Clinical trial NCT02983799
Conditions: Relapsed Ovarian Cancer, BRCA Mutation, Platinum Sensitivity
Keywords: BRCA, ovarian, platinum, chemotherapy
Sponsor: AstraZeneca
Start date: 2016-12-22; Completion date: 2020-12-03
Enrollment: 272 participants; Allocation: NA; Intervention model: PARALLEL

Brief summary:
This is a non-randomized, open-label study to assess olaparib tablets as a treatment for subjects with different homologous recombination deficiency (HRD) tumor status and with platinum-sensitive, relapsed, high-grade serous or high-grade endometrioid ovarian cancer. Subjects should have received at least 1 prior line of platinum-based chemotherapy.

Detailed description:
This is a Phase II, open-label, non-randomized, multi-center study assessing the efficacy and safety of olaparib tablets 300 mg (two 150 mg tablets) given orally twice daily (bid) in subjects with platinum-sensitive or partially platinum-sensitive, relapsed, high-grade serous or high-grade endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received at least 1 prior line of platinum-based chemotherapy.

The study will assess the effectiveness of olaparib tablets as measured by the objective response rate (ORR) as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, in subjects with germline BRCA mutations (gBRCAm), somatic BRCA mutations (sBRCAm), or potential aberrations in homologous recombination deficiency (HRD) as determined by myChoice® HRD, as well as in subjects without identifiable HRD. This study will utilize Myriad BRACAnalysis CDx® for germline BRCA analysis and a tumor test (myChoice® HRD) for tumor BRCA analysis and HRD status. Four cohorts will be identified based upon the genetic testing described above:

* Cohort 1: gBRCAm,
* Cohort 2: sBRCAm and germline BRCA wild type,
* Cohort 3: myChoice® HRD positive (genomic instability positive) and BRCA wild type (BRCAwt) (no BRCA mutation),
* Cohort 4: myChoice® HRD negative (genomic instability negative) and BRCAwt (no BRCA mutation).

Arms: arm 1: germline BRCA mutant arm 2: somatic BRCA mutant, germline BRCA wild type arm 3: genomic instability positive and no BRCA mutation arm 4: genomic instability negative and no BRCA mutation
Interventions: intervention 1: OLAPARIB
Intervention descriptions: intervention 1: 300 mg olaparib tablets taken orally twice daily

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
Drug Substance
Olaparib
Study Code
D0816L00003
Version
3.0
Date
10 October 2017
Non-Randomized, Open-Label Phase II Study to Assess Olaparib Tablets as 
a Treatment for Subjects with Different HRD Tumor Status and with 
Platinum-Sensitive, Relapsed, High-Grade Serous or High-Grade 
Endometrioid Ovarian, Fallopian Tube, or Primary Peritoneal Cancer That
Have Received at Least 1 Prior Line of Chemotherapy 
Sponsor: AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, Wilmington, DE 19809




Clinical Study Protocol
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
3 (138)
Synopsis and Section 8.2: The sample size text was modified to reflect the changes in cohort 
enrollment (minimum of 30 subjects, maximum of 90 subjects per cohort). 
Synopsis and Section 9.3: The anticipated enrollment duration was reduced from 30 months to 
approximately 20 months.
Section 3.5, Section 4.1, and Section 5.6.1: The protocol was revised to state that prior to any 
cohorts being closed to enrollment, subjects may enroll in the study and initiate treatment prior to 
the Myriad BRACAnalysis CDx® and myChoice® homologous recombination deficiency (HRD)
tests being reported; however, subjects will not be allocated into a cohort until the results are 
received by the Investigator. Once the test results are received by the Investigator, the subject will 
be allocated into the appropriate cohort.  Once a cohort reaches 90 subjects, the cohort will be 
closed, and subjects may not initiate treatment until their Myriad BRACAnalysis CDx® and 
myChoice® HRD tests are completed, the results are received by the Investigator, and it is confirmed 
an open-cohort is available for which the subject is eligible.
Section 4, Table 4, Section 4.1, Section 5.6.1: A pre-screening option was added. The Myriad 
testing may be submitted in advance of the 28-day screening window if the subject consents to the 
appropriate pre-screening informed consent form.
Table 4, Section 4.2.1, Section 4.2.5, Section 5.6.1, Section 5.6.5, Table 6, and Section 8.4.6: 
Collection of mandatory blood samples for circulating tumor deoxyribonucleic acid analysis was 
added at baseline and disease progression. 
Section 3.9, Section 4, Section 4.2.5, and previous Section 4.3.1: The text was revised and deleted as 
necessary to clarify that subjects must be discontinued from the active study treatment phase if they 
have objective radiological disease progression according to Response Evaluation Criteria in Solid 
Tumors v1.1. 
Section 4.3.2: Text was modified to clary that follow-up after the final data cut-off refers to the final 
data cut-off for the primary endpoint analysis.
Section 1.4 and Section 5.6.1: It was clarified that additional tumor samples (10 to 20 slides) will 
also be collected for a mandatory tumor biopsy at screening and at objective radiological disease 
progression, if there is a tumor that can be biopsied and it is not clinically contraindicated.
Section 8.5.4, An informal interim analysis was added. The informal interim analysis in each cohort 
will take place after 15 subjects have had at least 1 radiologic tumor response assessment in the first 
6 months of the study. If no responses (CR or PR) are observed in the first 15 subjects in a cohort, in 
consultation with the Steering Committee, the cohort will be closed to further enrollment.  However, 
if there is at least 1 confirmed objective response in the first 15 subjects, that would justify 
continuing enrollment up to a maximum of 90 subjects.  Enrollment will continue until these interim 
analyses have been completed and a decision is made by the Study Steering Committee. 
Additionally annual updates of relevant study data may be generated for the purpose of reporting at 
appropriate oncology conferences, as specified in the statistical analysis plan.  




Clinical Study Protocol
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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severe renal impairment (CrCl ! 30 mL/min) or end-stage renal disease; if subjects develop 
severe impairment or end-stage renal disease olaparib must be discontinued.”
Sections 1.1, 1.2, 1.2.1, 1.3.2, and 1.3.2.1: Text was updated to reflect the approval of the olaparib 
tablet formulation, as well as results from Study 19 and SOLO-2, as appropriate. 
Section 3.8.2 and Appendix E: The duration of contraception requirements was clarified and 
language was modified to clarify the contraception requirements should be started from the signing 
of informed consent. 
Section 4.2.5 and Table 6 (Study Plan): The visit window for the study discontinuation visit was 
corrected from ± 7 days to + 7 days. 
Appendix E: Acceptable non-hormonal birth control methods were clarified. The definition of 
abstinence was modified to “Acceptable non-hormonal birth control methods include: Total/True 
abstinence: When the subject refrains from any form of sexual intercourse and this is in line with 
their usual and/or preferred lifestyle; this must continue for the total duration of the trial and for at 
least 1 month after the last dose of study drug. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods, or declaration of abstinence solely for the duration of a 
trial) and withdrawal are not acceptable methods of contraception;” from “Acceptable 
Non-hormonal birth control methods include: Total sexual abstinence.  Abstinence must continue 
for the total duration of study treatment and for at least 1 month after the last dose for female 
subjects.  Periodic abstinence (e.g., calendar ovulation, symptothermal post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.” 
Table 6 (Study Plan) and Section 5.2.5.1: The pregnancy testing requirements were modified to add 
testing at Day 29 and at regular intervals (monthly).
Minor edits were made throughout the document to correct grammatical errors and inconsistencies.
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and the opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.




Clinical Study Protocol Synopsis
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
7 (138)
applicable subjects.  At the end of this additional 12 months of survival follow-up, updated 
overall survival (OS) and safety analyses will be conducted and the study will be closed.  
Study design
This is a Phase II, open-label, non-randomized, multi-center study assessing the efficacy and 
safety of olaparib tablets 300 mg
in 
subjects with platinum-sensitive or partially platinum-sensitive, relapsed, high-grade serous or 
high-grade endometrioid ovarian, fallopian tube, or primary peritoneal cancer, who have 
received at least 1 prior line of platinum-based chemotherapy.  
The study will assess the effectiveness of olaparib tablets as measured by the objective 
response rate (ORR) as determined by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1, in subjects with germline BRCA mutations (gBRCAm), somatic BRCA 
mutations (sBRCAm), or potential aberrations in homologous recombination deficiency 
(HRD) as determined by myChoice® HRD, as well as in subjects without identifiable HRD.  
This study will utilize Myriad BRACAnalysis CDx® for germline BRCA analysis and a tumor 
test (myChoice® HRD) for tumor BRCA analysis and HRD status.  Note: The Myriad testing 
may be submitted in advance of the 28-day screening window if the subject consents to the 
appropriate pre-screening informed consent form.
Four cohorts will be identified based upon the genetic testing described above:
#
Cohort 1: gBRCAm,
#
Cohort 2: sBRCAm and germline BRCA wild type,  
#
Cohort 3: myChoice® HRD positive (genomic instability positive) and 
BRCA wild type (BRCAwt) (no BRCA mutation),  
#
Cohort 4: myChoice® HRD negative (genomic instability negative) and 
BRCAwt (no BRCA mutation).
Cohort enrollment rules:
The objective response will be monitored on an ongoing basis for subjects in each cohort.  If 
no responses (complete response [CR] or partial response [PR]) are observed in the first 
15 subjects in a cohort, in consultation with the Steering Committee, this cohort will be closed 
to further enrollment.  However, if there is at least 1 confirmed objective response in the first 
15 subjects, that would justify continuing enrollment up to a maximum of 90 subjects.  This 
stopping rule applies to all cohorts. Enrollment in each cohort will continue while objective 
response is being assessed for the futility assessment. The objective response will be assessed 
as per protocol, i.e., allowing 6 months of follow up.
Up to approximately 300 subjects are to be treated with olaparib, unless early stopping criteria 
are met.  
CCI


Clinical Study Protocol Synopsis
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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A data cut-off for analysis of all primary and secondary endpoints will occur approximately 
6 months after the last subject enrolled has commenced study treatment (received at least 
1 dose of olaparib).  The study will remain open for an additional 12 months after this data 
cut-off for survival follow-up for applicable subjects. At the end of this additional 12 months 
of survival follow-up, updated OS and safety analyses will be conducted and the study will be 
closed.  Subjects are, however, permitted to continue to receive olaparib beyond the closure of 
the database if, in the opinion of the Investigator, they are continuing to receive benefit from 
treatment with olaparib. During this time, adverse events of special interest and serious 
adverse events (SAEs) must still be collected and reported until 30 days after the subject 
finally stops taking olaparib. 
All subjects who enrolled and received at least 1 dose of olaparib will be followed for 
survival. Subjects will be contacted to assess survival every 12 weeks following disease 
progression until death, withdrawal of consent, or study closure.
A Study Steering Committee composed of representatives from AstraZeneca and key 
Investigators/scientific advisors will be responsible for providing recommendations to US 
Medical Affairs leadership at AstraZeneca based on Investigator input, review, and oversight 
of study execution, scientific conduct, and analysis of study data. The accountabilities and 
requirements of the Steering Committee members will be outlined in the Steering Committee 
Charter.
Objectives
Primary Objective:
Outcome Measure:
To determine the clinical effectiveness of 
olaparib treatment in each of 4 cohorts 
assessed using ORR according to RECIST 
v1.1 criteria (Investigator determined).
•
ORR, defined as the percentage of subjects 
with a best overall response of confirmed CR 
or PR (at any time up to and including the 
defined analysis cut-off point) divided by the 
number of subjects in the efficacy analysis 
set.


Clinical Study Protocol Synopsis
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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Secondary Objectives:
Outcome Measures:
To determine the clinical effectiveness of 
olaparib treatment in each of 4 cohorts 
assessed using:
•
Duration of response (DoR),
•
Cancer antigen (CA)-125 response 
rate,
•
Disease control rate (DCR),
•
Progression-free survival (PFS),
•
Time to any progression (TTAP), 
•
OS, and
•
Homologous recombination repair 
mutation (HRRm) gene panel status 
related to clinical outcome.
•
DoR, for those subjects with a confirmed 
response of CR or PR, response duration will 
be measured from the date of the 
measurement criteria for CR or PR are first 
met until the date of documented objective 
progression or death in the absence of disease 
progression.
•
CA-125 response rate, defined as the 
percentage of subjects with a CA-125 
response according to Gynecological Cancer 
Intergroup criteria (GCIG) divided by the 
number of subjects evaluable for CA-125 
response.
•
DCR, defined as the percentage of subjects 
with a best overall response of confirmed CR 
or PR (at any time up to and including the 
defined analysis cut-off point) or who have 
demonstrated stable disease for at least 
8 weeks from first dose, divided by the 
number of subjects in the efficacy analysis 
set.
•
PFS, defined as the time from the date of the 
first dose of olaparib to the earlier date of 
assessment of objective progression (per 
RECIST v1.1 criteria) or death by any cause 
in the absence of progression.
•
TTAP, defined as the time from the date of
the first dose of olaparib to the earlier date of 
CA-125 progression (GCIG criteria) or 
RECIST v1.1 progression, or death by any 
cause in the absence of progression.
•
OS, defined as the time from the date of the 
first dose of olaparib to the date of death from 
any cause.
•
HRD status as per HRRm gene panel 
assessment (positive or negative) will be 
correlated with clinical outcome (ORR, 
defined above) for subjects enrolled in the 
2 cohorts with BRCAwt (cohorts 3 and 4).






Clinical Study Protocol Synopsis
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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will be used for summarizing categorical (discrete) data.  Confidence intervals (CIs), when 
presented, will generally be constructed at the 95% level.
The ORR, DCR, and CA-125 response rate will be presented together with the exact 95% CI 
calculated using the Clopper-Pearson method.  Time-to-event outcomes (DoR, PFS, TTAP, 
and OS) will be analyzed using the Kaplan-Meier method and will be presented as the median 
and 95% CI together with event rates at clinically relevant time points.  Kaplan-Meier curves 
will also be generated.
















Clinical Study Protocol
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AESI
Adverse events of special interest
ALT
AML
Alanine aminotransferase
Acute myeloid leukemia
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
bid
Twice daily
BRCAm
BRCA mutation
BRCAwt
BRCA wild type
CA
Cancer antigen 
CI
Confidence interval
Cmax
Maximum concentration
Cmin
Minimum concentration
CR
Complete response
CrCl
Creatinine clearance
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
CYP
Cytochrome P-450 
DCR
Disease control rate
DNA
Deoxyribonucleic acid 
DoR
Duration of response
DSB
Double-stranded break
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group: a performance status using scales 
and criteria to assess how a subject’s disease is progressing
eCRF
Electronic case report form
EDC
Electronic data capture
FDA
Food and Drug Administration


Clinical Study Protocol
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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Abbreviation or 
special term
Explanation
gBRCA
Germline BRCA
gBRCAm
Germline BRCA mutation
gBRCAwt
Germline BRCA wild type
GCIG
Gynecological Cancer Intergroup
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GMP
Good Manufacturing Practice 
HR
Hazard ratio
HRD
Homologous recombination deficiency
HRR
Homologous recombination repair 
HRRm
Homologous recombination repair mutation 
IB
Investigator Brochure 
ICH
International Conference on Harmonisation
INR
International normalized ratio
IP
Investigational product 
IRB
Institutional review board
LIMS
Laboratory Information Management System 
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities 
MRI
Magnetic resonance imaging
NCI
National Cancer Institute 
NE
Not evaluable
ORR
Objective response rate 
OS
Overall survival
PARP
Polyadenosine 5’diphosphoribose (poly [ADP ribose]) polymerase
PD
Progressive disease
PFS
Progression-free survival
PGx
Pharmacogenetic
PK
Pharmacokinetic
PLD
PEGylated liposomal doxorubicin 
PR
Partial response
RECIST
Response Evaluation Criteria in Solid Tumors


Clinical Study Protocol
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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Abbreviation or 
special term
Explanation
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
sBRCAm
Somatic BRCA mutation
SD
Stable disease
SSB
Single-stranded break
t½
Terminal half-life
TBL
Total bilirubin
TL
Target lesion
TTAP
Time to any progression 
Tumor BRCAm
Tumor BRCA mutation (composed of gBRCA or somatic BRCA 
mutations)
ULN
Upper limit of normal
US
United States




Clinical Study Protocol
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
24 (138)
BRCA and HRD
Numerous deoxyribonucleic acid (DNA) single-stranded breaks (SSBs) occur naturally as the 
result of normal metabolic activities and environmental factors, including ultraviolet light and 
radiation. Polyadenosine 5’diphosphoribose (poly [ADP ribose]) polymerase (PARP) plays an 
important role in identifying and repairing SSBs. PARP inhibition is an approach to targeting 
tumors with deficiencies in DNA repair mechanisms.  PARP enzymes are essential for 
repairing DNA SSBs.  Inhibiting PARPs leads to the persistence of SSBs, which are then 
converted to the more serious DNA double-stranded breaks (DSBs) during the process of 
DNA replication.  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 DSBs. In normal cells, DSBs are repaired by a DNA repair 
mechanism called homologous recombination repair (HRR). Cells with homologous 
recombination deficiency (HRD), resort to the more error prone repair mechanism called 
non-homologous end joining. 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 (Farmer et al 2005, McCabe et al 2006).
The most common function-altering mutations associated with HRD are a mutation in the 
breast and ovarian cancer susceptibility genes BRCA1 or BRCA2, which encode for 2 critical 
proteins in the homologous recombination repair pathway. BRCA1 and BRCA2 mutations that 
are defined as deleterious and suspected deleterious mutations are associated with 
loss-of-function of the protein. 
BRCA1 and BRCA2 defective tumors are intrinsically sensitive to PARP inhibitors, both in 
tumor models in vivo (Rottenberg et al 2008, Gelmon et al 2011, Hay et al 2009) and in the 
clinic (Fong et al 2009).  The mechanism of action for olaparib is thought to result from the 
trapping of inactive PARP onto the SSBs, preventing their repair (Helleday 2011, Murai et al 
2012).  Olaparib, a PARP inhibitor, has been shown to inhibit selected tumor cell lines in vitro 
and in xenograft and primary explant models, as well as in genetic BRCA knock-out models, 
either as a stand-alone treatment or in combination with established chemotherapies.
Individuals with germline BRCA mutations (gBRCAms) will carry 1 mutant allele and 1 wild 
type allele, while their cancer cells would have lost the wild type copy of the BRCA gene. 
Normal cells in subjects who carry a gBRCAm can therefore repair DSBs with the functioning 
wild type BRCA allele. However, in cancer cells, the loss of heterozygosity leaves the 
non-functional germline BRCA (gBRCA) allele as the sole copy. In this way, PARP inhibition 
takes advantage of this difference and preferentially kills the cancer cells with minimal 
toxicity to normal cells (Rottenberg et al 2008, Gelmon et al 2011, Hay et al 2009).


Clinical Study Protocol
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
25 (138)
Olaparib
The US FDA approved the tablet formulation of olaparib in August 2017. 
The FDA approval of the tablet formulation is as follows:
#
For the maintenance treatment of adult patients with recurrent epithelial 
ovarian, fallopian tube, or primary peritoneal cancer, who are in complete 
or partial response to platinum-based chemotherapy.
#
For the treatment of adult patients with deleterious or suspected 
deleterious germline BRCA-mutated advanced ovarian cancer who have 
been treated with 3 or more prior lines of chemotherapy. Patients for this 
indication are selected for therapy based on an FDA-approved companion 
diagnostic for olaparib.
The maintenance indication with the tablet formulation was based on 2 randomized, 
placebo-controlled, double-blind, multicenter studies in patients with recurrent ovarian cancer 
who were in response to platinum-based therapy.
SOLO-2 (NCT01874353) was a double-blind, placebo-controlled trial in which patients 
(N=295) with gBRCA-mutated ovarian, fallopian tube, or primary peritoneal cancer were 
randomized (2:1) to receive olaparib tablets 300 mg orally twice daily (bid) or placebo until 
unacceptable toxicity or PD. Randomization was stratified by response to last platinum 
chemotherapy (complete versus partial) and time to disease progression in the penultimate 
platinum-based chemotherapy prior to enrollment (6 months to 12 months versus 
> 12 months). All patients had received at least 2 prior platinum-containing regimens and 
were in response (complete or partial) to their most recent platinum-based regimen. All 
patients had a deleterious or suspected deleterious gBRCAm as detected either by a local test 
(n= 236) or central Myriad Clinical Laboratory Improvement Amendments test (n=59), 
subsequently confirmed by BRAC Analysis CDx (n= 286). The major efficacy outcome was 
investigator-assessed progression-free survival (PFS) evaluated according to Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additional endpoints included overall 
survival (OS).
SOLO-2 demonstrated a statistically significant improvement in investigator-assessed PFS in 
patients randomized to olaparib as compared with placebo (Table 1 and Figure 1). Results 
from a blinded independent review were consistent. At the time of the analysis of PFS, OS
data were not mature with 24% of events.


Clinical Study Protocol
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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Table 1
Efficacy Results ∃SOLO-2 (Investigator Assessment)
Olaparib tablets 
(n=196)
Placebo
(n=99)
Progression-Free Survival
Number of events (%)
107 (54.6%)
80 (80.8%)
Median, months
19.1
5.5
Hazard ratioa (95% confidence interval)
0.30 (0.22, 0.41)
p-valueb
<0.0001
a
Hazard ratio from the stratified proportional hazards model, stratified by response to last platinum 
chemotherapy (complete versus partial) and time to disease progression in the penultimate platinum-based 
chemotherapy prior to enrollment.
b
The p-value is derived from a stratified log-rank test.
Source: SOLO-2
Figure 1
Kaplan-Meier Curves of Investigator-Assessed Progression-Free 
Survival ∃SOLO-2
Source: SOLO-2
Study 19 (NCT00753545) was a double-blind, placebo-controlled trial in which patients 
(N=265) with platinum-sensitive ovarian cancer who had received 2 or more previous 
platinum-containing regimens were randomized (1:1) to receive olaparib capsules 400 mg 
orally bid or placebo until unacceptable toxicity or PD. Randomization was stratified by 


Clinical Study Protocol
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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response to last platinum chemotherapy (CR versus PR), time to disease progression in the 
penultimate platinum-based chemotherapy (6 months to 12 months versus > 12 months), and 
descent (Jewish versus non-Jewish). The major efficacy outcome measure of the study was 
investigator-assessed PFS evaluated according to RECIST, v1.0.
The median age of patients treated with olaparib (n=136) was 58 years (range: 21 to 89) and 
59 years (range: 33 to 84) among patients treated with placebo (n=129). Eastern Cooperative 
Oncology Group (ECOG) performance status was 0 in 81% of patients receiving olaparib and 
74% of patients receiving placebo. Of all patients, 97% were White, 19% were enrolled in the 
US or Canada, 45% were in CR following their most recent platinum chemotherapy regimen, 
and 40% had a progression-free interval of 6 months to 12 months since their penultimate 
platinum. Prior bevacizumab therapy was reported for 13% of patients receiving olaparib and 
16% of patients receiving placebo. A retrospective analysis for gBRCAm status, some 
performed using the Myriad test, indicated that 36% (n=96) of patients from the 
Intent-to-Treat population had deleterious gBRCAm, including 39% (n=53) of patients on 
olaparib and 33% (n=43) of patients on placebo.
Study 19 demonstrated a statistically significant improvement in investigator-assessed PFS in 
patients treated with olaparib versus placebo (Table 2 and Figure 2).
Table 2
Efficacy Results ∃Study 19 (Investigator Assessment)
Olaparib capsules
(n=136)
Placebo
(n=129)
Progression-Free Survival
Number of events (%)
60 (44%)
94 (73%)
Median, months
8.4
4.8
Hazard ratioa (95% confidence interval)
0.35 (0.25, 0.49)
p-valueb
<0.0001
Overall Survivalc
Number of events (%)
98 (72%)
112 (87%)
Median, months
29.8
27.8
Hazard ratioa (95% confidence interval)
0.73 (0.55, 0.95)
a
Hazard ratio from the stratified proportional hazards model, stratified by response to last platinum 
chemotherapy and time to disease progression in the penultimate platinum-based and Jewish and non-
Jewish descent.
b
The p-value is derived from a stratified log-rank test.
c
Without adjusting for multiple analyses.
Source: Study 19


Clinical Study Protocol
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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Figure 2
Kaplan-Meier Curves of Investigator-Assessed Progression-Free 
Survival ∃Study 19
Source: Study 19
The US FDA approved the capsule formulation of olaparib in December 2014 for 
monotherapy in subjects with deleterious or suspected deleterious gBRCAm (as detected by 
an FDA-approved test) advanced ovarian cancer who have been treated with 3 or more prior 
lines of chemotherapy.  
This was based on Study 42 (Kaufman et al 2015) in which olaparib (400 mg bid 8 capsules) 
was given to 193 subjects in an advanced ovarian cancer cohort, of whom 178 had ovarian 
cancer, 4 had fallopian tube cancer, and 11 had primary peritoneal cancer; 148 (77%) of those 
in the ovarian cancer cohort had a germline mutation in BRCA1, 44 (23%) had a BRCA2
mutation, and 1 had a germline mutation in both BRCA1 and BCRA2. These subjects were 
heavily pretreated, with a mean number of 4.3 prior regimens. All subjects had received prior 
platinum therapy and were considered to be platinum-resistant or not suitable for further 
platinum therapy. The objective response rate (ORR) in this study was 31.1% 
(95% confidence interval [CI] = 24.6-38.1%), medium PFS was 7 months (54.6% 
progression-free at 6 months), and medium OS was 16.6 months (64.4% alive at 12 months).


