A Phase 3, Randomized Open-label Study of Pembrolizumab (MK-3475) Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) Who Are Unselected for Homologous Recombination Repair Defects and Have Failed Prior Treatment With One Next-generation Hormonal Agent (NHA) and Chemotherapy (KEYLYNK-010)
Phase: PHASE3
Conditions: Prostatic Neoplasms
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
A Phase 3, Randomized Open-label Study of Pembrolizumab (MK-3475)
Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Participants 
with Metastatic Castration-resistant Prostate Cancer (mCRPC) Who are 
Unselected for Homologous Recombination Repair Defects and Have 
Failed Prior Treatment with One Next-generation Hormonal Agent (NHA) 
and Chemotherapy (KEYLYNK-010)
02-May-2022
NCT03834519

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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized Open-label Study of Pembrolizumab (MK-3475) 
Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Participants with Metastatic 
Castration-resistant Prostate Cancer (mCRPC) Who are Unselected for Homologous 
Recombination Repair Defects and Have Failed Prior Treatment with One Next-generation 
Hormonal Agent (NHA) and Chemotherapy (KEYLYNK-010)
Protocol Number: 010-06
Compound Number: MK-7339
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
141,337
EudraCT
2018-004118-16
Approval Date: 02 May 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 06
02-MAY-2022
Protocol amended consistent with recommendations of the eDMC after an interim 
review of the data; specifically, to discontinue the study due to futility. Participants 
still on treatment may have the option to continue receiving study intervention or SOC 
if they are deriving clinical benefit, until criteria for discontinuation are met.
Amendment 05
23-AUG-2021
Addition of a contraindication for concurrent administration of abiraterone and 
radium-223 during abiraterone treatment including a minimum washout period after 
the last dose of abiraterone. Addition of a consideration for dose reduction of 
medicinal products that are metabolized by CYP2D6 and have a narrow therapeutic 
index to potentially prolong the QT interval. Minor administrative changes to ensure 
consistency and clarity throughout the protocol.
Amendment 04
02-APR-2021
Administrative updates to incorporate recently authored protocol template language 
for VOP related to rPFS endpoint with BICR and to update IMP/NIMP classification 
of active comparators based on guidance issued by European Commission. 
Minor administrative changes identified after Protocol Amendment 03 was finalized
to ensure consistency and clarity throughout the protocol.
Amendment 04 supersedes Amendment 03; Amendment 03 was not released to any 
regulatory agencies or to IRB/ERCs.
Amendment 03
26-FEB-2021
Administrative updates to incorporate recently authored protocol template language 
for VOP related to rPFS endpoint with BICR and to update IMP/NIMP classification 
of active comparators based on guidance issued by European Commission. 
Minor administrative changes identified after Protocol Amendment 02 to ensure 
consistency and clarity throughout the protocol.
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Document
Date of Issue
Overall Rationale
Amendment 02
06-NOV-2019
Administrative updates to add missing standard safety causality/intensity language in 
Appendix 3 that was inadvertently truncated during publishing of the original 
protocol, and to correct the duplicate numbering of exclusion criterion #12 during 
publishing of the PA01. Minor administrative changes identified after Protocol 
Amendment 01 to ensure consistency and clarity throughout the protocol.
Amendment 01
05-JUL-2019
Administrative updates to address HA requests.
Minor administrative changes throughout the protocol to ensure consistency and 
clarity.
Original Protocol
18-JAN-2019
N/A
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 06
Overall Rationale for the Amendments:
Protocol amended consistent with recommendations of the eDMC after an interim review of the data; specifically, to discontinue the 
study due to futility. Participants still on treatment may have the option to continue receiving study intervention or SOC if they are 
deriving clinical benefit, until criteria for discontinuation are met.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis, Hypotheses, 
Objectives, and Endpoints
Section 3 Hypotheses, 
Objectives, and Endpoints
Statement added:
NOTE: As of Amendment 06, participants 
who are still on study treatment and deriving 
clinical benefit will no longer have tumor 
response assessments by BICR. However, 
local tumor imaging assessments should 
continue per SOC schedule. In addition, 
ePRO assessments will no longer be 
performed and biomarker samples will no 
longer be collected. Updated analyses are 
described in Section 9.
As the result of the efficacy IA indicated futility, further 
tumor scans and response assessments by BICR, and 
ePRO assessments, and collection of additional samples 
for biomarker evaluation are considered unnecessary.
1.1 Synopsis, Estimated 
Duration of Study
9.7.1 Efficacy Interim 
Analyses and Table 15
9.9 Sample Size and Power 
Calculations
The estimated duration of the study has 
been changed from approximately 29 
months to approximately 40 months.
The actual duration of the study is 40 months.
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Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis, Study 
Governance Committees
Statement added that as of Amendment 06, 
the Executive Oversight Committee and 
eDMC are no longer applicable.
These committees will no longer review the study data.
1.3.1 Initial Treatment Phase 
(Pembrolizumab Plus 
Olaparib Versus Abiraterone 
Acetate or Enzalutamide)
Added statement: 
NOTE: As of Amendment 06, participants 
who are still on study treatment and 
deriving clinical benefit will no longer 
have tumor response assessments by 
BICR. However, local tumor imaging 
assessments should continue per SOC
schedule. In addition, ePRO assessments 
(FACT-P, EQ-5D-5L, BPI-SF, Analgesic 
Log) will no longer be performed and 
biomarker samples (blood for: CTC count, 
genetic analysis, RNA analysis, plasma 
biomarker analysis, serum biomarker 
analysis, and ctDNA analysis) will no 
longer be collected. Updated analyses are 
described in Section 9.
As of Amendment 06, these assessments and sample 
collections are considered unnecessary.
