A Randomized, Open-label Study to Assess the Efficacy and Safety of Olaparib Versus Enzalutamide or Abiraterone Acetate in Chinese Men With Metastatic Castration-Resistant Prostate Cancer Who Have Failed Prior Treatment With a New Hormonal Agent and Have BRCA1/2 Mutations (PROfound-CN)
Phase: PHASE4
Conditions: Metastatic Castration-resistant Prostate Cancer
Sponsor: AstraZeneca

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Clinical Study Protocol  
Study Intervention 
Olaparib 
Study Code 
D081LC00002 
Version 
3.0 
Date 
13 Apr 2023 
A Randomized, Open-label Study to Assess the Efficacy and 
Safety of Olaparib Versus Enzalutamide or Abiraterone Acetate in 
Chinese Men with Metastatic Castration-Resistant Prostate 
Cancer Who Have Failed Prior Treatment with a New Hormonal 
Agent and Have BRCA1/2 Mutations  
(PROfound-CN)  
Sponsor Name: AstraZeneca AB 
Legal Registered Address: 151 85 Södertälje, Sweden 
Regulatory Agency Identifier Number(s): Not applicable  
 
This CSP has been subject to a peer review according to AstraZeneca Standard procedures. 
The CSP is publicly registered and the results are disclosed and/or published according to the 
AstraZeneca Global Policy on Bioethics and in compliance with prevailing laws and 
regulations. 
Redacted for Public Disclosure

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Protocol Number: D081LC00002 
Amendment Number: 2 
Study Intervention: Olaparib 
Study Phase: IV 
Short Title: Clinical Study to Assess the Efficacy and Safety of Olaparib in Chinese 
Patients with Metastatic Castration-Resistant Prostate Cancer Who Have Failed Prior 
Treatment with a New Hormonal Agent and Have BRCA1/2 Mutations 
Acronym: PROfound-CN 
Medical Monitor Name and Contact Information will be provided separately 
International co-ordinating investigator Prof. Fangjian Zhou 
Redacted for Public Disclosure

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 2 (Version 3.0) 
[13-Apr -2023] 
Amendment 1 (Version 2.0) 
[12-Apr-2022] 
Original Protocol (Version 1.0) 
[01-Apr-2021] 
 
Redacted for Public Disclosure

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Amendment 2 (13-Apr-2023) 
Overall Rationale for the Amendment: 
Redacted for Public Disclosure

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
1.3 Schedule of Activities on 
Table 1 and Table 2 
5.2 Exclusion Criteria  
6.6.3 Management of 
Toxicities Related to Olaparib 
8.2.4 Clinical Safety 
Laboratory Assessments 
Table 13 Laboratory Safety 
Variables 
Table 27 Definition of HBV 
Reactivation 
Modify Exclusion 
Criteria 8, add new tests 
at screening and follow-
up. Update toxicity 
management guidance 
for hepatitis B. 
To broaden eligibility 
to allow patients with 
past/resolved or 
chronic hepatitis B to 
enter the study 
provided they meet 
certain pre-defined 
criteria, and to 
provide monitoring 
methods and toxicity 
management 
guidance for these 
participants. This 
change is based on 
the absence of 
hepatotoxicity or risk 
of hepatitis B 
reactivation for 
Olaparib 
monotherapy based 
on current knowledge 
and, therefore to 
permit more 
inclusive eligibility 
on this study.  
Substantial 
2.1.3 Olaparib 
Update olaparib 
approval information in 
China. 
Updated olaparib 
approval information 
in China. 
Non-substantial 
2.2.3 Overall Benefit:Risk 
Conclusion 
Removal of data 
monitoring committee 
description. 
Data monitoring 
committee is not 
applicable for this 
study. 
Non-substantial 
5.1 Inclusion Criteria 
Inclusion Criteria 9: 
Correct the unit of 
Hemoglobin from g/L to 
g/dL. 
Typo correction on 
the unit of 
Hemoglobin. 
Non-substantial 
5.2 Exclusion Criteria 
Exclusion Criteria 6: 
Text regarding 
determination of 
participant eligibility 
updated. 
Clarification needed 
to reinforce 
Investigator’s sole 
accountability with 
determination of 
participant eligibility. 
Non-substantial 
5.2 Exclusion Criteria 
Modify Exclusion 
Criteria 12, to clarify 
To simplify 
description of 
Non-substantial 
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what kind of prior anti-
cancer therapy will be 
prohibited. 
previous treatment 
requirement. 
5.2 Exclusion Criteria 
Updated requirement of 
prior palliative 
radiotherapy in 
Exclusion Criteria 13 . 
According to general 
clinical practice. 
Non-substantial 
6.7 Continued Access to Study 
Intervention after the End of 
the Study 
6.8 Treatment of Overdose 
8.3.16 Reporting of Overdose 
Update section name of 
6.7. 
Separate “overdose” 
section into “6.8 
Treatment of Overdose” 
and “8.3.16 Reporting 
of Overdose”. 
Clinical study 
protocol template 
update. 
Non-substantial 
8.3.15 Medication Error 
Added Drug Abuse and 
Drug Misuse definition. 
Be consistent with 
current AZ process.  
Non-substantial 
8.5.1.1 Mandatory Tumor 
Sample Collection 
Retention period of 
remaining tissue 
samples changed from 
“maximally 5 years after 
study intervention is 
approved for marketing 
in China” to “within one 
year of CSR”. 
Be consistent with 
AZ requirements on 
sample retention in 
China. 
Non-substantial 
Appendix A1 Regulatory and 
Ethical Considerations 
Added sub-heading 
“Regulatory Reporting 
Requirements for 
Serious Breaches”. 
Update required to 
comply with 
regulatory 
requirement (e.g. EU 
CTR) and global 
company 
requirement. 
Non-substantial 
Appendix A6 Dissemination 
of Clinical Study Data 
Updated information 
about timelines for 
submission of trial 
results summaries to EU 
CTIS. 
Update required to 
comply with EU 
CTR. 
Non-substantial 
Appendix A7 Data Quality 
Assurance 
Updated information 
about retention timelines 
of records and 
documents to as 
required by local 
regulations. 
Update required to 
comply with EU 
CTR and global 
company 
requirement. 
Non-substantial 
Appendix A7 Data Quality 
Assurance 
Added text for Sponsor 
role in medical 
oversight and clinical 
reviews. 
Added for 
completeness. 
Non-substantial 
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Amendment 1 (12-Apr-2022) 
Overall Rationale for the Amendment: 
Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
1.1 Number of Participants Add wording “approximately” 
before “42 participants”. 
For operation 
flexibility. 
Non-substantial 
Table 1 Study Schedule – 
Screening (Part 1 and 2) 
Deleted empty line in this 
table. 
Formatting issue in 
original protocol. 
Non-substantial 
2.2.1 Risk Assessment 
Downgrade of pneumonitis 
from important potential risk 
to potential risk. And the 
addition of the new adverse 
drug reaction of venous 
thromboembolic events. 
Changed based on 
Investigator Brochure 
Edition 21 updated 
information. 
Non-substantial 
Figure 1 Study Design 
For stratification factors, 
clarify “measurable” as 
“measurable disease”: 
Clarify the 
stratification factor 
Non-substantial 
5.2 Exclusion Criteria 
Correct the exclusion criteria 
number for criteria number 3 
to number 6. 
Formatting issues, 4-6 
bullet points have been 
missed in original 
protocol. 
Non-substantial 
Table 6 Investigational 
Products 
Change description “HDPE 
bottles with child resistant 
closures” to “blisters and 
cartons”. Change “bottle” to 
“unit”. 
The Package of 
Olaparib changes from 
the bottle to carton and 
blister. 
Non-substantial 
Table 6 Investigational 
Products 
Delete “c. Each dosing 
container will contain 
sufficient medication for at 
least each treatment period 
plus overage. Multiple bottles 
of study treatment will be 
required for dispensing in 
order to make up the desired 
dose”. 
Should be deleted, 
dispensing of drug is 
managed through the 
IRT. 
Non-substantial 
6.4 Study Intervention 
Compliance 
Change “bottle” to “blisters 
and carton(s)” and “carton(s)”. 
The package of 
Olaparib changes from 
Non-substantial 
Appendix B4 Medication 
Error 
Added detailed Drug 
Abuse and Drug Misuse 
definition and examples. 
Be consistent with 
current AZ process. 
Non-substantial 
Table 26 Supportive 
Medications/Therapies 
Updated description of 
bone-targeted treatment. 
According to general 
clinical practice. 
Non-substantial 
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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
the bottle to carton and 
blister. 
Table 13 Laboratory 
Safety Variables 
Remove the "Total white 
blood cell count" in Table 13. 
Both "Leukocyte 
count" and "Total 
white blood cell count" 
display in table 13, it is 
duplicate. 
Non-substantial 
8.3.2.3 Adverse Event 
Variables 
Add NCI-CTCAE version 
number 5.0 in “Severity of 
AE”. 
To clarify NCI-
CTCAE version being 
used for this study. 
Non-substantial 
8.3.7 Disease Progression 
Add section number “8.3.7” 
before section name. 
Formatting issue, 
missing section 
information for this 
part. 
Non-substantial 
8.3.11 Adverse Events of 
Special Interest 
Change wording “Adverse 
Events of Special Interest for 
olaparib are the Important 
Identified Risk of MDS/AML, 
and the Important Potential 
Risks of new primary 
malignancy (other than 
MDS/AML) and 
pneumonitis.” to “Adverse 
Events of Special Interest for 
olaparib are the Important 
Identified Risk of MDS/AML, 
the Important Potential Risk of 
new primary malignancy 
(other than MDS/AML) and 
the Potential Risk of 
pneumonitis.” 
Changed based on 
Investigator Brochure 
Edition 21 updated 
information. 
Non-substantial 
9.2 Sample Size 
Determination 
Add wording “approximately” 
before “42 randomly”. 
For operation 
flexibility. 
Non-substantial 
Appendix D8 Laboratory 
Tests 
Add wording "In this study, a 
local laboratory will be used 
for safety tests and the Hy’s 
Law Laboratory Kit for central 
laboratories is not applicable 
for this study. " 
Central lab is not 
applicable for Hy’s 
Law test. 
Non-substantial 
Appendix E Guidelines for 
Evaluation of Objective 
Tumor Response Using 
RECIST 1.1 Criteria 
(Response Evaluation 
Delete “Plain X-ray:  
Plain X-ray may be used as a 
method of assessment for bone 
NTLs and to identify the 
presence of new bone lesions.” 
Bone lesions will not 
be included in the 
RECIST soft tissue 
assessment. 
Non-substantial 
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Section # and Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
Criteria in Solid Tumors) 
in Soft Tissue and PCWG-
3 (Prostate Cancer 
Working Group Criteria 3) 
in Bone Lesions  
Appendix E Guidelines for 
Evaluation of Objective 
Tumor Response Using 
RECIST 1.1 Criteria 
(Response Evaluation 
Criteria in Solid Tumors) 
in Soft Tissue and PCWG-
3 (Prostate Cancer 
Working Group Criteria 3) 
in Bone Lesions  
Delete “Bone lesions (see 
exception below for soft tissue 
component).” in “Non-
measurable Lesions at 
Baseline” 
Bone lesions will not 
be included in the 
RECIST soft tissue 
assessment. 
Non-substantial  
Appendix E Guidelines for 
Evaluation of Objective 
Tumor Response Using 
RECIST 1.1 Criteria 
(Response Evaluation 
Criteria in Solid Tumors) 
in Soft Tissue and PCWG-
3 (Prostate Cancer 
Working Group Criteria 3) 
in Bone Lesions  
In “Special Considerations 
Regarding Lesion 
Measurability at Baseline”, 
delete “Bone scan, PET scan, 
or plain X-ray are not 
considered adequate imaging 
techniques to measure bone 
lesions; however, these 
techniques can be used to 
confirm the presence or 
disappearance of bone 
lesions.”   
Change wording “Blastic 
lesions are considered non-
measurable” to “Blastic 
lesions are not part of the 
RECIST assessment and must 
be evaluated via PCWG3 (see 
page 120).”  
Bone lesions will not 
be included in the 
RECIST soft tissue 
assessment. 
Non-substantial 
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TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................ 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
TABLE OF CONTENTS .................................................................................................... 10 
LIST OF FIGURES ............................................................................................................ 13 
LIST OF TABLES .............................................................................................................. 13 
1 
PROTOCOL SUMMARY ................................................................................ 15 
1.1 
Synopsis ........................................................................................................... 15 
1.2 
Schema ............................................................................................................. 19 
1.3 
Schedule of Activities ....................................................................................... 20 
2 
INTRODUCTION ............................................................................................ 29 
2.1 
Study Rationale ................................................................................................ 29 
2.1.1 
BRCAm Metastatic Castration-resistant Prostate Cancer.................................... 30 
2.1.2 
Current Treatment Options ................................................................................ 31 
2.1.3 
Olaparib ............................................................................................................ 31 
2.2 
Benefit:Risk Assessment ................................................................................... 32 
2.2.1 
Risk Assessment ............................................................................................... 32 
2.2.2 
Benefit Assessment ........................................................................................... 33 
2.2.3 
Overall Benefit:Risk Conclusion ....................................................................... 34 
3 
OBJECTIVES AND ENDPOINTS ................................................................... 35 
4 
STUDY DESIGN ............................................................................................. 36 
4.1 
Overall Design .................................................................................................. 36 
4.2 
Scientific Rationale for Study Design ............................................................... 37 
4.2.1 
Rationale for the tBRCAm Assay in China ........................................................ 38 
4.3 
Justification for Dose ........................................................................................ 38 
4.4 
End of Study Definition .................................................................................... 38 
5 
STUDY POPULATION .................................................................................... 38 
5.1 
Inclusion Criteria .............................................................................................. 39 
5.2 
Exclusion Criteria ............................................................................................. 41 
5.3 
Lifestyle Considerations ................................................................................... 43 
5.3.1 
Meals and Dietary Restrictions ......................................................................... 44 
5.3.2 
Contraception ................................................................................................... 44 
5.3.3 
Blood Donation ................................................................................................ 44 
5.4 
Screen Failures ................................................................................................. 44 
6 
STUDY INTERVENTION ............................................................................... 45 
6.1 
Study Intervention(s) Administered ................................................................... 45 
6.2 
Preparation/Handling/Storage/Accountability of Interventions .......................... 47 
6.3 
Measures to Minimise Bias: Randomization and Blinding ................................ 48 
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6.4 
Study Intervention Compliance ......................................................................... 50 
6.5 
Concomitant Therapy ........................................................................................ 51 
6.5.1 
Other Concomitant Medication ......................................................................... 52 
6.6 
Dose Modification ............................................................................................ 52 
6.6.1 
Dose Reductions for Olaparib ........................................................................... 52 
6.6.2 
Dose Reductions for Abiraterone Acetate and Enzalutamide ............................. 53 
6.6.3 
Management of Toxicities Related to Olaparib .................................................. 53 
6.6.3.1 
Management of Hematological Toxicity ............................................................ 54 
6.6.3.2 
Management of Non-hematological Toxicity ..................................................... 55 
6.6.3.3 
Renal Impairment ............................................................................................. 57 
6.6.4 
Management of Toxicities related to Enzalutamide and Abiraterone Acetate ..... 58 
6.7 
Continued Access to Study Intervention after the End of the Study ................... 58 
6.8 
Treatment of Overdose ...................................................................................... 58 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................... 59 
7.1 
Discontinuation of Study Intervention ............................................................... 59 
7.1.1 
Follow-up of Participants Post Discontinuation of Study Intervention ............... 61 
7.1.2 
Follow-up of Participants to PFS2 ..................................................................... 61 
7.1.3 
Follow-up for Survival ...................................................................................... 61 
7.2 
Participant Withdrawal from the Study.............................................................. 61 
7.3 
Lost to Follow-up ............................................................................................. 62 
8 
STUDY ASSESSMENTS AND PROCEDURES .............................................. 63 
8.1 
Efficacy Assessments ........................................................................................ 64 
8.1.1 
Imaging Tumor Assessments ............................................................................. 64 
8.1.1.1 
CT and MRI Scans Tumor Assessments (RECIST 1.1)...................................... 66 
8.1.1.2 
Bone Scans Tumor Assessment (Based on PCWG3 Criteria)............................. 66 
8.1.2 
Tumor Evaluation ............................................................................................. 66 
8.1.3 
Central Reading of Scans .................................................................................. 68 
8.1.4 
Time to Second Progression or Death................................................................ 68 
8.1.5 
Symptomatic Skeletal-related Events ................................................................ 69 
8.1.6 
PSA Assessments .............................................................................................. 69 
8.1.7 
Overall Survival ................................................................................................ 69 
8.1.8 
Clinical Outcome Assessments.......................................................................... 69 
8.2 
Safety Assessments ........................................................................................... 69 
8.2.1 
Physical Examinations ...................................................................................... 69 
8.2.2 
Vital Signs ........................................................................................................ 70 
8.2.3 
Electrocardiograms ........................................................................................... 70 
8.2.4 
Clinical Safety Laboratory Assessments ............................................................ 71 
8.2.4.1 
Coagulation ...................................................................................................... 72 
8.2.4.2 
Bone Marrow or Blood Cytogenetic Samples .................................................... 72 
8.2.4.3 
Hepatitis B Blood Test ...................................................................................... 73 
8.2.5 
Other Safety Assessments ................................................................................. 73 
8.2.5.1 
ECOG Performance Status ................................................................................ 73 
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8.3 
Adverse Events and Serious Adverse Events ..................................................... 73 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ................ 74 
8.3.2 
Follow-up of AEs and SAEs ............................................................................. 74 
8.3.2.1 
Adverse Events After the 30-day Follow-up Period ........................................... 74 
8.3.2.2 
Follow-up of Unresolved Adverse Events ......................................................... 75 
8.3.2.3 
Adverse Event Variables ................................................................................... 75 
8.3.3 
Causality Collection .......................................................................................... 76 
8.3.4 
Adverse Events Based on Signs and Symptoms ................................................ 76 
8.3.5 
Adverse Events Based on Examinations and Tests ............................................ 76 
8.3.6 
Hy’s Law .......................................................................................................... 77 
8.3.7 
Disease Progression .......................................................................................... 77 
8.3.8 
New Cancers..................................................................................................... 77 
8.3.9 
Lack of Efficacy ............................................................................................... 78 
8.3.10 
Deaths .............................................................................................................. 78 
8.3.11 
Adverse Events of Special Interest .................................................................... 78 
8.3.12 
Safety Data to be Collected Following the Final Data Cutoff of the Study ......... 79 
8.3.13 
Reporting of Serious Adverse Events ................................................................ 79 
8.3.14 
Pregnancy ......................................................................................................... 80 
8.3.14.1 
Paternal Exposure ............................................................................................. 80 
8.3.15 
Medication Error, Drug Abuse and Drug Misuse ............................................... 81 
8.3.15.1 
Timelines .......................................................................................................... 81 
8.3.15.2 
Medication Error............................................................................................... 81 
8.3.15.3 
Drug Abuse ....................................................................................................... 81 
8.3.15.4 
Drug Misuse ..................................................................................................... 81 
8.3.16 
Reporting of Overdose ...................................................................................... 81 
8.4 
Human Biological Samples ............................................................................... 82 
8.4.1 
Pharmacokinetics .............................................................................................. 82 
8.4.2 
Immunogenicity Assessments ........................................................................... 82 
8.4.3 
Pharmacodynamics ........................................................................................... 82 
8.5 
Human Biological Sample Biomarkers ............................................................. 82 
8.5.1 
Collection of Mandatory Samples for Biomarker Analysis ................................ 82 
8.5.1.1 
Mandatory Tumor Sample Collection ................................................................ 82 
8.5.1.2 
BRCA Mutation Testing of Tumor Biopsy Sample ............................................. 83 
8.5.1.3 
Collection, Analysis and Reporting of Tumor Samples ...................................... 83 
8.6 
Optional Genomics Initiative Sample ................................................................ 84 
8.7 
Medical Resource Utilization and Health Economics ........................................ 84 
9 
STATISTICAL CONSIDERATIONS ................................................................ 84 
9.1 
Statistical Hypotheses ....................................................................................... 84 
9.2 
Sample Size Determination ............................................................................... 84 
9.3 
Populations for Analyses ................................................................................... 85 
9.4 
Statistical Analyses ........................................................................................... 85 
9.4.1 
General Considerations ..................................................................................... 85 
9.4.2 
Efficacy ............................................................................................................ 86 
9.4.2.1 
Calculation or Derivation of Tumor Response Variables.................................... 86 
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9.4.2.2 
Primary Endpoint .............................................................................................. 87 
9.4.2.3 
Secondary Endpoint(s) ...................................................................................... 89 
9.4.3 
Safety ............................................................................................................... 93 
9.4.3.1 
Adverse Events ................................................................................................. 94 
9.4.3.2 
Other Significant Adverse Events (OAE) .......................................................... 95 
9.4.3.3 
Concomitant Medications ................................................................................. 95 
9.4.3.4 
Compliance and Exposure................................................................................. 95 
9.4.3.5 
Other Safety Data ............................................................................................. 96 
9.5 
Interim Analyses ............................................................................................... 96 
9.6 
Independent Data Monitoring Committee ......................................................... 97 
10 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS ........................................................................................ 98 
11 
REFERENCES ............................................................................................... 147 
 
LIST OF FIGURES 
Figure 1 
Study Design ........................................................................................... 20 
Figure 2  
Study Flow Chart ..................................................................................... 21 
Figure 3  
Assessment of Progression by BICR (prior to primary rPFS analysis) ...... 65 
LIST OF TABLES 
Table 1 
Study Schedule – Screening (Part 1 and 2) ............................................... 22 
Table 2 
Study Schedule – On Study Treatment and Discontinuation ..................... 23 
Table 3 
Study Schedule – Follow-up Post Discontinuation of Study Treatment .... 25 
Table 4 
Study Schedule – Participants Switching to Olaparib Following 
Radiological Progression ......................................................................... 27 
Table 5 
Objectives and Endpoints......................................................................... 35 
Table 6 
Investigational Products ........................................................................... 45 
Table 7 
Dose Reductions for Olaparib to Manage Adverse Events........................ 52 
Table 8 
Dose Reduction for Olaparib if Patient Develops Moderate Renal 
Impairment .............................................................................................. 52 
Table 9 
Dose Reductions for Olaparib if Patient Has to Start Taking a Strong or 
Moderate CYP3A Inhibitor ...................................................................... 53 
Table 10 
Management of Anemia ........................................................................... 54 
Table 11 
Management of Neutropenia, Leukopenia and Thrombocytopenia ........... 54 
Table 12 
Requirements for Documentation of Progression ..................................... 67 
Table 13 
Laboratory Safety Variables..................................................................... 71 
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Table 14 
Populations for Analysis .......................................................................... 85 
Table 15 
Summary of Imaging Modalities for Tumor Assessment ........................ 119 
Table 16 
RECIST 1.1 Evaluation of Target Lesions ............................................. 126 
Table 17 
RECIST 1.1 Evaluation of Non-Target Lesions ..................................... 127 
Table 18 
RECIST 1.1 Overall Visit Response ...................................................... 127 
Table 19 
Requirements for Documentation of Progression ................................... 130 
Table 20 
Bone Progression Status ........................................................................ 130 
Table 21 
Highly Effective Methods of Contraception (<1% Failure Rate) ............ 133 
Table 22 
Drugs Known to be Inducers of CYP3A4/5 ........................................... 135 
Table 23 
Drugs Known to be Inhibitors of CYP3A4/5 .......................................... 135 
Table 24 
Prohibited Medications/Therapies .......................................................... 136 
Table 25 
Restricted Medications/Therapies .......................................................... 137 
Table 26 
Supportive Medications/Therapies ......................................................... 139 
Table 27 
Definition of HBV Reactivation ............................................................... 57 
 