Clinical Study Protocol
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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In Study 20, a Phase II open-label, non-randomized study, women with advanced high-grade 
serous and/or undifferentiated ovarian carcinoma or triple-negative breast cancer received 
400 mg olaparib capsules bid. Subjects were stratified according to whether they had a BRCA1
or BRCA2 mutation or not. Ninety-one subjects were enrolled (65 with ovarian cancer and 
26 with breast cancer). In the ovarian cancer cohorts, confirmed objective responses were seen 
in 7 (41%; 95% CI = 22-64) of 17 subjects with BRCA1 or BRCA2 mutations and 11 (24%; 
95% CI =14-38) of 46 patients without BRCA mutation (BRCAm) (Gelmon et al 2011).
In Study 19 (Ledermann et al 2014), olaparib (400 mg bid capsules) or matching placebo 
(randomized 1:1) was given as maintenance monotherapy to 265 subjects with 
platinum-sensitive relapsed high-grade serious ovarian cancer. In subjects with a BRCAm
detected in their blood (gBRCAm) and/or tumor (somatic BRCA mutation [sBRCAm]), 
treatment with olaparib resulted in a significant increase in:
#
PFS versus placebo (hazard ratio [HR] = 0.18; 95% CI = 0.10-0.31; 
p < 0.0001).
In subjects without a BRCAm (i.e., BRCA wild type [BRCAwt]), maintenance treatment 
resulted in a smaller, but still statistically significant increase in PFS (HR = 0.54; 
95% CI = 0.34–0.85; p = 0.0075) (Ledermann et al 2014).
More recently, with longer follow-up from this study an OS clinical benefit for olaparib 
maintenance therapy in the overall and the BRCAm subject groups was observed (BRCAm 
OS HR = 0.62; 95% CI = 0.41-0.94; median 34.9 months olaparib, 30.2 months placebo) 
(Ledermann et al 2016).
Furthermore, clinical data in a small number of subjects within the sBRCAm subpopulation in 
Study 19 (Ledermann et al 2014) are consistent with the larger BRCA mutated dataset 
(gBRCA cohort), as fewer subjects on the olaparib arm reported progression events or death 
events. An exploratory analysis of tumor genetics in these subjects suggests that gBRCAm 
and sBRCAm in these tumors are indistinguishable in terms of their clonality and complete 
loss of the relevant BRCAwt allele.  
To date, the sBRCAm olaparib data is available from these 20 sBRCAm subjects in Study 19. 
In Study 19 (Ledermann et al 2014), 10 subjects received olaparib and 10 subjects received 
placebo and were retrospectively assessed for PFS and OS. See Table 3 below.


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Table 3
Progression and Death-Free Survival Events in sBRCAm Subjects in 
Study 19
Endpoint
Treatment
Events, n (%)
PFS
Olaparib 400 mg bid (n = 10)
Placebo (n = 10)
3 (30.0)
8 (80.0)
Overall survival
Olaparib 400 mg bid (n = 10)
Placebo (n = 10)
3 (30.0)
7 (70.0)
bid = twice daily; PFS = progression-free survival; sBRCAm = somatic BRCA mutation.
Source: Dougherty et al 2015
Hence, it is considered likely that olaparib may preferentially benefit subjects with sBRCAm 
tumors and subjects with loss-of-function mutations in other genes involved in the repair of 
double-stranded DNA breaks, i.e., those that are HRD and identified by a genetic scar (via 
Myriad’s myChoice® HRD test) might benefit from olaparib and will be assessed further in 
this study. 
Study tests
BRACAnalysis CDx®: The blood based BRACAnalysis CDx® test is the FDA-approved 
companion diagnostic test with olaparib for detection of gBRCA sequence variants.  Subjects 
determined to carry a deleterious or suspected deleterious mutation in BRCA1 or BRCA2 can 
be considered to have a gBRCAm. 
myChoice® HRD: The tumor based myChoice® HRD test simultaneously measures HRD
through detection of 3 types of large rearrangements: loss of heterozygosity, telomeric allelic 
imbalance, and large-scale state transitions; and detects sequence variants in the BRCA1 and 
BRCA2 genes. Therefore, myChoice® HRD will inform on HRD and BRCA. An HRD score is 
used to assess a subject’s level of deficiency in their tumor, and those carrying a deleterious or 
suspected deleterious mutation in BRCA1 or BRCA2 can be considered to have a tumor 
BRCAm.
Several research groups have used BRCAm ovarian and breast cancer as positive controls to 
develop such an assay (Abkevich et al 2012).  This study will use the Myriad myChoice®
HRD assay which was developed from the Abkevich et al approach as described by Timms et
al 2014.  The assay has been linked to sensitivity to platinum based chemotherapy and a 
similar assay was linked to response to another PARP inhibitor, but with a lower response rate 
than for BRCAm subjects (McNeish 2015).
myChoice® HRD is the first HRD test that can detect when a tumor has lost the ability to 
repair double-stranded DNA breaks, resulting in increased susceptibility to DNA-damaging 
drugs such as platinum drugs or PARP inhibitors. High myChoice® HRD scores reflective of 
DNA repair deficiencies are prevalent in all breast cancer subtypes, ovarian, and most other 
major cancers. In previously published data, Myriad showed that the myChoice® HRD test 


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predicted drug response to platinum therapy in certain subjects with triple-negative breast and 
ovarian cancers. 
A study by Wilcoxen et al showed that the myChoice® HRD diagnostic test is predictive of 
BRCA deficiency and supports its use to help identify subjects with advanced ovarian cancer 
who may respond to treatment with niraparib, a PARP inhibitor.  A total of 106 tumors from 
subjects with advanced ovarian cancer were evaluated for HRD and BRCA1/2 mutations.  The 
results showed that all BRCA deficient tumors (n = 26) were myChoice® HRD positive 
except 1. Additionally, the response to niraparib monotherapy was evaluated in 20 unique 
tumor models across a range of myChoice® HRD scores and all of the tumors that responded 
to niraparib were myChoice® HRD positive, irrespective of BRCA deficiency status 
(Wilcoxen et al 2015).
The double-blind, placebo-controlled, Phase III NOVA trial enrolled more than 500 subjects 
with recurrent ovarian cancer who were in a response to their most recent platinum-based 
chemotherapy. This trial demonstrated that niraparib significantly prolonged PFS compared to 
placebo control among subjects who were gBRCAm carriers (HR = 0.27, median PFS 
21.0 months vs. 5.5 months, p < 0.0001). For subjects without a gBRCAm, but whose tumors 
were determined to be HRD positive using the Myriad myChoice® HRD test, niraparib 
significantly prolonged PFS (HR = 0.38, median PFS 12.9 months vs. 3.8 months,
p < 0.0001).  Niraparib also showed statistical significance in the overall non-gBRCAm
cohort, which included subjects with both myChoice® HRD-positive and HRD-negative 
tumors (HR = 0.45, median PFS 9.3 months vs. 3.9 months p < 0.0001) (TESARO 2016).
In an exploratory analysis of olaparib from Study 19 (Ledermann et al 2014), there was some 
evidence suggesting that the HRD assay could identify BRCAwt subjects benefiting from 
olaparib maintenance therapy, although numbers were small (Hodgson et al 2015).  Hence,
there is a rationale and some supportive data to expect an increased PFS in this subject
population, but with an expectation of a potentially lower effect size.
Subjects will be recruited to this study using 2 assays, BRACAnalysis CDx® (gBRCA status) 
and myChoice® HRD (tumor BRCA status and HRD status), running in parallel for cohort 
assignment. 
Homologous recombination repair mutation (HRRm) gene panel: As a secondary 
objective, there will be a prospective baseline analysis using a test to assess germline 
mutations in a panel of genes from the HRR pathway. The panel is composed of 16 HRR 
pathway genes: BRCA1, BRCA2, ATM, RAD51B, RAD51C, RAD54L, RAD51D, 
FANC/BRIP1, FANCI, FANCL, FANCN(PALB2), BARD1, CHEK1, CHEK2, CDK12, and 
PPP2R2A.  The result of this HRRm test will not determine cohort assignment, and will only 
be conducted in those subjects assigned to the cohorts with BRCAwt.
Indeed, deficiencies in the HRR pathway, such as those resulting from mutations in HRR 
genes, may confer sensitivity to PARP inhibitors (McCabe et al 2006). 


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Study Code D0816L00003
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As predicted by the biology, the somatic BRCA1/2 mutations and mutations in 11 other HRR 
genes were reported to have a similar positive impact on OS and platinum responsiveness as 
germline BRCA1/2 mutations (Pennington et al 2014). Study 19 also demonstrated that 
subjects with mutated HRR genes had benefits to their PFS (Hodgson et al 2015). 
Exploratory analyses from the Study 19 (Ledermann et al 2014; Dougherty et al 2015) dataset 
showed that subjects with BRCAwt, but identified with HRD (either via myChoice® HRD or 
HRRm panel) derived benefit from olaparib therapy based on progression events (no ORR 
data available).
Table 4
Progression-Free Survival Hazard Ratio and 95% Confidence Interval 
by Cohort in Study 19
Subject Group
Number of subjects
PFS Hazard Ratio
95% CI
gBRCAm
95
0.17
0.09-0.31
gBRCAm + sBRCAm
135
0.18
0.10-0.31
gBRCAm + sBRCAm 
+ myChoice® HRD
positive
154
0.25
0.15-0.4
gBRCAm + sBRCAm 
+ HRRm panel 
positive
157
0.2
0.12-0.33
CI = confidence interval; gBRCAm = germline BRCA mutation; HRD = homologous recombination 
deficiency; HRRm = homologous recombination repair mutation; PFS = progression-free survival; 
sBRCAm = somatic BRCA mutation.
Source: Ledermann et al 2014; Dougherty et al 2015
Although there is limited PFS data and a lack of ORR data available for subjects treated with 
olaparib that were characterized by these 2 HRD assays (myChoice® HRD and HRRm), and 
with albeit limited PFS data, these data provide some promising evidence to predict that 
olaparib could generate responses in each of these populations relating subjects with 
sBRCAm, HRRm, and HRD (genetic scar/myChoice® HRD) status to a clinical outcome 
(ORR).  
1.2
Rationale for study design, doses, and control groups
The proposed Phase II study is designed to assess the benefit of olaparib tablets therapy in 
4 cohorts of subjects with different statuses of BRCAms/HRD by assessing the efficacy (in 
the form of objective response) and safety of olaparib tablets monotherapy. This study will 
further assess the benefit of olaparib tablets in subjects beyond gBRCA, where limited 
evidence currently exists for benefit with the capsule formulation, i.e., in subjects with 
identified by myChoice® HRD (genetic scar) and HRRm (mutations in an identified panel of 
genes associated with HRR). Limited or no reported data exists for the tablet formulation in 
the second line treatment setting for olaparib and will be further assessed in these study 
populations. 


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Version 3.0
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Subjects will be enrolled into 1 of 4 cohorts based on gBRCA status and myChoice® HRD test 
with ORR as the primary endpoint.  Homologous recombination repair mutation status 
relation to clinical outcome will be a secondary endpoint in this study and will be used to 
assess whether the gene panel additionally identified subjects who benefit from olaparib.  
Secondary endpoints will also include duration of response (DoR), disease control rate (DCR), 
cancer antigen (CA)-125 response rate, PFS, time to any progression (TTAP, either CA-125 
progression or objective progression or death), OS, mutation status of the HRRm related to 
clinical outcome, and safety assessments.  Exploratory correlative studies will be conducted to 
assess potential biomarkers that correlate with clinical outcomes.
Platinum and taxane based chemotherapy is standard of care front-line treatment for women 
with ovarian cancer. Sixty to 90 percent of women will demonstrate an objective response to 
this therapy. (Markman et al 1991) The vast majority of these women will either have 
recurrence or progression of their disease. The choice of therapy at that time depends in part 
on platinum sensitivity. If a patient has platinum sensitive ovarian cancer they are generally 
retreated with a platinum regimen with responses of 17% to 79% (Gore et al 1990, Aghajanian 
et al 2012). The introduction of PARP inhibitors has provided an effective treatment option 
for women with ovarian cancer (Study 19 and SOLO-2). PARP inhibitors are being utilized 
for patients with fewer previous lines of therapy.  The PARP inhibitor rucaparib was studied 
in relapsed, platinum-sensitive high-grade ovarian cancer in 204 evaluable patients, including 
121 (59%) patients after 1 previous line of platinum-based chemotherapy (Swisher et al 2017).
Results reported by Swisher et al were reported based on molecular profile, and not by line of 
therapy. Konecny (Konecny et al 2017) reported ORR in a subset of these patients treated 
with rucaparib:  In 57 platinum-sensitive patients whose immediate prior therapy was 
platinum-based, the investigator-assessed ORR was 70% (95% CI: 57-72) for the overall 
population, with 83% , 86%, and 52% ORRs observed in patients treated with 1, 2, or 3 or 
more prior lines, respectively. PARP inhibitors in second-line therapy for recurrent ovarian 
cancer thereby have ORR similar to standard chemotherapy.






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Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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BRCAm subjects, regardless of whether their mutation is detected by blood (germline) or 
tumor testing for BRCAm (Ledermann et al 2014) or other forms of HRD.  
1.3.2
Clinical benefit 
For specific information on the clinical benefit of olaparib monotherapy in subjects with 
platinum-sensitive relapsed gBRCAm ovarian cancer and in subjects without gBRCAm 
ovarian cancer, see the olaparib IB.
The FDA approval of the tablet formulation is as follows:
#
For the maintenance treatment of adult patients with recurrent epithelial 
ovarian fallopian tube or primary peritoneal cancer, who are in complete
response (CR) or partial response (PR) to platinum-based chemotherapy.
#
For the treatment of adult patients with deleterious or suspected 
deleterious germline BRCA-mutated advanced ovarian cancer who have 
been treated with 3 or more prior lines of chemotherapy. Patients for this 
indication are selected for therapy based on an FDA-approved companion 
diagnostic for olaparib.  
1.3.2.1
Clinical benefit of olaparib monotherapy in subjects with platinum-sensitive 
recurrent gBRCA mutated ovarian cancer 
The pooled analysis from 6 olaparib (Phases I and II) monotherapy clinical studies consisting 
of 300 subjects with gBRCA mutated relapsed ovarian cancer (including fallopian tube and 
primary peritoneal), of whom 273 had measurable disease and were evaluable for response, 
demonstrated an ORR with olaparib in the overall group of 36% (97/273) and 7.4 months 
DoR (AstraZeneca data on file). The majority of the subjects (n = 223) had received 3 or more 
prior lines of therapy and of these, 205 subjects had measurable disease. In these subjects, the 
response rate was 31% (64/205) and DoR was 7.8 months. Nineteen percent (n = 51) of the 
273 subjects with measurable disease were classified as platinum-sensitive. The response rate 
in the platinum-sensitive subjects was 53% (27/51) and the DoR was 8.2 months. 
The majority of the subjects in the pooled analysis (n = 193) were enrolled in Study 42
(Domcheck et al 2016), a Phase II, open-label, non-randomized, non-comparative, 
multi-center study to assess the efficacy and safety of olaparib (400 mg capsules) given orally 
bid in subjects 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 subjects 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 DoR was 7.4 months 
(Kaufman et al 2015). Subjects were also analyzed by their platinum sensitivity status, if their 
last treatment was platinum based, and in the group of subjects who were classed as 
platinum-sensitive (when time from last platinum to PD was > 6 months) but ineligible to 
receive further platinum (typically due to hypersensitivity reactions), the response rate with 


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Version 3.0
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olaparib was higher than in the group of subjects with platinum-resistant disease (60% [15/25] 
vs. 15% [6/40], respectively) (Domcheck et al 2016). 
Furthermore, 97 subjects in the pooled analysis were included from Study 12, a randomized, 
open-label, Phase II, dose-finding study of olaparib monotherapy (200 mg bid and 400 mg bid
capsule) vs. PEGylated liposomal doxorubicin (PLD) in gBRCAm ovarian cancer subjects 
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, respectively (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 
subjects in the trial (n = 48), showed an HR for PFS numerically higher for the olaparib 
400 mg 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 of 47% and 
26%, respectively. 
In SOLO-2 investigator-assessed PFS (primary endpoint) was significantly longer for patients 
receiving olaparib versus placebo (HR = 0.30, 95% CI = 0.22-0.41, P<0.0001; median
19.1 months versus 5.5 months, respectively). The evaluation of PFS by blinded independent 
central review also demonstrated a significant PFS benefit in favor of olaparib (HR = 0.25, 
95% CI = 0.18-0.35, P<0.0001; median 30.2 months versus 5.5months). The PFS benefit was 
supported by a significant improvement for olaparib in time to second progression 
(HR = 0.50, 95% CI = 0.34-0.72, P=0.0002), and a clinically meaningful improvement in time 
to first subsequent therapy or death (HR = 0.28, 95% CI = 0.21-0.38, P<0.0001) and time to 
second subsequent therapy or death (HR = 0.37, 95% CI = 0.26-0.53, P<0.0001). The OS data 
were immature at this data cut-off (maturity 24%) and median OS was not reached in either 
treatment group.
1.3.3
Safety and tolerability of olaparib
The tolerability profile of olaparib is characterized by clinical investigation and regulatory 
approval in 2014, including long term OS benefit (Ledermann et al 2016).  It is suitable for 
long-term dosing until disease progression in subjects with relapsed platinum-sensitive 
ovarian cancer who carry a gBRCAm.  For further information on the safety and tolerability 
of olaparib, including common adverse events, see the olaparib IB.
The most common adverse events considered to be associated with administration of olaparib 
include hematological effects (anemia, neutropenia, lymphopenia, thrombocytopenia, mean 
corpuscular volume elevation), decreased appetite, nausea and vomiting, diarrhea, dyspepsia, 
stomatitis, upper abdominal pain, dysgeusia, fatigue (including asthenia), increase in blood 
creatinine, headache, and dizziness. In a small number of subjects, pneumonitis, 
myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) and new primary 
malignancies have been reported. The cumulative incidences fall within that expected for the 
subject population under study in the reported literature. These events are considered potential 




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obtained via telephone contact with the subject, subject’s family, or by contact with the 
subject’s current physician.
See Figure 3 for a diagram of the study.




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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To determine the clinical effectiveness of 
olaparib treatment in each of 4 cohorts 
assessed using ORR according to RECIST 
v1.1 criteria (Investigator determined).
#
ORR, defined as the percentage of subjects with a 
best overall response of confirmed CR or PR (at 
any time up to and including the defined analysis 
cut-off point) divided by the number of subjects in 
the efficacy analysis set.


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Study Code D0816L00003
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2.2
Secondary objectives
Secondary Objectives:
Outcome Measures:
To determine the clinical effectiveness of 
olaparib treatment in each of 4 cohorts 
assessed using:
•
DoR,
•
CA-125 response rate,
•
DCR,
•
PFS,
•
TTAP, 
•
OS, and
•
HRRm gene panel status related to 
clinical outcome.
#
DoR, for those subjects with a confirmed response 
of CR or PR, response duration will be measured 
from the date of the measurement criteria for CR 
or PR are first met until the date of documented 
objective progression or death in the absence of 
disease progression.
#
CA-125 response rate, defined as the percentage
of subjects with a CA-125 response according to 
GCIG criteria divided by the number of subjects 
evaluable for CA-125 response.
#
DCR, defined as the percentage of subjects with a 
best overall response of confirmed CR or PR (at 
any time up to and including the defined analysis 
cut-off point) or who have demonstrated stable 
disease (SD) for at least 8 weeks from first dose, 
divided by the number of subjects in the efficacy 
analysis set.
#
PFS, defined as the time from the date of the first 
dose of olaparib to the earlier date of assessment 
of objective progression (per RECIST v1.1
criteria) or death by any cause in the absence of 
progression.
#
TTAP, defined as the time from the date of the 
first dose of olaparib to the earlier date of CA-125 
progression (GCIG criteria) or RECIST v1.1 
progression, or death by any cause in the absence 
of progression.
#
OS, defined as the time from the date of the first 
dose of olaparib to the date of death from any 
cause.
#
HRD status as per HRRm gene panel assessment 
(positive or negative) will be correlated with 
clinical outcome (ORR, defined above) for
subjects enrolled in the 2 cohorts with BRCAwt 
(cohorts 3 and 4).




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3.
Female subjects with histologically diagnosed relapsed high-grade serous ovarian 
cancer (including primary peritoneal and/or fallopian tube cancer) or high-grade 
endometrioid cancer;
4.
At least 1 lesion (measurable by RECIST v1.1) that can be accurately assessed at 
baseline by computed tomography (CT)/magnetic resonance imaging (MRI) and is 
suitable for repeated assessment;
5.
Subjects must have received at least 1 prior platinum-based line of chemotherapy 
for ovarian cancer. Note: There is no limit on the number of lines of chemotherapy;
6.
Subjects must be partially-platinum-sensitive (defined as progression 6 to 
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);
7.
Subjects must have normal organ and bone marrow function measured within 
28 days prior to administration of study treatment, as defined below:
∃
Hemoglobin ∀9.0 g/dL with no blood transfusion in the past 28 days;  
∃
Absolute neutrophil count (ANC) ∀1.5 × 109/L;
∃
Platelet count ∀100 × 109/L;
∃
Total bilirubin (TBL) ! 1.5 × institutional upper limit of normal (ULN);
∃
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic 
transaminase/alanine aminotransferase (ALT) (serum glutamic pyruvate 
transaminase ! 3 × institutional ULN, unless liver metastases are present in 
which case they must be ! 5 × ULN); and
∃
Subjects must have serum creatinine ! 1.5 × ULN, OR creatinine clearance 
estimated using the Cockcroft-Gault equation of ∀51 mL/min (below). 
Subjects with severe renal impairment (CrCl ! 30 mL/min) are excluded, 
regardless of measured serum creatinine.
Estimated creatinine clearance =
(140-age [years]) × weight (kg)    (× 0.85)a
serum creatinine (mg/dL) × 72
a for all female subjects in the study
8.
ECOG performance status 0 to 1 (see Appendix F);  
9.
Subjects must have a life expectancy ∀16 weeks;


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10.
Postmenopausal or evidence of non-childbearing status for women of childbearing 
potential: negative urine or serum pregnancy test within 28 days of study treatment 
and confirmed prior to treatment on Day 1;
#
Postmenopausal is defined as:
∃
Amenorrheic for 1 year or more following cessation of exogenous hormonal 
treatments,
∃
Luteinizing hormone and follicle stimulating hormone levels in the 
post-menopausal range for women under 50,
∃
Radiation-induced oophorectomy with last menses > 1 year ago,
∃
Chemotherapy-induced menopause with > 1 year interval since last menses, or
∃
Surgical sterilization (bilateral oophorectomy or hysterectomy);
#
Female subjects who are of childbearing potential, who are sexually 
active, must agree to the use of 2 highly effective forms of contraception 
in combination (see Appendix E for acceptable methods) from the 
signing of the informed consent and throughout the period of taking study 
treatment and for 1 month after the last dose of study medication, or they 
must totally/truly abstain from any form of sexual intercourse;
11.
Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations; and
12.
Formalin fixed, paraffin embedded tumor sample (either archival or fresh 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 or fresh tumor sample 
prior to enrollment, the subject is not eligible for the study.
3.2
Exclusion criteria
For inclusion in the study, subjects cannot 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 Representative staff and/or staff at the study site);
2.
Previous enrollment in the present study;
3.
Exposure to any investigational product (IP) within 30 days or 5 half-lives 
(whichever is longer) prior to start of study treatment;
4.
Any previous treatment with a PARP inhibitor, including olaparib;


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5.
Subjects who have platinum-resistant or refractory disease defined as progression 
during or within 6 months of the last platinum-based chemotherapy;
6.
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;
Stage 1, grade 1 endometrial carcinoma; or other solid tumors including lymphomas 
(without bone marrow involvement) curatively treated with no evidence of disease 
for ∀5 years.  Subjects with a history of localized triple negative breast cancer may 
be eligible, provided they completed their adjuvant chemotherapy more than 3 years 
prior to registration, and that the subject remains free of recurrent or metastatic 
disease;
7.
Resting ECG with clinically significant abnormal findings;
8.
Subjects receiving any systemic chemotherapy or radiotherapy (except for palliative 
reasons) within 3 weeks prior to study treatment;
9.
Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, 
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or 
cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate 
CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, 
verapamil). The required washout period prior to starting olaparib is 2 weeks;
10.
Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine, St. John’s Wort) or 
moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil).  The required 
washout period prior to starting olaparib is 5 weeks for enzalutamide or 
phenobarbital and 3 weeks for other agents;
11.
Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE]
grade 2) caused by previous cancer therapy, excluding alopecia;
12.
Subjects with MDS/AML or with features suggestive of MDS/AML;
13.
Subjects with pneumonitis or at risk of pneumonitis;
14.
Subjects with symptomatic uncontrolled brain metastases.  No stereotactic radiation 
or whole brain radiation within 28 days prior to Cycle 1, Day 1. A scan to confirm 
the absence of brain metastases is not required.  The subject can receive a stable 
dose of corticosteroids before and during the study as long as these were started at 
least 4 weeks prior to treatment.  Subjects with spinal cord compression, unless 
considered to have received definitive treatment for this and with evidence of 
clinically stable disease for 28 days;
15.
Major surgery within 2 weeks of starting study treatment, and subjects must have 
recovered from any effects of any major surgery;


Clinical Study Protocol
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
47 (138)
16.
Subjects considered a poor medical risk due to a serious, uncontrolled medical 
disorder, non-malignant systemic disease, or active, uncontrolled infection.  
Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent 
(within 3 months) myocardial infarction, uncontrolled major seizure disorder, 
unstable spinal cord compression, superior vena cava syndrome, extensive 
interstitial bilateral lung disease on High Resolution CT scan, or any psychiatric 
disorder that prohibits obtaining informed consent;
17.
Subjects unable to swallow orally administered medication, and subjects with 
gastrointestinal disorders likely to interfere with absorption of the study medication;  
18.
Breastfeeding women;  
19.
Immunocompromised subjects, e.g., subjects who are known to be serologically 
positive for human immunodeficiency virus;
20.
Subjects with a known hypersensitivity to olaparib or any of the excipients of the 
product;
21.
Subjects with known active hepatitis (i.e., Hepatitis B or C) due to risk of 
transmitting the infection through blood or other body fluids;
22.
Previous allogenic bone marrow transplant or double umbilical cord blood 
transplantation; or
23.
Whole blood transfusions in the last 120 days prior to entry into the study (packed 
red blood cells and platelet transfusions are acceptable; for timing refer to inclusion 
criterion number 7 [No blood transfusion can have occurred in the past 28 days]).
For procedures for withdrawal of incorrectly enrolled subjects, see Section 3.4.
3.3
Subject enrollment
Investigator(s) should keep a record, the subject screening log, of subjects who entered 
pre-study screening.
The Investigator(s) will:
1.
Obtain signed informed consent from the potential subject or their guardian/legal 
representative before any study specific procedures are performed;
2.
Assign the potential subject a unique enrollment number, beginning with ‘E#’; and
3.
Determine subject eligibility.  See Section 3.
If a subject withdraws from participation in the study, then her enrollment code cannot be 
reused.


