A Randomised, Double-blind, Placebo-controlled, Multicentre Phase III Study of Olaparib Plus Abiraterone Relative to Placebo Plus Abiraterone as First-line Therapy in Men With Metastatic Castration-resistant Prostate Cancer (PROpel Study)
Phase: PHASE3
Conditions: Metastatic Castration-resistant Prostate Cancer
Sponsor: AstraZeneca



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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY........................................................................................................... 2
TABLE OF CONTENTS...................................................................................................... 9
1.
PROTOCOL SUMMARY................................................................................ 20
1.1
Schedule of Activities (SoA)............................................................................. 20
1.2
Synopsis ........................................................................................................... 36
1.3
Schema............................................................................................................. 46
2.
INTRODUCTION............................................................................................ 47
2.1
Study rationale.................................................................................................. 47
2.2
Background ...................................................................................................... 49
2.2.1
Advanced prostate cancer and its treatment....................................................... 49
2.2.2
Homologous recombination repair genes in prostate cancer .............................. 51
2.2.3
Rationale for evaluating olaparib-abiraterone combination treatment in patients 
with mCRPC independent of HRR gene mutation status................................... 52
2.3
Benefit/risk assessment..................................................................................... 53
3.
OBJECTIVES AND ENDPOINTS................................................................... 54
3.1
Primary objectives ............................................................................................ 54
3.2
Secondary objectives ........................................................................................ 55
3.3
Safety objective ................................................................................................ 57
3.4
Exploratory objectives ...................................................................................... 57
4.
STUDY DESIGN ............................................................................................. 59
4.1
Overall design................................................................................................... 59
4.2
Scientific rationale for study design .................................................................. 62
4.3
Justification for dose......................................................................................... 63
4.4
End of study definition...................................................................................... 63
5.
STUDY POPULATION ................................................................................... 64
5.1
Inclusion criteria............................................................................................... 64
5.2
Exclusion criteria.............................................................................................. 67
5.3
Lifestyle restrictions ......................................................................................... 69
5.3.1
Meals and dietary restrictions............................................................................ 69
5.3.2
Contraception ................................................................................................... 70
5.3.3
Blood donation ................................................................................................. 70
5.4
Screen failures .................................................................................................. 70
6.
STUDY TREATMENTS.................................................................................. 70
6.1
Treatments administered................................................................................... 71
6.1.1
Investigational products.................................................................................... 71
6.1.2
Additional study drugs – abiraterone and prednisone/prednisolone.................... 72

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6.2
Preparation/handling/storage/accountability...................................................... 72
6.3
Measures to minimise bias: randomisation and blinding.................................... 72
6.3.1
Methods for ensuring blinding .......................................................................... 73
6.3.2
Methods for unblinding the study...................................................................... 74
6.4
Treatment compliance....................................................................................... 74
6.5
Concomitant therapy......................................................................................... 75
6.6
Dose modification............................................................................................. 77
6.6.1
Dose reductions for olaparib ............................................................................. 77
6.6.2
Dose reductions for abiraterone......................................................................... 78
6.7
Treatment after final DCO before the end of the study...................................... 78
7.
DISCONTINUATION OF TREATMENT AND PATIENT WITHDRAWAL . 79
7.1
Discontinuation of study treatment.................................................................... 79
7.1.1
Procedures for discontinuation of study treatment............................................. 80
7.2
Lost to follow-up .............................................................................................. 81
7.3
Withdrawal from the study................................................................................ 81
7.4
Discontinuation of the study ............................................................................. 83
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................. 83
8.1
Efficacy assessments......................................................................................... 84
8.1.1
Imaging tumour assessment .............................................................................. 84
8.1.1.1
RECIST 1.1 assessments (soft tissue lesions).................................................... 84
8.1.1.2
PCWG-3 assessment (bone lesions assessment)................................................ 85
8.1.2
Tumour evaluation............................................................................................ 85
8.1.2.1
Soft tissue lesions evaluation ............................................................................ 85
8.1.2.2
Bone lesions evaluation .................................................................................... 86
8.1.2.3
Central reading of scans.................................................................................... 87
8.1.3
Patient-reported outcomes................................................................................. 88
8.1.3.1
BPI-SF.............................................................................................................. 88
8.1.3.2
Analgesic log.................................................................................................... 89
8.1.3.3
Analgesic use scoring ....................................................................................... 89
8.1.3.4
FACT-P............................................................................................................ 90
8.1.3.5
EQ-5D-5L ........................................................................................................ 90
8.1.3.6
Administration of PRO questionnaires .............................................................. 91
8.1.4
Other assessments............................................................................................. 93
8.1.4.1
Time to first subsequent anticancer therapy or death (TFST)............................. 93
8.1.4.2
Overall survival (OS)........................................................................................ 93
8.1.4.3
Time to second progression or death (PFS2) ..................................................... 93
8.1.4.4
Symptomatic skeletal-related event (SSRE) ...................................................... 94
8.2
Safety assessments............................................................................................ 94
8.2.1
Clinical safety laboratory assessments............................................................... 94
8.2.1.1
Coagulation ...................................................................................................... 95
8.2.1.2
Bone marrow or blood cytogenetic samples ...................................................... 95
8.2.2
Physical examinations....................................................................................... 96
8.2.3
Vital signs......................................................................................................... 96

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8.2.4
Electrocardiogram............................................................................................. 96
8.2.5
Other safety assessments................................................................................... 97
8.2.5.1
ECHO or MUGA.............................................................................................. 97
8.3
Collection of adverse events ............................................................................. 97
8.3.1
Method of detecting AEs and SAEs .................................................................. 97
8.3.2
Time period and frequency for collecting AE and SAE information.................. 97
8.3.2.1
Adverse events after the 30 day follow-up period.............................................. 98
8.3.3
Follow up of AEs and SAEs ............................................................................. 99
8.3.4
Adverse event data collection............................................................................ 99
8.3.5
Causality collection......................................................................................... 100
8.3.6
Adverse events based on signs and symptoms................................................. 100
8.3.7
Adverse events based on examinations and tests ............................................. 100
8.3.8
Hy’s Law........................................................................................................ 101
8.3.9
Disease progression ........................................................................................ 101
8.3.10
New cancers ................................................................................................... 101
8.3.11
Lack of efficacy.............................................................................................. 101
8.3.12
Deaths ............................................................................................................ 101
8.3.13
Olaparib adverse events of special interest ...................................................... 102
8.4
Safety reporting and medical management...................................................... 103
8.4.1
Reporting of serious adverse events ................................................................ 103
8.4.1.1
Paternal exposure............................................................................................ 103
8.4.2
Medication Error, Drug Abuse, and Drug Misuse............................................ 104
8.4.2.1
Timelines........................................................................................................ 104
8.4.2.2
Medication Error............................................................................................. 104
8.4.2.3
Drug Abuse .................................................................................................... 104
8.4.2.4
Drug Misuse ................................................................................................... 104
8.4.3
Reporting Overdose........................................................................................ 104
8.4.4
Management of adverse events related to olaparib .......................................... 105
8.4.4.1
Management of haematological toxicity.......................................................... 106
8.4.4.2
Management of non-haematological toxicity................................................... 108
8.4.4.3
Renal impairment ........................................................................................... 109
8.4.5
Management of toxicities related to abiraterone .............................................. 110
8.5
Pharmacokinetics............................................................................................ 110
8.5.1
Determination of drug concentration............................................................... 110
8.5.2
Storage and destruction of pharmacokinetic samples....................................... 111
8.6
Pharmacodynamics......................................................................................... 111
8.7
Genetics.......................................................................................................... 111
8.7.1
Collection of mandatory genetic samples ........................................................ 111
8.7.1.1
Determination of HRR gene mutation............................................................. 112
8.7.2
Optional exploratory genetic sample ............................................................... 113
8.7.3
Storage and destruction of genetic samples ..................................................... 113
8.8
Biomarkers ..................................................................................................... 114
8.8.1
Storage, re-use and destruction of biomarker samples ..................................... 115
8.9
Medical resource utilisation and health economics.......................................... 115
8.9.1
Healthcare resource use .................................................................................. 115

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9.
STATISTICAL CONSIDERATIONS............................................................. 116
9.1
Statistical hypotheses...................................................................................... 116
9.2
Sample size determination .............................................................................. 116
9.3
Populations for analyses.................................................................................. 117
9.4
Statistical analyses.......................................................................................... 118
9.4.1
Efficacy analyses ............................................................................................ 119
9.4.1.1
Primary endpoint: radiological progression-free survival (rPFS) ..................... 119
9.4.1.2
Key secondary endpoint: overall survival........................................................ 123
9.4.2
Safety analyses ............................................................................................... 123
9.4.2.1
Adverse events................................................................................................ 124
9.4.2.2
Other significant adverse events (OAE) .......................................................... 124
9.4.2.3
Concomitant medications................................................................................ 124
9.4.2.4
Exposure......................................................................................................... 125
9.4.3
Other analyses ................................................................................................ 125
9.4.3.1
Secondary endpoint: Time to first subsequent anticancer therapy or death 
(TFST)............................................................................................................ 125
9.4.3.2
Secondary endpoint: Time to pain progression (TTPP) ................................... 125
9.4.3.3
Secondary endpoint: Time to opiate use.......................................................... 126
9.4.3.4
Secondary endpoint: Time to first symptomatic skeletal-related event (SSRE) 127
9.4.3.5
Secondary endpoint: Time to second progression or death (PFS2)................... 127
9.4.3.6
Secondary endpoint: Pain severity and worst pain........................................... 128
9.4.3.7
Secondary endpoint: Pain interference ............................................................ 128
9.4.3.8
Secondary endpoint: FACT-P ......................................................................... 128
9.4.3.9
Secondary endpoint: Pharmacokinetics ........................................................... 130
9.4.4
Multiplicity strategy for primary and key secondary endpoints........................ 130
9.4.5
China cohort ................................................................................................... 131
9.5
Interim analyses.............................................................................................. 131
9.5.1
Independent Data monitoring committee (IDMC)........................................... 132
10.
REFERENCES............................................................................................... 133
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................... 139
APPENDIX A
GUIDELINES FOR EVALUATION OF OBJECTIVE TUMOUR 
RESPONSE USING RECIST 1.1 CRITERIA (RESPONSE EVALUATION 
CRITERIA IN SOLID TUMOURS) IN SOFT TISSUE AND PCWG-3 
(PROSTATE CANCER WORKING GROUP CRITERIA 3) IN BONE 
LESIONS ....................................................................................................... 140
APPENDIX B
ECOG PERFORMANCE STATUS....................................................... 151
APPENDIX C
REGULATORY, ETHICAL AND STUDY OVERSIGHT 
CONSIDERATIONS...................................................................................... 152
APPENDIX D
ADVERSE EVENT DEFINITIONS AND ADDITIONAL SAFETY 
INFORMATION ............................................................................................ 157
APPENDIX E
HANDLING OF HUMAN BIOLOGICAL SAMPLES.......................... 163

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APPENDIX F
GENETICS............................................................................................ 166
APPENDIX G
ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW.............................. 170
APPENDIX H
MEDICAL DEVICE INCIDENTS: DEFINITION AND 
PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, AND 
REPORTING.................................................................................................. 175
APPENDIX I
ACCEPTABLE BIRTH CONTROL METHODS.................................... 176
APPENDIX J
PATIENT-REPORTED OUTCOMES.................................................... 178
APPENDIX K
CHANGES RELATED TO THE COVID-19 PANDEMIC ................... 186
APPENDIX L
OLAPARIB/PLACEBO PRODUCT-SPECIFIC GUIDANCE IN 
RELATION TO THE COVID-19 PANDEMIC .............................................. 187
LIST OF TABLES
Table 1
Schedule of assessments – Global study................................................... 21
Table 2
Schedule of assessments – China cohort .................................................. 29
Table 3
Primary objective..................................................................................... 55
Table 4
Secondary objectives ............................................................................... 55
Table 5
Safety objective ....................................................................................... 57
Table 6
Exploratory objectives ............................................................................. 58
Table 7
Identity of investigational product (olaparib)............................................ 71
Table 8
Prohibited medications............................................................................. 75
Table 9
Restricted concomitant medications and therapies.................................... 76
Table 10
Dose reductions for olaparib to manage adverse events............................ 78
Table 11
Dose reduction for olaparib if patient develops moderate renal 
impairment .............................................................................................. 78
Table 12
Dose reductions for olaparib if patient has to start taking a strong or 
moderate CYP3A inhibitor ...................................................................... 78
Table 13
Requirements for documentation of progression ...................................... 87
Table 14
Laboratory safety variables...................................................................... 94
Table 15
Management of anaemia ........................................................................ 106
Table 16
Management of neutropenia, leukopenia and thrombocytopenia ............ 106
Table 17
Dose reductions for olaparib .................................................................. 109
Table 18
Analysis populations – Global study...................................................... 117
Table 19
Analysis populations – China cohort...................................................... 118
Table 20
Definition of visit response for FACT-P, FACT-G, FAPSI-6, TOI, PCS 
and FWB ............................................................................................... 129
Table 21
Overall score response criteria ............................................................... 129

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Table 22
Details of planned analyses at each data cut-off ..................................... 132
Table 23
Summary of methods of assessment....................................................... 141
Table 24
Evaluation of target lesions.................................................................... 144
Table 25
Evaluation of non-target lesions............................................................. 145
Table 26
Overall visit soft tissue response ............................................................ 146
Table 27
Requirements for documentation of progression .................................... 148
Table 28
Bone progression status ......................................................................... 149
LIST OF FIGURES
Figure 1
Study design............................................................................................ 46
Figure 2
Study flow chart ...................................................................................... 61
Figure 3
Multiplicity strategy maintaining overall type 1 error rate...................... 131

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or special 
term
Explanation
ADT
Androgen deprivation therapy
AE
Adverse event
AESI
Adverse event of special interest
ALK-P
Alkaline phosphatase
ALT
Alanine aminotransferase
AML
Acute myeloid leukaemia
ANC
Absolute neutrophil count
AQA
Analgesic quantification algorithm
AR
Androgen receptor
AST
Aspartate aminotransferase
AUC0-8
Area under the plasma concentration-time curve from time zero to 8 hours post-
dose
AUCss
Area under the plasma concentration-time curve across the dosing interval at 
steady state
BICR
Blinded independent central review
BP
Blood pressure
BPI-SF
Brief Pain Inventory-Short Form
BRCA
Breast cancer susceptibility gene
BRCA1, BRCA2
Breast Cancer 1 gene or Breast Cancer 2 gene
BUN
Blood urea nitrogen
cfDNA
Cell-free DNA
CI
Confidence interval
CLss /F
Apparent total body clearance of drug from plasma after extravascular 
administration at steady state
Cmax ss
Maximum observed plasma (peak ) drug concentration at steady state
Cmin ss
Minimum observed plasma (peak ) drug concentration at steady state
CR
Complete response
CrCl
Creatinine clearance
CRO
Contract research organisation
CSP
Clinical study protocol
CT
Computed tomography
CTC
Circulating tumour cells

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Abbreviation or special 
term
Explanation
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
Circulating tumour DNA
CYP
Cytochrome P450
DAE
Discontinuation of investigational product due to adverse event
DCO
Data cut-off
DDI
Drug-drug interaction
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid 
DoR
Duration of response
DSB
Double strand break
dUCBT
Double umbilical cord blood transplantation
E-code
Enrolment code
EC
Ethics committee, synonymous to institutional review board (IRB) and 
independent ethics committee (IEC)
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
ePRO
Electronic patient-reported outcome
EQ-5D-5L
EuroQol 5-dimension, 5-level health state utility index
ESMO
European Society for Medical Oncology
EuroQoL
European Quality of Life
EWB
Emotional well-being
FACT-G
Functional Assessment of Cancer Therapy - General
FACT-P
Functional Assessment of Cancer Therapy - Prostate Cancer
FA DCO
Final formal analysis data cut-off
FAPSI-6
Functional Assessment of Prostate Cancer Symptoms Index-6
FDA
Food and Drug Administration
FFPE
Formalin fixed, paraffin embedded
FWB
Functional well-being
GCP
Good Clinical Practice
G-CSF
Granulocyte colony stimulating factor
Hb
Haemoglobin
Hct
Haematocrit

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Abbreviation or special 
term
Explanation
HOSPAD
Hospital Admission. An AstraZeneca module used to record resource use during 
unscheduled hospital visits and admissions
HR
Hazard ratio
HRD
Homologous recombination deficiency
HRQoL
Health-related quality of life
HRR
Homologous recombination repair
HRRm
Homologous recombination repair gene mutation
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent data monitoring committee
INR
International normalised ratio
IP
Investigational medicinal product
IRB
Institutional review board 
International 
Co-ordinating investigator
If a study is conducted in several countries, the International Co-ordinating 
investigator is the investigator co-ordinating the investigators and/or activities 
internationally
ITT
Intention-to-treat
KM
Kaplan–Meier
LHRH
Luteinising hormone-releasing hormone
mCRPC
Metastatic castration-resistant prostate cancer
MDS
Myelodysplastic syndrome
mHSPC
Metastatic hormone-sensitive prostate cancer
MMRM
Mixed model for repeated measures
MRI
Magnetic resonance imaging
MUGA
Multigated acquisition scan Cardiology A
NCA
Non-compartmental analysis
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NE
Non-evaluable
NED
No evidence of disease
NHA
New hormonal agent (eg, abiraterone, enzalutamide)
NL
New lesion
NRS
Numeric rating scale
NT-proBNP
N-terminal pro B-type natriuretic peptide
OAE
Other significant adverse event

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Abbreviation or special 
term
Explanation
OME
Oral morphine equivalents
OS
Overall survival
PARP
Polyadenosine 5’diphosphoribose [poly (ADP ribose)] polymerase
PCS
Prostate cancer subscale
PCWG-2
Prostate Cancer Working Group-2
PCWG-3
Prostate Cancer Working Group-3
PD
Progression of disease
PFS
Progression-free survival
PFS2
Time to second progression or death
PK
Pharmacokinetics
PR
Partial response
PRO
Patient-reported outcome
PSA
Prostate Specific Antigen
PT
Prothrombin
PTT
Partial thromboplastin time
PWB
Physical well-being
RECIST
Response Evaluation Criteria in Solid tumours. This study will use RECIST 
version 1.1. 
rPFS
Radiological progression-free survival
RTSM (IRT)
Randomisation and Trial Supply Management System (Interactive Response 
Technology)
SAE
Serious adverse event 
SAP
Statistical analysis plan
SD
Stable disease
SmPC
Summary of Product Characteristics
SoA
Schedule of activities
SOP
Standard operating procedure
SRC
Safety review committee 
SSB
Single strand breaks
SSRE
Symptomatic skeletal-related event (symptomatic fracture, need for radiation to 
bone metastasis, need for surgery for bone metastasis, or spinal cord compression)
SWB
Social well-being
TEAE
Treatment-emergent adverse event
TFST
Time to start of first subsequent anticancer therapy or death
TL
Target lesion

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Abbreviation or special 
term
Explanation
tlast
Time of last observed (quantifiable) concentration
tmax,ss  
Time to reach peak or maximum observed plasma concentration at steady state
TOI
Trial outcome index
TTPP
Time to pain progression
ULN
Upper limit of normal

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1.
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)
The schedule of study assessments is provided in Table 1 for the global study and Table 2 for 
the China cohort.

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Table 1
Schedule of assessments – Global study
Visit number
1
2
3
4
5
6
7
8+
Study 
treatment 
discontinuation
(+7 days of last 
study drug 
dose)
30-day 
follow-up 
after last 
dose of 
study 
medication 
(+7 days)
Survival
follow-up 
(±14 days
every 
12 weeks)
Details in 
CSP 
Section or 
Appendix
Week (visit 
window ± 3 days 
except visit 2)
Week -4 
to day 0 
(28 
days)
1
(day 
1)
3
(day 15)
5
(day 29)
7
(day 43)
9
(day 57)
11
(day 
71)
13+
Every 4 
weeks 
(starting 
week 13) 
Informed consent
X
Section 
5.1 & 
Appendix
C
Inclusion/exclusion 
criteria
X
Section 
5.1 and 
5.2
Routine clinical procedures
Demography
X
Family history of 
cancer
X
Medical and 
surgical history
X
Section 
5.1
Prior cancer 
therapies (includes 
radiotherapy, 
surgery, ADT and 
chemotherapy)
X
Section 
5.1
History of blood 
transfusionsa
X
Section 
5.1

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Visit number
1
2
3
4
5
6
7
8+
Study 
treatment 
discontinuation
(+7 days of last 
study drug 
dose)
30-day 
follow-up 
after last 
dose of 
study 
medication 
(+7 days)
Survival
follow-up 
(±14 days
every 
12 weeks)
Details in 
CSP 
Section or 
Appendix
Week (visit 
window ± 3 days 
except visit 2)
Week -4 
to day 0 
(28 
days)
1
(day 
1)
3
(day 15)
5
(day 29)
7
(day 43)
9
(day 57)
11
(day 
71)
13+
Every 4 
weeks 
(starting 
week 13) 
ECOG performance 
statusb
X
Xc
X
X
X
Appendix
B
Physical 
examinationd
X
Xc
Xe
Xe
Xe+
Section 
8.2.2
Vital signs (includes 
BP, pulse rate and 
body temperature)d
X
Xc
X
X
X
X
X
Section 
8.2.3
Weight
X
X
X
X
X
X
X
Section 
8.2.3
Electrocardiogramd,f
X
Every 12 weeks
X
X
Section 
8.2.4
Cardiac function 
(by ECHO or 
MUGA)g
X
As clinically indicatedg
Section 
8.2.5
Concomitant 
medication 
(including blood 
transfusions)
X
At every visit and may be conducted by phone if not tied to a scheduled visit
X
X
Section 
6.5
SSRE assessmenth
At every visit from randomisation up to and including treatment discontinuation visit (patients 
who discontinue study treatment and continue in the study should be followed for SSREs at 
every visit until disease progression)i
Section 
8.1.4.4

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Visit number
1
2
3
4
5
6
7
8+
Study 
treatment 
discontinuation
(+7 days of last 
study drug 
dose)
30-day 
follow-up 
after last 
dose of 
study 
medication 
(+7 days)
Survival
follow-up 
(±14 days
every 
12 weeks)
Details in 
CSP 
Section or 
Appendix
Week (visit 
window ± 3 days 
except visit 2)
Week -4 
to day 0 
(28 
days)
1
(day 
1)
3
(day 15)
5
(day 29)
7
(day 43)
9
(day 57)
11
(day 
71)
13+
Every 4 
weeks 
(starting 
week 13) 
Routine safety measurements
Adverse eventsj
X
At every visit and may be conducted by phone if not tied to a scheduled visit
X
X
Section 
8.3
Haematology
X
Xc
X
X
X
X
X
X
X
X
Section 
8.2.1
Coagulation factors
Xd
Section 
8.2.1.1
Clinical chemistry, 
electrolytes
X
Xc
X
X
X
X
X
Section 
8.2.1
Fasting glucose
X
Xc
Every 12 weeks
X
X
Section 
8.2.1
Serum lipids
X
Xc
Every 12 weeks
X
X
Section 
8.2.1
Chemistry: liver 
function 
X
Xc
X
X
X
X
X
X
X
X
Section 
8.2.1
Serum testosterone
X
Section 
8.2.1
Urinalysisd
X
Xc
As clinically indicated
Section 
8.2.1

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Visit number
1
2
3
4
5
6
7
8+
Study 
treatment 
discontinuation
(+7 days of last 
study drug 
dose)
30-day 
follow-up 
after last 
dose of 
study 
medication 
(+7 days)
Survival
follow-up 
(±14 days
every 
12 weeks)
Details in 
CSP 
Section or 
Appendix
Week (visit 
window ± 3 days 
except visit 2)
Week -4 
to day 0 
(28 
days)
1
(day 
1)
3
(day 15)
5
(day 29)
7
(day 43)
9
(day 57)
11
(day 
71)
13+
Every 4 
weeks 
(starting 
week 13) 
Secondary 
malignancies 
(including 
MDS/AML)k
X
X
Section 
8.3.10
Biomarker analyses
Local HRR gene 
mutation statusl
X
Section 
8.7
Bone marrow 
aspirate or blood 
cytogenetic sample 
for prolonged 
haematological 
toxicities 
As clinically indicated
Section 
8.2.1.2
Archival or newly 
collected FFPE 
tumour samplem
X
Section 
8.7.1
Blood sample for 
central germline 
HRR gene testing
Xn
Section 
8.7.1
Blood sample for 
central ctDNA 
analysis of HRR 
genes 
Xo
Section 
8.7.1

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Form Doc Number: AZDoc0070547 Parent Doc Number: AZDoc0017426
Visit number
1
2
3
4
5
6
7
8+
Study 
treatment 
discontinuation
(+7 days of last 
study drug 
dose)
30-day 
follow-up 
after last 
dose of 
study 
medication 
(+7 days)
Survival
follow-up 
(±14 days
every 
12 weeks)
Details in 
CSP 
Section or 
Appendix
Week (visit 
window ± 3 days 
except visit 2)
Week -4 
to day 0 
(28 
days)
1
(day 
1)
3
(day 15)
5
(day 29)
7
(day 43)
9
(day 57)
11
(day 
71)
13+
Every 4 
weeks 
(starting 
week 13) 
Pharmacokinetic measurements
Blood sample for 
pharmacokinetic 
analysis (subset of 
patients)
At visit 4, samples will be collected at the following times:
Pre-dose (- 30 min ± 15 min), and post-dose at 30 min ± 15 min, 2 ± 0.5 h, 3 ± 0.5 h, 5 ± 0.5 h and 8 ± 1ht
Section 
8.5
Efficacy measurements
BPI-SF, analgesic 
log (captured on 
ePRO device)
Xu
To be completed by patient daily for 7 consecutive days every 4 weeks (not required to be at site), with Day 1 as the baseline 
visit datev
Section 
8.1.3.1
EQ-5D-5L
Every 8 weeks from Day 1, at Week 52, then every 8 weeks; and at treatment discontinuation visitv
Section 
8.1.3.5
FACT-P
Every 4 weeks from Day 1 until Week 52, at Week 52, then every 8 weeks; and at treatment discontinuation visitv
Section 
8.1.3.4
Healthcare resource 
use (HOSPAD)
From Visit 2 onwards, to be completed by site staff at each hospitalisation and unscheduled visit
Section 
8.9.1
Opiate use
X
X
X
X
X
X
X
Section 
8.1.3.3
Prostate-specific 
antigen
X
X
X
X
X
X
Section 
8.2.1

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Visit number
1
2
3
4
5
6
7
8+
Study 
treatment 
discontinuation
(+7 days of last 
study drug 
dose)
30-day 
follow-up 
after last 
dose of 
study 
medication 
(+7 days)
Survival
follow-up 
(±14 days
every 
12 weeks)
Details in 
CSP 
Section or 
Appendix
Week (visit 
window ± 3 days 
except visit 2)
Week -4 
to day 0 
(28 
days)
1
(day 
1)
3
(day 15)
5
(day 29)
7
(day 43)
9
(day 57)
11
(day 
71)
13+
Every 4 
weeks 
(starting 
week 13) 
Tumour imaging 
CT/MRI and bone 
scanw
X
Every 8 weeks (±7 days) for the first 24 weeks, then every 12 weeks (±7 days) relative to the date of 
randomisationx
Section 
8.1.1
Subsequent cancer 
therapy following 
discontinuation of 
study treatmenty
X
X
Section 
6.5
Survivalz and 
second progression 
(PFS2) follow-upaa
X
Section
8.1.4.2
and 
Section 
8.1.4.3
Study treatment administration
Randomisation
X
Section 
6.3
Study drug 
dispensed/returned 
(daily dosing)
X
X
X
X
X
X
Sections 
6.1, 6.2
a
Include history of blood transfusion within the previous 120 days from the start of study treatment and the reasons, eg, bleeding or myelosuppression.
b
To be assessed a maximum of 14 days prior to randomisation.
c
If assessed within 7 days before randomisation, does not need to be repeated on Day 1 of study treatment unless the investigator or designee believes that it is likely to have changed significantly.
d
To be additionally performed if clinically indicated at any other time for all patients.  Patients with hypertension at baseline need to be monitored closely, and BP must be recorded at all visits.
e
The investigator or qualified designee will perform a symptom directed physical examination, as clinically indicated, prior to dosing on the day of each visit.

