not permitted.


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6.8
Management of haematological toxicity
6.8.1
Management of anaemia
Haemoglobin 
Action to be taken
Hb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2)
Give appropriate supportive treatment and investigate causality. 
Investigator judgement to continue olaparib with supportive treatment (eg 
transfusion) or interrupt dose for a maximum of 4 weeks. 
If repeat Hb< 10 but ≥ 8 g/dl, dose interrupt until Hb ≥ 10 g/dl for max of 4 
weeks and upon recovery dose reduce to 250 mg twice daily as a first step 
and to 200 mg twice daily as a second step may be considered
Hb < 8 g/dl
(CTCAE Grade 3)
Give appropriate supportive treatment (e.g. transfusion) and investigate 
causality. 
Interrupt olaparib until improved to Hb ≥ 10 g/dl.
Upon recovery dose reduce olaparib to 250 mg twice daily as a first step and 
to 200 mg twice daily as a second step in the case of repeat Hb decrease.
Common treatable causes of anaemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  In some cases 
management of anaemia may require blood transfusions.  For cases where patients develop 
prolonged haematological toxicity (≥2 week interruption/delay in study treatment due to CTC 
grade 3 or worse anaemia and/or development of blood transfusion dependence) , refer to 
Section 6.8.3 for the management of this.
6.8.2
Management of neutropenia, leukopenia and thrombocytopenia
Toxicity
Study treatment dose adjustment
CTCAE gr 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 gr 3-4
Dose interruption until recovered to CTCAE gr 1 or better for a maximum 
of 4 weeks. If repeat CTCAE gr 3-4 occurrence, dose reduce olaparib to 
250 mg twice daily as a first step and 200 mg twice daily as a second step
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by 
the investigator with close follow up and interruption of study drug if CTC grade 3 or worse 
neutropenia occurs. 
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not 
recommended, however, if a patient develops febrile neutropenia, study treatment should be 
stopped and appropriate management including G-CSF should be given according to local 


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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 CTC grade 3 or worse), refer to Section 6.8.3.  
6.8.3
Management of prolonged haematological toxicities while on study treatment
If a patient develops prolonged haematological toxicity such as:

≥2 week interruption/delay in study treatment due to CTC grade 3 or 
worse anaemia and/or development of blood transfusion dependence

≥2 week interruption/delay in study treatment due to CTC grade 3 or 
worse neutropenia (ANC < 1 x 109/L)

≥2 week interruption/delay in study treatment due to CTC grade 3 or 
worse thrombocytopenia and/or development of platelet transfusion 
dependence (Platelets < 50 x 109/L)
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If 
any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the 
patient should be referred to haematologist for further investigations. Bone marrow analysis 
and/or blood cytogenetic analysis should be considered at this stage according to standard 
haematological practice. Study treatment should be discontinued if blood counts do not 
recover to CTC gr 1 or better within 4 weeks of dose interruption.
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should 
be reported as an SAE and full reports must be provided by the investigator to AstraZeneca 
Patient Safety. Olaparib treatment should be discontinued if patient’s diagnosis of MDS 
and/or AML is confirmed.
6.9
Management of non-haematological toxicity
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each 
occasion. If the interruption is any longer than this the study monitor must be informed.  
Where toxicity reoccurs following re-challenge with study treatment, and where further dose 
interruptions are considered inadequate for management of toxicity, then the patient should be 
considered for dose reduction or must permanently discontinue study treatment.
Study treatment can be dose reduced to 250 mg bd as a first step and to 200 mg bd as a second 
step. Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse event occurs 
which the investigator considers to be related to administration of study treatment.


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6.9.1
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.
6.9.2
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 36% in the 
placebo treated patients and vomiting was reported in 34% of the olaparib treated patients and 
14% in 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, olaparib tablets can be taken with a light meal/snack (ie 2 pieces of toast or a 
couple of biscuits).
As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), generally 
a single agent antiemetic should be considered eg dopamine receptor antagonist, 
antihistamines or dexamethasone.
6.9.3
Interruptions for intercurrent non-toxicity related events
Study treatment dose interruption for conditions other than toxicity resolution should be kept 
as short as possible. If a patient cannot restart study treatment within 4 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with AZ 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.


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Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered. Because the AEs related to olaparib may include asthenia, 
fatigue and dizziness, patients should be advised to use caution while driving or using 
machinery if these symptoms occur. 
Table 7
Dose reductions for study treatment
Initial Dose
Following re-challenge post 
interruption: Dose reduction 1
Dose reduction 2
300mg twice daily
250mg twice daily
200mg twice daily
7
MANAGEMENT OF TOXICITY OF CHEMOTHERAPY
Dosing and treatment regimen information for weekly paclitaxel, topotecan, PLD and 
gemcitabine can be found in the local package inserts supplied with the drug. During patients’ 
participation in the study actions for chemotherapy related toxicity should comply with the 
prescribing information for toxicity management and dose reduction.  
8
STUDY GOVERNANCE AND OVERSIGHT
8.1
Data Monitoring Committee
This study will use an external Independent Data Monitoring Committee (IDMC) to perform 
interim reviews of accumulating study safety data.  This committee will be composed of 
therapeutic area experts and a statistician, who are not employed by AstraZeneca, and do not 
have any major conflict of interest. Following the review the IDMC will recommend whether 
the study should continue unchanged, be terminated, or be modified in any way.  Once the 
IDMC has reached a recommendation, a report will be provided to AstraZeneca.  The report 
will only include the recommendation and any potential protocol amendments.  It will not 
contain any unblinded information.  A separate IDMC charter will be developed which will 
contain details of the IDMC members and clearly define the responsibilities of the IDMC.
9
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
9.1
Identity of investigational product(s)
Table 8
Identity of investigational product
Investigational producta
Dosage form and strength
Manufacturer
Olaparib
Tablet – 150mg and 100mg
Soliqs or AbbVie on behalf of 
AstraZeneca
a Descriptive information for olaparib can be found in the olaparib Investigator’s Brochure


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Paclitaxel, topotecan, pegylated liposomal doxorubicin and gemcitabine will be sourced 
locally. Only under exceptional circumstances when this isn’t feasible these chemotherapies 
will be supplied through AstraZeneca. All comparator drugs do not need to be available for a 
site to enrol a patient as long as the comparator of choice is available.  Descriptive information 
for the chemotherapy can be found in the local package inserts supplied with the drug. If 
AstraZeneca is centrally supplying these drugs the package insert may not be in the language 
of the receiving market.  In this case, the investigator should use the local package insert 
information and local standard practices for use of these drugs. 
9.2
Dose and treatment regimens
For all centres, olaparib tablets will be packed in high-density polyethylene (HDPE) bottles 
with child-resistant closures.  Each dosing container will contain sufficient medication for at 
least 28 days plus overage.  Olaparib will be dispensed to patients on Day 1 and every 28 days 
until week 48 and then every 12 weeks thereafter until the patient completes the study, 
withdraws from the study or closure of the study. 
Patients randomised to olaparib will administered their randomised tablets orally at a dose of 
300 mg twice daily.
Olaparib is available as a film-coated tablet containing 150mg or 100mg of olaparib.  Tablets 
are to be taken orally, twice daily (bd).  Doses of olaparib should be taken at the same times 
each day approximately 12 hours apart.  All doses should be taken with approximately 240 
mL of water.  The IP tablets should be swallowed whole and not chewed, crushed, dissolved 
or divided.   
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted.  Should any patient enrolled on the 
study miss a scheduled dose for whatever reason (e.g., as a result of forgetting to take the 
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.
There is no maximum duration for taking IP treatment.  Patients will continue with olaparib 
until objective disease progression (determined by RECIST 1.1), however patients may 
continue with olaparib as long as in the investigator’s opinion they are benefiting from 
treatment and they do not meet any other discontinuation criteria.
For details about dose interruption and reduction please refer to Sections 6.7, 6.8, and 7. 
9.3
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.


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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 “Study Participation Card”. For emergency purposes the patient 
must be in possession of the emergency contact details at all times. 
9.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the bottle specifies the appropriate storage.
9.5
Compliance
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 olaparib.  Study site staff will make tablet counts at regular 
intervals during treatment.  Compliance will be assessed by the tablet count and the 
information will be recorded in the appropriate section of the eCRF.  After the tablet count has 
been performed, the remaining tablets will not be returned to the patient but will be retained 
by the investigative site until reconciliation is completed by the study monitor.  All patients 
must return their bottle(s) of olaparib at the appropriate scheduled visit, when a new bottle 
will be dispensed.  Patients will be instructed to notify study site personnel of missed doses.  
Dates of missed or held doses will be recorded by the patient on their patient diary and by the 
site staff on the eCRF.
Patients must return all containers and any remaining IP tablets at the end of the study.
9.6
Accountability
The IP provided for this study will be used only as directed in the study protocol.
The study personnel will account for all IP dispensed to and returned from the patient.
Study site personnel or the study monitor will account for IP received at the site, unused study 
drugs and for appropriate destruction.  Certificates of delivery, destruction or return should be 
signed. 
9.7
Concomitant and other treatments 
Any medications (with the detailed exceptions) which are considered necessary for the 
patient's welfare, and which it is believed will not interfere with the study medication, may be 
given at the discretion of the investigator, providing the medications, the doses, dates and 
reasons for administration are recorded.


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In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the 
study period must be recorded.  This includes any blood transfusions.
The reasons for the use, doses and dates of treatment should be recorded in the patient’s 
medical records and appropriate sections of the eCRF.
All medications (prescriptions or over the counter medications) continued at the start of study 
or started during the study or until 30 days from the end of the last IP dose and different from 
the study medication must be documented as per Table 1, Table 2, and Table 3.
9.7.1
Medications that may NOT be administered
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy, 
radiotherapy, biological therapy or other novel agent) is to be permitted while the patient is 
receiving study medication.  Hormone replacement therapy (HRT) is acceptable.
Live virus and bacterial vaccines should not be administered whilst the patient is receiving 
study medication and during the 30 day follow up period. An increased risk of infection by the 
administration of live virus and bacterial vaccines has been observed with conventional 
chemotherapy drugs and the effects with olaparib are unknown.
The use of any natural/herbal products or other “folk remedies” should be discouraged and use 
of these products, as well as use of all vitamins, nutritional supplements and all other 
concomitant medications must be recorded.
9.7.1.1
Olaparib and drug-drug interaction
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 eCRF. 
Effect of Other Drugs on Olaparib
CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of 
olaparib. Clinical studies to evaluate the impact of known CYP3A inhibitors and inducers  
have shown that co-administration of a potent CYP3A inhibitor increased olaparib Cmax 
1.42-fold (90% CI: 1.33-1.52) and increased mean AUC 2.70-fold (90% CI: 2.44-2.97) and 
that co-administration of a potent CYP inducer decreased Cmax by 71% (Treatment ratio: 
0.29; 90% CI: 0.24-0.33) and mean AUC by 87% (Treatment ratio: 0.13; 90% CI: 0.11-0.16). 
It is therefore recommended that known strong inhibitors or inducers of these isozymes should 
be avoided with olaparib.
While this is not an exhaustive list, it covers the known potent CYP3A4/5 inhibitors, which 
have most often previously been reported to be associated with clinically significant drug 
interactions:


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
ketoconazole, itraconazole, boosted protease inhibitors (ritonavir, 
indinavir, saquinavir, telithromycin, nelfinavir, boceprevir, telaprevir) 
and clarithromycin 
For patients taking any of the above, the required wash-out periods prior to starting study 
treatment is one week.
In addition, in vivo data have shown that co-administration with rifampicin (a known CYP 
inducer) reduces olaparib AUC by an average of 87%.  Therefore, to avoid potential 
reductions in exposure due to drug interactions, the following CYP3A4/5 inducers should be 
avoided:

phenytoin, rifampicin, rifapentin, rifabutin, carbamazepine, 
phenobarbital, nevirapine, modafinil and St John’s Wort (Hypericum 
perforatum) 
For patients taking any of the above, the required wash-out periods prior to starting study 
treatment for phenobarbital is 5 weeks, and for any of the others, 3 weeks.
After randomisation if the use of any potent inducers or inhibitors of CYP3A4/5 are 
considered necessary for the patient’s safety and welfare, the investigator must contact the 
Study Physician. A decision to allow the patient to continue in the study will be made on a 
case-by-case basis.
In vitro olaparib is a substrate for the efflux transporter Pgp. Clinical studies to evaluate the 
impact of specific Pgp inhibitors and inducers have not been conducted; however based on the
physical and absorption, distribution, metabolism and excretion properties of olaparib, there is
a low risk that a Pgp modulator could significantly alter systemic exposure to olaparib
Effect of Olaparib on Other Drugs
Olaparib can inhibit CYP3A4 and UGT1A1 in vitro.. Using basic models these findings 
suggest that olaparib has the potential to cause clinically significant interactions with other 
CYP3A4 substrates or UGT1A1 substrates in the liver or gastrointestinal (GI) tract. However, 
PBPK modelling predicted olaparib to be a weak CYP3A inhibitor in vivo and did not predict 
olaparib to be a UGT1A1 inhibitor in vivo. Therefore, caution should be exercised when 
substrates of CYP3A4 are combined with olaparib, in particular those with a narrow 
therapeutic margin (eg, simvastatin, cisapride, cyclosporine, ergot alkaloids, fentanyl, 
pimozide, sirolimus, tacrolimus and quetiapine). Substrates of UGT1A1 should also be given 
with caution in combination with olaparib (eg irinotecan, nintedanib, ezetimibe, raltegravir or 
buprenorphine).
Induction of CYP1A2, 2B6 and 3A4 has been shown in vitro with CYP3A4 being most likely 
to be induced to a clinically relevant extent. Based on an evaluation using enzyme activity,
olaparib was not considered an inducer of CYP2C9 and 2C19. It cannot be excluded that 
olaparib upon co administration may reduce the exposure to substrates of these metabolic 


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enzymes and transport protein. The efficacy of hormonal contraceptives may be reduced if co 
administered with olaparib.
In vitro olaparib has been shown to be an inhibitor of Pgp, OATP1B1, OCT1, OCT2, OAT3, 
MATE1 and MATE2K and is a weak inhibitor of BRCP. It cannot be excluded that olaparib 
may increase the exposure to substrates of Pgp (e.g. statins, digoxin, dabigatran, colchicine), 
OATP1B1 (eg, bosentan, glibenclamide, repaglinide, statins, and valsartan), OCT1 (eg, 
metformin), OCT2 (eg, serum creatinine), OAT3, MATE1 and MATE2K. In particular, 
caution should be exercised if olaparib is administered in combination with any statin.
9.7.1.2
Anticoagulant Therapy
Patients who are taking warfarin or acenocoumarol may participate in this trial; however, it is 
recommended that prothrombin time (international normalised ratio (INR) and activated 
partial thromboplastin time (APTT)) be monitored carefully at least once per week for the first 
month, then monthly if the INR is stable. Subcutaneous heparin is permitted.
9.7.1.3
Anti-emetics/Anti-diarrhoeals
From screening part 2 onwards, should a patient develop nausea, vomiting and / or diarrhoea, 
then these symptoms should be reported as AEs (see section 6.3.6) and appropriate treatment 
of the event given.
9.7.1.4
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 2 weeks as long as any bone 
marrow toxicity has recovered.  
9.7.1.5
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. 
9.7.1.6
Subsequent therapies for cancer 
Details of first and subsequent therapies for cancer and/or details of surgery for the treatment 
of the cancer, after discontinuation of treatment, will be collected.  Reasons for starting 
subsequent anti-cancer therapies including access to other PARP inhibitors or investigational 
drugs will be collected and included in the exploratory assessments of OS.


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9.8
Post Study Access to Study Treatment
No plans to provide olaparib after completion of the study treatment.
10 STATISTICAL ANALYSES
10.1 Statistical considerations
Analyses will be performed by AstraZeneca or its representatives.   
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first patient 
randomised and any subsequent amendments will be documented, with final amendments 
completed prior to database lock.
10.2 Sample size estimate
The sample size for this study was selected to be consistent with the research hypothesis as 
described in Section 1.2.
The primary endpoint of the study is ORR. With at least 223 subjects, recruited 2:1 olaparib: 
chemotherapy, the study will have >80% power to show a statistically significant difference in 
ORR at the two-sided 5% level, assuming a response rate of 25% on the chemotherapy arm 
and at least 45% on the olaparib arm for subjects with measurable disease at baseline 
accoridng to BICR. It is anticipated that approximately 90% of subjects will have measurable 
disease at baseline according to BICR and therefore to ensure adequate power, the sample size 
will have at least 250 subjects.
It is anticipated that the study recruitment period will be approximately 40 months and that the 
data-cut off for the primary analysis will occur in January 2019 or at a minimum of 6 months 
after LSI, whichever is sooner. This is to ensure sufficient patient follow-up to characterize 
duration of response (DoR) and satisfy a regulatory committment. No further analyses of ORR 
or PFS are planned beyond this point unless requested by Health Authorities.
10.3 Definitions of analysis sets
Table 9 gives a summary of outcome variables and analysis populations.
10.3.1 Full analysis set
The full analysis set (FAS) 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). 
10.3.2 Measurable disease analysis set (MDAS)
The measurable disease analysis set (MDAS) includes all patients in the FAS with measurable 
disease at baseline (as per RECIST 1.1):


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-
Measurable disease at baseline for the primary analysis is determined using BICR,
-
For reporting the investigator response, the measurable disease analysis set will be 
determined using the investigator reported measurable disease at baseline
10.3.3 Safety analysis set
All patients who received at least one dose of randomised study treatment, olaparib or 
chemotherapy, 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 chemotherapy patients who receive at least one dose of olaparib study 
treatment in error at any time). If a patient randomised to olaparib receives only 
chemotherapy treatment then they will be summarised as part of the chemotherapy arm.
Table 9
Summary of Outcome Variables and Analysis Populations
Outcome Variable
Populations
Efficacy Data
- Primary : ORR by BICR
Measurable disease 
(MDAS)
- Secondary : PFS (by BICR), PFS2, OS, time to earliest progression by 
RECIST 1.1, CA-125 or death, CA-125 response, TFST, TSST, TDT, 
symptom/QoL endpoints
Duration of Response (DoR) by BICR
FAS 
Measurable disease 
(MDAS)
Demography
FAS
Safety Data
- Exposure
Safety
- Adverse Events
Safety
- Lab measurements
Safety
- Vital Signs
Safety
10.4 Outcome measures for analyses
10.4.1 Calculation or derivation of efficacy variable(s)
At each visit patients will be programmatically assigned a RECIST visit response of CR, PR, 
SD, PD, NE depending on the status of their disease compared to baseline and previous 
assessments, based on the BICR review. This will be repeated using the investigator assessed 
RECIST data.


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10.4.1.1 Primary endpoint
Objective Response Rate (ORR) 
Best overall RECIST response (BoR) is calculated based on the overall visit responses from 
each RECIST assessment, described in Appendix E.  It is the best response a patient has had 
during their time in the study up until RECIST progression or the last evaluable assessment in 
the absence of RECIST progression.
Categorisation of best overall response will be determined programmatically based on the 
RECIST 1.1 criteria (Appendix E) for the BICR data, using the following response categories: 
complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) 
and not evaluable (NE).
Best overall response will be determined programmatically from the time point response using 
BICR data.  In addition, this will also be reported using investigator-recorded assessment.
For determination of a best response of SD, the earliest of the dates contributing towards a 
particular overall visit assessment will be used.  SD should be recorded at least 8 weeks +/- 1 
week, i.e. at least 49 days (to allow for the assessment window), after randomisation.  For 
CR/PR, the initial overall visit assessment which showed a response will use the latest of the 
dates contributing towards a particular overall visit assessment.
For patients whose disease progression event is death, BoR will be calculated based on data 
up until the last evaluable RECIST assessment prior to death.
For patients who die with no evaluable RECIST assessments, if the death occurred ≤17 weeks 
(i.e. 16 weeks ±1 week) after randomisation then BoR will be assigned to the progression 
(PD) category.  For patients who die with no evaluable RECIST assessments, if the death 
occurred > 17 weeks (i.e. 16 weeks ±1 week) after randomisation then BoR will be assigned 
to the non-evaluable (NE) category.
Progression events that have been censored due to them being >126 days (i.e. 16 weeks ± 7
days) after the last evaluable assessment will not contribute to the BoR derivation.
A patient will be classified as a responder if the RECIST 1.1 criteria for a CR or PR are 
satisfied at any time up to and including the defined analysis cut-off point. For each treatment 
group, the objective response rate (ORR) is the number of patients with a CR and PR divided 
by the number of patients in the measurable disease analysis set (MDAS). Only patients with 
measurable disease at enrolment can achieve an objective response of CR or PR which will 
not require confirmation due to the randomized controlled study design as per the RECIST 
guidelines. However, a sensitivity analysis of confirmed CR or PR will be conducted.


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10.4.1.2 Secondary endpoints
10.4.1.2.1 Time from randomisation to first progression (PFS)
The PFS endpoint is defined as the time from randomisation until the date of 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 assessment. Given the scheduled visit assessment scheme, for the first 48 
weeks from randomisation two missing visits will equate to more than 18 weeks since the 
previous RECIST assessment, allowing for early and late visits. After 48 weeks, two missing 
visits will equate to more than 26 weeks. 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 (17 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:
(a)
The date of progression will be determined based on the earliest of the scan dates of
the component that triggered the progression for the adjudicated reviewer selecting
PD or for either reviewer where both select PD as time point response and there is
no adjudication for BICR data.
(b)
For investigational site assessments, date of progression will be determined based
on the earliest of the RECIST assessment/scan dates of the component that triggered
the progression.
(c)
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. 
The PFS analysis will be based on the blinded independent central review (BICR) of the 
radiological scans. The BICR will be based on all RECIST assessment scan data provided by 
investigators, including the final RECIST assessment obtained from patients after progression 
has been determined according to RECIST 1.1 criteria by the investigator. A charter for the 
BICR will be developed in advance of the start of the study. A sensitivity analysis based on 


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the programmatically derived PFS based on investigator-recorded assessments will be carried 
out.
10.4.1.2.2 Time from randomisation to second progression (PFS2)
Time from randomisation to second progression is defined as the time from the date of 
randomisation to the earliest of the progression event subsequent to that used for the PFS 
endpoint or death. The date of second progression will be recorded by the investigator and 
defined according to local standard clinical practice and may involve any of objective 
radiological, clinical, CA-125 progression or death. Second progression status will be 
reviewed every 12 weeks following the progression event used for the PFS endpoint (the first 
progression) and status recorded. Patients alive and for whom a second disease progression 
has not been observed should be censored at the last time known to be alive and without a 
second disease progression, i.e. censored at the last progression assessment date if the patient 
has not had a second progression or death).
10.4.1.2.3 Overall Survival
Overall survival 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 date of data cut-off (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.
10.4.1.2.4 Time to earliest progression by RECIST 1.1 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:

Patients with elevated CA-125 pre-treatment (i.e. greater than the upper limit of
normal (ULN):
(a) If CA-125 does not fall to within the normal range whilst on treatment 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 2 occasions at least 1 week apart.
(b) Where CA-125 does fall to within the normal range whilst on study treatment
(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 2
occasions at least 1 week apart.

Patients with CA-125 in the normal range pre-treatment must show evidence of CA-
125 greater than, or equal to, 2 times the ULN on 2 occasions at least 1 week apart.

CA-125 progression will be assigned the date of the first measurement that meets the
criteria as noted.


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Time to progression by RECIST or CA-125 progression or death is defined as the time from 
randomisation to the earlier date of RECIST (based on BICR) 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 or their last 
available CA-125 measurement, whichever is the earliest at the time of the analysis. Since 
CA-125 is assessed more frequently than RECIST the two missed visit rule is based upon the 
RECIST schedule. Therefore if a patient dies, has RECIST progression or has CA-125 
progression after two or more missed RECIST assessments, then the patient will be censored 
using the last evaluable RECIST assessment where CA-125 was also collected. This will be 
defined as a RECIST assessment where the date of CA-125 sample is +/- 11 days (note the 
earliest date of the RECIST/CA-125 assessment will be used.).
If only one assessment is missing during this period, no censoring is required. Patients that do 
not have any evaluable RECIST assessments or any CA-125 results post-randomisation will 
be censored at the date of randomisation.
10.4.1.2.5 Duration of response (DoR)
Duration of response (DoR) will be defined as the time from the date of first documented 
response until date of documented progression or death in the absence of disease progression, 
the end of response should coincide with the date of progression or death from any cause used 
for the PFS endpoint. The time of the initial response will be defined as the latest of the dates 
contributing towards the first visit response of PR or CR.
If a patient does not progress following a response, then their duration of response will use the 
PFS censoring date as the date at which that patient is censored for DoR.
10.4.1.2.6 Time to Response (TTR)
The time to response is defined as the time from randomisation until the date of first 
documented response. The date of first documented response should coincide with that used 
for the DoR endopint.
Time to response will not be defined for those patients who do not have a documented 
response.
10.4.1.2.7 GCIG CA-125 response 
GCIG CA-125 response will be based on the GCIG criteria (Rustin et al 2004). Patients will 
be evaluable for CA-125 response if:

a pre-treatment CA-125 level (taken within 2 weeks prior to starting
treatment) is at least twice the upper limit of normal, and

there is no more than a 10% fall in CA-125 between the two pre-
treatment samples


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
the same assay method is used for each sample from the same patient
A response according to CA-125 will be considered to have occurred if there is at least a 50% 
reduction in CA-125 levels from the last pre-treatment sample.  The response must be 
confirmed and maintained for at least 28 days.  The date when the CA-125 level is first 
reduced by 50% is the date of the CA-125 response.  Note the GCIG criteria are not validated 
for this trial population.
10.4.1.2.8 Time to first subsequent chemotherapy or death (TFST)
As a supportive summary to PFS, time to start of first subsequent chemotherapy or death will 
be assessed.  Time to first subsequent chemotherapy or death is defined as the time from the 
date of randomisation to the earlier of first subsequent chemotherapy 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 chemotherapy. 
10.4.1.2.9 Time to study treatment discontinuation or death (TDT)
Time to study treatment discontinuation or death (TDT) will be assessed.  TDT is defined as 
the time from the date of randomisation to the earlier of the date of study treatment 
discontinuation or death.  Any patient not known to have died at the time of analysis and not 
known to have discontinued study treatment will be censored based on the last recorded date 
on which the patient was known to be alive.
10.4.1.2.10
Time to second subsequent chemotherapy or death (TSST)
As a supportive summary to PFS2, time to start of second subsequent chemotherapy or death 
will be assessed.  Time to second subsequent chemotherapy or death is defined as the time 
from the date of randomisation to the earlier of the date of second subsequent chemotherapy 
start date, or death date.  Any patient not known to have had a further second subsequent 
therapy or death will be censored at the last known time to have not received second 
subsequent chemotherapy.
10.4.1.2.11
FACT-O
Patient-reported health-related quality of life (HRQoL) will be assessed using the FACT-O 
questionnaire (Basen-Enquist K et al 2001). The FACT-O is composed of the following sub-
scales: physical, social/family, emotional, and functional well-being as well as the additional 
concerns scales consisting of specific ovarian cancer symptoms. 
The endpoint for health-related quality of life analysis will be the Trial Outcome Index (TOI), 
(Cella D et al 1993) an established single targeted index derived from the FACT-O 
questionnaire and it is considered to target the most relevant symptoms together with function 
and physical well-being and can be directly related to signs and symptoms and AEs. The TOI 
is composed of the following scales of the FACT-O: physical and functional well-being and 
additional concerns.