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Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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3.4
Procedures for handling incorrectly enrolled subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Subjects who 
are enrolled but subsequently are found not to meet all of the eligibility criteria must not be 
initiated on treatment and must be withdrawn from the study (see Section 3.10).
Where a subject does not meet all of the eligibility criteria but is incorrectly started on 
treatment, the Investigator should inform the AstraZeneca Representative Study Physician 
immediately, and a discussion should occur between the AstraZeneca Representative Study 
Physician and the Investigator regarding whether to continue or discontinue the subject from 
treatment.  The AstraZeneca Representative Study Physician must ensure all decisions are 
appropriately documented.
3.5
Methods for assigning cohorts
Eligible subjects will be enrolled into 1 of 4 cohorts based upon genetic testing performed by 
a central laboratory to achieve at least 30 subjects in each cohort:
#
Cohort 1: gBRCAm,
#
Cohort 2: sBRCAm and germline BRCA wild type,  
#
Cohort 3: myChoice® HRD positive (genomic instability positive) and 
BRCAwt (no BRCA mutation), or
#
Cohort 4: myChoice® HRD negative (genomic instability negative) and 
BRCAwt (no BRCA mutation).
Cohort enrollment rules:
The objective response will be monitored on an ongoing basis for subjects in each cohort.  If 
no responses (CR or PR) are observed in the first 15 subjects in a cohort, in consultation with 
the Steering Committee, this cohort will be closed to further enrollment.  However, if there is 
at least 1 confirmed objective response in the first 15 subjects, that would justify continuing 
enrollment up to a maximum of 90 subjects.  This stopping rule applies to all cohorts. 
Enrollment in each cohort will continue while the objective response is being assessed for the 
futility assessment. The objective response will be assessed as per protocol, i.e., allowing 
6 months of follow up.
All eligible subjects will provide a screening blood sample for the Myriad BRACAnalysis 
CDx® analysis and a screening tumor sample for the myChoice® HRD analysis.  Investigative 
sites will ship these samples to the central laboratory directly.  The testing results will be 
provided back to the Investigator within approximately 14 to 21 days.  The Myriad testing 
may be submitted in advance of the 28-day screening window if the subject consents to the 
appropriate pre-screening informed consent form. 


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Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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Prior to any cohorts being closed to enrollment, subjects may enroll in the study and initiate 
treatment prior to the Myriad BRACAnalysis CDx® and myChoice® HRD tests being 
reported; however, subjects will not be allocated into a cohort until the results are received by 
the Investigator. Once the test results are received by the Investigator, the subject will be 
allocated into the appropriate cohort.  Once a cohort reaches 90 subjects, the cohort will be 
closed, and subjects may not initiate treatment until their Myriad BRACAnalysis CDx® and 
myChoice® HRD tests are completed, the results are received by the Investigator, and it is 
confirmed there is an open cohort available for which the subject is eligible.
Any subject with a known BRCAm status is still required to have her BRCAm status 
confirmed using the Myriad BRCAnalysis CDx® test (gBRCA) or myChoice® HRD test 
(sBRCA).
Once the results are received by the Investigator, the subject’s cohort assignment will be 
determined and recorded in the study’s electronic data capture (EDC) system.
3.6
Methods for ensuring blinding (Not applicable)
3.7
Methods for unblinding (Not applicable)
3.8
Restrictions
For a listing of concomitant medications see Section 7.7.
3.8.1
Grapefruit juice
The subject must not consume grapefruit juice while on olaparib therapy.
3.8.2
Contraception
Women of childbearing potential and their partners, who are sexually active, must agree to the 
use of 2 highly effective forms of contraception in combination (as described in Appendix E). 
This should be started from the signing of the informed consent and continue throughout the 
period of taking study treatment and for 1 month after the last dose of study medication, or 
they must totally/truly abstain from any form of sexual intercourse (as described in 
Appendix E).
For details of acceptable methods of contraception refer to Appendix E Acceptable Birth 
Control Methods.
3.8.3
Breastfeeding/lactation
Women are not permitted to breastfeed during this study. Lactating women can be eligible if 
they stop breastfeeding prior to the first dose of the study drug until at least 30 days after the 
last dose of the study drug. 


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Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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3.9
Discontinuation of investigational product
Subjects may be discontinued from olaparib in the following situations:
#
Subject decision.  The subject is at any time free to discontinue treatment, 
without prejudice to further treatment;
#
Adverse event;
#
Severe non-compliance with the Clinical Study Protocol;
#
Investigator determines it is in the best interest of the subject to 
discontinue study treatment; 
#
Bone marrow findings consistent with MDS/AML; or
#
Objective progression according to RECIST v1.1 criteria.
3.9.1
Procedures for discontinuation of a subject from investigational product 
At any time, subjects are free to discontinue olaparib or withdraw from the active treatment 
phase of the study (i.e., olaparib and assessments – see Section 3.10), without prejudice to 
further treatment.  A subject who decides to discontinue olaparib will complete the Study 
Treatment Discontinuation Visit (see Section 4.2.5) and will be asked about the reason(s) for 
discontinuation and the presence of any adverse events.  Adverse events will be followed-up 
(see Section 6), and all study medications should be returned by the subject.
By discontinuing from study treatment, the subject then enters the survival follow-up phase of 
the study.  Subjects should be followed for progression (if discontinuation in the absence of 
progression) and survival following treatment discontinuation as per the study plan (see
Section 4.3 and Table 6).  Any subject who has not yet shown objective radiological disease 
progression at withdrawal from olaparib should continue to be followed as per RECIST v1.1.
Any subject discontinuing olaparib should be seen at 30 days post-discontinuation for the 
evaluations outlined in the study plan.  The subject’s tumor status should be assessed 
clinically, and, if appropriate, disease progression should be confirmed by radiological 
assessment via RECIST v1.1 criteria.  After discontinuation of study medication, the Principal 
Investigator/Sub-Investigator will perform the best possible observation(s), test(s), and 
evaluation(s), as well as give appropriate medication and all possible measures for the safety 
of the subject.  In addition, they will record in the electronic case report form (eCRF) the date 
of discontinuation, the reasons, manifestation, and treatment at the time of discontinuation.  If
a subject discontinues study treatment, the AstraZeneca Representative Study Physician must 
be informed immediately.  The Subject will be required to attend the treatment discontinuation 
visit.  
After discontinuation of the study medication at any point in the study, all ongoing adverse 
events or SAEs must be followed until resolution unless, in the Investigator’s opinion, the 
condition is unlikely to resolve due to the subject’s underlying disease, or the subject is lost to 


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Study Code D0816L00003
Version 3.0
Date 10 October 2017
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follow-up (see Section 6.3.2).  All new adverse events and SAEs occurring during the 
30 calendar days after the last dose of study medication must be reported (if SAEs, they must 
be reported to AstraZeneca Safety representative within 24 hours as described in Section 6.4)
and followed to resolution as above.  Subjects should be seen at least 30 days after 
discontinuing study medication to collect and/or complete adverse event information.  For 
guidance on reporting adverse events after the 30 day follow-up period see Section 6.3.1.1.
All subjects who received at least 1 dose of olaparib must be followed for progression and 
survival through the final analysis of all primary and secondary endpoints (approximately 
6 months after the last subject has commenced study treatment [received at least 1 dose of 
olaparib]) + an additional 12 months after the data cut-off for follow-up for survival for 
applicable subjects. At the end of this additional 12 months of survival follow-up, updated OS 
and safety analyses will be conducted and the study will be closed. Subjects are, however, 
permitted to continue to receive olaparib beyond the closure of the database if, in the opinion 
of the Investigator, they are continuing to receive benefit from treatment with olaparib.  
During this time, adverse events of special interest and SAEs must still be collected and 
reported until 30 days after the subject finally stops taking olaparib. See Section 4.3.
If a subject is withdrawn from the study, see Section 3.10. See Section 3.10.2 for details on 
subject replacement. 
For information regarding the withdrawal of consent for donated biological samples, see 
Section 5.6.9.
3.10
Criteria for withdrawal 
Reasons for withdrawal from the study:
#
Voluntary withdrawal by the subject who is at any time free to 
discontinue their participation in the study, without prejudice to further 
treatment (see Section 3.10.2);
#
Incorrectly enrolled subjects (i.e., the subject does not meet the required 
inclusion/exclusion criteria for the study) (see Section 3.4);
#
Subject lost to follow-up; or
#
Death.
3.10.1
Screen failures 
Screening failures are subjects who have signed informed consent and do not fulfill the 
eligibility criteria for the study, and therefore must not be enrolled.  
3.10.1.1
Laboratory re-screening
If a subject is determined to be a screen failure on the basis of a laboratory results, during the 
screening period (28 days), the laboratory value may be rechecked to determine if the value 


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Study Code D0816L00003
Version 3.0
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has changed to make the subject eligible. However, the 28-day screening period will not be 
extended. 
3.10.2
Withdrawal of the informed consent
Subjects are free to withdraw from the study at any time (olaparib and assessments), without 
prejudice to further treatment.
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events.  The Investigator will follow-up adverse events outside of the clinical 
study.  
If a subject withdraws from participation in the study, her enrollment code cannot be reused.  
Withdrawn subjects will be replaced if the subject is withdrawn prior to the first post-baseline 
objective response assessment.  Withdrawn subjects will not be replaced if the subject has had 
a post-baseline objective response assessment.  
If a subject withdraws consent, they will be specifically asked if they are withdrawing consent 
to:
#
Further participation in the study including any further survival follow-up 
(e.g., survival calls);
#
Withdrawal of consent to the use of their study generated data; or
#
Withdrawal to the use of any samples (see Section 5.6.9).
The status of ongoing, withdrawn (from the study), and “lost to follow-up” subjects at the time 
of an OS analysis should be obtained by the site personnel by checking the subject notes, 
hospital records, contacting the subject’s general practitioner, and checking publicly available 
death registries.  In the event that the subject has actively withdrawn consent to the processing 
of their personal data, the vital status of the subject can be obtained by site personnel from 
publicly available resources where it is possible to do so under applicable local laws.
For information regarding the withdrawal of consent for donated biological samples, see 
Section 5.6.9.
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, study subjects are placed at 
undue risk because of clinically significant findings that:
#
Meet individual stopping criteria or are otherwise considered significant;
#
Are assessed as causally related to study medication; or
#
Are not considered to be consistent with continuation of the study.


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Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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Regardless of the reason for study termination, all data available for the subject at the time of 
study discontinuation must be recorded in the eCRFs.  
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests. See Section 9.3 for timelines for planned study 
completion. 
4.
STUDY PLAN AND TIMING OF PROCEDURES 
This is a Phase II, open-label, non-randomized, multi-center cohort study assessing the 
efficacy and safety of olaparib tablets 300 mg
in 
subjects with platinum-sensitive or partially platinum-sensitive, relapsed, high-grade serous or 
high-grade endometrioid ovarian, fallopian tube, or primary peritoneal cancer, who have 
received at least 1 prior line of platinum-based chemotherapy.  
The study will assess the effectiveness of olaparib tablets as measured by the ORRs as 
determined by RECIST v1.1, in subjects with gBRCAm, sBRCAm, or potential aberrations in 
HRD as determined by myChoice® HRD, as well as in subjects without identifiable HRD.  
This study will utilize Myriad BRACAnalysis CDx® for germline BRCA analysis and a tumor 
test (myChoice® HRD) for tumor BRCA analysis and HRD status. The Myriad testing may be 
submitted in advance of the 28-day screening window if the subject consents to the 
appropriate pre-screening informed consent form. 
Four cohorts will be identified based upon genetic testing:
#
Cohort 1: gBRCAm,
#
Cohort 2: somatic BRCA mutated (sBRCAm) and germline BRCA wild 
type,  
#
Cohort 3: myChoice® HRD positive (genomic instability positive) and 
BRCA wild type (BRCAwt) (no BRCA mutation),  
#
Cohort 4: myChoice® HRD negative (genomic instability negative) and 
BRCAwt (no BRCA mutation).
For the cohort enrollment stopping rules, see Section 3.5 and Section 8.5.4.
This study consists of an up to 28-day screening period (Day -28 to Day -1) once the subject 
signs the main study consent. See Section 4.1.
Following the screening period, eligible subjects will enter the active treatment period of the 
study. Study visits will be conducted at Day 1 (Visit 2), Day 8 (Visit 3), Day 15 (Visit 4), 
Day 22 (Visit 5), Day 29 (Visit 6), and on Day 1 of a 4-week visit period up to 52 weeks (if 
not progressed and still on treatment), then on Day 1 of a 12-week visit period relative to date 
CCI


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Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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of enrollment.  For a list of specific procedures and assessments conducted during the active
treatment period, see Section 4.2. When the subject discontinues olaparib, the Study 
Treatment Discontinuation Visit will be conducted (see Section 4.2.5). 
Subjects should be discontinued from active study treatment phase if they have objective 
radiological disease progression according to RECIST v1.1 (see Appendix G) and complete 
the Study Treatment Discontinuation Visit as per the study plan. 
A data cut-off for analysis of all primary and secondary endpoints will occur approximately 
6 months after the last subject enrolled has commenced study treatment (received at least 
1 dose of olaparib).  The study will remain open for an additional 12 months after this data 
cut-off for survival follow-up for applicable subjects.  At the end of this additional 12 months 
of survival follow-up, updated OS and safety analyses will be conducted and the study will be 
closed.  Subjects are, however, permitted to continue to receive olaparib beyond the closure of 
the database if, in the opinion of the Investigator, they are continuing to receive benefit from 
treatment with olaparib.  During this time, adverse events of special interest and SAEs must 
still be collected and reported until 30 days after the subject finally stops taking olaparib. See 
Section 4.3.2.
Assessments for survival will be made every 12 weeks (± 1 week) following objective 
radiological disease progression (RECIST v1.1). See Section 4.4.
A Follow-up Visit will be conducted 30 days after the discontinuation of olaparib (see 
Section 4.3.1).


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Study Code D0816L00003
Version 3.0
Date 10 October 2017
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Table 6
Study Plan – On Study Treatment and Discontinuation 
Visit Number
1
2
3
4
5
6
Subsequent on 
treatment visits 
every 4 weeks a
Tumor assessment 
visits every 8 or 
12 weeks b
Visit No. 7 
onwards
Study 
treatment 
discontinued c
Follow-up 
30 days after 
last dose of 
study 
medication d
Overall 
Survival 
Follow-up e
Day
-28 
to -1
1
8
15
22
29
Day 1 of next visit 
period f
Visit Window
± 3d
± 3d
± 3d
± 3d
± 3d
+ 7d
± 7d
± 7d
Informed consent g
X
Demographics
X
Surgical and medical history
X
Prior cancer therapies including 
radiotherapy
X
Inclusion/exclusion criteria 
(history of blood transfusions) h
X
Enrollment
X
Physical examination i
X
X
X
Vital signs, body weight, 
height, (Includes BP, pulse, and 
temperature), and ECG i, j
X
X
X
ECOG performance status
X
X
X
X
Hematology/clinical chemistry k
X 
X
X
X
X
X
X
X
X
Urinalysis
X


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Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
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Table 6
Study Plan – On Study Treatment and Discontinuation 
Visit Number
1
2
3
4
5
6
Subsequent on 
treatment visits 
every 4 weeks a
Tumor assessment 
visits every 8 or 
12 weeks b
Visit No. 7 
onwards
Study 
treatment 
discontinued c
Follow-up 
30 days after 
last dose of 
study 
medication d
Overall 
Survival 
Follow-up e
Day
-28 
to -1
1
8
15
22
29
Day 1 of next visit 
period f
Visit Window
± 3d
± 3d
± 3d
± 3d
± 3d
+ 7d
± 7d
± 7d
Pregnancy test l
X
X
X
X
X
Blood sample for determination 
of BRCA status via Myriad m,n
X
Blood sample for disease 
specific marker (CA-125) o
X
X
X
X
Tumor Assessment (CT or MRI 
according to RECIST v1.1)
X p
Every 8 weeks (± 1 week) from receipt of first dose of 
study drug (Visit 2) for 48 weeks and every 12 weeks 
(± 1 week) thereafter until PD has been determined by the 
Investigator according to RECIST v1.1 criteria (including 
confirmatory RECIST scan).
Adverse events (continuous 
from the time of informed 
consent) q
X
X
X
X
X
X
X
X
X
Concomitant medications 
including blood transfusions
X
X
X
X
X
X
X
X
X
Olaparib  dispensed/returned r
X
X
X
X




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Study Code D0816L00003
Version 3.0
Date 10 October 2017
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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.  Subjects must be followed until RECIST PD.  If an 
unscheduled assessment was performed and the subject has not progressed, every attempt should be made to perform the subsequent assessments at 
their scheduled visits.  Subjects who are determined to have PD according to RECIST v1.1 criteria (including confirmatory RECIST scan) by the 
Investigator may have additional scans performed per the site’s standard of care. Scans will be collected through disease progression.
c.
Subjects should be discontinued from study treatment if they have objective radiological disease progression according to RECIST v1.1 (see 
Appendix G) and complete the Study Treatment Discontinuation Visit as per the study plan. 
d.
During the follow-up period, subjects will be followed for PFS (CA-125 and radiographic evidence of progression per site standards) until database 
lock/end of study, and assessed for overall survival.
e.
Assessments for survival should be made every 12 weeks (± 1 week) following disease progression.  Survival information may be obtained via 
telephone or email contact with the subject, subject’s family, or by contact with the subject’s current physician.  
f.
Visit 7 equals Day 57 (Week 8), then Visit 8 equals Day 85 (Week 12), etc.
g.
Informed consent for pre-screening will be taken specifically for myChoice® HRD (central Myriad HRD tumor) and BRACAnalysis CDx® (gBRCA 
testing). A separate informed consent needs to be signed to begin study procedures for the overall study.
h.
All inclusion/exclusion criteria including history of blood transfusion within previous 120 days from informed consent and the reasons (e.g., bleeding 
or myelosuppression). 
i.
Height will only be recorded at screening. Temperature and weight only required if clinically indicated.  Physical examination should be performed 
according to the schedule; after the baseline assessment it is not necessary to record the details on an eCRF unless related to an adverse event/SAE.  
Any clinically significant changes should be recorded as adverse events.
j.
The ECG at screening should be performed within 7 days prior to starting the study treatment. Electrocardiograms should be performed once the 
subject has been in the supine position for at least 5 minutes in each case.
k.
Coagulation tests are only required if clinically indicated.  For a list of all required laboratory tests, please refer to Section 5.2.1.  All enrolled 
subjects will have safety blood samples taken weekly during the first month on treatment followed by monthly assessments until discontinuation of 
study treatment.  Safety blood samples will be taken at the 30-day Follow-up Visit as well.  
l.
Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to starting treatment and a confirmatory 
test on Day 1 before initiating olaparib treatment; and at the timepoints shown in Table 6 during study treatment, and at the 30 day follow up visit.
Pregnancy testing for women of childbearing potential should be conducted at regular intervals (eg, monthly). If results are positive, the subject is 
ineligible/must be discontinued from the study. 
m. Subjects with an unknown gBRCA status will have their blood and tumor tested with the myChoice® HRD and BRACAnalysis CDx® in parallel at 
pre-screening (if consented) or at screening, if not previously performed by Myriad during pre-screening.
n.
Subjects with known gBRCA status from the local laboratory must provide a blood and tumor sample at screening for confirmatory purposes.  Their 
involvement in the study will not be affected by the result of the Myriad test.
o.
CA-125 will be tested at baseline and every month thereafter until objective disease progression, based on progressive serial elevation of serum 
CA-125 according to the modified GCIG criteria. Samples should be taken pre-dose at Visit 2.
p.
RECIST assessments will be performed using CT/MRI of the chest, abdomen, and pelvis, with other regions as clinically indicated for the 
assessment of disease, no more than 28 days prior to study treatment start and as close as possible to the start of study treatment. A CT examination 
with intravenous contrast media administration is the preferred method. An MRI should be used where CT is not feasible or it is medically 
contraindicated.




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4.1
Enrollment/screening period
Procedures will be performed according to the Study Plan, Table 6.  
During screening, consenting subjects are assessed to ensure that they meet study eligibility 
criteria per Section 3.  Subjects who do not meet these criteria must not be enrolled in the 
study.
Subjects will be considered enrolled once the subject has signed the Informed Consent Form
(full study) and has met all inclusion and none of the exclusion criteria. Note: Prior to any 
cohort being filled, subjects can initiate study drug treatment prior to cohort assignment. Once 
a cohort has been closed to further enrollment, subjects may not initiate treatment until the 
Myriad BRACAnalysis CDx® and myChoice® HRD testing demonstrates the subject is 
eligible for an open cohort, at which point the subject may initiate study drug. If the results 
demonstrate the subject was eligible for a closed cohort, the subject will be discontinued from 
the study. See Section 3.5 for information about cohort assignment.
The following procedures can be performed at pre-screening if the subject has consented to 
pre-screening:
#
Obtain informed consent specifically for central Myriad HRD tumor 
(myChoice® HRD) and gBRCA testing (BRACAnalysis CDx®);
#
Obtain blood sample for determination/confirmation of BRCA status via 
Myriad BRACAnalysis CDx® (see Table 8); and
#
Obtain archival tumor sample and/or baseline tumor sample for Myriad 
testing; subjects must provide a tumor sample to be considered for the 
study – the sample can either be an archival sample or a new baseline 
tumor sample (see Section 5.6);
The following procedures will be performed at screening (Day -28 to Day -1):
#
Obtain informed consent specifically for central Myriad HRD tumor
(myChoice® HRD) and gBRCA testing (BRACAnalysis CDx®) if not 
previously obtained through pre-screening consent;
#
Obtain informed consent for overall study; and
#
Confirm eligibility based on all inclusion/exclusion criteria (see 
Sections 3.1 and 3.2);
∃
Obtain demographics and medical and surgical history;
∃
Obtain prior cancer therapies, including radiotherapy;






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4.2.2
Study Visit 3, Day 8 to Visit 5, Day 22
The following procedures will be performed at Visit 3, Day 8; Visit 4, Day 15; and Visit 5, 
Day 22 (% 3 days):
#
Obtain blood sample for hematology/clinical chemistry (see Section 5.2.1
and Table 8);
#
Assess and record concomitant medications including blood transfusions;
and
#
Assess subject for adverse events (continuous from time of informed 
consent).
4.2.3
Study Visit 6, Day 29
The following procedures will be performed at Visit 6, Day 29 (% 3 days):
#
Obtain blood sample for hematology/clinical chemistry (see Section 5.2.1
and Table 8);
#
Obtain blood sample for disease specific marker (CA-125) (see 
Section 5.2.1.4 and Table 8);
#
Assess and record concomitant medications including blood transfusions;
#
Assess subject for adverse events (continuous from time of informed
consent); and
#
Dispense/return olaparib.
4.2.4
Study Visit 7, Day 57, and every 4 weeks onwards
Subsequent on-treatment visits for the active treatment period will take place on Day 1 of a 
4-week visit period up to 52 weeks (if not progressed and still on treatment), then on Day 1 of 
a 12-week visit period relative to date of enrollment until PD (RECIST v1.1). Subsequent 
on-treatment visits for subjects who remain on treatment post-progression should take place 
every 12 weeks. Tumor assessment visits will be performed at the end of every 8 weeks 
(± 1 week) up to 48 weeks, then every 12 weeks (± 1 week) relative to date of enrollment until 
PD (RECIST v1.1). Subjects will be contacted to assess for survival every 12 weeks following 
disease progression until death, withdrawal of consent, or study closure. See Section 4.4. 