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f
The electrocardiogram should be performed within 7 days prior to randomisation.  The 12-weekly assessments should be counted from the date of randomisation.
g
Patient must have a left ventricular ejection fraction measurement of at least 50% by ECHO (preferable) or MUGA, a maximum of 14 days prior to randomisation.  The method used for individual 
patients pre-randomisation should preferably be used for any clinically indicated future assessments.
h
An SSRE is defined by any of the following or a combination thereof: use of radiation therapy to bone in order to prevent or relieve skeletal complications, occurrence of new symptomatic 
pathological bone fractures (vertebral or nonvertebral, resulting from minimal or no trauma), occurrence of radiologically confirmed spinal cord compression, or a tumour-related orthopaedic 
surgical intervention.
i
For patients who discontinue study treatment for reasons other than objective disease progression, and who continue in the study, any SSREs determined at an imaging visit should be recorded 
under an unscheduled visit in eCRF.
j
All ongoing AEs/SAEs and any new AEs/SAEs identified during the 30-calendar-day follow-up period after the last dose of study treatment must be followed to resolution.
k
Because some cases of MDS/AML or new primary malignancies may develop on or after discontinuing treatment with study treatment, investigators will be asked during the regular follow-up if 
the patient has developed MDS/AML or a new primary malignancy and will be prompted to report any case as an SAE (or an AE if at least 1 of the criteria for an SAE is not met, such as for non-
melanoma skin cancers) even after discontinuation of therapy and regardless of the investigator’s assessment of causality or knowledge of the treatment assignment.
l
Collect any locally available HRR gene mutation data from analysis of, eg, blood, tumour tissue, and/or plasma.
m
For randomised patients only.  Archival or newly collected FFPE biopsies must be submitted.  Confirmation is required in clinical notes regarding availability of a sample that meets the specimen 
guidelines outlined in the Laboratory Manual during the screening period; however, the sample will only be submitted to AstraZeneca once the patient has been randomised.  This sample may also 
be used to develop current or future diagnostic tests.
n
If the sample is not collected for any reason during visit 2, it should be collected at any visit thereafter.  This sample may also be used to develop current or future diagnostic tests.
o
If the sample is not collected for any reason during visit 2, it should be collected at visit 3.  This sample may also be used to develop current or future diagnostic tests.
p
If the sample is not collected at visit 8, it should be collected at visit 9.
q
Progression sample may be collected at either a scheduled visit or an unscheduled visit per site preference.
r
Central testing.
s
Blood sample for pharmacogenomics reflects Genomic Initiative Sample.
t
Approximately 50 patients assigned to each treatment arm at pre-agreed sites will have pharmacokinetic assessment samples taken. Sampling times: Pre-dose (- 30 min ± 15 min); post-dose, 30 
min ± 15 min, 2 ± 0.5 h, 3 ± 0.5 h, 5 ± 0.5 h, 8 ± 1 h.
u
To be completed by the patient daily for any 7 consecutive days during screening (not required to be at site).
v
Patient-reported outcomes assessments will continue until 12 weeks after confirmed progressive disease.
w
Tumour assessment will be performed using a CT or MRI scan for soft tissue of chest, abdomen, and pelvis and a bone scan for whole body.  Any other areas of disease involvement should be 
additionally imaged based on the signs and symptoms of individual patients.  Baseline assessments should be performed no more than 28 days before the start of study treatment, and ideally 
should be performed as close as possible to the start of study treatment.  Follow-up assessments will be performed every 8 weeks (±7 days) for the first 24 weeks and then every 12 weeks (±7 
days) relative to the date of randomisation until objective disease progression as defined by RECIST 1.1 (soft tissue) and PCWG-3 criteria (bone), regardless of discontinuation of study treatment 
or initiation of subsequent anticancer therapy.  A confirmatory bone scan is required to confirm progression due to new bone lesions, preferably at the next scheduled visit for a bone scan and at 
least 6 weeks later.  The date of progression is the date of the first bone scan documenting the 2 new lesions.  If there is no confirmatory scan this is not PD.  Any other sites at which new disease 
is suspected should also be appropriately imaged.  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent 
assessments at the patient’s scheduled visits.
x
Patients who discontinue study treatment before disease progression should continue follow-up tumour assessments until objective disease progression as defined by RECIST 1.1 (soft tissue) and 
PCWG-3 criteria (bone), regardless of initiation of subsequent anticancer therapy.  After the initial assessment of progression, whether the patient receives a subsequent therapy or not, the patient 
should have 1 follow-up scan collected preferably at the next (and no later than the next) scheduled imaging visit, and no less than 6 weeks after the prior assessment of PD.
y
All anticancer treatments (including, but not limited to, chemotherapy and targeted agents), and the investigator’s opinion of response to these treatments plus the date of progression, following 
discontinuation of study treatment, must be recorded.
z
The status of ongoing, withdrawn (from the study) and “lost to follow-up” patients at the time of an overall survival analysis should be obtained by the site personnel by checking the patients' 
notes, hospital records, contacting the patients' general practitioner, and checking publicly available death registries, if allowable per local regulations.  In the event that the patient has actively
withdrawn consent to the processing of their personal data, the vital status of the patient can be obtained by site personnel from publicly available resources where it is possible to do so under 
applicable local laws (see Section 7.3).  In addition to their regular 12 weekly contact, patients will be contacted in the 7 days following a specified date (data cut-off date) for the survival analysis.

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Visit number
1
2
3
4
5
6
7
8+
Study 
treatment 
discontinuation
(+7 days of last 
study drug
dose)
30-day 
follow-up 
after last 
dose of 
study 
medication 
(+7 days)
Survival
follow-up 
(±14 days 
every 
12 weeks)
Details in 
CSP 
Section or 
Appendix
Week (visit 
window ± 3 days 
except visit 2)
Week -4 
to day 0 
(28 
days)
1
(day 
1)
3
(day 15)
5
(day 29)
7
(day 43)
9
(day 57)
11
(day 
71)
13+
Every 4 
weeks 
(starting 
week 13) 
Medical and 
surgical history
X
Section 
5.1
Prior cancer 
therapies (includes 
radiotherapy, 
surgery, ADT and 
chemotherapy)
X
Section 
5.1
History of blood 
transfusionsa
X
Section 
5.1
ECOG performance 
statusb
X
Xc
X
X
X
Appendix
B
Physical 
examinationd
X
Xc
Xe
Xe
Xe+
Section 
8.2.2
Vital signs (includes 
BP, pulse rate and 
body temperature)d
X
Xc
X
X
X
X
X
Section 
8.2.3
Weight
X
X
X
X
X
X
X
Section 
8.2.3
Electrocardiogramd,f
X
Every 12 weeks
X
X
Section 
8.2.4

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Visit number
1
2
3
4
5
6
7
8+
Study 
treatment 
discontinuation
(+7 days of last 
study drug
dose)
30-day 
follow-up 
after last 
dose of 
study 
medication 
(+7 days)
Survival
follow-up 
(±14 days 
every 
12 weeks)
Details in 
CSP 
Section or 
Appendix
Week (visit 
window ± 3 days 
except visit 2)
Week -4 
to day 0 
(28 
days)
1
(day 
1)
3
(day 15)
5
(day 29)
7
(day 43)
9
(day 57)
11
(day 
71)
13+
Every 4 
weeks 
(starting 
week 13) 
Cardiac function 
(by ECHO or 
MUGA)g
X
As clinically indicatedg
Section 
8.2.5
Concomitant 
medication 
(including blood 
transfusions)
X
At every visit and may be conducted by phone if not tied to a scheduled visit
X
X
Section 
6.5
SSRE assessmenth
At every visit from randomisation up to and including treatment discontinuation visit (patients 
who discontinue study treatment and continue in the study should be followed for SSREs at 
every visit until disease progression)i
Section 
8.1.4.4
Routine safety measurements
Adverse eventsj
X
At every visit and may be conducted by phone if not tied to a scheduled visit
X
X
Section 
8.3
Haematology
X
Xc
X
X
X
X
X
X
X
X
Section 
8.2.1
Coagulation factors
Xd
Section 
8.2.1.1
Clinical chemistry, 
electrolytes
X
Xc
X
X
X
X
X
Section 
8.2.1
Fasting glucose
X
Xc
Every 12 weeks
X
X
Section 
8.2.1

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Visit number
1
2
3
4
5
6
7
8+
Study 
treatment 
discontinuation
(+7 days of last 
study drug
dose)
30-day 
follow-up 
after last 
dose of 
study 
medication 
(+7 days)
Survival
follow-up 
(±14 days 
every 
12 weeks)
Details in 
CSP 
Section or 
Appendix
Week (visit 
window ± 3 days 
except visit 2)
Week -4 
to day 0 
(28 
days)
1
(day 
1)
3
(day 15)
5
(day 29)
7
(day 43)
9
(day 57)
11
(day 
71)
13+
Every 4 
weeks 
(starting 
week 13) 
Serum lipids
X
Xc
Every 12 weeks
X
X
Section 
8.2.1
Chemistry: liver 
function 
X
Xc
X
X
X
X
X
X
X
X
Section 
8.2.1
Serum testosterone
X
Section 
8.2.1
Urinalysisd
X
Xc
As clinically indicated
Section 
8.2.1
Secondary 
malignancies 
(including 
MDS/AML)k
X
X
Section 
8.3.10
Biomarker analyses
Bone marrow 
aspirate or blood 
cytogenetic sample 
for prolonged 
haematological 
toxicities 
As clinically indicated
Section 
8.2.1.2
Archival or newly 
collected FFPE 
tumour samplel
X
Section 
8.7.1

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Visit number
1
2
3
4
5
6
7
8+
Study 
treatment 
discontinuation
(+7 days of last 
study drug
dose)
30-day 
follow-up 
after last 
dose of 
study 
medication 
(+7 days)
Survival
follow-up 
(±14 days 
every 
12 weeks)
Details in 
CSP 
Section or 
Appendix
Week (visit 
window ± 3 days 
except visit 2)
Week -4 
to day 0 
(28 
days)
1
(day 
1)
3
(day 15)
5
(day 29)
7
(day 43)
9
(day 57)
11
(day 
71)
13+
Every 4 
weeks 
(starting 
week 13) 
Subsequent cancer 
therapy following 
discontinuation of 
study treatmentr
X
X
Section 
6.5
Survivals and 
second progression 
(PFS2) follow-upt
X
Section
8.1.4.2
and 
Section 
8.1.4.3
Study treatment administration
Randomisation
X
Section 
6.3
Study drug 
dispensed/returned 
(daily dosing)
X
X
X
X
X
X
Sections 
6.1, 6.2
a
Include history of blood transfusion within the previous 120 days from the start of study treatment and the reasons, eg, bleeding or myelosuppression.
b
To be assessed a maximum of 14 days prior to randomisation.
c
If assessed within 7 days before randomisation, does not need to be repeated on Day 1 of study treatment unless the investigator or designee believes that it is likely to have changed significantly.
d
To be additionally performed if clinically indicated at any other time for all patients.  Patients with hypertension at baseline need to be monitored closely, and BP must be recorded at all visits.
e
The investigator or qualified designee will perform a symptom directed physical examination, as clinically indicated, prior to dosing on the day of each visit.
f
The electrocardiogram should be performed within 7 days prior to randomisation.  The 12-weekly assessments should be counted from the date of randomisation.
g
Patient must have a left ventricular ejection fraction measurement of at least 50% by ECHO (preferable) or MUGA, a maximum of 14 days prior to randomisation.  The method used for individual 
patients pre-randomisation should preferably be used for any clinically indicated future assessments.

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h
An SSRE is defined by any of the following or a combination thereof: use of radiation therapy to bone in order to prevent or relieve skeletal complications, occurrence of new symptomatic 
pathological bone fractures (vertebral or nonvertebral, resulting from minimal or no trauma), occurrence of radiologically confirmed spinal cord compression, or a tumour-related orthopaedic 
surgical intervention.
i
For patients who discontinue study treatment for reasons other than objective disease progression, and who continue in the study, any SSREs determined at an imaging visit should be recorded 
under an unscheduled visit in eCRF.
j
All ongoing AEs/SAEs and any new AEs/SAEs identified during the 30-calendar-day follow-up period after the last dose of study treatment must be followed to resolution.
k
Because some cases of MDS/AML or new primary malignancies may develop on or after discontinuing treatment with study treatment, investigators will be asked during the regular follow-up if 
the patient has developed MDS/AML or a new primary malignancy and will be prompted to report any case as an SAE (or an AE if at least 1 of the criteria for an SAE is not met, such as for non-
melanoma skin cancers) even after discontinuation of therapy and regardless of the investigator’s assessment of causality or knowledge of the treatment assignment.
l
For randomised patients only.  Archival or newly collected FFPE biopsies must be submitted.  Confirmation is required in clinical notes regarding availability of a sample that meets the specimen 
guidelines outlined in the Laboratory Manual during the screening period; however, the sample will only be submitted to AstraZeneca once the patient has been randomised.  This sample may also 
be used to develop current or future diagnostic tests.
m
Central testing.
n
To be completed by the patient daily for any 7 consecutive days during screening (not required to be at site).
o
Patient-reported outcomes assessments will continue until 12 weeks after confirmed progressive disease.
p
Tumour assessment will be performed using a CT or MRI scan for soft tissue of chest, abdomen, and pelvis and a bone scan for whole body.  Any other areas of disease involvement should be 
additionally imaged based on the signs and symptoms of individual patients.  Baseline assessments should be performed no more than 28 days before the start of study treatment, and ideally 
should be performed as close as possible to the start of study treatment.  Follow-up assessments will be performed every 8 weeks (±7 days) for the first 24 weeks and then every 12 weeks 
(±7 days) relative to the date of randomisation until objective disease progression as defined by RECIST 1.1 (soft tissue) and PCWG-3 criteria (bone), regardless of discontinuation of study 
treatment or initiation of subsequent anticancer therapy.  A confirmatory bone scan is required to confirm progression due to new bone lesions, preferably at the next scheduled visit for a bone 
scan and at least 6 weeks later.  The date of progression is the date of the first bone scan documenting the 2 new lesions.  If there is no confirmatory scan this is not PD.  Any other sites at which 
new disease is suspected should also be appropriately imaged.  If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the 
subsequent assessments at the patient’s scheduled visits.
q
Patients who discontinue study treatment before disease progression should continue follow-up tumour assessments until objective disease progression as defined by RECIST 1.1 (soft tissue) and 
PCWG-3 criteria (bone), regardless of initiation of subsequent anticancer therapy.  After the initial assessment of progression, whether the patient receives a subsequent therapy or not, the patient 
should have 1 follow-up scan collected preferably at the next (and no later than the next) scheduled imaging visit, and no less than 6 weeks after the prior assessment of PD.
r
All anticancer treatments (including, but not limited to, chemotherapy and targeted agents), and the investigator’s opinion of response to these treatments plus the date of progression, following 
discontinuation of study treatment, must be recorded.
s
The status of ongoing, withdrawn (from the study) and “lost to follow-up” patients at the time of an overall survival analysis should be obtained by the site personnel by checking the patients' 
notes, hospital records, contacting the patients' general practitioner, and checking publicly available death registries, if allowable per local regulations.  In the event that the patient has actively 
withdrawn consent to the processing of their personal data, the vital status of the patient can be obtained by site personnel from publicly available resources where it is possible to do so under 
applicable local laws (see Section 7.3).  In addition to their regular 12 weekly contact, patients will be contacted in the 7 days following a specified date (data cut-off date) for the survival analysis.
t
Second progression is based on investigator assessment according to local standard clinical practice and includes radiological, PSA progression and clinical progression. Second progression status 
will be reviewed every 12 weeks following the progression event used for the primary variable PFS (ie, first progression) and the start of the next-line anticancer therapy.
ADT, Androgen-deprivation therapy; AE, Adverse event; AML, Acute myeloid leukaemia; BP, Blood pressure; BPI-SF, Brief Pain Inventory-Short Form; CT, Computed tomography; ECHO, 
Echocardiography; ECOG, Eastern Cooperative Oncology Group; ePRO, Electronic patient-reported outcomes; EQ-5D-5L, EuroQol 5-dimension, 5-level, health state utility index; FACT-P, Functional 
Assessment of Cancer Therapy - Prostate Cancer; FFPE, Formalin-fixed, paraffin-embedded; HOSPAD, An AstraZeneca module used to record resource use during unscheduled hospital visits and 
admissions; HRR, Homologous recombination repair; INR, International normalized ratio; MDS, Myelodysplastic syndrome; MRI, Magnetic resonance imaging; MUGA, Multigated acquisition scan; 
NT-proBNP, N-terminal pro B-type natriuretic peptide; PCWG-3, Prostate Cancer Working Group 3; PD, Progressive disease; PFS2, Time to second progression or death; PT, Prothrombin time; PTT, 
Partial thromboplastin time; RECIST, Response Evaluation Criteria in Solid Tumours; SAE, Serious AE; SSRE, Symptomatic skeletal-related event.  

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To determine the efficacy of the combination of 
olaparib and abiraterone vs placebo and 
abiraterone by assessment of rPFS in patients with 
mCRPC who have received no prior cytotoxic 
chemotherapy or NHA at mCRPC stage.
rPFS, defined as the time from randomisation to 
1) radiological progression, assessed by investigator per 
RECIST 1.1 (soft tissue) and PCWG-3 criteria (bone), 
or 2) death from any cause, whichever occurs first.
mCRPC, Metastatic castration-resistant prostate cancer; NHA, New hormonal agent; PCWG-3, Prostate Cancer 
Working Group 3; rPFS, Radiological progression-free survival; RECIST 1.1, Response Evaluation Criteria in 
Solid tumours version 1.1.
Secondary Objectives:
Outcome Measures:
To determine the efficacy of the combination of 
olaparib and abiraterone vs placebo and 
abiraterone by assessment of OS in patients with 
mCRPC who have received no prior cytotoxic 
chemotherapy or NHA at mCRPC stage.
OS, defined as the time from randomisation to death from 
any cause.
To determine the efficacy of the combination of 
olaparib and abiraterone vs placebo and 
abiraterone as assessed by time to start of first 
subsequent anticancer therapy or death (TFST) in 
patients with mCRPC who have received no prior 
cytotoxic chemotherapy or NHA at mCRPC 
stage.
TFST, ie, the time from randomisation to 1) the start of 
the first subsequent anticancer therapy or 2) death from 
any cause.a
To determine the efficacy of the combination of 
olaparib and abiraterone vs placebo and 
abiraterone as assessed by time to pain 
progression (TTPP) in patients with mCRPC who 
have received no prior cytotoxic chemotherapy or 
NHA at mCRPC stage.
TTPP is defined as the time from randomisation to pain 
progression based on the Brief Pain Inventory-Short 
Form (BPI-SF) Item 3 “worst pain in 24 hours” and 
opiate analgesic use (analgesic quantification algorithm 
[AQA] score).b
To further evaluate the efficacy of the 
combination of olaparib and abiraterone vs 
placebo and abiraterone by assessment of time to 
opiate use, time to an SSRE, and PFS2 in patients 
with mCRPC who have received no prior 
cytotoxic chemotherapy or NHA at mCRPC 
stage.
•
Time to opiate use: The time from randomisation to 
the first opiate use for cancer-related pain.
•
Time to an SSRE: the time from randomisation to 
the first SSRE.  An SSRE is defined as use of 
radiation therapy to bone in order to prevent or 
relieve skeletal complications, occurrence of new 
symptomatic pathological bone fractures (vertebral 
or non-vertebral, resulting from minimal or no 
trauma), occurrence of radiologically confirmed 
spinal cord compression or a tumour-related 
orthopaedic surgical intervention.
•
PFS2: The time from randomisation to second 
progression on next-line anticancer therapy by 
investigator assessment of radiological progression, 
clinical symptomatic progression, PSA progression 
or death.

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To assess the effect of the combination of 
olaparib and abiraterone vs placebo and 
abiraterone on disease related symptoms and 
HRQoL using BPI-SF and Functional 
Assessment of Cancer Therapy (FACT) - Prostate 
Cancer (FACT-P) questionnaires in patients with 
mCRPC who have received no prior cytotoxic 
chemotherapy or NHA at mCRPC stage.
•
BPI-SF: progression in pain severity domain, 
change in pain interference domain.
•
FACT-P total score, FACT-G total score, trial 
outcome index, functional well-being, physical 
well-being, prostate cancer subscale, and FACT 
Advanced Prostate Symptom Index-6 (FAPSI-6).
To evaluate tumour and blood samples collected 
from patients with mCRPC who have received no 
prior cytotoxic chemotherapy or NHA at mCRPC 
stage for mutations in BRCA1, BRCA2, ATM and 
11 other HRR genes.
Note: blood samples will not be collected for 
HRR gene mutation status testing in the China 
cohort
HRR gene mutation status.
To determine steady-state exposure to abiraterone 
and its active metabolite Δ4-abiraterone in the 
presence and absence of olaparib.
To determine steady-state exposure to olaparib 
when co-administered with abiraterone.
Note: this objective is not applicable for the 
China cohort
•
Plasma concentration data at steady state for 
olaparib, abiraterone, and Δ4-abiraterone in the 
subset of patients evaluable for PK.
•
If sufficient data are available, PK parameters at 
steady state (eg, maximum concentration [Cmax,ss], 
time to Cmax,ss [tmax,ss], minimum concentration 
[Cmin,ss], and partial area under the concentration-
time curve [AUC0-8]) will be calculated in the PK 
patient subset. In addition, the area under the curve 
at steady state (AUCss) and the apparent clearance 
(CLss/F) for olaparib and the metabolite to parent 
ratios for Cmax,ss, Cmin,ss and AUC0-8 for 
Δ4-abiraterone will be determined. The time of last 
concentration (tlast) will also be determined as a 
diagnostic parameter. 
a
Subsequent systemic anticancer therapies (excluding radiotherapy) will be reviewed prior to data unblinding 
to assess which represent clinically important treatments intended to control prostate cancer.  Any patient not 
known to have died at the time of the analysis and not known to have had a further anticancer therapy will be 
censored at the last known time to have not received subsequent therapy, ie, the last follow-up visit where this 
was confirmed.
b
Pain progression is defined as follows: 1) for patients who are asymptomatic at baseline, a ≥2-point change 
from baseline in the average (4-7 days) Brief Pain Inventory-Short Form (BPI-SF) Item 3 score observed at 
2 consecutive evaluations (with at least 2 weeks between the end of the initial visit and the start of the subsequent 
visit) OR initiation of opioid use for pain; 2) for patients who are symptomatic at baseline (average BPI-SF 
Item 3 score >0 and/or currently taking opioids), a ≥2-point change from baseline in the average BPI-SF Item 3 
score observed at 2 consecutive visits and an average worst pain score ≥4, and no decrease in average opioid use 
(≥1-point decrease in analgesic quantification algorithm [AQA] score from a starting value of 2 or higher) OR 
any increase in opioid use (eg, 1-point change in AQA score) at 2 consecutive follow-up visits (with at least 2 
weeks between the end of the initial visit and the start of the subsequent visit).  Any patient who has more than 
2 consecutive visits that are not evaluable for pain progression will be censored at the last evaluable assessment.

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AQA, Analgesic quantification algorithm; ATM, Ataxia-telangiectasia mutated; AUC0-8, Area under the plasma 
concentration-time curve in 0-8 h; AUCss, Area under the plasma concentration-time curve at steady state; 
BPI-SF, Brief Pain Inventory-Short Form; BRCA1, Breast Cancer 1 gene; BRCA2, Breast Cancer 2 gene; CLss/F, 
Clearance at steady state; Cmax,ss, Maximum plasma concentration at steady state; Cmin,ss, Minimum plasma 
concentration at steady state; FACT G, Functional Assessment of Cancer Therapy – General; FACT-P, 
Functional Assessment of Cancer Therapy - Prostate Cancer; FAPSI-6, FACT Advanced Prostate Symptom 
Index-6; HRR, Homologous recombination repair; HRQoL, Health-related quality of life; mCRPC, Metastatic 
castration-resistant prostate cancer; NHA, New hormonal agent; OS, Overall survival; PFS2, Time from 
randomisation to second progression or death; PK, Pharmacokinetics; PSA, prostate-specific antigen; SSRE, 
Symptomatic skeletal-related event; TFST, Time to start of first subsequent anticancer therapy or death; tmax,ss, 
Time to Cmax,ss; TTPP, Time to pain progression.
Safety Objective:
Outcome Measures:
To evaluate the safety and tolerability of the 
combination of olaparib and abiraterone vs 
placebo and abiraterone in patients with mCRPC 
who have received no prior cytotoxic 
chemotherapy or NHA at mCRPC stage.
AEs and SAEs, physical examination findings, vital signs 
(including BP and pulse rate), ECG findings and 
laboratory test results (including clinical chemistry and 
haematology parameters)
AE, Adverse event, BP, Blood pressure; ECG, Electrocardiogram, mCRPC, Metastatic castration-resistant 
prostate cancer; NHA, New hormonal agent; SAE, Serious adverse event.

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Upon site initiation, a consultation with the sponsor may occur during the screening process to 
ensure appropriate randomisation into the study as per defined eligibility criteria in the 
protocol, as per Section 5.
Patients will receive oral treatment with olaparib 300 mg twice daily + abiraterone 1000 mg 
once daily or placebo twice daily + abiraterone 1000 mg once daily.  Patients in both 
treatment groups will also receive either prednisone or prednisolone 5 mg twice daily since 
abiraterone is indicated in combination with prednisone or prednisolone for the treatment of 
patients with mCRPC.
The randomisation scheme will be stratified on the following factors:

Metastases: bone only vs visceral vs other

Docetaxel treatment at mHSPC stage: yes vs no
The primary endpoint of this double-blind study will be radiological progression-free survival 
(rPFS) as assessed by investigators using the Response Evaluation Criteria in Solid Tumours 
version 1.1 (RECIST 1.1; soft tissue) and Prostate Cancer Working Group 3 criteria 
(PCWG-3; bone) for all randomised patients.
The key secondary endpoint is overall survival (OS), and other secondary endpoints will 
include time to start of first subsequent anticancer therapy or death (TFST), time to pain 
progression (TTPP), time to opiate use for cancer related pain, time to a symptomatic 
skeletal-related event (SSRE), disease-related symptoms/health-related quality of life 
(HRQoL), time from randomisation to second progression or death (PFS2), and subgroup 
analyses by HRR gene mutation status. 
Safety assessments will include reporting of adverse events (AEs) and serious adverse events 
(SAEs), physical examinations, vital signs (including blood pressure [BP] and pulse rate), 
electrocardiograms (ECGs), and laboratory tests (including clinical chemistry and 
haematology).
Exploratory endpoints will include the exploration of blood, plasma, tumour and genetic 
biomarkers for the assessment of resistance mechanisms, predictive biomarkers of efficacy, 
drug combination mechanism of response, research into factors that may influence 
development of cancer and/or response to treatment, and investigation into healthcare resource 
utilisation.
The study schema is depicted in Figure 1.
Study Period:
Global study:

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
First patients enrolled Q4 2018 / Last patient enrolled Q1 2020

Estimated date of last patient completed Q4 2022 
China cohort:

Estimated first patients enrolled Q2 2021 / Estimated last patient enrolled Q3 2022

Estimated date of last patient completed Q2 2026
Number of Patients:
Approximately 720 patients were planned to be enrolled into this study.  At the time of this 
protocol amendment, enrolment had completed and a total of 796 patients were randomised in 
a 1:1 ratio to treatment with either olaparib and abiraterone or placebo and abiraterone. In 
addition, the China cohort will randomise approximately 108 additional patients at sites in 
China, after the completion of global enrolment.
Target patient population
All patients randomised in the study will be selected based on the following key criteria:

Treatment setting: All patients must have confirmed prostate adenocarcinoma and 
metastatic status defined as at least 1 documented metastatic lesion on either a bone scan 
or a computed tomography (CT)/magnetic resonance imaging (MRI) scan.  Patients must 
be treatment naïve at mCRPC stage, eg, patients should not have received any cytotoxic 
chemotherapy, NHA, or other systemic treatment in the mCRPC setting; androgen-
deprivation therapy (ADT) is an exception.  Prior to mCRPC stage, treatment with 
second-generation antiandrogen agents (except abiraterone) without prostate specific 
antigen (PSA) progression/clinical progression/radiological progression during treatment 
is allowed, provided the treatment was stopped at least 12 months before randomisation.  
Treatment with first-generation antiandrogen agents before randomisation is allowed, but 
there must be a washout period of 4 weeks.  Docetaxel treatment is allowed during
neoadjuvant/adjuvant treatment for localised prostate cancer and at mHSPC stage, as long 
as no signs of failure or disease progression occurred during or immediately after such 
treatment.  Patients should be candidates for abiraterone therapy with documented 
evidence of progressive disease defined by PSA progression and/or radiological 
progression.  Patients must have normal organ and bone marrow function measured 
within 28 days prior to administration of study treatment.  Prior to randomisation, sites 
must confirm availability of either an archival formalin-fixed, paraffin-embedded (FFPE) 
tumour tissue sample, or a new biopsy taken during the screening window, which meets 
the minimum pathology and sample requirements.

Medical conditions: Patients will not be eligible for the study if they have a known 
additional malignancy that has had progression or has required active treatment in the last 
5 years.  Patients should not have myelodysplastic syndrome/acute myeloid leukaemia 
(MDS/AML) or features suggestive of MDS/AML; clinically significant cardiovascular 
disease in the past 6 months, severe or unstable angina, atrial fibrillation or other cardiac 

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arrhythmia requiring therapy, or New York Heart Association Class II-IV heart failure or 
cardiac ejection fraction measurement of <50% during screening as assessed by 
echocardiography or multigated acquisition scan; a planned or scheduled cardiac surgery 
or percutaneous coronary intervention procedure; had a prior revascularisation procedure.  
Patients should not have any chronic medical condition requiring a systemic dose of 
corticosteroid >10 mg prednisone/prednisolone per day.  Patients with brain metastases 
are not allowed.