1.3.2 Second Course Phase
4.1 Overall Design, Second 
Course Treatment
6.6.7 Second Course
8.2.1.4 Second Course 
(Retreatment) Tumor 
Imaging
Statement added:
NOTE: As of Amendment 06, the study 
will be stopped due to futility and second 
course treatment is not an option for 
participants. There are currently no 
participants in the Second Course Phase.
To update the status of the Second Course Phase of the 
study.
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Section # and Name
Description of Change 
Brief Rationale 
2.3 Benefit/Risk Assessment
Added paragraph describing the safety and 
efficacy results of the IA leading to the 
determination of futility.
Added statement:
Selected analyses of safety endpoints will 
be performed at the end of the study. There 
will be no further analyses of efficacy and 
PRO endpoints.
To inform of the decision to stop this clinical study.
4.1 Overall Design
Statement regarding Amendment 06 added 
to beginning of the section.
To provide the rationale for closing MK-7339-010.
5.2 Exclusion Criteria
Added clarification to criterion #49 that 
the duration of contraception required is 
listed in inclusion criterion #12. 
To correct an inconsistency in eligibility criteria for male 
contraception.
6.1 Study Intervention(s) 
Administered
Added statement:
As of Amendment 06, the study is being 
stopped for futility. However, participants 
currently still on study treatment may have 
the option of continuing with study 
intervention or SOC treatment, as 
appropriate, if they are deriving clinical 
benefit.
To clarify that participants may continue to receive study 
intervention or SOC if deriving clinical benefit.
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Section # and Name
Description of Change 
Brief Rationale 
7.1 Discontinuation of Study 
Intervention
Added the subbullet:
o
As of Amendment 06, central tumor 
response assessments will no longer be 
performed. However, participants still 
on study treatment and deriving 
clinical benefit and are continuing to 
receive study intervention or SOC, will 
be assessed locally by the investigator 
for disease progression per SOC 
schedule.
To clarify that participants still on-treatment with study 
intervention or SOC at the time of Amendment 06, 
because they are deriving clinical benefit, will be 
assessed locally for disease progression. Imaging scans 
will no longer be collected by vendor for central review 
for efficacy endpoints, as there will be no further efficacy 
analyses. Imaging will be performed per local SOC at the 
treating physician’s discretion for patient management.
8.2.1 Tumor Imaging and 
Assessment of Disease
Added statements:
As of Amendment 06: Central tumor 
response assessments will be discontinued.
Imaging scans will no longer be submitted 
to iCRO nor read by BICR. The 
subsections below are retained for 
reference. 
However, for participants who are still 
onstudy treatment and deriving clinical 
benefit and will continue on-study 
intervention or SOC treatment until criteria 
for discontinuation are met, local tumor 
imaging should continue per SOC
schedule. 
As of Amendment 06, further efficacy assessments are 
considered unnecessary.
To clarify that participants still receiving study 
intervention or SOC at the time of this amendment 
because they are deriving clinical benefit will continue 
with local tumor imaging per SOC schedule.
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Section # and Name
Description of Change 
Brief Rationale 
8.2.4 PROs and Quality of 
Life Assessments
Added statement: 
As of Amendment 06: PROs and Quality 
of Life assessments will be discontinued.
The subsections below are retained for 
reference.
As of Amendment 06, ePRO and Quality of Life
assessments are considered unnecessary.
8.10 Biomarkers
Added statement: 
As of Amendment 06: Biomarker sample 
collections will be discontinued. The 
subsection below is retained for reference.
As of Amendment 06, collection of these samples is
considered unnecessary.
8.11 Medical Resource 
Utilization and Health 
Economics
Added statement: 
As of Amendment 06: Medical Resource 
Utilization and Health Economics data 
collection will be discontinued. The 
section below is retained for reference.
As of Amendment 06, assessment of these data is
considered unnecessary.
8.12.5.2 Efficacy Follow-up 
Visits
As of Amendment 06: Efficacy Follow-up 
Visits will be discontinued.
As of Amendment 06, these assessments are considered 
unnecessary.
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Section # and Name
Description of Change 
Brief Rationale 
8.12.5.3 Survival Follow-up 
Contacts
Added statement:
As of Amendment 06: Survival Follow-up 
visits will be discontinued. Those 
participants remaining on study treatment 
at the time of Amendment 06 should 
continue to be monitored in the study 
through the AE reporting period (Section 
8.4). The section below is retained for 
reference.
As of Amendment 06, this follow-up is only for 
participants remaining on study at the time of this 
amendment, and participants will be followed for the 
duration of the AE reporting period.
9 Statistical Analysis Plan
9.1 Statistical Analysis Plan 
Summary
9.6 Statistical Methods
9.7 Interim Analyses
9.7.2 Safety Interim 
Analyses
9.8 Multiplicity
9.9 Sample Size and Power 
Calculations
Added statement:
As of Amendment 06: The Statistical 
Analysis Plan is amended as follows:
Added note describing the results of the 
safety and efficacy IAs that led to the 
determination to stop the study due to 
futility.
In Sections 9, 9.1, and 9.6, added 
statement:
Selected analyses of safety endpoints will 
be performed at the end of the study; there 
will be no further analyses of efficacy and 
PRO endpoints.
In Sections 9, 9.1, 9.6, 9.7, 9.8, and 9.9, a 
statement was added that the prespecified 
final analysis of the study described in the 
SAP will not be performed.
To describe the results of the IAs and to specify which 
analyses will be conducted as of Amendment 06.
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Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
Sponsor entity name and address change.
Merck  Sharp & Dohme Corp. underwent an entity name 
and address change to Merck Sharp & Dohme LLC, 
Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address.