LIST OF APPENDICES 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations ......................... 99 
Appendix B 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 105 
Appendix C 
Handling of Human Biological Samples ................................................ 111 
Appendix D 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ......................................................................... 113 
Appendix E 
Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors) in Soft 
Tissue and PCWG-3 (Prostate Cancer Working Group Criteria 3) in 
Bone Lesions ......................................................................................... 119 
Appendix F 
Contraception Requirements .................................................................. 132 
Appendix G 
Concomitant Medications ...................................................................... 134 
Appendix H 
Changes Related to the COVID-19 Pandemic ........................................ 140 
Appendix I 
Olaparib/Investigator’s Choice of NHA Product-specific Guidance in 
Relation to the COVID-19 Pandemic ..................................................... 141 
Appendix J 
Abbreviations ........................................................................................ 143 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A Randomized, Open-label Study to Assess the Efficacy and Safety of 
Olaparib Versus Enzalutamide or Abiraterone Acetate in Chinese Men with Metastatic 
Castration-Resistant Prostate Cancer Who Have Failed Prior Treatment with a New Hormonal 
Agent and Have BRCA1/2 Mutations (PROfound-CN) 
Short Title: Clinical Study to Assess the Efficacy and Safety of Olaparib in Chinese Men 
with Metastatic Castration-Resistant Prostate Cancer Who Have Failed Prior Treatment with a 
New Hormonal Agent and Have BRCA1/2 Mutations 
Rationale: 
Olaparib (LynparzaTM), originally developed by AstraZeneca, is a potent inhibitor of 
polyadenosine 5’diphosphoribose polymerase (PARP). PARP inhibition is a novel approach to 
targeting tumors with deficiencies in DNA repair mechanisms. PARP enzymes are essential 
for repairing single-strand DNA breaks (SSBs). Inhibiting PARPs leads to the persistence of 
SSBs, which are then converted to double-strand DNA breaks (DSBs) during the process of 
DNA replication. During the process of cell division, DSBs can be efficiently repaired in 
normal cells by homologous recombination repair (HRR). Tumors with homologous 
recombination deficiencies, such as metastatic castration-resistant prostate cancer (mCRPC) in 
patients with BRCA1, BRCA2, ATM or other HRR gene mutations, cannot accurately repair 
the DNA damage, which may become lethal to cells as it accumulates. In such tumor types, 
olaparib may offer a potentially efficacious and less toxic cancer treatment compared with 
currently available taxane-based chemotherapy regimens. In Study D081DC00007 
(PROfound), 15 HRR genes were selected based on a mechanistic role in HRR and/or 
preclinical and clinical observations. For this study, only patients with BRCA1 and BRCA2 
mutations will be included.  
Mutations in the BRCA genes are the most prevalent HRR gene mutations in mCRPC (with 
BReast CAncer gene 2 [BRCA2] more prevalent than BRCA1). Enrichment of BRCA1/2 
mutations in advanced prostate cancer has been widely documented in the literature. BRCA2 
mutations are associated with a particular aggressive phenotype, leading to their high 
prevalence. A retrospective case-case analysis of BRCA1/2 and ataxia telangiectasia mutated 
(ATM) germline mutations in advanced and low-risk localized prostate cancer patients 
indicated that mutation carrier status was significantly associated with a more advanced 
prostate cancer diagnosis and progression of the prostate cancer. 
In 2018, prostate cancer was estimated to be the fifth/seventh most common cause of cancer 
death in men and the second/sixth most commonly newly diagnosed cancer in men, 
worldwide/in China, respectively. Most early-stage prostate cancer cases are amenable to 
curative therapy, however, advanced stages are life-threatening. Globally, for patients with 
metastatic disease, the 5-year survival rate is 31%. In China, nearly 54% of the disease is de 
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novo metastatic. For decades, androgen deprivation therapy has been the standard treatment 
for prostate cancer, achieved by surgical or medical castration. Post-castration, the 
development of castration-resistant prostate cancer (CRPC) is only a matter of time. Almost 
all patients dying from prostate cancer will have mCRPC with 90% of overall mortality in 
mCRPC patients due to the underlying malignant disease.  
No single mCRPC standard of care (SoC) exists; the currently approved agents have not been 
developed for a post-new hormonal agent (NHA) setting. Upon progression on NHA therapy, 
the treatment effect of either a sequential NHA or taxane diminishes substantially. For patients 
who have progressed on an NHA who have not received taxane chemotherapy, median overall 
survival (OS) is approximately 8.6 to 12.5 months. Docetaxel may be administered as second-
line therapy, however the efficacy of post-NHA docetaxel appears markedly reduced. 
Treatment with the NHA abiraterone had modest effect on efficacy (median OS 14.8 months) 
in mCRPC patients post-chemotherapy. Clinical practice in China is similar to that in Western 
countries, however, no standard second-line therapy is listed in the Chinese guidelines. 
Furthermore, for BRCAm mCRPC patients no targeted therapy is currently available in China 
as limited studies have been conducted in Chinese patients. 
Subgroup analyses in participants with a BRCA1 or BRCA2 mutation from the PROfound 
study indicate that olaparib provides clinically meaningful and substantial benefit compared to 
investigator’s choice of NHA: 6.8 month improvement in median rPFS (9.8 vs 3.0 months 
respectively; HR 0.22; 95% CI 0.15, 0.32), 5.7 month improvement in OS (median OS 20.1 vs 
14.4 months respectively; HR 0.63; 95% CI 0.42, 0.95). Based on the PROfound study results, 
olaparib has been approved by the US FDA for adult patients with deleterious or suspected 
deleterious germline or somatic HRRm (including BRCAm) mCRPC, who have failed prior 
treatment with abiraterone or enzalutamide (de Bono et al 2020). In the EU and Japan, the 
approved indication is mCRPC patients with BRCA1 or BRCA2 mutation who have 
progressed following prior therapy that included a new hormonal agent. Given that no targeted 
therapy for BRCAm mCRPC is currently available in China due to limited studies conducted 
in this population and the efficacy results in the BRCAm population from PROfound, there is a 
clear rationale for evaluating the potential of olaparib for the treatment of Chinese BRCAm 
mCRPC patients who have failed prior treatment with a new hormonal agent. 
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Objectives and Endpoints 
Objectives 
Outcome measure 
Primary 
To determine the efficacy (as assessed by rPFS) of 
olaparib in participants with mCRPC and deleterious 
or suspected deleterious BRCA1/2 mutations 
rPFS by BICR assessment using RECIST 1.1 (soft 
tissue) and PCWG3 (bone) criteria 
Secondary 
To determine the efficacy (as assessed by ORR) of 
olaparib in participants with mCRPC and deleterious 
or suspected deleterious BRCA1/2 mutations 
Confirmed ORR by BICR assessment in participants 
with measurable disease using RECIST 1.1 (soft 
tissue) and PCWG3 (bone) criteria 
To determine the efficacy (as assessed by OS) of 
olaparib in participants with mCRPC and deleterious 
or suspected deleterious BRCA1/2 mutations 
Overall Survival (OS) 
To further assess the efficacy of olaparib in 
participants with mCRPC and deleterious or 
suspected deleterious BRCA1/2 mutations 
• 
Time from first dose to the first SSRE 
• 
Time from partial or complete response by BICR 
assessment in participants with measurable 
disease (RECIST 1.1) to progression (DoR) 
• 
Time from randomization to opiate use for 
cancer-related pain 
• 
Proportion of participants achieving a ≥50% 
decrease in PSA from baseline to the lowest 
post-baseline PSA result, confirmed by a second 
consecutive PSA assessment at least 3 weeks 
later (PSA50 response) 
• 
Time from randomization to second progression 
by investigator assessment of radiological or 
clinical progression or death (PFS2) 
 
Safety 
To evaluate the safety and tolerability of olaparib 
Safety and tolerability will be evaluated in terms of 
AEs/SAEs, vital signs (including blood pressure and 
pulse), clinical laboratory results (including clinical 
chemistry/hematology parameters), and ECGs. 
 
Overall Design 
Disclosure Statement: This is a Phase IV, randomized, open-label, 2-arm, multicenter study 
assessing the efficacy and safety of olaparib compared with SoC (enzalutamide or abiraterone 
acetate) in Chinese men with mCRPC. 
Participant Population: 
The target population of interest in this study is participants with mCRPC who have failed 
prior treatment with a NHA and have BRCA1/2 mutations.  
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Biomarker selection: All participants must have a documented tumor (tissue) qualifying 
mutation(s) in BRCA1 or BRCA2 (referred to as BRCA1/2), predicted to be deleterious or 
suspected deleterious. All participants must provide a formalin fixed and paraffin embedded 
(FFPE) tumor sample for tissue-based BRCA1/2 mutation testing (China-based central testing 
lab). 
Treatment setting: All participants must have mCRPC and have received and failed prior 
treatment with an NHA (eg, abiraterone acetate or enzalutamide). Prior receipt of other 
anti-prostate cancer therapies, including docetaxel, cabazitaxel, radium-223, and sipuleucel-T 
is permitted but not mandatory. Participants must not have received previous treatment with a 
DNA-damaging cytotoxic chemotherapy (eg, prior platinum-based chemotherapy and 
mitoxantrone are not permitted) or a PARP inhibitor, including olaparib. 
Number of Participants: 
Approximately 700 participants with mCRPC will be screened to achieve approximately 42 
participants with BRCAm mCRPC randomly assigned to study intervention. Refer to Section 
9.2 for further information. 
Intervention Groups and Duration: 
After all Part 1 eligibility criteria have been met, tissue will be submitted for BRCAm testing. 
Participants must have a confirmed qualifying BRCA1/2 status to be eligible for the study. 
Following confirmation of eligibility during screening Part 2 (28-day screening period), 
enroled participants will be randomized in a 2:1 ratio to olaparib or to investigator’s choice of 
NHA (enzalutamide or abiraterone acetate). Randomization will be stratified based on prior 
receipt of taxane chemotherapy (yes vs no) and presence of measurable disease at baseline 
(yes vs no).Participants in the olaparib group will receive olaparib 300 mg oral tablets, twice 
daily. Participants in the investigator’s choice of NHA group will receive either enzalutamide 
160 mg oral capsules/tablets once daily or abiraterone acetate 1000 mg oral tablets (plus 
prednisone 5 mg oral tablets twice daily). Participants will continue to receive study 
intervention until Blinded Independent Central Review (BICR)-assessed radiological 
progression, or after the date of data cut-off (DCO) for the primary analysis until investigator-
assessed radiological progression, as long as they do not meet any of the criteria for treatment 
discontinuation.  
Participants in the investigator’s choice of NHA group will be permitted to switch to olaparib, 
upon objective radiological progression by BICR or, if after the date of DCO for the primary 
analysis, upon investigator-assessed radiological progression.  
Participants may continue to receive olaparib as long as they are continuing to show clinical 
benefit, as judged by the investigator and in the absence of discontinuation criteria. 
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Follow-up of participants post discontinuation of study intervention: 
After study intervention discontinuation, all participants will undergo an end-of-treatment visit 
(within 7 days of discontinuation) and will be followed up for safety assessments 30 (+ 7) 
days after their last dose of study intervention (ie, the safety follow-up visit). 
Participants who have discontinued study intervention in the absence of objective radiological 
progression will be followed up with tumor assessments every 8 weeks (± 7 days) according 
to the Schedule of Activities (SoA) until radiological progression or death regardless of 
whether or not the participant started a subsequent anticancer therapy, unless they have 
withdrawn all consent to study-related assessments. 
In addition, after intervention discontinuation, all participants will be followed up for second 
progression and survival status every 12 weeks (± 14 days) from the date of randomization 
until death, withdrawal of consent, or the end of the study (ie, progression/survival follow-up), 
as per the SoA. 
See Section 6.7 for a description of assessments following study DCOs. 
Independent Data Monitoring Committee: No 
Statistical methods 
The primary analysis of radiological progression-free survival (rPFS) will be performed when 
approximately 21 rPFS events have occurred across both intervention groups (50% maturity). 
The hazard ratio (HR; olaparib vs. investigator choice) together with its corresponding 95% 
confidence interval (CI) and p-value (descriptive) will be presented (a HR less than 1 will 
favor olaparib). The HR for rPFS will be estimated using a Cox Proportional Hazards Model 
(with ties=Efron and the stratification variables previous taxane [yes, no] and measurable 
disease [yes, no] as covariates) and the 2-sided CI will be calculated using a profile likelihood 
approach. It is anticipated that this analysis will be performed 21 months after the first 
participant has been recruited. The key secondary endpoint of overall survival will be 
analyzed using the same methodology specified for the primary endpoint; objective response 
rate will be analyzed using a logistic regression model adjusting for the stratification variable.  
No formal testing of hypotheses will be performed as the study is designed to demonstrate the 
same trend of treatment effect in Chinese men as in the PROfound study, and thus no 
adjustment for multiplicity will be made. 
Safety data will be summarized descriptively and will not be formally analyzed unless 
otherwise specified. 
1.2 
Schema 
The study design diagram is provided in Figure 1. 
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Figure 1 
Study Design 
 
a 
Investigator’s choice of either enzalutamide (160 mg qd) or abiraterone (1000 mg qd plus prednisone 
[5 mg bid]). 
1.3 
Schedule of Activities 
The study flow chart is provided in Figure 2. The procedures for this study are presented in 
the SoAs: screening - Part 1 and 2 (Table 1), on study treatment and discontinuation (Table 2), 
follow-up post discontinuation of study treatment (Table 3) and participants switching to 
olaparib (Table 4). 
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Figure 2  
Study Flow Chart 
 
a 
Sections 5.1 and 5.2. 
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Table 1 
Study Schedule – Screening (Part 1 and 2) 
 
Part 1 
All participants 
Part 2 
 
Day  
 
-28 to -1 
 
Informed consent 
X 
X 
Demographics 
X 
 
Medical and surgical history 
 
X 
Family history of cancer 
X 
 
Prior cancer therapies including radiotherapy 
 
X 
Inclusion/exclusion criteria 
X (all * criteria) f 
X 
ECOG Performance status (0-2) 
 
X 
Physical examination, body weight 
 
X 
Vital signs (includes BP, pulse, and temperature) 
 
X 
ECG 
 
X 
Hematology/clinical chemistry/coagulation a  
 
X 
Blood sample for testosterone 
 
X 
Urinalysis 
 
X 
Tumor tissue sample for BRCA1/2 status b c  
X 
 
HBs Ag, anti-HBc and anti-HBs  
 
X 
HBV DNA h 
 
X 
Tumor Assessment (Bone scan and CT/MRI) d 
 
X 
Adverse Events (from time of consent) e 
X 
X 
Concomitant medications 
 
X g 
a 
Coagulation test should be performed at screening and if clinically indicated. For a list of all required 
laboratory tests please refer to Section 8.2.4. 
b 
Participants must have a confirmed qualifying BRCA 1/2 status based on the tBRCAm assay to be eligible 
for the study (Section 8.6.1). 
c 
Tissue submitted for central BRCAm status testing with the tBRCAm assay only after all (*) eligibility 
criteria in Part 1 have been met. 
d 
RECIST 1.1 assessments will be performed using CT scans of the chest, abdomen, and pelvis (or MRI 
where CT is contraindicated). Any other areas of disease involvement should be additionally imaged based 
on the signs and symptoms of individual participants. Bone scans will be performed as detailed in 
Section 8.1.2, consistent with PCWG3 criteria. Baseline assessments should be performed no more than 
28 days before the date of randomization, and ideally, should be performed as close as possible to the start 
of study treatment. 
e 
In screening part 1, only SAEs related to study procedures must be reported (AEs do not require reporting). 
From screening part 2 onwards - all AEs/SAEs must be reported. 
f 
See Sections 5.1 and 5.2 for marked eligibility (*) criteria.  
g 
Includes all medication being taken from the start of screening part 2 and onwards. 
h     If either HBsAg or anti-HBc is positive, HBV DNA (viral load) must be tested at screening. 
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Table 2 
Study Schedule – On Study Treatment and Discontinuation 
Visit number 
2 
3 
4 
5 
6 
7 
Visit No. 8 
onwards 
Study treatment 
discontinued 
Safety  
follow-up 
Week 
0 
(Day 1) 
4 
8 
12 
16 
20 
24, 
and every 
subsequent 
8 weeks 
Last dose of study 
drug 
30 days after 
last dose 
Visit window 
 
± 7 d 
± 7 d 
± 7 d 
± 7 d 
± 7 d 
± 7 d 
± 7 d 
+ 7 d 
Randomization 
X 
 
 
 
 
 
 
 
 
Physical exam, body weight a  
Xb 
 
 
 
 
 
 
 
 
Vital signs (includes BP, pulse 
and temperature) a 
Xb 
 
 
 
 
 
 
 
 
ECOG performance status  
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG a 
Xb 
 
 
 
 
 
 
 
 
Hematology/clinical chemistry c 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
HBV DNA, HBsAg l 
Every 12 weeks (± 7 days) relative to the date of randomisation 
 
X 
Urinalysis a 
Xb 
 
 
 
 
 
 
 
 
Tumor Assessment (bone scan 
and CT/MRI) d e  
Every 8 weeks (± 1 week) relative to the date of randomization until 
radiological progression  
X f 
 
SSRE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
PSA g 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
including blood transfusions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Opioid use i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study treatment 
dispensed/returned  
X 
X 
X 
X 
X 
X 
X j 
X 
 
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Table 2 
Study Schedule – On Study Treatment and Discontinuation 
Visit number 
2 
3 
4 
5 
6 
7 
Visit No. 8 
onwards 
Study treatment 
discontinued 
Safety  
follow-up 
Week 
0 
(Day 1) 
4 
8 
12 
16 
20 
24, 
and every 
subsequent 
8 weeks 
Last dose of study 
drug 
30 days after 
last dose 
Visit window 
 
± 7 d 
± 7 d 
± 7 d 
± 7 d 
± 7 d 
± 7 d 
± 7 d 
+ 7 d 
Subsequent cancer therapy 
following discontinuation of 
study treatment k 
 
 
 
 
 
 
 
 
X 
a 
To be additionally performed if clinically indicated at any other time. 
b 
If assessed within 7 days before randomization and meets the stated eligibility criteria (if applicable), it does not need to be repeated on Day 1 of study 
treatment unless investigator believes that it is likely to have changed significantly.  
c 
Safety blood samples do not need to be repeated on Day 1 of study treatment if assessed at least 3 weeks after the last dose of chemotherapy but within 
7 days before starting study treatment, unless the investigator believes that it is likely to have changed significantly. Coagulation test should be performed at 
screening and if clinically indicated. For a list of all required laboratory tests please refer to Section 8.2.4. 
d 
Follow-up assessments will be performed every 8 weeks (± 7 days) relative to the date of randomization until radiological progression as assessed by BICR, 
and post primary analysis, as assessed by investigator. Whole body bone scan and CT/MRI of the chest, abdomen and pelvis should be conducted, and any 
other sites at which new disease is suspected should also be appropriately imaged. If an unscheduled assessment was performed and the participant has not 
progressed, every attempt should be made to perform the subsequent assessments at their scheduled visits. 
e 
Bone progression observed by bone scan requires confirmation by bone scan at least 6 weeks later (see Section 8.1.2). Soft tissue progression observed by 
CT or MRI, according to RECIST 1.1 criteria, does not require a confirmatory scan. 
f 
Patients who discontinue study treatment before disease progression should continue follow-up tumor 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. 
g 
PSA values while on the study will not be reported to the site prior to final analysis. 
h 
All ongoing AEs/SAEs and any new AEs/SAEs identified during the 30 calendar days follow-up period after last dose of study medication must be 
followed to resolution . 
i 
Opioid use will be captured by the site in the eCRF. 
j 
Sufficient study treatment should be dispensed for at least each treatment period plus overage, however additional treatment can be dispensed to participants 
to last longer in accordance with local practice. 
k 
All anti-cancer treatments (including, but not limited to, chemotherapy and targeted agents), and the investigator’s opinion of response to them, post 
discontinuation of study treatment need to be recorded. 
l      If either HBsAg or anti-HBc is positive at screening, HBV DNA and HBsAg must be tested every 12 weeks (± 7 days) relative to the date of randomisation 
during the interventional period and at 30-day safety follow-up. Refer to sections 5.2 and 8.2.4 for more detail. 
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Table 3 
Study Schedule – Follow-up Post Discontinuation of Study Treatment 
Visit number 
Off-treatment follow-up for 
progression 
For participants who discontinue 
therapy prior to radiological 
progression a 
2nd Progression and survival 
follow-up 
Follow-up after radiological 
progression 
Visit frequency 
Every 8 weeks per original schedule 
until radiological progression  
Every 12 weeks  
Visit window 
± 7 da 
± 14 d 
Adverse Events 
X b 
X b  
Tumor Assessment (bone scan 
and CT/MRI) 
X c 
 
Opioid use d 
X d 
X d 
Secondary malignancies 
including MDS/AML e  
X 
X 
Subsequent cancer therapy 
following discontinuation of 
study treatment f 
X 
X 
Time to second progression g 
 
X g 
Survival h 
 
X 
a 
Visit schedule for participants who discontinue study treatment prior to radiological progression determined 
by BICR. This includes participants with ≥ 2 new lesions on a bone scan that has not been confirmed by a 
second scan ≥6 weeks later (see Section 8.1.2). Visits continue every 8 weeks (± 7 days) per original study 
schedule until documentation of radiological progression as assessed by BICR. Following radiological 
progression participants move to follow-up for 2nd progression and survival with visits every 12 weeks 
(± 14 days) relative to the randomization date. Until the primary rPFS analysis all imaging assessment and 
study treatment should continue until objective disease progression as assessed by BICR. There is no plan 
for BICR to read any scans dated after the date of DCO for the primary analysis. There will be no need to 
request confirmation of BICR PD after this time point, and the investigator-assessed radiological 
progression will prevail. 
b 
All ongoing AEs/SAEs and any new AEs/SAEs identified during the 30 calendar days follow-up period 
after last dose of study medication must be followed to resolution . 
c 
Imaging assessments (CT/MRI and bone scan) will be performed as per the original schedule every 8 weeks 
(± 7 days) relative to date of randomization until radiological progression as assessed by BICR and post 
primary analysis, by investigator. Bone progression observed by bone scan requires confirmation by bone 
scan at least 6 weeks later (see Section 8.1.2). Soft tissue progression observed by CT or MRI, according to 
RECIST 1.1 criteria, does not require confirmation. 
d 
Opioid use will be captured by the site in the eCRF. After treatment discontinuation, only participants with 
no on-treatment opioid use need to be followed until first opioid use. Continued use does not need to be 
recorded. 
e 
Since some cases of MDS/AML or new primary malignancies develop after discontinuing treatment with 
olaparib, investigators will be asked during the regular follow-up if the participant has developed 
MDS/AML or a new primary malignancy and prompted to report any cases as a SAE (or AE if at least one 
of the criteria for SAE is not met, such as for non-melanoma skin cancers, see Appendix B 2) even after 
discontinuation of therapy and regardless of investigator’s assessment of causality or knowledge of the 
treatment arm (see Sections 8.3.11 and 8.3.2.1). 
f 
All anti-cancer treatments post discontinuation of study treatment (including, but not limited to, 
chemotherapy and targeted agents), and the investigator’s opinion of response need to be recorded. 
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g 
Second progression is based on investigator assessment according to local standard clinical practice and 
includes both radiological 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). 
h 
The status of ongoing, withdrawn (from the study) and “lost to follow-up” participants at the time of an 
overall survival analysis should be obtained by the site personnel by checking the participants notes, 
hospital records, contacting the participants general practitioner and checking publicly available death 
registries, if allowable per local regulations. In the event that the participant has actively withdrawn consent 
to the processing of their personal data the vital status of the participant can be obtained by site personnel 
from publicly available resources where it is possible to do so under applicable local laws (see 
Section 7.1.1). In addition to their regular 12 weekly contact, participants will be contacted in the 7 days 
following a specified date (data cut-off date) for the survival analysis. 
 
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a 
Visit schedule for participants who switch to olaparib post BICR-assessed radiological progression or post 
primary analysis by investigator-assessed radiological progression. Visits every 4 weeks (± 7 days) for 
24 weeks following initiation of olaparib, then visits every 12 weeks (± 14 days). 
b 
Only required at initiation of olaparib treatment. To be additionally performed if clinically indicated at any 
other time. 
c 
All ongoing AEs/SAEs and any new AEs/SAEs identified during the 30 calendar days follow-up period 
after last dose of study medication must be followed to resolution . 
Table 4 
Study Schedule – Participants Switching to Olaparib Following 
Radiological Progression 
Visit number 
Switch to olaparib 
treatment visits 
Treatment 
discontinued 
Safety follow-
up 
2nd Progression 
and survival 
follow-up 
Visit Frequency 
Every 4 weeks for 
24 weeks, then 
every 12 weeks a 
Date last dose of 
olaparib 
30 days after 
last dose of 
olaparib 
Every 12 weeks 
after last dose of 
olaparib 
Visit window 
± 7 d 
± 7 d 
+ 7 d 
± 14 d 
Switch to olaparib ICF 
X 
 
 
 
Physical exam, body weight b 
X b 
 
 
 
Vital signs (includes BP, 
pulse and temperature) b 
X b 
 
 
 
ECG b 
X b 
 
 
 
Hematology/clinical 
chemistry 
X 
X 
X 
 
Urinalysis b 
X b 
 
 
 
HBV DNA, HBsAg 
X 
every 12 weeks (if 
either HBsAg or 
anti-HBc is positive) 
 
X 
 
Adverse Events c 
X 
X 
X 
 
Concomitant medications 
including blood transfusions 
X 
X 
X 
 
Opioid use d 
X d 
X d 
X d 
X d 
Study treatment 
dispensed/returned 
X 
 
 
 
Subsequent cancer therapy 
following discontinuation of 
randomized treatment e 
X 
X 
X 
X 
Secondary malignancies 
including MDS/AML f  
X 
X 
X 
X 
Second Progression g 
X 
X 
 