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The following procedures will be performed at Visit 7, Day 57 (% 3 days) and every 4 weeks 
onward (i.e., Visit 8 [Day 85], Visit 9 [Day 113], etc.) through the active treatment period:
#
Assess functional status using the ECOG performance status scale (see 
Appendix F);
#
Obtain blood sample for hematology/clinical chemistry (see Section 5.2.1
and Table 8);
#
Obtain blood sample for disease specific marker (CA-125) (see 
Section 5.2.1.4 and Table 8);
#
Assess tumor (CT or MRI according to RECIST v1.1) (see 
Section 5.1.1);
∃
Note: The tumor assessments according to RECIST v1.1 will be performed 
every 8 weeks (% 1 week) from the first dose of study drug (Visit 2) for 
48 weeks, and then every 12 weeks (% 1 week) (relative to the date of 
enrollment) thereafter until determined by the Investigator according to 
RECIST v1.1 criteria (including confirmatory RECIST scan).
#
Assess and record concomitant medications including blood transfusions;
#
Assess subject for adverse events (continuous from time of informed
consent); and
#
Dispense/return olaparib.
4.2.5
Study Treatment Discontinuation Visit
Subjects should be discontinued from study treatment if they have objective radiological 
disease progression according to RECIST v1.1 (see Appendix G) and complete the 
Study Treatment Discontinuation Visit as per the study plan. 
The following procedures will be performed at the Study Treatment Discontinuation Visit
(+ 7 days):
#
Perform physical examination (see Section 5.2.2); 
#
Assess functional status using the ECOG performance status scale (see 
Appendix F);
#
Obtain blood sample for hematology/clinical chemistry (see Section 5.2.1
and Table 8);
#
Obtain blood sample for disease specific marker (CA-125) (see 
Section 5.2.1.4 and Table 8);




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During the follow-up period, subjects will be followed for PFS (CA-125 and radiographic 
evidence of progression per site standards) until database lock/end of study and assessed for 
OS.
4.3.2
Follow-up after final data cut-off for the primary endpoint analysis/end of 
study
After data cut-off for the primary endpoint (ORR), during the additional 12 months of
follow-up, subjects will be assessed for adverse events (see Section 6.3.1.1), and assessed for 
survival every 3 months until the closure of the study. 
At the end of the additional 12 months of survival and safety follow-up, the study will be 
closed. Subjects who are receiving treatment at this time can either choose to discontinue from 
olaparib, or where the Investigator believes subjects are gaining clinical benefit, subjects may 
continue to receive olaparib off study. AstraZeneca will continue to supply olaparib after 
completion of this study until either olaparib tablets are licensed in the US, or it is determined 
that the benefit-to-risk profile does not support continued development of olaparib, or the 
FDA has deemed the drug not approvable. In all these scenarios, AstraZeneca will work with 
Investigators on the proper transition of subjects to alternative therapies if possible. 
4.4
Survival follow-up
All subjects who enrolled and received at least 1 dose of olaparib will be followed for 
survival. Subjects will be contacted to assess for survival status every 12 weeks following 
disease progression until death, withdrawal of consent, or study closure.  Survival information 
may be obtained via telephone or email contact with the subject, subject’s family, or by 
contact with the subject’s current physician.  The vital status of the subject can be obtained by 
site personnel from publicly available resources where it is possible to do so under applicable 
local laws.
5.
STUDY ASSESSMENTS
An EDC system will be used for data collection and query handling.  The Investigator will 
ensure that data are recorded in the eCRF as specified in the Clinical Study Protocol and in 
accordance with the instructions provided.
The Investigator will ensure 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 tumor assessments (RECIST v1.1)
The baseline tumor assessment will be performed no more than 28 days prior to study 
treatment start (Visit 2) and as close as possible to study treatment start.  Following the 


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baseline tumor assessment, subsequent tumor assessments according to RECIST v1.1 should 
be performed at the end of every 8 weeks (± 1 week) from first dose of study drug (Visit 2) for 
48 weeks and every 12 weeks (± 1 week) (relative to the date of enrollment) thereafter until 
PD. If an unscheduled assessment was performed and the subject has not progressed, every 
attempt should be made to perform the subsequent assessments at their scheduled visits.  
Subjects who are determined to have PD according to RECIST v1.1 criteria (including 
confirmatory RECIST scan) by the Investigator may have additional scans performed per the 
site’s standard of care.  All treatment decisions will be based on the Investigator’s assessment 
of the scans.  
A copy of all tumor assessment scans will be collected by an AstraZeneca Representative 
through disease progression. 
All subjects should have RECIST assessments until documented evidence of objective 
radiological progression in accordance with RECIST v1.1, irrespective of treatment decisions 
(i.e., RECIST follow-up until progression even if a subject discontinues study treatment prior 
to progression and/or receives a subsequent therapy prior to progression).  
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 (per RECIST
v1.1) will be by chest (in those subjects 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 tumor burden used at baseline must be 
used at each subsequent follow-up assessment. A CT examination with intravenous contrast 
media administration is the preferred method. An MRI should be used where CT is not 
feasible or it is medically contraindicated. For brain lesion assessment, MRI is the preferred 
method. Subjects must be followed-up until RECIST disease progression.
Radiological examinations performed in the conduct of this study should be retained at the site 
as source data.
It is important to follow the assessment schedule as closely as possible.  If scans are 
performed outside of the scheduled visit ± 1 week window interval and the subject has not 
progressed, every attempt should be made to perform the subsequent scans at their scheduled 
time points (± 1 week).  
5.1.2
Tumor evaluation
RECIST v1.1 criteria will be used to assess subject response to treatment for determination of
PFS times, ORR, and DoR.  The RECIST v1.1 guidelines for measurable, non-measurable, 
target and non-target lesions (TLs), and the objective tumor response criteria (CR, PR, SD, or 
PD) are presented in Appendix G.


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Note: The biopsied tumor sample taken at screening should not be assessed as a TL as part of 
the RECIST assessments if there are other lesions available.  The biopsy should be taken after 
the baseline scan has been performed. 
Although CA-125 is measured in this study, it will not be directly used for assessing objective 
response or progression, and subjects should be continued on treatment until objective 
radiological disease progression as per RECIST v1.1 as assessed by the Investigator, or when 
they meet any discontinuation criteria (see Section 3.9).  After documentation of disease
progression, subjects will be followed for survival.    
If the Investigator is in doubt as to whether progression has occurred, particularly with 
response to non-TL or the appearance of a new lesion, treatment should continue until the next 
scheduled assessment, or sooner if clinically indicated, and the Investigator should reassess 
the subject’s status.  If repeat scans confirm progression, then the date of the initial scan 
should be declared as the date of progression.  
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in the presence of 
SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of 1 or more non-TLs is usually 
not sufficient to qualify for unequivocal progression status.
5.2
Safety assessments
For the timing of individual measurements, refer to the study plan (see Table 6). Adverse 
events will be collected continuously throughout the active treatment period including the 
follow-up period.
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology, coagulation,
and urinalysis will be taken at the times indicated in the study plan (see Table 6). Note: Safety 
blood samples (e.g., clinical chemistry, hematology, coagulation, etc.) do not need to be 
repeated on Visit 2 (Day 1) of the 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 the values are likely to have changed significantly. 
Additional safety samples (e.g., clinical chemistry, hematology, coagulation, etc.) 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, hematology, and urinalysis will be performed at a local laboratory at 
or near to the investigative site.  Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site.


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The following laboratory variables will be measured:
Table 7
Laboratory Safety Variables
Hematology/Hemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Hemoglobin 
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
B- Leukocyte differential count (absolute count)
S/P-Alkaline phosphatase 
B-Platelet count
S/P-Aspartate transaminase 
B-Absolute neutrophil count
S/P-Alanine transaminase 
S/P-Albumin
Urinalysis (dipstick)
S/P-Potassium
U-Hb/erythrocytes/blood 
S/P-Calcium, total
U-Protein/albumin 
S/P-Sodium
U-Glucose 
S/P-Urea or blood urea nitrogen 
B = blood; P = plasma; S = serum; U = urine.
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 the 
site as source data for laboratory variables.  For information on how adverse events based on 
laboratory tests should be recorded and reported, see Section 6.3.
In case a subject shows an AST or ALT ∀3 × ULN or TBL ∀2 × ULN, please refer to 
Appendix D, for further instructions.
5.2.1.1
Coagulation 
Activated partial thromboplastin time (APTT) will be performed if clinically indicated.  
International normalized ratio (INR) will be performed if clinically indicated unless the 
subject is receiving warfarin.  Subjects taking warfarin may participate in this study; however, 
it is recommended that INR be monitored carefully at least once per week for the first month, 
then monthly if the INR is stable.  
Each coagulation test result will be recorded in the eCRF.
5.2.1.2
Urinalysis 
Urinalysis by dipstick should be performed as stated in Table 6.  Microscopic analysis should 
be performed by the hospital’s local laboratory, if required, checking for the safety variables 
listed in Table 7.  For information on how adverse events based on laboratory tests should be 
recorded and reported, see Section 6.3.


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5.2.1.3
Bone marrow or blood cytogenetic samples 
Bone marrow or blood cytogenetic samples may be collected for subjects with prolonged 
hematological toxicities as defined in Section 6.7.1.
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity.  If it is not 
possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to carry out the tests on a blood sample.  Full reports must be 
provided by the Investigator for documentation on the Patient Safety database.  These data are 
not required to be entered into the eCRF.
5.2.1.4
Disease specific tumor marker samples (CA-125)
As part of the routine safety blood samples, all subjects will supply blood samples for CA-125 
(2 mL) assessment at the beginning of each 4-week period prior to the subject receiving study 
treatment.  
It is important to follow the assessment schedule as closely as possible.  If CA-125 assessment 
is performed outside of the scheduled visit ± 1-week window interval, every attempt should be 
made to assess the CA-125 at the scheduled time points.  Subjects will be evaluated until 
objective disease progression (RECIST v1.1), based on progressive serial elevation of serum 
CA-125 according to the modified GCIG criteria. For the modified GCIG criteria, see 
Appendix H.
Further assessment of CA-125 post-serological progression will be at the discretion of the 
Investigator according to local clinical practice.
Objective response rates based on the Investigator review of RECIST v1.1, CA-125 response 
rates, and the percentage of subjects who had a RECIST response and/or a CA-125 response 
will be summarized.
5.2.2
Physical examination
A complete physical examination will be performed and will 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. Note: After the baseline assessment it is not 
necessary to record the details on an eCRF unless the details are related to an adverse 
event/SAE.
5.2.3
ECG
5.2.3.1
Resting 12-lead ECG
The ECG at screening should be performed within 7 days prior to starting the study treatment. 
Electrocardiograms will also be performed at Day 1 and at the Follow-up Visit.
Electrocardiograms will be performed according to local practice with the site’s ECG 
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Twelve-lead ECGs will be obtained after the subject has been rested in a supine position for at 
least 5 minutes in each case.  The Investigator or qualified 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.
Electrocardiograms will be recorded at 25 mm/sec.  All ECGs should be assessed by the 
Investigator as to whether they are clinically significantly abnormal/not clinically significantly 
abnormal.  If there is a clinically significant abnormal finding, the Investigator will record it as 
an adverse event in the eCRF.  The original ECG traces must be stored in the subject medical 
record as source data.
5.2.4
Vital signs
Height will be assessed at screening only. Weight will be assessed at screening and as 
clinically indicated, according to the study plan (see Table 6).
Any changes in vital signs should be recorded as an adverse event, if applicable.  For 
information on how adverse events based on changes in vital signs should be recorded and 
reported, see Section 6.3.
5.2.4.1
Pulse and blood pressure
Blood pressure and pulse will be assessed at screening, baseline, and at the Follow-up Visit, 
according to the study plan (see Table 6).
Blood pressure and pulse rate will be measured preferably using a semi-automatic blood 
pressure recording device with an appropriate cuff size after 10 minutes rest.  
The date of collection and measurement will be recorded on the appropriate eCRF.
5.2.4.2
Body temperature
Body temperature will be measured in degrees Celsius according to local practice. The 
measurements and dates at screening, baseline, and at the Follow-up Visit (see Table 6) 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 28 days prior to the start of study treatment, on Day 1 of the study prior to 
commencing treatment, at the time points shown in Table 6 during study treatment and at the 
30 day follow up visit. Pregnancy testing for women of childbearing potential should be 
conducted at regular intervals (e.g., monthly). Tests will be performed by the hospital’s local 
laboratory.  If results are positive, the subject is ineligible/must be discontinued from study
treatment immediately. 




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the Investigator. Once the test results are received by the Investigator, the subject will be 
allocated into the appropriate cohort.  Once a cohort reaches 90 subjects, the cohort will be 
closed, and subjects may not initiate treatment until their Myriad BRACAnalysis CDx® and 
myChoice® HRD tests are completed, the results are received by the Investigator, and it is 
confirmed there is an open cohort available for which the subject is eligible.
All local procedures for genetic counseling must be followed for subjects who do not know 
their gBRCA status at study entry. 
Samples will be collected and shipped after the subject has signed informed consent. Myriad 
screening test results will be reported back to the investigative site for clinical assessment.  
Residual blood (or its derivatives) may be used to evaluate future companion diagnostic tests 
and for additional exploratory work.  Note: The Myriad testing may be submitted in advance 
of the 28-day screening window if the subject consents to the appropriate pre-screening 
informed consent form.
As part of the subject’s consent, residual tumor or blood (or derivatives) may be used to 
evaluate future 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 BRCAm or HRD status and its role in 
response).  Information regarding tumor/blood sample collection can be found in the 
laboratory manual.
5.6.2
Collection of pharmacogenetic samples
The subject’s consent to participate in the PGx research components of the study is 
mandatory.  
The blood sample for genetic research will be obtained from the subjects at Visit 2.  Although 
genotype is a stable parameter, early sample collection is preferred to avoid introducing bias 
through excluding subjects who may withdraw due to an adverse event, as such subjects
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 1 sample should 
be collected per subject for PGx during the study.
Samples will be collected, labeled, stored, and shipped as detailed in the laboratory manual.
5.6.3
Storage, re-use, and destruction of pharmacogenetic samples
The processes adopted for the coding and storage of samples for analysis are important to 
maintain subject confidentiality.  Samples MAY be stored for a maximum of 15 years from 
the end of the study, 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 CSR
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 




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Any samples identified as Infectious Category A materials should not be shipped and no 
further samples will be taken from the subject unless agreed with AstraZeneca Representative
and appropriate labeling, shipment, and containment provisions are approved.
5.6.8
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each site will keep full traceability of collected biological 
samples from the subjects while in storage at the investigative site until shipment or disposal 
(where appropriate), and will keep documentation of receipt of arrival.
The sample receiver will keep 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.
The AstraZeneca Representative will keep oversight of the entire life cycle through internal 
procedures, monitoring of study sites, and auditing of external laboratory providers.
Samples retained for further use will be stored in the AstraZeneca Biobank. For information 
regarding the logistics for samples see the laboratory manual.
5.6.9
Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analyzed,
AstraZeneca is not obliged to destroy the results of this research.
Collection of the biological samples is an integral part of the study; if the subject withdraws 
consent prior to receiving the first dose, the subject will be withdrawn from further study 
participation; however, if the subject withdraws consent after receiving the first dose, the
subject may continue in the study.
The Principal Investigator will:
#
Ensure that the AstraZeneca Representative is immediately notified of the 
subject’s withdrawal of informed consent to the use of donated samples;
#
Ensure that biological samples from that subject, if stored at the 
investigative site, are immediately identified, disposed of /destroyed, and 
the action documented;


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#
Ensure 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; and
#
Ensure that the subject and the AstraZeneca Representative are informed 
about the sample disposal.
The AstraZeneca Representative will ensure that the central laboratory(ies) holding the 
samples is/are immediately informed about the withdrawn consent to use donated biological 
samples, and that samples are disposed of/destroyed and the action documented and returned 
to the study site.
5.7
Blood volume
The total study volume of blood that will be drawn from each subject will vary, depending
upon the length of time that the subject remains in the study and on treatment.  
Safety laboratory assessments will be performed locally at each study site’s laboratory by 
means of their established methods.  The number of samples/blood volumes is therefore 
subject to site-specific change.  For specific information regarding collection and 
documentation of laboratory samples see the laboratory manual. 
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 subject in this study is 
shown in Table 8.


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Table 8
Estimated Maximum Volume of Blood to be Drawn from Each Subject*
Assessment
Sample vol.  
(mL)
No.  of 
samples -
screening
No.  of 
samples 
Month 1 
(Including 
Day 29)
Months
2-6
Treatment 
Discontinuation 
Visit and 30 day 
Follow-up Visit
Objective 
radiological 
disease 
progression
Total vol.  
(mL)
Safety
Clinical chemistry (locally 
assessed)
5
1
5
1(×4)
1(×2)
60
Hematology (locally 
assessed)
5
1
5
1(×4)
1(×2)
60
Blood sample: Prospective Myriad BRCA
test for subjects with unknown BRCA
status or for confirmation of BRCA status 
for those with previous results
10
1
10
Blood cytogenetic analysis
Site 
dependent
Depends on 
the blood 
smear result
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(×2)
1(×4)
1(×1) (only 
treatment 
discontinuation 
visit)
16
 
Total volume (mL)
*The total study volume of blood that will be drawn from each subject will vary, depending upon the length of time that the subject remains in the study and 
on treatment.  
CA = Cancer antigen; 
; No. = number; vol. = volume. 
CCI
CCI
CCI
CCI
CCI
CCI


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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, ECG).  In clinical studies, an 
adverse event 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 adverse event is used to include both serious and non-serious adverse events.
6.1.1
Olaparib adverse events of special interest
Adverse events of special interest (AESI) are events of scientific and medical interest specific 
to the further understanding of olaparib’s safety profile and that require close monitoring and 
rapid communication by the Investigators to the AstraZeneca Safety Representative.  An AESI 
may be serious or non-serious.  However, AESIs for olaparib should be considered as SAEs as 
they are medically important and have been identified as important potential risks for olaparib
that are under close surveillance at AstraZeneca. The olaparib AESIs include MDS/AML, new 
primary malignancy (other than MDS/AML), and pneumonitis.  
ANY event of suspected or confirmed MDS/AML, new primary malignancy, or pneumonitis, 
regardless of the severity, should be treated as an SAE and reported to the AstraZeneca Safety
Representative according to SAE reporting processes and timelines (see Section 6.4). 
A targeted questionnaire will be sent to any Investigator reporting an AESI as an aid to 
provide further detailed information on the event.  During the study there may be other events 
identified as AESIs that require the use of a questionnaire to help characterize the event and 
gain a better understanding regarding the relationship between the event and study treatment.
6.2
Definitions of serious adverse event
An SAE is an adverse event occurring during any study phase (i.e., run-in, treatment, washout, 
follow-up), that fulfills 1 or more of the following criteria:
#
Results in death;
#
Is immediately life-threatening;
#
Requires in-subject hospitalization or prolongation of existing 
hospitalization;


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#
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; or
#
Is an important medical event that may jeopardize the subject or may 
require medical intervention to prevent 1 of the outcomes listed above.
For further guidance on the definition of an SAE, see Appendix A to the Clinical Study 
Protocol. For additional information on SAE reporting, see Section 6.4.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse events will be collected from time of signature of first informed consent for 
participating in the study, continuously throughout the active treatment period including the 
follow-up period.
Serious adverse events will be recorded from the time of informed consent for participating in 
the study. See Section 6.4.
After the data cut-off for the primary and secondary endpoint analyses, any ongoing adverse 
events/SAEs will be followed for resolution and included in the AstraZeneca Safety Database.
6.3.1.1
Adverse events after the 30 day follow-up period
For pharmacovigilance purposes and characterization, any case of MDS/AML or new primary 
malignancy occurring after the 30 day follow-up period should be reported to the AstraZeneca 
Safety Representative whether it is considered a non-serious adverse event
(e.g., non-melanoma skin cancer) or an SAE, and regardless of the Investigator’s assessment 
of causality.  Investigators will be asked during the regular follow-up for survival if the 
subject has developed MDS/AML or a new primary malignancy, and will be prompted to 
report any such cases.  
At any time after a subject has completed the study (i.e., no longer receiving study drug and
past the 30 day follow-up period), if an Investigator learns of any SAE, including sudden 
death of unknown cause, and he/she considers there is a reasonable possibility that the event is 
causally related to olaparib, the Investigator should notify the AstraZeneca Safety 
Representative.
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 
adverse events or SAEs occurring in former study subjects.  


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6.3.2
Follow-up of unresolved adverse events
Any SAE or non-serious adverse event that is ongoing at the time of the 30-day follow-up, 
must be followed-up to resolution, until the condition stabilizes, is judged by the Investigator 
to be no longer clinically significant, or until the subject is lost to follow-up.  AstraZeneca 
retains the right to request additional information for any subject with ongoing adverse 
event(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Variables 
The following variables will be collected for each adverse event:
#
Adverse event (verbatim),
#
The date when the adverse event started and stopped,
#
CTCAE grade and changes in CTCAE grade,
#
Whether the adverse event is serious or not,
#
Investigator causality rating against olaparib (yes or no),
#
Action taken with regard to olaparib,
#
Outcome, and
#
Adverse event caused subject’s withdrawal from study (yes or no).
In addition, the following variables will be collected for SAEs:
#
Date adverse event met criteria for an SAE,
#
Date Investigator became aware of an SAE,
#
Adverse event is serious due to,
#
Date of hospitalization,
#
Date of discharge,
#
Probable cause of death,
#
Date of death,
#
Autopsy performed,
#
Causality assessment in relation to study procedure(s),


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Causality assessment in relation to other medication, and
#
Description of adverse event.
Severity of adverse event
For each episode of an adverse event, all changes to the CTCAE grade attained, as well as the 
highest attained CTCAE (version 4.03) grade, should be reported.
It is important to distinguish between serious and severe adverse events.  Severity is a measure 
of intensity whereas seriousness is defined by the criteria in Section 6.2.  An adverse event of 
severe intensity need not necessarily be considered serious.  For example, nausea that persists 
for several hours may be considered severe nausea but not an SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but would be an SAE when it satisfies the criteria 
shown in Section 6.2.
The grading scales found in the National Cancer Institute (NCI) CTCAE version 4.03 will be 
utilized for all events with an assigned CTCAE grading.  For those events without assigned 
CTCAE grades, the recommendation is that the CTCAE criteria that convert mild, moderate,
and severe events into CTCAE grades should be used.
A copy of the CTCAE version 4.03 can be downloaded from the Cancer Therapy Evaluation 
Program website (http://ctep.cancer.gov).
6.3.4
Causality collection
The Investigator will assess causal relationship between olaparib 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 medications and study 
procedures.  Note: For SAEs that could be associated with any study procedure, the causal 
relationship is implied as ‘yes.’
A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol.
6.3.5
Adverse events based on signs and symptoms
All adverse events spontaneously reported by the subject or reported in response to the open 
question from the study personnel: ‘Have you had any health problems since the previous 
visit/you were last asked?,’ or revealed by observation, will be collected and recorded in the 
eCRF.  When collecting adverse events, 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.


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6.3.6
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital signs will be summarized in the 
CSR.  Deterioration as compared to baseline in protocol-mandated laboratory values, vital 
signs, and ECG abnormalities should therefore only be reported as adverse events if 1 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, or
#
The Investigator believes that the abnormality should be reported as an 
adverse event.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an adverse event, and the associated laboratory 
result/vital sign will be considered as additional information.  Wherever possible, the 
reporting Investigator should use the clinical, rather than the laboratory term (e.g., anemia
versus low hemoglobin value).  In the absence of clinical signs or symptoms, clinically 
relevant deteriorations in non-mandated parameters should be reported as adverse event(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should
not be reported as an adverse event/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 adverse event.
6.3.7
Hy’s Law
Potential Hy’s Law cases where a subject shows elevations in liver biochemistry may require 
further evaluation and occurrences of AST or ALT ∀3 × ULN together with TBL ∀2 × ULN 
and may need to be reported as SAEs.  Confirmed Hy’s Law cases should always be reported 
as SAEs. Please refer to Appendix D for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s Law.
6.3.8
Disease progression
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which olaparib is being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the signs and symptoms of the cancer.  The 
development of new, or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an adverse event.  Events which are 
unequivocally due to disease progression should not be reported as adverse events during the 
study.


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For this study, objective radiological disease progression will be determined as per 
RECIST v1.1. See Appendix G. 
6.3.9
New cancers
The development of a new primary cancer (including skin cancer) should be regarded as an 
adverse event (see Section 6.1.1 Olaparib Adverse Events of Special Interest).  New primary 
malignancies are those that are not the primary reason for the administration of the study 
treatment and have developed after the inclusion of the subject into the study.  They do not 
include metastases of the original cancer.  Symptoms of metastasis or the metastasis itself 
should not be reported as an adverse event/SAE, as they are considered to be disease 
progression.
6.3.10
Lack of efficacy
When there is deterioration in the cancer for which the study treatment(s) is being used, there 
may be uncertainty as to whether this is lack of efficacy or an adverse event.  In such cases, 
unless the Sponsor or the reporting physician considers that the study treatment contributed to 
the deterioration of the condition, the deterioration should be considered to be a lack of 
efficacy and not an adverse event.
6.3.11
Deaths
All deaths that occur during the study or within the protocol-defined 30-day follow-up period 
after the administration of the last dose of study treatment, must be reported as follows:
#
Death that is clearly the result of disease progression should be reported 
to the study monitor at the next monitoring visit and should be 
documented in the death eCRF, but should not be reported as an SAE.
#
Where death is not due (or not clearly due) to progression of the disease 
under study, the adverse event causing the death must be reported to the 
AstraZeneca Safety Representative as an SAE within 24 hours (see 
Section 6.4 for further details).  The report should contain a comment 
regarding the co-involvement of progression of disease, if appropriate, 
and should assign main and contributory causes of death.  This 
information can be captured in the death eCRF.
#
Deaths with an unknown cause should always be reported as SAEs.  A 
post-mortem evaluation may be helpful in the assessment of the cause of 
death, and if performed, a copy of the post-mortem results should be 
forwarded to the AstraZeneca Safety Representative within the usual 
timeframes.