Prior/concomitant therapy: Patients should not have received previous treatment with 
PARP inhibitor and/or CYP17 inhibitor.  Patients will not be eligible for the study if they 
are receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) 
within 3 weeks prior to study treatment.  Patients should not have major surgery within 
2 weeks of starting study treatment and patients must have recovered from any effects of 
any major surgery.
Treatments and treatment duration:
Treatments
Patients will receive oral treatment with olaparib 300 mg twice daily + abiraterone 1000 mg 
once daily or placebo twice daily + abiraterone 1000 mg once daily.  Patients in both 
treatment groups will also receive either prednisone or prednisolone 5 mg twice daily.
Duration of treatment
Patients need to start study treatment as soon as possible after randomisation and ideally on 
the same day of randomisation. 
Randomised patients will continue treatment until unequivocal radiological progressive 
disease is assessed by investigator (using RECIST 1.1 for soft tissues lesions and PCWG-3 
criteria for bone lesions), unacceptable toxicity occurs, or the patient withdraws consent.  
Following objective disease progression, further treatment options will be at the discretion of 
the investigator.  Patients may be allowed to continue study treatment if the investigator 
believes, and the AstraZeneca Study Physician concurs, that the patient could continue to 
receive clinical benefit, the patient is not experiencing serious toxicity, and there is no 
available better alternative treatment that could benefit the patient.  Crossover from 
placebo+abiraterone to olaparib+abiraterone is not allowed in this study.
Data Monitoring Committee
This study will use an external Independent Data Monitoring Committee (IDMC) to review 
accumulating study safety data.  The committee will also review efficacy data from the 
planned interim data cut-offs (DCOs).
Statistical methods
The full analysis set (all comers) will be used as the primary population for reporting efficacy 
and to summarise baseline characteristics.  The full analysis set comprises all patients 
randomised into the study and will be analysed according to randomised treatment 

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(intention-to-treat [ITT] principle).  The safety analysis set will be used for safety analyses.  
Any important deviations from randomised treatment will be listed and considered when 
interpreting the efficacy and safety data.
The primary objective of this study is to assess the efficacy of olaparib+abiraterone 
combination therapy versus placebo+abiraterone in terms of rPFS assessed by the investigator 
in patients with mCRPC who have received no prior cytotoxic chemotherapy or NHA.
Three DCOs are planned.  The 1-sided alpha of 0.025 is allocated to the rPFS assessment.  If 
the result for rPFS is statistically significant, the OS hypothesis will be tested in a hierarchical 
fashion.  A multiplicity testing procedure based on the graphical approach in group sequential 
trials of Maurer and Bretz (Maurer and Bretz 2013), analogous to a simple sequential 
gatekeeping method, strongly controls the overall family-wise 1-sided error rate of 2.5%.
The rPFS endpoint will be tested at DCO1 and DCO2.  The OS endpoint will be tested at 
DCO1, DCO2 and DCO3.  For each endpoint with interim analysis, O’Brien and Fleming 
spending function (Lan and DeMets 1983, O’Brien and Fleming 1979), calculated based upon 
actual observed events, will be used to strongly control the overall type 1 error, with the 
restriction that alpha spend for the OS interim analysis at DCO1 will not exceed 0.0005. 
Subgroup analyses will be conducted for rPFS to assess consistency of treatment effect across 
potential or expected prognostic factors, including HRR gene mutation status.
A sensitivity analysis will be conducted using rPFS as assessed for all patients by blinded 
independent central review (BICR) per RECIST 1.1 and PCWG-3 criteria.
The secondary endpoint, OS, will be analysed using the same methodology as specified for 
rPFS.  To describe the benefits of olaparib+abiraterone compared to placebo+abiraterone, time 
to opiate use, SSRE, HRQoL, and PFS2 will also be analysed.
Safety and tolerability data will be summarised using appropriate descriptive measures.
Pharmacokinetic (PK) sampling will be performed in a subset of patients, planned to include 
approximately 50 patients per treatment group (ie, olaparib+abiraterone or 
placebo+abiraterone), at specific timepoints after multiple dosing (see Table 1).  The plasma 
concentration-time data will be analysed using non-compartmental analysis (NCA) to 
determine the PK of olaparib, abiraterone, and Δ4-abiraterone (a metabolite of abiraterone) at 
steady state and to evaluate the effect of olaparib on abiraterone PK.  
Enrolment in the China cohort will commence after global enrolment is closed, to randomise 
approximately 108 additional patients from sites in China. The safety and efficacy analyses of 

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subjects from China will be performed separately (please see Section 9.4.5 for details).  
Pharmacokinetic samples will not be collected for patients in China.
1.3
Schema
The general study design is summarised in Figure 1.
Figure 1
Study design
BICR, Blinded independent central review; ECOG PS, Eastern Cooperative Oncology Group performance status; 
mCRPC, Metastatic castration-resistant prostate cancer; N, Number of patients; NHA, New hormonal agent; 
rPFS, Radiological progression-free survival.
Note: Patients will receive 5 mg prednisone or prednisolone twice daily in addition to randomised study 
treatment (olaparib/placebo twice daily + abiraterone once daily).
Note: China cohort will apply the same study design and will include approximately 108 additional patients 
randomised in China.

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2.
INTRODUCTION
Investigators should be familiar with the current olaparib (AZD2281) Investigator Brochure.
Olaparib (AZD2281, KU-0059436) is a potent polyadenosine 5’diphosphoribose (poly [ADP 
ribose]) polymerisation (PARP) inhibitor (PARP-1, -2 and -3) that is being developed as an 
oral therapy, both as a monotherapy (including maintenance) and for combination with 
chemotherapy and other anticancer agents.
PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair 
mechanisms.  PARP enzymes are essential for repairing DNA single strand breaks (SSBs).  
Inhibiting PARPs leads to the persistence of SSBs, which are then converted to the more 
serious DNA double strand breaks (DSBs) during the process of DNA replication.  During the 
process of cell division, DSBs can be efficiently repaired in normal cells by HRR.  Tumours 
with homologous recombination deficiencies (HRD), such as ovarian cancers in patients with 
BRCA1/2 mutations, cannot accurately repair the DNA damage, which may become lethal to 
cells as it accumulates.  In such tumour types, olaparib may offer a potentially efficacious and 
less toxic cancer treatment compared with currently available chemotherapy regimens.
AstraZeneca considers that the advanced prostate cancer patient population involved in this 
study falls under the advanced cancer, limited life expectancy definition outlined in ICH S9 
guideline "Non-clinical Evaluation For Anticancer Pharmaceuticals" and meets the 
requirements outlined in the guideline. 
2.1
Study rationale
There is accumulating evidence that second-generation androgen receptor (AR) signalling 
inhibitors might induce “BRCAness,” and there is potential synergy between AR inhibitors 
and PARP inhibitors in the treatment of mCRPC (Li et al 2017).  BRCAness is defined as 
molecular features that some sporadic cancers share with hereditary BRCA-mutation carriers 
that make them susceptible to similar treatments.  The concept for treating mCRPC patients 
with the combination of olaparib and abiraterone was largely based on the observation that 
PARP inhibition plus androgen deprivation could significantly reduce the growth of prostate 
cancer cells independent of HRR gene mutation status, in both in vitro and in vivo model 
systems (Schiewer et al 2012).  Further, the combination of ADT and olaparib have a 
synergistic effect on inducing synthetic lethality (Asim et al 2017).
Additional rationale for the current study is based on the results of a recent AstraZeneca 
sponsored study, Study D081DC00008 (Study 8; NCT01972217).  Study 8 was designed to 
explore the hypothesis that PARP inhibition acts synergistically with inhibition of the 
androgen pathway and that this effect is independent of a cell’s HRR gene mutation status, 
hence the study enrolled post-chemotherapy patients who were genetically unselected (ie, an 
‘all comers’ population).  Study 8 was a randomised, double-blind, placebo-controlled, 

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multicentre Phase II study of olaparib versus placebo when given in combination with 
abiraterone, in patients with mCRPC who had received prior chemotherapy containing 
docetaxel (second-line setting).  
Part A of the study was a safety run-in, conducted to assess the safety and tolerability of 
olaparib when given in addition to abiraterone and to recommend a dose of olaparib to be used 
for Part B of the study, also given in addition to abiraterone.  
 
 
 
 
 
Part B of the study was a randomised, double-blind, placebo-controlled comparison of the 
efficacy, safety and tolerability of the dose of olaparib selected from Part A, when given in 
addition to abiraterone, versus placebo in addition to abiraterone.  Eligible patients were aged 
18 years or older with mCRPC who had previously received docetaxel and were candidates 
for abiraterone treatment.  Patients were excluded if they had received more than 2 previous 
lines of chemotherapy, or had previous exposure to second-generation antihormonal drugs.  
Patients (n=142) were randomised (1:1), without stratification, to receive oral olaparib 300 mg 
twice daily or placebo in combination with oral abiraterone 1000 mg once daily and 
prednisone or prednisolone 5 mg twice daily.  The primary endpoint was investigator-assessed 
rPFS (based on RECIST 1·1 and PCWG-2).  Efficacy analyses were done in the 
intention-to-treat (ITT) population, which included all randomly assigned patients, and safety 
analyses included all patients who received at least 1 dose of olaparib or placebo.  Median 
rPFS was 13·8 months (95% Confidence Interval [CI] 10·8–20·4) with olaparib+abiraterone 
and 8·2 months (5·5-9·7) with placebo+abiraterone (HR 0·65, 95% CI 0·44–0·97, p=0·034).  
Median OS was 22.7 months (95% CI 17·4–29·4) in the olaparib and abiraterone group 
compared with 20.9 months (95% CI 17·6–26·3) in the placebo and abiraterone group.
The most common grade 1–2 AEs were nausea (26 [37%] patients in the olaparib group 
versus 13 [18%] patients in the placebo group, constipation (18 [25%] versus 8 [11%]), and 
back pain (17 [24%] versus 13 [18%]).  Thirty-eight (54%) of 71 patients in the olaparib and 
abiraterone group and 20 (28%) of patients in the placebo and abiraterone group had grade 3 
or worse AEs, including anaemia (in 15 [21%] of 71 patients versus 0 of 71), pneumonia (4 
[6%] versus 3 [4%]), and myocardial infarction (4 [6%] versus 0).  Increased toxicity seen in 
the olaparib group compared with the placebo group was expected, with many, but not all, 
observed AEs being consistent with the current safety profile for olaparib.  Serious adverse 
events were reported by 24 (34%) of 71 patients in the olaparib and abiraterone group and 13 
(18%) of 71 patients in the placebo and abiraterone group.  Seven (10%) of 71 patients in the 

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olaparib group had SAEs that were related to study treatment (anaemia [n=3], febrile 
neutropenia [n=1], pneumonitis [n=1], vomiting [n=1], general deterioration in physical health 
[n=1]) compared with 1 (1%) of 71 patients in the placebo group (gastroenteritis [n=1]).  
Seven (10%) of 71 patients in the olaparib and abiraterone group had serious cardiovascular 
events (myocardial infarction [n=4], fatal cardiac failure [n=1], chronic cardiac failure [n=1], 
fatal ischaemic stroke [n=1]) compared with 1 patient in the placebo group (thrombotic stroke 
[n=1]).  Time to onset of serious cardiovascular events ranged from 3 to 29 months in the 
olaparib and abiraterone group.  However, notable numerical imbalances were observed in 
relation to cardiovascular events (myocardial infarction, congestive heart failure, stroke) when 
olaparib was given in combination with abiraterone.  An imbalance was also seen for 
thrombotic events and those associated with fluid overload, whilst events of congestive heart 
failure were more severe in the olaparib group.  The patients who experienced cardiovascular 
events of concern were elderly (≥65 years), the events occurred late in the treatment with no 
apparent chronological pattern and they had a relatively high burden of cardiovascular risk 
factors.  Single or multiple cardiovascular risk factors (eg, hypertension, diabetes mellitus, 
hyperlipidaemia) were not obviously imbalanced between the treatment groups at baseline.  In 
the myocardial infarction cases, the reported data supported the diagnosis; however, details 
were limited for the 2 cases of congestive heart failure and the diagnoses were lacking 
supportive data on file.  In this study, meaningful interpretation of the findings in relation to 
cardiovascular events is limited by the small sample size, some imbalances in relevant 
demographic and baseline characteristics as well as cardiovascular risk factors, differences in 
duration of treatment and lack of confirmation of congestive heart failure diagnosis.  Further 
investigation is therefore needed in a Phase III trial with olaparib given in addition to 
abiraterone.
The current study, PROpel, is a Phase III study evaluating the efficacy, safety, and tolerability 
of olaparib versus placebo when given in addition to abiraterone in genetically unselected (ie, 
an ‘all-comers’ population) patients with mCRPC who have not received prior chemotherapy 
or NHAs for mCRPC (first-line setting).  It is proposed that this study will build on the 
knowledge gained from Study 8 and serve as confirmatory evidence of the clinical benefit, 
safety and tolerability of the combination of olaparib and abiraterone in the treatment of 
patients with mCRPC.
2.2
Background
2.2.1
Advanced prostate cancer and its treatment
Prostate cancer is the fourth most common cancer in both sexes combined and the second 
most common cancer in men.  An estimated 1.1 million men worldwide were diagnosed with 
prostate cancer in 2012, accounting for 15% of the cancers diagnosed in men.  With an 
estimated 307,000 deaths in 2012, prostate cancer is the fifth leading cause of death from 
cancer in men (6.6% of the total men deaths) (Globocan 2012).

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Prostate cancer is a heterogeneous disease and ADT with luteinising hormone-releasing 
hormone (LHRH) analogues or orchidectomy is usually initially effective at controlling 
metastatic disease.  However, patients inevitably progress from an androgen sensitive to a 
castration resistant phenotype which is not curable, and is associated with 90% of overall 
mortality being attributable to the underlying malignant disease (Scher et al 2015).  Since 
curative therapy is not possible in this setting, reducing disease burden and symptoms are 
critical objectives of any therapeutic intervention.
Recently, the treatment of mCRPC has significantly altered with the approval of new drugs.  
Several life-prolonging agents are now approved for the mCRPC population overall, notably 
including NHAs.  NHAs are potent, orally available treatment options with a favourable 
tolerability profile that have replaced docetaxel as the preferred choice of first-line therapy for 
mCRPC (Flaig et al 2016).  Both abiraterone and enzalutamide have demonstrated robust 
improvements in progression-free survival (PFS) and OS and have also shown a significantly 
prolonged time to initiation of cytotoxic chemotherapy (Ryan et al 2013, Beer et al 2014).  
However, patients eventually progress under available treatment options, eg, median PFS is 
approximately 16 months, and median OS is approximately 36 months with abiraterone 
treatment for first-line mCRPC.  There is an unmet medical need for new treatment options, 
either as a single agent for early-line therapy or as combination therapy to improve efficacy 
(ie, prolong the effective treatment period) and delay resistance.
Abiraterone is a pregnenolone-derived 3-pyridyl steroidal agent that selectively and 
irreversibly inhibits the CYP17A1 microsomal enzyme, encoded by the CYP17A1 gene. 
CYP17A1 has 2 separate activating properties: 17-α-hydroxylase (that catalyses the 17 α 
hydroxylation of C21 steroids, which are needed for the synthesis of cortisol in the adrenal 
gland); 17,20-lyase (that catalyses the breaking of the C17–21 bond, converting C21 
compounds to C19 steroids in the sex steroid synthesis pathway in both the adrenal gland and 
the testis) (Sonpavde et al 2011, Attard et al 2012). 
CYP17A1 inhibition blocks 2 critical stages in testosterone biosynthesis: conversion of 
pregnenolone to 17-OH-pregnenolone, and conversion of 17-OH-pregnenolone to 
dehydroepiandrosterone. 
Inhibition of CYP17 also results in deficient cortisol synthesis and the upregulation of the 
hypothalamic–pituitary–adrenal pathway with elevated levels of adrenocorticotropic hormone.  
This results in an increase in the steroid levels upstream of the CYP17A1 block, including 
corticosterone and deoxycorticosterone (Attard et al 2012).  This metabolic state stimulates 
both the glucocorticoid and the mineralocorticoid receptor, and their excess prevents 
adrenocortical insufficiency.  However, this secondary effect also results in an excess of 
secondary mineralocorticoids, which is characterised by fluid retention, hypertension and 

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hypokalaemia, and often requires intervention.  To prevent this side effect, abiraterone is 
normally administered with prednisone (Pia et al 2013).
2.2.2
Homologous recombination repair genes in prostate cancer 
Multiple loss-of-function alterations in genes that are involved in DNA repair, including 
homologous recombination repair, are associated with response to poly(adenosine 
diphosphate–ribose) polymerase (PARP) inhibition in patients with prostate and other cancers 
(de Bono et al 2020).
Between 24% to 30% of mCRPCs have loss of function mutations in genes involved in 
homologous recombination repair (HRR) of DNA double strand breaks (Abida et al 2017, 
Armenia et al 2018, Chung et al 2019, Mateo et al 2015, Robinson et al 2015, AstraZeneca 
data on file).  Mutations in the breast cancer susceptibility genes (BRCA1 and/or BRCA2) are 
the most prevalent HRR gene mutations (HRRm) in mCRPC (with BRCA2 more prevalent 
than BRCA1) with ATM (ataxia telangiectasia mutated) the second most frequently mutated 
HRR gene in mCRPC (Armenia et al 2018, Chung et al 2019, Mateo et al 2015, Robinson et 
al 2015).  Together the prevalence of BRCA1/2 and ATM mutations in mCRPC ranges from 
13% to 26.5%. The next most prevalent HRRm in mCRPC are CDK12 (1.3% to 8%), CHEK2
(1.4% to 4%), PALB2 (0.3% to 3%), and CHEK1 (0.9% to 2%).  The prevalence of other HRR 
gene mutations is very low (0% to 1.8%).  Due to the low prevalence of many of the HRR 
genes it is challenging to validate them individually. Therefore, based on their common 
mechanistic role in homologous recombination, and prior evidence from D081DC00007 
(PROfound; NCT02987543) cohort B suggesting that patients with PALB2, BARD1, BRIP1, 
CDK12, CHEK1, CHEK2, FANCL, RAD51B, RAD51C, RAD51D, and RAD54L mutations 
collectively benefited from monotherapy olaparib treatment, grouping of the genes together 
into a HRRm population is supported. PROfound was a randomised, open label, multicentre 
Phase III study of olaparib monotherapy versus physician’s choice of NHA (enzalutamide or 
abiraterone) that enrolled men with mCRPC who had disease progression on prior treatment 
with an NHA and who had a qualifying mutation (predicted to be deleterious or suspected 
deleterious) in one of 15 HRR genes. Of note, nonclinical data have emerged since PROfound 
was designed, showing weak evidence of PPP2R2A as an HRR gene.  
Enrichment of BRCA1/2, ATM and CDK12 mutations in advanced prostate cancer has been 
documented in the literature by several studies (Abida et al 2017, Armenia et al 2018, Chung 
et al 2019, Mateo et al 2018).  The high representation of BRCA2 mutations in 
advanced/metastatic prostate cancer is considered to be a consequence of BRCA2 mutations 
being associated with a particular aggressive phenotype (Castro et al 2013, Castro et al 2015, 
Chung et al 2019, Mateo et al 2018) rather than these mutations being acquired under 
treatment with standard therapies (eg, androgen receptor mutations and amplifications [Mateo 
et al 2018]).

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2.2.3
Rationale for evaluating olaparib-abiraterone combination treatment 
in patients with mCRPC independent of HRR gene mutation status
There is accumulating evidence that second-generation AR signalling inhibitors like 
abiraterone might induce “BRCAness,” and there is potential synergy between AR inhibitors 
and PARP inhibitors in the treatment of mCRPC (Li et al 2017).
The rationale for treating patients with mCRPC with the combination of olaparib and 
abiraterone was based on the observation that PARP inhibition plus androgen deprivation 
could significantly reduce the growth of prostate cancer cells independent of HRR gene 
mutation status, both in cell culture and model systems (Schiewer et al 2012).
Based on available data, there are 2 plausible mechanisms that may account for the biomarker 
independent activity of the olaparib-abiraterone combination.  The first hypothesis involves 
PARP-1 transcriptional roles: beyond its function in DNA repair, PARP-1 is implicated in 
modulation of transcription via various mechanisms (reviewed in Schiewer and Knudsen 
2014).  PARP-1’s transcriptional functions may be especially relevant in hormone dependent 
cancers such as breast and prostate cancer, as nuclear hormone receptors require catalytically 
active PARP-1 as a positive co-regulator of target gene expression (Ju et al 2006).  PARP-1 
co-regulation of AR is supported by the observation that PARP inhibition suppresses 
transcription of a number of AR targets, and this function is linked to reduced AR target gene 
expression and improved efficacy in a prostate cancer xenograft model treated with PARP 
inhibitors and surgical castration when compared with surgical castration or PARP inhibitor 
alone (Schiewer et al 2012).
The second mechanistic explanation that may account for HRR independent activity of 
olaparib in combination with abiraterone is induction of an HRR deficient phenotype (or 
BRCAness) through inhibition of AR signalling.  Several lines of evidence support this 
possibility (Polkinghorn et al 2013, Goodwin et al 2013, Tarish et al 2015, Asim et al 2017, Li 
et al 2017) including:

Up-regulation of HRR gene transcripts and protein levels in response to enhanced AR 
signalling in prostate cancer, 

Increased radioresistance in the presence of functional AR signalling, and 

Conversely, decreased HRR gene expression and DNA repair indices in ADT/NHA 
treated cells and tumour biopsies, correlated with increased damage sensitivity. 
Importantly, in the CRPC setting, inhibition of the AR signalling axis by NHAs such as 
enzalutamide are still able to induce BRCAness which sensitises cells and xenograft models to 
olaparib, despite resistance to the initial ADT (Asim et al 2017, Polkinghorn et al 2013, Li et 
al 2017). 

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Olaparib in combination with abiraterone (Study 8) provided clinical efficacy benefit for 
patients with mCRPC compared with abiraterone alone.  Although more SAEs were observed 
in patients who received olaparib and abiraterone than abiraterone alone, no difference in 
HRQoL outcomes were identified between the groups.  The data also suggest that the 
combination of olaparib and abiraterone might provide an additional clinical benefit to a broad 
population of patients with mCRPC. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of olaparib is 
provided in the Investigator’s Brochure.
2.3
Benefit/risk assessment
Data from the available pre-clinical studies and subsequent clinical development programme 
demonstrate that olaparib appears to be active and generally well tolerated in patients with 
solid tumours including those with BRCA mutated cancers.  In ovarian cancer, responses have 
been seen in all patient groups, including platinum resistant and refractory cancer. 
From the available data to date in patients with advanced cancer, there is no evidence of any 
unexpected toxicity following long-term olaparib monotherapy exposure. 
Adverse laboratory findings and/or clinical diagnoses considered to be causally associated 
with administration of olaparib monotherapy include haematological effects (anaemia, 
neutropenia, lymphopenia, thrombocytopenia, mean cell volume elevation and increase in 
blood creatinine), nausea and vomiting, decreased appetite, diarrhoea, dyspepsia, stomatitis, 
upper abdominal pain, dysgeusia, fatigue (including asthenia), headache, dizziness and cough.  
Most of these events are generally mild or moderate in intensity. 
In a relatively small number of patients, the adverse events of special interest of pneumonitis, 
MDS/AML, and new primary malignancies have been observed.  
The available evidence from across the olaparib clinical development programme supports a 
conclusion that there is a reasonable possibility of a causal relationship between olaparib and 
MDS/AML.  However, consistent with the low incidence seen across all indications, the 
incidence in men with mCRPC is <1.5%.  MDS/AML is an important identified risk for 
olaparib.  Patients in this study are monitored closely for signs and symptoms of MDS/AML.
Evidence from across the development programme for olaparib does not support a conclusion
that there is a causal relationship between olaparib and pneumonitis or new primary 
malignancies.  These are important potential risks for olaparib and are being kept under close 
surveillance. 
In Study 8, there were no safety findings new to the combination of olaparib and abiraterone 
that have not already been reported for each agent alone.  As expected, there was higher 

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toxicity in the olaparib+abiraterone group versus placebo+abiraterone, but the nature and 
severity of these events were consistent with the known safety profiles of olaparib and 
abiraterone, and were clinically manageable and reversible.  A higher percentage of patients 
had cardiovascular events (myocardial infarction, congestive heart failure, stroke) in the 
olaparib+abiraterone group compared with the placebo+abiraterone group.  Extensive 
interpretation of the cardiovascular findings in Study 8 is limited by the size of the safety 
analysis set, some imbalances in relevant demographic and baseline characteristics, 
differences in duration of treatment, and lack of confirmation of congestive heart failure 
diagnosis.  Based on the available safety data from Study 8, it is considered that the safety and 
tolerability profile of olaparib+abiraterone is acceptable in patients with mCRPC following
docetaxel containing chemotherapy.  The statistically significant and clinically meaningful 
rPFS improvement shown in the olaparib+abiraterone group of Study 8 suggests a positive 
benefit:risk of olaparib+abiraterone treatment in patients with mCRPC. 
Based on the available data on efficacy and safety it is believed that olaparib continues to 
demonstrate an overall positive benefit/risk balance to support its further clinical evaluation in 
patients with advanced prostate cancer, and in combination with abiraterone. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of olaparib may be found in the Investigator’s Brochure and the Development 
Safety Update Report.
See Section 9.5 and Appendix C for information regarding the Data Monitoring Committee.
The emergence of the novel coronavirus disease 2019 (COVID-19) could present a potential 
risk for patients. Risk mitigation factors have been implemented related to study conduct 
during the COVID-19 pandemic (see Appendix K) and for patient management in an event of 
COVID-19 infection and actions to be taken on study treatment administration (see 
Appendix L).
3.
OBJECTIVES AND ENDPOINTS
Following the completion of global enrolment to PROpel, a China cohort will randomise 
approximately 108 additional patients at sites in China. Data from the China cohort will be 
analysed separately from the global cohort (see Section 9.4.5).
3.1
Primary objectives
The primary objectives of the study and associated outcome measures are summarised in 
Table 3. 

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Table 3
Primary objective
Primary Objective:
Outcome Measures:
To determine the efficacy of the combination of 
olaparib and abiraterone vs placebo and 
abiraterone by assessment of rPFS in patients with 
mCRPC who have received no prior cytotoxic 
chemotherapy or NHA at mCRPC stage.
rPFS, defined as the time from randomisation to 
1) radiological progression, assessed by investigator per 
RECIST 1.1 (soft tissue) and PCWG-3 criteria (bone), 
or 2) death from any cause, whichever occurs first.
mCRPC, Metastatic castration-resistant prostate cancer; NHA, New hormonal agent; PCWG-3, Prostate Cancer 
Working Group 3; rPFS, Radiological progression-free survival; RECIST 1.1, Response Evaluation Criteria in 
Solid tumours version 1.1.
3.2
Secondary objectives
The secondary objectives of the study and associated outcome measures are summarised in 
Table 4.
Table 4
Secondary objectives
Secondary Objectives:
Outcome Measures:
To determine the efficacy of the combination of 
olaparib and abiraterone vs placebo and 
abiraterone by assessment of OS in patients with 
mCRPC who have received no prior cytotoxic 
chemotherapy or NHA at mCRPC stage.
OS, defined as the time from randomisation to death from 
any cause.
To determine the efficacy of the combination of 
olaparib and abiraterone vs placebo and 
abiraterone as assessed by time to start of first 
subsequent anticancer therapy or death (TFST) in 
patients with mCRPC who have received no prior 
cytotoxic chemotherapy or NHA at mCRPC 
stage.
TFST, ie, the time from randomisation to 1) the start of 
the first subsequent anticancer therapy or 2) death from 
any cause.a
To determine the efficacy of the combination of 
olaparib and abiraterone vs placebo and 
abiraterone as assessed by time to pain 
progression (TTPP) in patients with mCRPC who 
have received no prior cytotoxic chemotherapy or 
NHA at mCRPC stage.
TTPP is defined as the time from randomisation to pain 
progression based on the Brief Pain Inventory-Short 
Form (BPI-SF) Item 3 “worst pain in 24 hours” and 
opiate analgesic use (analgesic quantification algorithm 
[AQA] score).b

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To further evaluate the efficacy of the 
combination of olaparib and abiraterone vs 
placebo and abiraterone by assessment of time to 
opiate use, time to an SSRE, and PFS2 in patients 
with mCRPC who have received no prior 
cytotoxic chemotherapy or NHA at mCRPC 
stage.
•
Time to opiate use: The time from randomisation to 
the first opiate use for cancer-related pain.
•
Time to an SSRE: the time from randomisation to 
the first SSRE.  An SSRE is defined as use of 
radiation therapy to bone in order to prevent or 
relieve skeletal complications, occurrence of new 
symptomatic pathological bone fractures (vertebral 
or non-vertebral, resulting from minimal or no 
trauma), occurrence of radiologically confirmed 
spinal cord compression or a tumour-related 
orthopaedic surgical intervention.
•
PFS2: The time from randomisation to second 
progression on next-line anticancer therapy by 
investigator assessment of radiological progression, 
clinical symptomatic progression, PSA progression 
or death.
To assess the effect of the combination of 
olaparib and abiraterone vs placebo and 
abiraterone on disease related symptoms and 
HRQoL using BPI-SF and Functional 
Assessment of Cancer Therapy (FACT) - Prostate 
Cancer (FACT-P) questionnaires in patients with 
mCRPC who have received no prior cytotoxic 
chemotherapy or NHA at mCRPC stage.
•
BPI-SF: progression in pain severity domain, 
change in pain interference domain.
•
FACT-P total score, FACT-G total score, trial 
outcome index, functional well-being, physical 
well-being, prostate cancer subscale, and FACT 
Advanced Prostate Symptom Index-6 (FAPSI-6).
To evaluate tumour and blood samples collected 
from patients with mCRPC who have received no 
prior cytotoxic chemotherapy or NHA at mCRPC 
stage for mutations in BRCA1, BRCA2, ATM and 
11 other HRR genes.
Note: blood samples will not be collected for 
HRR gene mutation status testing in the China 
cohort
HRR gene mutation status.
To determine steady-state exposure to abiraterone 
and its active metabolite Δ4-abiraterone in the 
presence and absence of olaparib.
To determine steady-state exposure to olaparib 
when co-administered with abiraterone.
Note: this objective is not applicable for the 
China cohort
•
Plasma concentration data at steady state for 
olaparib, abiraterone, and Δ4-abiraterone in the 
subset of patients evaluable for PK.
•
If sufficient data are available, PK parameters at 
steady state (eg, maximum concentration [Cmax,ss], 
time to Cmax,ss [tmax,ss], minimum concentration 
[Cmin,ss], and partial area under the concentration-
time curve [AUC0-8]) will be calculated in the PK 
patient subset. In addition, the area under the curve 
at steady state (AUCss) and the apparent clearance 
(CLss/F) for olaparib and the metabolite to parent 
ratios for Cmax,ss, Cmin,ss and AUC0-8 for 
Δ4-abiraterone will be determined. The time of last 
concentration (tlast) will also be determined as a 
diagnostic parameter. 
a
Subsequent systemic anticancer therapies (excluding radiotherapy) will be reviewed prior to data unblinding 
to assess which represent clinically important treatments intended to control prostate cancer.  TFST is defined 
as the time from randomisation to the earlier of 1) the first subsequent anticancer therapy start date following 
study treatment discontinuation or 2) death from any cause.  Any patient not known to have died at the time of 

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abiraterone 1000 mg once daily.  At the time of this amendment to the protocol, enrolment
had completed with a total of 796 patients randomised.  Following the completion of global 
enrolment, the China cohort will randomise approximately 108 additional patients at sites in 
China, also in a 1:1 ratio.
Upon site initiation, a consultation with the sponsor may occur during the screening process to 
ensure appropriate randomisation into the study as per defined eligibility criteria in the 
protocol, as per Section 5.
Abiraterone is indicated in combination with prednisone or prednisolone for the treatment of 
patients with mCRPC.  Hence, patients in both treatment groups will also receive either 
prednisone or prednisolone 5 mg twice daily with the abiraterone in this study, but throughout 
this protocol the treatment will be referred to simply as abiraterone.
All patients will attend a screening visit within 28 days before starting study treatment.
Day 1 is defined as the randomisation date; study treatment needs to begin as soon as possible 
after randomisation, ideally within 24 hours.  Randomised patients will continue study 
treatment until unequivocal radiological progressive disease is assessed by investigator (using 
RECIST 1.1 for soft tissues lesions and PCWG-3 criteria for bone lesions), unacceptable 
toxicity occurs, or the patient withdraws consent. Following objective disease progression, 
further treatment options will be at the discretion of the investigator.  Patients may be allowed 
to continue study treatment if the investigator believes, and the AstraZeneca Study Physician 
concurs, that the patient could continue to receive clinical benefit, the patient is not 
experiencing serious toxicity, and there is no available better alternative treatment that could 
benefit the patient.  Crossover from placebo+abiraterone to olaparib+abiraterone is not 
allowed in this study.
The randomisation scheme will be stratified on the following factors:

Metastases: bone only vs visceral vs other

Docetaxel treatment at mHSPC stage: yes vs no
The primary endpoint of this double-blind study will be rPFS as assessed by investigator using 
RECIST 1.1 (soft tissue) and PCWG-3 criteria (bone) for all randomised patients. 
A study flow chart is illustrated in Figure 2 and the study design is summarised in Figure 1.