X 
Survival h 
X 
X 
X 
X 
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d 
Opioid use will be captured by the site in the eCRF. After treatment discontinuation, only participants with 
no on-treatment opioid use need to be followed until first opioid use. Continued use does not need to be 
recorded. 
e 
All anti-cancer treatments post discontinuation of study treatment (including, but not limited to, 
chemotherapy and targeted agents), and the investigator’s opinion of response need to be recorded. 
f 
Since some cases of MDS/AML or new primary malignancies develop after discontinuing treatment with 
olaparib, investigators will be asked during the regular follow-up if the participant has developed 
MDS/AML or a new primary malignancy and prompted to report any cases as a SAE (or AE if at least one 
of the criteria for SAE is not met, such as for non-melanoma skin cancers, see Appendix B 2) even after 
discontinuation of therapy and regardless of investigator’s assessment of causality or knowledge of the 
treatment arm (see Sections 8.3.11 and 8.3.2.1). 
g 
Second progression is based on investigator assessment according to local standard clinical practice and 
includes both radiological 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). 
h 
The status of ongoing, withdrawn (from the study) and “lost to follow-up” participants at the time of an 
overall survival analysis should be obtained by the site personnel by checking the participants notes, 
hospital records, contacting the participants general practitioner and checking publicly available death 
registries, if allowable per local regulations. In the event that the participant has actively withdrawn consent 
to the processing of their personal data the vital status of the participant can be obtained by site personnel 
from publicly available resources where it is possible to do so under applicable local laws (see 
Section 7.1.1). In addition to their regular 12 weekly contact, participants will be contacted in the 7 days 
following a specified date (data cut-off date) for the survival analysis. 
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2 
INTRODUCTION 
Olaparib (LynparzaTM, AZD2281, KU-0059436) is a potent polyadenosine 5’diphosphoribose 
[poly (ADP ribose)] polymerization (PARP) inhibitor (PARP-1, -2 and -3) that is being 
developed as an oral therapy, both as a monotherapy (including maintenance) and for 
combination with chemotherapy and other anti-cancer agents. 
2.1 
Study Rationale 
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair 
mechanisms. PARP enzymes are essential for repairing single-strand DNA breaks (SSBs). 
Inhibiting PARPs leads to the persistence of SSBs, which are then converted to double-strand 
DNA breaks (DSBs) during the process of DNA replication. During the process of cell 
division, DSBs can be efficiently repaired in normal cells by homologous recombination 
repair (HRR). Tumors with homologous recombination deficiencies (HRD), such as metastatic 
castration-resistant prostate cancer (mCRPC) in patients with BReast CAncer gene 1 
(BRCA1), BRCA2, ataxia telangiectasia mutated (ATM) or other HRR gene mutations, cannot 
accurately repair the DNA damage, which may become lethal to cells as it accumulates. In 
such tumor types, olaparib may offer a potentially efficacious and less toxic cancer treatment 
compared with currently available taxane-based chemotherapy regimens.  
BRCA1 and BRCA2 defective tumors are intrinsically sensitive to PARP inhibitors, both in 
tumor models in vivo (Hay et al 2009, Rottenberg et al 2008) and in the clinic (Fong et al 
2009). The mechanism of action for olaparib results from the trapping of inactive PARP onto 
the single-strand breaks preventing their repair (Helleday 2011, Murai et al 2012). Persistence 
of SSBs during DNA replication results in their conversion into the more serious DNA DSBs 
that would normally be repaired by HRR. Olaparib has been shown to inhibit selected tumor 
cell lines in vitro and in xenograft and primary explant models as well as in genetic BRCA 
knock-out models, either as a stand-alone treatment or in combination with established 
chemotherapies. 
In the Study D081DC00007 (PROfound), the following 15 HRR genes were selected based on 
a mechanistic role in HRR and/or pre-clinical and clinical observations: BRCA1, BRCA2, 
ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, 
RAD51C, RAD51D and RAD54L. For PROfound-CN (this study), only patients with BRCA1 
and BRCA2 mutations will be included, as justified below.  
Mutations in the BRCA genes (BRCA1 and/or BRCA2) are the most prevalent HRR gene 
mutations in mCRPC (with BRCA2 more prevalent than BRCA1) (Armenia et al 2018, Chung 
et al 2019, Mateo et al 2015, Robinson et al 2015). Enrichment of BRCA1/2 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 
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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 2015, 
Cheng et al 2015, Mateo et al 2018, Pritchard et al 2016) rather than these mutations being 
acquired under treatment with standard therapies (eg, androgen receptor mutations and 
amplifications [Mateo et al 2018]). Moreover, when BRCA1/2 and ATM germline mutations 
were analyzed in a retrospective case-case study of advanced and low-risk localized prostate 
cancer patients, the mutation carrier status was significantly associated with both a more 
advanced prostate cancer diagnosis and progression of the prostate cancer itself (Na et al 
2017). 
In summary, there is a high unmet medical need for treatment for mCRPC patients with BRCA 
mutations in China. 
AstraZeneca considers that the advanced castration-resistant prostate cancer patient population 
involved in this study falls under the advanced cancer limited life expectancy definition 
outlined in ICH S9 guideline “Nonclinical Evaluation For Anticancer Pharmaceuticals” and 
meets the requirements outlined in the guideline. 
2.1.1 
BRCAm Metastatic Castration-resistant Prostate Cancer 
Worldwide in 2018, prostate cancer was estimated to be the fifth most common cause of 
cancer death in men (358,989 deaths) and the second most commonly newly diagnosed cancer 
in men (1,276,106 new cases) (Globocan 2018). While the majority of prostate cancer cases 
are amenable to curative therapy if detected early, advanced stages constitute life-threatening 
disease. For patients diagnosed with metastatic disease, the 5-year survival rate is 31% 
(American Cancer Society 2020, Siegel et al 2020). Nearly 54% of the disease is de novo 
metastatic in China (Ma et al 2008). For decades, androgen deprivation therapy has been the 
standard treatment for prostate cancer, which can be achieved either by surgical or medical 
castration. However, post castration, the development of CRPC is only a matter of time. 
Almost all patients dying from prostate cancer will have mCRPC, and 90% of overall 
mortality in mCRPC patients is attributable to the underlying malignant disease (Scher et al 
2015).  
In China, prostate cancer is the seventh most common cause of cancer death in men (51,895 
deaths) and the sixth most commonly newly diagnosed cancer in men (99,322 new cases) 
(Globocan 2018). There are very limited data on the prevalence of BRCA mutations in 
Chinese patients with mCRPC. According to reports from Wei Y et al and Na R et al, the 
germline mutation prevalence of BRCA1/2 and ATM ranged from 7.55% to 18.18%. It should 
be noted that both studies had a limited sample size (53 and 22 patients, respectively). (Na et 
al 2017, Wei et al 2018). 
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2.1.2 
Current Treatment Options 
Currently, no clear single standard of care (SoC) for mCRPC exists as none of the currently 
approved agents have been developed for a post-new hormonal agent (NHA) setting. Once the 
disease progresses on NHA therapy, the treatment effect of either another sequential NHA or 
taxane diminished substantially. The median overall survival (OS) of patients who have 
progressed on an NHA but who have not previously received taxane chemotherapy appears to 
be between 8.6 months and 12.5 months (Azad et al 2015, Mezynski et al 2012), reflecting a 
high unmet medical need from CRPC patients for whom NHA has failed. Docetaxel may be 
administered as secondline therapy. The efficacy of docetaxel appears markedly reduced when 
given after NHA as compared to first-line use (Mezynski et al 2012, Schweizer et al 2014), 
likely attributable to at least partial cross-resistance between taxanes and NHA (van Soest et al 
2013). Similarly, NHA treatment with abiraterone had modest effect on efficacy (median OS 
of 14.8 months) in mCRPC patients post chemotherapy (de Bono et al 2011). Based on the 
results of Study D081DC00007 (PROfound), olaparib has been approved by the US FDA for 
adult patients with deleterious or suspected deleterious germline or somatic HRRm (including 
BRCAm) mCRPC, who have failed prior treatment with abiraterone or enzalutamide (de Bono 
et al 2020). In the EU and Japan, the approved indication is mCRPC patients with BRCA1 or 
BRCA2 mutation who have progressed following prior therapy that included a new hormonal 
agent. 
Clinical practice in China is similar to that in Western countries. In China, both chemotherapy 
with docetaxel and NHA (eg, abiraterone) are widely used in the first line treatment of 
mCRPC.   
Based on a subgroup analysis of the D081DC00007 (PROfound) study, which showed that 
olaparib demonstrated a substantial improvement in radiographic progression-free survival 
(rPFS) and overall survival (OS) versus abiraterone or enzalutamide in men with BRCA1/2 
mutations, olaparib has been granted conditional approval in China to treat adult patients with 
germline or somatic BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC) 
who have progressed following treatment that included a new hormonal agent (abiraterone, 
enzalutamide).PROfound-CN (this study) is a planned bridging trial with Chinese patients for  
continued approval. 
2.1.3 
Olaparib 
Olaparib (LynparzaTM), originally developed by AstraZeneca, is a potent inhibitor of PARP, 
which, compared to normal cells, kills cancer cells with DNA repair pathway deficiencies by 
using these defects. Olaparib traps PARP at the sites of DNA SSBs damage and prevents its 
repair (Murai et al 2012). During replication, the SSBs trapped with PARP are converted to 
DNA DSBs. DSBs are normally repaired by HRR, which is a high-fidelity process. In cancer 
cells with homologous recombination deficiency (HRD), DSBs cannot be effectively repaired 
resulting in preferential killing of cancer cells over normal cells. Defects in BRCA1 or BRCA2 
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(key HRR proteins) lead to the increase of sensitivity to PARP inhibitors (Farmer et al 2005). 
Several clinical trials are evaluating the efficacy of olaparib (monotherapy or combination 
therapy) in cancers with HRD including BRCA1 or BRCA2 mutations (germline and somatic). 
Olaparib capsules were approved in December 2014 by the US FDA and the European 
Commission. The majority of completed studies were performed with olaparib capsules; 
however most new olaparib studies, including Phase III registration studies and all studies in 
China, are being performed with olaparib tablets. 
In China, olaparib monotherapy is approved for the maintenance treatment of platinum-
sensitive relapsed (PSR) ovarian cancer (August 2018; SOLO2) and first-line maintenance 
treatment of BRCAm ovarian cancer (November 2019; SOLO1). Olaparib in combination with 
bevacizumab is approved as first-line maintenance treatment for adult patients with advanced 
epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial 
response to first-line platinum-based chemotherapy and whose cancer is associated with 
homologous recombination deficiency (HRD)-positive status (September 2022; PAOLA-1). 
A detailed description of the chemistry, pharmacology, mechanism of action, efficacy, and 
safety of olaparib is provided in the IB/prescribing information. 
2.2 
Benefit:Risk Assessment 
2.2.1 
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 tumors including those with BRCAm 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 hematological effects (anemia, 
neutropenia, lymphopenia, leukopenia, thrombocytopenia, mean corpuscular volume [MCV] 
elevation), nausea and vomiting, decreased appetite, diarrhea, dyspepsia, stomatitis, upper 
abdominal pain, dysgeusia, fatigue (including asthenia), increase in blood creatinine, 
headache, dizziness, hypersensitivity, rash, dermatitis, cough, dyspnea, angioedema, 
myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML), erythema nodosum and 
venous thromboembolic events.  
MDS/AML is an important identified risk for olaparib that occurs uncommonly in patients on 
treatment and during the 30-day safety follow-up, and < 1.5% at any time after starting 
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olaparib, including cases actively solicited during the long-term follow-up for OS. In the 
majority of cases, the event is fatal. The risk of MDS/AML is greatest in patients with PSR 
ovarian cancer and a higher chemotherapy burden at baseline. Considering the benefits of 
olaparib, this risk is not considered to impact the positive benefit risk profile of olaparib 
across the indications. 
In a relatively small number of patients, pneumonitis (potential risk) and new primary 
malignancies (important potential risk) have been observed. Evidence from across the 
development programme for olaparib does not support a conclusion that there is a causal 
relationship between olaparib and these events. These events remain adverse events of special 
interest (AESI) for olaparib and are being kept under close surveillance. Similarly, MDS/AML 
remains an AESI, despite being considered an adverse drug reaction, and is still subject to 
additional reporting requirements. 
Furthermore, the safety and tolerability profile of olaparib in the Study D081DC00007 
(PROfound), was consistent with the known safety and tolerability profile of olaparib and 
considered to be acceptable in men with mCRPC who had failed prior treatment with a NHA 
and had HRR gene mutations. 
2.2.2 
Benefit Assessment 
In Study D081DC00007 (PROfound), subgroup analyses indicated the greatest efficacy 
benefit of olaparib in the BRCAm subgroup compared to other subgroups. Subgroup analyses 
in participants with a BRCA1 or BRCA2 mutation indicated that olaparib provides clinically 
meaningful and substantial benefit compared to investigator’s choice of NHA: 78% reduction 
in risk of progression of disease (PD) or death with median radiological progression-free 
survival (rPFS) of 9.8 months for the olaparib group compared with median rPFS of 
3.0 months for the investigator’s choice of NHA group (hazard ratio [HR] 0.22; 95% 
confidence interval [CI] 0.15, 0.32); substantial improvement in confirmed objective response 
rate (ORR; 43.9% with olaparib vs 0% with NHA), 37% reduction in risk of death and 5.7 
month improvement in OS (median OS 20.1 vs 14.4 months respectively; HR 0.63; 95% CI 
0.42, 0.95). Considering that 69% of participants in the NHA arm received olaparib as a 
subsequent treatment following PD, the analysis of OS adjusting for investigator’s choice of 
NHA-treated participants receiving subsequent olaparib further supports the clinical benefit of 
olaparib observed (HR 0.29; 95% CI 0.10, 0.86). These results suggest that the true effect of 
olaparib is likely to be greater than observed in the unadjusted final OS analysis. 
Furthermore, subgroup analysis in the Asian population indicated a consistent treatment effect 
compared with global population in terms of rPFS, OS and ORR. In addition, a trend of 
substantial improvement of ORR, rPFS and OS for Asian participants with a BRCA1 or 
BRCA2 mutation was maintained with more than 1 year median OS improvement with 
olaparib treatment compared to NHA. 
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2.2.3 
Overall Benefit:Risk Conclusion 
Results of subgroup analyses from the PROfound study indicate that the BRCAm subgroup of 
mCRPC participants are considered sensitive to olaparib, that olaparib is anticipated to be 
effective for Chinese BRCAm mCRPC participants and a similar olaparib safety profile in 
Global and Asian BRCAm participants. Therefore, as olaparib has been found to be well 
tolerated across various cancer entities including the PROfound study, a positive benefit/risk 
profile is expected and no ethical issues are identified from exposing participants to olaparib 
within the planned registration trial. 
More detailed information about the known and expected benefits and risks of olaparib may 
be found in the current version of the olaparib IB/prescribing information. 
The emergence of the novel coronavirus disease 2019 (COVID-19) could present a potential 
risk for participants. Risk mitigation factors have been implemented related to study conduct 
during the COVID-19 pandemic (see Appendix H) and for patient management in an event of 
COVID-19 infection and actions to be taken on study treatment administration (see 
Appendix I). 
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3 
OBJECTIVES AND ENDPOINTS 
Table 5 
Objectives and Endpoints 
Objectives 
Outcome measure 
Primary 
To determine the efficacy (as assessed by rPFS) of 
olaparib in participants with mCRPC and deleterious 
or suspected deleterious BRCA1/2 mutations 
rPFS by BICR assessment using RECIST 1.1 (soft 
tissue) and PCWG3 (bone) criteria 
Secondary 
To determine the efficacy (as assessed by ORR) of 
olaparib in participants with mCRPC and deleterious 
or suspected deleterious BRCA1/2 mutations 
Confirmed ORR by BICR assessment in participants 
with measurable disease using RECIST 1.1 (soft 
tissue) and PCWG3 (bone) criteria 
To determine the efficacy (as assessed by OS) of 
olaparib in participants with mCRPC and deleterious 
or suspected deleterious BRCA1/2 mutations 
Overall Survival (OS) 
To further assess the efficacy of olaparib in 
participants with mCRPC and deleterious or 
suspected deleterious BRCA1/2 mutations 
• 
Time from first dose to the first SSRE 
• 
Time from partial or complete response by BICR 
assessment in participants with measurable 
disease (RECIST 1.1) to progression (DoR) 
• 
Time from randomization to opiate use for 
cancer-related pain 
• 
Proportion of participants achieving a ≥50% 
decrease in PSA from baseline to the lowest 
post-baseline PSA result, confirmed by a second 
consecutive PSA assessment at least 3 weeks 
later (PSA50 response) 
• 
Time from randomization to second progression 
by investigator assessment of radiological or 
clinical progression or death (PFS2) 
 
Safety 
To evaluate the safety and tolerability of olaparib 
Safety and tolerability will be evaluated in terms of 
AEs/SAEs, vital signs (including blood pressure and 
pulse), clinical laboratory results (including clinical 
chemistry/hematology parameters), and ECGs. 
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4 
STUDY DESIGN 
4.1 
Overall Design 
This randomized, multicenter, open-label study (PROfound-CN) is designed to assess the 
efficacy and safety of olaparib in Chinese men with mCRPC who have failed prior treatment 
with a NHA and have tumor BRCA1/2 mutations. 
Eligible participants will have histologically confirmed mCRPC; BRCAm status will be 
confirmed by central testing of tumor tissue. 
Approximately 42 participants will be randomized in a 2:1 ratio to olaparib 300 mg twice 
daily (bid) or to investigator’s choice of either enzalutamide 160 mg once daily (qd) or 
abiraterone acetate (1000 mg qd plus prednisone 5 mg bid). Randomization will be stratified 
based on prior receipt of taxane chemotherapy (yes vs no) and presence of measurable disease 
at baseline (yes vs no). 
All participants must have mCRPC and have received and failed prior treatment with an NHA 
(eg, abiraterone acetate or enzalutamide). Prior receipt of other anti-prostate cancer therapies, 
including docetaxel, cabazitaxel, radium-223, and sipuleucel-T is permitted but not 
mandatory. Participants must not have received previous treatment with a DNA-damaging 
cytotoxic chemotherapy (eg, prior platinum-based chemotherapy and mitoxantrone are not 
permitted) or a PARP inhibitor, including olaparib. 
All participants must have a documented tumor (tissue) qualifying mutation(s) in BRCA1 or 
BRCA2 (referred to as BRCA1/2), predicted to be deleterious or suspected deleterious. All 
participants must provide a formalin fixed and paraffin embedded (FFPE) tumor sample for 
tissue-based BRCA1/2 mutation testing (China-based central testing lab). 
Participants will receive study intervention until BICR-assessed radiographic progression or, 
if after the date of DCO for the primary analysis, until investigator-assessed radiological 
progression. 
Subjects Who Switch to Olaparib 
Once participants receiving investigator’s choice of NHA are determined to have objective 
radiological progression by Blinded Independent Central Review (BICR) or, if after the date 
of DCO for the primary analysis, participants are determined to have radiological progression 
by the investigator, they will be eligible to receive olaparib (300 mg bid), see Section 6.1 for 
further details. 
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4.2 
Scientific Rationale for Study Design 
Based on data from the TOPARP A study (Mateo et al 2015) a decision was made for Study 
D081DC00007 (PROfound) to require the presence of a qualifying tissue HRR gene mutation 
as an inclusion criterion for participants with mCRPC who have failed prior therapy with an 
NHA. Subjects in Cohort A had gene mutations in either BRCA1, BRCA2, or ATM whereas 
subjects in Cohort B had mutations in BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, 
PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L.  
The rationale for only using BRCA1 and BRCA2 in this study in Chinese men, is based upon 
the prevalence of these mutations and/or how well mutations in these genes are characterized 
to date. It is expected that qualifying mutations will be detectable in the tissue of about one 
out of 10 mCRPC participants. Additionally, based on results from Study D081DC00007 
(PROfound) it is anticipated that olaparib will be effective in Chinese BRCAm mCRPC 
participants (Section 2.2). 
The other main design elements of this study will be consistent with Study D081DC00007 
(PROfound). While the TOPARP A trial was limited to participants who had failed both NHA 
and a taxane, this study (like Study D081DC00007 [PROfound]) will also enroll patients not 
yet having received taxane chemotherapy for mCRPC as there is a medical need for 
participants failing NHA both pre- and post-taxane (see Section 2.1.2) and as the biological 
activity of olaparib is expected to be independent of prior taxane therapy. In Study 
D081DC00007 (PROfound), both participants with previous taxane use (72/106 [67.9%]) and 
no previous taxane use (34/56 [60.7%]) experienced clinical benefit with olaparib treatment. 
The randomization will be 2:1 (olaparib vs. enzalutamide or abiraterone acetate). 
Enzalutamide and abiraterone acetate were chosen as comparators for the following reasons: 
• 
Enzalutamide and abiraterone acetate are broadly approved for the treatment of mCRPC. 
Switch to the alternate NHA mirrors a relevant real-world scenario for a situation in 
which no single standard of care exists (Vogelzang et al 2016). 
• 
Similar efficacy compared to docetaxel in post-NHA setting (Sun and Chen 2010 and 
Suzman et al 2014), but oral availability and superior tolerability compared to taxanes 
make them the preferred treatment of choice. 
• 
Documented effectiveness both pre and post docetaxel (Beer et al 2014, de Bono et al 
2011, Ryan et al 2013 and Scher et al 2012). 
 
Due to the open-label design of the study, rigorous methodology will be employed to ensure 
robustness of the primary endpoint assessment with the primary analysis of rPFS based on 
BICR of all scans. Also, acknowledging the bone predominance of mCRPC and the particular 
challenges of determining bone progression in participants with high skeletal tumor burden 
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(Kluetz et al 2013), progression in bone will require confirmation by a repeat scan at least 
6 weeks later as outlined in detail by Prostate Cancer Working Group 3 (PCWG3) criteria 
(Scher et al 2016). 
4.2.1 
Rationale for the tBRCAm Assay in China 
In Study D081DC00007 (PROfound), the molecular analysis was performed by a designated 
central diagnostic provider (Foundation Medicine, Inc.) using a next-generation sequencing 
(NGS) assay, the investigational Lynparza HRR Assay.  
In this study, BRCA1/2 mutation testing will be performed using an investigational tumor 
tissue-based NGS assay (tBRCAm assay - formal name to be confirmed in the clinical study 
report [CSR]) at a central testing laboratory. The assay has been evaluated and shown high 
concordance with the assay used in Study D081DC00007 (PROfound). 
4.3 
Justification for Dose 
The dose used in TOPARP A (400 mg tablets bid) was chosen at a time when information on 
the relative clinical activity with the tablet formulation was not fully complete; as a 300 mg 
bid tablet dose is now considered maximally effective, is used across the ongoing olaparib 
development program, and is currently approved, this dose was chosen for Study 
D081DC00007 (PROfound) and subsequently for this study. 
4.4 
End of Study Definition 
A participant is considered to have completed the study if he has completed all phases of the 
study including the last visit. 
The study may be stopped if, in the judgment of AstraZeneca, study participants are placed at 
undue risk because of clinically significant findings. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
See Section 6.7 for details on participant management following the final DCO as well as 
following study completion. 
5 
STUDY POPULATION 
The target population of interest in this study is Chinese men with mCRPC who have failed 
prior treatment with a NHA and have a qualified BRCA1/2 mutation in their tumor sample. 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
Participants who do not meet the eligibility criteria requirements are screen failures; refer to 
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Section 5.4. 
5.1 
Inclusion Criteria 
Patients that already know they have a mutation in BRCA1 or BRCA2 gene that is predicted to 
be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of 
function) must fulfil all of the criteria below. Patients that do not know their mutation status, 
and who are being considered for this trial should be identified early so that the appropriate 
BRCA mutation screening procedures can be put in place in a timely manner. Patients that do 
not know their BRCA mutation status must fulfil all of the criteria marked with an asterisk (*) 
below prior to BRCA mutation testing being carried out. Prior to performing the BRCA testing, 
an investigator judgement of a patient’s potential eligibility for the study should be made 
according to details within Table 1 and by reviewing the inclusion/exclusion criteria. All 
inclusion criteria will then be assessed following confirmation that they harbor an appropriate 
BRCA mutation.  
Any patients that fulfil the eligibility criteria for the BRCA test, are required to have their 
eligibility assessed again prior to randomization. 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1 
*Participant must be ≥18 years at the time of screening.  
Type of Participant and Disease Characteristics 
2 
*Histologically confirmed diagnosis of prostate cancer. 
3 
*Candidate for treatment with enzalutamide or abiraterone acetate with documented 
current evidence of mCRPC where metastatic status is defined as at least 1 documented 
metastatic lesion on either bone scan or computed tomography (CT)/magnetic resonance 
imaging (MRI) scan. Participants whose disease spread is limited to regional pelvic 
lymph nodes or local recurrence (eg, bladder, rectum) are not eligible. 
4 
Participants must have progressed on prior NHA (eg, abiraterone acetate and/or 
enzalutamide) for the treatment of metastatic prostate cancer and/or castration-resistant 
prostate cancer (CRPC). Determination of progression is done per local investigator. 
5 
Serum testosterone levels ≤ 50 ng/dL (≤ 1.75 nmol/L) within (≤) 28 days before 
randomization. 
6 
*Participants without prior surgical castration must be currently taking and willing to 
continue luteinizing hormone-releasing hormone (LHRH) analog (agonist or antagonist) 
therapy throughout the duration of study treatment. 
7 
Radiological progression at study entry while on androgen deprivation therapy (or after 
bilateral orchiectomy). Determination of progression is done per local investigator. 
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8 
Deleterious or suspected deleterious BRCA1/2 mutation in tumor tissue (see 
Section 8.6.1).  
9 
Participants must have normal organ and bone marrow function measured within 
(≤) 28 days prior to administration of study treatment as defined below 
− 
Hemoglobin ≥ 10.0 g/dL with no blood transfusions in the past 28 days. 
− 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L. 
− 
Platelet count ≥ 100 × 109/L. 
− 
Total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) 
− 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; 
for participants with hepatic metastases, ALT and AST ≤ 5 × ULN. 
− 
Calculated creatinine clearance (CrCL) of ≥51 mL/min, as determined by 
Cockcroft-Gault (using actual body weight) or based upon a 24-hour urine test or 
another validated test as per local practice 
Estimated CrCL = 
(140-age [years]) × weight (kg) 
 
 
 
            serum creatinine (mg/dL) × 72 
10 *Eastern Cooperative Oncology Group (ECOG) performance status 0-2 with no 
deterioration over the previous 2 weeks prior to baseline or day of first dosing. 
(Section 8.2.5.1).  
11 *Minimum life expectancy of ≥ 16 weeks. 
Sex 
12 *Male 
Reproduction 
13 Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
14 Non-sterilized male participants who intend to be sexually active with a female partner of 
childbearing potential must be surgically sterile or using an acceptable method of 
contraception (see Appendix F) from Cycle 1 Day 1 throughout the total duration of the 
study and for 3 months after the last dose of study intervention to prevent pregnancy in a 
partner. Male participants must not donate or bank sperm during this same time period. 
Female partners of male participants should also use a highly effective form of 
contraception (see Appendix F) if they are of childbearing potential.  
Informed Consent 
15 *Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol.  
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5.2 
Exclusion Criteria  
Patients should not enter the study if any of the following exclusion criteria are fulfilled (any 
asterisked* are also applicable as an exclusion criteria for patients that are being screened to 
determine their BRCA mutation status via central testing); to perform the BRCA testing, 
investigator judgement of patient’s potential eligibility to the study should be assessed as per 
the SoA and by reviewing the exclusion criteria.  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1 
*As judged by the investigator, any evidence of a serious, uncontrolled medical disorder, 
non-malignant systemic disease or active, uncontrolled infection (examples include, but 
are not limited to, uncontrolled ventricular arrhythmia, recent [within 3 months] 
myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord 
compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on 
high resolution CT scan or any psychiatric disorder) which, in the investigator’s opinion, 
makes it undesirable for the participant to participate in the study or that would jeopardise 
compliance with the protocol. 
2 
*Refractory nausea and vomiting, chronic gastrointestinal disease or inability to swallow 
the formulated product that would preclude adequate absorption, distribution, 
metabolism, or excretion of olaparib. 
3 
*History of another primary malignancy except for malignancy treated with curative 
intent with no known active disease for ≥5 years before the first dose of study 
intervention and of low potential risk for recurrence. Exceptions include basal cell 
carcinoma of the skin and squamous cell carcinoma of the skin that has undergone 
potentially curative therapy and ductal carcinoma in situ. 
4 
*Participants with MDS/AML or with features suggestive of MDS/AML. 
5 
Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac 
conditions, as judged by the investigator (eg, unstable ischemia, uncontrolled 
symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, 
electrolyte disturbances, etc.), or patients with congenital long QT syndrome. 
6 
*Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAE] 
Grade >2) caused by previous anticancer therapy, excluding alopecia or toxicities related 
to the use of LHRH agonist or antagonist. Participants with irreversible toxicity that is not 
reasonably expected to be exacerbated by study intervention in the opinion of the 
Investigator may be included (eg, hearing loss). 
7 
*Spinal cord compression or brain metastases unless asymptomatic, stable, and not 
requiring steroids for at least 4 weeks prior to start of study intervention. 
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8 
*Participants with known active hepatis (ie, heptaitis B or C), participants are eligible if 
they  
a. Are negative for HBsAg (HBV surface antigen) and anti-HBc (hepatitis B core 
antibody) or 
b.  Are anti-HBc positive, HBs-Ag negative (past, resolved hepatitis B), and have 
undetectable HBV DNA viral load or 
c. Are HBsAg positive(chronic hepatitis B), and meet all of the conditions below: 
i. 
HBV DNA viral load < 2000 IU/mL 
ii. 
Have normal aminotransferase values, or, if liver metastases are present, abnormal 
aminotransferase, with a result of AST/ALT < 3 × ULN, which are not attributable 
to HBV infection. 
Note: any participants with chronic hepatitis should be under the care of a hepatologist as per 
local standard practice. 
Participants positive for hepatitis C virus (HCV) antibody are eligible only if PCR negative 
for HCV RNA. 
 