Throughout Document
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document
To ensure clarity and accurate interpretation of the intent 
of the protocol
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1
PROTOCOL SUMMARY ............................................................................................22
1.1
Synopsis.................................................................................................................22
1.2
Schema ..................................................................................................................27
1.3
Schedule of Activities (SoA)................................................................................28
1.3.1
Initial Treatment Phase (Pembrolizumab Plus Olaparib Versus 
Abiraterone Acetate or Enzalutamide).........................................................28
1.3.2
Second Course Phase...................................................................................40
2
INTRODUCTION..........................................................................................................44
2.1
Study Rationale....................................................................................................45
2.2
Background ..........................................................................................................46
2.2.1
Pharmaceutical and Therapeutic Background .............................................46
Inhibition of PD-1 as a Target for Cancer Therapy...........................46
Inhibition of PARP as a Target for Cancer Therapy..........................47
Homologous Recombination Repair in Solid Tumors.......................48
Overview of Prostate Cancer .............................................................49
Unmet Medical Need in Prostate Cancer...........................................49
Preclinical and Clinical Studies .........................................................51
Pembrolizumab in mCRPC................................................................51
Ongoing Clinical Studies in mCRPC.................................................51
2.2.1.8.1
Pembrolizumab ........................................................................51
2.2.1.8.2
Olaparib....................................................................................52
2.2.2
Information on Other Study-related Therapy ..............................................53
2.3
Benefit/Risk Assessment......................................................................................53
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................54
4
STUDY DESIGN............................................................................................................58
4.1
Overall Design......................................................................................................58
4.2
Scientific Rationale for Study Design.................................................................60
4.2.1
Rationale for Endpoints ...............................................................................61
Efficacy Endpoints.............................................................................61
Safety Endpoints................................................................................61
Patient-reported Outcomes.................................................................61
Planned Exploratory Biomarker Research.........................................62
4.2.1.4.1
Planned Genetic Analysis ........................................................64
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Future Biomedical Research..............................................................64
4.2.2
Rationale for the Use of Comparators .........................................................64
4.3
Justification for Dose...........................................................................................65
4.3.1
Pembrolizumab ............................................................................................65
4.3.2
Olaparib........................................................................................................66
4.3.3
Abiraterone Acetate .....................................................................................66
4.3.4
Enzalutamide................................................................................................66
4.4
Beginning and End of Study Definition .............................................................66
4.4.1
Clinical Criteria for Early Study Termination .............................................66
5
STUDY POPULATION ................................................................................................67
5.1
Inclusion Criteria.................................................................................................67
5.2
Exclusion Criteria................................................................................................71
5.3
Lifestyle Considerations......................................................................................75
5.3.1
Meals and Dietary Restrictions....................................................................75
5.4
Screen Failures.....................................................................................................75
5.5
Participant Replacement Strategy......................................................................76
6
STUDY INTERVENTION............................................................................................76
6.1
Study Intervention(s) Administered...................................................................76
6.2
Preparation/Handling/Storage/Accountability .................................................78
6.2.1
Dose Preparation..........................................................................................78
6.2.2
Handling, Storage, and Accountability........................................................78
6.3
Measures to Minimize Bias: Randomization and Blinding..............................79
6.3.1
Intervention Assignment..............................................................................79
6.3.2
Stratification.................................................................................................79
6.3.3
Blinding........................................................................................................79
6.4
Study Intervention Compliance..........................................................................79
6.5
Concomitant Therapy..........................................................................................80
6.5.1
Prohibited Concomitant Therapy.................................................................80
6.5.2
Rescue Medications and Supportive Care ...................................................83
6.5.3
Radiotherapy................................................................................................84
6.6
Dose Modification (Escalation/Titration/Other)...............................................84
6.6.1
Concomitant Combination Therapy.............................................................84
6.6.2
Dose Modification for Olaparib...................................................................84
Management of Hematologic Toxicities............................................84
Management of Prolonged Hematologic Toxicities ..........................86
Management of Nonhematologic Toxicity........................................87
6.6.2.3.1
Management of New or Worsening Pulmonary Symptoms ....87
6.6.2.3.2
Management of Nausea and Vomiting ....................................87
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6.6.2.3.3
Management of Renal Impairment ..........................................88
Interruptions for Intercurrent Nontoxicity-related Events.................88
Dose Reductions for Concurrent CYP3A4 Inhibitor Use..................89
6.6.3
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................89
Dose Modification and Toxicity Management for Immune-related 
AEs Associated with Pembrolizumab................................................89
Dose Modification and Toxicity Management of Infusion 
Reactions Associated with Pembrolizumab.......................................93
6.6.4
Management of Overlapping Toxicities ......................................................95
6.6.5
Dose Modification for Abiraterone Acetate ................................................95
Management of Hepatotoxicity..........................................................95
Management of Hypokalemia............................................................96
Management of Hypertension............................................................96
Management of Edema and Fluid Retention .....................................97
Management of Other AEs Believed to be Related to Abiraterone 
Acetate ...............................................................................................97
6.6.6
Dose Modification for Enzalutamide...........................................................98
6.6.7
Second Course .............................................................................................99
6.7
Intervention After the End of the Study..........................................................100
6.8
Clinical Supplies Disclosure..............................................................................100
6.9
Standard Policies................................................................................................100
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL..........................................................................................................100
7.1
Discontinuation of Study Intervention.............................................................100
7.2
Participant Withdrawal From the Study.........................................................102
7.3
Lost to Follow-up ...............................................................................................103
8