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Figure 2
Study flow chart
Bid, Twice daily; PCWG-3, Prostate Cancer Working Group 3; qd, Once daily; RECIST, Response Evaluation 
Criteria in Solid Tumours.
There are 3 DCOs planned.  The primary endpoint of rPFS will be formally analysed at DCO1 
and DCO2.  The key secondary endpoint of overall survival (OS) will be tested at DCO1, 
DCO2 and DCO3.  See Section 9 for further details.
The final data cut, DCO3, will occur approximately 48 months after the first patient is 
randomised, when a minimum follow-up of 32 months would be expected.  At DCO3, the 

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clinical study database will close to all new data (SAEs will continue to be recorded on the 
AstraZeneca Patient Safety database as described below).  Patients are, however, permitted to 
continue to receive study treatment beyond the closure of the database if, in the opinion of the 
investigator, they are continuing to receive benefit from treatment with study treatment.  For 
patients who do continue to receive treatment beyond the time of this DCO, investigators will 
continue to report all SAEs to AstraZeneca Patient Safety until 30 days after study treatment is 
discontinued, in accordance with Section 8.4.1 (Reporting of Serious Adverse Events).  If an 
investigator learns of any SAEs, including death, at any time after a patient has completed the 
study, and he/she considers there is a reasonable possibility that the event is causally related to 
the investigational product, the investigator should notify AstraZeneca, Patient Safety.  
Additionally, as stated in Section 8.3.3 (Follow-up of AEs and SAEs), any SAE or nonserious 
adverse event that is ongoing at the time of this data cut-off, must be followed up by the 
investigator for as long as medically indicated.
For an overview of the study design see Figure 1 Section 1.3. For details on treatments given 
during the study, see Section 6.1 Treatments Administered.  
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives 
and Endpoints.  
4.2
Scientific rationale for study design
Data in Phase II Study 8 demonstrated that in patients with mCRPC (second-line setting), the 
addition of olaparib to abiraterone results in a statistically significant and clinically 
meaningful improvement in rPFS over abiraterone alone, with an acceptable safety and 
tolerability profile.
The PROpel study will build on the knowledge gained from Study 8 and serve as confirmatory 
evidence of the clinical benefit, safety and tolerability of the combination of olaparib and 
abiraterone in the treatment of patients with mCRPC who have not received prior 
chemotherapy or NHA at mCRPC stage (first-line setting).  Patients who have had prior 
docetaxel treatment during neoadjuvant/adjuvant treatment for localised prostate cancer and at 
mHSPC stage will be permitted to enrol. 
The randomised, double-blind design of PROpel reduces potential for bias when assessing 
whether the combination of olaparib + abiraterone shows improved efficacy compared with 
abiraterone monotherapy.
The scientific rationale for combining olaparib with abiraterone in a biomarker unselected 
patient population is described in Sections 2.1 and 2.2.

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
Primary Completion Date – the date that the final participant is examined or receives 
an intervention for the purposes of final collection of data for the primary outcome 
measure, whether the clinical study concluded according to the pre-specified protocol 
or was terminated. In the case of clinical studies with more than one primary outcome 
measure with different completion dates, this term refers to the date on which data 
collection is completed for all of the primary outcomes.

Study Completion Date – is defined as the date the final participant is examined or 
receives an intervention for purposes of final collection of data for the primary and 
secondary outcome measures and AEs (for example, last participant’s last visit), 
whether the clinical study concludes according to the pre-specified protocol or is 
terminated.
A participant is considered to have completed the study if they have completed all phases of 
the study including the last visit.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow. AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with olaparib. 
See Appendix C 6 for guidelines for the dissemination of study results.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each patient should meet all the inclusion criteria and none of the exclusion criteria for this 
study in order to assigned/randomised to a study intervention.  Under no circumstances can 
there be exceptions to this rule.  Patients who do not meet the entry requirements are screen 
failures; refer to Section 5.4.
In this protocol, “enrolled” patients are defined as those who sign informed consent.  
“Randomised” patients are defined as those who undergo randomisation.
For procedures for withdrawal of incorrectly enrolled patients see Section 7.3.
5.1
Inclusion criteria
Patients are eligible to be included in the study only if all the following inclusion criteria 
and none of the exclusion criteria apply:

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Informed consent
1
Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent form and in the study 
protocol.
2
Provision of signed and dated, written informed consent form prior to any mandatory 
study specific procedures, sampling, and analyses.
3
For inclusion in i) the optional exploratory genetic research and ii) the optional biomarker 
research, patients must fulfil the following criteria:

Provision of informed consent for genetic research prior to collection of sample.

Provision of informed consent for biomarker research prior to collection of sample.
If a patient declines to participate in the optional exploratory genetic research or the optional 
biomarker research, there will be no penalty or loss of benefit to the patient.  The patient will 
not be excluded from other aspects of the study.
Age
4
Patients must be ≥18 years of age (or ≥19 years of age in South Korea) at the time of 
signing the informed consent form.  For patients enrolled in Japan who are <20 years of 
age, written informed consent should be obtained from the patient and from his legally 
acceptable representative.
Type of patient and disease characteristics
5
Histologically or cytologically confirmed prostate adenocarcinoma.
6
Metastatic status defined as at least 1 documented metastatic lesion on either a bone scan 
or a CT/MRI scan.
7
First-line mCRPC: 

Patients must be treatment naïve at mCRPC stage, eg, patients should not have 
received any cytotoxic chemotherapy, NHA, or other systemic treatment (approved 
drugs or experimental compounds) in the mCRPC setting.  ADT is an exception as 
specified in inclusion criterion 8.

Treatment with first-generation antiandrogen agents (eg, bicalutamide, nilutamide, 
and flutamide) before randomisation is allowed, but there must be a washout period 
of 4 weeks.

Docetaxel treatment is allowed during neoadjuvant/adjuvant treatment for localised 
prostate cancer and at mHSPC stage, as long as no signs of failure or disease 
progression occurred during or immediately after such treatment.

Prior to mCRPC stage, treatment with second-generation antiandrogen agents (except 
abiraterone) without PSA progression/clinical progression/radiological progression 

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during treatment is allowed, provided the treatment was stopped at least 12 months 
before randomisation.
8
Ongoing androgen deprivation with gonadotropin-releasing hormone analogue or bilateral 
orchiectomy, with serum testosterone <50 ng/dL (<2.0 nmol/L) within 28 days before 
randomisation.  Patients receiving ADT at study entry should continue to do so 
throughout the study.
9
Candidate for abiraterone therapy with documented evidence of progressive disease.  
Progressive disease at study entry defined as one or more of the following three criteria 
that occurred while the patient was on androgen deprivation therapy:

PSA progression defined by a minimum of two rising PSA levels with an interval of 
≥1 week between each determination.  The PSA value at the Screening visit should 
be ≥1 µg/L (1 ng/mL) (per PCWG-3 criteria);

Soft-tissue disease progression defined by RECIST 1.1;

Bone progression defined by appearance of 2 or more new lesions on a bone scan 
(per PCWG-3 criteria).  
10 Patients must have normal organ and bone marrow function measured within 28 days 
prior to administration of study treatment as defined below:

Haemoglobin ≥10.0 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 ≤1.5×institutional upper limit of normal (ULN).  Patients with known 
Gilbert’s disease who have serum bilirubin ≤3×ULN may be enrolled.

Serum potassium ≥3.5 mmol/L.

Serum albumin ≥3.0 g/dL.

Aspartate aminotransferase/alanine aminotransferase ≤2.5×ULN unless liver 
metastases are present, in which case values must be ≤5×ULN.

Creatinine clearance ≥51 mL/min, calculated using the Cockcroft-Gault equation for 
males or based on a 24-hour urine test:
Estimated creatinine clearance =
(140-age [years]) x weight (kg)
serum creatinine (mg/dL) x 72
11 Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (see Appendix B), 
with no deterioration over the previous 2 weeks.
12 The participant has, in the opinion of the investigator, a life expectancy of at least 
6 months. 

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13 Prior to randomisation, sites must confirm availability of either an archival FFPE tumour 
tissue sample, or a new biopsy taken during the screening window, which meets the 
minimum pathology and sample requirements in order to enable HRR status subgroup 
analysis of the primary endpoint rPFS.  If there is not written confirmation of the 
availability of tumour tissue prior to randomisation, the patient is not eligible for the 
study.
Reproduction
14 Male patients must use a condom during treatment and for 3 months after the last dose of 
olaparib + abiraterone when having sexual intercourse with a pregnant woman or with a 
woman of childbearing potential.  Female partners of male patients should also use a 
highly effective form of contraception (see Appendix I for acceptable methods) if they are 
of childbearing potential. Male patients should not donate sperm throughout the period of 
taking olaparib and for 3 months following the last dose of olaparib.
5.2
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
Medical conditions
1
Has a known additional malignancy that has had progression or has required active 
treatment in the last 5 years.  Exceptions include basal cell carcinoma of the skin, and 
squamous cell carcinoma of the skin that has undergone potentially curative therapy.
2
Patients with MDS/AML or with features suggestive of MDS/AML.
3
Clinically significant cardiovascular disease as evidenced by myocardial infarction or 
arterial thrombotic events (eg, stroke) in the past 6 months, severe or unstable angina, 
atrial fibrillation or other cardiac arrhythmia requiring therapy, or New York Heart 
Association Class II-IV heart failure or cardiac ejection fraction measurement of <50% 
during screening as assessed by echocardiography or multigated acquisition scan.
4
Planned or scheduled cardiac surgery or percutaneous coronary intervention procedure.
5
Prior revascularisation procedure (significant coronary, carotid, or peripheral artery 
stenosis).
6
Uncontrolled hypertension (systolic BP ≥160 mmHg or diastolic BP ≥95 mmHg).  
Patients with a history of hypertension are allowed provided BP is controlled by 
antihypertensive treatment.
7
History of uncontrolled pituitary or adrenal dysfunction.
8
Active infection or other medical condition that would make prednisone/prednisolone use
contraindicated.

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9
Any chronic medical condition requiring a systemic dose of corticosteroid >10 mg 
prednisone/prednisolone per day.
10 Patients who are 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 major seizure disorder, unstable spinal cord 
compression, superior vena cava syndrome, active pneumonitis, extensive interstitial 
bilateral lung disease on high-resolution CT scan, or any psychiatric disorder that 
prohibits obtaining informed consent and following the study procedures.
11 Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAEs] grade 
>2) caused by previous cancer therapy, excluding alopecia.
12 Patients with brain metastases.  A scan to confirm the absence of brain metastases is not 
required.
13 Patients with spinal cord compression are excluded unless they are considered to have 
received definitive treatment for this and have evidence of clinically stable disease for 
4 weeks.
14 Patients who are unevaluable for both bone and soft tissue progression as defined by 
meeting both of the following criteria:

A bone scan referred to as a superscan showing an intense symmetric activity in the 
bones.

No soft tissue lesion (measurable or nonmeasurable) that can be assessed by 
RECIST.
15 Patients who are unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication.
16 Immunocompromised patients, eg, patients who are known to be serologically positive for 
human immunodeficiency virus.
17 Patients with known active hepatitis infection (ie, hepatitis B or C).
Prior/concomitant therapy
18 Any previous treatment with PARP inhibitor, including olaparib.
19 Patients receiving any systemic chemotherapy or radiotherapy (except for palliative 
reasons) within 3 weeks prior to study treatment.  Patients who receive palliative 
radiotherapy need to stop radiotherapy 1 week before randomisation.
20 Any previous exposure to a CYP17 (17α-hydroxylase/C17,20-lyase) inhibitor (eg, 
abiraterone, orteronel).
21 Concomitant use of known strong CYP3A inhibitors (eg, itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg, 

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ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil).  The required washout 
period prior to starting study treatment is 2 weeks.
22 Concomitant use of known strong CYP3A inducers (eg, phenobarbital, enzalutamide, 
phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine or St John’s wort) 
or moderate CYP3A inducers (eg, bosentan, efavirenz or modafinil).  The required 
washout period prior to starting study treatment is 5 weeks for phenobarbital and 
enzalutamide and 3 weeks for other agents.
23 Major surgery within 2 weeks of starting study treatment and patients must have 
recovered from any effects of any major surgery.
24 Previous allogenic bone marrow transplant or double umbilical cord blood transplantation 
(dUCBT).
Prior/concurrent clinical study experience
25 Participation in another clinical study with an investigational product or investigational 
medical devices within 1 month of randomisation. 
26 History of hypersensitivity to olaparib or abiraterone, any of the excipients of olaparib or 
abiraterone, or drugs with a similar chemical structure or class to olaparib or abiraterone.
Other exclusions
27 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca and 
Merck staff and/or staff at the study site).
28 Judgment by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements.
29 Previous randomisation in the present study. 
5.3
Lifestyle restrictions
5.3.1
Meals and dietary restrictions
It is prohibited to consume grapefruit juice while on olaparib or placebo therapy.
Patients will be required to fast from at least 2 hours before until 1 hour after each dose of 
abiraterone, due to an effect of food on absorption.  Water can be allowed as desired.
On olaparib PK sampling day, patients should fast from 1 hour before taking the olaparib dose 
to 2 hours after (see Section 6.1.1). Note: PK samples will not be collected for patients in 
China.

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5.3.2
Contraception
Patients must use a condom when having sexual intercourse with a pregnant woman or with a 
woman of childbearing potential.  Female partners of male patients must use one highly 
effective form of contraception (as described in Appendix I) if they are of childbearing 
potential.  This should be started from the signing of the informed consent and continue 
throughout the period of taking study treatment and for at least 3 months after the last dose of 
olaparib, or they must totally/truly abstain from any form of sexual intercourse (as described 
in Appendix I).  Patients should not donate sperm throughout the period of taking olaparib and 
for 3 months following the last dose of olaparib.
For details of acceptable methods of contraception refer to Appendix I Acceptable Birth 
Control Methods.
5.3.3
Blood donation
Patients should not donate blood or plasma while participating in this study and for 3 months 
following the last dose of study treatment.
5.4
Screen failures
Screen failures are patients who do not fulfil the eligibility criteria for the study, and therefore 
must not be randomised.  These patients should have the reason for study withdrawal recorded 
in the electronic case report form (eCRF) (ie, patient does not meet the required 
inclusion/exclusion criteria) and the patient should also be registered in the randomisation and 
trial supply management system (interactive response technology) (RTSM [IRT]) as ‘screen 
failed’.  This reason for study withdrawal is only valid for screen failures (not randomised 
patient). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened once, upon the AstraZeneca Study Physician’s approval and agreement.  
Re-screened patients should be assigned the same patient number (enrolment code [E-code]) 
as for the initial screening.  Re-screening should be documented (in the eCRF/RTSM [IRT] 
and source data) so that its effect on study results, if any, can be assessed. 
A patient who is rescreened is not required to sign another ICF if the rescreening occurs 
within 28 days from the previous ICF signature date.
6.
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study 
participant according to the study protocol.  Study treatment in this study refers to olaparib, 
placebo or abiraterone. 

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6.1.2
Additional study drugs – abiraterone and prednisone/prednisolone
Abiraterone with supportive prednisone or prednisolone is background treatment; these will be 
sourced locally or centrally as commercially available materials.  Patients will be administered 
abiraterone 1000 mg once daily.  The initial dosage of 1000 mg once daily will be in 
combination with prednisone or prednisolone 5 mg administered orally twice daily.  
Abiraterone must be taken on an empty stomach.  No food should be consumed for at 
least 2 hours before the dose of abiraterone is taken and for at least 1 hour after the dose 
of abiraterone is taken.  The tablets should be swallowed whole with water and not 
crushed or chewed, in full accordance with local prescribing information. 
Adverse events management and dose modifications strategies of abiraterone and prednisone 
or prednisolone during the study is at the investigators’ discretion based on local prescribing 
information of abiraterone.
6.2
Preparation/handling/storage/accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only patients randomised in the study may receive study treatment and only authorised site 
staff may dispense study treatment.  At site, all study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the investigator and authorised site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
Unused study treatment should be destroyed as per site/country local regulations and 
guidelines. 
6.3
Measures to minimise bias: randomisation and blinding
All patients will be centrally assigned to randomised study treatment using an RTSM (IRT).  
Before the study is initiated, the telephone number and call-in directions for the RTSM (IRT) 
and/or the log-in information and directions for the RTSM (IRT) will be provided to each site.
Eligible patients will be randomised in a 1:1 ratio (treatment 1: treatment 2).  The actual 
treatment given to individual patients will be determined by a randomisation scheme that has 
been loaded into the RTSM (IRT) database.  The randomisation scheme will be produced by a 
computer software program called AZRand (AZ Global Randomisation system) that 
incorporates a standard procedure for generating random numbers.

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Patient eligibility will be established before treatment randomisation.  Once the eligibility of a 
patient has been confirmed, the investigator (or nominated assistant) should contact the RTSM 
(IRT) Centralised Randomisation Centre for allocation of randomised therapy.  Patients will 
be identified to the Centralised Randomisation Centre using E-code (and patient initials/date 
of birth, if permissible under local regulations). 
It is recommended that patients commence study treatment as soon as possible after 
randomisation and ideally on the same day of randomisation.
If a patient withdraws from the study, then his enrolment/randomisation code cannot be 
reused.  Withdrawn patients will not be replaced. 
If a patient is continuing to derive benefit from olaparib at the end of the study, then they may 
continue to receive treatment as open labelled drug via manual supply once the RTSM (IRT) 
has been closed.  Following objective disease progression, further treatment options will be at 
the discretion of the investigator.  Patients may be allowed to continue study treatment if the 
investigator believes, and the AstraZeneca Study Physician concurs, that the patient could 
continue to receive clinical benefit, the patient is not experiencing serious toxicity, and there is 
no available better alternative treatment that could benefit the patient.  Crossover from 
placebo+abiraterone to olaparib+abiraterone is not allowed in this study.  At the end of the 
study (ie, at final analysis) the study will be unblinded.
6.3.1
Methods for ensuring blinding
The study will be conducted in a double-blind manner.  The study medications will be 
identical and presented in the same packaging to ensure blinding of the study medication.
The patient, the investigator and study centre staff will be blinded to study drug allocation. 
No member of the extended study team at AstraZeneca, at the investigational centres, or any 
Contract Research Organisation (CRO) handling data will have access to the randomisation 
scheme until the study is formally unblinded as a result of meeting the primary objective.  
Exceptions are relevant persons within the Pharmaceutical Development Supply Chain at 
AstraZeneca or their designee, where the information is needed to package study drug, the 
drug safety departments at AstraZeneca, and personnel providing the analysis of PK samples.  
Investigators will only be unblinded to treatment allocation in cases of medical emergency.  
The treatment codes and results will be kept strictly within AstraZeneca to safeguard the 
integrity of the blind, and hence to minimise any possible bias in data handling.
An independent third-party vendor will provide unblinded data to the IDMC for their review 
per the IDMC charter but AstraZeneca and CRO staff and investigators involved in the study 
will remain blinded at this time.  See Section 9.5.1 for further details.

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6.3.2
Methods for unblinding the study
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the investigator(s) at the study centre from the RTSM (IRT).  
Routines for this will be described in the RTSM (IRT) user manual that will be provided to 
each centre.  The treatment code should not be broken except in medical emergencies when 
the appropriate management of the patient requires knowledge of the treatment randomisation.  
The investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to a patient to the AstraZeneca staff.  Overdose will not normally be 
considered a reason for breaking the blind.  If the treatment code is broken the investigator(s) 
must document and report to AstraZeneca.  AstraZeneca retains the right to break the code for 
SAEs that are unexpected and are suspected to be causally related to an investigational 
product and that potentially require expedited reporting to regulatory authorities.  Treatment 
codes will not be broken for the planned analyses of data until all decisions on the evaluability 
of the data from each individual patient have been made and documented.  If the blind is 
broken, the date, time and reason will be recorded in the RTSM (IRT), and any associated AE 
report.  If a patient’s study drug is unblinded by the investigator, or designee, the patient will 
be withdrawn from study drug as described in Section 7.3.  The study will be centrally 
unblinded at the time of first meeting the primary objective, but patients and investigators will 
remain blinded until after the database is verified and closed.
For the BICR, blinded data will be provided.
6.4
Treatment compliance 
Patients should be given clear instructions on how and when to take their study treatment.  
Patients will self-administer study treatment.  Study site staff will make tablet counts at 
regular intervals during treatment.  After the tablet count has been performed, the remaining 
tablets will not be returned to the patient but will be retained by the investigative site until 
reconciliation is completed by the study monitor.  All patients must return their bottle(s) of 
study treatment at the appropriate scheduled visit, when a new bottle will be dispensed.  
Patients will be instructed to notify study site personnel of missed doses.  
Exception: Tablet counts do not have to be recorded on eCRF for locally supplied drug, but all 
study drug usage, including any missing doses, still needs to be recorded in the appropriate 
Section of the eCRF.
Any change from the dosing schedule, dose interruptions, dose reductions, dose 
discontinuations should be recorded in the eCRF.
Patients must return all containers and any remaining tablets at the end of the study. For 
overdosing see Section 8.4.3.

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6.5
Concomitant therapy
The use of any natural/herbal products or other traditional remedies should be discouraged, 
but use of these products, as well as any medication or vaccine including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements that the patient is receiving at the 
time of enrolment or receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
Anti-emetics/Anti-diarrhoeals
From screening onwards, should a patient develop nausea, vomiting and / or diarrhoea, then 
these symptoms should be reported as AEs (see Section 8.3) and appropriate treatment of the 
event given.
Prohibited and restricted concomitant medications and therapies
Prohibited and restricted concomitant mediation and therapies are described in Table 8 and 
Table 9. 
Avoid concomitant strong CYPsA4 inducers and CYP2D6 substrates with abiraterone; 
for more details of restrictions and cautions required when administering concomitant 
medications with abiraterone, please refer to abiraterone local prescribing information.
Table 8
Prohibited medications
Prohibited medication/class of drug:
Anticancer therapy: 
Chemotherapy
Immunotherapy
Radiotherapy (except palliative)
Biological therapy
Other novel agents
Patients must not receive any other concurrent anticancer 
therapy, including investigational agents, while on study 
treatment.  However, continuous ADT with an LHRH 
agonist/antagonist (unless bilateral orchiectomy) must 
be continued during the trial.  Patients may receive 
bisphosphonates or denosumab at any point before or 
during the study for the prevention of skeletal related 
events in patients with bone metastases as clinically 
indicated and in line with local prescribing information.
Live virus vaccines
Live bacterial vaccines
Not permitted while the patient is receiving study 
medication and during the 30 day follow-up period. 
An increased risk of infection by the administration of live 
virus and bacterial vaccines has been observed with 
conventional chemotherapy drugs and the effects with 
olaparib are unknown.
ADT, Androgen-deprivation therapy; LHRH, Luteinising hormone-releasing hormone.

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Restricted concomitant medications
Table 9
Restricted concomitant medications and therapies
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which the medication is allowed):
Strong CYP3A inhibitors: eg, itraconazole, 
telithromycin, clarithromycin, boosted protease 
inhibitors, indinavir, saquinavir, nelfinavir, 
boceprevir, and telaprevir
Moderate CYP3A inhibitors: eg, ciprofloxacin, 
erythromycin, diltiazem, fluconazole, and 
verapamil 
Strong or moderate CYP3A inhibitors should not be taken 
with olaparib.  If there is no suitable alternative 
concomitant medication the dose of olaparib should be 
reduced for the period of concomitant administration.  The 
dose reduction of olaparib should be recorded in the eCRF 
with the reason documented as concomitant CYP3A 
inhibitor use. 
•
Strong CYP3A inhibitors – reduce the dose of 
olaparib to 100 mg twice daily for the duration of 
concomitant therapy with the strong inhibitor and for 
5 half-lives afterwards.
•
Moderate CYP3A inhibitors – reduce the dose of 
olaparib to 150 mg twice daily for the duration of 
concomitant therapy with the moderate inhibitor and 
for 3 half-lives afterwards.
•
After the washout of the inhibitor is complete, the 
olaparib dose can be re-escalated.
Strong CYP3A inducers: eg, phenobarbital, 
phenytoin, rifampicin, rifabutin, rifapentine, 
carbamazepine, nevirapine, enzalutamide, and 
St John’s wort
Moderate CYP3A inducers: eg, bosentan, efavirenz, 
and modafinil
Strong or moderate CYP3A inducers should not be taken 
with olaparib.
If the use of any strong or moderate CYP3A inducers is 
considered necessary for the patient’s safety and welfare 
this could diminish the clinical efficacy of olaparib.
If a patient requires use of a strong or moderate CYP3A 
inducer they must be monitored carefully for any change in 
efficacy of olaparib.
CYP3A4 substrates with narrow therapeutic 
margin: eg, cisapride, cyclosporine, ergot alkaloids, 
fentanyl, pimozide, sirolimus, tacrolimus, and 
warfarin 
Sensitive CYP3A4 substrates: eg, buspirone, 
felodipine, fluticasone, lovastatin, quetiapine, 
saquinavir, sildenafil, and simvastatin 
CYP2B6 substrates: eg, bupropion and efavirenz
OATP1B1 substrates: eg, bosentan, glibenclamide, 
repaglinide, statins, and valsartan
OCT1, MATE1 and MATE2K substrates: 
eg, metformin
OCT2 substrates: eg, cimetidine and metformin
OAT3 substrates: eg, furosemide and methotrexate
BCRP substrates: eg, methotrexate and rosuvastatin
P-gp substrates: eg, simvastatin, pravastatin, 
dabigatran, digoxin, and colchicine
Effect of olaparib on other drugs
Based on limited in vitro data, olaparib may increase the 
exposure to substrates of CYP3A4, OATP1B1, OCT1, 
OCT2, OAT3, MATE1 and MATE2K.
Based on limited in vitro data, olaparib may reduce the 
exposure to substrates of 2B6 (and potentially substrates of 
CYP2C9, CYP2C19, and P-gp).  The efficacy of some 
hormonal contraceptives may be reduced if 
co-administered with olaparib.
Caution should be observed if substrates of these 
isoenzymes or transporter proteins are co-administered.
Appropriate clinical monitoring is recommended for 
patients receiving P-gp substrates or CYP3A substrates 
with a narrow therapeutic margin concomitantly with 
olaparib.

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Table 9
Restricted concomitant medications and therapies
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which the medication is allowed):
Anticoagulant therapy
Patients who are taking warfarin may participate in this 
trial; 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.  Non-vitamin K antagonist 
oral anticoagulants (NOACs), subcutaneous heparin and 
low molecular weight heparin may be given concomitantly 
with olaparib and INR monitoring is not required. If 
NOACs are used, it is preferable to avoid CYP3A 
substrates (eg, apixaban and rivaroxaban) if possible.
Palliative radiotherapy
Palliative radiotherapy may be used for the treatment of 
pain at the site of bony metastases.  Study treatment should 
be discontinued for a minimum of 3 days before a patient 
undergoes therapeutic palliative radiation treatment.  Study 
treatment should be restarted within 4 weeks as long as any 
bone marrow toxicity has recovered.
INR, International normalised ratio.
Subsequent therapies for cancer 
Details of first and subsequent therapies for cancer and/or details of surgery for the treatment 
of the cancer, after discontinuation of treatment, will be collected.  Reasons for starting 
subsequent anticancer therapies including access to other PARP inhibitors or investigational 
drugs will be collected and included in the exploratory assessments of OS.
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the
patient’s safety and well-being, may be given at the discretion of the investigator and recorded 
in the appropriate sections of the eCRF.
In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the 
study period must be recorded in the eCRF.
6.6
Dose modification
6.6.1
Dose reductions for olaparib
In case a dose reduction is necessary, olaparib will be administered as described in Table 10, 
Table 11 and Table 12.