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6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to olaparib or to the 
study procedure(s).  All SAEs will be recorded in the eCRF. See Section 6.3 for adverse event 
recording information. 
If any SAE occurs in the course of the study, then Investigators or other site personnel will 
inform the appropriate AstraZeneca Safety Representatives within 1 day, i.e., immediately,
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca Safety Representatives will work with the Investigator to ensure 
that all the necessary information is provided to the AstraZeneca 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 will inform 
AstraZeneca Safety Representatives of any follow-up information on a previously reported 
SAE within 1 calendar day, i.e., immediately, but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an adverse event is serious in the EDC
system, an automated email alert is sent to the designated AstraZeneca Safety Representative.
If the EDC system is not available, then the Investigator or other study site personnel will 
report an SAE to the appropriate AstraZeneca Safety Representative by telephone. If the 
eCRF is not available, paper back-up forms should be used (including SAE, pregnancy, and 
overdose forms).  
The AstraZeneca Safety Representative will advise the Investigator/study site personnel how 
to proceed.  
Safety Contact Information: Medpace Clinical Safety
Medpace SAE hotline – USA:
Telephone: +1-800-730-5779, ext. 12999 or +1-513-579-9911, ext. 12999
Fax: +1-866-336-5320 or +1-513-579-0444
e-mail: medpace-safetynotification@medpace.com
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 maximum tolerated dose is 300 mg bid (tablet).


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Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately.
#
An overdose with associated adverse events is recorded as the adverse 
event diagnosis/symptoms on the relevant adverse event modules in the 
eCRF and on the Overdose eCRF module.
#
An overdose without associated symptoms is only reported on the 
Overdose eCRF module.
If an overdose on an AstraZeneca study medication occurs in the course of the study, then the 
Investigator or other site personnel will inform appropriate AstraZeneca Safety 
Representatives immediately, or no later than 24 hours of when he or she becomes aware of 
the overdose.
The designated AstraZeneca Safety Representative works with the Investigator to ensure that 
all relevant information is provided to the AstraZeneca Representative data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the AstraZeneca Safety 
Representative.
6.6.1
Maternal exposure
If a subject becomes pregnant during the course of the study, olaparib should be discontinued 
immediately.
The outcomes of any conception occurring from the date of the first dose of study medication 
until 1 month after the last dose of study medication must be followed-up and documented.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
olaparib 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 adverse 
events.  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 subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
will inform the appropriate AstraZeneca Safety Representatives within 1 day, i.e., 
immediately, but no later than 24 hours of when he or she becomes aware of the pregnancy.










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6.7.2.1
Management of new or worsening pulmonary symptoms 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities occur 
in the absence of a clear diagnosis, an interruption in study treatment dosing is recommended 
and further diagnostic workup (including a high resolution CT scan) should be performed to 
exclude pneumonitis.
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then study treatment can be restarted, if deemed appropriate by the 
Investigator.  If significant pulmonary abnormalities are identified, these need to be discussed 
with the AstraZeneca Representative Study Physician.
If a subject experiences a dose interruption > 4 weeks the subject cannot restart study 
medication. See Section 6.7. 
6.7.2.2
Management of nausea and vomiting
Events of nausea and vomiting are known to be associated with olaparib treatment.  In 
study D0810C00019, nausea was reported in 71% of the olaparib treated subjects and 36% of
the placebo treated subjects, and vomiting was reported in 34% of the olaparib treated subjects 
and 14% of the placebo treated subjects.  These events are generally mild to moderate 
(CTCAE grade 1 or 2) in 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 around 
9 months and for vomiting around 6 to 7 months.
No routine prophylactic anti-emetic treatment is required at the start of study treatment;
however, subjects should receive appropriate anti-emetic treatment at the first onset of nausea 
or vomiting and as required thereafter, in accordance with local treatment practice guidelines.  
Alternatively, olaparib tablets can be taken with a light meal/snack (i.e., 2 pieces of toast or a 
couple of biscuits). Note: For adverse events of nausea and vomiting, an additional eCRF is 
required.
As per international guidance on anti-emetic use in cancer subjects (European Society for 
Medical Oncology, National Comprehensive Cancer Network), generally a single agent 
anti-emetic should be considered, e.g., dopamine receptor antagonist, antihistamines, or 
dexamethasone.


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6.7.2.3
Renal impairment
If subsequent to study entry and while still on study therapy, a subject’s estimated creatinine 
clearance (CrCl) decreases to become < 51 mL/min, retesting should be performed promptly.  
A dose reduction is recommended for subjects who meet the following criteria during the 
course of the study:
#
Baseline CrCl ∀51 mL/min who have on study a CrCl < 51 mL/min,
#
Baseline CrCl < 51 mL/min but had serum creatinine ! 1.5 × ULN, and 
then on study had a clinically meaningful lower CrCl value.
 
Olaparib has not been studied in subjects with severe renal impairment (CrCl ! 30 mL/min) or 
end-stage renal disease; if subjects develop severe impairment or end-stage renal disease
olaparib must be discontinued.
6.7.2.4
Interruptions for intercurrent non-toxicity related events
Study treatment dose interruption for conditions other than toxicity resolution should be kept 
as short as possible.  If a subject cannot restart study treatment within 4 weeks for resolution 
of intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with the AstraZeneca Representative Study Physician. See Section 6.7. 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions, are to be recorded in the eCRF.  
Study treatment should be stopped at least 3 days prior to planned surgery.  After surgery,
study treatment can be restarted when the wound has healed.  No stoppage of study treatment 
is required for any needle biopsy procedure.
Study treatment should be discontinued for a minimum of 3 days before a subject undergoes 
palliative radiation treatment.  Study treatment should be restarted within 4 weeks as long as 
any bone marrow toxicity has recovered.
Because the adverse events related to olaparib may include asthenia, fatigue, and dizziness, 
subjects should be advised to use caution while driving or using machinery if these symptoms 
occur.  
6.8
Study governance and oversight
A Study Steering Committee composed of representatives from AstraZeneca and key 
Investigators/scientific advisors will be responsible for providing recommendations to US 
Medical Affairs leadership at AstraZeneca based on Investigator input, review, and oversight 
of study execution, scientific conduct, and analysis of study data. The accountabilities and 
CCI




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Investigator. Subjects who continue to gain clinical benefit are allowed to continue olaparib 
post-study completion.  AstraZeneca will continue to supply olaparib tablets after completion 
of this study until olaparib tablets are approved and commercially available and subjects will 
then be transferred to commercially available olaparib tablets. 
Dose Reductions 
For guidance on dose reductions for management of adverse events, refer to Section 6.7.
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors 
cannot be avoided, see Section 7.7.  
7.3
Labeling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfill GMP Annex 13 requirements for labeling.  Label 
text will be translated into local language. 
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions. The 
olaparib label on the bottle specifies the appropriate storage. 
7.5
Compliance
The administration of all study medications (including olaparib) should be recorded in the 
appropriate sections of the eCRF.
Subjects should be given clear instructions on how and when to take their study treatment.  
Subjects will self-administer olaparib.  Study site staff will perform 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 subject but will be retained 
by the investigative site until reconciliation is completed by the study monitor.  All subjects 
must return their bottle(s) of olaparib at the appropriate scheduled visit, when a new bottle 
will be dispensed. Subjects will be instructed to notify study site personnel of missed doses.  
Subjects must return all containers and any remaining tablets at the end of the study.
7.6
Accountability
The study drug provided for this study will be used only as directed in the Clinical Study 
Protocol.
The study site personnel or study monitor will account for olaparib received at the site, unused 
study drugs, and for appropriate destructions. Certificates of delivery, destruction, or return 
should be signed. 


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Study drug will not be distributed to the study site until the contract is concluded between the 
study site and the AstraZeneca Representative.  The IP Storage Manager is responsible for 
managing the study medication from receipt by the study site until the return of all unused 
study medication to the AstraZeneca Representative.  AstraZeneca will provide the study 
documents ‘Procedures for drug accountability’ and ‘Procedures for drug storage,’ which 
describe the specific requirements.  The Investigator(s) is responsible for ensuring that the 
subject has returned all unused study medication.
7.7
Concomitant and other treatments 
The use of any natural/herbal products or other traditional remedies should be discouraged, 
but use of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the eCRF.
Medications that may NOT be administered
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy [hormone 
replacement therapy is acceptable], radiotherapy, biological therapy, or other novel agent) is 
to be permitted while the subject is receiving study medication.
Live virus and live bacterial vaccines should not be administered whilst the subject is 
receiving study medication and during the 30-day follow-up period. An increased risk of 
infection by the administration of live virus and bacterial vaccines has been observed with 
conventional chemotherapy drugs and the effects with olaparib are unknown.
Restricted concomitant medications
Strong or Moderate CYP3A inhibitors 
Known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, boosted 
protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate 
CYP3A inhibitors (ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) should not 
be taken with olaparib.
If there is no suitable alternative concomitant medication, then the dose of olaparib should be 
reduced for the period of concomitant administration. The dose reduction of olaparib should 
be recorded in the CRF with the reason documented as concomitant CYP3A inhibitor use.
#
Strong CYP3A inhibitors – reduce the dose of olaparib to 100 mg bid for 
the duration of concomitant therapy with the strong inhibitor and for 
5 half-lives afterwards.
#
Moderate CYP3A inhibitors – reduce the dose of olaparib to 150 mg bid
for the duration of concomitant therapy with the moderate inhibitor and 
for 3 half-lives afterwards.


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#
After the washout of the inhibitor is complete, the olaparib dose can be 
re-escalated.
Strong or Moderate CYP3A inducers
Strong (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide, and St John’s Wort) and moderate CYP3A inducers (e.g., bosentan, 
efavirenz, modafinil) of CYP3A should not be taken with olaparib.
If the use of any strong or moderate CYP3A inducers are considered necessary for the 
subject’s safety and welfare, this could diminish the clinical efficacy of olaparib.
If a subject requires use of a strong or moderate CYP3A inducer then they must be monitored 
carefully for any change in efficacy of olaparib.
P-gp inhibitors
It is possible that co-administration of P-gp inhibitors (e.g., amiodarone, azithromycin) may 
increase exposure to olaparib. Caution should therefore be observed.
Effect of olaparib on other drugs
Based on limited in vitro data, olaparib may increase the exposure to substrates of CYP3A4, 
P-gp, OATP1B1, OCT1, OCT2, OAT3, MATE1, and MATE2K. 
Based on limited in vitro data, olaparib may reduce the exposure to substrates of CYP3A4, 
2B6, 2C9, 2C19, and P-gp. 
The efficacy of hormonal contraceptives may be reduced if co-administered with olaparib. 
Caution should therefore be observed if substrates of these isoenzymes or transporter proteins 
are co-administered.
Examples of substrates include:
#
CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, 
ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine
#
CYP2B6 – bupropion, efavirenz
#
CYP2C9 – warfarin 
#
CYP2C19 – lansoprazole, omeprazole, S-mephenytoin
#
P-gp – simvastatin, pravastatin, digoxin, dabigatran, colchicine
#
OATP1B1 – bosentan, glibenclamide, repaglinide, statins, valsartan


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#
OCT1, MATE1, MATE2K – metformin
#
OCT2  – serum creatinine
#
OAT3 – furosemide, methotrexate
Anticoagulant therapy
Oral anticoagulants are permitted. Subjects who are taking warfarin may participate in this 
study; however, it is recommended that INR be monitored carefully at least once per week for 
the first month, then monthly thereafter, if the INR is stable. For Coumadin-like agents, 
prothrombin time should be checked at baseline and followed closely (as clinically indicated).
Subcutaneous heparin and low molecular weight heparin are permitted. 
Anti-emetics/Anti-diarrheals
From screening onwards, should a subject develop nausea, vomiting, and/or diarrhea, then 
these symptoms should be reported as adverse events (see Section 6) and appropriate 
treatment of the event should be given.
Palliative radiotherapy 
Palliative radiotherapy may be used for the treatment of pain at the site of bony metastases 
that were present at baseline, provided the Investigator does not feel that these are indicative 
of clinical disease progression during the study period.  Study treatment should be 
discontinued for a minimum of 3 days before a subject undergoes therapeutic palliative 
radiation treatment.  Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered (i.e., if a subject has not recovered from bone marrow toxicity 
within 4 weeks they should be discontinued from the study).  
Administration of other anti-cancer agents
Subjects must not receive any other concurrent anti-cancer therapy, including investigational 
agents, while on study treatment. Subjects may continue the use of bisphosphonates or 
denosumab for bone disease and corticosteroids for the symptomatic control of brain 
metastases provided the dose is stable before and during the study and they were started at 
least 4 weeks prior to beginning study treatment. 
Subsequent therapies for cancer 
Details of first and subsequent therapies for cancer and/or details of surgery for the treatment 
of the cancer, after discontinuation of treatment, will be collected until database lock for ORR. 
Reasons for starting subsequent anti-cancer therapies, including access to other PARP 
inhibitors or investigational drugs, will be collected until database lock for ORR.








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8.3.1
Efficacy analysis set
The efficacy analysis set comprises all subjects who received at least 1 dose of olaparib and 
had a baseline tumor assessment.
8.3.2
Safety analysis set
The safety analysis set comprises all subjects who received at least 1 dose of olaparib.
8.4
Outcome measures for analyses
8.4.1
Calculation or derivation of efficacy variable(s)
At each visit, subjects will be assigned a visit response of CR, PR, SD, PD, or not evaluable 
(NE) based on RECIST v1.1 guidelines, based on the Investigator’s assessment. 
8.4.2
Primary endpoint
The ORR rate is defined as the percentage of subjects with measurable disease with at least
1 visit response of CR or PR that is confirmed at least 4 weeks later.  Data obtained up until 
progression, or last evaluable assessment in the absence of progression, will be included in the 
assessment of ORR.  However, any CR or PR that occurred after a further anti-cancer therapy 
was received will not be included in the numerator for the ORR calculation. Subjects lacking 
valid data to assign a response status will be included in the denominator for the response rate 
calculation based on the efficacy analysis set.
In the case where a subject has 2 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 subject will be defined as a responder.  Similarly, if a subject has visit responses of 
CR, NE, CR, then as long as the time between the 2 visits of CR is greater than 4 weeks, a 
best response of CR will be assigned.
8.4.3
Secondary endpoints 
8.4.3.1
Duration of response
The DoR will be defined as the time from the date of first documented response (that is
subsequently confirmed) until the date of documented objective PD or death in the absence of 
PD.  The end of response should coincide with the date of PD 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 the response is not confirmed (per 
RECIST v1.1), it will not be included.  If a subject does not progress following a response, 
then the subject’s DoR will use the PFS censoring time.
8.4.3.2
CA-125 response rate
The CA-125 response will be based upon the latest GCIG guidelines.  Serum samples will be 
collected for CA-125 tumor markers on all subjects at baseline (within 2 weeks prior to 
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A response according to CA-125 has occurred if there is at least a 50% reduction in 
CA-125 levels from the baseline sample.  The response must be confirmed and maintained for 
at least 28 days.  Subjects can be evaluated according to CA-125 only if they have a baseline 
sample that is at least twice the ULN and within 2 weeks prior to starting treatment.
Those subjects who have both a CA-125 response and whose CA-125 level falls to within the 
normal range, can be classified as CA-125 complete responders.
The CA-125 response rate is defined as the percentage of subjects achieving a CA-125 
response.  The CA-125 CR Rate is defined as the percentage of subjects achieving a CA-125 
response with the CA-125 level additionally falling within the normal range. The CA-125 
response rate will be analyzed on a subset of the efficacy analysis set (i.e., excluding subjects 
whose baseline CA-125 level is not ∀2 × ULN and/or not assessed within 2 weeks of starting 
treatment with olaparib) (Rustin et al 2011). 
8.4.3.3
Disease control rate
The DCR is defined as the percentage of subjects who have a best overall response of 
confirmed CR or PR or SD at ∀8 weeks divided by the number of subjects in the efficacy 
analysis set, prior to any PD event.
8.4.3.4
Progression-free survival
Progression-free survival is defined as the time from the date of first dose of olaparib until the 
date of objective radiological disease progression (Investigator assessed via RECIST v1.1) or 
death (by any cause in the absence of disease progression) regardless of whether the subject 
withdraws from therapy or receives another anticancer therapy prior to disease progression.  
Subjects who have not progressed or died at the time of analysis will be censored at the time 
of the latest date of assessment from their last evaluable efficacy assessment.  However, if the 
subject progresses or dies after 2 or more missed visits, the subject will be censored at the 
time of the latest evaluable assessment.  Given the scheduled visit assessment scheme, 
2 missing visits will equate to more than 18 weeks (or 26 weeks after 1 year) since the 
previous RECIST v1.1 assessment, allowing for early and late visits.  If the subject has no 
evaluable visits or does not have a baseline assessment, they will be censored at Day 1 unless 
they die within 2 visits of baseline (18 weeks allowing for visit window).  
The PFS time will always be derived based on scan/assessment dates and not visit dates.  
Assessments/scans contributing towards a particular visit may be performed on different 
dates.  The following rules will be applied:
#
Date of progression will be determined based on the earliest of the 
assessment/scan dates of the component that triggered the progression.  
#
When censoring a subject for PFS, the subject will be censored at the 
latest of the assessment/scan dates contributing to a particular overall 
visit assessment.


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Overall visit assessments will be determined for each assessment (scheduled or unscheduled) 
and will contribute to the derivation of PFS.
Objective radiological progression is defined as at least a 20% increase in the sum of the 
diameters of the TLs (compared to previous minimum sum) and an absolute increase of 
> 5 mm, an overall non-TL assessment of progression, or a new lesion.
8.4.3.5
Time to earliest progression by RECIST or CA-125, or death
The CA-125 progression will be based upon the latest GCIG guidelines.  Progression or 
recurrence based on serum CA-125 levels will be defined on the basis of a progressive serial 
elevation of serum CA-125 according to the following criteria:
#
Subjects with elevated CA-125 pre-treatment and normalization of 
CA-125 must show evidence of CA-125 ∀2 × ULN on 2 occasions at 
least 1 week apart;
#
Subjects with elevated CA-125 before treatment, which never normalizes, 
must show evidence of CA-125 ∀2 times the nadir value on 2 occasions 
at least 1 week apart; or
#
Subjects with CA-125 in the reference range before treatment must show 
evidence of CA-125 ∀2 × ULN on 2 occasions at least 1 week apart.
Cancer antigen-125 progression will be assigned the date of the first measurement that meets 
the criteria as noted.  Subjects are not evaluable for CA-125 if they have received mouse 
antibodies (unless the assay used has been shown not to be influenced by human anti-mouse 
antibody) or if there has been medical and/or surgical interference with their peritoneum or 
pleura (e.g., paracentesis) during the previous 28 days.  
For the purpose of this endpoint, a subject may be declared to have PD on the basis of either 
the objective RECIST v1.1 criteria or the GCIG CA-125 criteria.  The date of progression will 
be the date of the earlier of the 2 events if both are documented.
Time to earliest progression is defined as the time from the date of the first dose of olaparib 
until the earliest of CA-125 progression or RECIST progression, or death from any cause.
Subjects without a CA-125 progression or objective radiological progression by RECIST v1.1 
who are still alive at the time of analysis will be censored at their last evaluable RECIST 
assessment or their last available CA-125 measurement, whichever is the most recent at the 
time of analysis. If a subject progresses or dies after 2 or more missed RECIST and CA-125 
assessments, then the subject will be censored at the time of their last evaluable assessment. 
8.4.3.6
Overall survival
Overall survival is defined as the time from the date of first dose of olaparib until death due to 
any cause.  Any subject not known to have died at the time of analysis will be censored based 
on the last recorded date on which the subject was known to be alive.




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will be used for summarizing categorical (discrete) data.  Confidence intervals, when 
presented, will generally be constructed at the 95% level.
8.5.1
Analysis of the primary variable
The ORR will be presented together with the exact 95% CI according to the Clopper-Pearson 
method.
8.5.2
Analysis of the secondary variable(s)
The DCR and CA-125 response rate will be presented together with the exact 95% CI 
according to the Clopper-Pearson method.
Kaplan-Meier plots of PFS will be presented for each cohort of subjects.  Summaries of the 
number and percentage of subjects experiencing a PFS event, and the type of event 
(progression or death) will be provided along with median PFS and 95% CIs.
The analyses of PFS will be based on Investigator assessment according to RECIST v1.1 
guidelines, and using all scans regardless of whether they were scheduled or not.  The 
estimated PFS rates at 6 months, 12 months, and 24 months will be summarized (using the 
Kaplan-Meier curves) if appropriate.
Other time-to-event endpoints (OS, TTAP, DoR) will be described as for PFS. 
The safety analyses will consist of assessment of safety and exposure profiles in terms of 
adverse events/SAEs, laboratory data/vital signs, and ECG that will be collected for all 
subjects. Appropriate summaries of laboratory data/vital signs and adverse events/SAEs will 
be produced for all subjects in the safety analysis set per NCI-CTCAE. 
Further details will be provided in the SAP.  
8.5.3
Subgroup analysis 
Subgroup analyses will not be considered within individual cohorts given the limited sample 
size.
However, for all subjects in the 2 BRCAwt cohorts (myChoice® HRD positive and negative) 
clinical outcomes will be presented according to HRRm status (HRRm positive versus HRRm 
negative).
8.5.4
Interim analysis
In each cohort, an informal interim analysis will take place after 15 subjects have had at least 
1 radiologic tumor response assessment in the first 6 months of the study. If no responses (CR 
or PR) are observed in the first 15 subjects in a cohort, in consultation with the Steering 
Committee, the cohort will be closed to further enrollment.  However, if there is at least 
1 confirmed objective response in the first 15 subjects, that would justify continuing 
enrollment up to a maximum of 90 subjects.  Enrollment will continue until these interim 
analyses have been completed and a decision is made by the Study Steering Committee. 




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samples are handled in accordance with the laboratory manual, and that 
study medication accountability checks are being performed;
#
Perform source data verification (a comparison of the data in the eCRFs 
with the subject’s medical records at the hospital or practice and other 
records relevant to the study) including verification of informed consent 
of participating subjects.  This will require direct access to all original 
records for each subject (e.g., clinic charts); and
#
Ensure withdrawal of informed consent to the use of the subject’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the subject.
The AstraZeneca Representative will be available between visits if the Investigator(s) or other 
staff at the site needs information and advice about the study conduct.
9.2.1
Source data
Refer to the Clinical Study Agreement for location of source data.
9.2.2
Study agreements
The Principal Investigator at each site 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 the Clinical Study Protocol shall prevail with respect to the conduct of the study and 
the treatment of subjects, and in all other respects not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail.
Agreements between the AstraZeneca Representative and the Principal Investigator should be 
in place before any study-related procedures can take place, or subjects are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement.
9.3
Study timetable and end of the study
All subjects who enrolled and received at least 1 dose of olaparib will be followed for 
survival. Subjects will be contacted to assess survival every 12 weeks following disease 
progression until death, withdrawal of consent, or study closure.
A data cut-off for analysis of all primary and secondary endpoints will occur approximately 
6 months after the last subject enrolled has commenced study treatment (received at least 
1 dose of olaparib).  The study will remain open for an additional 12 months after this data 
cut-off for survival follow-up for applicable subjects.  At the end of this additional 12 months 
of survival follow-up, updated OS and safety analyses will be conducted and the study will be 


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closed.  Subjects are, however, permitted to continue to receive olaparib beyond the closure of 
the database if, in the opinion of the Investigator, they are continuing to receive benefit from 
treatment with olaparib.  During this time (i.e., the 12 months of survival follow-up), AESIs
and SAEs must still be collected and reported until 30 days after the subject finally stops 
taking olaparib. See Sections 6.3.1, 6.3.1.1, and 6.4 for details of adverse event/SAE 
reporting. 
The anticipated enrollment period is approximately 20 months. The study is expected to start 
in approximately Q4 2016 and to end by approximately Q1 2020.
The study may be terminated at individual sites if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with olaparib. See Section 3.11.
9.4
Data management by Medpace
Data management will be performed by Medpace, according to the Data Management Plan.  
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of MedDRA.  Medications will be classified according to the AstraZeneca 
Drug Dictionary.  Classification coding will be performed by Medpace.
The data collected through third party sources will be obtained and reconciled against study 
data.
Data queries will be raised for inconsistent, impossible, or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, signed, and locked, clean file will be declared and 
the final database will be locked.
SAE reconciliation
Serious adverse event reconciliation reports are produced and reconciled with the Patient
Safety Database and/or the investigational site.  
Data associated with human biological samples
Data associated with biological samples will be transferred from the laboratory(ies) (internal 
or external) to the AstraZeneca Representative.