STUDY ASSESSMENTS AND PROCEDURES......................................................103
8.1
Administrative and General Procedures .........................................................104
8.1.1
Informed Consent.......................................................................................104
General Informed Consent...............................................................104
Consent and Collection of Specimens for Future Biomedical 
Research...........................................................................................104
8.1.2
Inclusion/Exclusion Criteria ......................................................................105
8.1.3
Participant Identification Card...................................................................105
8.1.4
Medical History .........................................................................................105
8.1.5
Prior and Concomitant Medications Review.............................................105
Prior Medications.............................................................................105
Concomitant Medications................................................................105
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8.1.6
Assignment of Screening Number.............................................................106
8.1.7
Assignment of Treatment/Randomization Number...................................106
8.1.8
Study Intervention Administration ............................................................106
Timing of Dose Administration.......................................................106
8.1.8.1.1
Pembrolizumab ......................................................................106
8.1.8.1.2
Olaparib..................................................................................107
8.1.8.1.3
Abiraterone Acetate + Prednisone or Prednisolone...............107
8.1.8.1.4
Enzalutamide..........................................................................108
8.1.9
Discontinuation and Withdrawal ...............................................................108
Withdrawal From Future Biomedical Research ..............................108
8.1.10
Participant Blinding/Unblinding................................................................109
8.1.11
Calibration of Equipment...........................................................................109
8.2
Efficacy Assessments .........................................................................................109
8.2.1
Tumor Imaging and Assessment of Disease..............................................109
Initial Tumor Imaging......................................................................112
Tumor Imaging During the Study....................................................112
End of Treatment and Follow-up Tumor Imaging...........................112
Second Course (Retreatment) Tumor Imaging................................113
8.2.2
Prostate-specific Antigen Assessments......................................................114
8.2.3
Tumor Tissue Collection............................................................................115
8.2.4
PROs and Quality of Life Assessments.....................................................115
Functional Assessment of Cancer Therapy-Prostate (FACT-P)......115
EQ-5D-5L ........................................................................................115
Brief Pain Inventory-Short Form (BPI-SF) and Analgesic Log ......116
8.3
Safety Assessments.............................................................................................116
8.3.1
Physical Examinations...............................................................................116
Full Physical Examination...............................................................116
Directed Physical Examination........................................................117
8.3.2
Vital Signs..................................................................................................117
8.3.3
Electrocardiograms ....................................................................................117
8.3.4
Clinical Safety Laboratory Assessments ...................................................117
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)........................................................................................118
8.3.5
Performance Assessments..........................................................................118
Eastern Cooperative Oncology Group Performance Scale..............118
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ..................................................................................118
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................118
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....120
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.120
8.4.4
Regulatory Reporting Requirements for SAE ...........................................121
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................121
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................121
8.4.7
Events of Clinical Interest (ECIs)..............................................................122
8.5
Treatment of Overdose......................................................................................122
8.6
Pharmacokinetics...............................................................................................123
8.7
Pharmacodynamics............................................................................................123
8.8
Future Biomedical Research Sample Collection.............................................123
8.9
Planned Genetic Analysis Sample Collection..................................................123
8.10
Biomarkers .........................................................................................................124
8.11
Medical Resource Utilization and Health Economics.....................................124
8.12
Visit Requirements.............................................................................................124
8.12.1
Screening....................................................................................................125
8.12.2
Treatment Period........................................................................................125
8.12.3
Discontinuation Visit .................................................................................125
8.12.4
Discontinued Participants Continuing to be Monitored in the Study ........125
8.12.5
Posttreatment Visits ...................................................................................126
Safety Follow-up Visit.....................................................................126
Efficacy Follow-up Visits................................................................126
Survival Follow-up Contacts ...........................................................126
8.12.6
Survival Status ...........................................................................................127
9
STATISTICAL ANALYSIS PLAN ...........................................................................127
9.1
Statistical Analysis Plan Summary...................................................................128
9.2
Responsibility for Analyses/In-house Blinding ...............................................129
9.3
Hypotheses/Estimation ......................................................................................130
9.4
Analysis Endpoints.............................................................................................130
9.4.1
Efficacy Endpoints.....................................................................................130
Primary.............................................................................................130
Key Secondary.................................................................................130
Secondary.........................................................................................130
Exploratory ......................................................................................131
9.4.2
Safety Endpoints........................................................................................131
9.4.3
PRO Endpoints...........................................................................................131
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Time to Pain Progression.................................................................131
9.5
Analysis Populations..........................................................................................132
9.5.1
Efficacy Analysis Populations...................................................................132
9.5.2
Safety Analysis Populations ......................................................................132
9.5.3
PRO Analysis Population ..........................................................................132
9.6
Statistical Methods.............................................................................................132
9.6.1
Statistical Methods for Efficacy Analyses.................................................133
OS ....................................................................................................133
rPFS..................................................................................................133
TFST ................................................................................................135
Analysis Strategy for Key Efficacy Endpoints................................135
9.6.2
Statistical Methods for Safety Analyses ....................................................136
9.6.3
Analysis Methods for PRO Endpoints.......................................................137
9.6.4
Demographic and Baseline Characteristics ...............................................138
9.7
Interim Analyses ................................................................................................138
9.7.1
Efficacy Interim Analyses..........................................................................138
9.7.2