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Table 10
Dose reductions for olaparib to manage adverse events
Initial Dose
Following re-challenge post-
interruption: Dose reduction 1
Dose reduction 2
300 mg twice daily
250 mg twice daily
200 mg twice daily
Table 11
Dose reduction for olaparib if patient develops moderate renal 
impairment
Initial Dose
Moderate renal impairment (calculated creatinine clearance by 
Cockcroft-Gault equation or based on a 24-hour urine test, between 
31 and 50 mL/min): Dose reduction 
300 mg twice daily
200 mg twice daily
Table 12
Dose reductions for olaparib if patient has to start taking a strong or 
moderate CYP3A inhibitor
Initial Dose
Strong CYP3A inhibitor
Moderate CYP3A inhibitor
300 mg twice daily
100 mg twice daily
150 mg twice daily
For guidance on dose reductions for management of AEs (including renal impairment) refer to 
Section 8.4.4.
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors 
cannot be avoided see Section 6.5.
When dose reduction is necessary due to olaparib-related AEs, patients will take 1 x 150 mg 
tablet and 1 x 100 mg tablet twice daily or 2 x 100 mg tablet twice daily (see Section 8.4.4).  
In the case that a patient has to take a strong or moderate CYP3A inhibitor, dose reduction is 
necessary and the patient will take 1 x 150 mg tablet twice daily or 1 x 100 mg tablet twice 
daily (see Section 6.5).  These dose reductions should be documented in the eCRF.  Dose 
re-escalation is allowed after the discontinuation of the strong or moderate CYP3A inhibitor, 
provided there are no olaparib-related AEs of grade 2 or above. 
6.6.2
Dose reductions for abiraterone
In case dose reductions are necessary for abiraterone, the investigator should refer to 
abiraterone local prescribing information for further details.  These dose reductions should be 
documented in the eCRF.
6.7
Treatment after final DCO before the end of the study
AstraZeneca will continue to supply olaparib within the current study after final DCO until 
either olaparib is licenced in that country, or it is determined that the benefit to risk profile 

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does not support continued development of olaparib, or the national health authority has 
deemed the drug not approvable.
AstraZeneca will continue to supply olaparib in the continued access phase of this study 
while, in the opinion of the Investigator, the participant is benefiting.
In the event that product development reaches a point where alternative product supply 
options become available, then these alternative product supply options will be discussed by 
AstraZeneca with the Investigator. AstraZeneca will work with the Investigator to transition 
the participant(s) to alternative supply, where possible.
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, participant(s) currently receiving treatment with olaparib may then be 
transitioned to such a study, and the current study would reach its end. The roll-over or 
extension study would ensure treatment continuation with visit assessments per its protocol, as 
applicable. Any participant who would be eligible to move to such a study would be given a 
new informed consent, as applicable. Participants are to be followed in accordance with the 
Medical Standard of Care and as deemed appropriate by the investigators. It is recommended 
that investigators continue to observe ongoing participants at the frequency employed prior to 
the DCO.
Protocol dose modification and stopping criteria are to be followed while a participant is 
receiving olaparib. A change in the dose/schedule of olaparib should only occur for safety 
reasons, based on the investigator’s judgement, and should generally follow the approach for 
dose reduction and discontinuation as described in this protocol.
7.
DISCONTINUATION OF TREATMENT AND PATIENT
WITHDRAWAL
7.1
Discontinuation of study treatment 
Patients may be discontinued from study treatment in the following situations.  Note that 
discontinuation from study treatment does NOT equal complete withdrawal from the study 
(all efforts should be made to keep patients who withdraw from treatment on study):

Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment

Adverse event

Severe non-compliance with the Clinical Study Protocol 

Bone marrow findings consistent with MDS/AML

Radiological progressive disease is confirmed by the investigator (RECIST 1.1 or 
PCWG-3 criteria), unless in the investigator's opinion, and the AstraZeneca Study 

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Physician concurs, that the patient is benefiting from the treatment, provided patient does 
not meet any other discontinuation criteria as outlined in this section. 
See the schedule of activities (SoA; Section 1.1) for data to be collected at the time of 
treatment discontinuation and follow-up and for any further evaluations that need to be 
completed.
All reasons for discontinuation of study treatment must be documented in the eCRF (see 
Section 7.1.1). 
7.1.1
Procedures for discontinuation of study treatment
The investigator should instruct the patient to contact the site before or at the time if study 
treatment is stopped.  A patient that decides to discontinue study treatment will always be 
asked about the reason(s) and the presence of any AEs.  The date of last intake of study 
treatment should be documented in the eCRF.  All study treatment should be returned by the 
patient at their next on-site study visit or unscheduled visit.  Patients permanently 
discontinuing study treatment should be given locally available standard of care therapy, at the 
discretion of the investigator.
Any patient discontinuing study treatment should be seen at 30 days’ post-discontinuation for 
the evaluations and sample collections outlined in the study schedule.  The patient’s tumour 
status should be assessed clinically and, if appropriate, disease progression should be 
confirmed by radiological assessment. 
After discontinuation of the study medication at any point in the study, all ongoing AEs or 
SAEs must be followed until resolution unless, in the investigator’s opinion the condition is 
unlikely to resolve due to the patients underlying disease, or the patient is lost to follow-up 
(see Section 7.2).  All new AEs and SAEs occurring during the 30 calendar days after the last 
dose of study medication must be reported (if SAEs, they must be reported to AstraZeneca 
within 24 hours as described in Section 8.4.1) and followed to resolution as above.  Patients 
should be seen at least 30 days after discontinuing study medication to collect and / or 
complete AE information.  For guidance on reporting AEs after the 30-day follow-up period 
see Section 8.3.2.1.
Any patient who has not yet shown objective radiological disease progression at withdrawal 
from study treatment should continue to be followed as per RECIST 1.1 and PCWG-3 as 
detailed in Section 8.1.1.1.
All patients must be followed for survival, up to the final analysis.
Discontinuation of study treatment, for any reason, does not impact on the patient’s 
participation in the study.  The patient should continue attending subsequent study visits and 

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data collection should continue according to the study protocol.  If the patient does not agree 
to continue in-person study visits, a modified follow-up must be arranged to ensure the 
collection of endpoints and safety information.  This could be a telephone contact with the 
patient, a contact with a relative or treating physician, or information from medical records.  
The approach taken should be recorded in the medical records.  A patient that agrees to 
modified follow-up is not considered to have withdrawn consent or to have withdrawn from 
the study.
Note: Patients who discontinue 1 of the study treatments, eg, discontinue abiraterone 
and remain on olaparib, or vice versa, should continue to be seen and have assessments 
performed as outlined in the SoA (see Section 1.1).  Once both olaparib and abiraterone 
treatment are permanently discontinued, procedures should be followed for the 
discontinuation and follow-up visits.  
The date and reasons for discontinuation of study treatment should be captured in the eCRF.
7.2
Lost to follow-up
A patient will be considered potentially lost to follow-up if he fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:

The site must attempt to contact the patient and reschedule the missed visit as 
soon as possible and counsel the patient on the importance of maintaining the 
assigned visit schedule.

Before a patient is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the patient or next of kin by eg, repeat 
telephone calls, certified letter to the patient´s last known mailing address or local 
equivalent methods.  These contact attempts should be documented in the 
patient’s medical record. 

Efforts to reach the patient should continue until the end of the study.  Should the 
patient be unreachable at the end of the study the patient should be considered to 
be lost to follow-up with unknown vital status at end of study and censored at 
latest follow-up contact.
7.3
Withdrawal from the study
Reasons for withdrawal from the study:

Voluntary withdrawal by the patient who is at any time free to discontinue their 
participation in the study, without prejudice to further treatment.

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
Incorrectly randomised patients ie, the patient does not meet the required 
inclusion/exclusion criteria for the study.

Patient lost to follow-up (see Section 7.2).

Death
A patient may withdraw from the study (eg, withdraw consent), at any time (investigational 
product and assessments) at his own request, without prejudice to further treatment.
A patient who considers withdrawing from the study must be informed by the investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records). 
If the patient withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a patient withdraws from the study, he may request destruction of any samples taken, and 
the investigator must document this in the site study records.  
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE.  The investigator will follow up patients as medically indicated.  The patient will be 
asked to return electronic patient-reported outcome (ePRO) devices.
AstraZeneca or its delegate will request investigators to collect information on patients’ vital 
status (dead or alive; date of death when applicable) at the end of the study from publicly 
available sources, in accordance with local regulations.  Knowledge of the vital status at study 
end in all patient is crucial for the integrity of the study. 
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent 
to: 

To further participation in the study including any further follow-up (eg, survival 
calls) 

Withdrawal of consent to the use of their study generated data

Withdrawal to the use of optional and/or mandatory biological samples (all 
biomarker samples that are not already analysed can be requested to be destroyed)
The status of ongoing, withdrawn (from the study) and “lost to follow-up” patients at the time 
of an OS analysis should be obtained by the site personnel by checking the patient notes, 
hospital records, contacting the patient’s general practitioner and checking publicly available 
death registries.  If the patient has actively withdrawn consent to the processing of their 
personal data, the vital status of the patient can be obtained by site personnel from publicly 
available resources where it is possible to do so under applicable local laws.

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See SoA, Table 1, for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed.  All study treatment should be 
returned by the patient.
After withdrawal from the study, patients will continue to receive standard treatment 
according to their own doctor’s discretion. 
7.4
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings that are not considered to be consistent 
with continuation of the study.
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF.  All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA (see Section 1.1).
The investigator will ensure that data are recorded on the eCRF.  The web-based data capture 
system will be used for data collection and query handling. 
The investigator ensures the accuracy and completeness for eCRFs, which includes legibility 
and timeliness of the data recorded and of the provision of answers to data queries according 
to the Clinical Study Agreement.  The investigator will sign the completed eCRFs.  A copy of 
the completed eCRF will be archived at the study site.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study treatment.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria.  The investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  

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Procedures conducted as part of the patient’s routine clinical management (eg, blood count) 
and obtained before signing of the informed consent form (ICF) may be utilised for screening 
or baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
The maximum amount of blood collected from each patient over the duration of the study, 
including any extra assessments that may be required, will not exceed approximately 300 mL.  
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Efficacy assessments
8.1.1
Imaging tumour assessment
In this study the preferred assessment of soft tissue lesions are CT/MRI scans using the 
RECIST 1.1 criteria and the bone lesions are assessed on bone scintigraphy scans using the 
PCWG-3 criteria.  The RECIST 1.1 and PCWG-3 assessments should follow the same 
schedule.  The baseline assessments of all imaging modalities should be performed as close as 
possible to the start of study treatment and no more than 4 weeks (-28 days) before 
randomisation/treatment assignment.  Following the baseline assessment, subsequent 
assessments should be performed every 8 weeks (± 7 days) until week 24 and every 12 weeks 
(± 7 days) thereafter, relative to the date of randomisation, until objective radiological disease 
progression is confirmed by the investigator.  After the initial assessment of progression, 
whether the patient receives a subsequent therapy or not, the patient should have 1 follow-up 
scan collected preferably at the next (and no later than the next) scheduled imaging visit, and 
no less than 6 weeks after the prior assessment of progression of disease (PD).  The
assessments by different imaging modalities, for example CT and bone scintigraphy, can be 
done on different days but should all be performed within assessment schedule.  It is 
important to follow the imaging assessment schedule as closely as possible (see Section 1.1, 
SoA Table 1).  However, tumour assessment can be performed at any time when PD is 
suspected.  If the scans are performed outside of scheduled visit window interval, and the 
patient has not progressed, every attempt should be made to perform the subsequent scans at 
their scheduled time points. 
Radiological examinations performed during the study should be retained at site as source 
data.
8.1.1.1
RECIST 1.1 assessments (soft tissue lesions)
The imaging modalities used for RECIST assessment will be CT or MRI scans of the chest, 
abdomen and pelvis.  Any other areas of disease involvement should be additionally 
investigated based on the signs and symptoms of individual patients.  During the assessments 
subsequent to baseline any other sites at which new disease is suspected should also be 
appropriately imaged.  The modality of assessment of tumour burden used at baseline must be 

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used at each subsequent visit.  In this study, bone lesions will not be included in the RECIST 
soft tissue assessment.  
8.1.1.2
PCWG-3 assessment (bone lesions assessment)
Bone lesions will be assessed on whole body bone scintigraphy (bone scans).  Positive hot 
spots on the bone scan should be considered significant and unequivocal sites of malignant 
disease to be recorded as metastatic bone lesions.  Bone lesions will be assessed on bone scan 
only and will not be part of the RECIST 1.1 malignant soft tissue assessment.
8.1.2
Tumour evaluation
Disease progression will be deemed to have occurred if 1 or more of the following criteria is 
met:

Soft tissue disease progression as defined by RECIST 1.1

Bone lesion progression by PCWG-3 (Table 13)

Death
RECIST 1.1 and PCWG-3 criteria will be used together to assess patient response to treatment 
by determining PFS times.  The RECIST 1.1 guidelines for measurable, non-measurable, 
target and non-target lesions and the objective tumour response criteria are presented in 
Appendix A, together with the PCWG-3 guidelines.
8.1.2.1
Soft tissue lesions evaluation
Categorisation of objective tumour response assessment on soft tissue lesions will be based on 
the RECIST 1.1 criteria of response: CR (complete response), PR (partial response), SD 
(stable disease), NED (no evidence of disease) and PD (progression of disease).  Target lesion 
(TL) progression will be calculated in comparison to when the tumour burden was at a 
minimum (ie, smallest sum of diameters previously recorded on study).  In the absence of 
progression, tumour response (CR, PR, and SD) will be calculated in comparison to the 
baseline tumour measurements obtained before starting treatment. 
For patients with non-measurable soft tissue lesions only at baseline, categorisation of 
objective tumour response assessment will be based on the RECIST 1.1 criteria of response: 
CR, PD and Non-CR/Non-PD.
Patients with bone metastasis only and no soft tissue disease at baseline will still be assessed 
according to RECIST criteria.  The only RECIST visit response possible will be NED if the 
patient remains without soft tissue lesion, PD if a new soft tissue lesion is identified or not 
evaluable (NE) in rare situations when insufficient data exist.

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If the investigator is in doubt as to whether progression has occurred, particularly with regard 
to non-target lesions or the appearance of a new lesion, it is advisable to continue treatment 
and reassess the tumour burden at the next scheduled assessment or sooner if clinically 
indicated.  If repeat scans confirm progression, then the date of the initial scan should be 
declared as the date of progression.  New bone lesions should not be counted in the RECIST 
assessment.
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of 1 or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status.
8.1.2.2
Bone lesions evaluation
Categorisation of tumour progression of bone lesions will be based on the PCWG-3 criteria.  
Positive hot spots on the bone scan should be considered significant and unequivocal sites of 
malignant disease to be recorded as metastatic bone lesions.  
Progression on a bone scan is defined as:
At the first visit after baseline:

If 2 or more new metastatic bone lesions are observed on the bone scan from the first 
visit after baseline, a confirmatory scan performed at the next schedule visit (and a 
minimum of 6 weeks later), must show 2 or more additional new metastatic bone 
lesions (for a total of 4 or more new metastatic bone lesions since the baseline 
assessment). 
All other visits from the second visit after baseline:

For patients without progression at the first visit after baseline, the scan from this first 
visit after baseline now serves as new reference for all subsequent scans, ie, assuming 
all visits are acquired according to schedule, all bone scans after week 8 are compared 
to the week 8 scan.  If 2 or more new metastatic bone lesions are observed on scans 
obtained after the first visit after baseline assessment compared to the new reference, a 
confirmatory scan performed preferably no later than the next scheduled visit and at 
least 6 weeks later, must show the persistence of, or an increase in, the 2 or more 
metastatic bone lesions. 
The date of radiological progression is the date of the first scan documenting the 2 new 
lesions.  If the investigator is in doubt as to whether progression has occurred, it is advisable 

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to continue study treatment and reassess the bone lesion status at the next scheduled 
assessment, or sooner if clinically indicated.
The requirements for determination and confirmation of radiological progression by either 
bone scan (bone progression) or CT/MRI (soft tissue progression) are summarised in 
Table 13.
Table 13
Requirements for documentation of progression
Visit Date
Criteria for Bone Progression
Criteria for Soft Tissue 
Progression
First visit after baseline (expected 
week 8)

2 or more new lesions 
compared to baseline bone 
scan.

Requires confirmation at 
least 6 weeks later with >2 
additional lesions compared 
to the first scan after baseline

Progressive disease on CT or 
MRI by RECIST 1.1

No confirmation required.
From the 2nd visit after baseline

2 or more new lesions 
compared to the first bone 
scan after baseline.

Requires confirmation at 
least 6 weeks later for 
persistence or increase in 
number of lesions

Progressive disease on CT or 
MRI by RECIST 1.1

No confirmation required.
CT, Computed tomography; MRI, Magnetic resonance imaging; RECIST, Response Evaluation Criteria in Solid 
tumours.
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
study schedule in Table 1.
8.1.2.3
Central reading of scans
An independent review of all scans used in the assessment of tumours will be conducted.  All 
imaging assessments including unscheduled visit scans should be collected in DICOM format 
on an ongoing basis and sent to an AstraZeneca appointed CRO to enable BICR.  Results of 
this independent review will not be communicated to investigators, and the management of 
patients will be based solely upon the results of the RECIST 1.1 and PCWG-3 assessment 
conducted by the investigator.
All treatment decisions will be based on site assessment of scans.  After the primary PFS 
analysis, central review of scans will no longer be required, and investigators will be advised 
when to stop sending copies of the scans to the CRO conducting the central review.  Note this 

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also applies to the China Cohort, following the final rPFS analysis for the China Cohort, 
which will occur after the analysis for the global study.
8.1.3
Patient-reported outcomes
The following patient-reported outcomes (PRO) questionnaires will be electronically 
administered in this study: Brief Pain Inventory-Short Form (BPI-SF), Functional Assessment 
of Cancer Therapy-Prostate Cancer (FACT-P); and the EuroQol 5-dimension, 5-level health 
state utility index (EQ-5D-5L).  
Patients must complete the PRO questionnaires in the following order: First the BPI-SF and 
analgesic log, then the FACT-P questionnaire, and then the EQ-5D-5L.  If the participant does 
not complete the PROs, the REVPRDI form must be completed during a site visit by a site 
staff to capture the reason the assessment was not completed by the patient.
8.1.3.1
BPI-SF
The BPI-SF (see Appendix J) is a validated, 15-item domain-specific instrument designed to 
assess the severity of pain and the impact/interference of pain on daily functions (Cleeland 
and Ryan 1994).  The BPI-SF will be scored according to the user guide (Cleeland 2009).  All 
BPI-SF pain items including “worst pain” is scored on a 0-10 numeric rating scale (NRS) with 
0=No Pain and 10=Worst Pain Imaginable.  This instrument consists of 2 domains: pain 
severity and pain interference.  The pain severity domain consists of 4 items (item #3, item #4, 
item #5, and item #6) which assess pain at its “worst,” “least,” “average,” and “now” (current 
pain) respectively on the 11-point NRS.  These 4 items may be averaged as a composite pain 
severity score or they may be interpreted individually (Dworkin et al 2005, Turk et al 2006, 
Dworkin et al 2008, Food and Drug Administration 2009).  In this study, the “worst pain” 
(item 3) will be used as a single item in assessing pain progression.  A composite pain severity 
score from all the 4 items will also be evaluated as ‘pain severity progression’.  A 2- or more 
point change in the average pain severity or in “worst pain” item is considered clinically 
meaningful.
The pain interference domain score is a mean of 7 items: general activity (item #9A), mood 
(item #9B), walking ability (item #9C), normal work (item #9D), relations with other people 
(item #9E), sleep (item #9F), and enjoyment of life (item #9G), each scored on an 11-point 
NRS from 0 (Does not interfere) to 10 (Completely interferes).  Based on the BPI-SF scoring 
manual, the following items are not used in scoring pain severity or pain interference domains: 
items #1, #2, #7 and #8. Item #7 (a free text field) describing pain medication use is captured 
separately in more detail using the Analgesic Log.
The BPI-SF analgesic log (captured on ePRO device) will be completed by the patient as 
specified in the SoA (Section 1.1).

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8.1.3.2
Analgesic log
The analgesic log will be implemented using the ERT Medication Module™, a component of 
the ERT eCOA System that serves for accurately tracking patient consumption of concomitant 
and/or rescue medications.  The Medication Module allows medication data capture via the 
ERT eCOA Universal App, followed by the review and management of that data by sites and 
sponsors.  The Medication Module provides a consistent, easier-to-use and more efficient tool 
as compared to paper-based reporting.  Using the module, patients will record all analgesic 
medication dosages and dosage times.    The Medication Module includes the 2 main 
components and a report: 
(a) Global Master Medication List – This list will be developed collaboratively by ERT 
and AstraZeneca and will contain all approved analgesic drug names including generic 
names and formulations.  The list will be updated over the course of the study via an 
approval workflow process, when necessary.
(b) eCOA Universal App Medication Diary – The medication diary will allow patients to 
record analgesic medications between visits and identify when any new medications not 
previously approved have been taken.
(c)  Medication Report – This interactive report allows sites to see when their patients 
have taken new medications, resolve those medications through an approval workflow, 
and remotely update the tailored list of medications available on a patients’ eCOA 
Universal App.
The analgesic log is study specific (not generic) and screenshots will be available and 
submitted along with the Clinical Study Protocol to the Institutional Review Board 
(IRB)/Ethics Committees (ECs).
8.1.3.3
Analgesic use scoring
Although information on all analgesics used by patients in pain control will be collected using 
the analgesic log, only changes in opiate are considered in pain progression evaluation in line 
with FDA recommendation.  Opiates consumed by patients will be converted into oral 
morphine equivalents (OMEs) as defined in Chung et al 2014.  The analgesic quantification 
algorithm (AQA) developed by Chung et al 2014 will be used to quantify and score analgesic 
use in the study.  The AQA is an 8-point scale that assigns a score as follows:
•
0=No analgesic 
•
1=Non-opioid analgesics 
•
2=Weak opioids (eg, codeine, tramadol) 
•
3=Strong opioids ≤75 mg OME per day 

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•
4=Strong opioids >75–150 mg OME per day
•
5=Strong opioids >150–300 mg OME per day
•
6=Strong opioids >300–600 mg OME per day
•
7=Strong opioids >600 mg OME per day
Opiate analgesic use (AQA score) will be assessed at timelines specified in the SoA 
(Section 1.1).  The average daily OME will require at least 4 days of data and will be used to
assign the AQA score.  An increase of 1 point or more in the AQA score from a starting value 
of 1 or higher OR ≥ 2 points in AQA score from a starting value of 0 is considered a clinically 
meaningful increase in opiate use.  Similarly, a decrease of 1 point or more in the AQA score 
from a starting value of 2 or higher is considered a clinically meaningful decrease in opiate 
use.
8.1.3.4
FACT-P
The FACT-P (Appendix J) is a disease-specific 39-item questionnaire included for the 
purpose of assessing HRQoL and prostate cancer-specific symptoms.  It is a well-established 
measure of HRQoL/health status commonly used in prostate cancer clinical studies.  The 
FACT-P was developed specifically for patients with advanced prostate cancer and has been 
found to be reliable and valid in this population (Esper et al 1997).  The FACT-P consists of 5 
subscales: Physical Well-Being (PWB; 7 items), Functional Well-Being (FWB; 7 items), 
Emotional Well-Being (EWB; 6 items), Social Well-Being (SWB; 7 items), and Additional 
Concerns or Prostate Cancer Subscale (PCS) specific to prostate cancer (12 items). All 
FACT-P questions are scored on a 5-point Likert scale from 0 to 4 (0 being not at all and 4 
being very much).  Negatively stated items are reversed by subtracting the response from 4. 
For all subscales, symptoms index, and individual item scores, the higher the score, the better 
the HRQoL/symptom. In addition to the Total and Subscale scores, the FACT-P also supports 
the calculation of the Functional Assessment of Cancer Therapy-General (FACT-G) total 
score (sum of PWB, SWB, EWB and FWB scores), a Trial Outcome Index (TOI) score (the 
sum of the PWB, FWB and PCS scores), and the FACT Advanced Prostate Symptom Index-6 
(FAPSI-6), a symptom score made up of 6 items from within the FACT-P (3 pain items, 1 
fatigue item, 1 weight loss item, and 1 condition getting worse item).
FACT-P assessments will be at timelines as specified in the SoA (Section 1.1).  Scoring of the 
FACT-P will be based on the user manual.
8.1.3.5
EQ-5D-5L
The EQ-5D is a standardised measure of health status developed by the European Quality of 
Life (EuroQoL) Group in order to provide a simple, generic measure of health for clinical and 
economic appraisal (EuroQol Group 1990), see Appendix J.  Applicable to a wide range of 

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health conditions and treatments, it provides a simple descriptive profile and a single index 
value for health status that can be used in the clinical and economic evaluation of health care 
as well as in population health surveys.  The questionnaire assesses 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression.  Each dimension has 
5 response options (no problems, slight problems, moderate problems, severe problems, and 
extreme problems) that reflect increasing levels of difficulty (EuroQol Group 2013).  Since 
2009, the EuroQoL group has been developing a more sensitive version of the EQ5D (the 
EQ-5D-5L), which expands the range of responses to each dimension from 3 to 5 levels of 
increasing severity (Herdman et al 2011).  Preliminary studies indicate that the 5 level (5L) 
version improves upon the properties of the 3 level (3L) measure in terms of reduced ceiling 
effect, increased reliability, and an improved ability to differentiate between different levels of 
health (Pickard et al 2007, Janssen et al 2008a, Janssen et al 2008b).  The patient will be asked 
to indicate his current health state by selecting the most appropriate level in each of the 
5 dimensions.  The questionnaire also includes a visual analogue scale, where the patient will 
be asked to rate current health status on a scale of 0 to 100, with zero being the worst 
imaginable health state. 
EQ-5D-5L assessments will be at timelines as specified in the SoA (Section 1.1).
8.1.3.6
Administration of PRO questionnaires
During the study, each patient will take 1 handheld device home for completing all ePRO 
assessments (ePROs will be self-administered by the patients using these handheld devices).  
The analgesic use log using the ERT Medication Module™ will also be administered 
electronically alongside the ePROs.
All assessments should be completed according to the following parameters:

Without assistance from site staff or relatives/friends according to the assessment 
schedules (see SoA, Section 1.1).

Before any other study procedures are conducted at a given visit.

Before being seen by a study nurse or physician.
Each centre must allocate the responsibility for the administration of the ePROs to a specific 
individual (eg, a research nurse or study coordinator) and, if possible, assign a backup person 
to cover if that individual is absent.  Approximately 15 to 30 minutes is required for patients 
to complete the questionnaires.  Patients may complete some of the ePROs (FACT-P and 
EQ-5D-5L [see Sections 8.1.3.4 and 8.1.3.5]) at study sites if the assessment time point 
coincides with a scheduled site visit; otherwise, patients may complete the ePROs at home.  
Similarly, during the post-progression period, patients should complete ePROs at home or at 
the study site if a scheduled visit coincides with the time point.  If patients have had scans or 

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other tests at an outside facility or missed a scheduled data collection site visit, ePROs should 
still be completed by the patient at home for that scheduled visit within the window period.
The significance and relevance of the data should be explained carefully to participating 
patients so that they are motivated to comply with data collection.  Reminders should be sent 
to patients at home as needed to ensure compliance with the assessment schedules.
The following best practice guidelines should be followed when collecting PRO data via an 
electronic device:

PRO questionnaires completed at site visits must be completed prior to treatment 
administration and ideally before any discussions of health status to avoid biasing the 
patient’s responses to the questions.  As feasible, site staff should also ensure PRO 
questionnaires are completed prior to other study procedures, such as collection of 
laboratory samples, to further minimize bias.

When each instrument is due to be completed, the following order should be observed: 
BPI-SF, Analgesic Log, FACT-P, and then EQ-5D-5L.

PRO questionnaires must be completed by the patient in private.

The research nurse or appointed site staff must explain to the patient the value and 
relevance of study participation and inform them that these questions are being asked 
to find out, directly from them, how they feel.  The research nurse or appointed site 
staff should also stress that the information is confidential.  Therefore, if the patients 
have any medical problems, they should discuss them with the doctor or research nurse 
separately from the ePRO assessment.

The research nurse or appointed site staff must train the patient on how to use the 
ePRO device, using the materials and training provided by the ePRO vendor, and 
provide guidance on whom to call if there are problems with the device if the patient is 
completing the ePRO at home.

The research nurse or appointed site staff should remind patients that there are no right 
or wrong answers.

The research nurse or appointed staff must avoid clarifying items in order to avoid 
bias.

The patient should not receive help from relatives, friends, or clinic staff to answer the 
PRO questionnaires.  If a patient uses visual aids (eg, spectacles or contact lenses) for 

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reading and does not have them when he attends the clinic, the patient will be 
exempted from completing the PROs at the clinic.

Site staff must not read or complete the PRO questionnaires on behalf of the patient.  If 
the patient is unable to read the questionnaire (eg, is blind or illiterate), that patient is 
exempted from completing PRO questionnaires and may still participate in the study.  
Patients exempted in this regard should be flagged appropriately by the site staff.