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Data relating to the FACT-O will be self-reported through patient questionnaires according to 
the study plan. Patients will be asked to report their health-related quality of life over the 
course of the previous 7 days.  All patients will be asked to complete the FACT-O.  The 
FACT-O questionnaire will be administered at baseline, at Day 29 then in line with the 
RECIST assessments every 8 weeks (+/- 1 week) up to Week 32 (8 months) regardless of 
treatment discontinuation or disease progression.
The Trial Outcome Index (TOI) score will be derived from the sum of the scores of the 25 
items included in the physical well-being (7 items), functional well-being (7 items), and 
ovarian cancer subscale (11 items) of the FACT-O questionnaire version 4. The total FACT-O 
score will also be calculated which is made up of the sum of the individual subscale scores: 
physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), 
functional well being (FWB) and ovarian cancer subscale (Additional Concerns).
The scores will be derived in accordance with the FACT-O Scoring Manual.  A number of 
items are negatively stated and need to be reversed by subtracting the response from “4”. The 
scoring manual identifies that the following items need to be reversed prior to summarizing: 
GP1-7, GE1, GE3-6, O1-3, C2, and B5. After reversing proper items, scores are summarized 
and multiplied by the number of items in the domain. For each subscale, if less than 50% of 
the subscale items are missing, the subscale score will be divided by the number of non-
missing items and multiplied by the total number of items on the subscale. If at least 50% of 
the items are missing, that subscale also will be treated as missing. The reason for any missing 
assessment will be identified. If data are missing at random, the above techniques will be 
used. If there is evidence that the missing data are systematic, missing values will be handled 
to ensure that any possible bias is minimised.  The TOI score ranges from 0-100 and the 
FACT-O from 0-152.  For all Functional Assessment of Chronic Illness Therapy (FACIT) 
scales and symptom indices, a higher score indicates a higher HRQoL.  
The actual change from baseline in TOI score will be derived for each visit where there is 
available data.  For example; at visit X, the calculation will be (TOI score at visit X – Baseline 
TOI score). Actual change from baseline for the individual domain scores will be calculated in 
a similar way.
A change of at least 10 points in TOI score will be considered as a clinically relevant or a 
minimally important difference (Osoba et al 2005). 
The population for analyses of HRQoL (TOI) will include a subset of the FAS population who 
have baseline TOI score. 
The definitions of the visit response for Health Related QoL are outlined below (Table 10).
Best Overall TOI improvement (improvement in the absence of subsequent cancer therapy) 
will be defined as a change from baseline in the TOI of +10 points or more (Osoba et al 2005) 
sustained for at least 28 days, the denominator consisting of a subset of the FAS population 
who have baseline TOI.  It will be derived as the best symptom improvement response the 
patient achieved, based on evaluable QoL data collected from randomisation up to the earliest 


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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 11).
Table 10
Health Related QoL Visit Response
Score
Change from baseline
Visit response
TOI 
≥ +10
Improved
≤ -10
Worsened
Otherwise
No change
Table 11
Health Related Quality of Life: Change rates - overall score
Best Overall TOI score response
Criteria
Improved
Two visit responses of “improved” a minimum of 28 days apart 
without an intervening visit response of “worsened”
No change
Does not qualify for overall score response of “improved”. Two 
visit responses of either “no change” or “improved and “no 
change” a minimum of 28 days apart without an intervening visit 
response of “worsened”
Worsened
Does not qualify for overall score response of “improved” A 
visit response of “worsened” without a response of “improved” 
or “no change” within 28 days.
Other
Does not qualify for one of the above.
A TOI improvement rate (in the absence of subsequent cancer therapy) will be calculated as 
the % of all analysed patients with a best overall score response of improved. In the 
calculation of the proportion of patients that have a response of Improved, No Change or 
Worsened, the denominator used in the calculation will use the number evaluable for that 
individual TOI domain score at baseline.
10.4.2 Calculation or derivation of safety variable(s)
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, vital signs 
and ECG.  These will be collected for all patients.  Appropriate summaries of these data will 
be presented.
10.4.2.1 Other significant adverse events (OAE)
During the evaluation of the AE data, an AstraZeneca or designated CRO medically qualified 
expert will review the list of AEs that were not reported as SAEs and DAEs.  Based on the 
expert’s judgement, significant adverse events of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered OAEs and reported as 


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such in the Clinical Study Report.  A similar review of laboratory/vital signs/ECG data will be 
performed for identification of OAEs.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment.
10.4.3 Calculation or derivation of pharmacokinetic variables
The pharmacokinetic (PK) analysis of the plasma concentration data for olaparib will be 
performed at AstraZeneca R&D or by a CRO identified by AstraZeneca R&D. The actual 
sampling times will be used in the PK calculations. Non-linear mixed effects modelling 
(NONMEM) will evaluate the pharmacokinetic characteristics of olaparib, quantify variability 
in the pharmacokinetics, identify demographic or pathophysiological covariates which may 
explain the observed variability, estimate steady state Cmax, AUC and Cmin and explore 
exposure-response relationships.
10.4.4 Calculation or derivation of pharmacodynamic variable(s) 
Not applicable.
10.4.5 Calculation or derivation of pharmacogenetic variables
To be defined in an exploratory analysis plan.
10.4.6 Calculation or derivation of health economic variables
10.4.6.1 Resource Utilisation
Frequency of resource use including type, length of stay and procedures undertaken, and the 
primary symptom/reason for the hospitalisation or hospital attendance will be estimated.
10.4.6.2 EQ-5D-5L
The EQ-5D is a standardised measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal. 
Applicable to a wide range of health conditions and treatments, it provides a simple 
descriptive profile and a single index value for health status that can be used in the clinical and 
economic evaluation of health care. 
The EQ-5D-5L index comprises five dimensions of health (mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression). For each dimension, respondents select 
which statement best describes their health on that day from a possible five options of 
increasing levels of severity (no problems, slight problems, moderate problems, severe 
problems and unable to/ extreme problems).  A unique EQ-5D health state is referred to by a 
five digit code allowing for a total of 3125 health states.  For example, state 11111 indicates 
no problems on any of the five dimensions. This data will be converted into a weighted health 
state index by applying scores from EQ-5D value sets elicited from general population 
samples (the base case will be the UK valuation set, with other country value sets applied in 


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scenario analyses). Where values sets are not available, the EQ-5D-5L to EQ-5D-3L 
crosswalk will be applied. In addition to the descriptive system, respondents also assess their 
health today on a visual analogue scale, ranging from 0 (worst imaginable health) to 100 (best 
imaginable health). This score is reported separately.
The evaluable population will comprise all patients who receive study treatment as safety 
analysis set and have a baseline EQ-5D-5L assessment.
10.5 Methods for statistical analyses
The treatment comparison is olaparib 300 mg bd versus physician’s choice of chemotherapy.
Results of all statistical analysis will be presented using a 95% confidence interval and 2-sided 
p-value.
The following table details which endpoints are to be patient to formal statistical analysis, 
together with pre-planned sensitivity analyses making clear which analysis is regarded as 
primary for that endpoint.


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Table 12
Formal Statistical Analyses to be Conducted and Pre-Planned 
Sensitivity Analyses
Endpoints Analysed
Notes
ORR (Objective response rate)
Primary analysis: stratified logistic regression using 
BICR assessment in the MDAS
Sensitivity / supportive analyses:
1) Ascertainment bias analysis: Stratified logistic 
regression using investigator assessments in the MDAS
2) Stratified logistic regression based on BICR for all 
patients with evaluable disease. Patients with evaluable 
disease include all of those in the MDAS and patients 
with non-target lesions at baseline and non-measurable 
disease at baseline. (Only required if the evaluable 
disease population differs from the MDAS.).
3) Stratified logistic regression based on BICR for all 
patients in the FAS. (Only required if the FAS 
population differs from the MDAS).
4) Stratified logistic regression based on responses 
confirmed by BICR in the MDAS.
5) Stratified logistic regression based on responses 
confirmed by investigator assessment in the MDAS.
6) Deviation bias (if meaningful to do): stratified 
logistic regression using BICR assessments.
7) Supportive: CA-125 response per treatment arm 
(descriptive only); CA-125 and/or RECIST response 
per treatment arm (descriptive only) based on BICR for 
RECIST


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Table 12
Formal Statistical Analyses to be Conducted and Pre-Planned 
Sensitivity Analyses
Endpoints Analysed
Notes
PFS (Time from randomisation to first 
progression or death)
Primary analysis: Stratified log-rank test using BICR 
assessments
Sensitivity/supportive analysesa:
1) Evaluation time bias analysis; stratified log-rank test 
using BICR assessments
2) Attrition bias analysis (using alternative censoring 
rules); stratified log-rank test using BICR assessments
3) Ascertainment bias analysis; stratified log-rank test 
using investigator assessments
4) Deviation bias (if meaningful to do); stratified 
log-rank test using BICR assessments
PFS2 (Time from randomisation to second 
progression or death)
Primary analysis: stratified log rank test based on 
investigator assessment of second progression
Overall Survival (Time from randomisation 
to death due to any cause)
Primary analysis:  stratified log-rank test 
Supportive analysis: KM plot of time to censoring for 
OS
Time to earliest progression by RECIST 1.1 
or CA-125 or death 
Primary analysis: stratified log-rank test using BICR 
assessment
TFST (Time to first subsequent therapy 
or death)
Stratified log rank test using eCRF data
TSST (Time to second subsequent therapy 
or death)
Stratified log rank test using eCRF data
TDT (Time to study treatment 
discontinuation or death)
Stratified log rank test using eCRF data
Change from baseline in TOI score
Primary: Mean change from baseline in TOI score 
analysed by MMRM
Supportive: Proportion improved (in the absence of 
subsequent cancer therapy) in TOI score analysed 
using logistic regression


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10.5.1 Multiplicity strategy for primary and key secondary endpoints
In order to describe the nature of the benefits of olaparib maintenance treatment, ORR, PFS, 
PFS2, and OS will be tested at a 2-sided significance level of 5%.
However, in order to strongly control the type I error at 2.5% 1-sided, a multiple testing 
procedure will also be employed across the primary endpoint and secondary endpoints 
intended for key label claims (i.e. ORR, PFS, PFS2 and OS). There is no requirement to adjust 
for multiplicity due to ORR or PFS interim analyses, since there are no planned interim ORR 
or PFS analyses with the opportunity to make an early claim of efficacy.
A hierarchical testing strategy will be employed where ORR is tested first using the full test 
mass (full test mass = alpha 5% 2 sided) and key secondary endpoints of PFS, PFS2 and OS 
will then be tested using a multiple testing procedure with a recycling strategy (i.e., the MTP 
will recycle the test mass to the endpoint not yet rejected in the hierarchy outlined in Figure 
3).
Figure 3
Multiple Testing Procedure
PFS will only be tested if the null hypothesis (of no difference) for ORR is rejected. PFS2 will 
only be tested if the null hypothesis (of no difference) is rejected for both ORR and PFS. OS 
will only be tested if the null hypothesis (of no difference) is rejected for ORR, PFS and PFS2. 
An additional PFS2 and OS analysis will only be conducted with further follow up (~60% OS 
events) if both ORR and PFS are statistically significant based on the primary analysis and the 
null hypotheses for PFS2 and/or OS are not rejected at the time of the primary analysis. If an 
additional analysis is conducted for PFS2 and OS, to control for multiple testing due to an 
interim and final analysis a Lan DeMets spending function (Lan and DeMets 1983) that 
approximates an O’Brien Fleming approach will be used to account for multiplicity.


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10.5.2 Analysis of the primary variable(s)
10.5.2.1 Objective Response Rate (ORR)
The data cut-off for the primary analysis will occur in January 2019 or at a minimum of 6 
months after LSI, whichever is sooner. No further analyses of ORR are planned beyond this 
point unless requested by Health Authorities.
For each treatment arm, best overall RECIST response (BoR) will be summarised by n (%) for 
each category (CR, PR, SD, PD and NE). No formal statistical analyses are planned. BOR will 
be presented based on the BICR data and also the investigator recorded data.
ORR will be analysed using logistic regression adjusted by the stratification factors. If the 
number of responses in the individual stratum are too small for a meaningful analysis (less 
than 5 responses per stratum), a pre-specified strategy to account for such a situation, will be 
applied. Further details will be documented in the Statistical Analysis Plan.. Results of the 
analysis will be presented in terms of an odds ratio (olaparib vs. chemotherapy) together with 
its associated 95% CI and 2-sided p-value (based on twice the change in log-likelihood 
resulting from the addition of a treatment factor to the model). CIs will be profile likelihood 
CIs (e.g. using the option ‘LRCI’ in SAS procedure GENMOD). ORR will be analysed for the 
BICR data and also the investigator recorded data.
A response of CR or PR will not require confirmation due to the randomized controlled study 
design as per the RECIST guidelines.
10.5.2.2 Subgroup analysis for the primary endpoint (ORR)
Subgroup analyses will be conducted comparing ORR between treatments. The purpose of the 
subgroup analyses is to assess the consistency of treatment effect across potential or expected 
prognostic factors. If there are too few events available for a meaningful analysis of a 
particular subgroup (it is not considered appropriate to present analyses where there are less 
than 20 patients in a subgroup), the relationship between that subgroup and ORR will not be 
formally analysed. In this case, only descriptive summaries will be provided.
The following subgroups of the full analysis set will be analysed for ORR
Stratification factors

•Selected study chemotherapy (paclitaxel/topotecan/pegylated liposomal
doxorubicin/gemcitabine)

•Number of prior chemotherapy regimens received for ovarian cancer (2 or 3 vs. 4 or
more)

•Time to disease progression on last platinum based chemotherapy received prior to
randomisation (6 – 12 months / > 12 months)

Additional subgroups of interest include:


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•
BRCA mutation type, e.g. BRCA1, BRCA2 or BRCA1/2 (both)

•Age at randomisation (<65 vs. ≥65)

•Region

•Race

•ECOG performance status at baseline (0, 1, or 2)
Other baseline variables may also be assessed if there is clinical justification.
For each subgroup, the ORs (olaparib: physician’s choice of chemotherapy) and associated 
CIs will be calculated from an adjusted logistic regression model, provided there are enough 
responses for a meaningful analysis. The model will include stratification factors. No 
adjustment to the significance level for testing will be made since all these subgroup analyses 
will be considered exploratory and may only be supportive of the primary analysis of ORR.
The ORR analysis will be repeated excluding any patients who did not have a gBRCA 
mutation status confirmed by the Myriad test. The response rate in each treatment arm will be 
presented. No formal statistical analyses will be conducted.
10.5.2.3 Sensitivity analyses for the primary endpoint (ORR)
(a) Ascertainment bias
A stratified logistic regression will be repeated using the programatically derived RECIST 
using investigator assessed ORR. The OR and 95% Confidence Interval will be presented.
If there is an important discrepancy between the primary analysis using BICR assessments and 
this sensitivity analysis using investigator assessments, then the proportion of patients with 
site but no central confirmation of objective response will be summarised.
Disagreements between investigator and central reviews of RECIST objective response will 
be presented for each treatment group. The summary will include the early discrepancy rate 
which is the frequency of central review declared responses before the investigator review as a 
proportion of all central review responses and the late discrepancy rate which is the frequency 
of central review declared responses after the investigator review as a proportion of all 
responses.
(b) Subjects with evaluable disease at baseline
As a sensitivity analysis to the primary ORR analysis, the analysis will be repeated including 
all patients with evaluable disease at baseline. This will include all patients in the Measurable 
Disease Analysis Set (MDAS) and patients with non-measurable disease at baseline, but 
presenting with non-target lesions at baseline. No formal statistical analyses will be 
conducted.


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(c) Full Analysis Set
As a sensitivity analysis to the primary ORR analysis, the analysis will be repeated including 
all randomised patients. (All patients in the FAS). No formal statistical analyses will be 
conducted.
(d) Confirmed response
A sensitivity analysis of confirmed CR or PR will be conducted. A confirmed response of 
CR/PR means that a response of CR/PR is recorded at 1 visit and confirmed by repeat imaging 
not less than 4 weeks after the visit when the response was first observed with no evidence of 
progression between the initial and CR/PR confirmation visit. Data obtained up until 
progression, or last evaluable assessment in the absence of progression, will be included in the 
assessment of ORR. Patients who discontinue treatment without progression, receive a 
subsequent anti-cancer therapy (note that for this analysis radiotherapy is not considered a
subsequent anti-cancer therapy) and then respond will not be included as responders in the 
ORR (i.e. both visits contributing to a response must be prior to subsequent therapy for the 
patient to be considered as a responder).
In the case where a patient has two non-consecutive visit responses of PR, then, as long as the 
time between the 2 visits of PR is greater than 4 weeks and there is no PD between the PR 
visits, the patient will be defined as a responder. Similarly, if a patient has visit responses of 
CR, NE, CR, then, as long as the time between the 2 visits of CR is greater than 4 weeks, then 
a best response of CR will be assigned.
(e) Deviation bias (if meaningful to do)
As a sensitivity analysis to the primary endpoint of ORR, an analysis excluding patients with 
deviations that may affect the efficacy of the trial therapy will be performed if > 10% of 
patients:
• did not have the intended disease or indication or
• did not receive any randomised therapy
A stratified logistic regression will be repeated using the BICR RECIST data, using the same 
ties and stratification factors as described for the primary analysis of ORR. The OR and 95% 
CI will be presented.
10.5.3 Analysis of the secondary variable(s) 
10.5.3.1 PFS analysis
PFS will be analysed using a log rank test stratified by the stratification factors.If the number 
of events in the individual stratum are too small for a meaningful analysis (less than 5 events 
per stratum), a pre-specified strategy to account for such a situation, will be applied. Further 
details will be documented in the Statistical Analysis Plan. The hazard ratio (HR) and 


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confidence interval will be estimated from the U and V statistics obtained directly from the 
LIFETEST model with inclusion of STRATA terms for the stratification variables, if 
applicable (and using the Breslow approach for handling ties).
The HR and its confidence interval will be estimated from the log-rank as follows (Berry et al 
1991 and Sellke et al 1983)
HR = exp(U/V)
95% CI for HR = (exp{U/V – 1.96/ √V}, exp{U/V + 1.96/ √V})
Where U 


i
i
i
e
d
)
(
1
1
is the log-rank test statistic (with d1i and e1i the observed and expected 
events in group 1) and √V the standard deviation of the log-rank test statistic as produced in 
the LIFETEST output.  
The HR (olaparib vs. chemotherapy) together with its corresponding 95% confidence interval 
(CI) and p-value will be presented (a HR less than 1 will favour olaparib).  
Any patients mis-stratified in the IVRS will be included in the stratified log rank test using the 
baseline data collected in the IVRS.
A Kaplan-Meier (KM) plot of PFS will be presented by treatment group. Summaries of the 
number and percentage of patients experiencing a PFS event, and the type of event (RECIST 
or death) will be provided along with median PFS for each treatment arm.
The assumption of proportionality will be assessed. Note that in the presence of non-
proportionality, the HR will be interpreted as an average HR over the observed extent of 
follow-up.  Proportionality will be tested firstly by producing plots of complementary log-log
(event times) versus log (time) and, if these raise concerns, a time dependent covariate would 
be fitted to assess the extent to which this represents random variation.  
The PFS analysis will be based on the programmatically derived PFS based on BICR 
assessments, and using all scans regardless of whether they were scheduled or not. 
The estimated PFS rates at 6 months and 12 months will be summarised (using the KM curve) 
and presented by treatment group.
The number of patients prematurely censored will be summarised by treatment arm together 
with baseline prognostic factors of the prematurely censored patients.  A patient is defined as 
prematurely censored if they had not progressed and the latest scan prior to DCO was more 
than one scheduled tumour assessment interval (+ 2 weeks) prior to the DCO date.
As patients will be randomised, imbalances in demographic factors between the treatment 
groups are not anticipated.  However if any imbalances should occur, the HR and associated 
confidence interval calculated from a Cox Proportional Hazards model containing treatment, 
stratification variables and these additional demographic variables, may be reported.  


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10.5.3.1.1 Subgroup analysis for PFS
Subgroup analyses will be conducted comparing PFS between treatments. The purpose of the 
subgroup analyses is to assess the consistency of treatment effect across potential or expected 
prognostic factors.  If there are too few events available for a meaningful analysis of a 
particular subgroup (it is not considered appropriate to present analyses where there are less 
than 20 events in a subgroup), the relationship between that subgroup and PFS will not be 
formally analysed.  In this case, only descriptive summaries will be provided.
The following subgroups of the full analysis set will be analysed for PFS
Stratification factors

Selected study chemotherapy (paclitaxel/topotecan/pegylated liposomal 
doxorubicin/gemcitabine)

Number of prior chemotherapy regimens received for ovarian cancer (2 
or 3 vs. 4 or more)

Time to disease progression on last platinum based chemotherapy 
received prior to randomisation (6 – 12 months / > 12 months)
Additional subgroups of interest include:

Measurable versus non-measurable disease

BRCA mutation type, e.g. BRCA1, BRCA2 or BRCA1/2 (both) 

Age at randomisation (<65 vs. ≥65) 

Region

Race

ECOG performance status at baseline (0, 1, or 2)
Other baseline variables may also be assessed if there is clinical justification. 
For each subgroup, the HRs (olaparib: physician’s choice of chemotherapy) and associated 
CIs will be calculated from a Cox proportional hazards model (ties = Efron) that contains the 
treatment term, factor and treatment-by-factor interaction term.  The treatment effect HRs for 
each treatment comparison along with their confidence intervals will be obtained for each 
level of the subgroup from this single model.  The HRs and 95% CIs will be presented on a 
forest plot including the HR and 95% CI from the overall population (using the primary 
analysis).  


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No adjustment to the significance level for testing of subgroups will be made since all these 
subgroup analyses will be considered exploratory and may only be supportive of the primary 
analysis of PFS.
The presence of quantitative interactions will be assessed by means of an overall global 
interaction test.  This will be performed in the overall population by comparing the fit of a 
Cox proportional hazards model including treatment, all covariates (stratification factors), and 
all covariate-by-treatment interaction terms, with one that excludes the interaction terms and 
will be assessed at the 2-sided 10% significance level. If the fit of the model is not 
significantly improved then it will be concluded that overall the treatment effect is consistent
across the subgroups.
If the global interaction test is found to be statistically significant, an attempt to determine the 
cause and type of interaction will be made. Stepwise backwards selection will be performed 
on the saturated model, whereby (using a 10% level throughout) the least significant 
interaction terms are removed one-by-one and any newly significant interactions re-included 
until a final model is reached where all included interactions are significant and all excluded 
interactions are non-significant.  Throughout this process all main effects will be included in 
the model regardless of whether the corresponding interaction term is still present.  This 
approach will identify the factors that independently alter the treatment effect and prevent 
identification of multiple correlated interactions. 
Any quantitative interactions identified using this procedure will then be tested to rule out any 
qualitative interaction using the approach Gail and Simon 1985.
The PFS analysis will be repeated excluding any patients who did not have a gBRCA 
mutation status confirmed by the Myriad test.  A Kaplan-Meier (KM) plot of PFS will be 
presented by treatment group. Summaries of the number and percentage of patients 
experiencing a PFS event, and the type of event (RECIST or death) will be provided along 
with median PFS for each treatment arm. No formal statistical analyses will be conducted.
10.5.3.1.2 Sensitivity analyses for PFS
Sensitivity analyses will be performed to assess the possible presence of time-assessment bias 
(i.e., differential assessment times between treatment groups).
Summary statistics for the number of weeks between the time of progression and the last 
evaluable RECIST assessment prior to progression will be presented for each treatment group.
(a)
Evaluation-Time bias
Sensitivity analyses will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled time points. The midpoint 
between the time of progression and the previous evaluable RECIST assessment will be 
analysed using a stratified log rank test, as described for the primary PFS analysis. This 
approach has been shown to be robust to even highly asymmetric assessment schedules (Sun 
and Chen 2010). This approach will use the BICR RECIST assessments.