Safety Interim Analyses.............................................................................139
9.8
Multiplicity .........................................................................................................139
9.8.1
rPFS............................................................................................................140
9.8.2
OS ..............................................................................................................141
9.8.3
TFST ..........................................................................................................142
9.8.4
Safety Analyses..........................................................................................143
9.9
Sample Size and Power Calculations ...............................................................143
9.10
Subgroup Analyses.............................................................................................145
9.11
Compliance (Medication Adherence)...............................................................145
9.12
Extent of Exposure.............................................................................................145
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................146
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......146
10.1.1
Code of Conduct for Clinical Trials...........................................................146
10.1.2
Financial Disclosure...................................................................................148
10.1.3
Data Protection...........................................................................................148
Confidentiality of Data ....................................................................149
Confidentiality of Participant Records.............................................149
Confidentiality of IRB/IEC Information..........................................149
10.1.4
Committees Structure.................................................................................149
Executive Oversight Committee......................................................149
External Data Monitoring Committee .............................................149
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10.1.5
Publication Policy......................................................................................150
10.1.6
Compliance with Study Registration and Results Posting Requirements .150
10.1.7
Compliance with Law, Audit, and Debarment ..........................................150
10.1.8
Data Quality Assurance .............................................................................151
10.1.9
Source Documents .....................................................................................152
10.1.10
Study and Site Closure...............................................................................152
10.2
Appendix 2: Clinical Laboratory Tests............................................................153
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................155
10.3.1
Definition of AE ........................................................................................155
10.3.2
Definition of SAE ......................................................................................156
10.3.3
Additional Events Reported in the Same Manner as SAE.........................157
10.3.4
Recording AE and SAE .............................................................................157
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................161
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................162
10.5
Appendix 5: Contraceptive Guidance..............................................................163
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................164
10.7
Appendix 7: Country-specific Requirements..................................................169
10.7.1
Laboratory Testing.....................................................................................169
10.7.2
Country-specific Requirements .................................................................169
Germany...........................................................................................169
10.8
Appendix 8: Description of the Prostate Cancer Working Group (PCWG) 
Process for Assessment of Bone Lesions..........................................................170
10.8.1
Imaging Methods .......................................................................................170
10.8.2
Documentation of Bone Lesions at Baseline.............................................170
10.8.3
Assessment of Bone Response at Subsequent Imaging Time Points ........170
10.8.4
Descriptions of Bone Response Categories ...............................................171
No Evidence of Disease...................................................................171
Nonprogression (Non-PD)...............................................................171
Unconfirmed Progressive Disease (PDu) ........................................171
Progressive Disease (PD).................................................................171
Confirmation of Progression............................................................171
New Lesions Within the Flare Window (<12 Weeks).....................171
New Lesions Outside the Flare Window (>12 Weeks) ...................172
10.8.5
Superscan ...................................................................................................172
10.8.6
Management After Confirmed PD.............................................................172
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10.9
Appendix 9: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................173
10.10 Appendix 10: Abbreviations .............................................................................174
10.11 Appendix 11: Eastern Cooperative Oncology Group Performance Status..177
11
REFERENCES.............................................................................................................178
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values ...........................................69
Table 2
Study Interventions....................................................................................77
Table 3
Management of Anemia.............................................................................85
Table 4
Management of Neutropenia, Leukopenia, and Thrombocytopenia .........86
Table 5
Olaparib Dose Reduction to Manage Moderate Renal Impairment...........88
Table 6
Olaparib Dose Reduction with a Strong or Moderate CYP3A4 
Inhibitor......................................................................................................89
Table 7
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .........................................................90
Table 8
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ..................................................................................................93
Table 9
Abiraterone Acetate Dose Modification Guidelines for Drug-related 
Adverse Events ..........................................................................................98
Table 10
Enzalutamide Dose Modification Guidelines for Drug-related Adverse
Events.........................................................................................................99
Table 11
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events...............................................................120
Table 12
Censoring Rules for Primary and Sensitivity Analyses of rPFS..............134
Table 13
Efficacy Analysis Methods for Key Efficacy Endpoints.........................135
Table 14
Analysis Strategy for Safety Parameters..................................................137
Table 15
Summary of Interim and Final Analyses .................................................139
Table 16
Efficacy Boundaries and Properties for rPFS..........................................141
Table 17
Efficacy Boundaries and Properties for Overall Survival Analyses........142
Table 18
Efficacy Boundaries and Properties for TFST.........................................143
Table 19
Protocol-required Safety Laboratory Assessments..................................153
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LIST OF FIGURES
Figure 1
Study Diagram ...........................................................................................27
Figure 2
Change in Prostate-specific Antigen........................................................114
Figure 3
Multiplicity Graph for One-sided Alpha Reallocation Strategy..............140
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized Open-label Study of Pembrolizumab (MK-3475) 
Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Participants with Metastatic 
Castration-resistant Prostate Cancer (mCRPC) Who are Unselected for Homologous 
Recombination Repair Defects and Have Failed Prior Treatment with One Next-generation 
Hormonal Agent (NHA) and Chemotherapy (KEYLYNK-010)
Short Title: Phase 3 Study of Pembrolizumab Plus Olaparib Versus Abiraterone Acetate or 
Enzalutamide in mCRPC
Acronym: KEYLYNK-010
Hypotheses, Objectives, and Endpoints:
In men with mCRPC, unselected for homologous recombination repair (HRR) gene 
mutations, whose disease has progressed during prior NHA treatment and chemotherapy:
NOTE: As of Amendment 06, participants who are still on study treatment and deriving 
clinical benefit will no longer have tumor response assessments by BICR. However, local 
tumor imaging assessments should continue per SOC schedule. In addition, ePRO
assessments will no longer be performed and biomarker samples will no longer be collected. 
Updated analyses are described in Section 9.
Primary Objectives
Primary Endpoints
To compare pembrolizumab plus olaparib to 
abiraterone acetate or enzalutamide with respect 
to overall survival (OS)
Hypothesis 1: The combination of pembrolizumab 
plus olaparib is superior to abiraterone acetate or 
enzalutamide with respect to OS.