The patient should be given sufficient time to complete the PRO questionnaires at his 
own speed.
The research nurse or appointed site staff must monitor compliance to ensure all data is 
captured.  Compliance must be checked at each study visit to identify problems early.  If a 
patient’s compliance drops below 85%, they will be flagged in the routine compliance report 
generated by the ePRO system and a check-in call from the site to ask the patient if he has any 
difficulties is highly recommended.
8.1.4
Other assessments
8.1.4.1
Time to first subsequent anticancer therapy or death (TFST)
All anticancer treatments (including, but not limited to, chemotherapy and targeted agents), 
and the investigator’s opinion of response to these treatments plus the date of progression, 
following discontinuation of study treatment, must be recorded.
Subsequent systemic anticancer therapies (excluding radiotherapy) will be reviewed prior to 
data unblinding to assess which represent clinically important treatments intended to control 
prostate cancer.  Any patient not known to have died at the time of the analysis and not known 
to have had a further anticancer therapy will be censored at the last known time to have not 
received subsequent therapy, ie, the last follow-up visit where this was confirmed.
8.1.4.2
Overall survival (OS)
Assessments for survival will be conducted every 12 weeks following objective disease 
progression or treatment discontinuation; see Figure 2.  
Survival information may be obtained via telephone contact with the patient, patient’s family, 
by contact with the patient’s current physician, or local death registries as described in 
Section 7.3. 
8.1.4.3
Time to second progression or death (PFS2)
Following the progression event used for the primary variable rPFS (the first progression), 
patients will be assessed every 12 weeks for second progression on next-line anticancer 
therapy by investigator assessment of radiological progression, clinical symptomatic 
progression, PSA progression or death (PFS2).  The patient’s status at first progression will be 

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used as the reference for assessment of PFS2.  RECIST 1.1 and PCWG-3 assessments will not 
be collected for assessment of PFS2.  The date of PFS2 assessment and investigator opinion of 
progression status (progressed or nonprogressed) at each assessment will be recorded in the 
eCRF.
8.1.4.4
Symptomatic skeletal-related event (SSRE)
Assessments for SSREs will be conducted at every visit from randomisation up to the 
discontinuation visit as defined in the SoA (Section 1.1).  
8.2
Safety assessments 
Planned time points for all safety assessments are provided in the SoA (see Section 1.1).
8.2.1
Clinical safety laboratory assessments
See Table 14 for the list of clinical safety laboratory tests to be performed and the SoA 
(Section 1.1) for the timing and frequency.  All protocol-required laboratory assessments, as 
defined in Table 1 must be conducted in accordance with the laboratory manual and the SoA.
The investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables.  
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7.
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator.  The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
The clinical chemistry, haematology and urinalysis will be performed at a local laboratory at 
or near to the investigator site.  Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site. 
Table 14
Laboratory safety variables
Haematology (whole blood)
Chemistry: electrolytes 
(serum/plasma)
Chemistry: liver function 
(serum/plasma)
B-Haemoglobin (Hb)
S/P-Potassium
S/P-Creatinine
B-Haematocrit (Hct)
S/P-Calcium, total
S/P-Bilirubin, total
B-Red blood cell (RBC) count
S/P-Sodium
S/P-Bilirubin, direct
B-White blood cell (WBC) count 
with differential
S-Carbon dioxide (CO2) or 
bicarbonate (HCO3-)
S/P-Alkaline phosphatase (ALK-P)

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B-Leukocyte count
S-Chloride (Cl)
S/P-Aspartate aminotransferase 
(AST)
B-Absolute neutrophil count
S-Magnesium
S/P-Alanine aminotransferase 
(ALT)
B-Absolute lymphocyte count
S-Phosphorus 
Amylase
B-Platelet count
S/P-Albumin
B-Mean cell volume (MCV)
Fasting glucose (plasma/whole 
blood)
S/P-Urea or blood urea nitrogen 
(BUN)
P/B-Fasting glucose
S/P-Total protein
Coagulation factors
S/P-Lactate dehydrogenase (LDH)
Prothrombin (PT)
Serum lipids
S-Gamma-glutamyl transferase 
(GGT) (at screening only)
Activated partial thromboplastin 
time (aPTT)
S-Cholesterol
International normalised ratio 
(INR)
S-High density lipoprotein (HDL)
S-Low density lipoprotein (LDL)
Urinalysis (dipstick)
S-Triglycerides
U-Hb/erythrocytes/blood 
Additional tests
U-protein/Albumin 
S-Prostate specific antigen (PSA)
Microscope examination of 
abnormalities
S-Testosterone, total
NB. In case a patient shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN please refer to 
Appendix G ‘Actions required in cases of increases in liver biochemistry and evaluation of Hy’s Law’, for 
further instructions.
ULN, Upper limit of normal.
8.2.1.1
Coagulation
Tests for prothrombin time (PT), partial thromboplastin time (PTT), and international 
normalised ratio (INR) will be performed at timelines as specified in the SoA (Section 1.1).
Patients taking warfarin may participate in this study; however, it is recommended that INR be 
monitored carefully at least once per week for the first month, then monthly if the INR is 
stable.
Each coagulation test result will be recorded in the eCRF.
8.2.1.2
Bone marrow or blood cytogenetic samples
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
haematological toxicities as defined in Section 8.4.4.1.

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Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity.  If it is not 
possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to carry out the tests on a blood sample.  Full reports must be 
provided by the investigator for documentation on the Patient Safety database.  These data are 
not required to be entered into eCRF.
8.2.2
Physical examinations
A complete physical examination will be performed at screening and include an assessment of 
the following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal (including spine 
and extremities) and neurological systems.
A symptom-directed physical examination will be performed at other timelines as specified in 
the SoA (Section 1.1). 
A symptom-directed physical examination will be additionally performed if clinically 
indicated at any other time for all patients.  Patients with hypertension at baseline need to be 
monitored closely, and BP must be recorded at all visits. 
Investigators should pay special attention to clinical signs related to previous serious illnesses; 
new or worsening abnormalities may qualify as AEs, see Section 8.3.7 for details.
8.2.3
Vital signs
Vital signs (including blood pressure, pulse rate and body temperature) will be assessed at 
timelines as specified in the SoA (Section 1.1).
Weight will be assessed at timelines as specified in the SoA (Section 1.1).
The date of collection and measurement will be recorded on the appropriate eCRF.
Any changes in vital signs should be recorded as an AE, if applicable.  For information on 
how AEs based on changes in vital signs should be recorded and reported, see Section 8.3.7. 
8.2.4
Electrocardiogram
Twelve-lead resting ECGs will be performed at timelines as specified in the SoA 
(Section 1.1).
Twelve-lead resting ECGs are required within 7 days of start of study treatment and will be 
additionally performed every 12 weeks during the study treatment period, study treatment 

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discontinuation visit, 30-days follow-up visit, and if clinically indicated at any other time for 
all patients. 
The investigator or designated physician will review each of the timed 12-lead resting ECGs 
on each of the study days when they are collected.
ECGs will be recorded at 25 mm/sec.  All ECGs should be assessed by the investigator as to 
whether they are clinically significantly abnormal / not clinically significantly abnormal.  If 
there is a clinically significant abnormal finding, the investigator will record it as an AE on the 
eCRF.  The original ECG traces must be stored in the patient medical record as source data.
8.2.5
Other safety assessments 
8.2.5.1
ECHO or MUGA
Assessments will be performed at screening and thereafter as clinically indicated.  Patient 
must have a left ventricular ejection fraction measurement of at least 50% by echocardiogram 
(ECHO) (preferable) or multigated acquisition scan Cardiology A (MUGA), a maximum of 14 
days prior to randomisation.  The same method used for pre-randomisation assessment 
preferably should also be used when clinically indicated later.
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this Section.
The definitions of an AE or SAE can be found in Appendix D.
Adverse events will be reported by the patient (or, when appropriate, by a caregiver, 
surrogate, or the patient's legally authorised representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE.  For information on how to follow-up AEs 
see Section 8.3.3.
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.
8.3.2
Time period and frequency for collecting AE and SAE information 
Adverse events, including SAEs, will be collected from time of signature of informed consent 
form, throughout the treatment period, including study treatment discontinuation (+7 days of 

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last study drug dose), and the 30-day (+7 days) follow-up after last study drug dose.  
Assessments may be conducted by phone if not tied to a scheduled visit.
All ongoing AEs/SAEs and any new AEs/SAEs identified during the 30-calendar-day 
follow-up period after the last dose of study treatment must be followed to resolution.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix D.  The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs in former study patients.  
However, if the investigator learns of any SAE, including a death, at any time after a patient’s 
last visit and he/she considers the event to be reasonably related to the Study treatment or 
study participation, the investigator may notify the sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix D.
8.3.2.1
Adverse events after the 30 day follow-up period 
For Pharmacovigilance purposes and characterisation, any SAE of MDS/AML or new primary 
malignancy occurring after the 30-day follow-up period should be reported to AstraZeneca 
Patient Safety regardless of investigator’s assessment of causality or knowledge of the 
treatment arm.  Investigators will be asked during the regular follow-up for overall survival if 
the patient has developed MDS/AML or a new primary malignancy and prompted to report 
any such cases.
At any time after a patient has completed the study, if an investigator learns of any SAE 
including sudden death of unknown cause, and he/she considers there is a reasonable 
possibility that the event is causally related to the investigational product, the investigator 
should notify AstraZeneca, Patient Safety.
If patients who are gaining clinical benefit are allowed to continue study treatment post data 
cut off and/or post study completion, then all SAEs must continue to be collected and reported 
to Patient Safety within the usual timeframe.
Otherwise, after study treatment completion (ie, after any scheduled post-treatment follow-up 
period has ended) there is no obligation to actively report information on new AEs or SAEs 
occurring in former study patients.  This includes new AEs/SAEs in patients still being 
followed up for survival but who have completed the post-treatment follow-up period 
(30 days).

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8.3.3
Follow up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each patient 
at subsequent visits/contacts.  All SAE/non-serious AEs/AEs of special interest (as defined in 
Appendix D and Section 8.3.13) will be followed until resolution, stabilisation, the event is 
otherwise explained, or the patient is lost to follow-up.
Any AEs that are unresolved at the patient’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically indicated, 
but without further recording in the eCRF.  AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.
Any SAE or non-SAE that is ongoing at the time of the 30-day follow-up, must be followed 
up to resolution unless the event is considered by the investigator to be unlikely to resolve, or 
the patient is lost to follow-up.  AstraZeneca retains the right to request additional information 
for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.4
Adverse event data collection
The following variables will be collected for each AE

AE (verbatim)

The date when the AE started and stopped

CTCAE grade and changes in CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the olaparib/placebo (yes or no)

Action taken with regard to olaparib/placebo and abiraterone, prednisone or prednisolone

AE caused patient’s withdrawal from study (yes or no)

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date investigator became aware of SAE

AE is serious due to 

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

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
Causality assessment to other medication

Description of AE
8.3.5
Causality collection
The investigator will assess causal relationship between study treatment and each AE, and 
answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that 
the event may have been caused by the olaparib or abiraterone?’
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix D to the Clinical 
Study Protocol.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: ‘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 AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the Clinical Study Report.  Deterioration as compared to baseline in protocol-
mandated laboratory values, vital signs and ECG abnormalities should therefore only be 
reported as AEs if they fulfil any of the SAE criteria or are the reason for discontinuation of 
treatment with the Investigational Product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.

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Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study (see Sections 8.3.9 and 8.3.10).
8.3.8
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
≥3xULN together with total bilirubin ≥2xULN will need to be reported as SAEs if criteria for 
Potential Hy’s Law (PHL) are met.  Please refer to Appendix G for further instruction on 
cases of increases in liver biochemistry and evaluation of Hy’s Law.
8.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the Investigational Product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new, or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an AE.  Events, which are unequivocally 
due to disease progression, should not be reported as an AE during the study.
8.3.10
New cancers
The development of a new primary cancer should be reported as an AE (see Section 8.3.13
Olaparib adverse events of special interest) and would in most cases meet seriousness criteria 
(with the exception of some non-melanoma skin cancers).  New primary malignancies are 
those that are not the primary reason for the administration of the study treatment and have 
developed after the inclusion of the patient into the study.  They do not include metastases of 
the original cancer.  Symptoms of metastasis or the metastasis itself should not be reported as 
an AE/SAE, as they are considered to be disease progression.
8.3.11
Lack of efficacy
When there is deterioration in the cancer, for which the study treatment(s) is being used, there 
may be uncertainty as to whether this is lack of efficacy or an AE.  In such cases, unless the 
Sponsor or the reporting physician considers that the study treatment contributed to the 
deterioration of the condition, or local regulations state to the contrary, the deterioration 
should be considered to be a lack of efficacy and not an AE.
8.3.12
Deaths
All deaths that occur during the study, or within the protocol-defined 30-day post-study 
follow-up period after the administration of the last dose of study treatment, must be reported 
as follows:

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
Death clearly the result of disease progression should be reported to the study monitor at 
the next monitoring visit and should be documented in the DEATH eCRF but should not 
be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to the study monitor as a SAE within 24 hours
(see Section 8.4.1 for further details).  The report should contain a comment regarding the 
co-involvement of progression of disease, if appropriate, and should assign main and 
contributory causes of death.  This information can be captured in the ‘death eCRF’.
Deaths with an unknown cause should always be reported as a SAE.  A post-mortem may be 
helpful in the assessment of the cause of death, and if performed a copy of the post-mortem 
results should be forwarded to AstraZeneca within the usual timeframes.
8.3.13
Olaparib adverse events of special interest
Adverse events of special interest (AESIs) are events of scientific and medical interest specific 
to the further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca.  AESIs for olaparib are the Important 
Identified Risk of MDS/AML, and the Important Potential Risk of new primary malignancy 
(other than MDS/AML), and the Potential Risk of pneumonitis.  All AESIs will be recorded in 
the eCRF.
A questionnaire will be sent to any investigator reporting an AESI to the safety database, as an 
aid to provide further detailed information on the event.  During the study, there may be other 
events identified as AESIs that require the use of a questionnaire to help characterise the event 
and gain a better understanding regarding the relationship between the event and study 
treatment.
8.3.14
Safety data to be collected following the final DCO of the study 
For patients, continuing to receive olaparib + abiraterone or abiraterone treatment after the 
final DCO, it is recommended that the patients continue site visits and Investigators monitor 
the patients’ safety laboratory results prior to and periodically during treatment with olaparib 
+ abiraterone or abiraterone in order to manage AEs in accordance with the olaparib or 
abiraterone dose modification and toxicity management guidelines (see Section 8.4.4). 
China cohort: All data after the final DCO and database closure will be recorded in the patient 
notes, with the exception of SAEs and pregnancy will not otherwise be reported for the 
purposes of this study. All SAEs that occur in participants still receiving Olaparib (or within 
the 30 days following the last dose of Olaparib) after the final DCO must be reported as 
detailed in Section 8.4.1.

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8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day ie, immediately but no later than 24 hours of when he or she becomes 
aware of it.
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site staff how to proceed 
investigators or other site personnel send relevant CRF modules by fax to the designated 
AstraZeneca representative. 
The reference document for definition of expectedness/listedness is the Investigators Brochure 
for olaparib and the European Union SmPC for the abiraterone, prednisone and prednisolone.
For further guidance on the definition of a SAE, see Appendix D of the Clinical Study 
Protocol.
8.4.1.1
Paternal exposure 
Patients should refrain from fathering a child or donating sperm during the study and for 
3 months following the last dose.

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Pregnancy of the patients’ partners is not considered to be an AE.  However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) occurring from the date of the first dose until 3 months after 
the last dose should, if possible, be followed up and documented. 
8.4.2
Medication Error, Drug Abuse, and Drug Misuse
8.4.2.1
Timelines
If an event of medication error, drug abuse or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one day, ie, immediately but no later than 24 hours of when they become aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within one (initial fatal/life-threatening or follow-up 
fatal/life-threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the event of medication error, drug abuse, or misuse (see Section 8.4.2) 
and within 30 days for all other events
8.4.2.2
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.
The full definition and examples of medication error can be found in Appendix D 8.
8.4.2.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix D 8.
8.4.2.4
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
The full definition and examples of drug misuse can be found in Appendix D 8.
8.4.3
Reporting Overdose
Investigators should be advised that any patient who receives a higher dose than that intended 
should be monitored closely, managed with appropriate supportive care and followed up 
expectantly.

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There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established.  In the event of overdose with abiraterone, please 
see local prescribing information.
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 for olaparib is 300 mg twice 
daily (tablet).  Abiraterone must be used according to local prescribing information.
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately.

An overdose with associated Aes is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the Ecrf and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF module.
If an overdose on an IMP or AstraZeneca NIMP occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 
one or 5 calendar days for overdoses associated with an SAE (see Section 8.3.2) and within 
30 days for all other overdoses.
8.4.4
Management of adverse events related to olaparib
Any toxicity observed during the course of the study could be managed by interruption of the 
dose of olaparib or dose reductions (Table 17).  Repeat dose interruptions are allowed as 
required, for a maximum of 4 weeks on each occasion.  If the interruption is any longer, the 
study team must be informed.  Olaparib can be dose reduced to 250 mg twice daily as a first 
step and to 200 mg twice daily as a second step.  If the reduced dose of 200 mg twice daily is 
not tolerable, no further dose reduction is allowed and olaparib should be discontinued. 
Once dose is reduced, escalation is not permitted (except following concomitant treatment 
with CYP3A4 inhibitors – see Section 6.5).
For management of toxicities for patients treated with abiraterone see Section 8.4.5.
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF.

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8.4.4.1
Management of haematological toxicity
Management of anaemia
Anaemia should be managed as described in Table 15.
Table 15
Management of anaemia
Haemoglobin
Action to be taken
Hb < 10 but ≥ 8 g/dL 
(CTCAE Grade 2)
First occurrence:
Give appropriate supportive treatment and investigate causality. 
Investigator judgement to continue olaparib with supportive treatment (eg, 
transfusion) or interrupt dose for a maximum of 4 weeks. Olaparib can be 
restarted if Hb has recovered to >9 g/dL.
Subsequent occurrences:
If Hb <10 but ≥9 g/dL investigator judgement to continue olaparib with 
supportive treatment (eg transfusion) or dose interrupt (for max of 4 weeks) and 
upon recovery dose reduction may be considered (to 250 mg twice daily as a first 
step and to 200 mg twice daily as a second step).
If Hb <9 but ≥8 g/dL, dose interrupt (for max of 4 weeks) until Hb ≥9 g/dL and 
upon recovery dose reduction may be considered (to 250 mg twice daily as a first 
step and to 200 mg twice daily as a second step). 
Hb < 8 g/dL
(CTCAE Grade 3)
Give appropriate supportive treatment (eg, transfusion) and investigate causality. 
Interrupt olaparib for a maximum of 4 weeks until improved to Hb ≥9 g/dL.
Upon recovery dose reduce to 250 mg twice daily as a first step and to 200 mg 
twice daily as a second step in the case of repeat Hb decrease.
CTCAE, Common Terminology Criteria for Adverse Events; Hb, Haemoglobin.
Common treatable causes of anaemia (eg, iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  In some cases, 
management of anaemia may require blood transfusions.  For cases where patients develop 
prolonged haematological toxicity (≥2-week interruption/delay in olaparib due to CTCAE 
grade 3 or worse anaemia and/or development of blood transfusion dependence), refer to 
guidance later in this section for the management of this. 
Management of neutropenia, leukopenia and thrombocytopenia
Neutropenia, leukopenia and thrombocytopenia should be managed as described in Table 16.
Table 16
Management of neutropenia, leukopenia and thrombocytopenia
Toxicity
Olaparib dose adjustment
CTCAE Grade 1-2
Investigator judgement to continue treatment or if dose interruption, this should 
be for a maximum of 4 weeks; appropriate supportive treatment and causality 
investigation

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

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Patient Safety.  Olaparib should be discontinued if patient’s diagnosis of MDS and/or AML is 
confirmed.
8.4.4.2
Management of non-haematological toxicity
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each 
occasion.  If the interruption is any longer than this the study monitor must be informed.  
Where toxicity reoccurs following re-challenge with olaparib, and where further dose 
interruptions are considered inadequate for management of toxicity, then the patient should be 
considered for dose reduction or must permanently discontinue study treatment.
Olaparib can be dose reduced to 250 mg twice daily as a first step and to 200 mg twice daily 
as a second step.  Olaparib must be interrupted if any National Cancer Institute (NCI)-CTCAE 
grade 3 or 4 adverse event occurs which the investigator considers to be related to 
administration of olaparib.
Management of new or worsening pulmonary symptom
If new or worsening pulmonary symptoms (eg, dyspnoea) or radiological abnormalities occur 
in the absence of a clear diagnosis, an interruption in olaparib 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 olaparib can be restarted, if deemed appropriate by the investigator.  If 
significant pulmonary abnormalities are identified, these need to be discussed with the 
AstraZeneca Study Physician.
Management of nausea and vomiting
Events of nausea and vomiting are known to be associated with olaparib treatment.  These 
events are generally mild to moderate (CTCAE grade 1 or 2) severity, intermittent and 
manageable on continued treatment.  The first onset generally occurs in the first month of 
treatment for nausea and within the first 6 months of treatment for vomiting.  For nausea, the 
incidence generally plateaus at around 9 months, and for vomiting at around 6 to 7 months.
No routine prophylactic anti-emetic treatment is required at the start of olaparib treatment; 
however, patients should receive appropriate anti-emetic treatment at the first onset of nausea 
or vomiting and as required thereafter, in accordance with local treatment practice guidelines.  
Alternatively, olaparib tablets can be taken with a light meal/snack (ie, 2 pieces of toast or a 
couple of biscuits).

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As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), generally 
a single agent antiemetic should be considered eg, dopamine receptor antagonist, 
antihistamines or dexamethasone.
Interruptions for intercurrent non-toxicity related events
Dose interruption of olaparib for conditions other than toxicity resolution should be kept as 
short as possible.  If a patient cannot restart olaparib within 4 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with the AstraZeneca study physician.
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF. 
Olaparib should be stopped at least 3 days prior to planned surgery.  After surgery, olaparib 
can be restarted when the wound has healed.  No stoppage of olaparib is required for any 
needle biopsy procedure.
Olaparib should be discontinued for a minimum of 3 days before a patient undergoes radiation 
treatment.  Olaparib should be restarted within 4 weeks as long as any bone marrow toxicity 
has recovered.
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, patients 
should be advised to use caution while driving or using machinery if these symptoms occur. 
Table 17
Dose reductions for olaparib
Initial Dose
Following re-challenge post-
interruption: Dose reduction 1
Dose reduction 2
300 mg twice daily
250 mg twice daily
200 mg twice daily
8.4.4.3
Renal impairment
If subsequent to study entry and while still on study therapy, a patient’s estimated creatinine 
clearance (CrCl) falls below the threshold for study inclusion (≥51 mL/min), retesting should 
be performed promptly. 
A dose reduction is recommended for patients who develop moderate renal impairment 
(calculated creatinine clearance by Cockcroft-Gault equation or based on a 24-hour urine test 
of between 31 and 50 mL/min) for any reason during the course of the study: the dose of 
olaparib should be reduced to 200 mg twice daily.

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Because the CrCl determination is only an estimate of renal function, in instances where the 
CrCl falls to between 31 and 50 mL/min, the investigator should use his or her discretion in 
determining whether a dose change or discontinuation of therapy is warranted.
Olaparib has not been studied in patients with severe renal impairment (creatinine clearance 
≤30 mL/min) or end-stage renal disease; if patients develop severe impairment or end stage 
disease it is recommended that olaparib be discontinued.
8.4.5
Management of toxicities related to abiraterone
Please refer to the respective, locally applicable prescribing information (eg, Zytiga 
Prescribing Information, Zytiga SmPC) for further details.
8.5
Pharmacokinetics
Pharmacokinetic sampling will be performed in a subset of patients, planned to include 
approximately 50 patients per treatment group (ie, olaparib+abiraterone or 
placebo+abiraterone), at specific timepoints after multiple dosing.  The PK analysis of the 
plasma concentration data for olaparib, abiraterone and Δ4-abiraterone will be performed at 
AstraZeneca Research & Development or by a clinical research organisation identified by 
AstraZeneca Research & Development.  The actual sampling times will be used in the PK 
calculations.
The plasma concentration-time data will be analysed using non-compartmental analysis 
(NCA) to determine the PK of olaparib, abiraterone, and Δ4-abiraterone (a metabolite of 
abiraterone) at steady state and to evaluate the effect of olaparib on abiraterone PK.  PK 
samples are to be taken as a blood sample for determination of plasma concentrations of 
olaparib, abiraterone and Δ4-abiraterone per the SoA (Section 1.1).  The actual date and time 
of dosing on the PK study day must be recorded in the eCRF and source data.  IP dosing 
confirmation for the 3-day-period prior to the PK study day should be recorded in source data. 
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory manual.
Note: these samples will not be collected from patients in China.
8.5.1
Determination of drug concentration
Samples for determination of drug concentration in plasma will be analysed by analytical test 
sites on behalf of AstraZeneca, using appropriate validated bioanalytical methods and 
analytical methods.  Samples collected at pre-dose, 30 minutes, 2 hours, 5 hours, and 8 hours 
post-dose will be used to analyse olaparib plasma concentration.  Samples collected at 

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pre-dose, 30 minutes, 2 hours, 3 hours, 5 hours, and 8 hours post-dose will be used to analyse 
abiraterone and Δ4-abiraterone concentrations.  Full details of the analytical methods used 
will be described in a separate bioanalytical report.
Full instructions for collection, labelling, storage and shipment of samples are provided in the 
Laboratory manual.  Results will only be reported for samples shipped within a timeframe for 
which the stability of olaparib in the samples has been validated and shown to be acceptable.
8.5.2
Storage and destruction of pharmacokinetic samples
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalisation or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
requested for future analyses.  
Pharmacokinetic samples may be destroyed or anonymised by pooling.  Additional analyses 
may be conducted on the anonymised, pooled PK samples to further evaluate and validate the 
analytical method.  Any results from such analyses may be reported separately from the 
Clinical Study Report.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the Clinical Study 
Report but separately in a Bioanalytical Report.
 
8.6
Pharmacodynamics
Please refer to Sections 8.7 and 8.8 for pharmacodynamic parameters evaluated in this study.
8.7
Genetics
8.7.1
Collection of mandatory genetic samples
The patient’s consent to participate in the genetic research components of the study is 
mandatory. 
The baseline blood samples for genetic research (germline and circulating tumour DNA 
[ctDNA], respectively), and archival or newly collected tumour tissue sample that meets the 
specimen guidelines outlined in the Laboratory Manual will be obtained from the patients at 
timelines as specified in the SoA (Section 1.1).  Upon randomisation, the tumour specimen 
should be shipped to the central laboratory per the instructions specified in the Laboratory 
Manual.

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Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.  
In the event of a tumour tissue test failure, a replacement tumour sample may be requested 
from the patient.  If a replacement sample is not available, the patient can continue in the 
study.
Note: FFPE samples for central tissue HRR testing will be collected for the China cohort.
8.7.1.1
Determination of HRR gene mutation
AstraZeneca or designated organisations will investigate the genetic samples for alterations in 
genes in the HRR pathway.  These analyses are required to establish the presence or absence 
of a deleterious or suspected deleterious HRR gene mutation in the germline or tumour.  Other 
hereditary or sporadic cancer linked genes will be tested as part of these commercial next 
generation sequencing tests.  Data and samples collected as part of the study may be used for 
development of current or future diagnostic tests, as required.
Genetic samples (ctDNA and tumour tissue) will be tested for mutations in the following 
14 genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, 
RAD51B, RAD51C, RAD51D, and RAD54L.  
Germline blood testing (Myriad myRisk) will be performed to determine germline versus 
somatic HRRm status in the following genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, 
CHEK2, PALB2, RAD51C, and RAD51D.  The Myriad myRisk test is not able to assess 
mutations in CDK12, CHEK1, FANCL, RAD51B, and RAD54L.
Mutation status
Mutation status will be determined using a ctDNA-based test (FoundationOne Liquid CDx) or 
a tumour tissue test (FoundationOne CDx). 
Patients will be classified into one of three categories of mutation status:

HRRm: Any deleterious or suspected deleterious HRR gene mutation detected.

Non-HRRm: No deleterious or suspected deleterious HRR gene mutation detected.

Unknown: Patients where mutation testing was not performed or where mutation testing 
failed.
HRRm testing for the China cohort
For the China cohort, HRR mutation status will be determined using a tissue based HRR test 
at a China-based central laboratory.   Although the genetic testing (HRR) is retrospective, the 
provision of tumour sample is mandatory.  Patients must consent to the use of tumour samples 
for HRRm analysis and future diagnostic development work.  Sample requirements will be 
provided in the Laboratory Manual.

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Population
Description
PK Analysis Set
Note: This analysis is not applicable for the China 
cohort
All patients who received at least 1 dose of 
randomised study drug and provided at least 1 post-
dose analysable plasma sample for PK analysis will 
be included in the PK analysis set.  Patients with 
major protocol deviations including changes to the 
procedures that may impact the quality of the data, or 
any circumstances that can alter the evaluation of the 
PK may be excluded from the PK analysis set.
BICR, Blinded independent central review; BoR, Best overall response; DCR, Disease control rate; DoR, 
Duration of response; EFR, Evaluable for response; FAS, Full analysis set; ITT, Intention-to-treat; PK, 
Pharmacokinetics.
Table 19
Analysis populations – China cohort
Population
Description
China Full Analysis Set
The China full analysis set comprises all patients 
randomised into the study in China and will be 
analysed according to randomised treatment (ITT 
principle).  Any important deviations from 
randomised treatment will be listed and considered 
when interpreting the efficacy and safety data.
China Safety Analysis Set
The safety analysis set will consist of all randomised 
patients in the China cohort who received any amount 
of olaparib, placebo or abiraterone.  Safety data will 
not be formally analysed but summarised using the 
safety analysis set, according to the treatment 
received.  If a patient receives at least one dose of 
olaparib study treatment they will be summarised in 
the olaparib and abiraterone arm for safety 
summaries.  If a patient randomised to olaparib and 
abiraterone receives placebo and abiraterone (or 
abiraterone only), they will be summarised in the 
placebo and abiraterone treatment group for safety 
summaries. 
FAS, Full analysis set; ITT, Intention to treat
9.4
Statistical analyses
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment arm.  Continuous variables will be summarised by the number of observations, 
mean, standard deviation, median, minimum, and maximum.  Categorical variables will be 
summarised by frequency counts and percentages for each category.  Unless otherwise stated, 
percentages will be calculated out of the population total for the corresponding treatment arm.