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(b)
Attrition bias
Attrition bias will be assessed by repeating the primary PFS analysis except that the actual 
PFS event times, rather than the censored times, of patients who progressed or died in the 
absence of progression immediately following two, or more, non-evaluable tumour 
assessments will be included. In addition, patients who take subsequent therapy prior to 
progression or death will be censored at their last evaluable assessment prior to taking the 
subsequent therapy. 
Additionally a Kaplan-Meier plot of the time to censoring where the censoring indicator of the 
primary PFS analysis is reversed will be presented.
(c)
Ascertainment bias
A stratified log-rank test will be repeated using the programmatically derived RECIST using 
investigator assessed PFS.  The HR and 95% Confidence Interval will be presented.  
If there is an important discrepancy between the primary analysis using BICR assessments and 
this sensitivity analysis using investigator assessments, then the proportion of patients with 
site but no central confirmation of progression will be summarised.  The approach of imputing 
an event at the next visit in the central review analysis may help inform the most likely HR 
value, but only if an important discrepancy exists.  
Disagreements between investigator and central reviews of RECIST progression will be 
presented for each treatment group.  The summary will include the early discrepancy rate 
which is the frequency of central review declared progressions before the investigator review 
as a proportion of all central review progressions and the late discrepancy rate which is the 
frequency of central review declared progressions after the investigator review as a proportion 
of all discrepancies.
(d)
Deviation bias (if meaningful to do)
As a sensitivity analysis to the primary PFS analysis, an analysis excluding patients with 
deviations that may affect the efficacy of the trial therapy will be performed if > 10% of 
patients:

did not have the intended disease or indication or

did not receive any randomised therapy
A stratified log-rank test will be repeated using the BICR RECIST data, using the same ties 
and stratification factors as described for the primary analysis of PFS. The HR and 95% CI 
will be presented.


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10.5.3.2 Analysis of PFS2 endpoint
An initial PFS2 analysis will be performed at the same time as the primary analysis of ORR 
and will use the same methodology and model as the PFS analysis. If the number of events in 
the individual stratum are too small for a meaningful analysis (less than 5 events per stratum), 
a pre-specified strategy to account for such a situation, will be applied. Further details will be 
documented in the Statistical Analysis Plan. If there are less than 20 events, descriptive 
summaries will be provided only. A further analysis of PFS2 will be performed when the OS 
data are approximately 60% mature only if both ORR and PFS are statistically significant 
based on the primary analysis and the null hypotheses for PFS2 and/or OS are not rejected at 
the time of the primary analysis.
The analysis of PFS2 will be repeated excluding any patients who did not have a gBRCA
mutation status confirmed by the Myriad test.  The same methodology and model will be used 
and the HR and associated 95% CI from a Cox Proportional Hazards model will be reported.
10.5.3.3 Analysis of OS endpoint
OS data will be analysed at the time of the primary analysis of ORR and will use the same 
methodology and model as the PFS analysis If the number of deaths in the individual stratum 
are too small for a meaningful analysis (less than 5 deaths per stratum), a pre-specified 
strategy to account for such a situation, will be applied. Further details will be documented in 
the Statistical Analysis Plan. If there are less than 20 deaths, descriptive summaries will be 
provided only. A further analysis of OS will be performed when the OS data are 
approximately 60% mature, only if both ORR and PFS are statistically significant based on 
the primary analysis and the null hypotheses for PFS2 and/or OS are not rejected at the time of 
the primary analysis.
A Kaplan-Meier plot of the time to censoring where the censoring indicator of the primary OS 
is reversed will be generated.
The analysis of OS will be repeated excluding any patients who did not have a gBRCA
mutation status confirmed by the Myriad test.  The same methodology and model will be used 
and the HR and associated 95% CI from a Cox Proportional Hazards model will be reported.
10.5.3.4 Time to earliest progression by RECIST 1.1 or CA-125 or death
Time to earliest progression by RECIST 1.1, CA-125 or death will be performed at the same 
time as the primary analysis and will use the same methodology and model as the PFS 
endpoint. 
The analysis of time to earliest progression by RECIST 1.1, CA-125 or death will be repeated 
excluding any patients who did not have a gBRCA mutation status confirmed by the Myriad 
test.  The same methodology and model will be used and the HR and associated 95% CI from 
a Cox Proportional Hazards model will be reported.
No multiplicity adjustment will be applied as this is viewed as a supportive endpoint (to PFS).


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10.5.3.5 Time to first subsequent chemotherapy or death (TFST)
As a supportive analysis for PFS, time to start of first subsequent chemotherapy or death will 
be analysed using the same methodology and model as that used for the primary analysis of 
PFS.  The HR for the treatment effect together with its 95% CI will be presented.  In addition, 
a Kaplan Meier plot of time to start of first subsequent chemotherapy or death will be 
presented by treatment arm.  No multiplicity adjustment will be applied as this is viewed as a 
supportive endpoint.
The analysis of TFST will be repeated excluding any patients who did not have a gBRCA
mutation status confirmed by the Myriad test.  The same methodology and model will be used 
and the HR and associated 95% CI from a Cox Proportional Hazards model will be reported.
A summary table of first subsequent therapies by treatment arm will be provided.
10.5.3.6 Time to study treatment discontinuation (TDT)
Similarly as a supportive analysis for PFS, time to study treatment discontinuation or death 
will be analysed using the same methodology and model as that used for the primary analysis 
of PFS.  The HR for the treatment effect together with its 95% CI will be presented.  In 
addition, a Kaplan Meier plot of time to study treatment discontinuation or death will be 
presented by treatment arm.  No multiplicity adjustment will be applied as this is viewed as a 
supportive endpoint.
The analysis of TDT will be repeated excluding any patients who did not have a gBRCA
mutation status confirmed by the Myriad test.  The same methodology and model will be used 
and the HR and associated 95% CI from a Cox Proportional Hazards model will be reported.
10.5.3.7 Time to second subsequent chemotherapy or death (TSST)
As a supportive analysis for PFS2, time to start of second subsequent chemotherapy or death 
will be analysed using the same methodology and model as that used to analyse PFS2.  The 
HR for the treatment effect together with its 95% CI will be presented.  In addition, a Kaplan 
Meier plot of time to start of second subsequent chemotherapy or death will be presented by 
treatment arm.  No multiplicity adjustment will be applied as this is viewed as a supportive 
endpoint.
The analysis of TSST will be repeated excluding any patients who did not have a gBRCA
mutation status confirmed by the Myriad test.  The same methodology and model will be used 
and the HR and associated 95% CI from a Cox Proportional Hazards model will be reported.
A summary table of second subsequent therapies by treatment arm will be provided.
10.5.3.8 Duration of Response (DoR) and CA-125 response
Descriptive data will be provided for the DoR in responding patients (i.e. median duration of 
response and 95% CIs) by treatment arm, including the associated Kaplan-Meier curves 
(without any formal comparison of treatment arms or p-value attached).


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In addition, the number and percentage of patients reporting a CA-125 response, an objective 
RECIST 1.1 response and both a CA-125 and/or objective RECIST response will be tabulated.
10.5.3.9 Time to response (TTR)
The TTR will be summarised (i.e. number of patients [%] based upon the number of 
responders for each cohort) by the scheduled assessment timepoint that the response was first 
observed. Additionally, descriptive summary statistics (i.e. minimum, maximum, median, Q1 
and Q3) will also be presented.
10.5.3.10
FACT-O
The analysis population for HRQoL data will be the subset of the FAS.
Change from baseline in TOI score will be regarded as the primary analysis of the FACT-O 
questionnaire and will be analysed using a mixed model for repeated measures (MMRM) 
analysis of the change from baseline in TOI score for each visit.  The primary analysis will be 
to compare the average treatment effect from the point of randomisation for the first 8 months 
(which will include visit data obtained at baseline, weeks 4, 8, 16 and 32). Other timepoints 
and the study discontinuation visit and the safety follow-up visit will be excluded from this 
analysis but may be included on supportive summaries and graphical displays as appropriate.
The MMRM model will include patient, treatment, visit and treatment by visit interaction as 
explanatory variables and the baseline TOI score as a covariate. Treatment, visit and treatment 
by visit interaction will be fixed effects in the model; patient will be included as a random 
effect.  The treatment by visit interaction will remain in the model regardless of significance.  
Calculation of a suitable adjusted mean estimate will be detailed in the SAP that will estimate 
the average treatment effect over visits which gives each visit equal weight.  The adjusted 
mean estimates and corresponding 95% confidence intervals will be presented for the overall 
treatment comparison and by visit for each treatment group.
Descriptive statistics and graphs will be reported for the TOI by visits as well as change in 
these scores from baseline.  These will also be reported for the physical well-being (PWB), 
social well being (SWB), emotional well being (EWB), functional well-being (FWB) and the 
ovarian cancer subscale (Additional Concerns) domains.
Summary tables of Trial Outcome Index (TOI) best change rates will be provided. TOI 
improvement rate will be analysed using a logistic regression model and using the same 
covariates as used in the PFS analyses. If there are <5 patients with a response of improved no 
analysis will be performed.  If there are <50 patients with a response in a treatment group a 
Fisher’s exact test will be considered and mid p-values used. The results of the analysis will 
be presented in terms of an odds ratio together with its associated profile likelihood 95% 
confidence intervals and p-values (based on twice the change in log-likelihood resulting from 
the addition of a treatment factor to the model).
Summary tables of best change rates and analysis of improvement rates will be performed for 
the physical well being (PWB), social well being (SWB), emotional well being (EWB), 


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functional well being (FWB) and the ovarian cancer subscale (Additional Concerns) domains
for both change from baseline and improvement rates. P-values will not be calculated for 
these supportive analyses.
10.5.4 Analysis of Exploratory Endpoints
10.5.4.1 Cancer Therapy Satisfaction Questionnaire (CTSQ-16)
The treatment satisfaction score (as measured by the Satisfaction with Therapy scale of the 
CTSQ-16) and patient-reported feelings measured by the ‘feelings about side-effects’ domain 
of the Cancer Therapy Satisfaction Questionnaire (CTSQ-16) will be summarised by 
treatment arm. 
10.5.4.2 Analysis of Healthcare Resource Use
An exploratory health economic analysis of resource use will be estimated, including 
descriptive statistics relating frequency of hospitalisations and hospital admission, type of 
attendance, length of stay and procedures undertaken, and the primary symptom/reason for the 
attendance.
10.5.4.3 Health State Utility – EQ-5D-5L
Descriptive statistics will be reported for EQ-5D-5L health state utility values and the visual 
analogue score by visit, as well as change in these scores from baseline. Further details of the 
exploratory analysis will be outlined in the statistical analysis plan (SAP).
The scores for each of the EQ-5D-5L health state utility values and visual analogue will be 
summarised in terms of mean changes from baseline at each post-baseline assessment (with n, 
standard deviation, min, max presented). If less than 50% of the items in one health state are 
missing, the mean scores for the completed items will be used for imputation. If 50% or more 
of the items in one health state are missing, that subscale will be treated as missing.
10.5.4.4 Patient Global Impression of Change – PGIC 
Descriptive statistics will be reported for PGIC for week 24 and discontintuation. Further 
details of the exploratory analysis will be outlined in the statistical analysis plan (SAP).
10.5.4.5 Impact of switching to PARP inhibitors (or other potentially active 
investigational agents) on Overall Survival Analyses
Exploratory analyses of OS adjusting for impact of subsequent PARP inhibitor trial or 
treatment may be performed if a sufficient proportion of patients receive the therapies of 
interest.  Methods such as Rank Preserving Structural Failure Time (RPSFT) (Robins et al 
1991), Inverse Probability of Censoring Weighting (IPCW) (Robins 1993) and other methods 
in development will be explored.  The decision to adjust and final choice of methods will be 
based on a blinded review of the data and the plausibility of the underlying assumptions.  
Baseline and time-dependent characteristics will be explored, and summaries of baseline 
characteristics will be summarised for patients receiving physician’s choice of chemotherapy, 
splitting between those that have and haven’t received a PARP inhibitor at the time of the 


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analyses.  Further detail will be provided in the SAP and Payer Analysis Plan. These analyses 
are intended to support reimbursement appraisals.
10.5.4.6 Exploratory translational science endpoints
Full statistical methods for exploratory endpoints will be defined in a separate translation 
science analysis plan.  
Biomarker data will be summarised descriptively using tables and plots.  If the data is 
available at the time of developing the CSR then the biomarker data will be included in the 
CSR.  Otherwise the biomarker data will be reported in a separate addendum to the CSR (if 
applicable).  Further details on the data summaries and plots for the biomarker data for the 
CSR will be provided in the SAP.
BRCA status will be summarised for all patients based on the central Myriad test result.  This 
will highlight any patients with a negative BRCA result from the central test.
10.5.5 Interim analysis
No formal statistical interim analyses for ORR or PFS are planned for this trial. The data cut-
off for primary analysis will occur in January 2019 or at a minimum of 6 months after LSI, 
whichever is sooner. PFS2 and OS will be analysed at the time of the primary analysis. An 
additional PFS2 and OS analysis will only be conducted with further follow up (~60% OS 
events) if both ORR and PFS are statistically significant based on the primary analysis and the 
null hypotheses for PFS2 and/or OS are not rejected at the time of the primary analysis.
This study will use an external Independent Data Monitoring Committee (IDMC) to perform 
interim reviews of accumulating study safety data. This committee will be composed of 
therapeutic area experts and a statistician, who are not employed by AZ, and do not have any 
major conflict of interest. Following the review, the IDMC will recommend whether the study 
should continue unchanged, be terminated, or be modified in any way. Once the IDMC has 
reached a recommendation, a report will be provided to AstraZeneca. The report will only 
include the recommendation and any potential protocol amendments and it will not contain 
any unblinded information or reference to the confidential considerations of the committee to 
have led to their recommendation.  A separate IDMC charter will be developed which will 
contain any details of the IDMC members and clearly define the responsibilities of the IDMC.
In addition to the periodic review of safety data by an IDMC, the safety of all AstraZeneca 
clinical studies is closely monitored on an on-going basis by AstraZeneca representatives in 
consultation with the Patient Safety Department. Issues identified will be addressed; this could 
involve, for instance, amendments to the study protocol and letters to investigators.


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11 STUDY AND DATA MANAGEMENT
11.1 Training of study site personnel
Before the first patient is entered into the study, a designated AstraZeneca representative will 
review and discuss the requirements of the Clinical Study Protocol and related documents 
with the investigational staff and also train them in any study specific procedures and the 
WBDC and/or any ePROs system(s) utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
11.2 Monitoring of the study
During the study, a designated AstraZeneca representative will have regular contacts with the 
study site, including visits to:

Provide information and support to the investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data 
are being accurately and timely recorded in the CRFs, that biological 
samples are handled in accordance with the Laboratory Manual and that 
study drug accountability checks are being performed

Perform source data verification (a comparison of the data in the CRFs 
with the patient’s medical records at the hospital or practice, and other 
records relevant to the study) including verification of informed consent 
of participating patients. This will require direct access to all original 
records for each patient (e.g., clinic charts)

Ensure withdrawal of informed consent to the use of the patient’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the patient.
The designated AstraZeneca representative will be available between visits if the 
investigator(s) or other staff at the centre needs information and advice about the study 
conduct.


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11.2.1 Source data
Refer to the Clinical Study Agreement for location of source data.
11.2.2 Study agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca or designated CRO and the Principal Investigator should be 
in place before any study-related procedures can take place, or patients are enrolled.
11.2.3 Archiving of study documents
The investigator follows the principles outlined in the Clinical Study Agreement (CSA).
11.3 Study timetable and end of study
The end of this study is defined as ‘the date of the last visit of the last patient undergoing the 
study’. 
At the time of study analysis completion (final analysis per CSP or any interim analysis 
resulting in decision of no more data collection required) number of patients can still be on 
study drug. These patients are to continue treatment as long as beneficial in investigator 
opinion. 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 
olaparib. 
Patients’ treatment can be continued:
- Within current study
- Within special rollover or safety extension study if available
- Within drug supply program (commercial supply or other compassionate use program) if 
applicable
In case of treatment continuation within current study:
Assessment will revert to standard of care at particular site.
There would be no more data collection except SAE reporting. Clinical Study Database would 
be closed.


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Paper form process would be used for SAE reporting. All SAEs, overdoses and pregnancies 
would be reported until 30 days after last dose.
Study drug would be supplied to sites manually outside of IXRS system. Drug dispensation 
and reconciliation will be handled by site on each patient’s visit.
Study would be opened until last patient treated. Final Last Subject Last visit will be defined 
as last patient’s treatment discontinuation.
In case of special Rollover or Safety Extension Study available
for patients remaining in this study after analysis finalized, they can be transferred to such 
umbrella protocol. 
Rollover or Safety Extension study has to be fully approved by Regulatory and Ethics bodies 
applicable for patient’s site.
Such study would ensure proper treatment continuation with visits assessment per its protocol.
Visits assessments will be covering minimum needed for safety oversight. Can cover as well 
assessments found as required for long term use analysis.
Any patient that would be proposed to move to such study, would be given with new Informed 
Consent Form.
If study drug would be approved on market for use in disease under study indication
patients may be discontinued and switched to marketed product. Drug supply options can be 
available depending on the country and would be proposed to patient when found as best way 
to continue treatment by both AZ and investigator.
For patients who do continue to receive treatment beyond the time of this data cut-off, 
Investigators will continue to report all SAEs to AstraZeneca Patient Safety until 30 days after 
study treatment is discontinued, in accordance with Section 6.4. If an Investigator learns of 
any SAEs, including death, at any time after a patient has completed the study, and he/she 
considers there is a reasonable possibility that the event is causally related to the 
investigational product, the Investigator should notify AstraZeneca, Patient Safety. 
Additionally as stated in Section 6.3, any SAE or non-serious adverse event that is ongoing at 
the time of this data cut-off, must be followed up to resolution unless the event is considered 
by the investigator to be unlikely to resolve, or the patient is lost to follow-up.
The study is expected to start in Q4 2014 and to end by Q1 2021, or when the study transition 
to PART (post-analysis treatment) will be finalized.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 


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entire study prematurely if concerns for safety arise within this study or in any other study 
with olaparib.
11.4 Data management 
Data management will be performed by 
. 
The data collected through third party sources will be obtained and reconciled against study 
data.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the WHODRUG.  All coding will be performed by the Medical 
Coding Team at 
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 Study Plans.  Quality control procedures will be 
applied to each stage of data handling to ensure that all data are reliable and have been 
processed correctly.  The Plans will also clarify the roles and responsibilities of the various 
functions and personnel involved in the data management process.
When all data have been coded, validated, and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data Management of genotype data
Exploratory genotype data generated in this study will be stored in the AstraZeneca 
genotyping LIMS database, or other appropriate secure system within AstraZeneca and/or 
third party contracted to work with AstraZeneca to analyse samples.  The results from this 
exploratory genetic research may be reported in the CSR.
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory (ies) internal or 
external to AstraZeneca.


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Management of external data
Data from external providers (e.g. central laboratories) will be validated as appropriate to 
ensure it is consistent with the clinical data and included in the final database.
In the case of biomarker (tumour tissue or blood for exploratory analyses) data, the results of 
any analyses will not be recorded in the database, but information relating to the processing of 
the sample, including the original date of biopsy (historical tumour tissue sample and the 
actual date the sample(s) were collected) will be recorded in the eCRF and database.
Site staff will enter PRO booklet data into the WBDC system.
12 ETHICAL AND REGULATORY REQUIREMENTS
12.1 Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
12.2 Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
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.  The exception to the above is the results of the Myriad gBRCA test, 
this will be made available to the investigator and patient.
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, a Study 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.
12.3 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.


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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 Ethics Committee 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, the final version of the 
Informed Consent Form, is approved by the national regulatory authority or a notification to 
the national regulatory authority is done, according to local regulations.
AstraZeneca or designated CRO will handle the distribution of any of these documents to the 
national regulatory authorities.
AstraZeneca or designated CRO will provide Regulatory Authorities, Ethics Committees and 
Principal Investigators with safety updates/reports according to local requirements.
For the US and Canada, may also be applicable to other countries, each Principal Investigator 
is responsible for providing the Ethics Committees/IRB with reports of any serious and 
unexpected adverse drug reactions from any other study conducted with the investigational 
product.  AstraZeneca or designated CRO will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.
12.4 Informed consent
The Principal Investigator(s) at each centre will:

Ensure each patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the 
study, including any information on the mandatory and optional sampling 
e.g. BRCA testing and tumour biopsies.

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


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
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.
12.5 Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator, the Principal Investigator and AstraZeneca or designated CRO.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols.
AstraZeneca or designated CRO will distribute any subsequent amendments and new versions 
of the protocol to each Principal Investigator(s). For distribution to Ethics Committee see 
Section 12.3.
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
12.6 Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements.  The investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the centre.


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sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and 
in combination with platinum drugs. Proc Natl Acad Sci. 2008;105(44):17079-84.
Rustin et al 2004
Rustin, GJS et al. New guidelines to evaluate the response to treatment in solid tumors 
(ovarian cancer). J Natl Cancer Inst 2004; 96(6):487-488
Siegel et al 2013
Siegel R, Naishadham D and Jemal A.  Cancer Statistics, 2013.  CA Cancer J Clin 
2013;63:11-30.
Sellke et al 1983
Sellke, T. and Siegmund, D. Sequential analysis of the proportional hazards model. 
Biometrika 1983; 70: 315-326
Sun and Chen 2010
Sun X, Chen C: Comparison of Finkelstein’s Method With the Conventional Approach for 
Interval-Censored Data Analysis. Stat Biopharm Research 2:97-108, 2010
Tan et al 2008
Tan D, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, et al. “BRCAness” 
syndrome in ovarian cancer: a case-control study describing the clinical features and outcome 
of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J 
Clin Oncol 26:5530-36.
Vay et al 2011
Vay A, Kumar S, Seward S, Semaan A, Schiffer CA, Munkarah AR, et al.  Therapy-related 
myeloid leukemia after treatment for epithelial ovarian carcinoma: an epidemiological 
analysis.  Gynecologic Oncology 2011;123:456-60.


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SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D0816C00010
Edition Number
4
Date
30 October 2018
A Phase III, Open Label, Randomised, Controlled, Multi-centre Study to 
assess the efficacy and safety of Olaparib Monotherapy versus Physician’s 
Choice Single Agent Chemotherapy in the Treatment of Platinum Sensitive 
Relapsed Ovarian Cancer in Patients carrying germline BRCA1/2 
Mutations








Statistical Analysis Plan 
Study Code D0816C00010
Edition Number 4
Date 30 October 2018
5
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................3
SIGNATURE OF 
 STUDY STATISTICIAN ...............................................4
TABLE OF CONTENTS.....................................................................................5
LIST OF ABBREVIATIONS ..............................................................................7
AMENDMENT HISTORY................................................................................ 11
1.
STUDY DETAILS............................................................................................. 15
1.1
Study objectives................................................................................................. 15
1.2
Study design ...................................................................................................... 17
1.3
Number of subjects ............................................................................................ 20
2.
ANALYSIS SETS ............................................................................................. 20
2.1
Definition of analysis sets .................................................................................. 20
2.1.1
Full analysis set (FAS)....................................................................................... 20
2.1.2
Measurable disease analysis set (MDAS) ........................................................... 20
2.1.3
Safety analysis set.............................................................................................. 21
2.1.4
PK Analysis Set ................................................................................................. 21
2.2
Violations and deviations ................................................................................... 22
3.
PRIMARY AND SECONDARY VARIABLES................................................. 23
3.1
Derivation of RECIST visit responses ................................................................ 23
3.1.1
Target lesions (TLs)........................................................................................... 23
3.1.2
Non-Target Lesions (NTLs) and new lesions...................................................... 28
3.1.3
Overall visit response......................................................................................... 29
3.1.4
Independent review............................................................................................ 30
3.2
Outcome variables ............................................................................................. 30
3.2.1
Objective Response Rate (ORR) ........................................................................ 31
3.2.2
Progression free survival (PFS).......................................................................... 32
3.2.3
Time from randomisation to second progression (PFS2)..................................... 33
3.2.4
Overall survival (OS)......................................................................................... 34
3.2.5
Time to earliest progression by RECIST 1.1 or CA-125 or death........................ 34
3.2.6
Duration of Response (DoR).............................................................................. 35
3.2.7
Time to Response (TTR).................................................................................... 35
3.2.8
CA-125 response................................................................................................ 35


Statistical Analysis Plan 
Study Code D0816C00010
Edition Number 4
Date 30 October 2018
6
3.2.9
Time to first subsequent chemotherapy or death (TFST) .................................... 36
3.2.10
Time to study treatment discontinuation or death (TDT) .................................... 36
3.2.11
Time to second subsequent chemotherapy or death (TSST)................................ 37
3.3
Patient reported outcome variables..................................................................... 37
3.3.1
FACT-O ............................................................................................................ 37
3.3.2
Cancer Therapy Satisfaction Questionnaire (CTSQ-16)...................................... 41
3.4
Safety................................................................................................................. 42
3.4.1
Adverse events (AEs)......................................................................................... 42
3.4.2
Treatment exposure............................................................................................ 43
3.4.3
Dose intensity .................................................................................................... 43
3.4.4
Laboratory data.................................................................................................. 45
3.4.5
Electrocardiograms (ECGs)................................................................................ 45
3.4.6
Vital signs.......................................................................................................... 45
3.4.7
General considerations for safety assessments.................................................... 45
3.5
Health Economic Endpoints............................................................................... 47
3.5.1
Hospital Resource Use ....................................................................................... 47
3.5.2
EQ-5D-5L (exploratory analysis) ....................................................................... 47
3.6
Pharmacokinetic Endpoints................................................................................ 48
4.
ANALYSIS METHODS.................................................................................... 49
4.1
Analysis methods............................................................................................... 49
4.1.1
Multiplicity........................................................................................................ 52
4.1.2
Primary variable - Objective Response Rate (ORR) ........................................... 54
4.1.2.1
Subgroup analysis for the primary endpoint (ORR)............................................ 54
4.1.2.2
Sensitivity analyses for the primary endpoint (ORR).......................................... 56
4.1.3
Progression free survival (PFS).......................................................................... 58
4.1.4
Progression free survival 2 (PFS2) ..................................................................... 65
4.1.5
Overall survival (OS)......................................................................................... 65
4.1.6
Time to first subsequent therapy or death (TFST) and time to second 
subsequent therapy or death (TSST)................................................................... 66
4.1.7
Time to study treatment discontinuation or death (TDT) .................................... 67
4.1.8
Time to earliest progression by RECIST 1.1, CA-125 or death........................... 67
4.1.9
Duration of Response (DoR) and CA-125 Response........................................... 67
4.1.10
FACT-O ............................................................................................................ 68
4.1.11
Exploratory analyses.......................................................................................... 69
4.1.12
Safety................................................................................................................. 70
4.1.13
Demographic and baseline characteristics data................................................... 74
4.1.14
Treatment exposure............................................................................................ 76
4.1.15
Pharmacokinetic analysis ................................................................................... 76
4.1.16
Data cut-offs ...................................................................................................... 77
5.
INTERIM ANALYSES ..................................................................................... 77
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 77
7.
REFERENCES .................................................................................................. 78