9 
*Immunocompromized participants, eg, those who are known to have tested positive for 
human immunodeficiency virus (HIV) or active tuberculosis infection (clinical evaluation 
that may include clinical history, physical examination and radiological findings, or 
tuberculosis testing in line with local practice). 
Prior/Concomitant Therapy 
10 *Any previous treatment with PARP inhibitor, including Olaparib. 
11 *Any previous treatment with DNA-damaging cytotoxic chemotherapy, except if for non-
prostate cancer indication and last dose > 5 years prior to randomization. For example, 
participants who have received prior mitoxantrone or platinum-based chemotherapy for 
prostate cancer are excluded.  
- 
Prior estramustine is allowed 
12 Patients receiving any systemic chemotherapy or radiotherapy (except for palliative 
reasons) within 3 weeks prior to study treatment. (Bone-targeted therapy with denosumab 
or zoledronic acid is allowed.) 
13 Patients who receive palliative radiotherapy need to stop radiotherapy 1 week before 
randomisation. 
14 Major surgical procedure (excluding placement of vascular access) or significant 
traumatic injury within 3 weeks of the first dose of study intervention or an anticipated 
need for major surgery during the study. 
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15 *Concomitant use of known strong cytochrome P450 (CYP)3A inhibitors (eg, 
itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or 
cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A 
inhibitors (eg, ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The 
required washout period prior to starting olaparib is 2 weeks (see Appendix G). 
16 *Concomitant use of known strong (eg, phenobarbital, phenytoin, rifampicin, rifabutin, 
rifapentine, carbamazepine, nevirapine and St John’s wort) or moderate CYP3A inducers 
(eg, bosentan, efavirenz, modafinil). The required washout period prior to starting 
olaparib is 5 weeks for phenobarbital and 3 weeks for other agents (see Appendix G). 
17 *Previous allogeneic bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT). 
Prior/Concurrent Clinical Study Experience 
18 *Previous randomization in the present study. 
19 Exposure to an investigational product within 30 days or five half-lives (whichever is the 
longer) prior to randomization. 
20 *Participants with a known hypersensitivity to any of the agents included in the study 
intervention, including olaparib, any of the excipients of olaparib or the comparator agent. 
Diagnostic assessments 
21 Subjects inevaluable 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 non-measurable) that can be assessed by 
Response Evaluation Criteria in Solid Tumors (RECIST). 
Other Exclusions 
22 *Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). 
23 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements. 
 
5.3 
Lifestyle Considerations 
Restrictions relating to concomitant therapies are described in Appendix G. 
The following restrictions apply while the participant is receiving study intervention and for 
the specified times before and after. 
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5.3.1 
Meals and Dietary Restrictions 
It is prohibited to consume grapefruit juice while on olaparib therapy. 
5.3.2 
Contraception  
Non-sterilized male participants who intend to be sexually active with a female partner of 
childbearing potential must be surgically sterile or using an acceptable method of 
contraception (see Appendix F) from the time of screening throughout the total duration of the 
study and the drug washout period (3 months after the last dose of study intervention) to 
prevent pregnancy in a partner. Male participants must not donate or bank sperm during this 
same time period. Female partners of male participants should also use a highly effective form 
of contraception (see Appendix F) if they are of childbearing potential. 
For details of acceptable methods of contraception refer to Appendix F.  
5.3.3 
Blood Donation 
Participants should not donate blood or blood components while participating in this study and 
for 3 months after the last dose of study intervention. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse event (SAE). 
Participants who are ineligible for the study based on BRCA1/2 status will be screen failed in 
the interactive voice response system (IVRS)/interactive web response system (IWRS) and 
electronic case report form (eCRF), should not continue with any remaining screening 
evaluations and are not permitted to enter the main study phase or be re-screened for study.  
In exceptional cases, where a participant has met BRCA1/2 status and has screen failed 
eligibility for other criteria, the participant may be re-evaluated for study eligibility, as 
determined by the AstraZeneca physician, provided that they have not previously been 
randomized, assigned or received treatment.  
Where a participant is permitted to re-screen (by the AstraZeneca study physician), the same 
E-code initially assigned by the IVRS/IWRS should be used. The rationale and approval will 
be documented in the investigator site file.  
Participant enrolment and randomization is described in Section 6.3. 
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6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the clinical study protocol (CSP). 
6.1 
Study Intervention(s) Administered 
AstraZeneca will supply olaparib. 
Investigator’s choice of NHA agents (abiraterone acetate and enzalutamide) will be sourced 
locally or centrally and should be administered according to local prescribing information, 
including any treatment restrictions. Abiraterone acetate must be dosed with prednisone in 
accordance with the approved label (prednisolone is permitted for use instead of prednisone if 
necessary).  
Dose modifications are described in Section 6.6. 
Table 6 
Investigational Products 
ARM Name 
Olaparib 
Investigator’s choice of 
NHA  
Investigator’s choice of 
NHA 
Intervention 
Name 
Olaparib a 
Abiraterone acetate b 
Enzalutamide 
Type  
drug 
drug 
drug 
Dose 
Formulation 
tablet 
tablet 
capsule/tablet 
Unit Dose 
Strength(s) 
150 mg;  
100 mg available if dose 
reductions are required 
250 mg and/or 500 mg  
40 mg  
Dosage Level(s) 
300 mg (2 x 150 mg 
tablets) bid 
1,000 mg qd 
160 mg qd 
Route of 
Administration 
oral 
oral 
oral 
Use 
experimental 
active comparator 
active comparator 
IMP and NIMP 
IMP 
IMP  
IMP  
Sourcing 
Provided centrally by 
AstraZeneca 
Provided centrally by 
AstraZeneca or locally by 
the study site, subsidiary, or 
designee.  
Provided centrally by 
AstraZeneca or locally by 
the study site, subsidiary, or 
designee.  
Packaging and 
Labeling 
Study intervention will 
be provided in blisters 
and cartons. Each unit 
will be labelled per GMP 
If provided by AstraZeneca, 
study treatment will be 
labeled in accordance with 
If provided by AstraZeneca, 
study treatment will be 
labeled in accordance with 
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Annex 13 and local 
regulatory guidelines. 
GMP Annex 13 and per 
country requirements 
GMP Annex 13 and per 
country requirements 
a 
Descriptive information for olaparib can be found in the olaparib IB/prescribing information. Manufacturer 
will be included in the quality section of the IMPD. 
b 
With prednisone. 
 
Olaparib 
Olaparib is available as film-coated tablet containing 150 mg or 100 mg of olaparib. 
Participants will be administered olaparib orally twice daily at 300 mg bid continually. 
Two × 150 mg olaparib tablets should be taken at the same times each day, approximately 
12 hours apart with one glass of water. If required, dose reductions to 250 mg bid and a 
further dose reduction to 200 mg bid are permitted, however once dose is reduced, no return to 
the higher dose will be allowed. 
The tablets should be swallowed whole and not chewed, crushed, dissolved or divided. 
Olaparib tablets can be taken with or without food.  
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted. Should any subject enroled on the 
study miss a scheduled dose for whatever reason (eg, as a result of forgetting to take the 
tablets or vomiting), the subject will be allowed to take the scheduled dose up to a maximum 
of 2 hours after that scheduled dose time. If greater than 2 hours after the scheduled dose time, 
the missed dose is not to be taken and the subject should take their allotted dose at the next 
scheduled time. 
Abiraterone acetate 
Abiraterone acetate will be administered orally at 1,000 mg once daily. Four × 250 mg or two 
× 500 mg tablets should be taken at a similar time each day in combination with prednisone 
5 mg administered orally twice daily (each prednisone dose approximately 12 hours apart). 
Participants should take abiraterone acetate doses at a similar time each day. Abiraterone 
acetate must be taken on an empty stomach. No food should be consumed for at least two 
hours before the dose of abiraterone acetate and one hour after the dose of abiraterone acetate. 
The tablets should be swallowed whole with water and not crushed or chewed, in full 
accordance with local prescribing information. 
Enzalutamide 
Enzalutamide will be administered orally at 160 mg once daily. Four × 40 mg capsules/tablets 
should be taken at a similar time each day. Capsules/tablets should be swallowed whole and 
can be taken with or without food, in full accordance with local prescribing information. 
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Duration of Treatment 
Participants will continue to receive study intervention until BICR-assessed radiographic 
progression, or after the date of DCO for the primary analysis until investigator-assessed 
radiological progression, as long as they do not meet any of the criteria for treatment 
discontinuation.  
Participants Who Switch to Olaparib 
Once participants receiving investigator’s choice of NHA, are determined to have objective 
radiological progression by BICR or, if after the date of DCO for the primary analysis, upon 
investigator-assessed radiological progression, they will be eligible to receive olaparib 
(300 mg bid). 
If a participant has been deemed to have objective disease progression according to 
investigator assessment, but not by BICR, he is not eligible to switch to olaparib at that time. 
Participants should continue to receive randomized study treatment until progression 
determined by BICR. 
The following criteria must be met in order for a participant to switch to olaparib: 
• 
No intervening anti-cancer therapy following discontinuation of randomized treatment 
• 
Any unresolved toxicities from prior therapy should be controlled, and be no greater than 
CTCAE grade 1 at the time of starting olaparib treatment 
 
If subjects are not eligible to switch to olaparib, or choose not to switch, they will enter into 
the follow-up phase of the study (see Table 4), and should discuss other treatment options 
with the investigator. 
Participants may continue to receive olaparib as long as they are continuing to show clinical 
benefit, as judged by the investigator and in the absence of discontinuation criteria 
(Section 7.1). 
Dose Reductions  
For guidance on dose reductions refer to Section 6.6. 
6.2 
Preparation/Handling/Storage/Accountability of Interventions 
1 
The investigator or designee (eg, unblinded pharmacist) must confirm appropriate 
temperature conditions have been maintained during transit for all study intervention 
received and any discrepancies are reported and resolved before use of the study 
intervention. 
2 
Only participants enroled in the study may receive study intervention and only authorized 
site staff may dispense study intervention. At site, all study intervention must be stored in 
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a secure, environmentally controlled, and monitored (manual or automated) area at the 
site in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff. 
3 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
4 
Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Reference Manual. 
The investigator’s choice of NHA agent(s) will either be locally sourced by the study site or 
centrally supplied by AstraZeneca and will be administered according to Prescribing 
Information or treatment guidance in general use by the investigating site. Under certain 
circumstances when local sourcing by the study site is not feasible, AstraZeneca will centrally 
supply the drug, which will be labeled with local language translated text in accordance with 
regulatory guidelines. 
6.3 
Measures to Minimise Bias: Randomization and Blinding 
Participant Enrolment and Randomization 
Study using 
IVRS/IWRS 
All participants will be centrally assigned to randomized study intervention using an 
IVRS/IWRS. Before the study is initiated, the call/log-in directions and user guides 
for the IVRS/IWRS will be provided to each site.  
Study intervention will be dispensed at the study visits summarized in SoA or per 
investigator’s choice of NHA after DCO.  
Returned study intervention should not be re-dispensed to the participants. 
If a participant withdraws from the study, then his enrolment/randomization code cannot be 
reused. Withdrawn participants will not be replaced. 
Investigators should keep a record (ie, the participant screening log) of participants who 
entered screening. 
At screening/baseline (Days -28 to -1), the investigators or suitably trained delegate will: 
•
Obtain signed informed consent before any study-specific procedures are performed. If
laboratory or imaging procedures were performed for alternate reasons prior to signing
consent, these can be used for screening purposes with consent of the participant.
However, all screening laboratory and imaging results must have been obtained within
28 days of randomization.
•
Participants will be identified to the IVRS/IWRS per country regulations. Obtain a unique
7-digit enrolment number (E-code), through the IVRS/IWRS in the following format
(ECCNNXXX: CC being the country code, NN being the center number, and XXX being
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the participant enrolment code at the centre). This number is the participant’s unique 
identifier and is used to identify the participant on the eCRFs. 
• 
Obtain sample and send for centralized BRCA1/2 testing. Obtaining the sample should be 
given the highest priority and, as such, the sample may be obtained and sent for central 
testing prior to the 28-day screening window (after obtaining signed informed consent) in 
order to permit analysis prior to randomization. Screening procedures may be performed 
while BRCA1/2 status is being assessed. 
• 
Determine participant eligibility (see Sections 5.1 and 5.2). 
 
At randomization, once the participant is confirmed to be eligible, the investigator or suitably 
trained delegate will: 
• 
Select the NHA treatment (abiraterone acetate or enzalutamide, based on the most 
appropriate option for the participant) that the participant would receive if randomized to 
the investigator’s choice of NHA group, prior to randomization of the participant. This 
must be completed for all participants. The information will be recorded in the 
IVRS/IWRS system. 
• 
Assign a randomized treatment group via the IVRS/IWRS. Randomization codes will be 
assigned strictly sequentially within each stratum as participants become eligible for 
randomization. The system will randomize the eligible participant to 1 of the 2 treatment 
groups.  
 
If the participant is ineligible, the IVRS/IWRS should be accessed to terminate the participant 
in the system. 
Participants will begin treatment on Day 1. Participants must not be randomized and treated 
unless all eligibility criteria have been met. 
Procedures for Handling Incorrectly Enroled or Randomized Participants 
Participants who fail to meet the eligibility criteria should not, under any circumstances, be 
enroled or receive study medication. There can be no exceptions to this rule. Participants who 
are enroled but subsequently found not to meet all the eligibility criteria must not be 
randomized or started on study intervention and must be withdrawn from the study. 
Where a participant does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the investigator regarding whether to continue or discontinue the participant 
from treatment. The AstraZeneca study physician must ensure all decisions are appropriately 
documented and that the potential benefit/risk profile remains positive for the participant. 
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Methods for Assigning Treatment Groups 
The actual treatment given to participants will be determined by the randomization scheme in 
the IVRS/IWRS. The randomization scheme will be produced by a computer software 
programme that incorporates a standard procedure for generating randomization numbers. One 
randomization list will be produced for each of the randomization strata. A blocked 
randomization will be generated and randomization will be balanced within the IVRS/IWRS 
at the central level. Participants will be randomized in a 2:1 ratio to olaparib or investigator’s 
choice of NHA (enzalutamide or abiraterone acetate). The randomization will be stratified by 
previous taxane use (yes, no) and whether subject had measurable disease (yes, no). 
Randomization codes will be assigned strictly sequentially, within each stratum and country, 
as participants become eligible for randomization. The IVRS/IWRS will provide the kit 
identification number to be allocated to the participant at the randomization visit and 
subsequent treatment visits. 
Methods for Ensuring Blinding 
Not applicable. 
6.4 
Study Intervention Compliance 
When participants self-administer study intervention(s) at home, patients should be given 
clear instructions on how and when to take their study treatment and compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by counting returned 
tablets/capsules during the site visits and documented in the source documents and eCRF.  
A record of the number of tablets/capsules dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded in the eCRF.  
After the tablet count has been performed, the remaining tablets will not be returned to the 
patient but will be retained by the investigative site until reconciliation is completed by the 
study monitor. All patients must return their blisters and carton(s) of study treatment at the 
appropriate scheduled visit, when new carton(s) will be dispensed. Patients will be instructed 
to notify study site personnel of missed doses. 
Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF. 
The Investigational Product Storage Manager is responsible for managing the study 
intervention from receipt by the study site until the destruction or return of all unused study 
intervention. The investigator(s) is responsible for ensuring that the participant has returned all 
unused study intervention. 
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6.5 
Concomitant Therapy 
Any concomitant treatment, procedure, or other medication considered necessary by the 
investigator for the participant’s safety and wellbeing, or vaccine (including over-the-counter 
or prescription medicines, vitamins, and/or herbal supplements) that the participant is 
receiving from the time of screening or receives during the study including the 30-day 
follow-up period following the last dose of study intervention must be recorded in the eCRF 
along with: 
• 
Reason for use. 
• 
Dates of administration including start and end dates. 
• 
Dosage information including dose and frequency. 
 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
If any concomitant therapy is administered due to new or unresolved AE, it should be 
recorded. 
Participants must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the investigator. 
Restricted, prohibited, and permitted concomitant medications/therapies are described in more 
detail in Appendix G 2. 
For agents in the investigator’s choice of NHA (abiraterone acetate or enzalutamide) group, 
refer to the local Prescribing Information with regard to warnings, precautions, and 
contraindications.  
Drug-drug Interactions 
Guidance regarding potential interactions with concomitant medications is provided in 
Appendix G 1. 
Strong or moderate CYP3A inhibitors are restricted (see Appendix G 2). If there is no suitable 
alternative concomitant medication, then the dose of olaparib should be reduced for the period 
of concomitant administration (see Appendix G 2). Strong or moderate CYP3A inducers are 
restricted (see Appendix G 2). Co-administration of enzalutamide with strong CYP2C8 
inhibitors may increase exposure to enzalutamide and thus should be avoided if possible; for 
enzalutamide dose modification guidance if participants must be co-administered a strong 
CYP2C8 inhibitor, see Appendix G 2. 
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Cli ni cal St u d y Pr ot oc ol  – 3. 0 
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Ol a pari b  - D 0 8 1 L C 0 0 0 0 2 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 5 2 of 1 5 1 
 
A nti -e m etics/ A nti-di arr he als  
Fr o m scr ee ni n g Part 2 o n war ds, s h o ul d a patie nt de vel o p na usea, v o miti n g a n d/ or diarr hea, 
t he n t hese s y m pt o ms s h o ul d be r e p orte d as A Es ( Secti o n 8. 3 ) a n d a p pr o priate treat me nt of t he 
e ve nt gi ve n. 
S u bse q ue nt T her a pies f or C a ncer  
Details of first a n d s u bse q ue nt t her a pies f or ca ncer a n d/ or details of s ur ger y f or t he treat me nt 
of t he ca ncer, after disc o nti n uati o n of treat me nt, will be c ollecte d. 
 
6. 5. 1  
Ot her C o nc o mit a nt Me dic ati o n  
Me dicati o n ot her t ha n t hat descri be d a b o ve, w hic h is c o nsi dere d necessar y f or t he patie nt’s 
saf et y a n d well bei n g, ma y be gi ve n at t he discreti o n of t he i n vesti gat or a n d rec or de d i n t he 
a p pr o priate secti o ns of t he e C R F.  
I n a d diti o n, a n y u n pla n ne d dia g n ostic, t hera pe utic or s ur gical pr oce d ure perf or me d d uri n g t he 
st u d y peri o d m ust be r ec or de d i n t he e C R F. 
6. 6  
D os e M o dific ati o n  
6. 6. 1  
D ose Re d ucti o ns f or Ol a p ari b  
I n case a d ose r e d ucti o n is necessar y, ola pari b will be a d mi nistere d as descri be d i n Ta ble  7, 
Ta ble  8 a n d Ta ble  9. 
Ta ble  7 
D ose Re d ucti o ns f or Ol a p ari b t o M a n a ge A d verse E ve nts  
I niti al d ose 
F oll o wi n g re -c h alle n ge p ost -
i nte rr u pti o n: D ose re d ucti o n 1 
D ose re d ucti o n 2  
3 0 0 m g t wic e dail y  
2 5 0 m g t wic e dail y  
2 0 0 m g t wic e dail y  
 
Ta ble  8 
D ose  Re d ucti o n  f or  Ol a p ari b  if  P atie nt  De vel o ps  M o der ate  Re n al  
I m p air m e nt 
I niti al d ose 
M o der ate r e n al i m p air me nt d ose r e d ucti o n 
a 
3 0 0 m g t wic e dail y  
2 0 0 m g t wic e dail y  
a 
Calc ulate d Cr C L b y C oc kcr oft -Ga ult e q uati o n or base d o n a 2 4 h o ur uri ne t est bet wee n 3 1 a n d 5 0 m L/ mi n)  
 
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

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Table 9 
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 adverse events (AEs; including renal 
impairment) refer to Table 7, Table 8 and Section 6.6.3. 
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors 
cannot be avoided see Table 9 and Appendix G.  
6.6.2 
Dose Reductions for Abiraterone Acetate and Enzalutamide 
For agents in the investigator’s choice of NHA (abiraterone acetate or enzalutamide) group, 
refer to the local Prescribing Information with regard to dose reductions. 
6.6.3 
Management of Toxicities Related to Olaparib 
Dose modification guidelines for olaparib-related toxicities are shown below. Appropriate and 
optimal treatment of the toxicity is assumed prior to considering dose modifications. Prior to 
discontinuation of study intervention due to toxicities, please consult with the study physician.  
Any toxicity observed during the course of the study may be managed by interruption of the 
dose of study treatment or dose reductions. Repeat dose interruptions are allowed as required, 
for a maximum of 4 weeks on each occasion. If the interruption is any longer, the study team 
must be informed. 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 study treatment should be discontinued.  
Once dose is reduced, escalation is not permitted (except following concomitant treatment 
with CYP3A4 inhibitors, see Appendix G 2). 
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6.6.3.1 
Management of Hematological Toxicity 
6.6.3.1.1 
Management of Anemia 
Table 10 
Management of Anemia 
Hemoglobin 
Action to be taken 
Hb < 10 but ≥ 8 g/dL 
(CTCAE Grade 2) 
Give appropriate supportive treatment, continue to monitor and investigate 
causality.  
• 
For first incidence: investigator judgement to continue olaparib with 
supportive treatment (eg, transfusion) or interrupt dose for a maximum of 
4 weeks. Study treatment can be restarted if Hb HAS recovered to > 9g/dL. 
• 
For repeat incidence (after recovery of first event) 
° 
If Hb < 10 but ≥ 9 g/dL investigator judgement to continue olaparib 
with supportive treatment (eg, transfusion) or dose interrupt (for 
maximum 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 maximum 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), continue to monitor and 
investigate causality.  
Interrupt olaparib for a maximum of 4 weeks until improved to Hb ≥ 9 g/dL. 
Upon recovery dose reduce olaparib to 250 mg twice daily as a first step and to 
200 mg twice daily as a second step in the case of repeat Hb decrease.  
 
Common treatable causes of anemia (eg, iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed. In some cases, 
management of anemia may require blood transfusions. For cases where participants develop 
prolonged hematological toxicity (≥ 2 week interruption/delay in study treatment due to CTC 
grade 3 or worse anemia and/or development of blood transfusion dependence), refer to 
Section 6.6.3.1.3 for the management of this. 
6.6.3.1.2 
Management of Neutropenia, Leukopenia and Thrombocytopenia 
Table 11 
Management of Neutropenia, Leukopenia and Thrombocytopenia 
Toxicity 
Study treatment dose adjustment 
CTCAE Grade 1-2 
Investigator judgement to continue study treatment or if dose interruption, this 
should be for a maximum of 4 weeks; appropriate supportive treatment and 
causality investigation 
CTCAE Grade 3-4 
Dose interruption for a maximum of 4 weeks until recovered to CTCAE grade 1 
or better. 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. 
 
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Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by 
the investigator with close follow-up and interruption of study drug if CTC grade 3 or worse 
neutropenia occurs. 
Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is not 
recommended, however, if a subject develops febrile neutropenia, study treatment should be 
stopped and appropriate management including G-CSF should be given according to local 
hospital guidelines. Please note that G-CSF should not be used within at least 24 h (7 days for 
pegylated G-CSF) of the last dose of study treatment unless absolutely necessary. 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 
For cases where participants develop prolonged hematological toxicity (≥2 week 
interruption/delay in study treatment due to CTC grade 3 or worse), refer to Section 6.6.3.1.3. 
6.6.3.1.3 
Management of Prolonged Hematological Toxicities While on Study Treatment 
If a subject develops prolonged hematological toxicity such as: 
• 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anemia and/or 
development of blood transfusion dependence 
• 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse neutropenia 
(ANC < 1 x 109/L) 
• 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets 
< 50 x 109/L) 
 
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If 
any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the 
subject should be referred to hematologist for further investigations. Bone marrow analysis 
and/or blood cytogenetic analysis should be considered at this stage according to standard 
hematological practice. Study treatment should be discontinued if blood counts do not recover 
to CTC grade 1 or better within 4 weeks of dose interruption. 
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should 
be reported as a SAE and full reports must be provided by the investigator to AstraZeneca 
Patient Safety. Olaparib treatment should be discontinued if subject’s diagnosis of MDS 
and/or AML is confirmed. 
6.6.3.2 
Management of Non-hematological Toxicity 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each 
occasion. If the interruption is any longer than this the study monitor must be informed. 
Where toxicity reoccurs following re-challenge with study treatment, and where further dose 
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interruptions are considered inadequate for management of toxicity, then the subject should be 
considered for dose reduction or must permanently discontinue study treatment. 
Study treatment can be dose reduced to 250 mg bid as a first step and to 200 mg bid as a 
second step. Treatment 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 study treatment. 
6.6.3.2.1 
Management of New or Worsening Pulmonary Symptoms  
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormalities occur 
in the absence of a clear diagnosis, an interruption in study treatment dosing is recommended 
and further diagnostic workup (including a high resolution CT scan) should be performed to 
exclude pneumonitis. 
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then study treatment can be restarted, if deemed appropriate by the 
investigator. If significant pulmonary abnormalities are identified, these need to be discussed 
with the Study Physician. 
6.6.3.2.2 
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 study treatment, 
however, participants should receive appropriate anti-emetic treatment at the first onset of 
nausea or vomiting and as required thereafter, in accordance with local treatment practice 
guidelines. Alternatively, olaparib tablets can be taken with a light meal/snack (ie, 2 pieces of 
toast or a couple of biscuits). 
As per international guidance on anti-emetic use in cancer participants (European Society for 
Medical Oncology, National Comprehensive Cancer Network), generally a single agent 
antiemetic should be considered eg, dopamine receptor antagonist, antihistamines or 
dexamethasone. 
6.6.3.2.3 
Interruptions for Intercurrent Non-toxicity Related Events 
Study treatment dose interruption for conditions other than toxicity resolution should be kept 
as short as possible. If a subject cannot restart study treatment within 4 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with the AstraZeneca study physician. See Table 7 for dose reductions for olaparib 
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to manage AEs.  
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF.  
Study treatment should be stopped at least 3 days prior to planned surgery. After surgery, study 
treatment can be restarted when the wound has healed. No stoppage of study treatment is 
required for any needle biopsy procedure. 
Study treatment should be discontinued for a minimum of 3 days before a subject undergoes 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered. 
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, participants 
should be advised to use caution while driving or using machinery if these symptoms occur.  
6.6.3.2.4 
Hepatitis B 
For participants with past/resolved or chronic hepatitis B: In case of HBV reactivation* during 
the interventional period, study treatment should be interrupted and the participant should be 
referred to a hepatologist. Following proper care, study treatment can be restarted when 
exceptions of exclusion criteria #8 are met and after discussion with AZ study physician.  
Participants with chronic hepatitis B should be under the care of a hepatologist as per local 
standard practice. 
* For HBV reactivation, please refer to table 27 for detailed definitions. 
Table 27 
Definition of HBV Reactivation 
 
Baseline serologies 
 
Definition for HBV reactivation 
HBsAg 
HbcAb 
DNA 
+ 
+ 
Undetectable 
HBV DNA >100 IU/ml 
+ 
+ 
Detectable 
HBV DNA > 100 fold,  2 log compared 
to baseline value  
- 
 