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Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of study drug, except for efficacy variables.  For efficacy variables, baseline is 
defined as the last visit prior to randomisation. 
Results of all statistical analysis will be presented using a 95% CI and p-value, unless 
otherwise stated.
9.4.1
Efficacy analyses
9.4.1.1
Primary endpoint: radiological progression-free survival (rPFS)
Progression-free survival is defined as the time from randomisation until the earlier date of 
radiological progression or death (by any cause in the absence of progression), regardless of 
whether the patient withdraws from randomised therapy or receives another anticancer therapy 
prior to progression.
Patients who have not progressed (ie, who have a CR, PR, or SD by RECIST 1.1, and 
non-progressive disease by PCWG-3) and not died at the time of analysis will be censored at 
the time of the earliest date of their last evaluable RECIST assessment (taking the latest target 
lesion, non-target lesion or new lesion scan date) or bone scan assessment that showed 
non-progressive disease (compared to week 8 or compared to baseline at the week 8 visit) (if 
the RECIST and bone scans are at different visits). If the RECIST and bone scan assessments 
are performed at the same visit, then the patient will be censored at the latest of the previous 
RECIST1.1 and bone scan assessments.
However, if the 2 or more consecutive scheduled radiological assessments immediately prior 
to progression or death were not evaluable, the patient will be censored at the time of the latest 
evaluable RECIST 1.1 and bone scan assessment prior to the 2 or more missed assessments.  
If the patient has no evaluable visits or does not have baseline data, he will be censored at 
Day 1 (the date of randomisation) unless he dies within 2 visits of baseline (in which case the 
patient’s date of death will be used).  The rPFS time will always be derived based on 
scan/assessment dates, not visit dates.
The overall visit response will be derived using the algorithm shown in Appendix A Table 26. 
The definitions for the visit bone progression status for bone lesions are shown in Appendix A
Table 28.
When the investigator is in doubt as to whether progressive disease has occurred and, 
therefore, reassesses the patient at a later date, the date of the initial scan should be declared as 
the date of progression if the repeat scans confirm progression.

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Analysis methods
The primary objective of this study is to assess the efficacy of olaparib+abiraterone 
combination therapy vs placebo+abiraterone in terms of rPFS assessed by the investigator in 
patients with mCRPC who have received no prior cytotoxic chemotherapy or NHA.
The rPFS will be analysed using a log rank test stratified by the following factors if 
applicable:

Metastases: bone only vs visceral vs other

Docetaxel treatment at mHSPC stage: yes vs no
Although it is expected that there will be enough rPFS events in each stratum to allow a 
meaningful analysis, if a stratum for either treatment arm contains less than 5 events, then a 
pooling strategy will be employed.  The levels of strata will be collapsed until the minimum 
5 event criterion is achieved for the primary rPFS endpoint. Once the pooling strategy is 
decided, unless there are less than 5 events in a stratum in either treatment, all sensitivity and 
secondary efficacy analyses will be conducted in accordance with the corresponding final 
pooling strategy.  The details will be provided in the SAP.
Stratification variables will be defined according to data from the RTSM (IRT).  If there are 
any patients who were mis-stratified, a sensitivity analysis may be carried out using the
baseline data collected in the eCRF.
The HR and CI will be estimated using a Cox Proportional Hazards Model (with ties=Efron 
and the stratification variables as covariates) and the 2-sided CI will be calculated using a 
profile likelihood approach. 
The HR (olaparib+abiraterone combination therapy vs. placebo+abiraterone) together with its 
corresponding 95% CI and p-value will be presented (a HR less than 1 will favour 
olaparib+abiraterone combination therapy).
A Kaplan-Meier (KM) plot of rPFS will be presented by treatment group.  Summaries of the 
number and percentage of patients experiencing a progression or death event, and the type of 
event (RECIST 1.1 or bone progression or death) will be provided along with median rPFS for 
each treatment arm.
The same analysis model will be used for the subgroup analysis and sensitivity analysis 
described in the following sections, unless indicated otherwise.
The assumption of proportionality will be assessed.  Note that in the presence of 
non-proportionality, the HR will be interpreted as an average HR over the observed extent of 

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follow-up.  Proportionality will be tested firstly by producing plots of complementary log-log 
(event times) versus log (time) and, if these raise concerns, a time dependent covariate would 
be fitted to assess the extent to which this represents random variation.
The primary analysis will be based on the investigator assessment of rPFS using all scans 
regardless of whether they were scheduled or not.
Subgroup analysis
To assess the consistency of treatment effect across potential or expected prognostic factors, 
the HRs and associated 2-sided CIs will be estimated using a Cox proportional hazard model 
that contains treatment term, subgroup, and treatment-by-subgroup interaction term for the 
subgroups described below.  If there are too few responders or events available for a 
meaningful analysis of a particular subgroup (it is not considered appropriate to present 
analyses where there are less than 5 events in either treatment group per subgroup), the 
relationship between that subgroup and the endpoint will not be formally analysed.  In this 
case, only descriptive summaries will be provided. 
The stratification factors in the primary analysis model are not included for the subgroup 
analyses.
The primary analysis of rPFS will be repeated for the following subgroups, based upon the 
randomisation stratification factors:

Metastases (bone only, visceral or other)

Docetaxel treatment at mHSPC stage (yes or no)
Values collected on the eCRF will be used to define subgroups for stratification factors.
The following subgroup analyses will also apply (HRRm subgroups are defined in 
Section 8.7.1.1):

HRRm status subgroup (HRRm, non-HRRm, unknown) based on a ctDNA-based test 
(FoundationOne Liquid CDx)

HRRm status subgroup (HRRm, non-HRRm, unknown) based on a tissue test 
(FoundationOne CDx)

HRRm status subgroup (HRRm, non-HRRm, unknown) based on a germline blood test 
(Myriad my Risk) (when data are available)

Eastern Cooperative Oncology Group (ECOG) performance status at baseline (0 or 1)

Age at randomisation (<65, ≥65)

Region (Asia, Europe, North and South America)

Race (White, Black/African-American, Asian, Other)

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
Baseline Prostate specific antigen (PSA) (above/below median baseline PSA of the 
patients across both treatment groups)
Sensitivity analysis
A sensitivity analysis will be conducted using rPFS as assessed for all patients by BICR per 
RECIST 1.1 and PCWG-3 criteria.  In addition, to assess the sensitivity of the primary rPFS 
analysis, the following supportive analyses will be performed:
a) Evaluation-time bias
Sensitivity analyses will be performed to assess possible evaluation-time bias that may 
be introduced if scans are not performed at the protocol-scheduled time points.  The 
midpoint between the time of progression and the previous evaluable assessment 
(RECIST or PCWG-3) will be analysed as described for the primary analysis of rPFS.  
Note that midpoint values resulting in non-integer values should be rounded down.  
For patients whose death was treated as a rPFS event, the date of death will be used to 
derive the rPFS time used in the analysis.  This approach has been shown to be robust 
to even highly asymmetric schedules (Sun and Chen 2010).
b) Attrition bias
Attrition bias will be assessed by repeating the primary rPFS analysis except that the 
actual rPFS event times, rather than the censored time, of patients who progressed or 
died in the absence of progression immediately following 2, or more, missed tumour 
assessments will be included.  In addition, patients who take subsequent therapy prior 
to progression or death will be censored at their last evaluable assessment prior to 
taking the subsequent therapy.
c) Censoring bias
A Kaplan-Meier plot of the time to censoring will be produced where the censoring 
indicator of the primary rPFS analysis is reversed.
d) Sensitivity analysis using unequivocal clinical progression in addition to radiological 
progression
Repeating primary rPFS analysis with the addition of unequivocal progression as an 
event.  Where unequivocal clinical progression is defined as, cancer pain requiring 
initiation of opioids, need to initiate cytotoxic chemotherapy, radiation therapy or 
surgical intervention for complications due to tumour progression or deterioration in 
ECOG performance to ≥Grade 3.

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e) Sensitivity analysis for confirmation of bone progression
Repeat primary rPFS analysis with revised confirmation criteria for bone progression 
where bone progression accompanied by unequivocal clinical progression does not 
require a confirmatory bone scan.
f)
Sensitivity analysis censoring patients with subsequent therapy or discontinuation of 
study drug
g) Deviation bias
If greater than 10% of patients in either treatment group have important protocol 
deviations that may affect the efficacy, the rPFS analysis will be repeated excluding 
these patients.  Details are described in the SAP.
9.4.1.2
Key secondary endpoint: overall survival
Overall survival is defined as the time from randomisation to death from any cause.  Any 
patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive.  Note: Survival calls will be made 
in the week following the date of DCO for the analysis, and if patients are confirmed to be 
alive or if the death date is post the DCO date these patients will be censored at the date of 
DCO.
Analysis methods
Analysis of OS will be performed using the same methods as in the analysis of rPFS, similarly 
stratified by metastases category and docetaxel treatment at mHSPC stage.
A KM plot of OS will be presented by treatment group.  Summaries of the number and 
percentage of deaths and those alive and censored will be provided along with median time to 
death for each treatment arm.
Subgroup Analysis
The subgroup analyses described in Section 9.4.1.1 for rPFS will be repeated for OS.
9.4.2
Safety analyses
Safety and tolerability will be assessed in terms of AEs and SAEs, physical examination 
findings, vital signs (including BP and pulse rate), ECG findings and laboratory test results 
(including clinical chemistry and haematology parameters).  These will be collected for all 
patients. 

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Analysis methods
The analyses for the safety variables described in this section will be presented using the 
safety analysis set and will be investigated using descriptive statistics by count and percentage 
for discrete variables and by minimum, maximum, mean, median, and standard deviation for 
continuous variables.
9.4.2.1
Adverse events
An AE is the appearance of or worsening of any pre-existing condition, undesirable sign(s), 
symptom(s), or medical condition(s) occurring after signing the informed consent.  All AEs 
will be coded using the MedDRA® dictionary to provide the system organ class and preferred 
term for each AE.  AEs will be grouped separately as AE onset before and after first dose of 
study drug.
Any AE commencing (or worsening) on the same day as the first dose of study treatment, will 
be assumed to occur after study treatment has been administered.  A treatment-emergent AE 
(TEAE) will therefore be defined as an AE with the start date on or after the first dose date, 
and up to and including the 30-day (±7 days) follow-up visit after discontinuation of study 
treatment, until the time of the final analysis (rPFS).
9.4.2.2
Other significant adverse events (OAE)
During the evaluation of the AE data, an AstraZeneca or designated CRO medically qualified 
expert will review the list of AEs that were not reported as SAEs and discontinuation of 
investigational product due to adverse event (DAEs).  Based on the expert’s judgement, 
significant AEs of particular clinical importance may, after consultation with the Global 
Patient Safety Physician, be considered OAEs and reported as such in the Clinical Study 
Report.  A similar review of laboratory/vital signs/ECG data will be performed for 
identification of OAEs.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment.
9.4.2.3
Concomitant medications
Concomitant medications will be classified and summarised according to the WHO Drug 
Dictionary.
Concomitant medications will be classed as either:
1. Concomitant medications starting prior to first dose (pre-study)

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2. Concomitant medications starting on or after first dose date (on study).  Medications 
that start on the same day as the first dose of study treatment will be assumed to occur 
after study treatment has been administered and be classified as on-study.
The number of subjects receiving a medication will be summarised by treatment group. A 
subject is only counted once if receiving the medication more than once.  Disallowed 
medications will be listed.
9.4.2.4
Exposure
Study drug exposure (days) will be defined as time from first dose of the study drug to last 
dose. Exposure will be defined as:
Last dose date – first dose date + 1.
The duration of exposure, interruptions, and reductions of study treatment will be summarised.  
The percentage of the actual dose delivered relative to the intended dose through the end of 
treatment and the percentage of the actual dose delivered relative to the intended dose until 
progression will also be summarized.
9.4.3
Other analyses
9.4.3.1
Secondary endpoint: Time to first subsequent anticancer therapy or death 
(TFST)
Time to first subsequent anticancer therapy is defined as the time from randomisation to the 
earlier of the first subsequent anticancer therapy start date following study treatment 
discontinuation or death from any cause.  Any patient not known to have died at the time of 
the analysis and not known to have had a further anticancer therapy will be censored at the last 
known time to have not received subsequent therapy, ie, the last visit where this was 
confirmed.
Analysis methods
Time to first subsequent anticancer therapy will be analysed using the same methods as in the 
analysis of rPFS, stratified by metastases category and docetaxel treatment at mHSPC stage.
A KM plot of time to first subsequent anticancer therapy will be presented by treatment group.  
Summaries of the number and percentage of patients with subsequent anticancer therapy will 
be provided along with median time to first subsequent anticancer therapy for each treatment 
arm.
9.4.3.2
Secondary endpoint: Time to pain progression (TTPP)
Time to pain progression is defined as time from randomisation to pain progression based on 
the BPI-SF Item 3 “worst pain in 24 hours” and opiate analgesic use (AQA score).

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Pain progression is defined as follows: 
1
For patients who are asymptomatic at baseline, a ≥2 point change from baseline in the 
average (4-7 days) BPI SF Item 3 score observed at 2 consecutive evaluations (with at 
least 2 weeks between the end of the initial visit and the start of the subsequent visit) OR 
initiation of opioid use for pain; 
2
For patients who are symptomatic at baseline (average BPI SF Item 3 score >0 and/or 
receiving opioids), a ≥2 point change from baseline in the average BPI SF Item 3 score 
observed at 2 consecutive visits and an average worst pain score ≥4, and no decrease in 
average opioid use (≥1-point decrease in AQA score from a starting value of 2 or higher) 
OR any increase in opioid use (eg, 1 point change in AQA score) at 2 consecutive 
follow-up visits (with at least 2 weeks between the end of the initial visit and the start of 
the subsequent visit).  Any patient who has more than 2 consecutive visits that are not 
evaluable for pain progression will be censored at the last evaluable assessment.
3
Patients with insufficient data to derive a time to event/censoring will be censored at 
Study Day 1.
Analysis methods
Time to pain progression will be analysed using the same methods as in the analysis of rPFS, 
stratified by metastases category and docetaxel treatment at mHSPC stage.
A KM plot of time to pain progression will be presented by treatment group. Summaries of the 
number and percentage of patients experiencing pain progression will be provided along with 
median time to pain progression for each treatment arm.  
9.4.3.3
Secondary endpoint: Time to opiate use
Time to opiate use is defined as the time from randomisation to the first opiate use for 
cancer-related pain.  Patients who have not received opiates during the study or died prior to 
receiving opiates will be considered censored at the last known on study date of no opiate use.  
Patients receiving opiates at baseline will not be included in this analysis.
Analysis methods
Time to opiate use will be analysed using the same methods as in the analysis of rPFS, 
stratified by metastases category and docetaxel treatment at mHSPC stage.
A KM plot of time to opiate use will be presented by treatment group. Summaries of the 
number and percentage of patients using opiate will be provided along with median time to 
opiate use for each treatment arm.

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9.4.3.4
Secondary endpoint: Time to first symptomatic skeletal-related event (SSRE) 
Time from randomisation to first symptomatic skeletal–related event as defined by any of the 
following or a combination thereof:

Use of radiation therapy to prevent or relieve skeletal symptoms

Occurrence of new symptomatic pathological bone fractures (vertebral or non-
vertebral).  Radiologic documentation is required

Occurrence of spinal cord compression.  Radiologic documentation is required

Orthopaedic surgical intervention for bone metastasis
Patients who have not experienced any of the above conditions will be censored at time of 
death, or time of last SSRE assessment.
Analysis methods
Time to first symptomatic skeletal–related event will be analysed using the same methods as 
in the analysis of rPFS, stratified by metastases category and docetaxel treatment at mHSPC 
stage.
A KM plot of time to SSRE will be presented by treatment group.  Summaries of the number 
and percentage of patients experiencing SSRE will be provided along with median time to 
SSRE for each treatment arm.
9.4.3.5
Secondary endpoint: Time to second progression or death (PFS2)
Time to second progression or death is defined as the time from randomisation to second 
progression on next-line anticancer therapy following study treatment discontinuation, by 
investigator assessment of radiological progression, clinical symptomatic progression, PSA 
progression or death, whichever occurs earlier.
Analysis methods
Time from randomisation to second progression will be analysed using the same methods as 
in the analysis of rPFS, stratified by metastases category and docetaxel treatment at mHSPC 
stage.
A KM plot of time to second progression will be presented by treatment group.  Summaries of 
the number and percentage of patients experiencing second progression will be provided along 
with median time to second progression for each treatment arm.

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9.4.3.6
Secondary endpoint: Pain severity and worst pain
Pain severity is based on the BPI-SF pain severity domain. Worst pain is based on BPI-SF 
Item 3 “worst pain in 24 hours” item.  Absolute and change from baseline scores of pain 
severity and worst pain will be evaluated.
Analysis methods
Change from baseline in the BPI-SF pain severity domain will be analysed using a mixed 
model for repeated measures (MMRM) analysis of all the post-baseline pain severity scores 
for each visit.  The study discontinuation visit and the safety follow-up visit will be excluded 
from this analysis.  Restricted maximum likelihood (REML) estimation will be used.  The 
model will include treatment, visit and treatment by visit interaction as explanatory variables 
and the baseline pain severity score as a covariate, along with the baseline pain severity score 
by visit interaction and the stratification variables determined by the primary pooling strategy.  
Treatment, visit, treatment by visit interaction, baseline pain severity score, baseline pain 
severity score by visit interaction, and the stratification variables will be fixed effects in the 
model.  All model terms, including treatment by visit interaction, will remain in the model 
regardless of significance.  The analysis will be repeated for the BPI-SF worst pain.  The 
details will be described in the SAP.
9.4.3.7
Secondary endpoint: Pain interference
The BPI-SF pain interference domain includes 7 items: general activity (item #9A), mood 
(item #9B), walking ability (item #9C), normal work (item #9D), relations with other people 
(item #9E), sleep (item #9F), and enjoyment of life (item #9G).  The pain interference domain 
is scored as the mean of the 7 interference items.  The mean can be used if more than 50% of 
the total items, or 4 of 7, have been completed on a given administration (Cleeland 2009).  
Absolute and change from baseline scores of pain interference will be evaluated.
Analysis methods
Change from baseline in BPI-SF pain interference domain will be analysed using MMRM as 
per the pain severity endpoint (Section 9.4.3.6). 
9.4.3.8
Secondary endpoint: FACT-P 
FACT-P total score, FACT-G total score, TOI, FWB, PWB, PCS, and FAPSI-6, absolute and 
change from baseline scores for each time point will be calculated for each treatment group.
Table 20 details how visit responses will be defined for the FACT-P total, FACT-G total, 
TOI, FAPSI-6, PCS, PWB, and FWB scores (Cella et al 2009, Webster et al 2003).
A visit response of ‘Improved’, ‘No Change’, ‘Worsened’ or ‘Not evaluable’, as defined 
according to Table 20 and Table 21 will be calculated for each patient for scales assessing 

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prostate cancer symptoms, impact on FWB etc: FACT-P Total, FACT-G Total, TOI, 
FAPSI-6, PCS, PWB, and FWB subscales.
Table 20
Definition of visit response for FACT-P, FACT-G, FAPSI-6, TOI, PCS 
and FWB
FACT-P scale
Maximum change from baseline
FACT-P-Total
10
FACT-G-Total
7
FAPSI-6
3
TOI
9
PCS
3
FWB, PWB
3
FACT-G, Functional Assessment of Cancer Therapy-General; FACT-P, Functional Assessment of Cancer 
Therapy-Prostate Cancer; FAPSI-6, Functional Assessment of Prostate Cancer Symptoms Index-6; FWB, 
Functional Well-Being; PCS, Prostate cancer symptoms; PWB, Physical Well-Being; TOI, Trial outcome index.
The criteria shown in Table 21 will be used to assign a best QoL response based on individual 
visit responses in accordance with the score thresholds in Table 20 (further details will be 
provided in the SAP).  Patients with no evaluable baseline or no post-baseline PRO 
assessments with be assigned to ‘non-evaluable’ for best QoL response.
Table 21
Overall score response criteria
Overall score response
Criteria
Non-evaluable
Has no evaluable baseline or no post-baseline PRO assessments.
Improved
Two consecutive visit responses of ‘improved’
No change
Does not qualify for overall score response of ‘improved’.  Two consecutive visit 
responses of either ‘no change’, or ‘improved’ and ‘no change’
Worsened
Does not qualify for overall score response of ‘improved’ or ‘no change’. A visit 
response of ‘worsened’
Other
Does not qualify for 1 of the above
Analysis methods
FACT-P total score, FACT-G total score, TOI, FWB, PWB, PCS, and FAPSI-6, will be 
summarised using mean, standard deviation, median and range by treatment group for each
visit until there are less than one third of patients with evaluable data.  The absolute and 
change from baseline scores for each time point will be calculated by treatment group.  
Change from baseline in FACT-P total score, FACT-G total score, TOI, FWB, PWB, PCS, 
and FAPSI-6 will be analysed using MMRM as per the pain severity endpoint 
(Section 9.4.3.6).  

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The proportion of patients with best responses of ‘Improved’, ‘No Change’ and “Worsened” 
will be summarised descriptively as number of patients and corresponding percentages for 
each category by treatment group.  Responses will be compared between treatment groups 
using logistic regression, adjusting for metastases status, docetaxel treatment at mHSPC stage.  
Patients who died or discontinued prior to assessment will be classified as ‘Other’.  Overall 
improvement rate will be defined as the proportion of patients with a best overall QoL 
response of “Improved” based on Table 21.
Time to deterioration in FACT-P (FACT-P total score, FACT-G total score, TOI, FWB, PWB, 
PCS, and FAPSI 6) will be analysed using the same method as in the analysis of rPFS.  The 
HRs and 95% CIs will be presented on a forest plot.  Patients who died or discontinued prior 
to assessment will be censored at Study Day 1.
9.4.3.9
Secondary endpoint: Pharmacokinetics 
Pharmacokinetic sampling will be performed in a subset of at least 50 patients per treatment 
group (ie, olaparib+abiraterone or placebo+abiraterone) at specific timepoints after multiple 
dosing according to the schedule of assessments. 
Analysis methods
The plasma concentration-time data will be analysed using NCA to determine the PK of 
olaparib, abiraterone, and Δ4-abiraterone at steady state and to evaluate the effect of olaparib 
on abiraterone PK.  The effect of HRRm status on the PK of olaparib, abiraterone, and 
Δ4-abiraterone will be evaluated if deemed feasible.
9.4.4
Multiplicity strategy for primary and key secondary endpoints
The statistical hypotheses are described and defined in Section 9.1.  The 1-sided alpha of 
0.025 is fully allocated to Ha0 (rPFS).  If the result for rPFS is statistically significant, Hb0 (OS) 
will be tested in a hierarchical fashion.  A multiplicity testing procedure based on the 
graphical approach in group sequential trials of Maurer and Bretz (Maurer and Bretz 2013), 
analogous to a simple sequential gatekeeping method, strongly controls the overall 
family-wise 1-sided error rate of 2.5%.
The rPFS endpoint will be tested at DCO1 and DCO2.  The OS endpoint will be tested at 
DCO1, DCO2 and DCO3.  For each endpoint with interim analysis, O’Brien and Fleming 
spending function (Lan and DeMets 1983, O’Brien and Fleming 1979), calculated based upon 
actual observed events, will be used to strongly control the overall type 1 error, with the 
restriction that alpha spend for the OS interim analysis at DCO1 will not exceed 0.0005.
The multiplicity strategy is illustrated in Figure 3:

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Figure 3
Multiplicity strategy maintaining overall type 1 error rate
OS, Overall survival; rPFS, Radiological progression-free survival.
9.4.5
China cohort
Following the completion of global enrolment, the China cohort will randomise approximately 
108 additional patients at sites in China.  The safety and efficacy data collected will be 
summarised and analysed separately to the global study safety and efficacy analysis sets (as 
defined in Section 9.3).
The primary analysis of efficacy for the China cohort will be an assessment of radiological 
progression (rPFS) (RECIST 1.1 and PCWG-3) on the China full analysis set, as defined in 
Section 9.3.  Where data permit, summaries and analysis of secondary supportive efficacy 
endpoints (including at least but not limited to ORR, time to pain progression, TFST, PFS2 
and OS) will be performed for the China cohort.  Efficacy analyses for the China cohort will 
be performed when the rPFS data from the patients in this cohort are of similar maturity to 
those of the global cohort where significant clinical efficacy is established in the global 
cohort.  The detailed analysis plan will be documented in the China supplementary SAP.
When assessing safety and tolerability, summaries will be produced separately for the China 
cohort based on the China safety analysis set. The China safety analysis set includes all 
patients who are randomised as part of the China cohort and receive at least one dose of 
randomised study treatment.
9.5
Interim analyses
The interim efficacy analyses will be monitored and reviewed by the IDMC at DCO1.  When 
pre-specified interim efficacy boundaries are achieved, AstraZeneca will be contacted, and the 
Unblinded Review Committee may be activated.  More details can be found in the Unblinded 
Review Committee Charter and in Section 9.5.1.  The AZ study team remain blinded during 
this initial review period, as described in Section 6.3.1. 

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10.
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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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Appendix A
Guidelines for Evaluation of Objective Tumour Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumours) in Soft Tissue and PCWG-3 (Prostate Cancer 
Working Group Criteria 3) in Bone Lesions
INTRODUCTION
This appendix details the implementation of RECIST 1.1 Guidelines (Eisenhauer et al 2009) 
and PCWG-3 guidelines (Scher et al 2016) for the D081SC00001 study with regards to 
assessment of tumour burden including protocol-specific requirements for this study.
ASSESSMENT OF SOFT TISSUE DISEASE USING RECIST 1.1 CRITERIA
Definition of measurable, non-measurable, target and non-target lesions
In this study, bone lesions will not be included in the RECIST assessment as target lesions, 
non-target lesions (NTL) or new lesions. The guidelines for bone lesion assessments are 
defined in the bone lesion section of this appendix document.
Measurable:
A lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in 
the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with 
computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for 
accurate repeated measurements.
Non-measurable:

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 to <15 mm short axis at baseline*).

Truly non-measurable lesions include the following: leptomeningeal disease, ascites, 
pleural / pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, abdominal masses/abdominal organomegaly identified by physical 
examination that is not measurable by CT or MRI.

Previously irradiated lesions**
* Nodes with <10 mm short axis are considered non-pathological and should not be recorded 
or followed as NTL.
**Localised post-radiation changes which affect lesion sizes may occur.  Therefore, lesions 
that have been previously irradiated will not be considered measurable and must be selected as 
Non-Target Lesions (NTL) at baseline and followed up as part of the NTL assessment.

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Special cases:

Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in the 
same subject, these should be selected as target lesions.
Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as 
target lesions (TL) at baseline.
Non-target lesions:
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline (except bone lesions which will be assessed as defined in bone lesion section of this 
appendix).
Methods of assessment
The same method of assessment and the same technique should be used to characterise 
each identified and recorded lesion at baseline and during follow-up visits.
A summary of the methods to be used for RECIST assessment is provided below and those 
excluded from tumour assessments for this study are highlighted, with the rationale provided.
Table 23
Summary of methods of assessment
Target Lesions
Non-Target Lesions
New Lesions
CT (preferred)
MRI
CT (preferred)
MRI 
X-ray, Chest x-ray
CT (preferred)
MRI 
X-ray, Chest x-ray
Ultrasound
FDG-PET
CT and MRI 
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and identification 
of any new lesions. 
In the D081SC00001 study it is recommended that CT examinations of the chest, abdomen 
and pelvis will be used to assess tumour burden at baseline and follow-up visits.  CT 
examination with intravenous contrast media administration is the preferred method.  MRI 

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should be used where CT is not feasible or it is medically contraindicated.  For brain lesion 
assessment, MRI is the preferred method.
Every effort should be made to maintain the radiologic imaging modality used at baseline 
throughout subsequent assessments. 
Chest X-ray
In the D081SC00001 study, chest x-ray assessment will not be used for assessment of TL as 
they will be assessed by CT examination or MRI examination.  Chest X-ray can, however, be 
used to assess NTL and to identify the presence of new lesions.
Ultrasound 
In the D081SC00001 study, ultrasound examination will not be used for assessment of TL and 
NTL as it is not a reproducible method, does not provide an accurate assessment of tumour 
size and it is subjective and operator dependent.  Ultrasound examination can, however, be 
used to identify the presence of new lesions.  If new clinical symptoms occur and an 
ultrasound is performed then new lesions should be confirmed by CT or MRI examination.
Endoscopy and laparoscopy 
In the D081SC00001 study, endoscopy and laparoscopy will not be used for tumour 
assessments as they are not validated in the context of tumour assessment.
Tumour markers 
In the D081SC00001 study tumour markers will not be used for tumour response assessments 
as per RECIST 1.1.
In this study the following marker (PSA) are being collected for separate analysis.  However, 
the results will not contribute to tumour response based on RECIST 1.1 assessment.
Cytology and histology 
In the D081SC00001 study histology and cytology will not be used for tumour response 
assessments as per RECIST 1.1 and tumour response assessments will be performed on 
radiological criteria only. 
FDG-PET scan 
In the D081SC00001 study FDG-PET scans may be used as a method for identifying new 
lesions, according with the following algorithm:  New lesions will be recorded where there is 
positive FDG uptake* not present on baseline FDG-PET scan or in a location corresponding 

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to a new lesion on CT/MRI at the same follow-up visit.  If there is no baseline FDG-PET scan 
available, and no evidence of new lesions on CT/MRI scans then follow-up CT/MRI 
assessments should be continued, scheduled as per protocol or clinically indicated, in order to 
confirm new lesions.
* A positive FDG-PET scan lesion should be reported only when an uptake greater than twice 
that of the surrounding tissue is observed.
Tumour response evaluation 
Schedule of evaluation
Baseline assessments should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based 
on signs and symptoms of individual subjects and should be performed no more than 28 days 
before the start of study treatment. Follow-up assessments will be performed every 8 weeks (± 
7 days) after randomisation within the first 24 weeks, and then every 12 weeks until objective 
disease progression assessed by investigator  as defined by RECIST 1.1 (soft tissue) or 
PCWG-3 (bone). Any other sites at which new disease is suspected should also be adequately 
imaged at follow-up.
If an unscheduled assessment was performed and the subject has not progressed, every 
attempt should be made to perform the subsequent assessments at their originally scheduled 
visits.  This schedule is to be followed in order to minimise any unintentional bias caused by 
some subjects being assessed at a different frequency than other subjects.
Target lesions (TL)
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved should be identified as TL at baseline.  
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions), but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimeters.  At baseline the sum of the diameters for all TL will be calculated and reported as 
the baseline sum of diameters.  At follow-up visits the sum of diameters for all TL will be 
calculated and reported as the follow-up sum of diameters.