Statistical Analysis Plan 
Study Code D0816C00010
Edition Number 4
Date 30 October 2018
7
LIST OF ABBREVIATIONS
The following abbreviations and special terms are used in this study Statistical Analysis Plan.
Abbreviation or 
special term
Explanation
AE
Adverse event 
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
Baseline
Refers to the most recent assessment of any variable prior to dosing with 
study treatment
bd
Twice daily
BICR
Blinded Independent Central Review
BoR
Best Overall RECIST Response
BP
Blood pressure
BRCA
Breast Cancer susceptibility gene
BRCA mutation or 
BRCAm
Breast Cancer susceptibility gene mutation (see gBRCA mutation or 
gBRCAm)
CA-125
Cancer Antigen – 125
CI
Confidence Interval 
CR
Complete response
CRF / eCRF 
Case Report Form (electronic)
CSR
Clinical Study Report
CT
Computed tomography
CTC / CTCAE
Common Terminology Criteria for Adverse Event
CTSQ-16
Cancer Therapy Satisfaction Questionnaire
DAE
Discontinuation of Investigational Product due to Adverse Event
DCO
Data Cut Off
DBL
Database Lock
DNA
Deoxyribonucleic acid 
DoR
Duration of response
dp
Decimal places
ECG
Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group: A performance status using scales 
and criteria to assess how a patient’s disease is progressing
EQ-5D-5L / EQ-5D
EuroQoL five dimensions, five level (EQ-5D-5L) health state utility index


Statistical Analysis Plan 
Study Code D0816C00010
Edition Number 4
Date 30 October 2018
8
Abbreviation or 
special term
Explanation
EWB
Emotional well being
FACIT
Functional Assessment of Chronic Illness Therapy
FACT-O
Functional Assessment of Cancer Therapy – Ovarian: A multidimensional 
questionnaire for patients with ovarian cancer
FAS
Full Analysis Set
FIGO
International Federation of Gynecology and Obstetrics
FSI
First Subject In
FWB
Functional well being
gBRCA
Germline BRCA
gBRCA mutation or 
gBRCAm
The term "gBRCA mutation" is used to refer to a germline BRCA1 or 
BRCA2 mutation 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
gBRCA wt
gBRCA wildtype
GCIG
Gynecologic Cancer Intergroup 
HDU
High Dependency Unit
HR
Hazard Ratio
HRQoL
Health-related Quality of Life
IDMC
Independent Data Monitoring Committee
ICU
Intensive Care Unit
IPCW
Inverse Probability of Censoring Weighting
IVRS
Interactive Voice Response System
KM
Kaplan Meier
LD
Longest diameter
MDAS
Mg
Measurable disease analysis set
Milligram
MRI
Magnetic resonance imaging
MTP
Multiple Testing Procedure
NCI
National Cancer Institute
NE
Not evaluable
NONMEM
Non-Linear Mixed Effects Modelling
NTL
Non-target lesions
OAE
Other Significant Adverse Event


Statistical Analysis Plan 
Study Code D0816C00010
Edition Number 4
Date 30 October 2018
9
Abbreviation or 
special term
Explanation
OR
ORR
Odds Ratio
Objective response rates
OS
Overall survival
PARP
Polyadenosine 5’diphosphoribose [poly (ADP ribose)] polymerisation
PD
Progressive disease
PFS / PFS1
Progression Free Survival
PFS2
Time from randomisation to second progression
PK
Pharmacokinetic
PKPD
Pharmacokinetic pharmacodynamic
PLD
Pegylated liposomal doxorubicin
po
Per os (by mouth, orally)
PS
Performance Status
PR
Partial response
PWB
Physical well being
Q
Question
QoL
Quality of Life
RECIST
Response Evaluation Criteria In Solid Tumours.  This study will use 
RECIST version 1.1
RPSFT
Rank Preserving Structural Failure Time
SAE
Serious adverse event 
SD
Stable disease
SDTM
Study Data Tabulation Model
SWB
Social well being
Study treatment
Olaparib or chemotherapy
TA
Therapeutic Area
tBRCA mutation or 
tBRCAm
The term "tBRCA mutation" is used to refer to a somatic tumour BRCA1 or 
BRCA2 mutation 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
TDT
Time from randomisation to study treatment discontinuation or death
TFST
Time from randomisation to first subsequent therapy or death
TL
Target lesions
TOI
Trial Outcome Index


Statistical Analysis Plan 
Study Code D0816C00010
Edition Number 4
Date 30 October 2018
10
Abbreviation or 
special term
Explanation
TSST
Time from randomisation to second subsequent therapy or death
ULN
Upper limit of normal
wt
Wildtype (patients without evidence of BRCA1 or BRCA2 deleterious or 
suspected deleterious mutations)


Statistical Analysis Plan 
Study Code D0816C00010
Edition Number 4
Date 30 October 2018
11
AMENDMENT HISTORY
Date
Brief description of changes
13 November 2017
1.
Update the rules for missing RECIST visits to cover the time between 
the 8 week and 12 week schedules
2.
Added clarification of how the missing visit rule will be implemented 
for the time to RECIST 1.1 or CA-125 progression or death
3.
Clarification that ORR will be summarised for all patients in the FAS 
with measurable disease and also for all patients in the FAS
4.
Clarification of the rules for censoring for PFS2, TFST and TSST
5.
Updated to reflect the missing data rules for TOI and FACT-O and to 
add in details of the analysis of total FACT-O
6.
Update of the duration of a cycle from 21 to 28 days
7.
Clarification added for the conversion of the intended dose units for 
the dose intensity derivations
8.
Addition of details on the plan for PK data
9.
Addition of the details on the precision to which the p-values, hazard 
rations, odds ratios and confidence intervals will be presented
10. Clarification added on the derivation of age
11. Prior cytoreductive surgery removed from subgroups as this cannot be 
derived
12. Kaplan-Meier plot for investigator assessed data added for PFS
13. Change in the number of events required for subgroup analyses to be 
performed
14. Removal of a selection of sensitivity analysis tables, figures and 
listings to reduce the volume of outputs generated
15. Update to the criteria for the analysis of TOI
16. Summary of PGIC added
17. Correction of CTSQ-16 to indicate that this is assessed at Week 24
18. Clarification that treatment emergent AEs include those that worsen 
after the first dose of study medication
19. Clarification of the data cut-off process
20. Primary objective and endpoint changed from PFS to ORR
21. Number of randomised patients changed from 411 to 250
22. The data cut-off for the primary analysis will occur in January 
2019 or at a minimum of 6 months after LSI, whichever is 
sooner.
23. Time to response was added as a secondary objective
24. Figure 1, study flow chart was updated
25. Section 1.3 Number of subjects was updated to reflect the 
change in sample size from 411 to 250
26. Section 2.1, A measurable disease analysis set was added for the 
primary endpoint, ORR; A PK analysis set was added.


Statistical Analysis Plan 
Study Code D0816C00010
Edition Number 4
Date 30 October 2018
12
Date
Brief description of changes
27. Section 3.2 Outcome variables was updated to reflect changes 
based on the new primary objective and endpoint and time to 
response was added
28. Sections 3.2.2 and 3.2.5  PFS; the rules surrounding missed 
visits were clarified
29. Section 3.2.9. Clarification was added around the censoring for 
TFST and TSST (section 3.2.11)
30. Section 3.4.3. Rules were added for calculating doses
31. Section 4: Analysis methods were updated to reflect the change 
in number of patients and primary endpoint. Additional 
sensitivity and subgroup analyses were added for the new 
primary endpoint.
32. Section 4: Rules were added for imputing age where only a 
partial date of birth has been collected
33. Section 4.1.10 HRQoL MMRM analysis was amended to 
include data from week 48.
34. Section 4.1.13 Demographic tables added by measurable disease
35. Section 4.1.15 Additional information was added for a PK 
analysis
14 April 2018
1. Addition of on-treatment analyses for ORR and PFS
2. Addition of an unadjusted logistic regression analysis for ORR
3. Addition of an unadjusted Cox proportional hazards model for 
PFS
4. Addition of a forest plot for ORR
5. Addition of a pooling strategy for the stratification factors and 
clarification that the resultant pooled factors are the factors to be 
used in the analyses
6. Change to use the IVRS factors in the subgroup analyses for 
ORR and PFS and only perform subgroup analyses using the 
eCRF values in the case of mis-stratifications  
7. Change of subgroup analyses for ORR from adjusted to 
unadjusted for consistency with PFS subgroup analyses and 
correction to use the measurable disease analysis set
8. Change in the definitions for the early and late discrepancy rate 
for ORR and PFS
9. Removal of the missing data rules for FACT-O as the scoring 
manual will be followed
10. A baseline TOI score by visit interaction term was added to the 
MMRM model for TOI and removal of the random intercept
11. CA-125 response added to the secondary objective table as an 
outcome measure
12. Justification removed from the number of subjects section and 
analysis methods section for the duration of follow up as not 
needed for the SAP


Statistical Analysis Plan 
Study Code D0816C00010
Edition Number 4
Date 30 October 2018
13
Date
Brief description of changes
13. Table 1 formatting updated
14. Violations and deviations section simplified, minor deviations 
text removed and details on the deviation bias sensitivity 
analysis population moved to the corresponding section for the 
analysis
15. Update from best overall response to best objective response
16. Clarification added for the handling of missing data in terms of 
the best objective response
17. Clarification added to the section on independent review on 
adjudication and the data provided to the central reviewers
18. Clarification added that the sensitivity analysis of confirmed CR 
or PR will be conducted for both BICR and Investigator data
19. The formulae for the calculation of the PFS, TFST and TSST 
times have been added 
20. Clarification added that if a patient has a missing baseline scan 
and the die within 2 visits of baseline, then this will be counted 
as a PFS event. 
21. Clarification added for the censoring of DoR
22. Clarification added that alternative analysis methods may be 
explored if the FACT-O data has evidence of systematic missing 
values
23. Details adding from the scoring manual for CTSQ-16 to 
document how the domains will be derived
24. Stratified removed from the description of the logistic regression 
analysis in Table 8
25. CA-125 response moved to a separate row as a secondary 
endpoint in Table 8 
26. Clarification added that if there are patients who have not had at 
least 2 prior lines of chemotherapy, then they will be grouped 
with patients who have had 2 prior lines of chemotherapy for the 
ORR analysis
27. Clarification added to define stratum for the subgroup analyses 
for ORR for use in the rule for performing analyses based on the 
number of responses
28. Clarification added to indicate that additional analyses may be 
performed to explore the impact of confounding factors for ORR
29. Clarification added for the analysis method for sensitivity 
analyses for ORR in terms of the use of stratification factors
30. Clarification added to explicitly state that BICR will be used for 
specific sensitivity analyses
31. Details of the multiplicity approach removed from the PFS2 and 
OS sections as this is repeated


Statistical Analysis Plan 
Study Code D0816C00010
Edition Number 4
Date 30 October 2018
14
Date
Brief description of changes
32. Reference to summary of unblinding removed as this is an open 
label study
30 October 2018
1. Clarification added on the classification of the measurable 
disease analysis set in case of adjudication
2. Detail added for the two missed visit rule for PFS2
3. Clarfication on deriving CA-125 progression and response
4. Rules for missing TOI and total FACT-O scores
5. Update to handle missing date of birth
6. Subgroup added for PFS: measurable verus non-measurable 
disease at baseline
7. Update to the FACT-O mixed model for repeated measures 
anlaysis to only include visits performed whilst the patient is on 
treatment.


Statistical Analysis Plan 
Study Code D0816C00010
Edition Number 4
Date 30 October 2018
15
1.
STUDY DETAILS
1.1
Study objectives
Primary Objective:
Outcome Measure:

To determine the efficacy of olaparib vs. 
physician’s choice single agent 
chemotherapy by assessment of Objective 
Response Rate (ORR) using blinded 
independent central review (BICR) 

Objective Response Rate (ORR) by BICR using 
RECIST 1.1 criteria
Secondary Objective:
Outcome Measure:

To compare the efficacy of single agent 
olaparib versus physician’s choice single 
agent chemotherapy

Progression Free Survival (PFS) by BICR using 
RECIST 1.1 criteria

Time from randomisation to second progression 
(PFS2) by investigator assessment of 
radiological, clinical or CA-125 progression

Overall Survival (OS)

Time to earliest progression by BICR RECIST
1.1 or CA-125 or death

Time from randomisation to first subsequent 
therapy or death (TFST)

Time from randomisation to second subsequent 
therapy or death (TSST)

Time from randomisation to study treatment 
discontinuation or death (TDT)

Duration of response (DoR) by BICR using 
RECIST 1.1 criteria for evaluable patients

Time to Response (TTR) by BICR using RECIST 
1.1 criteria for evaluable patients

CA-125 response 

To compare the efficacy of single agent 
olaparib versus physician’s choice single 
agent chemotherapy on the Health-related 
Quality of Life (HRQoL) as measured by 
the trial outcome index (TOI) of the 
Functional Assessment of Cancer Therapy 
– Ovarian (FACT-O)

Mean change from baseline in TOI score

Proportion improved (in the absence of 
subsequent cancer therapy) in TOI score


Statistical Analysis Plan 
Study Code D0816C00010
Edition Number 4
Date 30 October 2018
16

To assess efficacy of olaparib in patients 
identified as having a deleterious or 
suspected deleterious variant in either of 
the BRCA genes using variants identified 
with current and future BRCA mutation 
assays (e.g. gene sequencing and large 
rearrangement analysis)

ORR (by BICR), PFS (by BICR), PFS2, OS, TDT, 
TFST and TSST, analyses will be performed in 
those patients whose gBRCAm status is 
confirmed by the central Myriad test (only 
required if population differs from the MDAS (for 
ORR) or FAS (for PFS))

Development and delivery of a BRCA mutation 
companion diagnostic

To determine exposure to olaparib 
following dosing at the 300 mg bd tablet 
dose and explore exposure-response 
relationships

Olaparib plasma concentration data. Population 
PK and PK-Pharmacodynamic (PD) analyses 
will be completed and reported separately from 
the clinical study report.
Safety Objective:
Outcome Measure:

To assess the safety and tolerability of 
single agent olaparib vs. physician’s 
choice single agent chemotherapy 

Adverse Events (AE), physical examination, vital 
signs including blood pressure (BP), pulse, 
electrocardiogram (ECG) and laboratory 
findings including clinical chemistry and 
haematology
Exploratory Objective:
Outcome Measure:

To assess the effect on patient self-
reported feelings about side-effects of 
single agent olaparib versus physician’s 
choice of single agent chemotherapy 
using the ‘Feelings about side-effects’ 
domain of the Cancer Therapy 
Satisfaction Questionnaire (CTSQ-16)

Treatment satisfaction score (as measured by 
the Satisfaction with Therapy scale of the 
CTSQ-16)

Patient-reported feelings measured by the 
‘feelings about side-effects’ domain of the 
Cancer Therapy Satisfaction Questionnaire 
(CTSQ-16)

To investigate the health economic impact 
of treatment and the disease on hospital 
related resource use and health state 
utility

Number, type and reason of hospitalisations 
and hospital attendances, procedures 
undertaken and hospital length of stay

Health state utility derived from the HRQoL 
instrument, the EuroQoL EQ5D-5L

To explore methods of estimating overall 
survival (OS) adjusting for the impact of 
the control arm receiving subsequent 
Polyadenosine 5’diphosphoribose [poly 
(ADP ribose)] polymerise (PARP) 
inhibitors or imbalances between the 

Overall survival adjusted for impact of 
subsequent PARP inhibitors (or other 
potentially active investigational agents (if 
appropriate, to support reimbursement 
appraisals)


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treatment arms for other potentially active 
agents

To determine the frequency of and 
describe the nature of BRCA mutation/s in 
tumour samples and to compare this with 
germline BRCA mutation status

BRCA1 and/or BRCA2 mutation status in 
tumour

To explore whether resistance 
mechanisms to olaparib can be identified 
through analysis of tumour and blood 
samples – archival tumour (mandatory if 
available), blood samples at baseline and 
on disease progression (mandated) and 
serial biopsies at baseline and disease 
progression (optional)

Future exploratory research into factors 
that may influence development of cancer 
and/or response to treatment (where 
response is defined broadly to include 
efficacy, tolerability or safety) may be 
performed on the collected and stored 
archival tumour samples (mandatory if 
available), blood samples at baseline and 
on disease progression (mandated) and 
serial biopsies at baseline and disease 
progression (optional)

To collect and store DNA according to 
each country’s local and ethical 
procedures for future exploratory 
research into genes/genetic variation that 
may influence response (i.e. distribution, 
safety, tolerability and efficacy) to study 
treatments and/or susceptibility to disease 
(optional)

Potential retrospective tissue biomarker 
research
The exploratory analyses may not be reported in the clinical study report (CSR).  If not, they 
will be reported separately.
1.2
Study design
This open label, randomised, controlled, multi-centre study will assess the efficacy and safety 
of single agent olaparib vs. standard of care, based on physician’s choice of single agent 
chemotherapy ( i.e. weekly paclitaxel, topotecan, pegylated liposomal doxorubicin or 
gemcitabine) in relapsed ovarian cancer patients who have received at least 2 prior lines of 
platinum based chemotherapy, who have progressed at least 6 months after their last platinum 
based chemotherapy and who carry a germline deleterious or suspected deleterious BRCA


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mutation. Non-platinum based chemotherapy in this setting can be given to prolong the 
platinum free interval and can be followed by further platinum treatment at a later relapse or 
can be considered for patients who are not warranted for further platinum treatment.  Due to 
different routes and schedules of administration of the study treatments and different toxicity 
profiles, the study is not feasible to be blinded. Given the open label design of the study, 
rigorous methodology will be employed to ensure robustness of the primary endpoint 
assessment with a primary analysis of ORR based on blinded independent central review 
(BICR) of all patient scans for patients with measurable disease at baseline. Secondary 
endpoints will include progression free survival (PFS) by BICR, time from randomisation to 
second progression assessed by the investigator (PFS2), overall survival (OS), CA-125 
response, safety assessments and health related quality of life (HRQoL).
The treatment groups include olaparib 300 mg po twice daily tablet continuously, or 
physician’s choice of chemotherapy. The investigator must declare prior to randomisation 
their choice of chemotherapy, i.e. weekly paclitaxel, topotecan, pegylated liposomal 
doxorubicin or gemcitabine. The randomisation scheme will be stratified based on:

Selected chemotherapy (weekly paclitaxel vs. topotecan vs. pegylated liposomal 
doxorubicin vs. gemcitabine)

Received prior chemotherapy regimens for ovarian cancer (2 or 3 prior lines of 
chemotherapy vs. 4 or more)

Time to disease progression after the end of the last platinum based chemotherapy (6-
12 mo vs. > 12 mo)
The study flow diagram is presented in Figure 1.


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Figure 1
Study Flow Chart  


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20
1.3
Number of subjects
The sample size for this study was selected to be consistent with the research hypothesis as 
described below.
Olaparib, administered as monotherapy improves objective response rate compared to 
physician’s choice of single agent standard of care chemotherapy (weekly paclitaxel, 
topotecan, pegylated liposomal doxorubicin (PLD) or gemcitabine) in patients with relapsed 
platinum sensitive ovarian cancer who have received at least 2 prior platinum based lines of 
chemotherapy and carry gBRCA mutation.
The primary endpoint of the study is ORR. With at least 223 subjects with measurable disease 
at baseline, randomised 2:1 olaparib: chemotherapy, the study will have >80% power to show 
a statistically significant difference in ORR at the two-sided 5% level, assuming a response 
rate of 25% on the chemotherapy arm and at least 45% on the olaparib arm for subjects with 
measurable disease at baseline according to BICR. It is anticipated that approximately 90% of 
subjects will have measurable disease at baseline according to BICR and therefore to ensure 
adequate power, the sample size will have at least 250 subjects.
It is anticipated that the study recruitment period will be approximately 40 months and that the 
data-cut off for the primary analysis will occur in January 2019 or at a minimum of 6 months 
after LSI, whichever is sooner. No further analyses of ORR or PFS are planned beyond this 
point unless requested by Health Authorities.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
Table 1 gives a summary of outcome variables and analysis populations.
2.1.1
Full analysis set (FAS)
The full analysis set (FAS) 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).
2.1.2
Measurable disease analysis set (MDAS)
The measurable disease analysis set (MDAS) includes all patients in the FAS with measurable 
disease at baseline (as per RECIST 1.1)
-
Measurable disease at baseline for the primary analysis is determined using BICR, 


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o
If the patient was not adjudicated, then the primary reader will be used to 
determine whether or not the subject had target lesions at baseline
o
If the patient was adjudicated, then the reader who the adjudicated selected will 
be used to determine whether or not the subject had target lesions at baseline
-
For reporting the investigator response, the measurable disease analysis set will be 
determined using the investigator reported measurable disease at baseline
2.1.3
Safety analysis set
All patients who received at least one dose of randomised study treatment, olaparib or 
chemotherapy, 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 chemotherapy patients who receive at least one dose of olaparib study 
treatment in error at any time). If a patient randomised to olaparib receives only 
chemotherapy treatment then they will be summarised as part of the chemotherapy arm.
2.1.4
PK Analysis Set
The PK analysis set includes all patients who receive an olaparib dose and provide evaluable 
plasma concentration data. Examples of events which may affect PK data evaluability include
study drug not taken according to protocol, disallowed surgical procedure, vomiting within 3 
hours of dosing and use of disallowed concomitant medication. The population will be defined 
by the study team clinical pharmacology scientist, pharmacometrician and statistician prior to 
any analyses being performed.
Table 1 Summary of Outcome Variables and Analysis Populations
Outcome Variable
Populations
Efficacy Data
-     Primary : ORR by BICR
Measurable disease (MDAS)
-
Secondary : PFS (by BICR), PFS2, OS, time 
to earliest progression by BICR RECIST 1.1, 
CA-125 or death, , CA-125 response, TFST, 
TSST, TDT, symptom/HRQoL endpoints
Full analysis set (FAS)
-
Duration of response (DoR) by BICR
Measurable disease (MDAS)
Demography
Full analysis set (FAS)
Safety Data
- Exposure
Safety
- Adverse Events
Safety
- Lab measurements
Safety


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Table 1 Summary of Outcome Variables and Analysis Populations
Outcome Variable
Populations
- Vital Signs
Safety
Plasma concentration data
PK
2.2
Violations and deviations
Important protocol deviations will be listed and summarised by randomised treatment group.  
None of the deviations will lead to any patients being excluded from any of the analysis sets 
described in Section 2.1.  The following general categories will be considered important 
deviations . This list is not exhaustive and the study team may highlight additional important 
protocol deviations at their discretion: :

Patients randomised but who did not receive olaparib or chemotherapy.

Patients who deviate from key entry criteria:

Female patients with histologically diagnosed relapsed high grade serous 
ovarian cancer (including primary peritoneal and/or fallopian tube cancer) or 
high grade endometrioid cancer (Inclusion criterion 3)

Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious 
or suspected deleterious (known or predicted to be detrimental/lead to loss of 
function) (Inclusion criterion 4)

Baseline RECIST scan > 28 days before randomisation

Baseline RECIST scan after study treatment is started

Patients who receive a different chemotherapy regimen to that stated prior to 
randomisation. (Note that the sites are asked to specify intended chemotherapy 
ahead of randomisation taking place.)

Patients who at some point receive the incorrect treatment (i.e. not their randomised 
treatment).  The likelihood of this is expected to be low given the open nature of the 
trial and the different modes of administration of the randomised treatments.
The summary will include all patients with a dispensing error but 
will also include information on how many of those patients received 
at least one dose of the wrong treatment (olaparib/chemotherapy) at 
any time.  Patients who receive the wrong treatment at any time will 
be included in the safety analysis set as described in Section 2.1.  


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All patients who failed any inclusion/exclusion criteria will be listed along with details of the 
failed criteria.  This information will also be summarised in terms of the number (%) of 
patients failing any of the inclusion/exclusion criteria and will be based on the FAS.
Other deviations may occur during the trial, which are not considered important and not 
believed to have any significant impact on the interpretation of the study results.  All of these 
deviations will be recorded by the study monitors but will not be listed or summarised as part 
of the CSR.
In addition to the programmatic determination of the deviations above, monitoring notes or 
summaries will be reviewed to determine any important post entry deviations that are not 
identifiable via programming, and to check that those identified via programming are correctly 
classified.  The final classification will be made prior to database lock.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Derivation of RECIST visit responses
Patients with measurable or non-measurable disease assessed at baseline by CT/MRI will be 
entered in this study.  
For all patients, the RECIST tumour response data will be used to determine each patient’s 
visit response according to RECIST version 1.1.  It will also be used to determine if and when 
a patient has progressed in accordance with RECIST and also their best objective response.  
Baseline radiological tumour assessments are to be performed no more than 28 days before 
randomisation and ideally should be performed as close as possible to the start of study 
treatment.  Tumour assessments are then performed every 8 weeks (±1 week) up to 48 weeks 
and then every 12 weeks (±1 week) following randomisation until objective disease 
progression as defined by modified RECIST 1.1.
If an unscheduled assessment was performed and the patient had not progressed, every 
attempt should be made to perform the subsequent assessments at their scheduled visits. This 
schedule is to be followed in order to minimise any unintentional bias caused by some patients 
being assessed at a different frequency than other patients.
At each visit, an overall visit response will be determined by the BICR or programmatically 
derived from the data provided by the investigator (i.e. not the investigator opinion) - using 
the information from target lesions (TL), non-target lesions (NTL) and new lesions.    
3.1.1
Target lesions (TLs)
Measurable disease is defined as having at least one measurable lesion, not previously 
irradiated, which is ≥ 10 mm in the longest diameter (except lymph nodes which must have 
short axis ≥ 15 mm) with CT or MRI and which is suitable for accurate repeated 
measurements. 