+ 
 
Undetectable 
Detection of any DNA (even if not 
quantifiable)  -or- HBs Ag (+) (ie, 
reverse seroconversion)  
6.6.3.3 
Renal Impairment 
If subsequent to study entry and while still on study therapy, a subject’s estimated CrCL falls 
below the threshold for study inclusion (≥ 51 mL/min), retesting should be performed 
promptly.  
A dose reduction is recommended for subjects who develop moderate renal impairment 
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(calculated creatinine clearance by Cockcroft-Gault equation of between 31 and 50 mL/min) 
for any reason during the course of the study; the dose of olaparib should be reduced to 
200 mg bid (Table 8). 
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 subjects with severe renal impairment (creatinine clearance 
≤ 30 mL/min) or end-stage renal disease; if subjects develop severe impairment or end-stage 
disease it is recommended that olaparib be discontinued. 
6.6.4 
Management of Toxicities related to Enzalutamide and Abiraterone 
Acetate 
For management of toxicities due to investigator’s choice of NHA (enzalutamide and 
abiraterone acetate) refer to the locally approved Prescribing Information or manage in 
accordance with institutional guidelines. 
6.7 
Continued Access to Study Intervention after the End of the Study 
As described in Section 4.4, the study will remain open until all participants have discontinued 
study intervention and completed their last expected visit/contact. 
After the final DCO for this study, AstraZeneca will continue to supply olaparib to participants 
who were randomized to receive olaparib until PD occurs as judged by the investigator or 
until meeting any other discontinuation criteria as defined in Section 7.1. Participants should 
be followed according to the institution's standard of care assessments. No further data 
collection is required, except for reporting of SAEs. 
Participants receiving investigator’s choice of NHA at progression (Section 4.1) will be given 
the option of switching to olaparib 300 mg bid and AstraZeneca will continue to supply this 
treatment as described above.  
Participants who were randomized to receive investigator’s choice of NHA who are not 
eligible to switch to olaparib, or choose not to switch, or participants who discontinue from 
the study, should continue appropriate treatment at the discretion of the investigator. 
6.8 
Treatment of Overdose 
Study treatment must only be used in accordance with the dosing recommendations in this 
protocol. Any dose or frequency of dosing that exceeds the dosing regimen specified in this 
protocol should be reported as an overdose. The Maximum Tolerated Dose is 300 mg bid 
(tablet). There is currently no recommended specific treatment in the event of overdose of 
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olaparib and possible symptoms of overdose are not established. For participants receiving 
SoC (Investigator’s choice of either enzalutamide or abiraterone), refer to the local Prescribing 
Information for treatment of cases of overdose. 
In the event of an overdose, the investigator/treating physician should: 
• Evaluate the participant to determine, in consultation with the Study Clinical Lead, if 
possible, whether study intervention should be interrupted or whether the dose should be 
reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities as medically 
appropriate and at least until the next scheduled follow-up. Refer to section 8.3.16 for 
details of AE/SAE reporting related to overdose. 
• Document the quantity of the excess dose as well as the duration of the overdose. 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. If study intervention is permanently discontinued, the participant will 
remain in the study to be evaluated for PD (if discontinuation in the absence of PD) and OS, 
per the SoA (Table 3). Any subject discontinuing investigational product should be seen at 
30 days post discontinuation for the evaluations outlined in the SoA (Table 2). The 
investigator should instruct the participant to contact the site before or at the time if study 
intervention is stopped. A participant that decides to discontinue study intervention will 
always be asked about the reason(s) and the presence of any AEs. The reason for 
discontinuation should be documented in the source document and the appropriate section of 
the eCRF. 
Participants who have permanently discontinued from further receipt of study intervention 
will need to be discontinued from the IVRS/IWRS. All study intervention should be returned 
by the participant at their next on-site study visit or unscheduled visit. 
Any patient discontinuing investigational product should be seen at 30 days post 
discontinuation for the evaluations and sample collections outlined in the study schedule. The 
patient’s tumor 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 
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(see Section 7.3). 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 8.3.13) 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 adverse events after the 30 day follow-up period 
see Section 8.3.2.1. 
Participants may be discontinued from study intervention in the following situations.  
• 
Subject decision: The subject is at any time free to discontinue treatment, without 
prejudice to future treatment. 
• 
Any AE that, in the opinion of the investigator or AstraZeneca, contraindicates further 
dosing. 
• 
Any AE that meets criteria for discontinuation defined in the dose modification guidelines 
for management of olaparib-related toxicities (see Section 6.6) or as defined in the local 
Prescribing Information for the investigator’s choice of NHA agents (abiraterone acetate 
and enzalutamide). 
• 
Severe non-compliance with the study protocol  
• 
Bone marrow findings consistent with MDS/AML 
• 
Objective radiological progression by BICR as defined in Section 8.1.2.  
• 
Unequivocal clinical progression: 
− 
Cancer pain requiring initiation of chronic administration of opioids, or 
− 
Immediate need to initiate cytotoxic chemotherapy, radiation therapy, or surgical 
intervention for complications due to tumor progression, or 
− 
Deterioration in ECOG performance status to ≥ Grade 3.  
• 
Initiation of restricted anticancer therapy (see Section 6.5). 
 
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study. Switching to olaparib will be permitted once participants receiving investigator’s 
choice of NHA are determined to have objective radiological progression by BICR or, if after 
the date of DCO for the primary analysis, upon investigator-assessed radiological progression 
(Section 6.1). 
Participants who have discontinued study intervention prior to objective radiological 
progression, regardless of whether or not they have commenced subsequent anticancer 
therapy, will be followed up with tumor assessments as indicated in the SoA until radiological 
PD or death regardless of whether or not the participant started a subsequent anticancer 
therapy, unless they have withdrawn all consent to study-related assessments.  
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See the SoA for data to be collected at the time of intervention discontinuation (ie, the 
end-of-treatment visit) and follow-up and for any further evaluations that need to be 
completed. 
7.1.1 
Follow-up of Participants Post Discontinuation of Study Intervention 
All participants who discontinue the study intervention will be followed up for safety 
assessments 30 days after their last dose of study intervention. Additional assessments to be 
performed at the time of the 30-day safety follow-up are detailed in the SoA.  
Participants who have discontinued study intervention prior to objective radiological 
progression, regardless of whether or not they have commenced subsequent anticancer 
therapy, will be followed up with tumor assessments as indicated in the SoA until radiological 
progression or death regardless of whether or not the participant started a subsequent 
anticancer therapy, unless they have withdrawn all consent to study-related assessments.  
7.1.2 
Follow-up of Participants to PFS2  
Following objective progression that is confirmed by BICR assessment, participants will have 
their subsequent progression status recorded every 12 weeks per local standard clinical 
practice to assess time from randomization to second progression by investigator assessment 
of radiological or clinical progression or death (PFS2). Assessments will be performed 
according to the local practice, and formal Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST 1.1) measurements will not be collected for assessment of PFS2. See 
Section 8.1.4 for additional information. 
7.1.3 
Follow-up for Survival 
Participants will be followed up for survival status as indicated in the SoA (Section 1.3) until 
death, withdrawal of consent, or the end of the study. Survival information may be obtained 
via telephone contact with the participant or the participant’s family, by contact with the 
participant’s current physician or by checking publicly available death registries, if allowable 
per local regulations. Additional assessments to be performed at the time of survival follow-up 
are detailed in the SoA (Section 1.3). 
7.2 
Participant 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. 
− 
Incorrectly enroled patients ie, the patient does not meet the required 
inclusion/exclusion criteria for the study. 
− 
Patient lost to follow-up. 
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− 
Death 
• 
A participant may withdraw from the study at any time at his own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon. 
• 
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options to ensure the collection of endpoints and 
safety information including new AEs and follow-up on any ongoing AEs and 
concomitant medications (eg, telephone contact at 30 days [+7 days] after study 
intervention is discontinued, a contact with a relative or treating physician, or information 
from medical records). 
• 
At the time of withdrawal from the study, if possible, an Early Study Intervention 
Discontinuation visit should be conducted, as shown in the SoA (Section 1.3). See SoA 
(Section 1.3) for data to be collected at the time of study withdrawal and follow-up and 
for any further evaluations that need to be completed. 
− 
The participant will discontinue the study intervention and be withdrawn from the 
study at that time. 
• 
If the participant 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 participant withdraws from the study, it should be confirmed if he still agrees for 
existing samples to be used in line with the original consent. If he requests withdrawal of 
consent for use of samples, destruction of any samples taken and not tested should be 
carried out in line with what was stated in the informed consent and local regulation. The 
investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team. 
 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he repeatedly fails to return for scheduled 
visits and no contact has been established by the time the study is completed (see Section 4.4), 
such that there is insufficient information to determine the participant’s status at that time. 
Participants who decline to continue participation in the study, including telephone contact, 
should be documented as “withdrawal of consent” rather than “lost to follow-up.” 
Investigators should document attempts to re-establish contact with missing participants 
throughout the study period. If contact with a missing participant is re-established, the 
participant should not be considered lost to follow-up and evaluations should resume 
according to the protocol. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
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• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, he will be considered to have been lost 
to follow-up from the study. 
• 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant during survival follow-up within legal and ethical boundaries for all 
participants randomized, including those who did not get study intervention. Public 
sources may be searched for vital status information. If vital status is determined as 
deceased, this will be documented and the participant will not be considered lost to 
follow-up. Sponsor personnel will not be involved in any attempts to collect vital status 
information. 
 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix A.In order to support key efficacy endpoints of PFS and OS analyses, the survival 
status of all participants in the Full Analysis and the Safety Analysis Sets should be 
re-checked; this includes those participants who withdrew consent or are classified as “lost to 
follow-up.” 
• 
Lost to follow-up – Site personnel should check hospital records and a publicly available 
death registry (if available), as well as checking with the participants’ current physician, 
to obtain a current survival status (the applicable eCRF modules will be updated). 
• 
In the event that the participant has actively withdrawn consent to the processing of their 
personal data, the survival status of the participant can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 1.3). Data collection 
following study analysis until the end of the study is described below.  
• 
Protocol waivers or exemptions are not allowed. 
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• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3) is essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Section 1.3). 
 
Data Collection Following Study Analysis until the End of the Study 
 
Following the DCO for the primary efficacy endpoint, central review of scans will be 
discontinued. Participants will continue with all other assessments as indicated in the SoA. 
For SAE and AE reporting and laboratory assessment collection after final analysis, see 
Section 8.3.12.After the final DCO and database closure, only SAEs will be reported for the 
purposes of this study (see Section 8.3.12). 
Following the DCO for the final analysis, all participants who remain in the study will 
continue the scheduled “progression/survival follow-up” site visits indicated in the SoA. 
8.1 
Efficacy Assessments 
8.1.1 
Imaging Tumor Assessments  
All imaging assessments including unscheduled visit scans should be collected on an ongoing 
basis and sent to an AstraZeneca appointed CRO to enable independent central review. Upon 
investigator-assessed objective disease progression as defined in Section 8.1.2, review of all 
scans will be conducted by BICR. The results will be reported back to the sites. All imaging 
assessments and study treatment should continue until objective disease progression as 
assessed by BICR (see Figure 3).  
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 randomization. 
Following the baseline assessment, subsequent assessments should be performed every 
8 weeks (± 7 days), relative to the date of randomization, until objective radiological disease 
progression by BICR, even after investigator has deemed objective disease progression, 
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irrespective of treatment decisions or dose interruptions. The assessments by different imaging 
modalities 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 
Table 2). If scans are performed outside of scheduled visit window interval, and the subject 
has not progressed, every attempt should be made to perform the subsequent scans at their 
originally scheduled time points. 
In order for participants randomized to investigator choice arm to be eligible to switch to 
olaparib, scheduled tumor assessments must continue until objective radiological disease 
progression as assessed by BICR, without any intervening systemic anti-cancer therapy 
following discontinuation of randomized study treatment (see Section 6.1).  
Until the primary rPFS analysis all imaging assessment and study treatment should continue 
until objective disease progression as assessed by BICR (see Figure 3). There is no plan for 
BICR to read any scans dated after the date of DCO for the primary analysis. There will be no 
need to request confirmation of BICR PD after this time point, and the investigator-assessed 
radiographic progression will prevail. 
Radiological examinations performed during the study should be retained at site as source 
data. 
Figure 3  
Assessment of Progression by BICR (prior to primary rPFS analysis) 
 
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8.1.1.1 
CT and MRI Scans Tumor Assessments (RECIST 1.1) 
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 participants. At assessments 
subsequent to baseline, any other sites at which new disease is suspected should also be 
appropriately imaged. The methods of assessment of tumor burden used at baseline must be 
used at each subsequent assessment. In this study, bone lesions will not be included in the 
RECIST soft tissue assessment.  
8.1.1.2 
Bone Scans Tumor Assessment (Based on PCWG3 Criteria) 
Bone lesions will be assessed by bone scintigraphy commonly performed with Technetium-99 
(bone scans). Bone lesions will be assessed by bone scan and will not be part of the RECIST 
1.1 malignant soft tissue assessment. Positive hot spots on the bone scan should be considered 
significant and unequivocal sites of malignant disease to be recorded as metastatic bone 
lesions.  
8.1.2 
Tumor Evaluation 
Disease progression will be deemed to have occurred if one or more of the following criteria 
is met: 
• 
Soft tissue disease progression as defined by RECIST 1.1 
• 
Bone lesion progression by bone scan (see Table 12) 
• 
Death. 
 
RECIST 1.1 criteria will be used to assess subject response to treatment by determining PFS, 
objective response rates (ORR), and DoR. Categorization of objective tumor response 
assessment will be based on the RECIST 1.1 criteria of response: CR, PR, SD and PD. Target 
lesion progression will be calculated in comparison to when the tumor burden was at a 
minimum (ie, smallest sum of diameters previously recorded on study). In the absence of 
progression, tumor response (CR, PR, and SD) will be calculated in comparison to the 
baseline tumor measurements obtained before starting treatment. If the investigator is in doubt 
as to whether progression has occurred, particularly with regard to NTLs or the appearance of 
a new lesion, it is advisable to continue treatment and reassess the tumor burden at the next 
scheduled assessment or sooner if clinically indicated. The RECIST 1.1 guidelines for 
measurable, non-measurable, target and non-target lesions and the objective tumor response 
criteria are presented in Appendix E. For ORR, a visit response of CR or PR must be 
confirmed by a later scan conducted at least 4 weeks after the initial response is observed. 
Bone lesions will be assessed by bone scan and will not be part of the RECIST 1.1 malignant 
soft tissue assessment. The definition for bone progression is based on PCWG3 criteria. 
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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 8 week scan: 
If 2 or more new metastatic bone lesions are observed on the first 8-week scan, the 
confirmatory scan performed (at least 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).  
Note - The first bone scan completed after baseline will be considered the ‘8-week scan’ regardless of whether it 
is taken at week 8 or at an unscheduled assessment.  
After the 8 week scan: 
For participants without progression at the 8 week scan, this scan now serves as new baseline 
for all subsequent scans, ie, 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 8-week 
assessment (compared to week 8 scan), a confirmatory scan performed at least 6 weeks later 
and preferably no later than the next scheduled visit must show the persistence of, or an 
increase in, the number of metastatic bone lesions compared to the prior scan. 
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 summarized in Table 
12: 
Table 12 
Requirements for Documentation of Progression 
Visit date 
Criteria for bone progression 
Criteria for soft tissue progression 
Week 8 
2 or more new lesions compared to baseline 
bone scan. 
Requires confirmation scan at least 6 weeks later 
with ≥2 additional lesions compared to week 8 
scan 
Progressive disease on CT or MRI by 
RECIST 1.1 
No confirmation scan required. 
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Table 12 
Requirements for Documentation of Progression 
Visit date 
Criteria for bone progression 
Criteria for soft tissue progression 
Week 16 or 
later 
2 or more new lesions compared to week 8 bone 
scan. 
Requires confirmation scan 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 scan required. 
 
It is important to follow the assessment schedule as closely as possible. Please refer to the 
study schedule in Section 1.3. 
8.1.3 
Central Reading of Scans  
All imaging assessments including unscheduled visit scans should be collected on an ongoing 
basis and sent to an AstraZeneca appointed Clinical Research Organization (CRO) to enable 
BICR. Upon documentation of radiological progression by the investigator, all imaging 
assessments for the given subject, including unscheduled visit scans, will be reviewed by 
BICR. Results of this independent review will be communicated to investigators. Participants 
should continue imaging assessments until BICR-assessed progression (see Section 8.1.1). 
An independent review of all scans used in the assessment of tumors will be conducted prior 
to the primary analysis of rPFS, including for participants without investigator-assessed 
progression.  
The primary analysis for this study will be based on the BICR of all radiological scans 
(CT/MRI and bone scans). 
After the primary rPFS 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. After rPFS analysis, all treatment decisions will be based on site 
assessment of scans. Ongoing collection of site review tumor assessment is required and must 
be recorded in the eCRF.  
Further details of the BICR will be documented in an Independent Review Charter. 
8.1.4 
Time to Second Progression or Death 
Following objective progression by BICR, participants will have their subsequent progression 
status recorded every 12 weeks per local standard clinical practice to assess PFS2. A 
participant’s PFS2 status is defined according to the local practice and may involve any of: 
objective radiological progression (preferred), symptomatic progression (but not PSA 
progression), or death. Scans will be performed according to the local practice and formal 
RECIST 1.1 and PCWG3 measurements will not be collected for assessment of PFS2. The 
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second progression event must have occurred during or after treatment with a subsequent 
therapy after the progression event used for the primary variable PFS or death. The date of 
PFS2 assessment and investigator opinion of progression status (progressed or 
non-progressed) at each assessment will be recorded in the source documents and the eCRF. 
8.1.5 
Symptomatic Skeletal-related Events 
Symptomatic skeletal-related events (SSREs) will be assessed at each visit during the 
treatment phase, up to and including the study treatment discontinued visit (see Table 2). 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 spinal cord compression, 
or a tumor related orthopedic surgical intervention. 
The occurrence of a SSRE alone, in the absence of disease progression, is discouraged as a 
reason to discontinue treatment or to initiate new systemic anti-cancer therapy. 
8.1.6 
PSA Assessments 
Blood samples will be collected for PSA assessment at baseline and at each visit during the 
treatment phase, up to and including the study treatment discontinued visit (Section 1.3). The 
samples will be analyzed by central laboratory. In order to prevent early withdrawal from 
treatment phase, PSA results will not be sent back to sites prior to final analysis. 
Samples will be collected, labeled, stored and shipped as detailed in the Laboratory manual. 
8.1.7 
Overall Survival  
Assessments for survival will be conducted every 12 weeks following objective PD or 
treatment discontinuation. Survival information may be obtained via telephone contact with 
the participant, participant’s family, by contact with the participant’s current physician, or 
local death registries as described in Section 7.1.3. 
8.1.8 
Clinical Outcome Assessments  
Clinical Outcome Assessments are not evaluated in this study. 
8.2 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 
Physical Examinations 
A complete physical examination will be performed as specified in the SoA (Section 1.3) and 
if clinically indicated at any other time. A complete physical examination will include 
assessments of the following: general appearance, respiratory, cardiovascular, abdomen, skin, 
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head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal 
(including spine and extremities), and neurological systems.  
Physical examination, as well as assessment of height and weight, will be performed at 
timelines as specified in the SoA; investigators should pay special attention to clinical signs 
related to previous serious illnesses, new or worsening abnormalities may qualify as AEs, see 
Section 8.3.5 for details. 
Weight measurements will not be recorded in the eCRF after Cycle 1 Day 1 (C1D1). If a 
patient’s weight change is clinically significant, it should be entered as an AE in the Adverse 
Events eCRF. 
8.2.2 
Vital Signs 
Vital signs will be performed at timelines as specified in the SoA (Section 1.3).  
Body temperature, pulse rate and blood pressure will be assessed. 
The date of collection and measurement of vital sign will be recorded on the appropriate 
eCRF. Vital signs will not be recorded in the eCRF after C1D1. If a participant’s vital signs 
are clinically significant, the medical term for the abnormality should be entered as an AE in 
the Adverse Events eCRF. 
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the participant in a quiet setting without distractions (eg, television, cell phones). 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute). The average of the 3 blood pressure readings will be recorded 
on the eCRF. 
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.5.  
8.2.3 
Electrocardiograms 
Single 12-lead ECGs will be performed at timelines as specified in the SoA after the 
participant has been resting semi-supine for at least 5 minutes and recorded while the 
participant remains in that position using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QT interval corrected by Fridericia’s formula 
(QTcF) intervals.  
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All ECGs should be assessed by the investigator as to whether they are clinically significantly 
abnormal. Any clinically significant abnormalities detected require triplicate ECG results. At 
each time point at which triplicate ECG are required, 3 individual ECG tracings should be 
obtained in succession, no more than 2 minutes apart. The full set of triplicates should be 
completed within 5 minutes. 
Situations in which ECG results should be reported as AEs are described in Section 8.3.5. 
8.2.4 
Clinical Safety Laboratory Assessments 
Blood and urine samples for determination of clinical chemistry, hematology, coagulation, and 
urinalysis will be taken at the visits indicated in the SoA (Section 1.3). 
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, hematology and urinalysis will be performed locally. Instructions for 
sample collection, labeling, processing, storage, and shipment will be provided in a separate 
laboratory manual provided to the sites. 
Abnormal clinically significant laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours).  
The following laboratory variables will be measured.  
Table 13 
Laboratory Safety Variables  
Hematology/Hemostasis (whole blood) 
Clinical chemistry (serum or plasma) 
Hemoglobin 
Creatinine 
Leukocyte count 
Bilirubin, total 
Leukocyte differential count (absolute count) 
ALP 
Platelet count 
AST 
Absolute neutrophil count 
ALT 
Absolute lymphocyte count 
Albumin 
B-Mean Cell volume (MCV) 
Potassium 
Total red blood cell count 
Calcium, total 
Hematocrit 
Sodium 
 
Urea nitrogen/blood urea nitrogen 
 
Protein, total 
Urinalysis 
Lactate dehydrogenase 
Hemoglobin/Erythrocytes/Blood  
Amylase 
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Hematology/Hemostasis (whole blood) 
Clinical chemistry (serum or plasma) 
Protein/Albumin  
Gamma-glutamyl transferase 
Glucose  
Glucose (fasting) 
 
Coagulation variables (aPTT, PTT, and INR) 
 
HBs Ag 
 
Anti-HBc 
 
Anti-HBs 
 
HBV DNA 
ALP, alkaline phosphatase; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, 
aspartate aminotransferase; INR, international normalized ratio; PTT, partial thromboplastin time. HBsAg, 
hepatitis B surface antigen; Anti-HBc, hepatitis B core antibody; Anti-HBs, hepatitis B surface antibody;  
 
The investigator should assess the available results with regard to clinically relevant 
abnormalities in the documentation. Any clinically significant abnormal laboratory values 
should be repeated as clinically indicated and recorded on the eCRF. Situations in which 
laboratory safety results should be reported as AEs are described in Section 8.3.5. 
All participants with Grade 3 or 4 laboratory values at the time of completion or 
discontinuation from study intervention must be followed and have further tests performed 
until the laboratory values have returned to Grade 1 or 2, unless these values are not likely to 
improve because of the underlying disease. 
NB. In case a participant shows an AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN 
please refer to Appendix D “Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law (HL)”, for further instructions.  
8.2.4.1 
Coagulation  
Activated partial thromboplastin time (aPTT) will be performed at screening and if clinically 
indicated.  
International normalized ratio (INR) will be performed at screening and if clinically indicated. 
Participants 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 eCRF. 
8.2.4.2 
Bone Marrow or Blood Cytogenetic Samples  
Bone marrow or blood cytogenetic samples may be collected for participants with prolonged 
hematological toxicities as defined in Section 6.6.3.1. 
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity. If it is not 
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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 Patients Safety database. These data are 
not required to be entered into eCRF. 
The investigator should assess the available results for clinically relevant abnormalities. The 
laboratory results should be signed and dated and retained at center as source data for 
laboratory variables. For information on how AEs based on laboratory tests should be 
recorded and reported, see Section 8.3.5. 
8.2.4.3 
Hepatitis B Blood Test 
HBsAg, anti-HBc and anti-HBs  blood tests will be performed at screening. And if either 
HBsAg or anti-HBc is positive, HBV DNA (viral load) and HBsAg should also be tested at 
screening, every 12 weeks (± 7 days) relative to the date of randomisation during the 
interventional period and at 30-day safety follow-up.  
8.2.5 
Other Safety Assessments 
8.2.5.1 
ECOG Performance Status 
ECOG performance status will be assessed at the times specified in the SoA (Section 1.3) 
based on the following: 
0 
Fully active; able to carry out all usual activities without restrictions. 
1 
Restricted in strenuous activity, but ambulatory and able to carry out light work or work 
of a sedentary nature (eg, light housework or office work). 
2 
Ambulatory and capable of self-care, but unable to carry out any work activities; up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled; unable to carry out any self-care and totally confined to bed or 
chair. 
5 
Dead. 
 
Any significant change from baseline or screening must be reported as an AE. 
8.3 
Adverse Events and Serious 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 B. 
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Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative).  
The investigator and any designees are responsible for detecting, documenting, recording, and 
reporting events that meet the definition of an AE. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
Adverse events and SAEs will be collected from the time of signature of the ICF, throughout 
the treatment period and until the 30-day follow-up period is completed*. Collection and 
reporting of AEs and SAEs after the final DCO is described in Section 8.3.12. 
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the sponsor. 
*Exception: In screening part 1, only SAEs related to study procedures must be reported (AEs 
do not require reporting). From screening part 2 onwards - all AEs/SAEs must be reported. 
8.3.2 
Follow-up of AEs and SAEs 
8.3.2.1 
Adverse Events After the 30-day Follow-up Period  
For Pharmacovigilance purposes and characterization, 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 subject has developed MDS/AML or a new primary malignancy and prompted 
to report any such cases.  
At any time after a subject 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 participants 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 participants. This includes new AEs/SAEs in participants still being 
followed up for survival but who have completed the post treatment follow-up period 
(30 days). 
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8.3.2.2 
Follow-up of Unresolved Adverse Events 
Any AEs that are unresolved at the participant’s last AE assessment 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 participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
8.3.2.3 
Adverse Event Variables 
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 (Appendix B). 
• 
Investigator causality rating against the study intervention(s) (yes or no). 
• 
Action taken with regard to study intervention(s). 
• 
Outcome. 
 
In addition, the following variables will be collected for SAEs, if applicable: 
• 
Date AE met criteria for SAE. 
• 
Date investigator became aware of SAE. 
• 
Seriousness criteria. 
• 
Date of hospitalization. 
• 
Date of discharge. 
• 
Probable cause of death. 
• 
Date of death. 
• 
Autopsy performed. 
• 
Causality assessment in relation to study procedure(s). 
• 
Causality assessment to other medication. 
• 
Description of AE. 
 