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10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements,
and the AstraZeneca policy on Bioethics and Human Biological Samples.
10.2
Subject data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician, or any other third party, unless 
required to do so by law.
Precautions are taken to preserve confidentiality and prevent genetic data being linked to the 
identity of the subject.  In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a subject.  For example, in the case of a 
medical emergency, an AstraZeneca Representative Study Physician or an Investigator might 
know a subject’s identity and also have access to her genetic data.  Also, Regulatory 
Authorities may require access to the relevant files, though the subject’s medical information 
and the genetic files would remain physically separate.
10.3
Ethics and regulatory review
An institutional review board (IRB) should approve the final Clinical Study Protocol, 
including the final version of the Informed Consent Form and any other written information 
and/or materials to be provided to the subjects.  The Investigator will ensure the distribution of 
these documents to the applicable IRB, and to the study site staff.
The opinion of the IRB should be given in writing.  The Investigator should submit the written 
approval to an AstraZeneca Representative before enrollment of any subject into the study.  
The IRB should approve all advertising used to recruit subjects for the study.
An AstraZeneca Representative should approve any modifications to the Informed Consent 
Form that are needed to meet local requirements.
If required by local regulations, the protocol should be re-approved by the IRB annually.
Before enrollment of any subject into the study, the final Clinical Study Protocol, including 
the final version of the Informed Consent Form, is approved by the national regulatory 
authority or a notification to the national regulatory authority is done, according to local 
regulations.


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AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, IRBs, and Principal Investigators with 
safety updates/reports according to local requirements.
Each Principal Investigator is responsible for providing the IRB with reports of any serious 
and unexpected adverse drug reactions from any other study conducted with olaparib.  
AstraZeneca will provide this information to the Principal Investigator so that he/she can meet 
these reporting requirements.
10.4
Informed consent
The Principal Investigator(s) at each site will:
#
Ensure each subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the 
study;
#
Ensure each subject is notified that they are free to discontinue from the 
study at any time;
#
Ensure that each subject is given the opportunity to ask questions and 
allowed time to consider the information provided;
#
Ensure each subject provides signed and dated informed consent before 
conducting any procedure specifically for the study;
#
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File;
#
Ensure a copy of the signed Informed Consent Form is given to the 
subject; and
#
Ensure that any incentives for subjects who participate in the study, as 
well as any provisions for subjects harmed as a consequence of study 
participation, are described in the Informed Consent Form that is 
approved by an Ethics Committee.
10.5
Changes to the protocol and Informed Consent Form 
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a Clinical Study Protocol amendment and, where required, in a new version of 
the Clinical Study Protocol (Revised Clinical Study Protocol).


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The amendment is to be approved by the relevant Ethics Committee and, if applicable, also 
the national regulatory authority, before implementation.  Local requirements are to be 
followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s).  For distribution to Ethics Committees, see Section 10.3.
If a protocol amendment requires a change to a site’s Informed Consent Form, AstraZeneca 
and the site’s Ethics Committee are to approve the revised Informed Consent Form before the 
revised form is used.  
If local regulations require, any administrative change will be communicated to, or approved 
by, each Ethics Committee.
10.6
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the site, 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 verify 
data were recorded, analyzed, and accurately reported according to the protocol, GCP, 
guidelines of the ICH, and any applicable regulatory requirements.  The Investigator will 
contact AstraZeneca immediately if contacted by a regulatory agency about an inspection at 
the site.
11.
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Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, et al.  Poly(ADP-ribose) 
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Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib 
maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a 
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Ledermann et al 2016
Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Overall survival 
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Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, et al.  High 
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Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life-threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the adverse 
event as it occurred, or it is suspected that use or continued use of the product would result in 
the subject’s death.  ‘Life-threatening’ does not mean that had an adverse event occurred in a 
more severe form, it might have caused death (e.g., hepatitis that resolved without hepatic 
failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (e.g., bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered adverse events if the illness or 
disease existed before the subject was enrolled in the study, provided that it did not deteriorate 
in an unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability, or incapacity, but may jeopardize the subject or may require 
medical intervention to prevent 1 or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
#
Angioedema not severe enough to require intubation but requiring 
intravenous hydrocortisone treatment;
#
Hepatotoxicity caused by paracetamol (acetaminophen) overdose 
requiring treatment with N-acetylcysteine;
#
Intensive treatment in an emergency room or at home for allergic 
bronchospasm;
#
Blood dyscrasias (e.g., neutropenia or anemia requiring blood 
transfusion, etc.) or convulsions that do not result in hospitalization; or
#
Development of drug dependency or drug abuse.


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


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


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materials at all times.  The IATA 650 biological sample containment 
standards are encouraged wherever possible when road or rail transport is 
used.




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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 Representative 
employee or contract laboratory staff working with the DNA).
The samples and data for genetic analysis in this study will be single coded.  The link between 
the subject enrollment/randomization code and the DNA number will be maintained and 
stored in a secure environment, with restricted access WITHIN the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca.  The link will be used 
to identify the relevant DNA samples for analysis, facilitate correlation of genotypic results 
with clinical data, allow regulatory audit, and trace samples for destruction in the case of 
withdrawal of consent.
Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 10 of the main Clinical Study Protocol.
Subject data protection
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician, or any other third party, unless 
required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an Investigator might know a subject’s 
identity and also have access to her genetic data.  Also, Regulatory Authorities may require 
access to the relevant files, though the subject’s medical information and the genetic files 
would remain physically separate.
Data management
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or third party contracted 
to work with AstraZeneca to analyze the samples.
The results from this genetic research may be reported in the Clinical Study Report for the 
main study, or in a separate report as appropriate.
Genotype data will be transferred to the clinical database, and merged with the clinical data 
from the main study, prior to the statistical analysis and reporting of the study.  


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Statistical Methods and Determination of Sample Size
The number of subjects that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A Statistical 
Analysis Plan will be prepared where appropriate.


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Appendix D
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.  Specific guidance on the managing liver abnormalities can 
be found in Section 6.3.7 of the Clinical Study Protocol.
During the course of the study, the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a subject meets 
potential Hy’s Law criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting potential Hy’s Law criteria to agree whether Hy’s 
Law criteria are met.  Hy’s Law criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than drug induced liver injury caused by the 
investigational medicinal product.  
The Investigator is responsible for recording data pertaining to potential Hy’s Law/Hy’s Law
cases and for reporting adverse events and serious adverse event (SAE) according to the 
outcome of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ∀3 × upper limit of 
normal (ULN) together with total bilirubin (TBL) ∀2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline phosphatase 
(ALP).  
Hy’s Law 
AST or ALT ∀3 × ULN together with TBL ∀2 × ULN, where no other reason, other than 
the investigational medicinal product, can be found to explain the combination of increases, 
(e.g., elevated ALP indicating cholestasis, viral hepatitis, another drug).  
For potential Hy’s Law and Hy’s Law the elevation in transaminases must precede or be 
coincident with (i.e., on the same day) the elevation in TBL, but there is no specified 
timeframe within which the elevations in transaminases and TBL must occur.


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Identification of Potential Hy’s Law Cases
In order to identify cases of potential Hy’s Law, it is important to perform a comprehensive 
review of laboratory data for any subject who meets any of the following identification criteria 
in isolation or in combination:
#
ALT ∀3 × ULN,
#
AST ∀3 × ULN, or
#
TBL ∀2 × ULN.
The Investigator will without delay review each new laboratory report and, if the 
identification criteria are met, will:
#
Notify the AstraZeneca Representative,
#
Determine whether the subject meets potential Hy’s Law criteria (see 
Definitions within this Appendix for definition) by reviewing laboratory 
reports from all previous visits, and
#
Promptly enter the laboratory data into the laboratory electronic case 
report form (eCRF).
Follow-up
Potential Hy’s Law Criteria not met
If the subject does not meet potential Hy’s Law criteria, the Investigator will:
#
Perform follow-up on subsequent laboratory results according to the 
guidance provided in the Clinical Study Protocol.
Potential Hy’s Law Criteria met
If the subject meets potential Hy’s Law criteria, the Investigator will:
#
Notify the AstraZeneca Representative who will then inform the central 
study team.
The Study Physician contacts the Investigator to provide guidance and to discuss and agree on 
an approach for the study subjects’ follow-up and the continuous review of data.  Subsequent 
to this contact the Investigator will:
#
Monitor the subject until liver biochemistry parameters and appropriate 
clinical symptoms and signs return to normal or baseline levels, or as 
long as medically indicated;


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#
Investigate the etiology of the event and perform diagnostic 
investigations as discussed with the Study Physician;  
#
Complete the 3 Liver eCRF modules as information becomes available; 
and
#
If at any time (in consultation with the AstraZeneca Representative Study 
Physician) the potential Hy’s Law case meets serious criteria, report it as 
a SAE using standard reporting procedures.
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where potential Hy’s Law
criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the 
AstraZeneca Representative Study Physician will contact the Investigator in order to review 
available data and agree on whether there is an alternative explanation for meeting potential 
Hy’s Law criteria other than drug-induced liver injury caused by the investigational medicinal 
product.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review, together with other subject matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an adverse event will be made, and 
subsequently, whether the adverse event meets the criteria for an SAE:
#
If the alternative explanation is not an adverse event, record the 
alternative explanation on the appropriate eCRF; or
#
If the alternative explanation is an adverse event/SAE, record the adverse 
event/SAE in the eCRF accordingly and follow the AstraZeneca standard
processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the investigational medicinal product:
#
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca 
standard processes.  
∃
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply, and


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∃
As there is no alternative explanation for the Hy’s Law case, a causality 
assessment of ‘related’ should be assigned.
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for Hy’s Law, then it is assumed that there is 
no alternative explanation until such time as an informed decision can be made:
#
Report an SAE (report term ‘Potential Hy’s Law’) applying serious 
criteria and causality assessment as per above.
#
Continue follow-up and review according to agreed plan.  Once the 
necessary supplementary information is obtained, repeat the review and 
assessment to determine whether Hy’s Law criteria are met.  Update the 
SAE report according to the outcome of the review.
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment 
This section is applicable to subjects with liver metastases who meet potential Hy’s Law
criteria on study treatment, having previously met potential Hy’s Law criteria at a study visit 
prior to starting study treatment.
At the first on-study treatment occurrence of potential Hy’s Law criteria being met the 
Investigator will:
#
Determine if there has been a significant change in the subjects’ 
condition* compared with the last visit where potential Hy’s Law criteria 
were met*:
∃
If there is no significant change, no action is required; or
∃
If there is a significant change, notify the AstraZeneca Representative, who 
will inform the central study team, then follow the subsequent process 
described in “Potential Hy’s Law Criteria met” of this Appendix.
* A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a subject meets potential Hy’s Law criteria on study treatment 
and has already met potential Hy’s Law criteria at a previous on-study treatment visit.


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The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
potential Hy’s Law is based on the nature of the alternative cause identified for the previous 
occurrence.  
The Investigator should determine the cause for the previous occurrence of potential Hy’s 
Law criteria being met and answer the following question:
#
Was the alternative cause for the previous occurrence of potential Hy’s 
Law criteria being met found to be the disease under study e.g., chronic 
or progressing malignant disease, severe infection, or liver disease, or did 
the subject meet potential Hy’s Law criteria prior to starting study 
treatment and at their first on study treatment visit as described in 
“Actions Required When Potential Hy’s Law Criteria are Met Before and 
After Starting Study Treatment?”
If No: follow the process described in “Potential Hy’s Law Criteria met” of this Appendix.
If Yes: Determine if there has been a significant change in the subject’s condition* compared 
with when potential Hy’s Law criteria were previously met:
#
If there is no significant change, no action is required; or
#
If there is a significant change, follow the process described in this 
Appendix.
* A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
References
Food and Drug Administration Guidance for Industry (issued July 2009) ‘Drug-induced liver 
injury: Premarketing clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf.


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Appendix E
Acceptable Birth Control Methods
Olaparib is regarded as a compound with medium/high fetal risk.
#
Women of childbearing potential and their partners, who are sexually 
active, must agree to the use of 2 highly effective forms of contraception 
in combination (as listed below). This should be started from the signing 
of informed consent and continue throughout the period of taking study 
treatment and for at least 1 month after last dose of study medication, or 
they must totally/truly abstain from any form of sexual intercourse (see 
below).
Acceptable non-hormonal birth control methods include:
#
Total/True abstinence: When the subject refrains from any form of sexual 
intercourse and this is in line with their usual and/or preferred lifestyle; 
this must continue for the total duration of the trial and for at least 
1 month after the last dose of study drug. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods, or 
declaration of abstinence solely for the duration of a trial) and withdrawal 
are not acceptable methods of contraception; 
#
Vasectomized sexual partner PLUS male condom.  With participant 
assurance that partner received post-vasectomy confirmation of 
azoospermia;
#
Tubal occlusion PLUS male condom; and/or
#
Intrauterine device PLUS male condom.  Provided coils are 
copper-banded.
Acceptable hormonal methods:
#
Normal and low-dose combined oral pills PLUS male condom;
#
Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the 
only highly efficacious progesterone-based pill;
#
Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom;
#
Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom;
#
Norelgestromin/ethinyl estradiol transdermal system PLUS male 
condom;


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#
Intrauterine system device (e.g., levonorgestrel releasing Intrauterine 
system-Mirena®) PLUS male condom; and/or
#
Intravaginal device (e.g., ethinyl estradiol and etonogestrel) PLUS male 
condom.


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Appendix F
Eastern Cooperative Oncology Group (ECOG) Performance 
Status
ECOG PERFORMANCE STATUS*
Grade 
ECOG
0 
Fully active, able to carry on all pre-disease performance without restriction
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair
5
Dead
* As published in Am. J. Clin. Oncol.:
Oken, MM, Creech, RH, Tormey, DC, Horton, J, Davis, TE, McFadden, ET, et al.: Toxicity And
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655.


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Appendix G
Response Evaluation Criteria in Solid Tumors Guidelines
(version 1.1)
Measurability of Tumor at Baseline
Definitions
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
Measurable
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
#
10 mm by computed tomography (CT) scan (CT scan slice thickness no 
greater than 5 mm);
#
10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as 
non-measurable); or 
#
20 mm by chest X-ray.
Measurable malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ∀15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline (i.e., screening for this 
study) and in follow-up (i.e., all measurements past screening for this study), only the short 
axis will be measured and followed.  See also notes below on “Baseline documentation of 
target and non-targeted lesions (TLs)” for information on lymph node measurement.
Non-measurable
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ∀10 to < 15 mm short axis), as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
and abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.


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Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment.
Bone Lesions
#
Bone scan, positron emission tomography scan or plain films are not 
considered adequate imaging techniques to measure bone lesions.  
However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.
#
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, that can be evaluated by cross-sectional imaging 
techniques such as CT or magnetic resonance imaging (MRI) can be 
considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above.
#
Blastic bone lesions are non-measurable.
Cystic Lesions
#
Lesions that meet the criteria for radiographically-defined simple cysts 
should not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts.
#
“Cystic lesions” thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability 
described above.  However, if non-cystic lesions are present in the same 
subject, these are preferred for selection as TLs.
Lesions with Prior Local Treatment
#
Tumor lesions situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are not considered measurable 
unless there has been demonstrated progression in the lesion.  
Specifications by Methods of Measurements
Measurement of Lesions
All measurements should be recorded in metric notation, using calipers, if clinically assessed.  
All baseline evaluations should be performed as close as possible to the treatment start and 
NEVER more than 4 weeks before the beginning of the treatment.


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Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation 
should always be performed rather than clinical examination unless the lesion(s) being 
followed cannot be imaged but is assessable by clinical exam.
Computed tomography, MRI: CT is the best currently available and reproducible method to 
measure lesions selected for response assessment.  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When 
CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  An MRI is also acceptable in certain situations (e.g., for 
body scans).
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a subject 
to be considered in complete response. 
Tumor Response Evaluation
Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. 
Baseline Documentation of “Target” and “Non-target” Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (representative of all involved organs) should be identified as target lesions 
(TLs) and will be recorded and measured at baseline (this means in instances where subjects 
have only 1 or 2 organ sites involved, a maximum of 2 and 4 lesions, respectively, will be 
recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
should be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement, in which circumstance the 
next largest lesion which can be measured reproducibly should be selected.
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  As noted above, pathological nodes which 
are defined as measurable and may be identified as TLs must meet the criterion of a short axis 
of ∀15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum.  The short axis of the node is the diameter normally used by radiologists to judge if a 
node is involved by solid tumor.  Nodal size is normally reported as 2 dimensions in the plane 
in which the image is obtained (for CT scan this is almost always the axial plane; for MRI the 
plane of acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the 
short axis.  For example, an abdominal node which is reported as being 20 mm × 30 mm has a 


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short axis of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with short 
axis ∀10 mm but < 15 mm) should be considered non-TLs. Nodes that have a short axis 
< 10 mm are considered non-pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all TLs 
will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then, as noted above, only the short axis is added into the sum.  The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be identified 
as non-TLs and should also be recorded at baseline.  Measurements are not required and these 
lesions should be followed as “present,” “absent,” or in rare cases “unequivocal progression.”  
In addition, it is possible to record multiple non-TLs involving the same organ as a single item 
on the case record form (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver 
metastases”).  
Response Criteria
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all TLs.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of TLs, taking as 
reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note: The appearance of 1 or more new lesions is also considered 
progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Special Notes on the Assessment of Target Lesions
Lymph nodes: Lymph nodes identified as TLs should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study.  This means that when lymph nodes are 
included as TLs, the “sum” of lesions may not be zero even if CR criteria are met, since a 
normal lymph node is defined as having a short axis of < 10 mm.  For PR, SD, and PD, the 
actual short axis measurement of the nodes is to be included in the sum of TLs.


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Target lesions that become “too small to measure”: While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or 
lymph nodes which are recorded as TLs at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
“too small to measure.”  When this occurs, it is important that a value be recorded in the 
electronic case report form.  If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm.  If the lesion is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned (Note: It is less likely that this rule will be used for lymph nodes since they usually 
have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well).  
This default value is derived from the 5 mm CT slice thickness (but should not be changed 
with varying CT slice thickness).  The measurement of these lesions is potentially 
non-reproducible; therefore, providing this default value will prevent false responses or 
progressions based upon measurement error.  To reiterate, however, if the radiologist is able to 
provide an actual measure, that should be recorded, even if it is below 5 mm.
Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the longest 
diameters of the fragmented portions should be added together to calculate the TL sum.  
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the “coalesced lesion.”
Evaluation of Non-target Lesions
This section provides the definitions of the criteria used to determine the tumor response for 
the group of non-TLs.  While some non-TLs may actually be measurable, they need not be 
measured and instead should be assessed only qualitatively at the time points specified in the 
Clinical Study Protocol.  
CR: Disappearance of all non-TLs and normalization of tumor marker level.  All lymph nodes 
must be non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD: Persistence of 1 or more non-TL(s) and/or maintenance of tumor marker 
level above the normal limits.
PD: Unequivocal progression (see comments below) of existing non-TLs (Note: The 
appearance of 1 or more new lesions is also considered progression).
Special Notes on Assessment of Progression of Non-target Disease
The concept of progression of non-target disease requires additional explanation as follows, 
when the subject also has measurable disease.  In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of 


Clinical Study Protocol Appendix G
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
135 (138)
substantial worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy.  A modest “increase” in the size of 1 or more non-TLs is usually not sufficient to 
qualify for unequivocal progression status.  The designation of overall progression solely on 
the basis of change in non-target disease in the face of SD or PR of target disease will 
therefore be extremely rare.  
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some 
“new” bone lesions may be simply healing or flare of preexisting lesions).  This is particularly 
important when the subject’s baseline lesions show PR or CR.  For example, necrosis of a 
liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of this 
is the subject who has visceral disease at baseline and while on study has a CT or MRI brain
scan ordered which reveals metastases.  The subject’s brain metastases are considered to be 
evidence of PD, even if he/she did not have brain imaging at baseline.  
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan.  
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment.  No confirmatory measurement for CR, PR, or SD is required in the 
study.
The subject’s best overall response assignment will depend on the findings of both target and 
non-target disease and will also take into consideration the appearance of new lesions.
Time Point Response
It is assumed that at each protocol-specified time point, a response assessment will occur.  
Table 14 provides a summary of the overall response status calculation at each time point for 
subjects who have measurable disease at baseline.


Clinical Study Protocol Appendix G
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
136 (138)
Table 14
Time Point Response: Subjects with Target (% Non-target) Disease
Missing Assessments and Inevaluable Designation
When no imaging/measurement is performed at all at a particular time point, the subject is not 
evaluable at that time point.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that time point, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned time point response.  This would be most likely to happen in 
the case of PD.  For example, if a subject had a baseline sum of 50 mm with 3 measured 
lesions and at follow-up only 2 lesions were assessed, but those gave a sum of 80 mm, the 
subject will have achieved PD status, regardless of the contribution of the missing lesion.  
Best Overall Response: All Time Points
The best overall response is determined once all the data for the subject is known.
Best response determination in studies where confirmation of CR or PR IS NOT required:
Best response in these studies is defined as the best response across all time points (e.g., a 
subject who has SD at first assessment, PR at second assessment, and PD on last assessment 
has a best overall response of PR).  When SD is believed to be best response, it must also meet 
the Clinical Study Protocol-specified minimum time from baseline.  If the minimum time is 
not met when SD is otherwise the best time point response, the subject’s best response 
depends on the subsequent assessments.  For example, a subject who has SD at first 
assessment, PD at second, and does not meet minimum duration for SD, will have a best 


Clinical Study Protocol Appendix G
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
137 (138)
response of PD.  The same subject lost to follow-up after the first SD assessment would be 
considered inevaluable.
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at 
a subsequent time point as specified in the Clinical Study Protocol. In this circumstance, the 
best overall response can be interpreted as in Table 15.
Table 15
Best Overall Response When Confirmation of CR and PR is Required
Special Notes on Response Assessment
When nodal disease is included in the sum of TLs and the nodes decrease to “normal” size 
(< 10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal, in order not to overstate progression should it 
be based on increase in size of the nodes.  As noted earlier, this means that subjects with CR 
may not have a total sum of “zero” in the electronic case report form.
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response; it is a reason for stopping study therapy.  The objective response status of 
such subjects is to be determined by evaluation of target and non-target disease.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
Source: Eisenhauera EA, Therasseb P, Bogaertsc J, Schwartzd LH, Sargente D, Ford R,
et al. New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1). European Journal of Cancer. 2009;45:228-247.


Clinical Study Protocol Appendix H
Drug Substance Olaparib
Study Code D0816L00003
Version 3.0
Date 10 October 2017
138 (138)
Appendix H
Gynecological Cancer Intergroup (GCIG) Guidelines
For definitions for response and progression agreed by the GCIG, see Rustin GJS, Vergote I, 
Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. Definitions for response and 
progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA-125 agreed by 
the Gynecological Cancer Intergroup (GCIG). Intl J Gynecol Cancer. 2011;21:419-423.



SAP_001.pdf: 
Statistical Analysis Plan, ANGEL 
Version number 4.0 
Form Doc Number: LDMS_001_00026934 
Parent Doc Number:  
 
Statistical Analysis Plan 
 
Study Code 
D0816L00003 
 
Edition Number 
2.0 
 
Date 
3 October 2019 
 
 
 
 
 
 
Non-Randomized, Open-Label Phase II Study to Assess Olaparib Tablets as 
a Treatment for Subjects with Different HRD Tumor Status and with 
Platinum-Sensitive, Relapsed, High-Grade Serous or High-Grade 
Endometrioid Ovarian, Fallopian Tube, or Primary Peritoneal Cancer That 
Have Received at Least 1 Prior Line of Chemotherapy 
 
 
 
 
 
 


PPD
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PPD


Statistical Analysis Plan  
Study Code: D0816L00003 
Edition: Number 2.0  
Date: 3 October 2019 
2
Non-Randomized, Open-Label Phase II Study to Assess Olaparib Tablets as 
a Treatment for Subjects with Different HRD Tumor Status and with 
Platinum-Sensitive, Relapsed, High-Grade Serous or High-Grade 
Endometrioid Ovarian, Fallopian Tube, or Primary Peritoneal Cancer That 
Have Received at Least 1 Prior Line of Chemotherapy
Study Statistician
          
Medical Monitor                            _______________________________________          __________________
Date
PPD
PPD


Statistical Analysis Plan  
Study Code: D0816L00003 
Edition: Number 2.0  
Date: 3 October 2019 
3
Non-Randomized, Open-Label Phase II Study to Assess Olaparib Tablets as 
a Treatment for Subjects with Different HRD Tumor Status and with 
Platinum-Sensitive, Relapsed, High-Grade Serous or High-Grade 
Endometrioid Ovarian, Fallopian Tube, or Primary Peritoneal Cancer That 
Have Received at Least 1 Prior Line of Chemotherapy
Global Product Statistician
Date
PPD


Statistical Analysis Plan  
Study Code: D0816L00003 
Edition: Number 2.0  
Date: 3 October 2019 
4
TABLE OF CONTENTS
PAGE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan  
Study Code: D0816L00003 
Edition: Number 2.0  
Date: 3 October 2019 
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Statistical Analysis Plan  
Study Code: D0816L00003 
Edition: Number 2.0  
Date: 3 October 2019 
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Statistical Analysis Plan  
Study Code: D0816L00003  
Edition: Number 2.0  
Date: 3 October 2019 
7 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event  
AESI 
Adverse event of special interest 
AML 
Acute myeloid leukemia 
APTT 
Activated partial thromboplastin time 
ATC 
Anatomic therapeutic class 
BMI 
Body mass index 
BoR 
Best objective response 
BRCAm 
BRCA mutation 
BRCAwt 
BRCA wild type 
CA-125 
Cancer antigen 125 
CA-125 RR 
Cancer antigen 125 Response Rate 
CI 
Confidence interval 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical study report 
DCR 
Disease control rate 
DoR 
Duration of response 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
gBRCAm 
Germline BRCA mutation 
gBRCAwt 
Germline BRCA wild type  
GCIG 
Gynecological Cancer Intergroup 
HRD 
Homologous recombination deficiency 
HRRm 
Homologous recombination repair mutation 
INR 
International Normalized Ratio 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDS 
Myelodysplastic syndrome 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Event 
NE 
Not evaluable 


Statistical Analysis Plan  
Study Code: D0816L00003  
Edition: Number 2.0  
Date: 3 October 2019 
8 
Abbreviation or 
special term 
Explanation 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
PT 
Preferred term 
RDI 
Relative dose intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
sBRCAm 
Somatic BRCA mutation 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SOC 
System organ class 
STD 
Standard deviation 
TEAE 
Treatment-emergent adverse event 
TL 
Target lesion 
TTAP 
Time to any progression 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 
 


Statistical Analysis Plan  
Study Code: D0816L00003  
Edition: Number 2.0  
Date: 3 October 2019 
9 
AMENDMENT HISTORY 
Date 
Brief description of change 
8 January 2018 
Initial Version 
3 October 2019 
Version 2.0.  
Updated language pertaining to coding of medical history, cancer therapies, Full 
Analysis Set, and determination of Adverse Events of Special Interest.  
Added language pertaining to safety summaries.  
Added language to define HRRm positive population and summary descriptions 
for Myriad gene panels.  
Visit window definitions added for applicable by visit summaries.  
 