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A patient can have a maximum of 5 measurable lesions recorded at baseline with a maximum 
of 2 lesions per organ (representative of all lesions involved suitable for accurate repeated 
measurement) and these are referred to as target lesions (TLs).  If more than one baseline scan 
is recorded then measurements from the one that is closest and prior to randomisation will be 
used to define the baseline sum of TLs.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly, should be selected.
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.
Note: For patients who do not have measurable disease at entry (i.e. no TLs) but have non-
measurable disease, evaluation of overall visit responses will be based on the overall NTL 
assessment and the absence/presence of new lesions (see Section 3.1.3 for further details).  If a 
patient does not have measurable disease at baseline then the TL visit response will be not 
applicable (NA).  
Table 2
TL Visit Responses 
Visit Responses
Description
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 diameters of TL, 
taking as reference the baseline sum of diameters as long 
as criteria for PD are not met
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 indicate an absolute increase of at least 5 mm
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD
Not Evaluable (NE)
Only relevant if any of the 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
Not Applicable (NA)
No target lesions are recorded at baseline


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Rounding of TL data
For calculation of PD and PR for TLs percentage changes from baseline and previous 
minimum should be rounded to 1 d.p. before assigning a target lesion response.  For example 
19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%
Missing TL data 
For a visit to be evaluable, all target lesion measurements should be recorded.  However, a 
visit response of PD should still be assigned if any of the following occurred:

A new lesion is recorded.

A NTL visit response of PD is recorded.

The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute 
increase of ≥ 5mm, from nadir even assuming the non-recorded TLs have 
disappeared.
Lymph nodes
For lymph nodes, if the size reduces to < 10 mm then these are considered non-pathological. 
However a size will still be given and this size should still be used to determine the TL visit 
response as normal.  In the special case where all lymph nodes are < 10 mm and all other TLs 
are 0 mm then although the sum may be >0 mm the calculation of TL response should be 
over-written as a CR. 
TL visit responses subsequent to CR
A CR can only be followed by CR, PD or NE.  If a CR has occurred then the following rules 
at the subsequent visits must be applied:

Step 1:  If all lesions meet the CR criteria (i.e. 0 mm or < 10 mm for lymph nodes) 
then response will be set to CR irrespective of whether the criteria for PD of TL is 
also met i.e. if a lymph node LD increases by 20% but remains < 10 mm. 

Step 2:  If some lesion measurements are missing but all other lesions meet the CR 
criteria (i.e. 0 mm or < 10 mm for lymph nodes) then response will be set to NE 
irrespective of whether when referencing the sum of TL diameters the criteria for 
PD is also met. 

Step 3:  If not all lesions meet the CR criteria and the sum of lesions meets the 
criteria for PD then response will be set to PD

Step 4:  If after steps 1 – 3 a response can still not be determined the response will 
be set to remain as CR


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TL too big to measure
If a target lesion becomes too big to measure this should be indicated in the database and a 
size (‘x’) above which it cannot be accurately measured should be recorded.  If using a value 
of x in the calculation of target lesion response would not give an overall visit response of PD, 
then this will be flagged and reviewed by the study team blinded to treatment assignment.  It 
is expected that a visit response of PD will remain in the vast majority of cases.  
TL too small to measure
If a target lesion becomes too small to measure a value of 5 mm will be entered into the 
database and used in TL calculations, unless the radiologist has indicated and entered a 
smaller value that can be reliably measured.  If a target lesion response of PD results then this 
will be reviewed by the study team blinded to treatment assignment.
Irradiated lesions/lesion intervention
Previously irradiated lesions (i.e. lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment.
Any TL (including lymph nodes), which has had intervention during the study (for example, 
irradiation / palliative surgery / embolisation), should be handled in the following way and 
once a lesion has had intervention then it should be treated as having intervention for the 
remainder of the study noting that an intervention will most likely shrink the size of tumours:

Step 1: the diameters of the TLs (including the lesions that have had intervention) 
will be summed and the calculation will be performed in the usual manner. If the 
visit response is PD this will remain as a valid response category. 

Step 2: If there was no evidence of progression after step 1, treat the lesion diameter 
(for those lesions with intervention) as missing and scale up as described below as 
long as there remain 1/3 of the TLs with missing measurements.  If the scaling 
results in a visit response of PD then the patient would be assigned a TL response of 
PD.  

Step 3: If after both steps PD has not been assigned, then if appropriate, a scaled 
sum of diameters will be calculated (as long as 1/3 of the TLs with interventions), 
and PR or SD then assigned as the visit response.  Patients with intervention are 
evaluable for CR as long as all non-intervened lesions are 0 (or <10mm for lymph 
nodes) and the lesions that have been subject to intervention also has a value of 0 
recorded.  If scaling-up is not appropriate due to too few non-missing sizes then the 
visit response will be set as NE.
If ≤ 1/3 of the target lesion measurements have interventions then the results will be scaled up 
based on the sizes at the nadir visit, to give an estimated sum of diameters and this will be 
used in calculations; this is equivalent to comparing the visit sum of diameters of the 


Statistical Analysis Plan 
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non-intervention lesions to the nadir sum of diameters excluding the lesions with 
interventions.
Example of scaling
Lesion
Longest diameter 
at nadir visit
Longest diameter 
at follow-up visit
1
7.2
7.1
2
6.7
6.4
3
4.3
4.0
4
8.6
8.5
5
2.5
Intervention
Sum
29.3
26
Lesion 5 has had an intervention at the follow-up visit. 
The sum of lesions 1-4 at the follow-up is 26 cm. The sum of the corresponding lesions at 
baseline visit is 26.8 cm.
Scale up as follows to give an estimated TL sum of 28.4cm:          
At subsequent visits the above steps will be repeated to determine the TL and overall visit 
response.  When calculating the previous minimum, lesions with intervention should be 
treated as missing and scaled up where appropriate (as per step 2 above).
CR will not be allowed as a TL response for visits where there is missing data.  Only PR, SD 
or PD (or NE) could be assigned as the TL visit response in these cases.  However, for visits 
with 1/3 lesion assessments not recorded, the scaled up sum of TLs diameters will be 
included when defining the nadir value for the assessment of progression.
Lesions that split in two
If a TL splits in two, then the LDs of the split lesions should be summed and reported as the 
LD for the lesion that split.
Lesions that merge
If two target lesions merge, then the LD of the merged lesion should be recorded for one of 
the TL sizes and the other TL size should be recorded as 0 mm.
cm
4.
28
3.
29
8.
26
26




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Change in method of assessment of target lesions
CT and MRI are the only methods of assessment that can be used within the trial. If a change 
in method of assessment occurs between CT and MRI, this will be considered acceptable and 
no adjustment within the programming is needed.  
If a change in method involves clinical examination (e.g. CT changes to clinical examination 
or vice versa), any affected lesions should be treated as missing.  
3.1.2
Non-Target Lesions (NTLs) and new lesions.
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.
Non-target lesion response will be derived based on the Investigator’s overall assessment of 
NTLs as follows:  
Table 3
NTL Visit Responses 
Visit Responses
Description
Complete Response (CR)
Disappearance of all NTLs present at baseline with all lymph 
nodes non-pathological in size (<10 mm short axis).
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.
Non-CR/Non-PD
Persistence of one or more NTLs with no evidence of 
progression.
Not Evaluable (NE)
Only relevant when one or some of the 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.
Not Applicable (NA)
Only relevant if there are no NTLs at baseline
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.


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Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression.
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: i.e. not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions 
at each visit should be listed alongside the TL and NTL visit responses.
A new lesion indicates progression so the overall visit response will be PD irrespective of the 
TL and NTL response.
If the question ‘Any new lesions since baseline’ has not been answered with Yes or No and 
the new lesion details are blank this is not evidence that no new lesions are present and should 
be treated as NE in the derivation of overall visit response.
Symptomatic deterioration is not a descriptor for progression of NTLs: it is a reason for 
stopping study therapy and will not be included in any assessment of NTLs.
Patients with ‘symptomatic 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.
3.1.3
Overall visit response
Table 4 defines how the previously defined TL and NTL visit responses will be combined 
with new lesion information to give an overall visit response.
Table 4
Overall Visit Responses
Target Lesions
Non-target lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non CR/Non PD
No
PR
CR
NE
No
PR
PR
Non PD or NE
No
PR
SD
Non PD or NE
No
SD
NA
Non CR/Non PD
No
SD (Non CR/Non PD)
NE
Non PD or NE
No
NE


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Table 4
Overall Visit Responses
Target Lesions
Non-target lesions
New Lesions
Overall Response
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive
disease, NE = not evaluable, NA = not applicable (only relevant if there were no TL/NTL at baseline).
3.1.4
Independent review
The independent review charter contains the details of the blinded independent central (BICR)
review conducted by the AstraZeneca-appointed central Core Imaging Laboratory and will be 
developed in advance of the start of the study. The independent data review will provide 
RECIST measurements and response for each visit for each patient at the time of primary Data 
Cut Off (DCO).  Prior radiotherapy will also be provided to the BICR to allow the selection of 
appropriate TLs.  The imaging scans will be reviewed by two independent radiologists using 
RECIST 1.1 and will be adjudicated, if required (i.e. two reviewers’ review the scans and 
adjudication is performed by a separate reviewer in case of a disagreement). After the primary 
analysis, BICR review of scans will no longer be required.
For each patient, the independent review will provide time point response data and the 
relevant scan dates for each time point (i.e. for visits where progression is/is not identified) 
with supporting measurements, assessments and clinical data (e.g. previous radiation reports)
and no programmatic derivation of visit response is necessary.
If adjudication is performed, the reviewer that the adjudicator agreed with will be selected as a 
single reviewer (note in the case of more than one review period, the latest adjudicator 
decision will be used).  In the absence of adjudication, the records for all visits for a single 
reviewer will be used.  The reviewer selected in the absence of adjudication will be the 
reviewer who read the baseline scan first.  The records from the single selected reviewer will 
be used to report all BICR RECIST information including dates of progression, visit response, 
censoring and changes in target lesion dimensions.  Endpoints (of ORR, PFS and DoR) will be 
derived programmatically from this information. 
3.2
Outcome variables
For the analyses that use BICR response data (CR, PR, SD, PD) the RECIST 1.1 assessments 
per BICR will be directly used.  For secondary and sensitivity analyses based on investigator 
assessments at each visit, patients will be programmatically assigned a RECIST visit response 
of CR, PR, SD, PD, NE depending on the status of their disease compared to baseline and 
previous assessments.


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3.2.1
Objective Response Rate (ORR)
Best overall RECIST response (BoR) is calculated based on the overall visit responses from 
each RECIST assessment (Table 4). It is the best response a patient has had during their time 
in the study up until RECIST progression or the last evaluable assessment in the absence of 
RECIST progression.
Categorisation of best overall response will be determined programmatically based on the 
RECIST criteria using the following response categories: complete response (CR), partial 
response (PR), stable disease (SD), progressive disease (PD) and not evaluable (NE). 
Best overall response will be determined programmatically from the time-point response from 
the BICR data. In addition, this will also be reported using investigator-recorded assessment.
For determination of a best response of SD, the earliest of the dates contributing towards a 
particular overall visit assessment will be used.  SD should be recorded at least 8 weeks +/- 1 
week, i.e. at least 49 days (to allow for the assessment window), after randomisation.  For 
CR/PR, the initial overall visit assessment that showed a response will use the latest of the 
dates contributing towar ds a particular overall visit assessment.
For patients whose progression event is death, BoR will be calculated based on data up until 
the last evaluable RECIST assessment prior to death.
For patients who die with no evaluable RECIST assessments, if the death occurred ≤ 17 weeks 
(i.e. 16 weeks ±1 week) after randomisation then BoR will be assigned to the progression 
(PD) category.  For patients who die with no evaluable RECIST assessments, if the death 
occurred 17 weeks (i.e. 16 weeks ±1 week) after randomisation, then BoR will be assigned 
to the non-evaluable (NE) category.
Progression events that have been censored due to them being >126 days (i.e. 16 weeks ± 7
days) after the last evaluable assessment the visit response of PD will not contribute to the 
BoR derivation..A patient will be classified as a responder if the RECIST 1.1 criteria for a CR 
or PR are satisfied at any time up to and including the defined analysis cut-off point. For each 
treatment group, the objective response rate (ORR) is the number of responders (patients with 
a CR or PR) divided by the number of patients in the measurable disease analysis set 
(MDAS). Only patients with measurable disease at enrolment can achieve an objective 
response of CR or PR which will not require confirmation for the primary outcome due to the 
randomised controlled study design as per the RECIST guidelines. However, a sensitivity 
analysis of confirmed CR or PR will be conducted for both BICR and Investigator data. A 
confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit and 
confirmed by repeat imaging not less than 4 weeks after the visit when the response was first 
observed with no evidence of progression between the initial and CR/PR confirmation visit. 
Data obtained up until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR. Patients who discontinue treatment without 
progression, receive a subsequent anti-cancer therapy (note that for this analysis radiotherapy 
is not considered a subsequent anti-cancer therapy) and then respond will not be included as 


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responders in the ORR (i.e. both visits contributing to a response must be prior to subsequent 
therapy for the patient to be considered as a responder).
In the case where a patient has two non-consecutive visit responses of PR, then, as long as the 
time between the 2 visits of PR is greater than 4 weeks and there is no PD between the PR 
visits, the patient will be defined as a responder. Similarly, if a patient has visit responses of 
CR, NE, CR, then, as long as the time between the 2 visits of CR is greater than 4 weeks, then 
a best response of CR will be assigned.
3.2.2
Progression free survival (PFS)
PFS is defined as the time from randomisation until the date of 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 anti-cancer therapy prior to disease progression (i.e. date of RECIST 
progression/death or censoring – date of randomisation + 1).  Patients who have not 
progressed or died at the time of analysis will be censored at the time of the latest date of 
assessment from their last evaluable 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 assessment, prior to progression.  
Given the scheduled visit assessment scheme and change in scanning frequency after 48 
weeks then the following rules will be used to define two missed visits:

If the latest evaluable assessment was on or prior to Week 33/Day 231 (Week 32 + 
one week) then two missed visits will equate to more than 18 weeks (8 x 2 + 2)

If the latest evaluable assessment was post Week 33/ Day 231 and on or prior to 
Week 47/Day 379 (Week 48 - one week) then two missed visits will equate to more 
than 22 weeks (8 + 12 + 2)

If the latest evaluable assessment was post Week 47/Day 379 (Week 48 - one week) 
then two missed visits will equate to more than 26 weeks (12 x 2 + 2)
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 (17 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:
(a)
The date of progression will be determined based on the earliest of the scan dates of 
the component that triggered the progression for the adjudicated reviewer selecting 
PD or of either reviewer where both select PD as time-point response and there is 
no adjudication for central review (BICR) data.  


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(b)
For investigational site assessments, date of progression will be determined based 
on the earliest of the RECIST assessment/scan dates of the component that triggered 
the progression.
(c)
When censoring a patient for PFS the patient will be censored at the latest of the 
RECIST assessment/scan dates contributing to the last evaluable 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.  
The PFS analysis will be based on the blinded independent central review (BICR) of the 
radiological scans.  The BICR will be based on all RECIST assessment scan data provided by 
investigators, including the final RECIST assessment obtained from patients after progression 
has been determined according to RECIST 1.1 criteria by the investigator.  A charter for the 
BICR will be developed in advance of the start of the study. A sensitivity analysis based on 
the programmatically derived PFS based on investigator-recorded assessments will be carried 
out.
The baseline RECIST assessment should be performed prior to randomisation but if an 
evaluable RECIST assessment occurs after randomisation but before treatment then this 
assessment will be used as the baseline assessment. If a patient does not have a baseline 
RECIST scan performed prior to the date of first dose of study treatment 
(olaparib/chemotherapy) then the patients will be censored at Day 1 in the analysis, unless
they die within two visits of baseline (17 weeks allowing for visit window)
3.2.3
Time from randomisation to second progression (PFS2)
Time from randomisation to second progression is defined as the time from the date of 
randomisation to the earliest of the progression event subsequent to that used for PFS endpoint
or death.  The date of second progression will be recorded by the Investigator and defined 
according to local standard clinical practice and may involve any of; objective radiological, 
clinical, CA-125 progression or death.  Second progression status will be reviewed every 12 
weeks following the progression event used for the PFS endpoint (the first progression) and 
status recorded. Patients alive and for whom a second disease progression has not been 
observed should be censored at the last time known to be alive and without a second disease 
progression, i.e. censored at the latest of the PFS or PFS2 assessment date if the patient has 
not had a second progression or death.  Patients who die in the absence of progression will 
have their death recorded as a progression event for both PFS and PFS2. However, if the 
patient experiences a second progression or dies after two or more missed visits, the patient will 
be censored at the time of the last PFS2 assessment prior to the two missed visits. Two missed 
visits will equate to more than 26 weeks (12 x 2 + 2).


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3.2.4
Overall survival (OS)
Overall survival 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 (SUR_DAT recorded within 
the SURVIVE module of the eCRF). Note: Survival calls will be made in the week following 
the date of data cut-off (DCO) for the analysis, and if patients are confirmed to be alive or if 
the death date is post the DCO date these patients will be censored at the date of DCO.  Death 
dates may be found by checking publicly available death registries. 
3.2.5
Time to earliest progression by RECIST 1.1 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 modified GCIG 
criteria:

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 after the date of 
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 2 or 
more consecutive visits at least 1 week apart
(b)
Where CA-125 does fall to within the normal range after the date of 
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 2 or more consecutive visits 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 2 or more 
consecutive visits at least 1 week apart after the date of randomisation. 

CA-125 progression will be assigned the date of the first measurement after the date 
of randomisation that meets the above criteria.
Time to progression by RECIST or CA-125 progression or death is defined as the time from 
randomisation to the earlier date of RECIST (based on BICR) 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 or their last available CA-125 measurement, whichever is the earliest at the time of 
the analysis. Since CA-125 is assessed more frequently than RECIST the two missed visit rule 
is based upon the RECIST schedule. Therefore if a patient dies, has RECIST progression or 
has CA-125 progression after two or more missed RECIST assessments, then the patient will 
be censored using the last evaluable RECIST assessment where CA-125 was also collected. 
This will be defined as a RECIST assessment where the date of CA-125 sample is +/- 11 days 


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(note the earliest date of the RECIST/CA-125 assessment will be used.). If only one 
assessment is missing during this period, no censoring is required. 
3.2.6
Duration of Response (DoR)
Duration of response (DoR) will be defined as the time from the date of first documented 
response until date of documented progression or death in the absence of disease progression, 
the end of response should coincide with the date of progression or death from any cause used 
for the PFS endpoint.  The time of the initial response will be defined as the latest of the dates 
contributing towards the first visit response of PR or CR.
Patients who have not progressed or died following a response, 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 assessment, prior to progression. If the patient has no 
evaluable visits or does not have a baseline assessment they will be censored at day 1.
3.2.7
Time to Response (TTR)
The time to response is defined as the time from randomisation until the date of first 
documented response.  The date of first documented response should coincide with that used 
for the DoR endpoint.
Time to response will not be defined for those patients who do not have a documented 
response.
3.2.8
CA-125 response 
Patients will be evaluable for CA-125 response (GCIG criteria; Rustin et al 2004;
http://ctep.cancer.gov/resources/gcig/respdef_nov2005.doc) if:

a pre-randomisation CA-125 level (taken within 2 weeks prior to the date of 
randomisation or on the date of randomisation) is at least twice the upper limit of 
normal, and 

there is no more than a 10% fall in CA-125 between the final 2 pre-randomisation 
samples (if 2 are taken)

the same assay method is used for each sample from the same patient


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A pre-randomisation sample will be defined to be a sample taken up to and including the day 
of randomisation.  The protocol states that CA-125 samples on this day should be taken prior 
to dosing of study treatment and consequently prior to randomisation.
A response according to CA-125 will be considered to have occurred if there is at least a 50% 
reduction in CA-125 levels from the last pre-randomisation sample.  The response must be 
confirmed and maintained for at least 28 days with no intervening change of >50%. Any 
intervening sample and the confirmatory sample must either be <= ULN or by <=1.1 x the 
initial response sample, if the initial response sample is > ULN. In addition, the confirmatory 
sample must be prior to any CA-125 progression event.  The date when the CA-125 level is 
first reduced by 50% is the date of the CA-125 response. Note the GCIG criteria are not 
validated for this trial population.
A variable will be derived to indicate patients who have had a RECIST response or a CA-125 
response.
3.2.9
Time to first subsequent chemotherapy or death (TFST) 
As a supportive summary to PFS, time to start of first subsequent chemotherapy or death 
(TFST) will be assessed. TFST is defined as the time from the date of randomisation to the 
earlier of first subsequent chemotherapy start date or death (i.e. date of first subsequent cancer 
therapy / death or censoring – date of randomisation +1).  Subsequent chemotherapies will be
reviewed to assess which represent clinically important treatments intended to control ovarian 
cancer.  Any patient not known to have had a first subsequent therapy or death will be 
censored at the last known time to have not received subsequent chemotherapy, i.e. the last 
follow-up visit where this was confirmed. Patients still on study medication who have not 
received a subsequent therapy will be censored on the last recorded date on which the patient 
was known to be alive. Patients who have permanently discontinued study medication who 
have not received a subsequent therapy will be censored on the date of the last assessment 
reported on the TTSCAPRX form that indicates that the first subsequent therapy has not been 
received or the date of last dose if the patient had no TTSCAPRX form completed.
3.2.10
Time to study treatment discontinuation or death (TDT) 
Time to study treatment discontinuation or death (TDT) will be assessed. TDT is defined as 
the time from randomisation to the earlier of the date of study treatment discontinuation or 
death. Any patient not known to have died at the time of analysis and not known to have 
discontinued study treatment will be censored based on the last recorded date on which the 
patient was known to be alive.
Note: Survival calls will be made in the week following the date of DCO for the analysis, and 
if patients are confirmed to be alive or if the death date is post the DCO date these patients 
will be censored at the date of DCO.


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3.2.11
Time to second subsequent chemotherapy or death (TSST) 
As a supportive summary to PFS2, time to start of second subsequent chemotherapy or death 
(TSST) will be assessed. TSST is defined as the time from the date of randomisation to the 
earlier of the second subsequent chemotherapy start date or death. (i.e. date of second 
subsequent cancer therapy / death or censoring – date of randomisation +1).  Any patient not 
known to have had a further second subsequent therapy or death will be censored at the last 
known time to have not received second subsequent chemotherapy, i.e. the last follow-up visit 
where this was confirmed. Patients still on study medication who have not received a second 
subsequent therapy will be censored on the last recorded date on which the patient was known 
to be alive. Patients who have permanently discontinued study medication who have not 
received a second subsequent therapy will be censored on the date of the last assessment 
reported on the TTSCAPRX form that indicates that the second subsequent therapy has not 
been received or the date of last dose if the patient had no TTSCAPRX form completed.
3.3
Patient reported outcome variables
3.3.1
FACT-O
Patient-reported health-related quality of life (HRQoL) will be assessed using the FACT-O 
questionnaire (Basen-Enquist K et al 2001). The FACT-O is composed of the following sub-
scales: physical, social/family, emotional, and functional well-being as well as the additional 
concerns ovarian cancer scale consisting of specific ovarian cancer symptoms. 
The endpoint for HRQoL analysis will be the Trial Outcome Index (TOI) (Cella D et al 1993),
an established single targeted index derived from the FACT-O questionnaire and it is 
considered to target the most relevant symptoms together with function and physical well-
being and can be directly related to signs and symptoms and AEs. The TOI is composed of the 
following scales of the FACT-O: physical and functional well-being and additional concerns.
Data relating to the FACT-O will be self-reported through patient questionnaires according to 
the study plan. Patients will be asked to report their HRQoL over the course of the previous 7 
days.  All patients will be asked to complete the FACT-O.  The FACT-O questionnaire will be 
administered at baseline, at Day 29 then in line with the RECIST assessments every 8 weeks 
(+/- 1 week) up to Week 48 regardless of treatment discontinuation or disease progression. 
The Trial Outcome Index (TOI) score will be derived from the sum of the scores of the 25 
items included in the physical well-being (7 items), functional well-being (7 items), and 
additional concerns ovarian cancer subscale (11 items [the subscale consists of 12 items, but 
item BMT7, asking about concerns about the ability to have children, should not be included 
in the calculations) of the FACT-O questionnaire version 4. The total FACT-O score will also 
be calculated which is made up of the sum of the individual subscale scores: physical well 
being (PWB), social well being (SWB), emotional well being (EWB), functional well being 
(FWB) and ovarian cancer subscale (Additional Concerns).
The scores will be derived in accordance with the FACT-O Scoring Manual. A number of 
items are negatively stated and need to be reversed by subtracting the response from “4”. The 


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scoring manual identifies that the following items need to be reversed prior to summarizing: 
GP1-7, GE1, GE3-6, O1-3, C2, and B5. After reversing proper items, the scores are derived. 
For each subscale, if less than 50% of the subscale items are missing, the subscale score will 
be divided by the number of non-missing items and multiplied by the total number of items on 
the subscale. If at least 50% of the items are missing, that subscale also will be treated as 
missing.
For the TOI score, if more than 80% of all items within the subscales within the domains 
included have non-missing responses, the TOI score will be divided by the number of non-
missing items and multiplied by 25 (the total number of items which could be included in the 
derivation of the endpoint). If less than or equal to 80% of items have non-missing responses, 
the TOI score will be treated as missing.
Similarly, for the total FACT-O score, if more than 80% of all items within the subscales 
within the domains included have non-missing responses, the score will be divided by the 
number of non-missing items and multiplied by the total number of items which could be 
included in the derivation of the endpoint. If less than or equal to 80% of items have non-
missing responses, the score will be treated as missing.
The reason for any missing assessment will be identified. If data are missing at random, the 
above techniques will be used. If there is evidence that the missing data are systematic,
missing values will be handled to ensure that any possible bias is minimised and alternative 
analysis methods may be explored. The TOI score ranges from 0-100 and the FACT-O from 
0-152.  For all Functional Assessment of Chronic Illness Therapy (FACIT) scales and 
symptom indices, a higher score indicates a higher HRQoL.  
The actual change from baseline in TOI score will be derived for each visit where there is 
available data. For example; at visit X, the calculation will be (TOI score at visit X – Baseline
TOI score). Actual change from baseline for the individual domain scores will be calculated in 
a similar way.
A change of at least 10 points in TOI score will be considered as a clinically relevant or a 
minimally important difference (Osoba et al 2005). In addition to deriving the visit response 
for TOI, the visit response for total FACT-O will be derived using a change of at least 15 
points.
The population for analyses of HRQoL (TOI) will include a subset of the FAS population who 
have baseline TOI score. Similarly, the population for analyses of total FACT-O will include a 
subset of the FAS population who have baseline FACT-O score.
The definitions of the visit response for HRQoL are outlined below (Table 5):


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Table 5 Health Related QoL Visit Response
Score
Change from baseline
Visit response
TOI 
≥ +10
Improved
≤ -10
Worsened
Otherwise
No change
Total FACT-O 
≥ +15
Improved
≤ -15
Worsened
Otherwise
No change
Best Overall TOI improvement (improvement in the absence of subsequent cancer therapy) 
will be defined as a change from baseline in the TOI of +10 points or more (Osoba et al 2005) 
sustained for at least 28 days, the denominator consisting of a subset of the FAS population 
who have baseline TOI. It will be derived as the best symptom improvement response the 
patient achieved, based on evaluable HRQoL 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 subject based on the individual 
visit responses (Table 6). Similarly, the best overall total FACT-O improvement will be 
derived.
Table 6 Health Related Quality of Life: Change rates - overall score.
Best Overall TOI (or total FACT-O) 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”


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Table 6 Health Related Quality of Life: Change rates - overall score.
Best Overall TOI (or total FACT-O) score 
response
Criteria
Worsened
Does not qualify for overall score response of 
“improved” A visit response of “worsened” 
without a response of “improved” or “no 
change” within 28 days
Other
Does not qualify for one of the above.
A TOI improvement rate (in the absence of subsequent cancer therapy) will be calculated as 
the % 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 TOI.
Similarly, a FACT-O improvement rate will be calculated.
Summary measures of overall compliance and compliance over time will be derived for the 
FACT-O form. These will be based upon:

Received forms = number of FACT-O forms received back plus the number not 
received back where the reason was ‘Subject too heavily affected by symptoms of 
disease under investigation’

Expected forms = number of patients still under HRQoL follow-up at the specified 
assessment time excluding patients in countries with no available translation. For 
patients that have progressed, the latest of progression and safety follow-up will be 
used to assess whether the patient is still under HRQoL follow-up at the specified 
assessment time.  Date of study discontinuation will be mapped to the nearest visit 
date to define the number of expected forms.