Severity of AE 
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 B 2. An AE of severe 
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intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Appendix B 2.  
The grading scales found in the NCI-CTCAE (Version 5.0) will be utilized 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). 
8.3.3 Causality Collection 
The investigator should assess causal relationship between study intervention 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 investigational product?”. 
For SAEs, causal relationship should 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 B. 
8.3.4 Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the participant 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. 
8.3.5 Adverse Events Based on Examinations and Tests 
The results from the CSP-mandated laboratory tests and vital signs will be summarized in the 
CSR.  
Deterioration as compared with 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, are the reason for discontinuation of treatment with the study intervention or are 
considered to be clinically relevant as judged by the investigator (which may include but is not 
limited to consideration as to whether treatment or non-planned visits were required or other 
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action was taken with the study intervention, eg, dose adjustment or study intervention 
interruption).  
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, anemia versus low hemoglobin 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 PD, should not be reported 
as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
8.3.6 Hy’s Law 
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN may 
need to be reported as SAEs. Please refer to Appendix D for further instruction on cases of 
increases in liver biochemistry and evaluation of HL.  
8.3.7 Disease Progression 
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the study intervention 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 PD and not an AE. Events, which are unequivocally due to PD, 
should not be reported as an AE during the study. 
8.3.8 
New Cancers 
The development of a new cancer should be regarded as an AE (see Section 8.3.11) and will 
generally meet at least one of the serious criteria (with the exception of some non-melanoma 
skin cancers). New primary cancers are those that are not the primary reason for the 
administration of study intervention and are identified after the participant’s inclusion in this 
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. 
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8.3.9 
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. 
8.3.10 
Deaths 
All deaths that occur during the study intervention period, or within the protocol-defined 
follow-up period after the administration of the last dose of study intervention, must be 
reported as follows: 
• 
Death clearly resulting from PD should be documented in the eCRF in the Statement of 
Death page. It should not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to PD under study, the AE causing the death 
must be reported as an SAE within 24 hours. It should also be documented in the 
Statement of Death page in the eCRF. The report should contain a comment regarding the 
co-involvement of PD, if appropriate, and should assign the main and contributory causes 
of death. 
• 
Deaths with an unknown cause should always be reported as an SAE and documented in 
the Statement of Death page in the eCRF, but every effort should be made to determine a 
cause of death. 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 
Patient Safety or its representative within the usual time frames. 
 
Deaths occurring after the protocol-defined follow-up period after the administration of the 
last dose of study intervention should be documented in the Statement of Death page. If the 
death occurred as a result of an event that started after the defined follow-up period and the 
event is considered to be due to a late-onset toxicity to study intervention, then it should also 
be reported as an SAE. 
8.3.11 
Adverse Events of Special Interest 
Adverse Events of Special Interest are events of scientific and medical interest specific to the 
further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. An AESI can be serious or non-serious. 
All AESIs will be recorded in the eCRF. Serious AESIs will be recorded and reported as per 
Section 8.3.13. 
Adverse Events of Special Interest for olaparib are the Important Identified Risk of 
MDS/AML, the Important Potential Risk of new primary malignancy (other than MDS/AML) 
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and the Potential Risk of pneumonitis.  
A questionnaire will be sent to any investigator reporting an AESI, as an aid to provide further 
detailed information on the event. During the study there may be other events identified as 
AESIs that require the use of a questionnaire to help characterise the event and gain a better 
understanding regarding the relationship between the event and study treatment. 
8.3.12 
Safety Data to be Collected Following the Final Data Cutoff of the 
Study  
For participants continuing to receive study treatment after the final DCO, AEs and SAEs will 
be collected, but only SAEs will be reported. In addition, it is recommended that investigators 
monitor the participant’s safety laboratory results periodically during treatment with study 
treatment in order to manage AEs, consistent with the dose modification guidelines for 
management of study intervention-related toxicities (see Section 6.6). All data after the final 
DCO and database closure will be recorded in the participant notes but, with the exception of 
SAEs, will not otherwise be reported for the purposes of this study. 
All SAEs that occur in participants still receiving study treatment (or within the 30 days 
following the last dose of study treatment) after the final DCO must be reported as detailed in 
Section 8.3.13.  
8.3.13 
Reporting of Serious Adverse Events 
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedure(s)*. All SAEs will be recorded in the eCRF. 
*Exception: In screening part 1, only SAEs related to study procedures must be reported.  
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 from 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 from 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 
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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.  
For further guidance on the definition of a SAE, see Appendix B. 
The reference document for definition of expectedness/listedness is the IB/prescribing 
information for olaparib and the prescribing information for the active comparator product.  
8.3.14 
Pregnancy 
All pregnancies and outcomes of pregnancy with conception dates following the first date of 
study intervention, including pregnancy in the partner of male participants, should be reported 
to AstraZeneca. 
8.3.14.1 
Paternal Exposure  
Non-sterilized male participants who intend to be sexually active with a female partner of 
childbearing potential should refrain from fathering a child or donating or banking sperm for 
the duration of the study (from the time of screening) and for 3 months after the last dose of 
study intervention.  
Participants in the investigator’s choice of NHA (enzalutamide or abiraterone acetate) group 
should follow the local Prescribing Information relating to contraception, the time limits for 
such precautions, and any additional restrictions for agents in the investigator’s choice of 
NHA (enzalutamide or abiraterone acetate) group. 
Pregnancy of the participant’s partner 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 of study intervention 
until 3 months after the last dose of study intervention should be followed up and documented 
in the medical record and provided to the AstraZeneca Patient Safety data entry site. Consent 
from the partner must be obtained before the information is collected and reported to 
AstraZeneca. 
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the investigator must obtain the consent of the participant’s partner. The local study team 
should adopt the Master Pregnant Partner Form in line with local procedures/requirements and 
submit it to the relevant Regulatory Authority/IRBs/IECs prior to use. 
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8.3.15 
Medication Error, Drug Abuse and Drug Misuse 
8.3.15.1 
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 calendar 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 8.3.13) 
and within 30 days for all other events. 
8.3.15.2 
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 B 4. 
8.3.15.3 
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 B 4. 
8.3.15.4 
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 B 4. 
8.3.16 
Reporting of Overdose 
Refer to Section 6.8 for definition and treatment of overdose. 
• An overdose with associated AEs is recorded as the AE diagnoses/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 
• An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
 
If an overdose on an IMP or AstraZeneca NIMP occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
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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 provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for overdoses associated with an SAE (see Section 8.3.13) and within 
30 days for all other overdoses. 
For participants receiving investigator’s choice of NHA (enzalutamide or abiraterone acetate) 
refer to the local Prescribing Information for treatment of cases of overdose. If any overdose is 
associated with an AE or SAE, record the AE/SAE diagnosis or symptoms in the relevant AE 
modules only of the eCRF. 
8.4 
Human Biological Samples 
8.4.1 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.4.2 
Immunogenicity Assessments 
Immunogenicity parameters are not evaluated in this study. 
8.4.3 
Pharmacodynamics 
Pharmacodynamics parameters are not evaluated in this study. 
8.5 
Human Biological Sample Biomarkers 
8.5.1 
Collection of Mandatory Samples for Biomarker Analysis 
Participant consent to the study includes participation in the mandatory biomarker assessment 
components of the study.  
Samples for biomarker assessment are required and will be collected from all participants in 
this study as specified in the SoA (Section 1.3). 
8.5.1.1 
Mandatory Tumor Sample Collection 
The provision of a FFPE tumor tissue sample during screening for central testing is mandatory 
in this study. Samples will be tested for BRCA1/2 gene mutation to evaluate their association 
with the observed clinical responses to olaparib. If the test results indicate that the participant 
has a qualifying mutation in the BRCA1 or BRCA2 genes, the participant is eligible for the 
study. 
Tumor tissue samples can be from either primary tumor (eg, transrectal biopsies or radical 
prostatectomy specimen) or metastatic biopsy. 
All samples will be tested for BRCA1/2 mutations in a China based central laboratory for 
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patient eligibility. No other local testing results, other commercially offered NGS analyses or 
other pre-existing molecular test results are accepted. 
FFPE tumor samples submitted to establish eligibility should be of sufficient quantity and 
quality to allow for tBRCA testing. The detailed sample requirements are described in the 
Laboratory Manual. Residual samples will be retained at the central testing laboratory to 
support potential Chinese regulatory filing or the development of companion diagnostic assays 
(CDx). Consent for use of the FFPE samples for BRCA testing, future diagnostic development 
and regulatory filing is mandatory. 
No future research and exploratory biomarker analysis will be conducted. Remaining tissue 
samples will be destroyed or repatriated within one year of CSR. 
For further details on Handling of Human Biological Samples, including storage, re-use and 
destruction, refer to Appendix C and the Laboratory Manual.  
8.5.1.2 
BRCA Mutation Testing of Tumor Biopsy Sample  
The BRCA results must be available prior to randomization. Therefore, a FFPE tumor sample 
(meets the tissue requirements outlined in the Laboratory Manual) will be submitted to a 
China based central laboratory for BRCA1/2 testing. The tumor testing will be conducted 
using a NGS assay based on DNA extracted from the provided FFPE tumor tissue. Only 
participants with positive BRCA1/2 mutations (deleterious or suspected deleterious) are 
eligible for this study. 
8.5.1.3 
Collection, Analysis and Reporting of Tumor Samples  
Tumor samples will be collected as detailed in the Laboratory Manual. Participants must 
consent to provide either archived FFPE samples, or a de novo tumor biopsy sample for 
analysis. Consideration should be given to the potential benefit to the subject (should he be 
eligible for study) in the context of the risk posed by the biopsy procedure. Tissue biopsy 
sampling should be conducted in accordance with expert guidelines, only by investigators 
experienced in performing these sampling methods in appropriate clinical settings. Samples 
that meet the minimal requirement as specified in the Laboratory Manual will be shipped to a 
central testing laboratory to determine BRCA1/2 status. 
If the initial testing is inconclusive due to technical test failure, a repeat may be carried out if 
additional sample is available and Human Genetics Resources approval has been obtained for 
use of the additional samples.  
Upon successful testing, a report will be issued to sites including information of the BRCA 
mutation status for subject eligibility assessment. 
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8.6 
Optional Genomics Initiative Sample 
Optional Genomics Initiative research is not applicable in this study. 
8.7 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study. 
9 
STATISTICAL CONSIDERATIONS 
Statistical analyses will be performed by AstraZeneca or its representatives.  
A comprehensive statistical analysis plan (SAP) will be prepared prior to first subject 
randomized and any subsequent amendments will be documented, with final amendments 
completed prior to unblinding of the data. 
All personnel involved with the analysis of the study will remain blinded at aggregate level 
until database lock and protocol violations identified. Prior to the database lock, any analysis 
tasks being performed will use a dummy random scheme (Section 6.3).  
9.1 
Statistical Hypotheses 
The hypothesis of interest with regards to the primary endpoint, rPFS assessed by BICR per 
RECIST 1.1 (soft tissue) and PCWG3 (bone) criteria, is:  
• 
H0: No difference between olaparib and investigator choice of enzalutamide or 
abiraterone acetate. 
• 
H1: Difference between olaparib and investigator choice of enzalutamide or abiraterone 
acetate. 
No formal testing of hypotheses will be performed as the study is designed to demonstrate the 
same trend of treatment effect in Chinese men as that shown in the PROfound study, and thus 
no adjustment for multiplicity will be made and all p-values generated will be regarded as 
descriptive.  
9.2 
Sample Size Determination 
Approximately 700 participants will be screened to achieve approximately 42 randomly 
assigned to study intervention. The primary rPFS analysis will be performed when 
approximately 21 rPFS events have occurred (50% maturity). Assuming a true underlying 
rPFS HR of 0.35, exponentially distributed data and a median rPFS of 3.4 months on the 
investigator choice arm, this translates to a median rPFS of 9.7 months on the experimental 
arm ie a 6.3-month benefit. With 42 patients, the study will have >90% probability to 
demonstrate the same trend of treatment effect (at least 50% retention of true HR, ie. HR 
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<0.675) as that shown in the PROfound study. 
With a recruitment period of approximately 17 months and a minimum follow-up period of 
4 months assumed, it is anticipated that this analysis will be performed 21 months after the 
first participant has been randomized, taking into account study dropout. 
9.3 
Populations for Analyses 
The following populations are defined: 
Table 14 
Populations for Analysis 
Population/Analysis set 
Description 
Enrolled 
All participants who sign the ICF. 
Full analysis set (FAS) 
All participants who are randomized in the study. The FAS will be used for all 
the efficacy analyses, except for ORR, DoR and BoR. Treatment groups will be 
compared on the basis of randomized study intervention, regardless of the 
treatment actually received. Participants who were randomized but did not 
subsequently receive study intervention are included in the analysis in the 
treatment group to which they were randomized. 
Evaluable for response 
(EFR) analysis set 
All participants in the FAS, who have measurable disease at baseline per 
RECIST 1.1 criteria. Measurable disease will be defined using the BICR 
assessment for analyses of BICR data, as well as using the investigator 
assessment data for analyses of investigator assessment. ORR, DoR and BoR will 
be analyzed using the EFR set. 
Safety analysis set 
All participants who have received at least 1 dose of study intervention.  
 
9.4 
Statistical Analyses 
The SAP will be finalized prior to first participant in and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints. 
9.4.1 
General Considerations 
• 
For qualitative variables, the population size (N for sample size and n for available data) 
and the percentage (of available data) for each class of the variable will be presented. 
Quantitative variables will be summarized using descriptive statistics, including n, mean, 
standard deviation (SD), median, minimum, and maximum values. Where appropriate, 
assessments will be summarized by visit. 
• 
The number of participants who were screened, randomized to treatment, received 
treatment and completed the study will be produced for each treatment group using the 
full analysis set. A summary table of analysis sets will be produced. Demographic and 
baseline characteristics will be summarized using the full analysis set. 
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• 
In general, missing data will not be imputed. For the date variables of historical data (ie, 
any data referring to the period prior to the informed consent date), if the year is missing 
then the value will not be imputed. If the month or day is missing, the value will be 
imputed: month will be imputed with June; day will be imputed as 15th. 
• 
The treatment comparison is olaparib versus investigator choice. Results of statistical 
analyses will be presented using corresponding 2-sided confidence intervals and 2-sided 
p-values, where appropriate.  
 
9.4.2 
Efficacy 
9.4.2.1 
Calculation or Derivation of Tumor Response Variables 
BICR RECIST 1.1 and PCWG3-based assessments 
A BICR of radiological scans will be performed on all participants.  
All images will be collected centrally. The imaging scans will be reviewed by 2 independent 
radiologists using RECIST 1.1 and PCWG3, and will be adjudicated, if required. For each 
participant, the BICR will define the overall visit response data (complete response [CR], 
partial response [PR], stable disease [SD], PD, Non-PD or not evaluable [NE]) and the 
relevant scan dates for each time point (ie, for visits where response or progression is/is not 
identified). Endpoints (rPFS, ORR, BoR, and DoR) will then be derived from the scan dates 
and overall visit responses.  
Further details of the BICR will be documented in an Independent Review Charter. 
Investigator RECIST 1.1 and PCWG3-based assessments  
All RECIST 1.1 and PCWG3 assessments, whether scheduled or unscheduled, will be 
included in the calculations. This is also regardless of whether a participant discontinues study 
intervention or receives another anticancer therapy.  
At each visit, participants will be programmatically assigned a RECIST 1.1 visit response of 
CR, PR, SD, PD, or NE depending on the status of their disease compared with baseline and 
previous assessments. Bone lesions will be assessed by bone scan and will not be part of the 
RECIST v1.1 malignant soft tissue assessment. Progression on a bone scan is identified using 
PCWG3. At each visit an overall assessment (Non-PD, PD or NE) of the bone lesion 
progression should be recorded by the investigator. Baseline will be assessed within 28 days 
prior to randomization.  
The visit responses for soft tissue (according to RECIST 1.1 criteria) and bone progression 
status (according to PCWG3 criteria) will be combined to give an overall radiological 
objective visit response. 
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The tumor response endpoints by investigator (rPFS, ORR, best observed response and DoR) 
will then be derived from the scan dates and overall visit responses. 
9.4.2.2 
Primary Endpoint 
9.4.2.2.1 
Radiological Progression-Free Survival (rPFS) 
Radiological progression-free survival is defined as the time from randomization to 
radiological progression (see Section 3), as assessed by BICR per RECIST version 1.1 (soft 
tissue) and PCWG3 criteria (bone), or, death due to any cause (ie, date of event or censoring – 
date of randomization + 1). The comparison will include all randomized participants, as 
randomized, regardless of whether the participant withdraws from randomized therapy, or 
receives another anti-cancer therapy prior to progression. Participants who have not 
progressed (defined as CR, PR or SD by RECIST 1.1 for soft tissue disease, or non-PD for 
bone disease (see Section 8.1.2 and Appendix E) or died at the time of analysis will be 
censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 or 
bone scan assessment. However, if the participant progresses or dies after 2 or more 
consecutive missed radiologic assessments, the participant will be censored at the time of the 
latest evaluable RECIST 1.1 or bone scan assessment prior to the 2 missed visits. 
If the participant has no evaluable visits or does not have baseline data, they will be censored 
at Day 1, unless they die within 2 visits of baseline (in which case their date of death will be 
used). 
The rPFS time will always be derived based on scan/assessment dates and not visit dates. 
CT/MRI and bone scans contributing toward a particular visit may be performed on different 
dates. For BICR (RECIST 1.1 and PCWG3) assessments, the following rules will be applied: 
1 
The date of progression will be determined based on the earliest of the scan dates of the 
component that triggered the progression for the adjudicated reviewer selecting PD or of 
the reviewer who read baseline first if there is no adjudication for ICR data.  
2 
When censoring a participant for rPFS, the participant will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 
 
The primary analysis will be based on the BICR of the radiological scans. A charter for the 
BICR will be developed in advance of the start of study. There is no plan for BICR to read any 
scans dated after the date of DCO for the primary analysis. There will be no need to request 
confirmation of BICR PD after this time point, and the investigator-assessed radiographic 
progression will prevail.  
Investigator-assessed radiographic progression  
CT/MRI and bone scans contributing toward a particular visit may be performed on different 
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dates. For investigator assessments, the following rules will be applied: 
1 
The date of progression will be determined based on the earliest of the dates of the 
component that triggered the progression.  
2 
When censoring a participant for rPFS, the participant will be censored at the latest of the 
dates contributing to a particular overall visit assessment. 
 
When the investigator is in doubt as to whether PD has occurred and therefore reassesses the 
subject at a later date, the date of the initial scan should be declared as the date of progression 
if the repeat scans confirm progression. 
Analysis Methods 
The HR for rPFS will be estimated using a Cox Proportional Hazards Model (with ties=Efron 
and the stratification variables previous taxane [yes, no] and measurable disease [yes, no] as 
covariates) and the 2-sided CI will be calculated using a profile likelihood approach. rPFS will 
also be analyzed using a stratified log rank test and a corresponding (descriptive) p-value will 
be generated. If there are less than 5 rPFS events within each stratum, then the levels of strata 
will be collapsed until the minimum 5 event criterion is achieved for the primary rPFS 
endpoint. All analyses (secondary analyses) will be conducted in accordance with the 
corresponding final pooling strategy. Further details of the pre-defined pooling strategy 
indicating the order in which the levels of stratum will be collapsed will be documented in the 
SAP. Stratification variables will be defined according to data from the IVRS/IWRS.  
The HR (olaparib vs. investigator choice) together with its corresponding 95% CI and p-value 
(from the log-rank test) will be presented (a HR less than 1 will favor olaparib).  
Any participants mis-stratified in the IVRS/IWRS will be included in the stratified log-rank 
test using the baseline data collected in the IVRS/IWRS. 
A Kaplan-Meier (KM) plot of rPFS will be presented by treatment group. Summaries of the 
number and percentage of participants 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 assumption of proportionality will be assessed. Note that in the presence of non-
proportionality, the HR will be interpreted as an average HR over the observed extent of 
follow-up. Proportionality will be tested firstly by producing plots of complementary log-log 
(event times) versus log (time) and, if these raise concerns, a time dependent covariate would 
be fitted to assess the extent to which this represents random variation. 
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T he pri mar y a nal ysis will be base d o n t he BI C R assess me nt of r P F S u si n g all sca ns re gar dless 
of w het her t he y wer e sc he d ule d or n ot.  
T he esti mate d r P F S r ates at 6 -m o nt hl y i nter vals fr o m ra n d o mizati o n will be s u m marize d 
( usi n g t he K M c ur ve) a n d pr ese nte d b y treat me nt gr o u p. 
A se nsiti vit y a nal ysis base d o n t he pr o gra m maticall y deri ve d r P F S base d o n i n vesti gat or 
r ec or de d assess me nts will be perf or me d. F urt her se nsiti vit y a nal yses t o e x pl ore t he r o b ust ness 
of t he pri mar y r P F S e n d p oi nt will be d oc u me nte d i n t he S A P.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. 4. 2. 3  
Sec o n d ar y E n d p oi nt(s)  
9. 4. 2. 3. 1  
C o nfir me d O bjecti ve Res p o nse R ate ( O R R)  
F or t he sec o n dar y e n d p oi nt O R R assesse d b y BI C R ( R E CI S T 1. 1 a n d P C W G 3), a nal ysi s will 
be base d o n t he E F R a nal ysis set. A re s p o n der will  be a n y s u bject wit h  a c o nfir me d best  
o ver all r es p o nse of P R or C R i n  t heir s oft tiss ue disease ass esse d  b y R E CI S T  1. 1, i n t he 
C CI
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absence of progression on bone scan assessed by PCWG3. A subject will be classified as a 
responder if the RECIST 1.1 criteria for a CR or PR are satisfied (as well as the absence of 
confirmed progression on bone scan assessed by PCWG3) at any time up to and including the 
defined analysis cut-off point. For each treatment group, the ORR is the number of 
participants with a CR or PR divided by the number of participants in the treatment group in 
the EFR analysis set. 
Additionally, analyses will also be performed on ORR assessed by investigator.  
Analysis Methods 
ORR will be assessed based on BICR assessed RECIST and bone scan data (using all scans 
regardless of whether they were scheduled or not) using the EFR analysis set. ORR will be 
compared between olaparib and investigator choice using a logistic regression model adjusting 
for the stratification variable, previous taxane (yes, no). The results of the analysis will be 
presented in terms of an odds ratio (an odds ratio greater than 1 will favor olaparib) together 
with its associated profile likelihood 95% CI (eg, using the option ‘LRCI’ in SAS procedure 
GENMOD) and p-value (based on twice the change in log-likelihood resulting from the 
addition of a treatment factor to the model).  
If there are not enough responses for a meaningful analysis using logistic regression then a 
Fisher’s exact test using mid p-values will be presented. The mid-p-value modification of the 
Fisher’s  exact test amounts to subtracting half of the probability of the observed table from 
Fisher's p-value. 
Fisher’s exact test mid p-value = Two sided p-value 
-  
Table probability 
            2 
Summaries will be produced that present the number and percentage of participants with a 
tumor response (CR/PR) per BICR and investigator assessment.  
For each treatment arm, BoR will be summarized by n (%) for each category (CR, PR, SD, PD 
and NE). No formal statistical analyses are planned for BoR. 
9.4.2.3.2 
Overall Survival 
OS is defined as the time from the date of randomization until death due to any cause. The 
comparison will include all randomized participants, as randomized, regardless of whether the 
participant withdraws from randomized therapy or receives another anti-cancer therapy. Any 
participant not known to have died at the time of analysis will be censored based on the last 
recorded date on which the participant was known to be alive. Note: Survival calls will be 
made in the week following the date of DCO for the analysis. If participants are confirmed to 
be alive or if the death date is after the DCO date, then these participants will be censored at 
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t he date of D C O . See Secti o n  7. 2  a n d Secti o n 7. 3  f or met h o ds t hat ca n be use d t o deter mi ne 
stat us of partici pa nts w h o wit h dr a w c o nse nt or are l ost t o f oll o w- u p. 
A n al ysis Met h o ds  
O S will be a nal yze d at t he ti me of t he pri mar y a nal ysis of r P F S wit h a p pr o xi matel y 2 9 % 
mat urit y e x pecte d at t his p oi nt, a n d  a n O S a nal ysis will als o be perf or me d wit h a p pr o xi matel y 
2 5 e ve nts ( 6 0 % mat urit y) esti mate d t o occ ur at a p pr o xi matel y 3 7 m o nt hs after first s u bject 
r a n d o mize d i n t he st u d y. O S will be a nal yze d usi n g t he sa me met h o d ol o g y s pecifie d f or r P F S, 
i n acc or da nce wit h t he p o oli n g str ate g y. T he p -val ue will be base d o n t he stratifie d l o g -ra n k 
test a n d H R a n d 9 5 % CI will be base d o n t he C o x m o del. 
Ka pla n -Meier pl ots will be pr ese nte d b y treat me nt gr o u p. S u m maries of t he n u m ber a n d 
per ce nta ge of deat hs a n d t h ose ali ve a n d ce ns ore d will be pr o vi de d al o n g wit h me dia n ti me t o 
deat h f or eac h tr eat me nt ar m.  
 
 
 
9. 4. 2. 3. 3  
Ti me t o First S y m pt o m atic S k elet al – Rel ate d E ve nt ( S S R E)  
Ti me fr o m r a n d o mizati o n t o first s y m pt o matic s keletal – relate d e ve nt as defi ne d b y a n y of t he 
f oll o wi n g or a c o m bi nati o n: 
•  
Use of r a diati o n t her a p y t o pr e ve nt or relie ve s keletal s y m pt o ms.  
•  
Occ urr e nce of ne w s y m pt o matic pat h ol o gical b o ne fract ures ( verte bral or n o n -verte bral). 
Ra di ol o gic d oc u me ntati o n is r e q uire d.  
•  
Occ urr e nce of s pi nal c or d c o m pressi o n. Ra di ol o gic d oc u me ntati o n re q uire d.  
•  
Ort h o pe dic s ur gical i nter ve nti o n f or b o ne metastasis.  
 