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Special cases:

For TL measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis. 

If the CT/MRI slice thickness used is > 5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the longest diameter should be recorded as 0 mm.

If a TL splits into 2 or more parts, then record the sum of the diameters of those parts. 

If 2 or more TL merge, then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s).  

If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned.  If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion. 

When a TL has had any intervention eg, radiotherapy, embolisation, surgery etc., during 
the study, the size of the TL should still be provided where possible.
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumour visit 
response for TL.
Table 24
Evaluation of target lesions
Complete Response (CR)
Disappearance of all target lesions since 
baseline.  Any pathological lymph nodes 
selected as target lesions must have a reduction 
in short axis to < 10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of the 
diameters of TL, taking as reference the baseline 
sum of diameters
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD
Progressive Disease (PD)
At least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the 
relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 
5 mm.

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Complete Response (CR)
Disappearance of all target lesions since 
baseline.  Any pathological lymph nodes 
selected as target lesions must have a reduction 
in short axis to < 10 mm.
Not Evaluable (NE)
Only relevant if any of the target lesions were 
not assessed or not evaluable or had a lesion 
intervention at this visit. Note:  If the sum of 
diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a 
target lesion response
Non-target lesions (NTL)
Evaluation of non-target lesions
All other lesions (or sites of disease), except for bone lesions, not recorded as TL should be 
identified as NTL at baseline.  Measurements are not required for these lesions, but their status 
should be followed at subsequent visits.  At each visit an overall assessment of the NTL 
response should be recorded by the investigator.  This section provides the definitions of the 
criteria used to determine and record overall response for NTL at the investigational site at 
each visit.
Table 25
Evaluation of non-target lesions
Complete Response (CR)
Disappearance of all non-target lesions since 
baseline. All lymph nodes must be non-
pathological in size (< 10 mm short axis).
Non CR/Non PD
Persistence of 1 or more NTL 
Progression (PD)
Unequivocal progression of existing non-target 
lesions.  
Unequivocal progression may be due to an 
important progression in 1 lesion only or in 
several lesions.  In all cases the progression 
MUST be clinically significant for the physician 
to consider changing (or stopping) therapy.
Not Evaluable (NE)
Only relevant when 1 or some of the non-target 
lesions were not assessed and, in the 
investigator's opinion, they are not able to 
provide an evaluable overall non-target lesion 
assessment at this visit.
Note:  For subjects without target lesions at 
baseline, this is relevant if any of the non-target 
lesions were not assessed at this visit and the 
progression criteria have not been met.

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To achieve ‘unequivocal progression’ on the basis of non-target lesions, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target lesions, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of 1 or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status.
New lesions
Details of any new soft tissue lesions will also be recorded with the date of assessment.  The 
presence of 1 or more new lesions is assessed as progression. 
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
Evaluation of overall visit soft tissue response
The overall visit response will be derived using the algorithm shown in Table 26.
Table 26
Overall visit soft tissue response
Target lesions
Non-Target lesions
New Lesions
Overall soft tissue 
response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non CR/Non PD 
No
PR
CR
NE
No 
PR
PR
Non PD or NE
No
PR
SD 
Non PD or NE
No
SD
NA
Non CR/Non PD
No
SD (Non CR/Non PD)
NA
NA
No
NED
NE
Non PD or NE
No
NE
NA
NE
No 
NE

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Target lesions
Non-Target lesions
New Lesions
Overall soft tissue 
response
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable, NED = no evidence of disease, NA = not applicable (only relevant if there were no TL and/or 
NTLs at baseline).
ASSESSMENT OF BONE LESION PROGRESSION USING PCWG-3 CRITERIA
Bone lesions will be assessed by bone scan and will not be part of the RECIST v1.1 malignant 
soft tissue assessment.
Method of assessment
Bone lesions identified on a whole body isotopic bone scan at baseline should be recorded and 
followed by the same method as per baseline assessment.  
In the D081SC00001 study isotopic bone scans will be used as a method of assessment to 
identify the presence of new bone lesions at follow-up visits.  New lesions will be recorded 
where a positive and unequivocal hot-spot that was not present on the baseline bone scan 
assessment is identified on a bone scan performed at any time during the study.  The 
investigator should consider the positive hot-spot to be a significant new site of malignant 
disease and represent true disease progression in order to record the new lesion.  
Tumour progression evaluation
Schedule of the evaluation
Baseline assessments should be performed no more than 28 days before the start of study 
treatment. Follow-up assessments will be performed every 8 weeks (± 7 days) after 
randomisation within the first 24 weeks, and then every 12 weeks until objective disease 
progression assessed by investigator as defined by RECIST 1.1 (soft tissue) or PCWG-3 
(bone). 
If an unscheduled assessment was performed and the subject has not progressed, every 
attempt should be made to perform the subsequent assessments at their originally scheduled 
visits.  This schedule is to be followed in order to minimize any unintentional bias caused by 
some subjects being assessed at a different frequency than other subjects.
Documentation of lesions

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All bone lesions (or sites of disease) should be identified at baseline.  Their status should be 
followed at subsequent visits.  At each visit an overall assessment of the bone lesion 
progression should be recorded by the investigator.  This section provides the definitions of 
the criteria used to determine and record bone progression at the investigational site at each 
visit.
Progression on a bone scan is identified using PCWG-3 as follows:

At the first visit after baseline:
If 2 or more new metastatic bone lesions are observed on the bone scan from the first 
visit after baseline, a confirmatory scan performed at the next schedule visit (and a 
minimum of 6 weeks later), must show 2 or more additional new metastatic bone lesions 
(for a total of 4 or more new metastatic bone lesions since the baseline assessment).

All others visits from the second visit after baseline:
For patients without progression at the first visit after baseline, the scan from this first 
visit after baseline now serves as new reference for all subsequent scans, ie, assuming all 
visits are acquired according to schedule all bone scans after week 8 are compared to the 
week 8 scan.  If 2 or more new metastatic bone lesions are observed on scans obtained 
after the first visit after baseline assessment compared to the new reference, a 
confirmatory scan performed preferably no later than the next scheduled visit and at least 
6 weeks later, must show the persistence of, or an increase in, the 2 or more metastatic 
bone lesions.
The date of progression is the date of the first scan documenting the 2 new lesions.  If the 
investigator is in doubt as to whether progression has occurred, it is advisable to continue 
study treatment and reassess the bone lesion status at the next scheduled assessment, or sooner 
if clinically indicated.
The requirements for determination and confirmation of radiological progression by either 
bone scan (bone progression) or CT/MRI (soft tissue progression) are summarised in 
Table 27.
Table 27
Requirements for documentation of progression
Visit Date
Criteria for Bone Progression
Criteria for Soft Tissue 
Progression
First visit after baseline (expected 
week 8)

2 or more new lesions 
compared to baseline bone 
scan.

Requires confirmation at 
least 6 weeks later with > 2 
additional lesions compared 
to the first scan after baseline

Progressive disease on CT or 
MRI by RECIST 1.1

No confirmation required.

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Visit Date
Criteria for Bone Progression
Criteria for Soft Tissue 
Progression
From the 2nd visit after baseline

2 or more new lesions 
compared to the first bone 
scan after baseline.

Requires confirmation at 
least 6 weeks later for 
persistence or increase in 
number of lesions

Progressive disease on CT or 
MRI by RECIST 1.1

No confirmation required.
CT, computed tomography; MRI, magnetic resonance imaging; RECIST, Response Evaluation Criteria in Solid 
tumours.
Evaluation of bone progression status
Table 28 provides the definitions for the visit bone progression status for bone lesions.
Table 28
Bone progression status
Bone progression status
Non Progressive Disease (Non-PD)
No evidence of progression, or appearance of 
1 new bone lesion, or non-fulfilment of the 
progression criteria including new  lesions 
without confirmation of progression
Progressive Disease (PD)
Bone lesions fulfilling the requirements for at 
least 2 new lesions and confirmation of 
progression
Not Evaluable (NE)
Only relevant if a follow-up bone scan is not 
performed
CENTRAL REVIEW
The Contract Research Organisation (CRO) appointed by AstraZeneca to perform the 
independent central review for this study will provide specification for radiological imaging 
protocols in standard acquisition guidelines documentation. 
REFERENCES
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer 
2009;45(2):228-47

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Scher et al 2016
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K. Trial design and objectives 
for castration-resistant prostate cancer: Updated recommendations from the Prostate Cancer 
Clinical Trials Working Group 3. J Clin Oncol 2016;34(12):1402-18

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Appendix B
ECOG Performance Status
Example of performance status (ECOG scale)
DESCRIPTION
ECOG GRADE
Fully active, able to carry on all pre-disease performance without 
restriction.
0
Restricted in physically strenuous activity, but ambulatory and able to carry 
out work of a light or sedentary nature, ie, light housework, office work.
1
Ambulatory and capable of self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
2
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair.
4

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Appendix C
Regulatory, Ethical and Study Oversight Considerations
C 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate
hazard to study patients.  
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
Regulatory Reporting Requirements for Serious Breaches

Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.

A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study.

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
If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
they become aware of it.

In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.

AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter 
details of serious breaches into the EMA CTIS. It is important to note that redacted 
versions of serious breach reports will be available to the public via CTIS.

The investigator should have a process in place to ensure that:

The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach

A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (e-mail address or telephone number) provided by AstraZeneca.
C 2
Financial disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
C 3
Informed consent process
The investigator or his/her representative will explain the nature of the study to the patient or 
his legally authorised representative and answer all questions regarding the study.  
Patients must be informed that their participation is voluntary.  Patients or their legally 
authorised representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
centre. 
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date and time the written consent was 
obtained.  The authorised person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  

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A copy of the ICF(s) must be provided to the patient or the patient’s legally authorised 
representative.  
If a patient declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the patient and he will not be excluded 
from other aspects of the study.
If a patient’s partner becomes pregnant during 3 months after the study, the partner is asked to 
sign the "Adult Study Informed Consent Form for Pregnant Partners of Study Patients" and 
provide information about the pregnancy accordingly.
A patient who is rescreened is not required to sign another ICF if the rescreening occurs 
within 28 days from the previous ICF signature date.
If subjects will be asked to consent to optional exploratory research using the remainder of 
mandatory samples, include text that addresses the use of remaining mandatory samples for 
optional exploratory research.  
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  The investigator or authorised designee will 
explain to each patient the objectives of the exploratory research.  Patients will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period.  The patient will give a separate agreement to allow any 
remaining specimens to be used for exploratory research.  Patients who decline to participate 
in this optional research will indicate this in the ICF.  If a patient withdraws consent to the use 
of donated biological samples, the samples will be disposed of/destroyed, and the action 
documented.  If samples have already been analysed at the time of the request, AstraZeneca 
will not be obliged to destroy the results of this research.
C 4
Data protection
Each patient will be assigned a unique identifier by the sponsor.  Any patient records or data 
sets transferred to the sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred.  
The patient must be informed that his personal study-related data will be used by the sponsor 
in accordance with local data protection law.  The level of disclosure must also be explained 
to the patient.  
The patient must be informed that his medical records may be examined by Clinical Quality 
Assurance auditors or other authorised personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.

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C 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to investigators.
C 6
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and
https://www.clinicaltrialsregister.eu/ as will the summary of the D081SC00001 study results 
when they are available.  The clinical trial and/or summary of D081SC00001 study results 
may also be available on other websites according to the regulations of the countries in which 
the D081SC00001 study is conducted. 
C 7
Data quality assurance
All patient data relating to the study will be recorded on an eCRF unless transmitted to the 
sponsor or designee electronically (eg, laboratory data).  The investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator in accordance with local regulations after study completion 
unless local regulations or institutional policies require a longer retention period.  No records 
may be destroyed during the retention period without the written approval of the sponsor.  No 
records may be transferred to another location or party without written notification to the 
sponsor.

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C 8
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site.
Data reported on the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained.  The investigator may need 
to request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available.
C 9
Publication policy
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission.  This allows the sponsor to protect proprietary information and to provide 
comments.  
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.

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Appendix D
Adverse Event Definitions and Additional Safety Information
D 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a patient or 
clinical study participant administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether it’s  
considered related to the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered.
D 2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils 1 or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity.  

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the patient or may require medical 
treatment to prevent 1 of the outcomes listed above.
D 3
Life-threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure).
D 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.

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D 5
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the patient or may require 
medical treatment 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 
judgement must be used.

Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion) or convulsions 
that do not result in hospitalisation

Development of drug dependency or drug abuse
D 6
Intensity rating scale:
The grading scales found in the revised National Cancer Institute CTCAE version 4.03 will be 
utilised for all events with an assigned CTCAE grading.  For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used.  A copy of the CTCAE can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).  The applicable 
version of CTCAE should be described clearly.
For each episode of an adverse event, all changes to the CTCAE grade attained as well as the 
highest attained CTC grade should be reported.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix D 2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix D 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix D 2.

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D 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a 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.
D 8
Medication Error, Drug Abuse and Drug Misuse
Medication Error

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For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error:

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication (excluding RTSM [IRT] errors)

Wrong drug administered to participant (excluding RTSM [IRT] errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from RTSM (IRT) - including those which lead to 1 of the 
above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non therapeutic effect.

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Any events of drug abuse, with or without associated AEs, are to be captured and forwarded 
to the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used 
both if the drug abuse happened in a study participant or if the drug abuse involves a person 
not enrolled in the study (such as a relative of the study participant).
Examples of drug abuse include but are not limited to:
• The drug is used with the intent of getting a perceived reward (by the study participant or a 
person not enrolled in the study)
• The drug in the form of a tablet is crushed and injected or snorted with the intent of getting 
high.
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant).
Examples of drug misuse include but are not limited to:
· The drug is used with the intention to cause an effect in another person
· The drug is sold to other people for recreational purposes
· The drug is used to facilitate assault in another person
· The drug is deliberately administered by the wrong route
· The drug is split in half because it is easier to swallow, when it is stated in the protocol that it 
must be swallowed whole
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· Only half the dose is taken because the study participant feels that he/she is feeling better 
when not taking the whole dose
· Someone who is not enrolled in the study intentionally takes the drug

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Appendix E
Handling of Human Biological Samples
E 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their life cycle.
The investigator at each centre keeps full traceability of collected biological samples from the 
patients while in storage at the centre until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers.
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.  This is not 
applicable in China since clinical samples will not be exported out of China.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
E 2
Withdrawal of Informed Consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the patient is 
withdrawn from further study participation.
The investigator:

Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca

Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site

Ensures that the patient and AstraZeneca are informed about the sample disposal.

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AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
E 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories (http://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx). For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number 
and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx)

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

Samples routinely transported by road or rail are 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 

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

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Appendix F
Genetics
F 1
Use/analysis of DNA
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity 
and progression of disease.  Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease aetiology; and/or molecular subtype of the disease being treated.  Therefore, 
where local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis from consenting patients.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications.  Genetic research may lead to better understanding of diseases, better diagnosis 
of diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications.  
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the patient´s DNA, ie, the 
entire genome. 
The results of genetic analyses may be reported in the clinical study report (CSR) or in a 
separate study summary.
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on Study treatment or Study treatments of this 
class or indication continues but no longer than 15 years from Last Patient Last Visit or other 
period as per local requirements.
F 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All patients will be asked to participate in this genetic research.  Participation is voluntary and 
if a patient declines to participate there will be no penalty or loss of benefit.  The patient will 
not be excluded from any aspect of the main study.

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Inclusion criteria

For inclusion in this genetic research, patients must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and: provide informed consent 
for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or the following:

Previous allogeneic bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT)
Withdrawal of consent for genetic research:  
Patients may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study.  Voluntary withdrawal will not 
prejudice further treatment.  Procedures for withdrawal are outlined in Section 7 of the main 
Clinical Study Protocol.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the patients at Visit 2 
randomisation.  Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding patients who may withdraw due to an adverse event (AE), 
such patients would be important to include in any genetic analysis.  If for any reason the 
sample is not drawn at Visit 2, it may be taken at any visit until the last study visit.  Only 
1 sample should be collected per patient for genetics during the study.  Samples will be 
collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 
15 years, from the date of Last Patient Last Visit, after which they will be destroyed.  DNA is 
a finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable only by the second, unique number.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organisation.  No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA).

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The link between the patient enrolment/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations.  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 permit tracing of 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 Appendix D.
Informed consent
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study the patient must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the patient and the original filed at the study centre.  The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely withdrawal from the genetic aspect of the study at 
any time.
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, or general physician 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 patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his genetic data.  In addition, Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organisations or health insurance companies.  This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease.  The researchers can 

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only use this information for health-related research purposes.  Researchers may see summary 
results, but they will not be able to see individual patient data or any personal identifiers.  
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical methods and determination of sample size
The number of patients 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 may be prepared where appropriate.
Study and site closure
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development.

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Appendix G
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
G 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Potential Hy’s Law (PHL) and Hy’s Law (HL).  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.  Specific guidance 
on managing liver abnormalities can be found in Section 8.3.8 of the Clinical Study Protocol.
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including local laboratory 
evaluations even if collected outside of the study visits; for example, PHL criteria could be 
met by an elevated ALT from a central laboratory and/or elevated total bilirubin from a local 
laboratory.
The investigator will also review Adverse Event (AE) data (for example, for AEs that may 
indicate elevations in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in the 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met.  
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the investigational product 
(IP).  
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AEs and Serious Adverse Events (SAEs) according to the outcome of the review 
and assessment in line with standard safety reporting processes.
G 2
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× upper limit of 
normal (ULN) together with total bilirubin ≥ 2×ULN at any point during the study following 
the start of study medication irrespective of an increase in alkaline phosphatase (ALP).  

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Hy’s Law (HL)
AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 ×ULN, where no other reason, other 
than the IP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in total bilirubin, but there is no specified time frame within which the 
elevations in transaminases and total bilirubin must occur.
G 3
Identification of potential Hy’s Law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

Total bilirubin ≥ 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 patient meets PHL criteria (see Appendix G 2 for definition) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF
G 4
Follow-up
G 4.1
Potential Hy’s Law criteria not met
If the patient does not meet PHL criteria the investigator will:

Inform the AstraZeneca representative that the patient has not met PHL criteria

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol
G 4.2
Potential Hy’s Law criteria met
If the patient does meet PHL criteria the investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Section8.4 Safety Reporting)

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
Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criteria ‘Important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting

For patients that met PHL criteria prior to starting IP, the investigator is not required to 
submit an SAE of PHL unless there is a significant change* in the patient’s condition
The AstraZeneca Study Physician contacts the investigator, to provide guidance, discuss and 
agree an approach for the study patients’ follow-up (including any further laboratory testing) 
and the continuous review of data.  Subsequent to this contact the investigator will:

Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms 
and signs return to normal or baseline levels, or as long as medically indicated, and 
completes the follow-up SAE Form as required

Investigate the aetiology of the event and perform diagnostic investigations as discussed 
with the AstraZeneca Study Physician

Complete the three Liver CRF Modules as information becomes available 
*A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation or 
in combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the AstraZeneca Study Physician if there is any uncertainty.
G 5
Review and assessment of Potential Hy’s Law cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the AstraZeneca 
Study Physician contacts the investigator in order to review available data and agree on 
whether there is an alternative explanation for meeting PHL criteria other than DILI caused by 
the IP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from the date PHL criteria were met.  The AstraZeneca Global Clinical Lead or equivalent 
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 must follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and total bilirubin 
elevations, a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE:

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
If the alternative explanation is not an AE, the investigator must record the alternative 
explanation on the appropriate CRF

If the alternative explanation is an AE/SAE, the investigator must update the previously 
submitted PHL SAE and AE CRFs accordingly with the new information (reassessing 
event term, causality and seriousness criteria) following the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and total 
bilirubin elevations other than the IP, the investigator must:

Send an updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes  

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made, and 
the investigator must:

Provide any further update to the previously submitted PHL SAE (report term now ‘Hy’s 
Law case’) ensuring causality assessment is related to IP and seriousness criteria is 
‘Medically important’, according to the CSP process for SAE reporting

Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met.  Update the previously submitted PHL SAE report 
following the CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
G 6
Actions required when potential Hy’s Law criteria are met before 
and after starting study treatment
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment.
At the first on-study treatment occurrence of PHL criteria being met, the investigator will 
determine if there has been a significant change in the patients’ condition* compared with the 
last visit where PHL criteria were met.* 

If there is no significant change, no action is required

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
If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Appendix D 5.

*A ‘significant’ change in the patient’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms.  The 
determination of whether there has been a significant change will be at the discretion of 
the investigator, this may be in consultation with the AstraZeneca Study Physician if there 
is any uncertainty.
G 7
Actions required for repeat episodes of Potential Hy’s Law
This section is applicable when a patient meets PHL criteria on study treatment, and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study (eg, chronic or progressing malignant disease, severe infection or liver 
disease), or did the patient meet PHL criteria prior to starting study treatment and at first on-
study treatment visit, as described in Appendix G 6?

If No: Follow the process described in Appendix G 4.1 for reporting a PHL case as an 
SAE.

If Yes: Determine if there has been a significant* change in the patient’s condition 
compared with when PHL criteria were previously met.

If there is no significant change, no action is required.

If there is a significant change, follow the process described in Appendix G 4 for 
reporting a PHL case as an SAE
*A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the investigator; this 
may be in consultation with the AstraZeneca Study Physician if there is any uncertainty.

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Appendix H
Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Not applicable.

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Appendix I
Acceptable Birth Control Methods
Male patients must use a condom when having sexual intercourse with a pregnant woman or 
with a woman of childbearing potential.  Female partners of male patients must use at least 
1 highly effective form of contraception if they are of childbearing potential (as listed below).  
This should be started from the signing of the informed consent and continue throughout the 
period of taking study treatment and for at least 3 months after the last dose of olaparib, or 
they must totally/truly abstain from any form of sexual intercourse (see below).  Male patients 
should not donate sperm throughout the period of taking olaparib and for 3 months following 
the last dose of olaparib.
Highly effective methods of contraception, defined as those that result in a low failure rate (ie, 
less than 1% per year) when used consistently and correctly, are described in the list below.  
Note that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette, which is considered highly effective]; and triphasic combined oral contraceptive 
pills).
Non-hormonal highly effective methods of contraception:

Total/true abstinence: When the patient 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 3 months after last dose for male patients. [Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods, or 
declaration of abstinence solely for the duration of a trial) and withdrawal are not 
acceptable methods of contraception.] 

Vasectomised sexual partner PLUS male condom (with participant assurance that partner 
received post-vasectomy confirmation of azoospermia).

Tubal occlusion PLUS male condom.

Intrauterine device (provided coils are copper banded) PLUS male condom.
Hormonal highly effective methods of contraception:

Combined pill PLUS male condom: Normal and low-dose combined oral pills.

Mini pill PLUS male condom: Progesterone-based oral contraceptive pill using 
desogestrel. Cerazette (Merck Sharp & Dohme) is currently the only highly efficacious 
progesterone-based pill available.

Injection PLUS male condom: Medroxyprogesterone injection (eg, Depo-Provera 
[Pfizer]).

Implants PLUS male condom: Etonorgestrel-releasing implants (eg, Nexplanon [Merck 
Sharp & Dohme]).

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
Patch PLUS male condom: Norelgestromin/ethinyl estradiol transdermal system (eg, 
Xulane).

Levonorgestrel-releasing intrauterine system (eg, Mirena [Bayer]) PLUS male condom.

Intravaginal devices (eg, ethinyl estradiol-/etonogestrel-releasing intravaginal devices 
such as NuvaRing [Merck Sharp & Dohme]) PLUS male condom.

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Appendix J
Patient-Reported Outcomes 

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Appendix K
Changes Related to the COVID-19 Pandemic 
Note: Changes below should be implemented only during study disruptions due to the 
COVID-19 pandemic (eg, during quarantines and resulting site closures, regional travel 
restrictions and considerations if site personnel or study participants become infected with 
SARS-CoV-2 or similar pandemic infection) during which participants may not wish to or 
may be unable to visit the study site for study visits. These changes should only be 
implemented if allowable by local/regional guidelines and following agreement from the 
Sponsor.
Remote Visit to Replace On-site Visit (where applicable)
A qualified health care professional from the study site or third party vendor service may visit 
a remote location as per local SOPs, as applicable. Supplies will be provided for a safe and 
efficient visit. The qualified health care professional will be expected to collect information 
per the CSP.
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the patients using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.
During the COVID-19 pandemic, on-site visits may be replaced by a telemedicine visit if 
allowed by local/regional guidelines. Having a telemedicine contact with the patients will 
allow adverse events and concomitant medication data to be collected according to study 
requirements to be reported and documented. 
Data Capture During Telemedicine or Remote Visits
Data collected during telemedicine or remote visits will be captured in the source documents 
by the qualified health care professional from the study site or third party vendor service, or 
from the patients themselves.

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Appendix L
Olaparib/placebo Product-specific Guidance in Relation to 
the COVID-19 Pandemic
Every effort should be made to follow the CSP.  For clarity, the Sponsor has provided in this 
Appendix a dose modification and management plan for study participants with confirmed or 
suspected COVID-19 who are being treated with olaparib/placebo.
L 1
Study Participant Risks during COVID-19
The risk-benefit balance should be carefully assessed for each patient enrolling in the study 
based on the known safety risks related to COVID-19 infections, individual needs, and local 
guidelines and restrictions. Treating investigators must continue to use their best clinical 
judgment in determining the most optimal care for patients and utmost diligence in 
determining their eligibility for study participation, continued study treatment, and overall 
assessment of benefit/risk of study treatment or participation.
L 2
Study Treatment Administration Impacted by COVID-19 
If an AE or SAE is associated with COVID-19, the investigator should determine whether the 
patient’s treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the clinical study protocol.
Treatment interruptions associated with COVID-19 (AE or logistical issues) should be 
reported according to the eCRF Completion Guidelines. 
For dosing discontinuations, where applicable, the dosing discontinuation guidelines should 
be followed, and the Treatment Discontinuation Form(s) completed. 
L 2.1
Olaparib/placebo: Product-specific Guidance in Relation to the 
COVID-19 Pandemic

Patients must continue to have safety assessments as per protocol schedule.  Alternative 
methods for safety assessments include using local laboratories; follow-up by phone 
contact or virtual visits can be used. 

If it becomes unfeasible to perform the required safety assessments for a patient, then 
study treatment should be interrupted until this can be resumed and the reason clearly 
documented, with reference to COVID-19. 

If a patient tests positive for the COVID-19 virus, interrupting olaparib/placebo treatment 
for 14 days or until symptoms resolve should be considered. Factors that should be taken 
into consideration might include: 

Severity of COVID-19 symptoms 

Status of safety blood results, particularly haemoglobin, neutrophils and lymphocytes 

Benefit risk for the individual patients including curative vs palliative intent of 
treatment and response to olaparib/placebo 

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
If patients present with new or worsening respiratory symptoms such as dyspnoea, cough 
and fever, or an abnormal chest radiologic finding is observed, olaparib/placebo treatment 
should be interrupted and prompt investigation initiated to determine whether symptoms 
are due to COVID-19 or potentially drug-induced pneumonitis. 

Olaparib is cleared by metabolism, predominantly by the CYP3A4/5 isozymes. Therefore, 
the use of olaparib/placebo with the concomitant use of strong inhibitors of these 
isoenzymes including some antibiotics and antivirals (eg telithromycin, clarithromycin, 
protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, 
boceprevir and telaprevir) is not recommended. 
Alternative secure delivery methods for drug supply may be permitted if the patient is unable 
to attend the site, but only provided the critical safety assessments have been performed and 
the delivery methods are in line with local regulatory requirements.
If a site is impacted by the COVID-19 pandemic so that study activities are unable to be 
performed, the AstraZeneca representative should be informed as soon as possible.  Described 
measures taken due to the COVID-19 pandemic are temporary measures and will be repealed 
back to the previous state as soon as the situation allows. 
L 3
Reference
Brahmer et al 2018
Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al.  
Management of Immune-Related Adverse Events in Patients Treated With Immune 
Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice 
Guideline. J Clin Oncol. 2018 Jun 10;36(17):1714-1768.  

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d081sc00001-csp-v2-china
Document Title:
D081SC00001 Clinical Study Protocol version 2 China
Document ID:
Doc ID-003923591
Version Label:
3.0 CURRENT LATEST APPROVED
Server Date
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02-Feb-2024 02:14 UTC
Jie Luo
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.