Evaluable forms = subset of expected FACT-O forms with at least one subscale that 
can be determined; or where REVPRDI form is ticked ‘Subject too heavily affected 
by symptoms of disease under investigation’
Thus the overall compliance rate is defined as number of patients with an evaluable baseline 
and at least one evaluable follow-up form (as defined above), divided by the number of 
patients expected to have completed at least a baseline FACT-O form.
Compliance over time will be calculated separately for each visit, including baseline, as the 
number of patients with an evaluable baseline form and a form at the time point (as defined 
above), divided by number of patients still expected to complete forms at that visit. Similarly 
the evaluability rate over time will be calculated separately for each visit, including baseline, 


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as the number of evaluable forms (per definition above), divided by the number of received 
forms.
3.3.2
Cancer Therapy Satisfaction Questionnaire (CTSQ-16)
The CTSQ-16 is a 16-item measure that assesses satisfaction with and preference for 
chemotherapy treatment, and for biological therapy in either pill or IV form, across three 
domains: Feelings about Side Effects, Satisfaction with Therapy, and Expectations of Therapy 
(Trask et al 2008). The CTSQ-16 questionnaire is in Appendix G of the Protocol. The 
questions should be scored as 5 for the leftmost response and 1 for the rightmost response. In 
the CRF this is coded with a score of 1 for the leftmost response and 5 for the rightmost 
response. Therefore, all the scores will be reversed by subtracting the score from 6 prior to 
following the scoring instructions from the CTSQ scoring manual detailed below. 
Questions (Q) 5, 6, 9 and 11 will be reversed again to calculate the domains by subtracting the 
score from 6. These reversed values will be referred to as Q5R, Q6R, Q9R and Q11R 
respectively. This means that Q5R, Q6R, Q9R and Q11R will be the values collected in the 
eCRF for this study and the remaining questions will be reversed compared to the value 
collected in the eCRF. 
For each domain, if the number of completed items is greater than or equal to the minimum 
number indicated in Table 7, then the domain is derived using the following formula:
Domain score = [(sum of completed item responses/number of completed items)-1]x25
However, if fewer items are completed than the minimum number indicated in Table 7, then 
the domain is not scored and a missing value is assigned.
Table 7 Summary of domain scoring for CTSQ domains
CTSQ domain
Description of content of items 
in domain
Item numbers
Total 
number 
of 
items
Minimum 
number of 
completed 
items 
required to 
score
Expectations of 
therapy
Return to normal life, Get rid of 
cancer, Prevent cancer from 
coming back, Stop cancer from 
spreading, Help you live longer
Q1, Q2, Q3, 
Q4, Q8
5
3
Feelings about 
side effects
Cancer therapy limited daily 
activities, Upset about side 
effects, Taking cancer therapy as 
difficult as expected, Were side 
effects as expected
Q5R, Q6R, 
Q11R, Q13 
4
4


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Table 7 Summary of domain scoring for CTSQ domains
CTSQ domain
Description of content of items 
in domain
Item numbers
Total 
number 
of 
items
Minimum 
number of 
completed 
items 
required to 
score
Satisfactions 
with therapy
Worth taking even with side 
effects, Think about stopping 
cancer therapy, How worthwhile 
was cancer therapy, Benefits 
meet expectations, Satisf. with 
form of cancer therapy, Satisf. 
with recent cancer therapy, 
Would you take this cancer 
therapy again 
Q7, Q9R, 
Q10, Q12, 
Q14, Q15, 
Q16 
7
5
3.4
Safety
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
data, vital signs, ECG and exposure. These will be collected for all patients.
3.4.1
Adverse events (AEs)
AEs and SAEs will be collected throughout the study, from informed consent until 30 days 
after the last dose of study treatment.  Any untoward event occurring subsequent to the 30-day 
follow-up AE reporting period that the investigator assesses as possibly related to the study 
treatment should also be reported as an AE.
Other significant adverse events (OAEs)
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and ‘Discontinuation of Investigational Product 
due to Adverse Events’ (DAEs).  Based on the expert’s judgement, significant AEs of 
particular clinical importance may, after consultation with the Global Patient Safety Physician, 
be considered other significant adverse events (OAEs) and reported as such in the CSR.  A 
similar review of laboratory/vital signs/ECG data will be performed for identification of 
OAEs.


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Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment.
3.4.2
Treatment exposure
The exposure to olaparib will be calculated for all patients who received olaparib, where the 
duration of exposure will be based on the planned administration as per protocol.  The 
following will be calculated:
Total (or intended) exposure of olaparib

Total (or intended) exposure = last dose date  – first dose date + 1
Actual exposure of olaparib

Actual exposure = intended exposure – total duration of dose interruptions, where 
intended exposure will be calculated as above.  Dose interruptions will include 
those where a patient forgot to take a dose.
Number of days on 300 mg olaparib bd

Number of days on 300 mg olaparib bd = actual exposure for the dose assigned.
Exposure to chemotherapy for patients in the chemotherapy arm will be measured by the 
number of cycles received.  For all four choices of chemotherapy regimen, a cycle 
corresponds to a period of 28 days.  If a cycle is prolonged due to toxicity, this should still be 
counted as one cycle.  
3.4.3
Dose intensity
The dose intensity will be calculated for both patients who receive olaparib and for those who 
receive chemotherapy.  Relative dose intensity (RDI) is the percentage of the actual dose 
intensity delivered relative to the intended dose intensity through to treatment discontinuation. 
Percentage intended dose (PID) is the percentage of the actual dose delivered relative to the 
intended dose through to progression.  Both will be derived using study treatment data up to 
the date of objective disease progression as defined by RECIST using the investigator site 
assessments.  If the investigator considered that it was in the patient’s best interest to continue 
study treatment past this time, this will not be included in the derivation of dose intensity.  
RDI and PID will be defined as follows:

RDI = 100% * d/D, where d is the actual cumulative dose delivered up to the earlier 
of progression (or a censoring event) or the actual last day of dosing and D is the 
intended cumulative dose up to the earlier of progression (or a censoring event) or 
the actual last day of dosing plus the protocol-defined post-dose rest period.


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
PID = 100% * d/D, where d is the actual cumulative dose delivered up to 
progression (or a censoring event) and D is the intended cumulative dose up to 
progression (or a censoring event).  D is the total dose that would be delivered, if 
there were no modification to dose or schedule.
For Chemotherapy, actual dose is the dose received reported in mg. Intended dose is the dose 
planned for the patient reported in mg/m2 and converted to mg by multiplying by their body 
surface area (m2) calculated from height and weight at baseline using the Mosteller formula.
Due to the possibility of rounding of the BSA calculations at the sites, the following rules will 
be applied:

For Paclitaxel, if the actual dose in mg/m2 rounded to the nearest 10 mg/m2 is equal to 
the planned dose in mg/m2 then the planned dose will be assumed to be equal to the 
actual dose

For PLD, if the actual dose in mg/m2 rounded to the nearest 10 mg/m2 is equal to the 
planned dose in mg/m2 then the planned dose will be assumed to be equal to the actual 
dose

For gemcitabine, if the actual dose in mg/m2 rounded to the nearest 100mg/m2 is equal 
to the planned dose in mg/m2 then the planned dose will be assumed to be equal to the 
actual dose

For topotecan, if the actual dose in mg/m2 rounded to the nearest 1mg/m2 is equal to 
the planned dose in mg/m2 then the planned dose will be assumed to be equal to the 
actual dose
Example of Dose Intensity
Study day
RDI
PID
patient
1
2
3
4
5
6
7
8
9
10
86%
60%
1
X
X
X
X
X
X
D
PD
70%
70%
2
X
X
X
X
X
X
X
O
O
O 
PD 
D
100%
100%
3
X
X
X
X
X
X
X
X 
PD 
D
X: 300mg dose taken, O: dose not taken, PD: Progressive Disease, D: Discontinued
Patients 1-2 progressed on Day 10, so the intended dose through to progression was 10 * 600 
mg of olaparib = 6000 mg and Patient 3 progressed on Day 8 and intended dose was 
600*8=4800 mg. 
Patient 1: 
received 600 mg of olaparib daily for 6 days, discontinued treatment for 
reasons other than progression on day 7, then progressed or died on day 10.


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RDI = (6 * 600 mg)/ 4200 mg = 86%
PID = (6 * 600 mg)/ 6000 mg = 60%
Patient 2: 
received 600 mg of olaparib daily for 7 days, did not discontinue treatment, but 
nevertheless did not receive another dose, then progressed or died on day 10.
RDI = PID = (7 * 600 mg)/ 6000 mg = 70% 
Patient 3: 
received 600 mg of olaparib daily for 8 days, and then progressed or died on 
same day 8.
RDI = PID = (8 * 600 mg)/ 4800 mg = 100%
3.4.4
Laboratory data
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, 
and urinalysis will be taken at the times indicated in the study schedule (see Tables 1, 2 and 3 
of the CSP).  For derivation of post baseline visit values considering visit window and to 
handle multiple records, derivation rules as described in Section 3.4.7 below will be used.
3.4.5
Electrocardiograms (ECGs)
ECGs are required during screening within 7 days prior to starting study treatment and when 
clinically indicated afterwards. 
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.  
3.4.6
Vital signs
Height will be assessed at screening only. Weight will be assessed at screening and as 
clinically indicated at any other time. Any changes in vital signs should be recorded as an AE, 
if applicable.
3.4.7
General considerations for safety assessments
Time windows will need defining for any presentations that summarise values by visit. The 
following conventions should also apply:

The time windows should be exhaustive so that data recorded at any time point has 
the potential to be summarised. Inclusion within the time window should be based 
on the actual date and not the intended date of the visit.

All unscheduled visit data should have the potential to be included in the 
summaries.


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
The window for the visits following baseline will be constructed in such a way that 
the upper limit of the interval falls half way between the two visits (the lower limit 
of the first post-baseline visit will be Day 2).  If an even number of days exists 
between two consecutive visits then the upper limit will be taken as the midpoint 
value minus 1 day.  
For example, the visit windows for laboratory data are:

Day 8, visit window 2 – 11

Day 15, visit window 12-18

Day 22, visit window 19-25

Day 29, visit window 25 – 42

Day 57, visit window 43 - 71
...

For summaries showing the maximum or minimum values, the maximum/minimum 
value recorded on treatment will be used (regardless of where it falls in an interval).

Listings should display all values contributing to a time point for a patient.

For visit based summaries:

If there is more than one value per patient within a time window then the 
closest value should be summarised, or the earlier in the event the values are 
equidistant from the nominal visit date.  The listings should highlight the value 
for that patient that went into the summary table, wherever feasible.

To prevent very large tables or plots being produced that contain many cells 
with meaningless data, for each treatment group visit data should only be 
summarised if the number of observations is greater than the minimum of 20 
and > 1/3 of patients dosed.

For summaries at a patient level, all values should be included, regardless of 
whether they appear in a corresponding visit based summary, when deriving a 
patient level statistic such as a maximum. 

Baseline will be defined as the last non-missing measurement prior to dosing with 
study treatment (olaparib or chemotherapy). For laboratory data and vital signs data, 
any assessments made on day 1 will be considered pre-dose. Where safety data are 
summarised over time, study day will be calculated in relation to date of first 
treatment (olaparib or chemotherapy)


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Missing safety data will generally not be imputed. However, safety assessment values of the 
form of “< x” (i.e., below the lower limit of quantification) or > x (i.e., above the upper limit 
of quantification) will be imputed as “x” in the calculation of summary statistics but displayed 
as “< x” or “> x” in the listings.
3.5
Health Economic Endpoints
3.5.1
Hospital Resource Use
Hospital resource use variables include the following:

Length of hospital stay

Reasons for hospitalisation

Length of any time spent in ICU/HDU

Outpatient/daytime attendances
The length of hospital stay will be calculated as the difference between the date of hospital 
discharge (or death date) and the start date of hospitalisation or start of study drug if the start 
of study drug is after start date of hospitalisation ( length of hospital stay = end date of 
hospitalisation – start date of hospitalisation + 1).  Patients with missing discharge dates will 
be calculated as the difference between the last day with available data and the start date of 
hospitalisation.
Sum of total duration of hospital stay will be considered for analysis if patient was admitted to 
hospital more than one time during study period. 
The length of ICU stay will be calculated using the same method as detailed above for the 
length of hospital stay.
3.5.2
EQ-5D-5L (exploratory analysis)
The EQ-5D is a standardised measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal. 
Applicable to a wide range of health conditions and treatments, it provides a simple 
descriptive profile and a single index value for health status that can be used in the clinical and 
economic evaluation of health care. 
The EQ-5D-5L index comprises five dimensions of health (mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression). For each dimension, respondents select 
which statement best describes their health on that day from a possible five options of 
increasing levels of severity (no problems, slight problems, moderate problems, severe 
problems and unable to/ extreme problems).  A unique EQ-5D health state is referred to by a 
five digit code allowing for a total of 3125 health states.  For example, state 11111 indicates 
no problems on any of the five dimensions. This data will be converted into a weighted health 


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state index by applying scores from EQ5D value sets elicited from general population samples 
(the base case will be the UK valuation set, with other country value sets applied in scenario 
analyses). Where values sets are not available, the EQ-5D-5L to EQ-5D-3L crosswalk will be 
applied. In addition to the descriptive system, respondents also assess their health today on a 
visual analogue scale, ranging from 0 (worst imaginable health) to 100 (best imaginable 
health). This score is reported separately.
The evaluable population will comprise all patients who receive study treatment as per safety 
analysis set and have a baseline EQ-5D-5L assessment.
Further details of the analysis of EQ-5D will be given in the payer analysis plan.
3.6
Pharmacokinetic Endpoints
Pharmacokinetic (PK) sampling is to be performed in a subset of approximately 65 evaluable 
patients from the olaparib treatment group. The sampling times are: Day 1 pre-dose & 1 hour
post-dose; Day 29 Pre-dose, 0.5-1 hour, 1-3 hours, 3-6 hours and 6-12 hours post dose.
The plasma concentration data will be listed and summarised (for Day 1 pre-dose & 1 hour 
post-dose and Day 29 Pre-dose time points only). Data from patients excluded from the PK 
analysis set will be included in the data listings, but not in the summary. Extra measurements 
(such as unscheduled or repeat assessments) will also not be included in summary table, but 
will be included in patient listings.
Plasma concentration data will be summarised using descriptive statistics, including n,
arithmetic mean, SD, coefficient of variation (%CV), median, minimum, and maximum
values. Additionally, geometric means and geometric %CV (%GCV) will be reported, the 
geometric mean will be calculated as the exponential of the arithmetic mean calculated from
data on a log scale. The %GCV was calculated as
1
)
(exp(
100
2 
s
where s was the SD of 
the data on a log scale. The plasma concentrations will be reported to the same precision as 
the source data. For descriptive statistics of concentrations, non-quantifiable (NQ) values of 
plasma concentrations will be handled as follows:

If, at a given time point, 50% or less of the plasma concentrations were NQ, the mean, 
SD, geometric mean, %CV, and %GCV were calculated by substituting the limit of 
quantification (LOQ) for values which are NQ.

If more than 50%, but not all, of the concentrations were NQ, the mean, geometric 
mean, SD, %CV, and %GCV were reported as not calculable (NC).

If all the concentrations were NQ, the geometric mean and mean were reported as NQ 
and the SD, %CV, and %GCV as NC.
The PK analysis of the plasma concentration data for olaparib will be performed at 
AstraZeneca R&D or by a CRO identified by AstraZeneca R&D. The actual sampling times 
will be used in the PK calculations. Non-linear mixed effects modelling (NONMEM) will 


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evaluate the pharmacokinetic characteristics of olaparib, quantify variability in the 
pharmacokinetics, identify demographic or pathophysiological covariates which may explain 
the observed variability, estimate steady state Cmax, AUC and Cmin and explore exposure-
response relationships. The pharmacokinetic analysis will be reported separately from the 
clinical study report.
4.
ANALYSIS METHODS
The data cut-off for the primary analysis will occur in January 2019 or at a minimum of 6 
months after LSI, whichever is sooner. No further analyses of ORR or PFS are planned 
beyond this point unless requested by Health Authorities.
An initial PFS, PFS2, OS, TFST, TSST and TDT analysis will be performed at the same time 
as the primary analysis of ORR. In addition, change from baseline in TOI and the TOI 
improvement rate will be analysed. At this time DoR and CA-125 response will be 
summarised descriptively. No adjustment will be applied for multiplicity for TFST, TSST, 
TDT and TOI as these are viewed as supportive endpoints.
4.1
Analysis methods
The treatment comparison is olaparib 300 mg bd vs chemotherapy.
ORR and DoR analyses will be performed on the measurable disease population (MDAS). All 
other efficacy analyses, including PFS, PFS2 and OS, will be performed on the FAS 
population. In addition to the main analyses of ORR, PFS, PFS2, OS, TDT, TFST and TSST, 
analyses of these endpoints will be performed in those patients whose gBRCAm status is 
confirmed by the Myriad test unless populations are the same.
Results of all statistical analysis will be presented using a 95% confidence interval and 2-sided 
p-value. Exact p-values should be presented using 3 decimal places for all values ≥0.001. The 
only categorical presentation to be used is when p<0.001. Hazard ratios, odds ratios and 
confidence interval limits are to be presented to 2 decimal places.
The following table details which endpoints are to be subject to formal statistical analysis, 
together with pre-planned sensitivity analyses making clear which analysis is regarded as 
primary for that endpoint.
Table 8 Formal Statistical Analyses to be Conducted and Pre-Planned Sensitivity Analyses
Endpoints Analysed
Notes
Analysis 
population
Objective Response Rate (Number of 
patients who have a CR or PR determined 
using RECIST 1.1 criteria divided by the 
Primary analysis: Logistic regression using 
BICR assessment in the MDAS
MDAS
Sensitivity / supportive analyses:


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Table 8 Formal Statistical Analyses to be Conducted and Pre-Planned Sensitivity Analyses
Endpoints Analysed
Notes
Analysis 
population
number of patients with measurable 
disease.)
1) Ascertainment bias analysis: Logistic 
regression using investigator assessments in 
the MDAS
MDAS
2) Logistic regression based on BICR for all 
patients with evaluable disease. Patients with 
evaluable disease include all of those in the 
MDAS and patients with non-target lesions at 
baseline and non-measurable disease at 
baseline. (Only required if the evaluable 
disease population differs from the MDAS.).
Evaluable 
disease subset of 
FAS
3) Logistic regression based on BICR for all 
patients in the FAS. (Only required if the 
FAS population differs from the MDAS).
FAS
4) Logistic regression based on confirmed 
BICR responses in the MDAS.
MDAS
5) Logistic regression based on confirmed 
investigator responses in the MDAS.
MDAS
6) Deviation bias (if meaningful to do); 
Logistic regression using BICR data
MDAS (excluding 
patients with 
deviations that may 
affect the efficacy 
of the trial)
7) On-treatment analysis: Logistic regression 
using BICR assessment for patients in the 
MDAS who received at least one dose of 
randomised treatment
All patients in 
the MDAS who 
received at least 
one dose of 
randomised 
treatment
8) Unadjusted logistic regression using BICR 
assessment in the MDAS
MDAS
PFS (Time from randomisation to first 
progression or death)
Primary analysis: stratified log-rank test 
using BICR assessments
FAS
Sensitivity/supportive analyses:
1) Evaluation time bias analysis: stratified 
log-rank test using BICR assessments
FAS
2) Attrition bias analysis (using alternative 
censoring rules): stratified log-rank test using 
BICR assessments
FAS


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Table 8 Formal Statistical Analyses to be Conducted and Pre-Planned Sensitivity Analyses
Endpoints Analysed
Notes
Analysis 
population
3) Ascertainment bias analysis: stratified log-
rank test using Investigator assessments
FAS
4) On-treatment analysis: Stratified log-rank 
test using BICR assessment for patients in 
the  FAS who received at least one dose of 
randomised treatment
All patients in 
the FAS that 
recevied at least 
one dose of 
randomised 
treatment
5) Deviation bias (if meaningful to do); 
stratified log-rank test using BICR data
FAS
(excluding patients 
with deviations that 
may affect the 
efficacy of the trial)
6) A Cox proportional hazards model
FAS
7) Unadjusted Cox proportional hazards 
model
FAS
PFS2 (Time from randomisation to 
second progression or death)
Primary analysis: stratified log rank test 
based on investigator assessment of second 
progression
FAS
Overall Survival (Time from 
randomisation to death due to any cause)
Primary analysis:  stratified log-rank test 
Supportive analysis: KM plot of time to 
censoring for OS
FAS
Time to earliest progression by RECIST 
1.1 or CA-125 or death 
Primary analysis: stratified log-rank test 
using BICR data 
FAS
TFST (Time to first subsequent therapy or 
death)
Stratified log rank test using eCRF data
FAS
TSST (Time to second subsequent therapy 
or death)
Stratified log rank test using eCRF data
FAS
TDT (Time to study treatment 
discontinuation or death)
Stratified log rank test using eCRF data
FAS
CA-125 response
CA-125 response per treatment arm 
(descriptive only); CA-125 and/or RECIST 
response per treatment arm (descriptive only) 
based on BICR for RECIST
FAS


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Table 8 Formal Statistical Analyses to be Conducted and Pre-Planned Sensitivity Analyses
Endpoints Analysed
Notes
Analysis 
population
Change from baseline in TOI score
Primary : Mean change from baseline in TOI 
score analysed by MMRM
Supportive : Proportion improved (in the 
absence of subsequent cancer therapy) in TOI 
score analysed using logistic regression
FAS
For the analysis of response rates and time to event endpoints, the following pooling strategy 
will be applied. If the number of responses / events in the individual stratum are too small for 
a meaningful analysis (less than 5 responses / events per stratum; a stratum is defined as 
strata1*strata2*…strataX*treatment; so with 2 stratification factors of each 2 levels and two 
treatments we have 2*2*2=8 stratum) stratification factors will be removed in the following 
order until there are at least 5 responses / events in each stratum: selected study chemotherapy 
(paclitaxel / topotecan / pegylated liposomal doxorubicin / gemcitabine); number of prior 
chemotherapy regimens received for ovarian cancer (2 or 3 vs. 4 or more); time to disease 
progression on last platinum based chemotherapy received prior to randomisation (6 – 12 
months / > 12 months). This will be done for each individual endpoint to be analysed and 
consequently the strata used in the analysis may vary by endpoint. All the sensitivities for 
each endpoint, will use the same strata as the primary model, for that endpoint, unless there 
are <5 events per stratum and then an andjusted model will be used. If required, unadjusted 
sensitivity analyses of each of the endpoints may also be performed.
4.1.1
Multiplicity 
In order to describe the nature of the benefits of olaparib maintenance treatment, ORR, PFS, 
PFS2, and OS will be tested at a 2-sided significance level of 5%.
However, in order to strongly control the type I error at 2.5% 1-sided, a multiple testing 
procedure will also be employed across the primary endpoint and secondary endpoints 
intended for key label claims (i.e. ORR, PFS, PFS2 and OS). There is no requirement to adjust 
for multiplicity due to ORR or PFS interim analyses, since there are no planned interim ORR 
or PFS analyses with the opportunity to make an early claim of efficacy.
A hierarchical testing strategy will be employed where ORR is tested first using the full test 
mass (full test mass = alpha 5% 2 sided) and key secondary endpoints of PFS, PFS2 and OS 
will then be tested using a multiple testing procedure with a recycling strategy (i.e., the MTP 
will recycle the test mass to the endpoint not yet rejected in the hierarchy outlined in Figure 
2).