Partici pa nts w h o ha ve  n ot e x perie nce d a n y of t he a b o ve c o n diti o ns will be ce ns ore d at ti me of 
deat h, or ti me of a nal ysis if t he s u bject is li vi n g.  
A n al ysis Met h o ds  
Ti me t o S S R E will be a nal yze d usi n g t he sa me met h o ds as i n t he a nal ysis of t he pri mar y 
e n d p oi nt r P F S, i n acc or da nce wit h t he p o oli n g strate g y. T he p-val ue will be base d o n t he 
str atifie d l o g-r a n k test usi n g pr e vi o us ta xa ne use a n d meas ura ble disease as strata a n d H R a n d 
9 5 % CI will be base d o n t he C o x m o del.  
A K M pl ot of ti me t o S S R E will be prese nte d b y treat me nt gr o u p. S u m maries of t he n u m ber 
a n d per ce nta ge of partici pa nts wit h s y m pt o matic s keletal relate d e ve nts a n d t h ose w h o are 
C CI
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censored will be provided along with median time to symptomatic skeletal related events for 
each treatment arm. 
9.4.2.3.4 
Duration of Response 
Duration of response (DoR) will be defined as the time from the date of first documented 
confirmed response (by BICR using RECIST 1.1 and PCWG3) until date of documented 
progression (by BICR) or death in the absence of disease progression. 
The end of response should coincide with the date of progression or death from any cause 
used for the rPFS endpoint. The time of the initial response will be defined as the latest of the 
dates contributing towards the first visit response of PR or CR. If a subject does not progress 
following a response, then their duration of response will use the rPFS censoring date as the 
date at which that subject is censored for DoR. The time to response is the time from 
randomization to the first onset of an objective tumor response. 
Analysis Methods 
Descriptive data will be provided for the duration of response in responding participants, 
including the associated KM curves (without any formal comparison of or p-value attached). 
9.4.2.3.5 
Time to Opiate Use for Cancer Pain 
Time to opiate use is defined as the time from randomization to the date of opiate use for 
cancer-related pain on participants who have not received any opiates at baseline. Participants 
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.  
Analysis Methods 
Time to opiate use will be analyzed at the time of the primary rPFS analysis using the same 
methods as in the analysis of rPFS, in accordance with the pooling strategy. The p-value will 
be based on the stratified log-rank test and HR and 95% CI will be based on the Cox model. 
A KM plot of time to opiate use will be presented by treatment group. Summaries of the 
number and percentage of participants using opiates will be provided along with median time 
to opiate use for each treatment arm. 
9.4.2.3.6 
Prostate Specific Antigen Response 
Prostate Specific Antigen (PSA) response is defined as the proportion of participants 
achieving a ≥50% decrease in PSA from baseline to the lowest post-baseline PSA result, 
confirmed by a second consecutive PSA assessment at least 3 weeks later. 
• 
A subject will be regarded as having a single PSA visit response if their PSA level at any 
post-dose visit is reduced by 50% or more compared with baseline. 
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• 
A subject will be regarded as having a confirmed PSA response if they have a reduction 
in PSA level of 50% or more compared with baseline that is confirmed at the next 
assessment at least 3 weeks later (ie, decrease relative to baseline of at least 50% 
documented on 2 consecutive occasions at least 3 weeks apart).  
Analysis Methods 
Proportion of participants achieving a PSA response and participants with a confirmed PSA 
response will be presented with 95% CIs. Best PSA percentage change from baseline and 
percentage change at 12 weeks will be summarized as continuous variables using descriptive 
statistics and will be graphically displayed using waterfall plots. 
9.4.2.3.7 
Time from Randomization to Second Progression or Death (PFS2) 
Defined as the time from randomization to investigator-assessed objective radiological 
progression on next-line treatment or death from any cause. 
Analysis Methods 
Time from randomization to second progression or death will be analyzed using the same 
methods as in the analysis of rPFS, in accordance with the pooling strategy. The p-value will 
be based on the stratified log rank test and HR and 95% CI will be based on the Cox model. 
A KM plot of time to second progression or death will be presented by treatment group. 
Summaries of the number and percentage of participants with second progression or death and 
those who are censored will be provided along with median time to second progression or 
death for each treatment arm.  
9.4.3 
Safety 
Safety analyses will be performed using the safety analysis set. Safety data will be presented 
using descriptive statistics unless otherwise specified.  
Safety profiles will be assessed in terms of AEs, vital signs (including BP and pulse rate), 
laboratory data (clinical chemistry and hematology), and physical examination. 
Summaries will be presented for scheduled visits only. Any unscheduled assessments will be 
listed. 
Baseline 
In general, the baseline value for statistical analysis is the last non-missing value prior to 
administration of the first dose of study intervention. Details will be described in the SAP. 
Additional tables, figures, or listings may be produced to aid interpretation. Further details of 
summaries of the safety data will be provided in the SAP. 
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9.4.3.1 
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. 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. 
Analysis Methods 
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) that will have been released for execution at AZ/designee.  
AEs will be presented for each treatment group by System Organ Class (SOC) and/or 
preferred term (PT) covering number and percentage of participants reporting at least one 
event and number of events where appropriate. 
AEs occurring prior to start of study intervention and treatment emergent AEs will be 
presented separately. 
An overview of AEs will present for each treatment group the number and percentage of 
participants with any AE, AEs with outcome of death, serious AEs, and AEs leading to 
discontinuation of study intervention, as well as AEs leading to study intervention dose 
interruptions and AEs leading to study intervention dose reduction as well as the number of 
individual occurrences in those categories.  
Separate AE tables will be provided taking into consideration relationship as assessed by the 
investigator, intensity by CTC grading, seriousness, death and events leading to 
discontinuation of study intervention as well as other action taken related to study treatment 
and other significant AEs (OAEs). 
An additional table will present number and percentage of participants with most common 
AEs. Most common (eg, frequency of >x%, ≥x%) will be defined in the SAP. 
Key subject information will be presented for participants with AEs with outcome of death, 
serious AEs, and AEs leading to discontinuation of study intervention. 
An AE listing for the safety analysis set will cover details for each individual AE. 
Full details of AE analyses will be provided in the SAP. 
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9.4.3.2 
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 adverse events leading 
to discontinuation (DAEs). Based on the expert’s judgement, significant AEs of particular 
clinical importance may, after consultation with the Global Subject Safety Physician, be 
considered OAEs and reported as such in the CSR. A similar review of laboratory/vital 
signs/ECG data will be performed for identification of OAEs. 
Examples of these are marked hematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment. 
Analysis Methods 
Refer to Section 9.4.3.1. 
9.4.3.3 
Concomitant Medications 
Concomitant medications will be classified according to the current version of the WHO Drug 
Dictionary. 
Concomitant medications will be classed as either: 
• 
Concomitant medications starting prior to first dose (pre-study) 
• 
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. 
 
Analysis Methods 
Concomitant medications will be summarized by the coded terms. The number of participants 
receiving a medication will be summarized by treatment group. A medication taken from the 
start of the screening part 2 and onwards is considered concomitant. A subject is only counted 
once if receiving the medication more than once. 
Disallowed medications will be listed. 
9.4.3.4 
Compliance and Exposure 
Study drug exposure (days) will be defined as time from first dose of olaparib to last dose. 
Exposure to investigator choice will be calculated in the same way. 
Exposure will be defined as: 
Last dose date – first dose date + 1. 
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If the last dose date is unknown, the soonest available date afterwards where it is confirmed 
that no drug is being taken will be used instead. 
Percentage compliance will be defined as: 
{(No. tablets dispensed in period – no. tablets returned from period)/ (no. days of study drug 
exposure in period * expected tablets per day)} * 100% 
Where expected tablets per day will take into account once daily or bid dosing. 
Overall compliance may be calculated over various periods if the dose has been modified, to 
take into account the differing expected tablets per day or the protocol-specified dose 
interruptions. Missed doses will not be adjusted for; the overall compliance will be reduced. 
Analysis Methods 
Listings and summaries of exposure and compliance will be produced for olaparib and 
investigator’s choice.  
The number of participants who discontinued study drug, and the reasons, will be summarized 
by treatment. 
9.4.3.5 
Other Safety Data 
Laboratory data 
Laboratory data (clinical chemistry and hematology) will be summarized. Shift tables will be 
provided for select tests, where shift from baseline to the worst value within the study will be 
summarized. Laboratory data outside the reference ranges will be indicated. 
Vital signs 
Vital signs, including BP (mmHg), body temperature (°C) and weight (kg), will be 
summarized at baseline. The baseline value is the last pre-dose assessment. 
The remaining safety variables will be presented using summary statistics for quantitative data 
and frequency counts for qualitative parameters. 
9.5 
Interim Analyses  
No interim analysis for rPFS prior to the primary analysis will be performed. An OS analysis 
will be performed at the time of the primary rPFS analysis and at a later OS DCO when it is 
expected that 25 OS events have occurred (60% maturity), it is anticipated that this OS 
analysis could be performed at approximately 37 months after the first participant has been 
randomized. 
Additional analyses of rPFS and/or OS may be performed to meet Regulatory Agency 
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requests, as required. 
9.6 
Independent Data Monitoring Committee 
Not applicable. 
 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
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Appendix A Regulatory, Ethical, and Study Oversight Considerations 
A 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 International Ethical Guidelines 
− 
Applicable ICH GCP Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, IB, 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 and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants. 
• 
AstraZeneca will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
Contract Research Organization but the accountability remains with AstraZeneca. 
 
Regulatory Reporting Requirements for Serious Adverse Events 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators. 
• 
For all studies except those utilising medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
 
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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. 
• 
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 
he or she becomes 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 European Medicines Agency (EMA) Clinical 
Trial Information System (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: 
o 
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 (email address or telephone number) provided by AstraZeneca. 
A 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. 
A 3 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to the 
participant or his legally authorized representative and answer all questions regarding the 
study. 
• 
Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 Code of Federal 
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Regulations 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act 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 participant was enroled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
 
Participants who are rescreened are required to sign a new ICF.The ICF will contain a separate 
section that addresses and documents the collection and use of any mandatory human 
biological samples. The investigator or authorized designee will explain to each participant the 
objectives of the analysis to be done on the samples and any potential future use. Participants 
may withdraw their consent at any time and for any reason during the retention period.  
A 4 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• 
The participant 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 and use of 
their data must also be explained to the participant in the informed consent.  
• 
The participant must be informed that his medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 
The participant’s samples will not be used for any purpose other than those described in the 
study protocol. 
A 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 CSP and letters to investigators.  
A 6 
Dissemination of Clinical Study Data 
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Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a year from global End of Trial Date in all participating countries, due to scientific 
reasons, as otherwise statistical analysis is not relevant. 
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a half a year from global End of Trial Date in all participating countries, due to 
scientific reasons, as otherwise statistical analysis is not relevant. 
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the main study results when they are available. The clinical study and/or 
summary of main study results may also be available on other websites according to the 
regulations of the countries in which the main study is conducted. 
A 7 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on the eCRF unless transmitted 
to AstraZeneca or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
• 
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. 
• 
Monitoring details describing strategy, including definition of study-critical data items 
and processes (eg, risk-based initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are included in the 
Monitoring Plan. 
• 
AstraZeneca or designee is responsible for medical oversight throughout the conduct of 
the study which includes clinical reviews of study data in accordance with the currently 
approved protocol. Monitoring details describing clinical reviews of study data from a 
medical perspective are included in more detail in the Study Level Medical Oversight 
Plan. 
• 
AstraZeneca or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
AstraZeneca assumes accountability for actions delegated to other individuals (eg, 
CROs). 
• 
Study monitors will perform ongoing source data verification as per the 
Monitoring Plan(s) to confirm that data entered into the eCRF by authorized site 
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personnel are accurate, complete, and verifiable from source documents; that the safety 
and rights of participants 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 as required by local regulations, according to the 
AstraZeneca Global retention and Disposal (GRAD) Schedule. No records may be 
destroyed during the retention period without the written approval of AstraZeneca. No 
records may be transferred to another location or party without written notification to 
AstraZeneca.  
 
A 8 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data reported on the eCRF or entered in 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. 
• 
Definition of what constitutes source data can be found in the Clinical Study Agreement. 
All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study are defined as source documents. Source data 
are contained in source documents (original records or certified copies). 
 
A 9 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
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 
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not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any Contract Research 
Organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participants 
and should assure appropriate participant therapy and/or follow-up. 
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.  
A 10 
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 multicenter studies only in their entirety and not as individual site data. In 
this case, a co-ordinating 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 B Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
B 1 
Definition of Adverse Events 
An AE is the development of any untoward medical occurrence (other than progression of the 
malignancy under evaluation) in a participant or clinical study participant administered a 
study intervention 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 or not considered related to the study 
intervention.  
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 intervention has been administered. 
B 2 
Definitions of Serious Adverse Event 
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria: 
• 
Results in death. 
• 
Is immediately life-threatening. 
• 
Requires in-participant hospitalization or prolongation of existing hospitalization.  
• 
Results in persistent or significant disability or incapacity.  
• 
Is a congenital abnormality or birth defect. 
• 
Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above. 
 
AEs for malignant tumors reported during a study should generally be assessed as Serious 
AEs. If no other seriousness criteria apply, the “Important Medical Event” criterion should be 
used. In certain situations, however, medical judgment on an individual event basis should be 
applied to clarify that the malignant tumor event should be assessed and reported as a 
Non-Serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as Non-Serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 
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The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (ie, it is not the tumor for which entry into the study is a criterion and that is 
being treated by the study intervention under study and is not the development of new or 
progression of existing metastasis to the tumor under study). Malignant tumors that – as part 
of normal, if rare, progression – undergo transformation (eg, Richter’s transformation of B cell 
chronic lymphocytic leukemia into diffuse large B cell lymphoma) should not be considered a 
new malignant tumor. 
Life-threatening 
“Life-threatening” means that the participant 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 
participant’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). 
Hospitalization 
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enroled in the study, provided that it did not deteriorate in an unexpected 
way during the study. 
Important Medical Event or Medical Treatment 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used. 
• 
Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 
 
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Intensity Rating Scale 
The grading scales found in the revised NCI-CTCAE latest version 5.0 will be utilized 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 B 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 B 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 B 2. 
B 3 
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 participant 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 
rechallenge. 
• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
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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 no available facts or arguments to suggest a 
causal relationship, 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. 
B 4 
Medication Error, Drug Abuse, and Drug Misuse 
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.  
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 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, eg, wrong route or wrong site of administration 
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• 
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 refridgerator when it should be at room 
temperature  
• 
Wrong participant received the medication (excluding IRT/RTSM errors) 
• 
Wrong drug administered to participant (excluding IRT/RTSM errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from IRT/RTSM - including those which led to one 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. 
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. 
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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 
• 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 C Handling of Human Biological Samples 
C 1 
Chain of Custody 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The investigator at each site keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site. 
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 record of receipt of arrival and onward 
shipment or disposal. 
AstraZeneca or delegated representatives will keep oversight of the entire lifecycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers. 
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
or destroyed according to local regulations or at the end of the retention period, whichever is 
the sooner. 
C 2 
Withdrawal of Informed Consent for Donated Biological Samples  
If a participant withdraws consent specifically to the subsequent use of donated biological 
samples, the samples will be disposed of or repatriated, and the action documented. If samples 
are already analyzed, AstraZeneca is not obliged to destroy the results of this research. The 
participant will be presented with the option to opt out of the subsequent use of the donated 
samples during the withdrawal process. If the participant decides to opt out, then the donated 
samples will be disposed of. If the participant withdraws consent without opting out for the 
subsequent use of the donated samples, then the samples will be used as per protocol.  
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent. 
The investigator: 
• 
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate. 
• 
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented. 
• 
Ensures that the participant and AstraZeneca are informed about the sample disposal. 
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AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified. 
C 3 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
LABELING AND SHIPMENT OF BIOHAZARD SAMPLES 
IATA (https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies 
infectious substances into 3 categories: Category A, Category B or Exempt 
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, for example, Ebola, Lassa fever virus. Infectious substances 
meeting these criteria which cause disease in humans or both in humans and animals must be 
assigned to UN 2814. Infectious substances which cause disease only in animals must be 
assigned to UN 2900. 
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, for example, Hepatitis A, C, D, and E 
viruses. They are assigned the following UN number and proper shipping name: UN 3373 – 
Biological Substance, Category B. They are to be packed in accordance with UN 3373 and 
IATA 650.  
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class. 
• 
Clinical study samples will fall into Category B or exempt under IATA regulations. 
• 
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging. 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf). 
• 
Biological samples transported in dry-ice require additional dangerous goods 
specification for the dry-ice content. 
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Appendix D Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law 
D 1 
Introduction 
This appendix describes the process to be followed in order to identify and appropriately 
report PHL cases and HL cases. It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries.  
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets 
potential 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 central and all 
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 TBL from 
a local laboratory.  
The investigator will also review 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 
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 study intervention.  
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
D 2 
Definitions 
PHL 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 × ULN together 
with TBL ≥ 2 × ULN at any point during the study following the start of study intervention 
irrespective of an increase in alkaline phosphatase.  
HL 
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than the 
study intervention, can be found to explain the combination of increases, eg, elevated alkaline 
phosphatase indicating cholestasis, viral hepatitis, another drug.  
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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
D 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 participant who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥ 3 × ULN. 
• 
AST ≥ 3 × ULN. 
• 
TBL ≥ 2 × ULN. 
 
Local laboratories being used 
The investigator will, without delay, review each new laboratory report and if the 
identification criteria are met will: 
• 
Determine whether the participant meets PHL criteria (see Section D 2 Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits. 
• 
Promptly enter the laboratory data into the laboratory eCRF. 
 
D 4 
Follow-up 
D 4.1 
Potential Hy’s Law Criteria Not Met 
If the participant does not meet PHL criteria the investigator will: 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP. 
 
D 4.2 
Potential Hy’s Law Criteria Met 
If the participant does meet PHL criteria the investigator will: 
• 
Notify the AstraZeneca representative who will then inform the central Study Team.  
• 
Within 1 day of PHL criteria being met, report the case as an SAE of PHL; serious 
criterion “Important medical event” and causality assessment “yes/related” according to 
CSP process for SAE reporting. 
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• 
For participants that met PHL criteria prior to starting study intervention, the investigator 
is not required to submit a PHL SAE unless there is a significant change# in the 
participant’s condition.  
• 
The study physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data. 
• 
Subsequent to this contact the investigator will: 
− 
Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Complete follow-up SAE Form as required. 
− 
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the study physician.  
− 
Complete the 3 Liver eCRF Modules as information becomes available.  
 
#A “significant” change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the study physician if there is any uncertainty. 
D 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 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 
study intervention, to ensure timely analysis and reporting to health authorities within 
15 calendar days from date PHL criteria was 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 will follow the 
instructions below. 
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF. 
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• 
If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca standard processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study intervention: 
• 
Send 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: 
• 
Provide any further update to the previously submitted SAE of PHL, (report term now 
“Hy’s Law case”) ensuring causality assessment is related to study intervention and 
seriousness criterion is medically important, according to 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 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. 
 
D 6 
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Intervention  
This section is applicable to participants with liver metastases who meet PHL criteria on study 
intervention, having previously met PHL criteria at a study visit prior to starting study 
intervention. 
At the first on-study intervention occurrence of PHL criteria being met the investigator will 
determine if there has been a significant change in the participant’s 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 Section D 4.2. 
 
D 7 
Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a participant meets PHL criteria on study intervention and has 
already met PHL criteria at a previous on study intervention 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 participant meet PHL criteria prior to starting study intervention and at their 
first on-study intervention visit as described in Section D 6 of this Appendix? 
If No: follow the process described in Section D 4.2 for reporting PHL as an SAE. 
If Yes: determine if there has been a significant change in the participant’s condition compared 
with when PHL criteria were previously met. 
• 
If there is no significant change no action is required. 
• 
If there is a significant change follow the process described in Section D 4.2 for reporting 
PHL as an SAE. 
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D 8 
Laboratory Tests 
Hy’s Law lab kit for central laboratories  
Additional standard chemistry and coagulation tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV  
IgM and IgG anti-HBc 
HBsAg 
HCV DNA a 
IgG anti-HCV 
HCV RNA a  
IgM anti-HEV 
HEV RNA 
Other viral infections 
IgM & IgG anti-CMV 
IgM & IgG anti-HSV 
IgM & IgG anti-EBV 
Autoimmune hepatitis 
Antinuclear antibody 
Anti-liver/kidney microsomal antibody 
Anti-smooth muscle antibody 
Metabolic diseases 
Alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin saturation 
CMV=cytomegalovirus; DNA=deoxyribonucleic acid; EBV=Epstein-Barr virus; GGT=gamma glutamyl transferase; 
HAV=hepatitis A virus; HBc=hepatitis B core antigen; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; 
HCV=hepatitis C virus; HEV=hepatitis E virus; HSV=herpes simplex virus; IgG=immuno-globulin G; 
IgM=immuno-globulin M; INR=international normalized ratio; LDH=lactate dehydrogenase; RNA=ribonucleic acid. 
a 
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive. 
In this study, a local laboratory will be used for safety tests and the Hy’s Law Laboratory Kit 
for central laboratories is not applicable for this study.  
D 9 
References 
Aithal et al 2011 
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case 
definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 
2011;89(6):806-15. 
FDA Guidance 2009 
Food and Drug Administration. Guidance for industry: Drug-induced liver injury: 
premarketing clinical evaluation. July 2009. Available from: URL: 
https://www.fda.gov/downloads/guidances/UCM174090.pdf. Accessed 08 October 2019. 
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Appendix E Guidelines for Evaluation of Objective Tumor Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumors) 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 D081LC00002 study with regards to 
assessment of tumor burden including protocol-specific requirements for this study. 
Investigator assessments will be based on the guidelines described in this appendix. 
Imaging Modalities and Acquisition Specifications for RECIST 1.1 
A summary of the imaging modalities that can be used for tumor assessment of TLs, NTLs 
and NLs is provided in Table 15. 
Table 12 
Summary of Imaging Modalities for Tumor Assessment 
Target Lesions  
Non-target lesions 
New lesions 
CT 
MRI 
CT 
MRI 
Plain X-ray 
Chest X-ray 
CT 
MRI 
Plain X-ray 
Chest X-ray 
18F-fluoro-deoxyglucose-PET/CT 
CT=computed tomography; MRI=magnetic resonance imaging; PET/CT=positron emission tomography/CT. 
 
Computed Tomography and Magnetic Resonance Imaging  
CT with IV contrast is the preferred imaging modality (although MRI with IV contrast is 
acceptable if CT is contraindicated) to generate reproducible anatomical images for tumor 
assessments (ie, for measurement of TLs, assessment of NTLs, and identification of NLs). It is 
essential that the same correct imaging modality, image acquisition parameters (eg, anatomic 
coverage, imaging sequences, etc), imaging facility, tumor assessor (eg, radiologist), and 
method of tumor assessment (eg, RECIST 1.1) are used consistently for each participant 
throughout the study. The use of the same scanner for serial scans is recommended, if 
possible. It is important to follow the image collection/tumor assessment schedule as closely 
as possible (refer to the SoA), and this on-study imaging schedule MUST be followed 
regardless of any delays in dosing or missed imaging visits. If an unscheduled assessment is 
performed (eg, to investigate clinical signs/symptoms of progression) and the participant has 
not progressed, every attempt should be made to perform the subsequent scan acquisitions at 
the next scheduled imaging visit. 
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body 
scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
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the chest is recommended over MRI due to significant motion artefacts (eg, heart, major blood 
vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse 
sequence. In general, local oncology diagnostic imaging parameters are applied for scan 
acquisition. It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. 
The most critical CT and MRI image acquisition parameters for optimal tumor evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval. 
a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the 
chest-abdomen (-pelvis). Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual participants. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a NL representing 
PD, careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points. This will enable better consistency not only of tumor 
measurements but also identification of new disease. 
Required anatomical regions to be imaged for assessment of tumor burden (TLs and/or NTLs) 
at baseline and follow-up visits vary according to the study, and these time points are specified 
in the SoA. Examples include the following: 
• 
IV contrast-enhanced CT of chest-abdomen (including the entire liver and both adrenal 
glands) (-pelvis). 
• 
Non-contrast CT of chest and IV contrast-enhanced abdomen (including the entire liver 
and both adrenal glands) (-pelvis). 
• 
IV contrast-enhanced CT or MRI of the head and neck. 
• 
IV contrast-enhanced MRI (preferred) or CT of the brain. 
 
For chest-abdomen (-pelvis) imaging, the following are scanning options in decreasing order 
of preference, with additional options (2 to 4) for consideration when participants have 
sensitivity to IV contrast or have compromised renal function: 
1. Chest-abdomen (-pelvis) CT with IV CT contrast (most preferred). 
2. Chest CT without IV-contrast + abdomen (-pelvis) MRI with IV MRI contrast, if CT IV 
contrast (iodine based) is medically contraindicated at any time during the study. 
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3. Chest-abdomen (-pelvis) CT without IV contrast, if both IV CT and MRI contrast are 
medically contraindicated or the participant has compromised renal function. 
4. Chest-abdomen (-pelvis) MRI with IV MRI contrast, if CT cannot be performed at any 
time during the study. 
 
b. IV contrast administration: Optimal visualization and measurement of metastases in solid 
tumors require consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. An adequate volume of a suitable contrast agent should be given so that the tumor 
lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given participant. Oral contrast is recommended to help visualise and 
differentiate structures in the abdomen and pelvis. 
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤5 mm thickness throughout the 
entire anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses >5 mm. If this 
occurs, the minimum size of measurable lesions at baseline should be twice the slice thickness 
of the baseline scans. 
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study. 
Chest X-ray 
Chest X-ray assessment will not be used for the assessment of TLs. Chest X-ray can, however, 
be used to assess NTLs and to identify the presence of NLs. However, there is preference that 
a higher resolution modality, such as CT, be used to confirm the presence of NLs. 
Isotopic bone scan  
Isotopic bone scan will not be used for the RECIST assessment. Bone lesions will be 
evaluated with the PCWG-3 criteria. Lytic or mixed bone lesions with a soft tissue component 
which is observed on CT/MRI can have the soft tissue component evaluated by RECIST 1.1.  
18F-fluoro-deoxyglucose-PET/CT 
18F-fluoro-deoxyglucose positron emission tomography (PET)/CT scans may be used as a 
method for identifying new extrahepatic lesions (but not intrahepatic lesions) for RECIST 1.1 
assessments according to the following algorithm: NLs will be recorded where there is 
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positive 18F-Fluoro-deoxyglucose uptake1 not present on baseline or prior 
18F-fluoro-deoxyglucose-PET scan or in a location corresponding to a NL on a companion 
CT/MRI collected close in time to the 18F-fluoro-deoxyglucose-PET scan. The PET portion of 
the PET/CT introduces additional data that may bias an investigator if it is not routinely or 
serially performed. Therefore, if there is no baseline or prior 18F-fluoro-deoxyglucose-PET 
scan available for comparison, and no evidence of NLs on companion CT/MRI scans, then 
follow-up CT/MRI assessments should continue as per the regular imaging schedule to verify 
the unequivocal presence of NLs. 
At present, low-dose or attenuation correction CT portions of a combined 
18F-fluoro-deoxyglucose-PET/CT scan are of limited use in anatomically based efficacy 
assessments, and it is therefore suggested that they should not substitute for dedicated 
diagnostic contrast-enhanced CT scans for tumor measurements by RECIST 1.1. In 
exceptional situations, if a site can document that the CT performed, as part of a PET/CT 
examination, is of identical diagnostic quality (with IV contrast) to a dedicated diagnostic CT 
scan, then the CT portion of the PET/CT can be used for RECIST 1.1 tumor assessments. 
Caution that this is not recommended because the PET portion of the CT introduces additional 
(PET) data that may bias an investigator if it is not routinely or serially performed. 
Ultrasound  
Ultrasound examination will not be used for RECIST 1.1 assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
not provide an accurate assessment of the true tumor size. Tumors identified by ultrasound 
will need to be assessed by correlative CT or MRI anatomical scan. 
Other Tumor Assessments 
Clinical Examination  
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST 1.1 assessments. Tumors identified by clinical examination will need 
to be assessed by correlative CT or MRI anatomical scans. 
Endoscopy and Laparoscopy  
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated 
in the context of tumor assessment. 
Histology and Cytology 
Histology or tumor markers on tumor biopsy samples will not be used as part of the tumor 
 
1 
A positive 18F-fluoro-deoxyglucose-PET scan lesion should be reported only when an uptake (eg, standard uptake 
value) greater than twice that of the surrounding tissue or liver is observed. 
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response assessment as per RECIST 1.1. 
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumor response assessment as per RECIST 1.1. 
Furthermore, an overall assessment of CR (all other disease disappears/reverts to normal) 
would be changed to PR if an effusion remains present radiologically. 
Measurability of Tumor Lesions at Baseline 
RECIST 1.1 Measurable Lesions at Baseline 
A tumor lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
for non-nodal lesions or ≥15 mm in short axis2 diameter for lymph node lesions with IV 
contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements. Please 
see additional RECIST 1.1 guidance below on measurability of intrahepatic hepatocellular 
carcinoma lesions and porta hepatis lymph nodes. 
Non-measurable Lesions at Baseline 
• 
Truly non-measurable lesions include the following: 
− 
Leptomeningeal disease. 
− 
Ascites, pleural effusion, or pericardial effusion. 
− 
Inflammatory breast disease. 
− 
Lymphangitic involvement of skin or lung. 
• 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline).3 
• 
Previously irradiated lesions.4 
• 
Brain metastasis. 
 