OS: the time from randomization to death 
due to any cause
To compare pembrolizumab plus olaparib to 
abiraterone acetate or enzalutamide with respect 
to radiographic progression-free survival (rPFS) 
per Prostate Cancer Working Group (PCWG)-
modified Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST 1.1) as assessed 
by blinded independent central review (BICR)
Hypothesis 2: The combination of pembrolizumab 
plus olaparib is superior to abiraterone acetate or 
enzalutamide with respect to rPFS per PCWG-
modified RECIST 1.1 as assessed by BICR.
rPFS: the time from randomization to 
radiographic progression or death due to 
any cause, whichever occurs first 
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Secondary Objectives
Secondary Endpoints
To compare pembrolizumab plus olaparib to 
abiraterone acetate or enzalutamide with respect 
to time to initiation of the first subsequent 
anticancer therapy (TFST)
Hypothesis 3: The combination of 
pembrolizumab plus olaparib is superior to 
abiraterone acetate or enzalutamide with respect 
to TFST. 
TFST: the time from randomization to 
initiation of the first subsequent anticancer 
therapy or death, whichever occurs first
To evaluate pembrolizumab plus olaparib 
versus abiraterone acetate or enzalutamide with 
respect to the objective response rate (ORR) 
and duration of response (DOR) per PCWG-
modified RECIST 1.1 as assessed by BICR
Objective response (OR): complete 
response (CR) or partial response (PR)
DOR: the time from the earliest date of 
first documented evidence of confirmed 
CR or PR until the earliest date of disease 
progression or death from any cause, 
whichever comes first
To compare pembrolizumab plus olaparib to 
abiraterone acetate or enzalutamide with respect 
to: 
Time to prostate-specific antigen (PSA) 
progression
Time to first symptomatic skeletal-related event 
(SSRE)
Time to radiographic soft tissue progression per 
soft tissue rules of PCWG-modified RECIST 
1.1 as assessed by BICR
Time to pain progression (TTPP)
Time to PSA progression: the time from 
randomization to PSA progression.  The 
PSA progression date is defined as the 
date of:
1) ≥25% increase and ≥2 ng/mL above the 
nadir, confirmed by a second value ≥3 
weeks later if there is PSA decline from 
baseline, or 2) ≥25% increase and 
≥2 ng/mL increase from baseline beyond 
12 weeks if there is no PSA decline from 
baseline.
Time to first SSRE: the time from 
randomization to the first symptomatic 
skeletal-related event, defined as:
- first use of external-beam radiation 
therapy (EBRT) to prevent or relieve 
skeletal symptoms;
- occurrence of new symptomatic 
pathologic bone fracture (vertebral or 
nonvertebral);
- occurrence of spinal cord compression;
- or tumor-related orthopedic surgical 
intervention,whichever occurs first
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Time to radiographic soft tissue 
progression: the time from randomization 
to radiographic soft tissue progression
TTPP: the time from randomization to 
pain progression as determined by Item 3 
of the Brief Pain Inventory-Short Form 
(BPI-SF) and by the Analgesic 
Quantification Algorithm (AQA) score
To evaluate the safety and tolerability of 
pembrolizumab plus olaparib versus abiraterone 
acetate or enzalutamide
Adverse events (AEs)
Study intervention discontinuations due to 
AEs
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
The treatment of participants with mCRPC
Population
Participants with mCRPC unselected for HRR whose 
disease has progressed on NHA and chemotherapy
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 40 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 780 participants will be randomized in this study.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admin.
Regimen/ 
Treatment 
Period
Use
Arm 1
Pembrolizumab
200 mg
Q3W
IV
Day 1 of each 
21-day cycle for 
up to 35 cycles
Experi-
mental
Olaparib
300 mg
BID
PO
Two 150 mg 
tablets BID
Experi-
mental
Arm 2
Abiraterone 
acetatea +
prednisone or
prednisolone
or
Enzalutamideb
1000 mg
5 mg
160 mg
QD
BID
QD
PO
PO
PO
Two 500 mg or 
four 250 mg 
tablets
5 mg BID
Four 40 mg 
capsules/tablets
or
two 80 mg 
tablets
SOC
Abbreviations: BID=twice daily; IV=intravenous; QD=once daily; PO=oral; Q3W=every 3 weeks; 
SOC=standard of care.
a Participants previously treated with enzalutamide.
b Participants previously treated with abiraterone acetate.
Total 
Number
2 arms
Duration of 
Participation
Each participant will be receiving assigned intervention for approximately 
2 years. After the end of treatment, each participant will be followed for at 
least 30 days.
Each participant will participate in the study from the time the participant 
signs the Informed Consent Form (ICF) through the final protocol-specified 
contact.
Each participant will be assigned to receive study intervention until disease 
progression is radiographically documented and verified by BICR per PCWG-
modified RECIST 1.1 guidelines, unacceptable adverse event(s) (AEs), 
intercurrent illness that prevents further administration of treatment, 
investigator’s decision to discontinue the participant, noncompliance with 
study intervention or procedure requirements or administrative reasons 
requiring cessation of treatment, or until the participant has received 35 cycles
of pembrolizumab (approximately 2 years). Participants who stop study 
intervention after receiving 35 cycles of pembrolizumab for reasons other than 
disease progression or intolerability, or participants who attain a complete 
response (CR) and stop study intervention may be eligible for up to 17 
additional cycles of pembrolizumab (approximately 1 year) upon experiencing 
disease progression (Section 6.6.7 ) if they meet the criteria for retreatment 
(Second Course phase) and the study is ongoing (Section 6.6.7).