 


Statistical Analysis Plan  
Study Code: D0816L00003  
Edition: Number 2.0  
Date: 3 October 2019 
10 
1. 
STUDY DETAILS 
This section outlines basic details of the study including the objectives, design aspects, and 
number of subjects to be included.  
1.1 
Study Objectives 
The primary, secondary, safety, and exploratory objectives of the study are as follows:  
Table 1: Primary Objective 
Primary Objective: 
Outcome Measure: 
To determine the clinical effectiveness of 
olaparib treatment in each of 4 cohorts 
assessed using ORR according to Response 
Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 criteria (Investigator 
determined).  
x 
The objective response rate (ORR), defined 
as the percentage of subjects with a best 
overall response of confirmed complete 
response (CR) or partial response (PR) (at 
any time up to and including the defined 
analysis cut-off point) divided by the 
number of subjects in the Efficacy Analysis 
Set and the Full Analysis Set (in a 
sensitivity analysis if the populations are 
different).  
 
The four cohorts to be included are:  
x Cohort 1: germline BRCA mutation (gBRCAm) 
x Cohort 2: somatic BRCA mutation (sBRCAm) and germline BRCA wild type 
(gBRCAwt)  
x Cohort 3: myChoice® homologous recombination deficiency (HRD) positive (genomic 
instability positive) and BRCAwt (no BRCA mutation) 
x Cohort 4: myChoice® HRD negative (genomic instability negative) and BRCAwt (no 
BRCA mutation) 


Statistical Analysis Plan  
Study Code: D0816L00003  
Edition: Number 2.0  
Date: 3 October 2019 
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Table 2: Secondary Objectives 
Secondary Objectives:  
Outcome Measures: 
To determine the clinical effectiveness of 
olaparib treatment in each of 4 cohorts 
assessed using:  
x 
Duration of response (DoR)  
x 
Cancer antigen (CA)-125 response 
rate 
x 
Disease control rate (DCR)  
x 
Progression-free survival (PFS) 
x 
Time to any progression (TTAP) 
x 
Overall survival (OS)  
x 
Homologous recombination repair 
mutation (HRRm) gene panel status 
related to clinical outcome 
x 
DoR, for those subjects with a confirmed 
response of CR or PR, response duration 
will be measured from the date of the 
measurement criteria for CR or PR are first 
met until the date of documented objective 
progression or death in the absence of 
progression.  
x 
CA-125 response rate (CA-125 RR), 
defined as the percentage of subjects with a 
CA-125 response according to 
Gynecological Cancer Intergroup (GCIG) 
criteria divided by the number of subjects 
evaluable for CA-125 response.  
x 
DCR, defined as the percentage of subjects 
with a best overall response of confirmed 
CR or PR (at any time up to and including 
the defined analysis cut-off point) or who 
have demonstrated stable disease (SD) for 
at least 8 weeks from first dose, divided by 
the number of subjects in the Efficacy 
Analysis Set.  
x 
PFS, defined as the time from the date of 
the first dose of olaparib to the earlier date 
of assessment of objective progression (per 
RECIST v1.1 criteria) or death by any 
cause in the absence of disease progression. 
x 
TTAP, defined as the time from the date of 
the first dose of olaparib to the earlier date 
of CA-125 progression (GCIG criteria) or 
RECIST v1.1 progression, or death by any 
cause in the absence of progression 
x 
OS, defined as the time from the date of the 
first dose of olaparib to the date of death 
from any cause.  
x 
HRD status as per HRRm gene panel 
assessment (positive or negative) will be 
correlated with clinical outcome (ORR, 
defined above) for subjects enrolled in the 2 
cohorts with BRCAwt (cohorts 3 and 4).  
 
 


Statistical Analysis Plan  
Study Code: D0816L00003 
Edition: Number 2.0  
Date: 3 October 2019 
12
Table 3: Safety Objective 
Safety Objective
Outcome Measures: 
To assess the safety and tolerability of single 
agent olaparib in each of 4 cohorts. 
x
Any adverse events (AEs), including 
serious adverse events (SAEs); physical 
examination; vital signs including blood 
pressure, pulse, and electrocardiogram; and 
collection of clinical chemistry/hematology 
parameters.
1.2
Study Design 
This Phase II, open-label, non-randomized, multi-center cohort study will assess the efficacy 
(ORRs) and safety of olaparib monotherapy in subjects who have received at least 1 prior line 
of platinum-based chemotherapy and have measurable disease, who have progressed at least 6 
months after their last platinum-based chemotherapy, and who either carry a germline 
deleterious or suspected deleterious BRCAm, have a BRCAm in their tumor, have a HRD
tumor assessed via the myChoice® HRD tumor test, or have wild type tumor type (BRCA and 
HRD).  
Approximately 450 subjects will be screened to identify up to approximately 300 subjects to 
be enrolled in 4 cohorts which will include at least 30 subjects in each. An individual cohort 
may continue enrollment up to 90 subjects (unless early stopping criteria are met) at which 
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Statistical Analysis Plan  
Study Code: D0816L00003  
Edition: Number 2.0  
Date: 3 October 2019 
13 
point the cohort will be closed to further enrollment. Once all 4 cohorts have at least 30 
subjects (unless early stopping criteria are met), the study will be closed to further enrollment. 
All subjects enrolled will receive olaparib tablets 300 mg (two 150 mg tablets) orally bid, in 4 
week cycles (i.e., a new bottle will be dispensed every 4 weeks) in the active treatment period 
of the study. 
Subjects will continue treatment with olaparib tablets 300 mg (two 150 mg tablets), bid, from 
enrollment (Visit 2) until objective radiological disease progression as per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by the Investigator, or when 
they meet any discontinuation criteria (see Study Protocol Section 3.9). After documentation 
of disease progression, subjects will be followed for survival. All subjects who enrolled and 
received at least 1 dose of olaparib will be followed for survival. Subjects will be contacted to 
assess survival status every 12 weeks following disease progression until death, withdrawal of 
consent, or study closure. Survival information may be obtained via telephone or email 
contact with the subject, subject’s family, or by contact with the subject’s current physician.  
A data cut-off for analysis of all primary and secondary endpoints will occur approximately 6 
months after the last subject enrolled has commenced study treatment (received at least 1 dose 
of olaparib). The study will remain open for an additional 12 months after this data cut-off for 
survival follow-up for applicable subjects. At the end of this additional 12 months of survival 
follow-up, updated OS and safety analyses will be conducted and the study will be closed. 
See Figure 1 below for the diagram of the study. The Study Plan for the study is provided in 
the Study Protocol Table 6. 
 


Statistical Analysis Plan, ANGEL 
Version number 4.0 
Form Doc Number: LDMS_001_00026934 
Parent Doc Number: 
Figure 1 
Study Diagram
      bid= twice daily; BRCAwt = BRCA wild type; CA = Cancer antigen; DCR = disease control rate;  DoR = duration of response; 
gBRCAm = germline BRCA mutation; gBRCAwt = germline BRCA wild type; HRD = homologous recombination deficiency; HRRm = homologous 
recombination repair mutation; neg = negative; OC = ovarian cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free 
survival; pos = positive; RECIST = Response Evaluation Criteria in Solid Tumors; sBRCAm = somatic BRCA mutation.; tBRCA = tumor BRCA; 
TTAP = time to any progression (earliest of CA-125 progression, RECIST progression, or death). 
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15
1.3
Number of Subjects 
This is a non-comparative Phase II study and each of the 4 cohorts will be analyzed 
separately; no statistical comparison will be made between the cohorts. 
  
  
Olaparib, administered as monotherapy to date, has reported ORRs in genetic BRCAm 
ovarian cancer in excess of 30%. 
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Statistical Analysis Plan  
Study Code: D0816L00003  
Edition: Number 2.0  
Date: 3 October 2019 
16 
2. 
ANALYSIS SETS 
2.1 
Definition of Analysis Sets 
x Full Analysis Set: comprises all subjects entered (including those who did not receive 
treatment but excludes screening failures). 
x Efficacy Analysis Set: comprises all subjects who received at least 1 dose of olaparib 
and had a baseline tumor assessment indicating measurable disease. 
x Safety Analysis Set: comprises all subjects who received at least 1 dose of olaparib. 
Table 6 provides a summary of outcome variables and analysis populations in the study. 
Table 6: Summary of Outcome Variables and Analysis Populations 
Outcome Variable 
Population 
Efficacy Data 
 
- Primary endpoint: ORR 
Efficacy, Fullb 
- Secondary endpoints: DoR, CA-125 RRa, DCR, PFS, TTAP, OS, 
HRRm  
Efficacy, Fullb 
Safety Data 
- Demography 
 
Full, Safetyb, Efficacyb 
- AEs 
Safety 
- Laboratory measurements 
Safety 
- Vital signs 
Safety 
a. 
CA-125 RR will be analyzed on a subset of the Efficacy Analysis Set (i.e., excluding subjects whose 
baseline CA-125 level is not t 2 × ULN and/or not assessed within 2 weeks of starting treatment with 
olaparib). 
b. 
Analysis set only to be used in tables and figures if the populations are different. 
CA = Cancer antigen; CA-125 RR = CA-125 response rate; DCR = disease control rate; DoR = duration of 
response; HRRm = homologous recombination repair mutation; ORR = objective response rate;  
OS = overall survival; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid 
Tumors; TTAP = time to any progression (earliest of CA-125, RECIST, or death); ULN = upper limit or normal. 
Efficacy analyses will be based primarily on the Efficacy Analysis Set while the Full Analysis 
Set will be used only for a sensitivity analysis in the case that the two populations are 
different.  
2.2 
Violations and Deviations 
A per-protocol analysis excluding subjects with specific important protocol deviations is not 
planned for this study. 


Statistical Analysis Plan  
Study Code: D0816L00003  
Edition: Number 2.0  
Date: 3 October 2019 
17 
Study deviations determined from the electronic case report form (CRF) module for 
inclusion/exclusion criteria will be listed. Any other deviations from monitoring notes or 
reports will be reported in an appendix in the clinical study report (CSR). 
3. 
STUDY OUTCOME VARIABLES 
This section describes the variables collected and derived for analysis of the primary, 
secondary, exploratory, and safety endpoints of the study. Data collection of these variables 
will occur at the times outlined in the Study Plan (see Study Protocol Table 6).  
3.1 
Primary Outcome Variable 
The primary outcome variable for this study is the ORR, defined as the percentage of subjects 
with measurable disease with at least 1 visit response of CR or PR (at any time up to and 
including the defined analysis cut-off point) that is confirmed at least 4 weeks later.  
Tumor response will be assessed by the Investigator according to RECIST v1.1 criteria (see 
Section 3.3.1). Data obtained up until progression, or last evaluable assessment in the absence 
of progression, will be included in the assessment of ORR.  However, any CR or PR that 
occurred after a further anti-cancer therapy was received will not be included in the numerator 
for the ORR calculation.  Subjects with a baseline assessment and all post-baseline tumor 
assessments of not evaluable (NE) will be included in the denominator of the response rate 
calculation. 
In the case where a subject has 2 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 progressive disease 
(PD) between the PR visits, the subject will be defined as a responder. Similarly, if a subject 
has visit responses of CR, NE, CR, then as long as the time between the 2 visits of CR is 
greater than 4 weeks, a best response of CR will be assigned. 
3.2 
Secondary Outcome Variables 
The secondary outcome variables considered in this study are DoR, CA-125 RR, DCR, PFS, 
TTAP (by RECIST, CA-125 or death), OS, and the relation of HRRm status to clinical 
outcomes.  
3.2.1 
Duration of Response 
The DoR is defined as the time from the date of first documented response (that is 
subsequently confirmed) until the date of documented objective PD or death in the absence of 
PD. 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. The end of response should coincide with the 
date of PD or death from any cause used for the PFS secondary endpoint.  If a subject does not 
progress following response, then the subject’s DoR will use the PFS censoring time as 
defined in Section 3.2.4.  


Statistical Analysis Plan  
Study Code: D0816L00003  
Edition: Number 2.0  
Date: 3 October 2019 
18 
If the response is not confirmed (per RECIST v1.1 Investigator’s assessment), the response 
will not be included. 
3.2.2 
CA-125 Response Rate 
The CA-125 RR is defined as the percentage of CA-125 evaluable subjects achieving a CA-
125 response (see Section 3.3.2). Additionally, the CA-125 CR rate is defined as the 
percentage of subjects achieving a CA-125 response with the CA-125 level additionally 
falling within the normal range.  
The CA-125 RR will be analyzed on a subset of the analysis set/s (i.e., excluding subjects 
whose baseline CA-125 level is not t 2 × upper limit of normal (ULN) and/or not assessed 
within 2 weeks of starting treatment with olaparib). 
3.2.3 
Disease Control Rate 
The DCR is defined as the percentage of subjects who have a best overall response of 
confirmed CR or PR or SD at t 8 weeks, prior to any PD event. 
3.2.4 
Progression-Free Survival 
The PFS will be defined as the time from the date of first dose of olaparib until the date of 
objective radiological disease progression (Investigator assessed via RECIST v1.1) or death 
(by any cause in the absence of disease progression) regardless of whether the subject 
withdraws from therapy or receives another anti-cancer therapy prior to disease progression.  
Objective radiological progression is defined as at least a 20% increase in the sum of the 
diameters of the target lesions (TLs) (compared to previous minimum sum) and an absolute 
increase of > 5 mm, an overall non-TL assessment of progression, or a new lesion. 
Subjects who have not progressed or died at the time of analysis will be censored at the time 
of the latest date of assessment from their last evaluable efficacy assessment.  However, if the 
subject progresses or dies after 2 or more missed visits, the subject will be censored at the 
time of the latest evaluable assessment prior to the two missed visits.   
Given the scheduled tumor assessment scheme (i.e., every 8 weeks for the first 48 weeks and 
every 12 weeks thereafter), the definition of 2 missed visits will change: 
x If the previous RECIST assessment is less than study Day 274 (i.e. week 39), then 
2 missing visits will equate to 18 weeks since the previous RECIST assessment, 
allowing for early and late visits (i.e. 2 x 8 weeks + 1 week for an early assessment + 1 
week for a late assessment).  
x If the previous RECIST assessment is between Week 39 and Week 49 (the missing 
visits occur during the transition from 8-weekly to 12-weekly assessments), then two 
missing visits will equate to 22 weeks (i.e., take the average of 8 and 12 weeks which 
gives 10 weeks and then apply same rationale, 2 x 10 weeks + 1 week for an early 
assessment + 1 week for a late assessment).  


Statistical Analysis Plan  
Study Code: D0816L00003  
Edition: Number 2.0  
Date: 3 October 2019 
19 
x If the previous RECIST assessment is after Day 344 (i.e. week 49), two missing visits 
will equate to 26 weeks (i.e., 2 x 12 weeks + 1 week for an early assessment + 1 week 
for a late assessment). 
If the subject has no evaluable visits or does not have a baseline assessment, they will be 
censored at Day 1 unless they die within 2 visits of baseline (18 weeks allowing for visit 
window). 
The PFS time will always be derived based on scan/assessment dates and not visit dates.  
Assessments/scans contributing towards a particular visit may be performed on different 
dates.  The following rules will be applied: 
x Date of progression will be determined based on the earliest of the assessment/scan 
dates of the component that triggered the progression.   
x When censoring a subject for PFS, the subject will be censored at the latest of the 
assessment/scan dates contributing to a particular overall visit assessment. 
Overall visit assessments will be determined for each assessment (scheduled or unscheduled) 
and will contribute to the derivation of PFS. 
3.2.5 
Time to Earliest Progression by RECIST or CA-125, or Death 
The TTAP is defined as the time from the date of the first dose of olaparib until the earliest of 
CA-125 progression or RECIST progression, or death from any cause.  
For the purpose of this endpoint, a subject may be declared to have PD on the basis of either 
the objective RECIST v1.1 criteria or the GCIG CA-125 criteria (see Section 3.3.2). 
Subjects without a CA-125 progression or objective radiological progression by RECIST v1.1 
who are still alive at the time of analysis will be censored at their last evaluable RECIST 
assessment or their last available CA-125 measurement, whichever is the most recent at the 
time of analysis. Since CA-125 is assessed more frequently than RECIST, the two missed 
visits rule is based upon the RECIST schedule. Therefore, if a subject dies, has RECIST 
progression or has CA-125 progression after two or more missed RECIST assessments, the 
subject will be censored at the last evaluable RECIST assessment prior to the two missed 
visits. 
3.2.6 
Overall Survival 
OS is defined as the time from the date of first dose of olaparib until death due to any cause. 
Any subject not known to have died at the time of analysis will be censored based on the last 
recorded date on which the subject was known to be alive. 
Assessments for survival should be made every 12 weeks following disease progression.  
Survival information may be obtained via telephone contact with the subject, subject’s family, 
or the subject’s current physician.  Survival data will be collected at the time of database lock 


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for the primary endpoint ORR and again at the end of the 12-month follow-up.  Survival calls 
will be performed in the week following the date of data cut-off for the analysis, and if 
subjects are confirmed to be alive or if the death date is past the data cut-off date, then these 
subjects will be censored at the date of data cut-off.   
Note, in the absence of survival calls being made, it may be necessary to use all relevant CRF 
fields to determine the last recorded date on which the subject is known to be alive for those 
subjects still on treatment. The last date known to be alive for each individual subject is 
defined as the latest among the following dates recorded on the CRF: 
x AE start and stop dates 
x Study treatment start and stop dates  
x Laboratory assessment dates  
x Dates of vital signs, physical exam, Eastern Cooperative Oncology Group (ECOG) 
performance status, and electrocardiogram (ECG) assessments 
x Disease assessment dates 
x Start and stop dates of concomitant medications including transfusions, procedures, 
and alternative anti-cancer therapy 
x Date of last known alive on survival status 
3.2.7 
HRRm Status 
Subjects in the 2 BRCAwt cohorts (3 and 4) will have their HRRm status tested (by HRRm 
gene panel) and will be categorized as HRRm positive or HRRm negative. Data from these 2 
BRCAwt cohorts will be combined and clinical outcomes will be presented according to 
HRRm status (HRRm positive versus HRRm negative) and by cohort within HRRm status. 
Assignment of HRRm status will be based on results of detection of deleterious/suspected 
deleterious mutation in one or more of the following genes in the Myriad HRRm gene panel 
assay: ATM, RAD51B, RAD51C, RAD54L, RAD51D, FANCJ/BRIP1, FANCL, FANCN 
(PALB2), BARD1, CHEK1, CHEK2, CDK12, PPP2R2A. 
Subjects with valid HRRm gene panel assay test result but with no deleterious/suspected 
deleterious mutation detected in above genes will be considered HRRm negative.  
Subjects with invalid or missing HRRm gene panel assay results will be considered missing. 


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3.3 
Calculation or Derivation of Efficacy Variables 
3.3.1 
RECIST Assessments 
At each visit (both scheduled and unscheduled), subjects will be assigned a visit response of 
CR, PR, SD, PD, or NE based on RECIST v1.1 guidelines based on the Investigator’s 
assessment. The overall visit response will be derived by the Investigator using the 
information from the TLs, NTLs and new lesions. There will be no programmatic rederivation 
of visit responses based on eCRF data for the primary assessment of overall response and only 
the Investigator’s assessment will be used. Programmatic derivations of visit responses based 
on TLs, NTLs and new lesions may be performed, if considered required as a sensitivity 
analysis. 
The baseline tumor assessment will be performed no more than 28 days prior to study 
treatment start (Visit 2) and as close as possible to study treatment start. Following the 
baseline tumor assessment, subsequent tumor assessments according to RECIST v1.1 should 
be performed at the end of every 8 weeks (± 1 week) from first dose of study drug (Visit 2) for 
48 weeks and every 12 weeks (± 1 week) (relative to the date of first dose) thereafter until PD. 
If an unscheduled assessment was performed and the subject has not progressed, every 
attempt should be made to perform the subsequent assessments at their scheduled visits. 
Subjects who are determined to have PD according to RECIST v1.1 criteria (including 
confirmatory RECIST scan) by the Investigator may have additional scans performed per the 
site’s standard of care. All treatment decisions will be based on the Investigator’s assessment 
of the scans.   
All subjects should have RECIST assessments until documented evidence of objective 
radiological progression in accordance with RECIST v1.1, irrespective of treatment decisions 
(i.e., RECIST follow-up until progression even if a subject discontinues study treatment prior 
to progression and/or receives a subsequent therapy prior to progression). 
A confirmed response of PR/CR means that a response of PR/CR is recorded at 1 visit 
(Investigator assessed) and confirmed by repeat imaging not less than 4 weeks after the visit 
when the response was first observed and with no evidence of progression between the initial 
and PR/CR confirmation visit. 
3.3.2 
CA-125 Assessments 
The CA-125 response or progression will be based upon the latest GCIG guidelines. Serum 
samples will be collected for CA-125 tumor markers on all subjects at baseline (within 2 
weeks prior to Cycle 1, Day 1), Day 1 of each cycle, and at the End-of-Study Treatment Visit.  
A response according to CA-125 is considered to have occurred if there is at least a 50% 
reduction in CA-125 levels from the baseline sample. The response must be confirmed and 
maintained for at least 28 days. Subjects are considered evaluable for CA-125 response if and 
only if they have a baseline sample that is at least twice the ULN and within 2 weeks prior to 
starting treatment.  


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Those subjects who have both a CA-125 response and whose CA-125 level falls to within the 
normal range will be classified as CA-125 complete responders.  
Progression based on serum CA-125 levels will be defined on the basis of a progressive serial 
elevation of serum CA-125 according to the following criteria: 
x Subjects with elevated CA-125 pre-treatment and normalization of CA-125 must show 
evidence of CA-125 t 2 × ULN on 2 occasions at least 1 week apart 
x Subjects with elevated CA-125 before treatment, which never normalizes, must show 
evidence of CA-125 t 2 times the nadir value on 2 occasions at least 1 week apart 
x Subjects with CA-125 in the reference range before treatment must show evidence of 
CA-125 t 2 × 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 
above.  Subjects are not evaluable for CA-125 assessments if they have received mouse 
antibodies (unless the assay used has been shown not to be influenced by human anti-mouse 
antibody) or if there has been medical and/or surgical interference with their peritoneum or 
pleura during the previous 28 days.  
3.4 
Safety Outcome Variables 
Safety and tolerability of olaparib will be assessed in terms of AEs, SAEs, Adverse Events of 
Special Interest (AESIs), AEs leading to discontinuation, deaths, laboratory assessments (e.g., 
clinical chemistry, hematology, coagulation, and urinalysis), electrocardiograms, physical 
examinations, vital signs, and ECOG performance status. Definitions and descriptions of these 
events can be found in the following subsections. Safety assessments will be performed at the 
times described in the Study Plan (see Study Protocol Table 6). Reporting of safety-related 
events will end 30 days after the last dose of olaparib. If olaparib treatment remains ongoing at 
the end of the study, safety reporting will continue until 30 days after the last dose of olaparib.   
3.4.1 
 Adverse Events 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
can be symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver), or the 
abnormal results of an investigation (e.g. laboratory findings, ECG). In clinical studies, an AE 
can include an undesirable medical condition occurring at any time, even if no treatment has 
been started (e.g. procedure-related condition).  
AEs will be collected from time of signature of first informed consent for participating in the 
study, continuously throughout the active treatment period including the follow-up period. 
The reporting period for AEs will terminate 30 days after the final dose of olaparib is taken.  