Special Considerations Regarding Lesion Measurability at Baseline 
• 
Bone lesions: 
− 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. 
 
2 
The short axis is defined as the longest in-plane axis perpendicular to the long axis. 
3 
Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or followed 
as NTLs. 
4 
Localized post-radiation changes that affect lesion size may occur. Therefore, lesions that have been previously 
irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of the NTL 
assessment. 
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− 
Blastic lesions are not part of the RECIST assessment and must be evaluated via 
PCWG3 (see page 120). 
• 
Cystic lesions thought to represent 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 participant, these should be selected over cystic 
lesions as TLs. 
 
RECIST 1.1 TL Selection at Baseline 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TLs at baseline. TLs should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis diameter 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 that can be measured reproducibly 
should be selected. 
Lymph nodes, in any location (local/regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal glands), 
a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a single 
organ. 
The site and location of each TL should be documented, as well as the longest axis diameter 
for non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in millimetres. At baseline, the sum of the diameters for all TLs will be calculated 
and reported as the baseline sum of diameters. At follow-up visits, the sum of diameters for all 
TLs will be calculated and reported as the follow-up sum of diameters. 
Special Cases for TL Assessment at Baseline 
• 
For TLs measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter. 
• 
When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass. Non-nodal lesions that coalesce 
should similarly be assessed by the longest axis diameter. 
• 
Tumor lesions selected for newly acquired screening biopsy should not be selected as 
TLs, unless imaging occurred at least approximately 2 weeks after biopsy, allowing time 
for healing. 
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• 
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 diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as a NL. 
 
RECIST 1.1 NTL Selection at Baseline 
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up. 
Evaluation of Tumor Response and Progression 
RECIST 1.1 TL Assessment at Follow-up 
This section defines the criteria used to determine objective tumor visit response for 
RECIST 1.1-defined TLs. The imaging modality, location, and scan date of each TL identified 
previously at baseline should be documented at follow-up visits with the long axis diameter 
for non-nodal lesions or short axis diameter for lymph node lesions. All measurements should 
be recorded in millimetres. The sum of the diameters for all TLs at each follow-up visit will be 
compared with the baseline sum of diameters (for response or SD) or to the smallest prior 
(nadir) sum of diameters (for progression). 
Special Cases for TL Assessment at Follow-up: 
• 
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL. 
• 
If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded. 
• 
If 2 or more TLs 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 the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion. If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate 
mass, the vector of the longest diameter of the coalesced mass should be used to 
determine the perpendicular vector for the maximal short axis diameter. 
• 
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. The choice of “Too large to measure” in the eCRF will trigger an 
overall visit response of PD. 
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• 
When a TL has had any intervention (eg, definitive radiotherapy, embolization, surgery, 
transarterial chemoembolization, etc) during the study, the size of the TL should still be 
provided where possible and the intervention recorded in the RECIST 1.1 eCRF for the 
current imaging visit and all subsequent visits. If a TL has been completely removed 
(surgery) or disappears, the longest diameter should be recorded as 0 mm. 
 
Table 13 
RECIST 1.1 Evaluation of Target Lesions 
CR 
Disappearance of all TLs since baseline. Any pathological lymph nodes 
selected as TLs must have a reduction in short axis diameter to <10 mm. 
PR 
At least a 30% decrease in the sum of the diameters of TL, taking as reference 
the baseline sum of diameters. 
SD 
Neither sufficient decrease in the sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD. 
PD 
At least a 20% increase in the sum of diameters of TLs, taking as reference the 
smallest previous sum of diameters (nadir). This includes the baseline sum if 
that is the smallest on study. In addition to the relative increase of 20%, the 
sum must demonstrate an absolute increase of at least 5 mm from nadir. 
NE 
Only relevant if any of the TLs at follow-up were not assessed or NE (eg, 
missing anatomy) or had a lesion intervention at this visit. Note: If the sum of 
diameters meets the PD criteria, PD overrides NE as a TL response. 
Not applicable 
Only relevant if no TLs present at baseline. 
CR=complete response; NE=not evaluable; PD=progression of disease; PR=partial response; SD=stable disease; TL=target 
lesion. 
 
RECIST 1.1 NTL Assessment at Follow-up 
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline. Measurements are not required for these lesions, but their status should be followed 
at subsequent visits. At each visit, an overall assessment of the NTL response should be 
recorded by the investigator. 
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumor burden has increased sufficiently to merit unequivocal progression by NTLs. 
A modest “increase” in the size of 1 or more NTLs is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be 
extremely rare. 
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Table 14 
RECIST 1.1 Evaluation of Non-Target Lesions 
CR 
Disappearance of all NTLs since baseline. All lymph nodes must be 
non-pathological in size (<10 mm short axis). 
Non CR/non PD 
Persistence of 1 or more NTLs. 
PD 
Unequivocal progression of existing NTLs. 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. 
NE 
Only relevant when 1 or some of the NTLs were not assessed and, in the 
investigator’s opinion, they are not able to provide an evaluable overall NTL 
assessment at this visit. 
Note: For participants without TLs at baseline, this is relevant if any of the NTLs 
were not assessed at this visit and the progression criteria have not been met. 
Not applicable 
Only relevant if no NTLs present at baseline. 
CR=complete response; NE=not evaluable; NTL=non-target lesion; PD=progression of disease; TL=target lesion. 
 
RECIST 1.1 NL Identification at Follow-up 
Details, including the imaging modality, the date of scan, and the location of any NLs will also 
be recorded in the eCRF. The presence of 1 or more NLs is assessed as progression. The 
finding of a NL should be unequivocal, ie, not attributable to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than 
tumor. If a NL is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the previously (pre-existing) NL has been assessed as 
unequivocal at a follow-up visit, and then the progression date should be declared using the 
date of the initial scan when the NL first appeared. 
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate PD. 
RECIST 1.1 Evaluation of Overall Visit Response at Follow-up 
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table 18. 
Table 15 
RECIST 1.1 Overall Visit Response 
Target lesions 
Non-target lesions 
New lesions 
Overall visit response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
NA 
CR 
No 
CR 
CR 
Non CR/Non PD  
No 
PR 
CR 
NE 
No  
PR 
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Target lesions 
Non-target lesions 
New lesions 
Overall visit response 
PR 
Non PD or NE or NA 
No 
PR 
SD  
Non PD or NE or NA 
No 
SD 
NA 
Non-CR/Non-PD 
No 
SD (non-CR/non-PD) 
NE 
Non PD or NE 
No 
NE 
NA 
NE 
No 
NE 
NA 
NA 
No 
NED 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Non-CR/Non-PD for overall response if only NTL (no TLs) are present at baseline. 
Note: An overall assessment of CR (all other disease disappears/reverts to normal) would be changed to PR if ascites remains 
present radiologically. 
CR=complete response; NA=not applicable (only relevant if there were no TLs at baseline or NTLs at baseline); NE=not 
evaluable; NED=no evidence of diseases (only relevant if there were neither target lesions nor non-target lesions at baseline); 
NTL=non-target lesion; PD=progression of disease; PR=partial response; SD=stable disease; TL=target lesion. 
 
The following overall visit responses are possible depending on the extent of tumor disease at 
baseline: 
• 
For participants with TLs (at baseline): CR, PR, SD, PD, or NE. 
• 
For participants with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE. 
• 
For participants with no disease at baseline: no evidence of disease (available as an option 
in the eCRF), PD, or NE. 
 
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 D081LC00002 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.  
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Tumor 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 
randomization 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 
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. 
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The requirements for determination and confirmation of radiological progression by either 
bone scan (bone progression) or CT/MRI (soft tissue progression) are summarized in 
Table 19. 
Table 16 
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 
tumors. 
 
Evaluation of bone progression status 
Table 20 provides the definitions for the visit bone progression status for bone lesions. 
Table 17 
Bone Progression Status 
Bone progression status 
Non Progressive Disease (Non-PD) 
No evidence of progression, or appearance of 1 new bone lesion, or 
non-fulfillment 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 Imaging 
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed imaging Contract Research Organization (iCRO) for quality control, 
storage, and for BICR. Digital copies of all original scans should be stored at the investigator 
site as source documents. Electronic image transfer from the sites to the iCRO is strongly 
encouraged. A BICR of images will be performed at the discretion of AstraZeneca.  
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The management of participants will be based in part upon the results of the tumor 
assessments conducted by the investigator. Further details of the BICR will be documented in 
an Independent Review Charter. 
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. 
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 F Contraception Requirements 
Olaparib is regarded as a compound with medium/high fetal risk. 
Contraception requirements for this study are as follows. 
F 1 
Male Participants with a Female Partner of Childbearing 
Potential 
Non-sterilized male participants (including males sterilized by a method other than bilateral 
orchidectomy, eg, vasectomy) who intend to be sexually active with a female partner of 
childbearing potential must be using an acceptable method of contraception such as male 
condom plus spermicide (condom alone in countries where spermicides are not approved) 
from Cycle 1 Day 1 throughout the total duration of the study and the drug washout period (3 
months after the last dose of olaparib) to prevent pregnancy in a partner.  
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. Male participants should refrain from sperm donation or banking 
throughout the period of taking olaparib and for 3 months following the last dose of olaparib. 
Vasectomized (ie, sterile) males are considered fertile and should still use a male condom plus 
spermicide as indicated above during the clinical study. 
Even if the female partner is pregnant, male participants should still use a condom plus 
spermicide (where approved), as indicated above during the clinical study, if there is a concern 
about damaging the developing fetus from drug in ejaculate. 
Female partners (of childbearing potential) of male participants must also use a highly 
effective method of contraception throughout this period (Table 21). 
F 2 
Highly Effective Methods of Contraception 
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table 21. 
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/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills). 
Participants in the investigator’s choice of NHA (abiraterone acetate or enzalutamide) group: 
Follow the local Prescribing Information relating to contraception, the time limits for such 
precautions, and any additional restrictions for agents in the investigator’s choice of NHA 
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(abiraterone acetate or enzalutamide) group. 
Table 18 
Highly Effective Methods of Contraception (<1% Failure Rate) 
Non-hormonal methods 
Hormonal methods 
• 
Total sexual abstinence (evaluate in relation to 
the duration of the clinical study and the 
preferred and usual lifestyle choice of the 
participant) 
• 
Vasectomized sexual partner (with participant 
assurance that partner received post-vasectomy 
confirmation of azoospermia) PLUS male 
condom 
• 
Tubal occlusion PLUS male condom 
• 
Intrauterine device (provided coils are 
copper-banded) PLUS male condom 
• 
Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®)a PLUS male condom 
• 
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a PLUS male condom 
• 
Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®) PLUS male 
condom 
• 
Intravaginal devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®) PLUS 
male condom 
• 
Combined pill: Normal and low dose combined 
oral contraceptive pill PLUS male condom 
• 
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®) PLUS 
male condom 
• 
Mini pill: Progesterone based oral contraceptive 
pill using desogestrel: Cerazette® is currently the 
only highly effective progesterone-based pill 
PLUS male condom 
a 
Hormonal methods not prone to drug-drug interactions. 
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Appendix G Concomitant Medications 
G 1 
Guidance Regarding Potential Interactions with Concomitant 
Medications 
The use of any natural/herbal products or other “folk remedies” should be discouraged, but 
use of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the eCRF. 
DRUGS INDUCING OR INHIBITING CYTOCHROME P450 (CYP) 3A4/5 
METABOLISM THAT ASTRAZENECA STRONGLY RECOMMENDS ARE NOT 
COMBINED WITH OLAPARIB 
Olaparib is metabolized by CYP3A4 and CYP3A5 enzymes. Therefore, inhibitors or inducers 
of CYP3A4/5 may increase or decrease exposure, respectively, to olaparib. 
A drug-drug interaction study of olaparib evaluated in participants showed that there is 
potential for olaparib to be a victim when co-administered with strong inducers of CYP3A4/5 
(olaparib concentrations are decreased when co-dosed with phenobarbital, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine, and St John’s wort).  
A drug-drug interaction study of olaparib evaluated in participants showed that there is 
potential for olaparib to be a victim when co-administered with strong inhibitors of CYP3A4/5 
(olaparib concentrations are increased when co-dosed with itraconazole, telithromycin, 
clarithromycin, boosted protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, 
telaprevir).  
Strong or moderate inducers of CYP3A should not be combined with olaparib and should be 
stopped at least 3 weeks (5 weeks for phenobarbital) before the first dose of olaparib. 
Strong or moderate inhibitors of CYP3A should not be combined with olaparib and should be 
stopped at least 2 weeks before the first dose of olaparib. 
The following are drugs known to be inducers of CYP3A4/5 (Table 22). 
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Table 19 
Drugs Known to be Inducers of CYP3A4/5 
Strong CYP3A4/5 inducers 
Moderate CYP3A4/5 inducers 
avasimibe 
carbamazepine 
mitotane 
nevirapine 
phenobarbital 
phenytoin 
rifabutin 
rifampin 
rifapentine 
St John’s wort 
semagacestata 
talviralinea 
bosentan 
efavirenz 
etravirine 
genistein 
lersivirine 
lopinavir 
modafinil 
nafcillin 
thioridazine 
tipranavir and ritonavirb 
a 
Not available on the United States market. 
b 
Ritonavir has dual effects of simultaneous CYP3A inhibition and induction; the net pharmacokinetic 
outcome during chronic ritonavir therapy is inhibition of CYP3A activity. 
 
The following are drugs known to be inhibitors of CYP3A4/5 (Table 23). 
Table 20 
Drugs Known to be Inhibitors of CYP3A4/5 
Strong CYP3A4/5 inhibitors 
Moderate CYP3A4/5 inhibitors 
boceprevir 
clarithromycin 
conivaptan 
elvitegravir/ritonavir 
fluconazole 
grapefruit juice a,b 
indinavir 
itraconazole 
ketoconazole 
lopinavir/RIT 
mibefradil 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
amprenavir 
aprepitant 
atazanavir 
casopitant 
cimetidine 
ciprofloxacin 
crizotinib 
cyclosporine 
darunavir 
diltiazem 
dronedarone 
erythromycin 
grapefruit juice b 
imatinib 
schisandra sphenanthera 
tofisopam 
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Table 20 
Drugs Known to be Inhibitors of CYP3A4/5 
Strong CYP3A4/5 inhibitors 
Moderate CYP3A4/5 inhibitors 
telaprevir 
telithromycin 
tipranavir/ritonavir 
troleandomycin 
voriconazole 
verapamil 
a 
Double-strength grapefruit juice 
b 
It is prohibited to consume grapefruit juice while on olaparib therapy. Participants should abstain from 
eating large amounts of grapefruit and Seville oranges (and other products containing these fruits eg, 
marmalade) during the study (eg, no more than half a grapefruit or 1 to 2 teaspoons [15 g] of Seville orange 
marmalade daily). 
 
This list is not intended to be exhaustive, and a similar restriction will apply to other agents 
that are known to strongly modulate CYP3A4/5 activity. Appropriate medical judgment is 
required. Please contact AstraZeneca with any queries you have on this issue. 
If the investigator feels that concomitant administration of medications or herbal supplements 
that strongly modulate CYP3A4/5 is essential (eg, to treat AEs) olaparib treatment should be 
discontinued. 
G 2 
Prohibited, Restricted and Permitted Concomitant 
Medications/Therapies 
Prohibited, restricted and permitted concomitant medications/therapies are described in 
Table 24, Table 25 and Table 26. Refer also to the dose modification guidelines for 
management of study intervention-related toxicities in Section 6.6. 
Table 21 
Prohibited Medications/Therapies 
Prohibited medication/class of drug/therapy 
Usage 
Anticancer therapy: 
• 
Chemotherapy 
• 
Immunotherapy 
• 
Hormonal therapy a, b 
• 
Radiotherapy (except palliative) 
• 
Biological therapy 
• 
Other novel agents 
Not permitted while the patient is receiving study 
medication 
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Table 21 
Prohibited Medications/Therapies 
Prohibited medication/class of drug/therapy 
Usage 
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. 
a 
Hormone Replacement Therapy (HRT) is acceptable. 
b 
Except LHRH agonist/antagonist which is required during treatment phase. 
 
Table 22 
Restricted Medications/Therapies 
Medication/class of drug/therapy 
Usage (including limits for duration permitted and 
special situations in which it’s allowed) 
Strong CYP3A inhibitors 
Moderate CYP3A inhibitors 
See Appendix G 1 
 
Strong or moderate CYP3A inhibitors should not be 
taken with olaparib. If there is no suitable alternative 
concomitant medication then the dose of olaparib 
should be reduced for the period of concomitant 
administration. The dose reduction of olaparib or 
study treatment should be recorded in the CRF with 
the reason documented as concomitant CYP3A 
inhibitor use.  
• 
Strong CYP3A inhibitors – reduce the dose of 
olaparib to 100 mg twice daily for the duration of 
concomitant therapy with the strong inhibitor and 
for 5 half-lives afterwards. 
• 
Moderate CYP3A inhibitors - reduce the dose of 
olaparib to 150 mg twice daily for the duration of 
concomitant therapy with the moderate inhibitor 
and for 3 half-lives afterwards. 
• 
After the washout of the inhibitor is complete, 
the olaparib dose can be re-escalated. 
Strong CYP3A inducers 
Moderate CYP3A inducers 
See Appendix G 1 
 
Strong or moderate CYP3A inducers should not be 
taken with olaparib. 
If the use of any strong or moderate CYP3A inducers 
are considered necessary for the patient’s safety and 
welfare this could diminish the clinical efficacy of 
olaparib. 
If a patient requires use of a strong or moderate 
CYP3A inducer then they must be monitored carefully 
for any change in efficacy of olaparib. 
Refer to local prescribing information for guidance on 
dose modification for abiraterone acetate and 
enzalutamide in situations where co-administration 
with strong CYP3A4 inducers cannot be avoided. 
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Medication/class of drug/therapy 
Usage (including limits for duration permitted and 
special situations in which it’s allowed) 
Strong CYP2C8 inhibitors 
 
Co-administration of enzalutamide with strong 
CYP2C8 inhibitors may increase exposure to 
enzalutamide and thus should be avoided if possible. If 
subjects must be co-administered a strong CYP2C8 
inhibitor, reduce the enzalutamide dose to 80 mg once 
daily (or per local prescribing information if different). 
If co-administration of the strong inhibitor is 
discontinued, the enzalutamide dose should be 
returned to the dose used prior to initiation of the 
strong CYP2C8 inhibitor. 
• 
CYP3A4 substrates: hormonal contraceptive, 
simvastatin, cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, sirolimus, 
tacrolimus and quetiapine 
• 
CYP2B6 substrates: bupropion, efavirenz 
• 
CYP2C9 substrates: warfarin  
• 
CYP2C19 substrates: lansoprazole, 
omeprazole, S-mephenytoin 
• 
P-gp substrates: simvastatin, pravastatin, 
digoxin, dabigatran, colchicine 
• 
OATP1B1 substrates: bosentan, 
glibenclamide, repaglinide, statins and 
valsartan 
• 
OCT1, MATE1 and MATE2K substrates: 
metformin 
• 
OCT2 substrates: serum creatinine 
• 
OAT3 substrates: furosemide, methotrexate 
Effect of olaparib on other drugs: 
Based on limited in vitro data, olaparib may increase 
the exposure to substrates of CYP3A4, P-gp, 
OATP1B1, OCT1, OCT2, OAT3, MATE1 and 
MATE2K. 
Based on limited in vitro data, olaparib may reduce the 
exposure to substrates CYP3A4, 2B6, 2C9, 2C19 and 
P-gp. 
Caution should be observed if substrates of these 
isoenzymes or transporter proteins are 
co-administered. 
• 
P-gp inhibitors: amiodarone, azithromycin 
Co-administration of P-gp inhibitors may increase 
exposure to olaparib. Caution should therefore be 
observed. 
Anticoagulant therapy 
Patients who are taking warfarin may participate in 
this trial; however, it is recommended that 
international normalized ratio (INR) be monitored 
carefully at least once per week for the first month, 
then monthly if the INR is stable. Subcutaneous 
heparin and low molecular weight heparin are 
permitted. 
CYP3A4/5 = Cytochrome P450 3A4/5; CYP2C8 = Cytochrome P450 2C8; P-gp = P glycoprotein 
 
 
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Table 23 
Supportive Medications/Therapies 
Supportive medication/class of drug/therapy 
Usage 
LHRH agonist/antagonist 
Continuous ADT with an LHRH agonist/antagonist 
(unless bilateral orchiectomy) must be continued 
during the trial. Since LHRH is standard of care, it 
will not be provided nor reimbursed. 
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) deemed 
necessary to provide adequate AE management, 
except for those medications identified as 
“prohibited,” as listed above  
To be administered as prescribed by the investigator 
except for those medications identified as 
“prohibited,” as listed in Table 24 
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy, 
etc]) except for those medications identified as 
“prohibited,” as listed above 
Should be used, when necessary, for all participants 
except for those medications identified as 
“prohibited,” as listed in Table 24 
Palliative radiotherapy may be used for the treatment 
of pain at the site of bony metastases that were present 
at baseline, provided the investigator does not feel that 
these are indicative of clinical disease progression 
during the study period. Olaparib should be 
discontinued for a minimum of 3 days before a subject 
undergoes therapeutic palliative radiation treatment. 
Olaparib should be restarted within 4 weeks as long as 
any bone marrow toxicity has recovered.  
Corticosteroids and/or bisphosphonates for the 
treatment of bone metastases  
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. 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 
 
Required for management of other medical 
conditions 
As required except for those identified as “prohibited,” 
as listed in Table 24. 
 
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Appendix H 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 participants 
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 participants will 
allow AEs 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 participants themselves. 
 
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Appendix I 
Olaparib/Investigator’s Choice of NHA 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/investigator’s choice of NHA. 
I 1 
Study Participant Risks during COVID-19 
The risk-benefit balance should be carefully assessed for each patient enroling 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 participants and utmost diligence in 
determining their eligibility for study participation, continued study treatment, and overall 
assessment of benefit/risk of study treatment or participation. 
I 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.  
I 2.1 
Olaparib/Investigator’s Choice of NHA: Product-specific Guidance in 
Relation to the COVID-19 Pandemic 
• 
Participants 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/investigator’s 
choice of NHA 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 hemoglobin, neutrophils and lymphocytes  
− 
Benefit risk for the individual participants including curative vs palliative intent of 
treatment and response to olaparib/investigator’s choice of NHA 
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• 
If participants present with new or worsening respiratory symptoms such as dyspnea, 
cough and fever, or an abnormal chest radiologic finding is observed, 
olaparib/investigator’s choice of NHA 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/investigator’s choice of NHA 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.  
I 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):1714-68.  
 
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Appendix J 
Abbreviations 
Abbreviation or Special 
Term 
Explanation 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase; 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
Anti-HBc 
Hepatitis B Core Antibody 
Anti-HBs 
Hepatitis B Surface Antibody 
aPTT 
activated partial thromboplastin time 
AQA 
Analgesic Quantification Algorithm 
AST 
aspartate aminotransferase 
ATM 
ataxia telangiectasia mutated 
BICR 
Blinded Independent Central Review 
bid 
twice daily 
BoR 
best objective response  
BP 
blood pressure 
BRCA1/2 
BReast CAncer gene 1/2 
BRCAm 
BReast CAncer gene mutation 
CI 
confidence interval 
CR 
complete response 
CrCL 
creatinine clearance 
CRO 
Clinical Research Organization 
CRPC 
castration-resistant prostate cancer 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cx 
crossover 
CYP 
cytochrome P450 
DAE 
adverse event leading to discontinuation 
DCO 
data cutoff 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid  
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Abbreviation or Special 
Term 
Explanation 
DoR 
duration of response 
DSB 
double-strand DNA break 
dUCBT 
double umbilical cord blood transplantation 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EFR 
Evaluable for response 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FFPE 
formalin fixed and paraffin embedded 
G-CSF 
Granulocyte colony-stimulating factor 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDPE 
high density polyethylene 
HIV 
human immunodeficiency virus 
HL 
Hy’s Law 
HR 
hazard ratio 
HRD 
homologous recombination deficiency 
HRR 
homologous recombination repair 
HRRm 
homologous recombination repair gene mutations 
IATA 
International Airline Transportation Association 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
iCRO 
imaging Contract Research Organization 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IMPD 
investigational medicinal product dossier 
INR 
international normalized ratio 
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Abbreviation or Special 
Term 
Explanation 
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. 
IRB 
Institutional Review Board 
IV 
intravenous 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
KM 
Kaplan-Meier 
LHRH 
luteinizing hormone-releasing hormone 
mCRPC 
metastatic castration-resistant prostate cancer 
MCV 
mean corpuscular volume 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
not evaluable 
NGS 
next-generation sequencing 
NHA 
new hormonal agent 
NIMP 
non-investigational medicinal product 
NL 
new lesion 
NTL 
non-target lesion 
OAE 
other significant AE 
ORR 
objective response rate 
OS 
overall survival 
PARP 
polyadenosine 5’diphosphoribose polymerase 
PCWG3 
Prostate Cancer Working Group 3 
PD 
progression of disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFS2 
time from randomization to second progression by investigator assessment of 
radiological or clinical progression or death 
PHL 
Potential Hy’s Law 
PR 
partial response 
PSA 
prostate specific antigen 
PSR 
Platinum-sensitive relapsed 
PT 
preferred term 
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Abbreviation or Special 
Term 
Explanation 
PTT 
partial thromboplastin time 
q8w 
every 8 weeks 
qd 
once daily 
QTcF 
QT interval corrected by Fridericia’s formula 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
RNA 
ribonucleic acid 
rPFS 
radiological progression-free survival 
SAE 
serious adverse event  
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SoA 
Schedule of Activities 
SoC 
Standard of care 
SOC 
System Organ Class 
SSB 
single-strand DNA break 
SSRE 
symptomatic skeletal related events 
TBL 
total bilirubin 
tBRCA 
BReast CAncer gene tissue 
tBRCAm 
BReast CAncer gene mutation tissue 
TEAE 
treatment emergent adverse event 
TL 
target lesion 
ULN 
upper limit of normal 
US 
United States  
WHO 
World Health Organization 
 
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11 
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Document Name: d081lc00002-csp-v3
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D081LC00002 Clinical Study Protocol version 3
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