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Figure 2
Multiple Testing Procedure
PFS will only be tested if the null hypothesis (of no difference) for ORR is rejected. PFS2 will 
only be tested if the null hypothesis (of no difference) is rejected for both ORR and PFS. OS 
will only be tested if the null hypothesis (of no difference) is rejected for ORR, PFS and PFS2. 
An additional PFS2 and OS analysis will only be conducted with further follow up (~60% OS 
events) if both ORR and PFS are statistically significant based on the primary analysis and the 
null hypotheses for PFS2 and/or OS are not rejected at the time of the primary analysis. If an 
additional analysis is conducted for PFS2 and OS, to control for multiple testing due to an 
interim and final analysis a Lan DeMets spending function (Lan and DeMets 1983) that 
approximates an O’Brien Fleming approach will be used to account for multiplicity.
If the null hypothesis is rejected for ORR and PFS then the 5% (2 sided) alpha level will be 
allocated to PFS2 for the interim and final analysis. Subsequently if the null hypothesis for 
PFS2 is rejected then OS will be controlled at the interim and primary time point by using the 
Lan DeMets (Lan and DeMets 1983) spending function that approximates an O’Brien 
Fleming approach, where the significance level applied at the interim depends upon the 
proportion of information available. 
If both ORR and PFS are statistically significant based on the primary analysis and the null 
hypotheses for PFS2 and/or OS are not rejected at the time of the primary analysis, a final 
analysis of PFS2 and OS will take place when there are approximately 60% deaths 
(approximately 150 events).  It is not known how many PFS2 events there will be at this final 
cut off.  Therefore, for the calculation of the significance level for the interim analysis of 
PFS2 it will be assumed that the proportion of information available for PFS2 is the same as 
that for OS.  
For example, if 50% of OS events required at the time of the primary OS analysis are
available at the time of the interim (i.e., 75/150 events have occurred), the 2-sided significance 
level to be applied for the OS interim analysis would be 0.31% and the 2-sided significance 
ORR
PFS
PFS2
OS


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level to be applied for the final OS analysis would be 4.7%.  The same 2-sided significance 
level would be used for PFS2.
If the number of OS events observed at the time of the interim is higher or lower than 75 the 
interim alpha will be adjusted accordingly.
4.1.2
Primary variable - Objective Response Rate (ORR) 
The data cut-off for the primary analysis will occur in January 2019 or at a minimum of 6 
months after LSI, whichever is sooner. No further analyses of ORR are planned beyond this 
point unless requested by Health Authorities.
For each treatment arm, Best Overall Response (BoR) will be summarised by n (%) for each 
category (CR, PR, SD, NED, PD, NE) based on the BICR and separately for the investigator’s 
assessment.  No formal statistical analyses are planned.  
The objective response rate (ORR) based on BICR and the ORR based on the investigator’s 
assessment will be summarised (i.e., number of patients (%)) by treatment group, in patients 
in the Measurable Disease Analysis Set(MDAS).
ORR (BICR and investigator data) will be analysed using logistic regression adjusted by the 
stratification factors decided from the pooling strategy. Results of the analysis will be 
presented in terms of an odds ratio (olaparib vs. chemotherapy) together with its associated 
95% CI and 2-sided p-value (based on twice the change in log-likelihood resulting from the 
addition of a treatment factor to the model). CIs will be profile likelihood CIs (e.g. using the 
option ‘LRCI’ in SAS procedure GENMOD).
Stratification variables will be defined according to data from the interactive voice/web 
response system (IVRS/IWRS). Although not anticipated, if patients are randomised in error 
when they have not previously had at least 2 prior lines of chemotherapy, then they will be 
grouped with patients who have had 2 prior lines of chemotherapy. If there are any patients 
who were miss-stratified, a sensitivity analysis of the primary ORR analysis will be carried 
out using the (correct) baseline data collected in the eCRF.
A response of CR or PR will not require confirmation due to the randomised controlled study 
design as per the RECIST guidelines. However, a sensitivity analysis of confirmed CR or PR 
will be conducted for both BICR and Investigator data.
4.1.2.1
Subgroup analysis for the primary endpoint (ORR)
Subgroup analyses will be conducted comparing ORR between treatments. The purpose of the 
subgroup analyses is to assess the consistency of treatment effect across potential or expected 
prognostic factors. If there are too few events available for a meaningful analysis of a 
particular subgroup (it is not considered appropriate to present analyses where there are less 
than 5 events in each stratum; a stratum is defined as strata1*strata2*…strataX*treatment; so 
with 2 stratification factors of each 2 levels and two treatments we have 2*2*2=8 stratum),), 
the relationship between that subgroup-level and ORR will not be formally analysed. In this 


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case, only descriptive summaries will be provided (response count and percentage). Options 
for pooling subgroups may be explored if clinically meaningful.
The subgroup analyses for the stratification factors will be based on the values entered into the 
IVRS, all other factors will be based on values recoreded on the eCRF as indicated below. If 
there are cases where patients are mis-stratified, then subgroups by stratification factors will 
be repeated using the (correct) data collected on the eCRF.
The following subgroups of the measurable disease analysis set will be analysed for ORR

Stratification factorsNumber of prior chemotherapy regimens received for ovarian 
cancer (2 or 3 vs. 4 or more)

Selected study chemotherapy (paclitaxel/topotecan/pegylated liposomal 
doxorubicin/gemcitabine)

Time to disease progression on last platinum based chemotherapy received prior to 
randomisation (6 – 12 months / > 12 months)
Additional subgroups of interest include:

Age at randomisation (<65, ≥65) - This will be determined from the date of birth 
(BIRTHDAT in the DEM module) and date of randomisation (RND_DAT in the 
CRIT1 module) on the eCRF at screening. Where a partial date of birth has been 
collected, the following imputation rules will be used:

If only the month and year of birth has been collected, the day of 
birth will be imputed as 15th

If only the year of birth has been collected, the day and month of 
birth will be imputed as 1st July

If the date of birth is completely missing, the age of the patient 
collected on the CRF will be used.

Region: to account for regional differences in clinical practice

Region 1 – North America (US, Canada, Mexico) vs RoW (Argentina, Belgium, 
Brazil, Czech Rep, Hungary, Israel, Italy, Poland, Spain, South Korea)

Region 2 - N America and Western Europe/Australia (US, Canada, Belgium, 
Italy, Spain, Mexico) vs Asia/non Western Europe (Argentina, Brazil, Poland, 
Hungary, Czech Rep, Israel, South Korea)


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
Race (White, Black/African-American, Asian or Native Hawaiian/Pacific Islander) 
- This will be determined from the response to “Race” (DEM module) on the eCRF 
at screening.

ECOG performance status at baseline (ECOG PS 0 [PSTAT=0] versus ECOG PS ≥ 
1 [PSTAT≥1]) - This will be determined from the response to “Performance status” 
(PSTAT module) on the eCRF at screening. 

Prior use of bevacizumab (Yes or No) - Patients with no prior bevacizumab 
reported will be included in the “No” category. Prior bevacizumab use will be 
identified using the previous ovarian cancer therapy eCRF page
Other baseline variables may also be assessed if there is clinical justification.
For each subgroup, the ORs (olaparib: physician’s choice of chemotherapy) and associated 
CIs will be calculated from an unadjusted logistic regression model. The ORs and 95% CIs 
will be presented on a forest plot including the OR and 95% CI from the overall population 
(using the unadjusted logistic regression model).  If necessary, additional analyses will be 
performed to explore the impact of confounding factors. No adjustment to the significance 
level for testing will be made since all these subgroup analyses will be considered exploratory 
and may only be supportive of the primary analysis of ORR. If necessary additonal analyses 
will be performed to explore the impact of confounding factors.
The primary ORR analysis will be repeated excluding any patients who did not have a 
gBRCA mutation status confirmed by the Myriad test, using an adjusted logistic regression 
model with the same ties and stratification factors as the primary ORR analysis. If there are < 
5 responses per stratum, the logistic regression will be unadjusted.
4.1.2.2
Sensitivity analyses for the primary endpoint (ORR)
(a) Ascertainment bias
An adjusted logistic regression will be repeated using the programmatically derived RECIST 
using investigator assessed ORR, using the same ties and stratification factors as the primary 
analysis, provided there are enough responses for a meaningful analysis. If there are not ≥ 5
responses per stratum, an unadjusted logistic regression will be performed. The OR and 95% 
Confidence Interval will be presented.
If there is an important discrepancy between the primary analysis using BICR assessments and 
this sensitivity analysis using investigator assessments, then the proportion of patients with 
site but no central confirmation of objective response will be summarised.
Disagreements between investigator and central reviews of RECIST objective response will 
be presented for each treatment group. The summary will include the early discrepancy rate 
which is the frequency of investigator review declared responses before the BICR review (≥2 
weeks earlier and including responses declared by investigator but not BICR) as a proportion 
of all investigator review responses and the late discrepancy rate which is the frequency of 


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investigator review declared responses after the BICR review (≥2 weeks later and including 
responses declared by BICR but not investigator) as a proportion of all discrepancies.
(b) Subjects with evaluable disease at baseline
As a sensitivity analysis to the primary ORR analysis, the analysis will be repeated including 
all patients with evaluable disease at baseline using BICR data. This will include all patients 
in the Measurable Disease Analysis Set (MDAS) and patients with non-measurable disease at 
baseline, but presenting with non-target lesions at baseline. The adjusted logistic regression 
model will use the same ties and stratification factors as the primary analysis, provided there 
are enough responses for a meaningful analysis. If there are not ≥ 5 responses per stratum, an 
unadjusted logistic regression will be performed.
(c) Full Analysis Set
As a sensitivity analysis to the primary ORR analysis, the analysis will be repeated including 
all randomised patients using BICR data. (All patients in the FAS). The adjusted logistic 
regression model will use the same ties and stratification factors as the primary analysis, 
provided there are enough responses for a meaningful analysis. If there are not ≥ 5 responses 
per stratum, an unadjusted logistic regression will be performed.
(d) Confirmed response
A sensitivity analysis of confirmed CR or PR will be conducted for both BICR and 
investigator assessments. A confirmed response of CR/PR means that a response of CR/PR is 
recorded at 1 visit and confirmed by repeat imaging not less than 4 weeks after the visit when 
the response was first observed with no evidence of progression between the initial and 
CR/PR confirmation visit. Data obtained up until progression, or last evaluable assessment in 
the absence of progression, will be included in the assessment of ORR. Patients who 
discontinue treatment without progression, receive a subsequent anti-cancer therapy (note that 
for this analysis radiotherapy is not considered a subsequent anti-cancer therapy) and then 
respond will not be included as responders in the ORR (i.e. both visits contributing to a 
response must be prior to subsequent therapy for the patient to be considered as a responder).
In the case where a patient has two non-consecutive visit responses of PR, then, as long as the 
time between the 2 visits of PR is greater than 4 weeks and there is no PD between the PR 
visits, the patient will be defined as a responder. Similarly, if a patient has visit responses of 
CR, NE, CR, then, as long as the time between the 2 visits of CR is greater than 4 weeks, then 
a best response of CR will be assigned.
The adjusted logistic regression model will use the same ties and stratification factors as the 
primary analysis, provided there are enough responses for a meaningful analysis. If there are 
not ≥ 5 responses per stratum, an unadjusted logistic regression will be performed.
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As a sensitivity analysis of the primary endpoint of ORR, the primary analysis will be 
repeated in all patients in the Measurable Disease Analysis Set who received at least one dose 
of randomised treatment.
An adjustedlogistic regression will be repeated using the BICR RECIST data, using the same 
ties and stratification factors as described for the primary analysis of ORR, provided there are 
enough responses for a meaningful analysis. If there are not ≥ 5 responses per stratum, an 
unadjusted logistic regression will be performed.  The OR and 95% CI will be presented.
(f) Deviation bias (if meaningful to do)
As a sensitivity analysis to the primary endpoint of ORR, an analysis excluding patients with 
deviations that may affect the efficacy of the trial therapy will be performed if > 10% of 
patients:

Were randomised but did not receive olaparib or chemotherapy.

Deviated from key entry criteria:

Female patients with histologically diagnosed relapsed high grade serous 
ovarian cancer (including primary peritoneal and/or fallopian tube cancer) or 
high grade endometrioid cancer (Inclusion criterion 3)

Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious 
or suspected deleterious (known or predicted to be detrimental/lead to loss of 
function) (Inclusion criterion 4)
An adjusted logistic regression will be repeated using the BICR RECIST data, using the same 
ties and stratification factors as described for the primary analysis of ORR. The adjusted 
logistic regression model will use the same ties and stratification factors as the primary 
analysis, provided there are enough responses for a meaningful analysis. If there are not ≥ 5
responses per stratum, an unadjusted logistic regression will be performed.  The OR and 95% 
CI will be presented.
(g) Unadjusted logistic regression using BICR assessment in the MDAS
As a sensitivity analysis of the primary endpoint of ORR, the primary analysis will be 
repeated with an unadjusted logisitic regression, using the BICR data for, all patients in the 
Measurable Disease Analysis Set. The OR and 95% CI will be presented.
4.1.3
Progression free survival (PFS) 
PFS will be analysed using a log-rank test stratified in accordance with the pre-defined 
pooling strategy.The HR and its confidence interval will be estimated from the U and V 


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statistics obtained directly from the LIFETEST model with inclusion of STRATA terms for 
the stratification variables, if applicable (and using the Breslow approach for handling ties).
The HR and its confidence interval will be estimated from the log-rank as follows (Berry et al 
1991 and Sellke et al 1983)
HR = exp(U/V)
95% CI for HR = (exp{U/V – 1.96/ √V}, exp{U/V + 1.96/ √V})
Where UΣ(d1i-e1i) is the log-rank test statistic (with d1i and e1i the observed and expected 
events in group 1) and √V the standard deviation of the log-rank test statistic as produced in 
the LIFETEST output.
Stratification variables will be defined according to data from the interactive voice/web 
response system (IVRS/IWRS). Although not anticipated, if patients are randomised in error 
when they have not previously had at least 2 prior lines of chemotherapy, then they will be 
grouped with patients who have had 2 prior lines of chemotherapy. If there are any patients 
who were miss-stratified, a sensitivity analysis of the primary PFS analysis will be carried out 
using the (correct) baseline data collected in the eCRF.
The HR (olaparib vs chemotherapy) together with its corresponding 95% CI and p-value will 
be presented (a HR less than 1 will favour olaparib).  
A Kaplan-Meier (KM) plot of PFS will be presented by treatment group with tick marks to 
identify censored observations. Summaries of the number and percentage of subjects 
experiencing a PFS event, and the type of event (RECIST or death) will be provided along 
with median PFS for each treatment.
The assumption of proportionality will be assessed. Note that in the presence of non-
proportionality, the HR will be interpreted as an average HR over the observed extent of 
follow-up.  Proportionality will be tested firstly by producing plots of complementary log-log
(event times) versus log (time) and, if these raise concerns, a time dependent covariate would 
be fitted to assess the extent to which this represents random variation.
The PFS analysis will be based on BICR assessments, and using all scans regardless of 
whether they were scheduled or not. 
The proportion of patients alive and progression free at 6, 12, 18 and 24 months will be 
summarised (using the KM curve) and presented by treatment group.
The number of patients prematurely censored will be summarised by treatment arm together 
with baseline prognostic factors of the prematurely censored patients.  A patient is defined as 
prematurely censored if they did not progress and the latest scan prior to DCO was more than 
one scheduled tumour assessment interval (+ 2 weeks) prior to the DCO date.


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In addition, duration of follow-up will be summarised using median time from randomisation 
to date of censoring (date last known to be non-progressor) in censored (not progressed) 
patients only, presented by treatment group.
As patients will be randomised, imbalances in demographic factors between the treatment 
groups are not anticipated.  However if any imbalances should occur, the HR and associated 
confidence interval calculated from a Cox Proportional Hazards model containing treatment, 
stratification variables and these additional demographic variables, may be reported.  
Subgroup analyses will be conducted comparing PFS between treatments. The purpose of the 
subgroup analyses is to assess the consistency of treatment effect across potential or expected 
prognostic factors.  If there are too few events available for a meaningful analysis of a 
particular subgroup (it is not considered appropriate to present analyses where there are less 
than 20 events per subgroup level), the relationship between that subgroup and PFS will not 
be formally analysed.  In this case, only descriptive summaries will be provided (progression
count and percentage). Options for pooling subgroups may be explored if clinically 
meaningful.
The subgroup analyses for the stratification factors will be based on the values entered into the
IVRS, all other factors will be based on values recorded on the eCRF as indicated below. If 
there are cases where patients are mis-stratified, then subgroups by stratification factors will 
be repeated using the (correct) data collected on the eCRF.
The following subgroups of the full analysis set will be analysed for PFS:
Stratification factors

Number of prior chemotherapy regimens received for ovarian cancer (2 or 3 vs. 4 or 
more) 

Selected study chemotherapy (paclitaxel/topotecan/pegylated liposomal 
doxorubicin/gemcitabine)

Time to disease progression on last platinum based chemotherapy received prior to 
randomisation (6 – 12 months / > 12 months)
Additional subgroups of interest include:

Measurable versus non measurable disease based on the blinded independent central 
review – This will be determined from the RECIST transfer for the blinded 
independent central review. If the patient was not adjudicated, then the patient has 
no measurable disease if there are no target lesions for the primary reviewer. If the 
patient was adjudicated, then the patient has no measurable disease if there are no 
target lesions for the reviewer that the adjudicator selected.


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
Measurable versus non measurable disease based on the investigator assessment –
This will be determined from the RECIST CRF. A patient has no measurable 
disease if there are no target lesions (the response to the question “Any target 
lesions present?” is “No”) in the investigator site assessment at screening

Age at randomisation (<65, ≥65) - This will be determined from the date of birth 
(BIRTHDAT in the DEM module) and date of randomisation (RND_DAT in the 
CRIT1 module) on the eCRF at screening. Where a partial date of birth has been 
collected, the following imputation rules will be used:

If only the month and year of birth has been collected, the day of 
birth will be imputed as 15th

If only the year of birth has been collected, the day and month of 
birth will be imputed as 1st July

If the date of birth is completely missing, the age of the patient 
collected on the CRF will be used.

Region: to account for regional differences in clinical practice
o
Region 1 – North America (US, Canada, Mexico) vs RoW 
o
(Argentina, Belgium, Brazil, Czech Rep, Hungary, Israel, Italy, Poland, Spain, 
South Korea)

Region 2 - N America and Western Europe/Australia (US, Canada, Belgium, 
Italy, Spain, Mexico) vs Asia/non Western Europe (Argentina, Brazil, Poland, 
Hungary, Czech Rep, Israel, South Korea)

Race (White, Black/African-American, Asian or Native Hawaiian/Pacific Islander) 
- This will be determined from the response to “Race” (DEM module) on the eCRF 
at screening.

ECOG performance status at baseline (ECOG PS 0 [PSTAT=0] versus ECOG PS ≥ 
1 [PSTAT≥1]) - This will be determined from the response to “Performance status” 
(PSTAT module) on the eCRF at screening. 

Prior use of bevacizumab (Yes or No) - Patients with no prior bevacizumab 
reported will be included in the “No” category. Prior bevacizumab use will be 
identified using the previous ovarian cancer therapy eCRF page
Other baseline variables may also be assessed if there is clinical justification.
For each subgroup, the HRs (olaparib: chemotherapy) and associated CIs will be calculated 
from a Cox proportional hazards model (ties = Efron) that contains the treatment term, factor 


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and treatment-by-factor interaction term.  The treatment effect HRs for each treatment 
comparison along with their CIs will be obtained for each level of the subgroup from this 
single model.  The HRs and 95% CIs will be presented on a forest plot including the HR and 
95% CI from the overall population (using the unadjusted Cox model).  If necessary, 
additional analyses will be performed to explore the impact of confounding factors.
No adjustment to the significance level for testing will be made since all these subgroup 
analyses will be considered exploratory and may only be supportive of the analysis of PFS.
The presence of quantitative interactions will be assessed by means of an overall global 
interaction test.  This will be performed in the overall population by comparing the fit of a 
Cox proportional hazards model including treatment, all covariates, and all covariate-by-
treatment interaction terms, with one that excludes the interaction terms and will be assessed 
at the 2-sided 10% significance level. If a covariate does not have more than 5 events per 
stratum (i.e. within each strata of the treatment*covariate interaction), then the covariate-by-
treatment interaction term will be omitted. Moreover, if the covariate does not have more than 
5 events per level of covariate then the main effect of the covariate will also be excluded. If 
the fit of the model is not significantly improved then it will be concluded that overall the 
treatment effect is consistent across the subgroups.
If the global interaction test is found to be statistically significant, an attempt to determine the 
cause and type of interaction will be made. Stepwise backwards selection will be performed 
on the saturated model, whereby (using a 10% level throughout) the least significant 
interaction terms are removed one-by-one and any newly significant interactions re-included 
until a final model is reached where all included interactions are significant and all excluded 
interactions are non-significant.  Throughout this process all main effects will be included in 
the model regardless of whether the corresponding interaction term is still present.  This 
approach will identify the factors that independently alter the treatment effect and prevent 
identification of multiple correlated interactions. 
Any quantitative interactions identified using this procedure will then be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985. 
The PFS analysis will be repeated excluding any patients who did not have a gBRCA 
mutation status confirmed by the central Myriad test. A KM plot of PFS in this subset of 
patients will be presented by treatment group. Summaries of the number and percentage of 
patients experiencing a PFS event and the type of event (RECIST or death) will be provided 
along with median PFS for each treatment arm. The HR and associated 95% CI will be 
reported using the same methodology as per the primary analysis of PFS.
PFS sensitivity analyses
Sensitivity analyses will be performed to assess the possible presence of time-assessment bias 
(i.e., differential assessment times between treatment groups).


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Summary statistics for the number of weeks between the time of progression and the last 
evaluable RECIST assessment prior to progression will be presented for each treatment group.
Summaries of the number and percentage of patients who miss two or more consecutive 
RECIST assessments and the number of patients who miss one RECIST assessment will be 
presented for each treatment group.
(a) Evaluation-time bias
Sensitivity analyses will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled time points. The midpoint 
between the time of progression and the previous evaluable RECIST assessment will be 
analysed using a stratified log-rank test, as described for the primary analysis of PFS.  This 
approach has been shown to be robust to even highly asymmetric assessment schedules (Sun 
and Chen 2010). To support this analysis, the mean of subject-level average inter-assessment 
times will be tabulated for each treatment.  This approach will use the BICR RECIST 
assessments.
(b) Attrition bias
Attrition bias will be assessed by repeating the primary PFS analysis except that the actual 
PFS event times, rather than the censored times, of subjects who progressed or died in the 
absence of progression immediately following two, or more, non-evaluable tumour 
assessments will be included. In addition, subjects who take subsequent therapy prior to 
progression or death will be censored at their last evaluable assessment prior to taking the 
subsequent therapy. 
Additionally a Kaplan-Meier plot of the time to censoring where the censoring indicator of the 
primary PFS analysis is reversed will be presented.
(c) Ascertainment bias
A stratified log-rank test will be repeated using investigator assessed RECIST data to 
programmatically derive PFS.  The HR and 95% CI will be presented. A Kaplan-Meier plot 
will also be presented for PFS based on the investigator assessed data.
If there is an important discrepancy between the primary PFS analysis using BICR 
assessments and this sensitivity analysis using Investigator assessments, then the proportion of 
subjects with site but no central confirmation of progression will be summarised.  The 
approach of imputing an event at the next visit in the central review analysis may help inform 
the most likely HR value, but only if an important discrepancy exists.
Disagreements between investigator and central reviews of RECIST progression will be 
presented for each treatment group.  The summary will include the early discrepancy rate 
which is the frequency of investigator review declared progressions before the BICR review 
(≥ 2 weeks earlier and including responses declared by investigator and not BICR) as a 


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proportion of all investigator review progressions and the late discrepancy rate which is the 
frequency of investigator review declared progressions after the BICR review (≥ 2 weeks later 
and including responses declared by BICR  and not investigator)  as a proportion of all 
discrepancies.
(d) On-treatment analysis
As a sensitivity analysis of the PFS endpoint, the analysis will be repeated in all patients in the 
full analysis set  who recevied at least one dose of randomised treatment.
A stratified log-rank test will be repeated using the BICR RECIST data, using the same ties 
and stratification factors as described for the primary analysis of PFS. The HR and 95% CI 
will be presented.
(e) Deviation bias (if meaningful to do)
As a sensitivity analysis to the PFS endpoint, an analysis excluding patients with deviations 
that may affect the efficacy of the trial therapy will be performed if > 10% of patients:

Were randomised but did not receive olaparib or chemotherapy.