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After the end of treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy of female partner as 
described under Section 8.4.5.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status 
until disease progression is documented radiographically per PCWG-modified 
RECIST 1.1 and verified by BICR, initiating a non-study cancer treatment, 
withdrawing consent, or becoming lost to follow-up. All participants will be 
followed for overall survival until death, withdrawal of consent, or the end of 
the study.
Once the participant has achieved the study objective or the study has ended, 
the participant is discontinued from this study.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
As of Amendment 06, the Executive Oversight Committee and Data Monitoring Committee 
are no longer applicable.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document is in Appendix 10.
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1.2
Schema
The study design is shown in Figure 1.
Figure 1
Study Diagram
Abbreviations: ABI=abiraterone acetate; BID=twice daily; CTx=chemotherapy; ENZA=enzalutamide; 
IV=intravenously; mCRPC=metastatic castration-resistant prostate cancer; NHA=next-generation hormonal 
agent; PO=orally; Q3W=every 3 weeks; QD=once daily.
Participants randomized to pembrolizumab (200 mg IV Q3W) + olaparib (300 mg PO BID) will receive 
pembrolizumab on Day 1 of each 3-week dosing cycle. Dosing with olaparib will begin on pembrolizumab 
Cycle 1 Day 1 and continue on a daily dosing schedule. Treatment with pembrolizumab will continue for up to 
35 cycles (approximately 2 years) unless a discontinuation criterion (Section 7.1) is met. 
If pembrolizumab is stopped due to toxicity, participants may continue to receive olaparib until a 
discontinuation criterion (Section 7.1) are met. If olaparib is stopped due to toxicity, participants may continue 
to receive pembrolizumab for up to 35 cycles or until a discontinuation criterion (Section 7.1) is met.
For participants randomized to ABI (1000 mg PO QD) + prednisone or prednisolone (5 mg PO BID) (if 
previously treated with ENZA) or to ENZA (160 mg PO QD) (if previously treated with ABI + prednisone or 
prednisolone), dosing will begin on Day 1 and continue on a daily dosing schedule until a discontinuation 
criterion (Section 7.1) is met.
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1.3
Schedule of Activities (SoA)
1.3.1
Initial Treatment Phase (Pembrolizumab Plus Olaparib Versus Abiraterone Acetate or Enzalutamide)
NOTE: As of Amendment 06, participants who are still on study treatment and deriving clinical benefit will no longer have 
tumor response assessments by BICR. However, local tumor imaging assessments should continue per SOC schedule. In 
addition, ePRO assessments (FACT-P, EQ-5D-5L, BPI-SF, Analgesic Log) will no longer be performed and biomarker 
samples (blood for: CTC count, genetic analysis, RNA analysis, plasma biomarker analysis, serum biomarker analysis, and 
ctDNA analysis) will no longer be collected. Updated analyses are described in Section 9.
Study Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 10
11 and 
beyond 
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-up 
Survival 
Follow-
up
Scheduling Window (Days)
-42 to -1
+3
±3 ±3
±3
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose
(+7 
days)
Q9W to 
Week 54, 
then 
Q12W (±7 
days)
Q12W
(±7 days)
Before discontinuing 
participants from therapy
(Section 7.1), submit the 
Treatment Termination & 
Disease Assessment Termination 
Form.
The Safety Follow-up is not 
needed if the Discontinuation 
Visit occurs ≥30 days after the 
last dose.
Administrative Procedures
Informed consent
X
Obtain written consent before
performing any protocol-specific 
procedures.  
Additional consent may be
required after initial disease 
progression.
Informed consent for future 
biomedical research 
(optional)
X
Participants can still participate in 
the study if they decline to sign the 
Future Biomedical Research ICF.
Inclusion/exclusion criteria
X
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Study Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 10
11 and 
beyond 
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-up 
Survival 
Follow-
up
Scheduling Window (Days)
-42 to -1
+3
±3 ±3
±3
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose
(+7 
days)
Q9W to 
Week 54, 
then 
Q12W (±7 
days)
Q12W
(±7 days)
Before discontinuing 
participants from therapy
(Section 7.1), submit the 
Treatment Termination & 
Disease Assessment Termination 
Form.
The Safety Follow-up is not 
needed if the Discontinuation 
Visit occurs ≥30 days after the 
last dose.
Participant identification 
card
X
Update at randomization.
Demographics and medical 
history
X
History of blood 
transfusions
X
Include history of blood 
transfusion within previous 
120 days from start of study 
intervention and the reasons, eg, 
bleeding or myelosuppression.
Prior and concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
Report all concomitant 
medications received within 
28 days before the date of 
randomization and up to 30 days 
after the last dose of study 
intervention.
Include blood transfusions during 
concomitant medication review 
and reasons for transfusions.
SSRE Evaluation
X
X
X
X
X
X`
X
X
X
X
X
X
HIV and hepatitis B and C 
status
X
Not required unless mandated by 
local health authority.
Refer to Appendix 7 for country-
specific requirements.
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Study Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 10
11 and 
beyond 
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-up 
Survival 
Follow-
up
Scheduling Window (Days)
-42 to -1
+3
±3 ±3
±3
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose
(+7 
days)
Q9W to 
Week 54, 
then 
Q12W (±7 
days)
Q12W
(±7 days)
Before discontinuing 
participants from therapy
(Section 7.1), submit the 
Treatment Termination & 
Disease Assessment Termination 
Form.
The Safety Follow-up is not 
needed if the Discontinuation 
Visit occurs ≥30 days after the 
last dose.
Randomization
X
Telephone contact or visit
X
Telephone contact or visit on 
Cycle 1 Day 8 (±3 days) will 
assess for development of early 
toxicity. An unscheduled visit can 
occur at any time if deemed 
necessary by the investigator.