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The grading scales found in the revised National Cancer Institute Common Terminology 
Criteria for Adverse Event (NCI-CTCAE) v4.03 will be utilized for all events with an 
assigned CTCAE grading. If a CTCAE grade is not given it will not be imputed. AEs will be 
coded and classified by system organ class (SOC) and preferred term (PT) according to the 
Medical Dictionary for Regulatory Activities (MedDRA, v19.0 or later). 
For each episode of an AE, all changes to the CTCAE grade attained, as well as the highest 
attained CTCAE grade, should be recorded. The assessment by the Investigator regarding the 
relationship between olaparib and the AE will also be recorded.  
3.4.1.1 
Adverse Events of Special Interest 
AESIs are events of scientific and medical interest specific to the further understanding of 
olaparib’s safety profile and that require close monitoring and rapid communication by the 
Investigators to the AstraZeneca Safety Representative. An AESI may be serious or 
non-serious; however, AESIs for olaparib should be considered as SAEs as they are medically 
important and have been identified as important potential risks for olaparib that are under 
close surveillance at AstraZeneca.  
The AESIs for olaparib include the following: 
x Myelodysplastic syndrome (MDS) / Acute Myeloid Leukemia (AML) 
x New primary malignancy (other than MDS/AML) 
x Pneumonitis  
3.4.2 
Clinical Laboratory Evaluations 
Blood and urine samples for determination of clinical chemistry, hematology, coagulation, 
and urinalysis parameters will be collected at the times indicated in the Study Plan (see Study 
Protocol Table 6). Additional safety samples may be collected if clinically indicated the 
discretion of the Investigator. The date, time of collection, and results will be recorded. Both 
scheduled and unscheduled visits will be included for analyses.  
The laboratory parameters to be collected are listed in Table 7 below. 


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Table 7: Laboratory Safety Variables 
 
3.4.2.1 
Coagulation Panel 
Coagulation tests are not required and will be collected only if clinically indicated. 
Coagulation parameters may include activated partial thromboplastin time (APTT) or 
International normalized ratio (INR), unless the subject is receiving warfarin (subjects 
receiving warfarin are permitted to participate in the study).   
Each coagulation test result will be recorded.  
3.4.3 
Vital Signs 
Vital signs measurements will be collected at the times indicated in the Study Plan (see Study 
Protocol Table 6) and includes systolic and diastolic blood pressure, respiratory rate, pulse 
rate, and body temperature. Height will be assessed at screening only. Weight and body 
temperature will be assessed at screening and as clinically indicated, according to the times 
indicated in the Study Plan. 
Systolic and diastolic blood pressure (mmHg) and pulse rate (beats/min) will be measured at 
the times indicated in the Study Plan with an appropriate cuff size after 10 minutes rest.   
Body temperature will be measured in degrees Celsius.   
Any changes in vital signs will be recorded as an AE, if applicable.  If classified as an AE, the 
corresponding information will be collected and recorded. 
3.4.4 
Electrocardiograms 
ECGs will be obtained at the times indicated in the Study Plan (see Study Protocol Table 6). 
Twelve-lead ECGs will be obtained after the subject has rested in a supine position for at least 


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5 minutes in each case. Electrocardiograms will be recorded at 25 mm/sec. All ECGs should 
be assessed by the Investigator as to whether they are clinically significantly abnormal/not 
clinically significantly abnormal. If there is a clinically significant abnormal finding, it will be 
classified as an AE and the data collection and recording procedures for AEs will be followed.  
3.4.5 
Physical Examination 
Physical examinations will be performed at the times indicated in Study Plan (see Study 
Protocol Table 6).  
The physical examination will include 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. 
After the baseline assessment the details of the physical examination will not be directly 
recorded unless in relation to an AE/SAE.  
3.4.6 
Other Safety Variables 
Bone marrow or blood cytogenetic samples may be collected for subjects with prolonged 
hematological toxicities (see Study Protocol Section 6.7.1).  
Other tests (e.g. serum or urine beta-human chorionic gonadotropin pregnancy test) will be 
recorded as indicated in the Study Plan (see Study Protocol Table 6). 
3.4.7 
Exposure and Relative Dose Intensity 
During the treatment period, subjects will continue with olaparib tablets 300 mg (two 150 mg 
tablets), bid, from enrollment (Visit 2) until objective radiological disease progression per 
RECIST v1.1 as assessed by the Investigator, or when they meet any discontinuation criteria.  
Total exposure to study treatment: 
x Total exposure (days) = date of last dose of study drug – date of first dose of study 
drug + 1 
Relative dose intensity (RDI) is the percentage of actual dose delivered relative to the 
intended dose through to treatment discontinuation.  
RDI will be calculated as follows: 
x RDI (%) = 100 * d/D  
where d is the actual cumulative dose delivered up to the actual last day of dosing (mg) and D 
is the intended cumulative dose up to the actual last day of dosing (mg). D is the total dose 
that would be delivered, if there were no modification to dose or schedule.   


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4.
ANALYSIS METHODS 
This is a non-comparative Phase II study and each of the 4 cohorts will be analyzed 
separately; no statistical comparison will be made between the cohorts.  
4.1
General Principles 
The statistical analyses for efficacy and safety data will be performed by Medpace Inc.  
The analyses of the data collected within this study will be descriptive only, with no formal 
statistical testing. Statistical analyses will be performed in SAS® v9.3 or higher.  
All analyses will be presented by cohort. Additionally, efficacy analyses in the 2 BRCAwt 
cohorts (3 and 4) will also be presented according to HRRm status (denoted HRRm positive 
and HRRm negative). 
Efficacy analyses will be performed using the Efficacy Analysis Set and the Full Analysis Set 
(in a sensitivity analysis if the populations are different).  
Safety analyses and exploratory analyses will be performed using the Safety Analysis Set. 
Demography and baseline characteristics data will be summarized based on the Full Analysis 
Set, Safety Analysis Set, and Efficacy Analysis Set. If the populations are identical to each 
other, they will be presented only once for the Full Analysis Set. 
By-subject listings will be presented based on the Full Analysis Set. 
4.1.1
Baseline and Data Consideration 
Unless otherwise specified, baseline is defined as the last non-missing value taken before the 
first dose of olaparib for all study variables. 
Study Day 1 will be considered as the date of the first dose of olaparib. 
Unscheduled visits will be considered for derivation of minimum and maximum post-baseline 
values.   
To allow for any presentations that summarize values by visit, visit windows will be defined 
according to Table 8 below. The upper limit of the interval falls half way between the two 
visits (the lower limit of the first post-baseline visit will be Day 2). The half way point is 
assumed to be the midpoint of the number of days between the visits, excluding both visit 
days.  If an odd number of days exist between two consecutive visits then the upper limit is 
taken as the midpoint value plus 0.5 day. 
CCI


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If there is more than one value per patient within a time window then the closest value will be 
summarized, or the earlier value in the event the values are equidistant from the nominal visit 
day. 
Table 8: Visit Window Definition 
Visit 
Day 
Laboratory Assessments 
Screening 
Up to Day 1 
Day -28 to -1 
Day 1 
Day 1 
Day 1 
Day 8 
Day 8 
Day 2 to Day 11 
Day 15 
Day 15  
Day 12 to Day 18 
Day 22 
Day 22 
Day 19 to Day 25 
Day 29 
Day 29 
Day 26 to Day 43 
Day 57 
Day 57 
Day 44 to Day 71 
Day 85 
Day 85 
Day 72 to Day 99 
Day 113 
Day 113 
Day 100 to Day 127 
Day 141 
Day 141 
Day 128 to Day 155 
Day 169 
Day 169 
Day 156 to day 183 
Day 197 
Day 197 
Day 184 to Day 211 
Day 225 
Day 225 
Day 212 to Day 239 
Day 253 
Day 253 
Day 240 to Day 267 
Day 281 
Day 281 
Day 268 to Day 295 
Day 309 
Day 309 
Day 296 to Day 323 
Day 337 
Day 337 
Day 324 to Day 351 
Day 365 
Day 365 
Day 352 to Day 407 
Day 449 
Day 449 
Day 408 to Day 491 


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Day 533 
Day 533 
Day 492 to Day 575 
Day 617 
Day 617 
Day 576 to Day 659  
Day 701 
Day 701 
Day 660 to Day 743 
Etc.  
 
 
  
For subsequent visits extending beyond Day 701, additional visit windows will be defined in 
the same manner.  
4.1.2 
Covariate Adjustment 
Adjustment for covariates is not applicable for the planned descriptive analysis.  
4.1.3 
Multicenter Studies 
No adjustments will be made for multiple study centers.  
4.1.4 
Multiple Comparisons 
No adjustments for multiple comparisons will be made for the planned descriptive analysis.  
4.1.5 
Missing Data 
Unrecorded data values will be recorded as missing. Only recorded (i.e. complete) data values 
will be used for statistical analyses. In general, invalid or missing values will not be imputed 
unless otherwise stated.  
To be conservative in reporting treatment-emergent adverse events (TEAEs), when an AE is 
proven to occur prior to the first dose of study drug, it is considered as a non-treatment-
emergent event. Otherwise, it is considered to be a TEAE. Therefore, if the start date of an AE 
is missing but the stop date is either overlapping into the treatment period or missing, the AE 
will be considered to be a TEAE, taking the worst-case approach. When partial dates are 
present in the data, both a partial start date and/or a partial stop date will be evaluated to 
determine whether it can be conclusively established that the AE started prior to the start of 
the study drug. If the above cannot be conclusively established based on the partial dates, then 
the AE will be considered as a TEAE.  In addition, an AE that begins more than 30 days after 
the last dose of study drug will not be considered as TEAE unless it is related to the study 
drug. 
Missing AE data, such as missing causality assessment (after data querying), will be assumed 
to be related to study drug.  
For classification of prior and concomitant medications, medications missing both start and 
stop dates, or having a start date prior to the first dose of the study drug and missing the stop 
date, or having a stop date after the start of the study drug and missing the start date, will be 


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considered as concomitant medications. When partial dates exist in the data, the same logic to 
that of the AEs described above will be used. 
Missing safety or exploratory 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. 
4.1.6 
Examination of Subgroups 
Exploratory subgroup analyses may be conducted to further describe the relationship between 
clinical outcomes and subject characteristics, including, but not limited to the number of lines 
of previous chemotherapy. 
4.2 
Analysis Methods 
No formal statistical tests will be performed; the statistical analyses for primary, secondary, 
exploratory, and safety endpoints will be purely descriptive.  
Unless otherwise specified, continuous variables will be summarized by the number of 
observations (n), mean, standard deviation (STD), median, Q1, Q3, minimum, and maximum. 
Categorical variables will be summarized by frequency counts and percentages for each 
category. Confidence intervals (CIs), when presented, will generally be constructed at the 2-
sided 95% level.  
4.2.1 
Study Population Data 
4.2.1.1 
Subject Disposition 
Subject disposition will be summarized for the Full Analysis Set. The following subject 
disposition categories will be summarized by cohort and overall:  
x Subjects who were enrolled 
x Subjects who were treated 
x Subjects who discontinued from study treatment 
x Subjects who discontinued from study  
For subjects who discontinued from study treatment and subjects who discontinued from 
study, a summary will be provided which lists the reasons for discontinuation.   
The number and percentage of subjects in each defined analysis population will also be 
tabulated. 
All subject disposition data will be presented in a by-subject listing.  


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4.2.1.2 
Protocol Deviations  
All protocol deviations determined to be reportable in the CSR per the study Protocol 
Deviation Plan will be presented in a by-subject listing.  
4.2.1.3 
Demographic and Baseline Characteristics 
Demographic characteristics including race, and ethnicity will be summarized with 
contingency tables. Age at informed consent (years), baseline height (cm), weight (kg), and 
body mass index (BMI) (kg/m2) will be summarized with descriptive statistics.  
Baseline disease characteristics will be collected during the Screening period. Time from 
diagnosis (months) will be summarized with summary statistics. Metastatic status, site of 
metastasis, primary tumor location, tumor grade, FIGO stage, baseline ECOG performance 
status, number of lines of prior cancer therapy, best response to last cancer therapy, prior 
radiotherapy, and HRRm status (for the 2 BRCAwt cohorts) will be summarized with 
contingency tables.  
Demographic and baseline disease characteristic information will be presented in a by-subject 
listing.  
4.2.1.4 
Medical History 
A complete medical and surgical history will be collected during the Screening period.  
All reported medical history conditions and prior surgeries will be presented in a by-subject 
listing.  
4.2.1.5 
Prior and Concomitant Medications 
Cancer therapies, prior medications, and concomitant medications will be coded using the 
World Health Organization Drug Dictionary Enhanced (WHO-DDE B2, September 2016 or 
later). Prior medications are medications used and stopped before the first dose of study drug. 
Concomitant medications are medications that were taken on or after the first dose of study 
drug.  
Concomitant medications will be summarized by anatomic therapeutic class (ATC) and PT for 
the Safety Analysis Set. Although a subject may have taken two or more medications, the 
subject is counted only once within an ATC classification. The same subject may contribute to 
two or more preferred terms in the same classification. Prior medications and cancer therapies 
will be summarized in the same manner.  
All prior and concomitant medications and cancer therapies will be presented in by-subject 
listings. 


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4.2.1.6 
Exposure and Compliance 
The total exposure to olaparib and the RDI will be summarized using descriptive statistics by 
cohort for the Safety Analysis Set.  The number and percentage of cycles of olaparib initiated 
will be tabulated.  
Additionally, the number and percentage of subjects with dose reduction, dose interruption, 
and dose modification will be presented along with the reasons for dose adjustment. 
All study drug administration data will be presented in a by-subject listing. 
4.2.2 
Primary Analysis 
The primary analysis will involve analysis of the ORR by cohort among subjects in the 
Efficacy Analysis Set and the Full Analysis Set (in a sensitivity analysis if the populations are 
different). The point estimate of the ORR along with the exact Clopper-Pearson 95% CI will 
be presented.   
In addition to the analysis described above, best objective response (BoR) will be summarized 
descriptively by cohort to show the number and percentage of subjects in each response 
category. BoR will be calculated based on the overall visit responses from each RECIST 
assessment by the investigator. BoR is defined as the best response (in the order of CR, PR, 
SD, PD) a subject has had following the first dose of study treatment, but prior to and 
including RECIST progression or the last evaluable assessment in the absence of RECIST 
progression. CR or PR must be confirmed. 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 minus 1 week, i.e. at least 49 days (to allow for an early 
assessment within the assessment window), after first dose of study treatment. For CR/PR, the 
initial overall visit assessment that showed a response will use the latest of the dates 
contributing towards a particular overall visit assessment. Subjects with no evaluable RECIST 
assessments after first dose of study treatment will be assigned to the NE category (unless 
there is evidence of progression, in which case the response will be assigned as PD). 
All tumor assessment data will be presented in by-subject listings. 
4.2.3 
Secondary Analyses 
Secondary analyses will be based on the Efficacy Analysis Set and the Full Analysis Set (in a 
sensitivity analysis if the populations are different) or a subset of these populations (e.g. those 
subjects that have exhibited a radiologically confirmed response). Each analysis will be 
presented separately for each cohort and no comparisons between cohorts will be made.    
4.2.3.1 
Duration of Response 
The Kaplan-Meier estimate of the median DoR and the Brookmeyer-Crowley 95% CI will be 
presented. Only subjects with a confirmed response will be included in this summary. 
Summaries will also be presented for the number and percentage of subjects experiencing 


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progression or death, and those who are censored. DoR at clinically relevant time points (e.g. 
6, 12, 18 and 24 months) will also be summarized.   
Kaplan-Meier plots of DoR will be presented. Swimmer plots that show the profile of each 
subject who responds will also be produced. 
4.2.3.2 
CA-125 Response Rate  
The CA-125 RR and CA-125 CR rate will be analyzed based on subjects who are evaluable 
for CA-125 response (subjects with baseline CA-125 ≥ 2 x ULN and/or within 2 weeks prior 
to starting olaparib).  
The CA-125 RR and CA-125 CR rate will be presented together with the exact Clopper-
Pearson 95% CI for CA-125 response evaluable subjects.   
In addition to the analysis described above, CA-125 values at each scheduled time point and 
change and percent change of CA-125 from baseline will be summarized descriptively. 
CA-125 assessments will be presented in a by-subject listing. 
4.2.3.3 
Disease Control Rate 
The DCR will be presented for the point estimate together with the exact Clopper-Pearson 
95% CI.   
4.2.3.4 
Progression Free Survival 
The number and percentage of subjects experiencing a PFS event and the type of event 
(progression or death), and subjects censored will be provided. The Kaplan-Meier estimate of 
the median PFS and the Brookmeyer-Crowley 95% CI will be presented. In addition, the 
proportion of subjects who are progression-free at clinically relevant time points (e.g. 6, 12, 
18 and 24 months) will also be summarized.   
Kaplan-Meier plots of PFS will be presented. 
The analyses of PFS will be based on Investigator assessment according to RECIST v1.1 
guidelines, and using all scans regardless of whether they were scheduled or not.   
4.2.3.5 
Time to Earliest Progression by RECIST or CA-125, or Death 
 
Summaries of the number and percentage of subjects experiencing a TTAP event and the type 
of event (progression per RECIST, CA-125 progression, CA-125 progression with RECIST 
progression, or death), and subjects censored will be provided. The Kaplan-Meier estimate of 
the median TTAP and the Brookmeyer-Crowley 95% CI will be presented. In addition, the 
proportion of subjects who are progression-free will be presented at clinically relevant time 
points (e.g. 6, 12, 18 and 24 months). 
Kaplan-Meier plots of TTAP will be presented. 


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4.2.3.6 
Overall Survival 
Summaries of the number and percentage of subjects experiencing death and subjects 
censored will be provided.  The Kaplan-Meier estimate of the median OS and Brookmeyer-
Crowley 95% CI will be presented. In addition, the OS rate at clinically relevant time points 
(e.g. 6, 12, 18 and 24 months) will also be summarized.  
Kaplan-Meier plots of OS will be presented. 
4.2.4 
Safety Analyses 
Safety and tolerability will be assessed in terms of AEs (including SAEs, AESIs, and AEs 
leading to discontinuation), deaths, clinical laboratory evaluations, vital signs, ECGs, physical 
examinations findings, and ECOG performance status. Safety analyses will be based on the 
Safety Analysis Set. 
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics by cohort and overall.  
4.2.4.1 
Adverse Events 
A TEAE is defined as an AE that emerges during the treatment period (from the first dose date 
of olaparib until 30 days after the last dosing date), having been absent at pre-treatment; or 
worsens in severity after treatment relative to the pre-treatment state. AESIs beginning after 
initiation of treatment will be included (i.e. treatment-emergent AESIs) in summaries.      
An overview of AEs will be provided which summarizes subject incidence of the following:  
x Any TEAEs 
x Drug-related TEAEs  
x NCI-CTCAE grade 3/4/5 TEAEs 
x Drug-related NCI-CTCAE grade 3/4/5 TEAEs 
x TEAE with an outcome of death 
x Drug-related TEAE with an outcome of death 
x Treatment-emergent SAEs 
x Drug-related treatment-emergent SAEs 
x Discontinuation due to TEAEs 
x Discontinuation due to drug-related TEAEs 


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34 
x AESIs 
x Drug-related AESIs 
The number and percentage of subjects with TEAEs will be tabulated by the maximum 
reported NCI-CTCAE grade, SOC and PT. Drug-related TEAEs, CTCAE grade 3/4/5 TEAEs, 
treatment-emergent SAEs, drug-related treatment-emergent SAEs, TEAEs leading to 
discontinuation of olaparib, and drug-related TEAEs leading to discontinuation of olaparib 
will be summarized in the same manner. For these summaries, subjects with multiple AEs will 
be counted only once by the maximum reported NCI-CTCAE grade within a given SOC and 
PT. 
AESIs will be summarized by SOC and PT. Summaries will include the number and 
percentage of subjects who have: 
x Any AESIs presented by outcome 
x Drug-related AESIs 
x Discontinuation due to AESIs 
Additional summaries including the time to onset, prevalence over time, and duration of AEs 
in certain PTs or groups of PTs may be generated.  
A by-subject listing of all AEs including verbatim term, PT, SOC, NCI-CTCAE grade, and 
relationship to study drug will be provided. Listings will also be provided of deaths, SAEs, 
AESIs, and AEs leading to discontinuation of olaparib. 
4.2.4.2 
Clinical Laboratory Evaluations 
Descriptive statistics will be provided for selected clinical laboratory parameters (clinical 
chemistry, hematology, and urinalysis) including absolute measurements and changes from 
baseline by scheduled time of evaluation. Changes from baseline by scheduled time of 
evaluation will include end of treatment, 30 day follow-up, maximum post-treatment value, 
and minimum post-treatment value. Both scheduled and unscheduled post-treatment visits will 
be considered for the summaries of the maximum and minimum post-treatment values.  
Abnormal laboratory results will be graded according to NCI-CTCAE version 4.03 as 
applicable. Shift tables, presenting the 2-way frequency tabulation for baseline and the worst 
post-treatment value (both decreased and increased separately) according to the NCI-CTCAE 
grade, will be provided for selected clinical laboratory tests. Both scheduled and unscheduled 
post-treatment visits will be considered in tabulation of the worst post-treatment value.  
The number and percentage of subjects with the following potentially clinically significant 
abnormal liver function tests will be summarized:  
x ALT ≥ 3 x ULN, ≥ 5 x ULN, ≥ 10 x ULN, and ≥ 20 x ULN   


Statistical Analysis Plan  
Study Code: D0816L00003 
Edition: Number 2.0  
Date: 3 October 2019 
35
x
AST ≥3 x ULN, ≥5 x ULN, ≥10 x ULN, and ≥20 x ULN   
x
ALT or AST ≥3 x ULN, ≥5 x ULN, ≥10 x ULN, and ≥20 x ULN   
x
Total bilirubin ≥2 x ULN  
x
ALP ≥1.5 x ULN and ≥ 3 x ULN 
x
Potential  Hy’s Law cases: ALT or AST ≥3xULN together with total bilirubin ≥2x 
ULN  
All clinical laboratory data will be presented in by-subject listings.   
4.2.4.3
Vital Signs 
Descriptive statistics will be provided for vital signs measurements (systolic and diastolic 
blood pressure, pulse rate, body temperature, and weight) by scheduled time of evaluation. 
All vital signs data will be presented in a by-subject listing.  
4.2.4.4
ECGs 
All ECG data will be presented in a by-subject listing.  
4.2.4.5
ECOG Performance Status 
A shift table presenting the 2-way frequency tabulation from the Screening period to the End-
of-Study Treatment Visit (or last visit on-study) and worst post-baseline classification will be 
provided for ECOG performance status.  
4.2.4.6
Physical Examination Findings 
Physical examination findings will be presented in a by-subject listing. Both scheduled and 
unscheduled visits will be included.  
4.2.4.7
Other Safety Analyses 
All other safety variables (e.g. pregnancy test) will be presented in by-subject listings.  
CCI


Statistical Analysis Plan  
Study Code: D0816L00003 
Edition: Number 2.0  
Date: 3 October 2019 
36
  
5.
INTERIM ANALYSES 
In each cohort, an informal interim analysis will take place after 15 subjects have had at least 
1 radiologic tumor response assessment in the first 6 months of the study. If no responses (CR 
or PR) are observed in the first 15 subjects in a cohort, in consultation with the Steering 
Committee, the cohort will be closed to further enrollment.  However, if there is at least 1 
confirmed objective response in the first 15 subjects, that would justify continuing enrollment 
up to a maximum of 90 subjects.  Enrollment will continue until these interim analyses have 
been completed and a decision is made by the Study Steering Committee.  
If a given cohort is terminated due to futility, certain analyses which require an objective 
radiological response (i.e. ORR and DoR) will not be calculated for that cohort only. Other 
analyses (e.g. safety analyses) will still be presented for a cohort terminating early for futility.  
The stopping boundary for the interim futility analysis was determined from Binomial 
probabilities.  With a true ORR of 5%, a cohort would terminate early for futility (no objective 
responses observed in the first 15 subjects) with a probability of 0.463, while with true ORRs 
of 10%, 20%, 40%, and 50%, a cohort would terminate early for futility with probabilities of 
0.206, 0.0352, 0.0005, and < 0.0001, respectively.
In addition, a descriptive analysis of ORR, secondary outcomes, and safety can be generated 
for abstract or presentation of the ongoing study at any time.  
6.
CHANGES OF ANALYSIS  
In Study Protocol D0816L00003 (Version 3.0; 10 October 2017) the Efficacy Analysis Set 
comprises all subjects who received at least 1 dose of olaparib and had a baseline tumor 
assessment. For the purposes of analysis for efficacy endpoints this definition has been 
extended with the requirement of ‘measureable disease’. The Full Analysis Set has also been 
added (see Section 2.1).   
7.
REFERENCES 
Brookmeyer, R. and Crowley, J. (1982). “A Confidence Interval for the Median Survival 
Time”. Biometrics. 38: 29–41.
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Statistical Analysis Plan  
Study Code: D0816L00003  
Edition: Number 2.0  
Date: 3 October 2019 
37 
Clopper, C. and Pearson, E. S. (1934). "The use of confidence or fiducial limits illustrated in 
the case of the binomial". Biometrika. 26: 404–413.