Deviated from key entry criteria:

Female patients with histologically diagnosed relapsed high grade serous 
ovarian cancer (including primary peritoneal and/or fallopian tube cancer) or 
high grade endometrioid cancer (Inclusion criterion 3)

Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious 
or suspected deleterious (known or predicted to be detrimental/lead to loss of 
function) (Inclusion criterion 4)
A stratified log-rank test will be repeated using the BICR RECIST data, using the same ties 
and stratification factors as described for the primary analysis of PFS. The HR and 95% CI 
will be presented.
(f) Cox proportional hazards model
An additional sensitivity analysis of PFS will be performed based on a Cox proportional 
hazards model. The hazard ratio (HR) and confidence interval (CI) will be estimated from a 
Cox Proportional Hazards model (with ties=Efron and the same stratification variables as the 
primary PFS analysis as covariates) and the CI will be calculated using a profile likelihood 
approach.
(g) Unadjusted Cox proportional hazards model
An additional sensitivity analysis of PFS will be performed based on an unadjusted Cox 
proportional hazards model. The hazard ratio (HR) and confidence interval (CI) will be 


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estimated from a Cox Proportional Hazards model (with ties=Efron) and the CI will be 
calculated using a profile likelihood approach.
4.1.4
Progression free survival 2 (PFS2)
An initial PFS2 analysis will be performed at the same time as the primary analysis (subject to 
the hierarchy defined in 4.1.1) and will use the same methodology and model as the PFS 
analysis, stratified in accordance with the pre-defined pooling strategy (defined in 4.1). . If 
there are less than 20 events in total at the time of the primary analysis, descriptive summaries 
will be provided only. A further analysis of PFS2 will be performed when the OS data are 
approximately 60% mature only if both ORR and PFS are statistically significant based on the 
primary analysis and the null hypotheses for PFS2 and/or OS are not rejected at the time of the 
primary analysis.
The type of progression (objective progression by RECIST, progression by CA-125, 
symptomatic progression or other) will also be summarised by treatment arm.
The analysis of PFS2 will be repeated excluding any patients who did not have a gBRCA
mutation status confirmed by the Myriad test. The HR and associated 95% CI from a log-rank 
will be reported as per the primary analysis of PFS2.
The sensitivity analysis outlined for PFS in Section 4.1.3 will not be repeated for PFS2.
Descriptive summaries of time from second progression to previous assessment by treatment 
arm will be provided. . For subjects, who have no previous assessment for second progression 
prior to the second progression event, the date of the first progression will be used.  
4.1.5
Overall survival (OS) 
OS data will be analysed at the time of the primary analysis and will use the same 
methodology and model as the PFS analysis, stratified in accordance with the pre-defined 
pooling strategy (defined in 4.1). If there are less than 20 deaths in total at the time of the 
primary analysis, descriptive summaries will be provided only. A further analysis of OS will 
be performed when the OS data are approximately 60% mature (approximately 150 deaths)
only if both ORR and PFS are statistically significant based on the primary analysis and the 
null hypotheses for PFS2 and/or OS are not rejected at the time of the primary analysis.
Subject to the hierarchy defined in 4.1.1, to control for multiple testing due to an interim and 
final analysis a Lan DeMets spending function (Lan and DeMets 1983) that approximates an 
O’Brien Fleming approach will be used.
The analysis of OS will be repeated excluding any patients who did not have a gBRCA
mutation status confirmed by the Myriad test. The HR and associated 95% CI from a log-rank 
will be reported as per the primary analysis of OS.
The sensitivity analysis outlined for PFS in Section 4.1.3 will not be repeated for OS.


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A summary of survival status at the time of analysis will be produced. This will summarise the 
number of patients who have died, who are still in survival follow-up, who are lost to follow-
up or who have withdrawn consent.
In addition, duration of follow-up will be summarised using medians:

In censored (not died) patients only: Time from randomisation to date of censoring 
(date last known to be alive)

In all patients: Time from randomisation to the date of death or to the date of 
censoring for censored patients.
Exploratory analyses of OS
Exploratory analyses of OS adjusting for impact of subsequent PARP inhibitor trial or 
treatment may be performed if a sufficient proportion of patients switch.  Methods such as 
Rank Preserving Structural Failure Time (RPSFT) (Robins et al 1991), Inverse Probability of 
Censoring Weighting (IPCW) (Robins 1993) and other methods in development will be 
explored.  The decision to adjust and final choice of methods will be based on a blinded 
review of the data and the plausibility of the underlying assumptions.  Baseline and time-
dependent characteristics will be explored, and summaries of baseline characteristics will be 
summarised for chemotherapy patients, splitting between those that have and haven’t switched 
at the time of the analyses.
4.1.6
Time to first subsequent therapy or death (TFST) and time to second 
subsequent therapy or death (TSST)
Time to first subsequent therapy or death (TFST) and time to second subsequent therapy or 
death (TSST) will be analysed at the same time as the primary analysis and will use the same 
methodology and model as the PFS endpoint, stratified in accordance with the pre-defined 
pooling strategy (defined in 4.1).. The HRs for the treatment effect together with 95% CIs will 
be presented.  KM plots will be presented by treatment arm.  In addition, the time between 
progression and starting subsequent therapy will be assessed.  
Summary tables of first and second subsequent therapies by treatment arm will be provided, as 
well as response to first and second subsequent therapy by treatment arm.
Further analyses of these endpoints may be performed when the OS data are approximately 
60% mature only if both ORR and PFS are statistically significant based on the primary 
analysis and the null hypotheses for PFS2 and/or OS are not rejected at the time of the primary 
analysis.
The analysis of time to earliest progression by RECIST 1.1, CA-125 or death will be repeated 
excluding any patients who did not have a gBRCA mutation status confirmed by the Myriad 
test. The HR and associated 95% CI from a log-rank will be reported as per the primary 
analysis of TFST.


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No multiplicity adjustment will be applied as this is viewed as a supportive endpoint.
4.1.7
Time to study treatment discontinuation or death (TDT)
Time to study treatment discontinuation or death (TDT) will be analysed at the same time as 
the primary analysis and using the same methodology and model as for the PFS endpoint, 
stratified in accordance with the pre-defined pooling strategy (defined in 4.1). The HR for the 
treatment effect together with 95% CIs will be presented.  A KM plot will be presented by 
treatment arm.  No multiplicity adjustment will be applied as this is viewed as a supportive 
endpoint.
Further analysis of this endpoint may be performed when the OS data are approximately 60% 
mature only if both ORR and PFS are statistically significant based on the primary analysis 
and the null hypotheses for PFS2 and/or OS are not rejected at the time of the primary 
analysis.
The analysis of TDT will be repeated excluding any patients who did not have a gBRCA
mutation status confirmed by the Myriad test. The HR and associated 95% CI from a log-rank
will be reported as per the primary analysis of TDT.
4.1.8
Time to earliest progression by RECIST 1.1, CA-125 or death
Time to progression by BICR RECIST 1.1, CA-125 or death will be performed at the same 
time as the primary analysis and will use the same methodology and model as the PFS 
endpoint, stratified in accordance with the pre-defined pooling strategy (defined in 4.1)..
The number (%) of patients reporting a CA-125 progression and a combined objective 
progression and/or CA-125 progression will be tabulated.
No multiplicity adjustment will be applied as this is viewed as a supportive endpoint (to PFS).
The analysis of time to earliest progression by RECIST 1.1, CA-125 or death will be repeated 
excluding any patients who did not have a gBRCA mutation status confirmed by the Myriad 
test.  The HR and associated 95% CI from a log-rank will be reported as per the primary 
analysis of Time to earliest progression by RECIST 1.1, CA-125 or death.
4.1.9
Duration of Response (DoR) and CA-125 Response
Any patients who experienced CR or PR which was first observed whilst receiving subsequent 
therapy after discontinuation of olaparib will be identified. In addition, the number and 
percentage of patients with a RECIST response based on investigator and/or a CA-125 
response will be summarised by treatment arm.
Median duration of response (DoR) derived using Kaplan-Meier methodology and median 
time to response will be summarised by treatment arm. A Kaplan-Meier plot of DoR will be 
presented by treatment arm.


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4.1.10
FACT-O
The analysis population for HRQoL data will be the subset of the FAS.
Change from baseline in TOI score will be regarded as the primary analysis of the FACT-O 
questionnaire and will be analysed using a mixed model for repeated measures (MMRM) 
analysis of the change from baseline in TOI score for each visit.  The primary analysis will be 
to compare the average treatment effect from the point of randomisation for the first 8 months 
(which will include visit data obtained at baseline, weeks 4, 8, 16, 24, 32, 40 and 48). Other 
timepoints and the study discontinuation visit and the safety follow-up visit will be excluded 
from this analysis but may be included on supportive summaries and graphical displays as 
appropriate. Only visits performed whilst the patient is on treatment will be included in the 
model using APHASE.
The MMRM model will include patient, treatment, visit and treatment by visit interaction as 
explanatory variables and the baseline TOI score and baseline TOI score by visit interaction,as 
a covariate. Treatment, visit and treatment by visit interaction will be fixed effects in the 
model; patient will be included as a random effect.  The treatment by visit interaction will 
remain in the model regardless of significance.  
An unstructured covariance matrix will be used to model the within-subject error and the 
Kenward-Roger approximation will be used to estimate the degrees of freedom. The following 
provides sample code for implementing the MMRM analysis: 
proc mixed data=TOI method = reml;
   class TRT VISIT SUBJECT;
   model TOISC = TRT VISIT TRT*VISIT TOIBL TOIBL*VISIT / s ddfm=kr;
   repeated VISIT / type=UN subject=SUBJECT;
   lsmeans TRT*VISIT / slice=VISIT pdiff diff alpha=0.05 cl;
where TRT is the randomised treatment, , VISIT is the visit, TOISC is the change from 
baseline in the TOI score, and TOIBL is the baseline TOI score.
If the fit of the unstructured covariance structure fails to converge, the following covariance 
structures will be tried in order until convergence is reached: toeplitz with heterogeneity, 
autoregressive with heterogeneity, toeplitz, and autoregressive.
The adjusted mean estimates and corresponding 95% confidence intervals will be presented 
by visit for each treatment group.
Descriptive statistics and graphs will be reported for the TOI by visits as well as change in 
these scores from baseline.  These will also be reported for physical well-being, functional 
well-being, additional concerns, the individual items of the additional concerns and the total 


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FACT-O.  Summary tables of Trial Outcome Index (TOI) best change rates (improvement, 
worsening, and no change) will be provided.
TOI improvement rate will be analysed using a logistic regression model (improved vs not 
improved) and adjusted by the same covariates as used in the primary ORR analyses. The 
results of the analysis will be presented in terms of an odds ratio together with its associated 
profile likelihood CIs and p-values (based on twice the change in log-likelihood resulting from 
the addition of a treatment factor to the model). However, if there are <5 patients with a 
response of improved in either of the two treatment groups, or if the model is not able to 
converge due to small numbers in the fitted covariate categories, then no logistic regression 
analysis will be performed and instead a Fisher’s exact test will be considered and mid p-
values used. Descriptive statistics will be shown irrespective of the number of responses in 
each treatment group.
FACT-O compliance (overall compliance and by visit compliance) will be summarised for 
each treatment group.
Summary tables of best change rates (improvement, worsening and no change, (Table 6)) and 
analysis of improvement rates will be performed for TOI and total FACT-O
4.1.11
Exploratory analyses
Cancer Therapy Satisfaction Questionnaire (CTSQ-16)
Data from the CTSQ-16 scores of treatment satisfaction (as measured by the Satisfaction with 
Therapy scale and the other sub-scales and items of the CTSQ-16) will be summarised by
treatment arm.  The questionnaire will be completed at Week 24 and at study treatment 
discontinuation (with no baseline assessment).
EQ-5D-5L
The evaluable population will comprise all patients who receive study treatment included in 
the safety analysis set and who have a baseline EQ-5D-5L assessment.
Descriptive statistics and listings will be reported for health state utility values and visual 
analogue scale by visits as well as change in these scores from baseline, and will be 
summarised by actual treatment group.  To support future economic evaluations of olaparib, 
additional appropriate analyses may be undertaken, for example, mean health state utility pre 
and post treatment, and pre and post progression.  These exploratory analyses may be carried 
out to support health authority appraisals and will consequently not be reported in the CSR. 
Further detail will be provided in the payer analysis plan.
Hospital Resource Use
Data will be listed on the number of outpatient (ambulatory and daytime) visits, 
hospitalisations (inpatient overnight admissions) by randomised treatment group for all 
patients who receive study treatment included in the safety analysis set. The total length of 


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hospital stay (number of nights) by ward type (e.g. general ward, intensive care/high 
dependency unit) by randomised group will also be listed.
To support future economic evaluations of olaparib, additional appropriate analyses may be 
undertaken. These exploratory analyses may be carried out to support health authority 
appraisals and will consequently not be reported in the CSR. Further detail will be provided in 
the payer analysis plan. 
Subsequent therapy
Subsequent therapies received after discontinuation of olaparib will be summarised and listed 
by treatment group, together with number of regimens received.  Patients who subsequently 
received a PARP inhibitor or entered a PARP inhibitor trial will be summarised and listed by 
treatment arm according to line of subsequent therapy, i.e. immediately after olaparib or as a 
later line, in addition to patients in the chemotherapy arm who subsequently received olaparib.
Patient Global Impression of Change
Patient Global Impression of Change will be summarized descriptively.
4.1.12
Safety
Safety data will be summarised and listed only. No formal statistical analyses will be 
performed on the safety data. All safety data will be summarised based on their treatment 
received (if a patient received at least one dose of Olaparib they will be summarised in the 
olaparib arm – see section 2.1.1).  In the unlikely event that any errors in treatment dispensing 
occurred, these errors will be listed.
Adverse events
All AEs, both in terms of Medical Dictionary for Regulatory Activities (MedDRA) preferred 
term and Common Toxicity Criteria for Adverse Events (CTCAE) grade, will be listed and 
summarised descriptively by count (n) and percentage (%) for each treatment arm. MedDRA 
dictionary will be used for coding. Any AE occurring before olaparib/chemotherapy treatment 
(i.e. before Study Day 1) and that did not worsen (have an increase in CTCAE grade) after 
first dose of olaparib/chemotherapy treatment will be included in the AE listings, but will not 
be included in the summary tables (unless otherwise stated). These will be referred to as ‘pre-
treatment’.  Any untoward event occurring subsequent to the 30-day follow-up AE reporting 
period that the investigator assesses as possibly related to the study treatment will also be 
included in the AE listings, but not in the summary tables.
The summary tables will include all AEs that had a start date or a worsening (increase in 
CTCAE grade) after the start of treatment up until the end of the 30 day follow-up period. The 
30 day follow-up period will be defined as 30 days following discontinuation of 
olaparib/chemotherapy treatment.


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All reported AEs will be listed along with the date of onset, date of resolution (if AE is 
resolved), investigator’s assessment of severity and relationship to study drug. Frequencies 
and percentages of patients reporting each preferred term will be presented (i.e. multiple 
events per patient will not be accounted for apart from on the episode level summaries). 
Summary information (the number and percent of patients by treatment) will be tabulated for:

All AEs 

All AEs causally related to study medication

AEs with CTCAE grade 3 or higher

AEs with CTCAE grade 3 or higher, causally related to study medication

AEs with outcome of death

AEs with outcome of death causally related to study medication

All SAEs

All SAEs causally related to study medication 

AEs leading to discontinuation of olaparib/chemotherapy

AEs leading to discontinuation of olaparib/chemotherapy, causally related to 
olaparib/chemotherapy

Other significant AEs

Other significant AEs causally related to olaparib/chemotherapy
An overall summary of the number and percentage of patients in each category will be 
presented, as will an overall summary of the number of episodes in each category.  In 
addition, a truncated AE table of most common AEs, showing all events that occur in at least 
5% of patients overall will be summarised by preferred term, by decreasing frequency.  This 
cut-off may be modified after review of the data.
Each AE event rate (per 1000 patient years) will also be summarised by preferred term within 
each system organ class. For each preferred term, the event rate will be presented and will be 
defined as the number of patients with that AE divided by the sum of the duration of therapy
plus 30 days for the safety follow up (for patients without the event) and the time to the AE 
(for patients with the event) in each group multiplied by 1000.
AEs will be assigned CTCAE grades (National Cancer Institute (NCI) CTCAE version 4.0) 
and summaries of the number and percentage of patients will be provided by maximum 


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reported CTCAE grade, system organ class, preferred term and actual treatment group. 
Fluctuations observed in CTCAE grades during study will be listed.
Summaries of the number and percentage of patients with AEs leading to dose change of 
olaparib/chemotherapy and also dose interruptions of olaparib/chemotherapy will be presented 
by preferred term and treatment group.  
In addition, AEs with outcome of death, SAEs, OAEs, AEs leading to discontinuation of 
treatment, AEs causally related to olaparib/chemotherapy and other significant AEs will be 
listed. 
A summary of deaths will be provided with number and percentage of patients by actual 
treatment group, categorised as:

Related to disease under investigation, 

AE outcome=death,

Both related to disease under investigation and with AE outcome=death, 

AE with outcome = death ≥ 30 days after last treatment dose, 

Deaths ≥ 30 days after last treatment dose, unrelated to AE or disease under 
investigation, and 

Patients with unknown reason for death. 
A corresponding listing will also be produced. 
Separate summaries will be produced that presents any events that occur prior to dosing or 
starting more than 30 days after discontinuing therapy.
Summary of long term tolerability
To assess long term tolerability, prevalence plots, life table plots and cumulative incidence
plots will be presented for:

Nausea

Vomiting

Any other events considered important after review of the safety data, provided 
there are ≥ 5% events overall.
A prevalence plot provides information on the extent to which the events may be an ongoing 
burden to patients. The prevalence at time t after first dose of study treatment is calculated as 
the number of patients experiencing the event divided by the number of patients receiving 


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study treatment or in safety follow-up at time t; generally, t is categorised by each day after 
dosing.  The prevalence is plotted over time split by treatment arm. Multiple occurrences of 
the same event are considered for each patient but a patient is only counted in the numerator 
whilst they are experiencing one of the occurrences of the event. 
For each of these AEs (i.e. Nausea, vomiting, other AEs as defined above), median time to 
first onset of the AE will be presented in patients with the specific AE of interest in the safety 
analysis set by actual treatment group.  Summary tables of time to first onset for each AE will 
also be produced (e.g. 1-28 days, 29-56 days, 57-84 days, 85-112 days, >112 days).  Median 
duration of the AE will be presented in patients who experienced each AE.    
A life table plot can be used to describe the time to onset of the event and specifically when 
patients are at most risk of first experiencing the event.  The hazard, or in other words, the 
probability of having an AE in a specified time period (e.g. 0-1 months, 1-3 months, 3-6 
months, etc.) given that the patient reaches that time period without having an event is plotted 
for each time period split by treatment.  
A cumulative incidence plot is a plot of the raw cumulative incidence and cumulative 
incidence function over time with the treatment arms presented on separate plots. The raw 
cumulative incidence is the actual probability that a patient will have experienced their first 
occurrence of the event by a given time point. The cumulative incidence function estimates 
the cumulative incidence if the DCO had not been imposed and all patients had completed 
safety follow-up (Pintilie M.).
Laboratory assessments
For all continuous laboratory assessments, absolute value, change from baseline and 
percentage change from baseline will be summarised using descriptive statistics at each 
scheduled assessment time by actual treatment group.  For categorical laboratory assessments, 
shift from baseline will be summarised using frequency and proportion at each scheduled 
assessment time by actual treatment group.
Shift tables for laboratory values by worst common toxicity criteria (CTC) grade will be 
produced, and for specific parameters separate shift tables indicating hyper- and hypo-
directionality of change will be produced.  For parameters with no CTCAE grading, shift 
tables from baseline to worst value on-treatment will be provided (i.e. on-treatment is defined 
as data collected up until the last dose of olaparib/chemotherapy). Shift tables for appropriate 
urinalysis values by worst grade may be also provided as appropriate. 
A scatter plot of alanine aminotransferase (ALT) versus total bilirubin, both expressed as 
multiples of the upper limit of normal (ULN), will be produced with reference lines at 3×ULN 
for ALT, and 2×ULN for total bilirubin.  The scatter plot will be repeated for aspartate 
aminotransferase (AST) versus total bilirubin with reference lines at 3×ULN for AST, and 
2×ULN for total bilirubin.  In each plot, total bilirubin will be in the vertical axis.


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Liver biochemistry test results over time for patients with elevated ALT or AST, and elevated 
total bilirubin (at any time) will be plotted (potential Hy’s Law cases).  Individual patient data 
where ALT or AST plus total bilirubin are elevated at any time will be listed also.
All laboratory summaries will be presented by actual treatment group.
Vital signs
Vital signs (SBP, DBP, pulse rate, body temperature and weight) will be summarised at 
baseline by actual treatment group.
4.1.13
Demographic and baseline characteristics data
The following will be summarised by randomised treatment group for the FAS (full analysis 
set) and separately for the Measurable disease analysis set (MDAS), unless indicated 
otherwise:-

Patient disposition (including screening failures and reason for screening failure) 

Important protocol deviations

Inclusion in analysis populations

Demographics (age, age group, sex, race and ethnicity)

Age will be derived as age at last birthday in whole years using the date of 
randomisation and date of birth. Where a partial date of birth has been 
collected, the following imputation rules will be applied in order to calculate 
the patient’s age for use in listings and summaries tables presenting age 
and/or age group and subgroup analyses based on age:

If only the month and year of birth has been collected, the day of 
birth will be imputed as 15th

If only the year of birth has been collected the day and month of 
birth will be imputed as 1st July

If the date of birth is completely missing, the derived age of the 
patient will also be missing.

Patient characteristics at baseline (height, weight, weight group, body mass index 
(BMI) and body mass index group)

Stratification factors recorded on the eCRF


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
Stratification factors according to the IVRS

Patient recruitment by country and centre (only for FAS)

Previous ovarian cancer therapy

Previous therapy for other cancer

Disease characteristics at baseline (ECOG performance status, BRCA mutation 
status at screening [BRCA1, BRCA2 or BRCA1/2], gBRCA category by Myriad 
testing [gBRCAm, gBRCA wt, gBRCA VUS, Missing], primary tumour location, 
histology type, tumour grade, FIGO stage, time from diagnosis to randomisation
and overall disease classification)

In the case of partial or missing dates of diagnosis for the calculation of the 
time from diagnosis:

If only the month and year has been collected, the day will be 
imputed as 15th

If only the year has been collected, the day and month will be 
imputed as 1st July

If the date is completely missing, the derived time from diagnosis 
will also be missing

Extent of disease

Disease related medical history (only for FAS)

Relevant surgical history (only for FAS)

Physical examination at baseline

Time from completion of previous platinum chemotherapy to randomisation

Disallowed concomitant medications

Allowed concomitant medications

Post-discontinuation cancer therapy

Blood and related products, colony stimulating factors and other anti-anaemic
preparations will be tabulated, including a summary only including patients with 
grade >=2 haemoglobin on treatment and the Number of concomitant blood 
transfusions over time.


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AZ drug dictionary (AZDD)  will be used for concomitant medication coding.
A listing containing both the eCRF BRCA results and the Myriad BRCA results will be 
produced.
If there is an additonal OS analysis, patients disposition data will also be summarised and 
listed at the time of updated OS analysis (approximately 60% maturity for OS).
4.1.14
Treatment exposure
The following summaries related to study treatment will be produced for patients in the safety 
analysis set who received at least one dose of olaparib:

Total exposure of olaparib.

Actual exposure of olaparib.

Number of days on 300 mg olaparib bd = actual exposure for the dose assigned.

Number of and reasons for dose reductions, dose interruptions, and dose 
modifications of olaparib. Dose reductions and dose interruptions will be based on 
investigator initiated dosing decisions. Dose interruptions/reductions due to 
“Subject Forgot to Take Dose” will be omitted from these summaries.

PID and RDI of olaparib (entire intended treatment period). 
The following summaries related to study treatment will be produced for patients in the safety 
analysis set who received chemotherapy by chemotherapy regimen:

Total number of cycles of chemotherapy received.

Number of and reasons for dose reductions and dose delays of chemotherapy

PID and RDI of chemotherapy (entire intended treatment period). 
For patients on study treatment at the time of the PFS analysis, the DCO date will be used to 
calculate exposure.
All treatment information data will be listed for the safety analysis set by randomised 
treatment group.
4.1.15
Pharmacokinetic analysis
The olaparib plasma concentration data obtained from the collected samples will be included 
in a listing for the CSR. This listing will be based on patients in the safety analysis set. The 
plasma concentration data for Day 1 pre-dose, 1 hour post-dose and Day 29 Pre-dose time will 
be summarized based on patients in the PK analysis set,


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The plasma concentration data will be analysed using nonlinear mixed effects modelling 
(NONMEM).The objectives and methods for population PK and PK-pharmacodynamic 
(PKPD) modelling will be described in a separate modelling analysis plan and the results of 
this analysis will be reported in a separate PK and PKPD modelling report.
4.1.16
Data cut-offs
The status of ongoing, withdrawn (from the study) and “lost to follow-up” patients at the time 
of the ORR analysis (initial OS analysis) and at the time of the final OS analysis (if 
applicable) should be obtained by the site personnel by checking the patient’s notes, hospital 
records, contacting the patient’s general practitioner and checking publicly available death 
registries. In the event that the patient has actively withdrawn consent 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.
5.
INTERIM ANALYSES
No formal statistical interim analyses for ORR or PFS are planned for this trial. The data cut-
off for the primary analysis will occur in January 2019 or at a minimum of 6 months after LSI, 
whichever is sooner. . PFS2 and OS will be analysed at the time of the primary analysis. An 
additional PFS2 and OS analysis will only be conducted with further follow up (~60% OS 
events) if both ORR and PFS are statistically significant based on the primary analysis and the
null hypotheses for PFS2 and/or OS are not rejected at the time of the primary analysis.
This study will use an external Independent Data Monitoring Committee (IDMC) to perform 
interim reviews of accumulating study safety data. This committee will be composed of 
therapeutic area experts and a statistician, who are not employed by AZ, and do not have any 
major conflict of interest. Following the review, the IDMC will recommend whether the study 
should continue unchanged, be terminated, or be modified in any way. Once the IDMC has 
reached a recommendation, a report will be provided to AstraZeneca. The report will only 
include the recommendation and any potential protocol amendments and it will not contain 
any unblinded information or reference to the confidential considerations of the committee to 
have led to their recommendation.  A separate IDMC charter will be developed which will 
contain any details of the IDMC members and clearly define the responsibilities of the IDMC.
In addition to the periodic review of safety data by an IDMC, the safety of all AstraZeneca 
clinical studies is closely monitored on an on-going basis by AstraZeneca representatives in 
consultation with the Patient Safety Department. Issues identified will be addressed; this could 
involve, for instance, amendments to the study protocol and letters to investigators.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
Section 10.5.3.2 in the protocol states: “The analysis of PFS2 will be repeated excluding any 
patients who did not have a gBRCA mutation status confirmed by the Myriad test. The same 


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methodology and model will be used and the HR and associated 95% CI from a Cox 
Proportional Hazards model will be reported.”
Section 4.2.4 in the SAP has been amended to “The analysis of PFS2 will be repeated 
excluding any patients who did not have a gBRCA mutation status confirmed by the Myriad 
test. The HR and associated 95% CI from a log-rank will be reported as per the primary 
analysis of PFS.”
The subset of patients with confirmed gBRCA mutation status will be analysed using the same 
methodology as the primary analysis for PFS and repeated for the following endpoints: PFS, 
PFS2, OS, time to earliest progression by RECIST1.1 or CA-125 or death, TFST, TDT and 
TSST. 
Section 10.4.1.2.1 PFS in the CSP had a typo. “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.” This has been amended to “ >=5mm ” in the SAP section 
3.2.2.
7.
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