Clinical Procedures/Assessments
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
AEs must be recorded up to 30 days 
after the last dose of study 
intervention.
SAEs must be recorded up to 
90 days after the last dose of study 
intervention, or 30 days after
cessation of study intervention if the 
participant initiates new anticancer 
treatment, whichever comes first.  
Treatment-related SAEs must be 
reported regardless of the time point 
when they occur.
New diagnosis of MDS or AML 
should be reported throughout the 
study including the follow-up phase.
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Study Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 10
11 and 
beyond 
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-up 
Survival 
Follow-
up
Scheduling Window (Days)
-42 to -1
+3
±3 ±3
±3
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose
(+7 
days)
Q9W to 
Week 54, 
then 
Q12W (±7 
days)
Q12W
(±7 days)
Before discontinuing 
participants from therapy
(Section 7.1), submit the 
Treatment Termination & 
Disease Assessment Termination 
Form.
The Safety Follow-up is not 
needed if the Discontinuation 
Visit occurs ≥30 days after the 
last dose.
Full physical examination
X
X
Directed physical 
examination
X
X
X
X
X
X
X
X
X
Perform as clinically indicated.
Vital signs, height, and 
weight
X
X
X
X
X
X
X
X
X
X
Height at screening only
Measure vital signs (temperature, 
blood pressure, heart rate, and 
respiratory rate) after 5 min rest, 
before study intervention 
administration. 
12-lead ECG
X
ECOG performance status
X
X
X
X
X
X
X
X
X
X
Obtain within 7 days of 
randomization. Obtain before
dosing. After Cycle 8, obtain at 
every other cycle (Cycle 10, 12, 
14, etc.)
Subsequent anticancer 
therapy status
X
X
X
Safety Follow-up Visit must take 
place before the start of new 
therapy.
Survival status
X
Updated survival status may be 
requested by the Sponsor at any 
time during the study.
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Study Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 10
11 and 
beyond 
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-up 
Survival 
Follow-
up
Scheduling Window (Days)
-42 to -1
+3
±3 ±3
±3
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose
(+7 
days)
Q9W to 
Week 54, 
then 
Q12W (±7 
days)
Q12W
(±7 days)
Before discontinuing 
participants from therapy
(Section 7.1), submit the 
Treatment Termination & 
Disease Assessment Termination 
Form.
The Safety Follow-up is not 
needed if the Discontinuation 
Visit occurs ≥30 days after the 
last dose.
Study Intervention Administration
Begin within 3 days of 
randomization
Olaparib dispensed (only 
participants randomized to 
pembrolizumab + olaparib)
X
X
X
X
X
X
X
X
Continuous dose of 300 mg BID.
Olaparib container returned 
(only participants 
randomized to 
pembrolizumab + olaparib)
X
X
X
X
X
X
X
X
Pembrolizumab (only 
participants randomized to 
pembrolizumab + olaparib)
X
X
X
X
X
X
X
X
200 mg IV Q3W on Day 1 of each 
cycle, up to a maximum of 
35 cycles
Abiraterone acetate + 
prednisone or prednisolone
dispensed (only 
participants receiving 
abiraterone acetate + 
prednisone or 
prednisolone)
X
X
X
X
X
X
X
X
Continuous dose of 1000 mg 
abiraterone acetate QD + 5 mg 
prednisone or prednisolone BID.
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Study Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 10
11 and 
beyond 
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-up 
Survival 
Follow-
up
Scheduling Window (Days)
-42 to -1
+3
±3 ±3
±3
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose
(+7 
days)
Q9W to 
Week 54, 
then 
Q12W (±7 
days)
Q12W
(±7 days)
Before discontinuing 
participants from therapy
(Section 7.1), submit the 
Treatment Termination & 
Disease Assessment Termination 
Form.
The Safety Follow-up is not 
needed if the Discontinuation 
Visit occurs ≥30 days after the 
last dose.
Abiraterone acetate and 
prednisone or prednisolone 
containers returned (only 
participants receiving 
abiraterone acetate + 
prednisone or 
prednisolone)
X
X
X
X
X
X
X
X
Enzalutamide dispensed
(only participants receiving 
enzalutamide) 
X
X
X
X
X
X
X
X
Continuous dose of 160 mg QD.
Enzalutamide container 
returned (only participants 
receiving enzalutamide)
X
X
X
X
X
X
X
X
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Study Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 10
11 and 
beyond 
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-up 
Survival 
Follow-
up
Scheduling Window (Days)
-42 to -1
+3
±3 ±3
±3
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose
(+7 
days)
Q9W to 
Week 54, 
then 
Q12W (±7 
days)
Q12W
(±7 days)
Before discontinuing 
participants from therapy
(Section 7.1), submit the 
Treatment Termination & 
Disease Assessment Termination 
Form.
The Safety Follow-up is not 
needed if the Discontinuation 
Visit occurs ≥30 days after the 
last dose.
Laboratory Procedures/Assessments (CENTRAL laboratory)
Screening laboratory tests are to 
be performed within 10 days of 
the first dose of study 
intervention.
After Cycle 1, predose 
laboratory tests may be 
performed up to 72 hours 
predose. Unresolved abnormal 
results associated with 
drug-related AEs should be 
followed until resolution. 
PT or INR and PTT/aPTT
X
PT or INR and aPTT/PTT should 
be monitored more closely in 
participants receiving 
anticoagulants during treatment 
and the Safety Follow-up period.
Complete blood count with 
differential
X
X
X
X
X
X
X
X
X
X
Comprehensive chemistry 
panel
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Urinalysis and thyroid function 
tests every other cycle (Cycle 8, 
10, 12, etc.)
T3 or FT3, FT4, and TSH
X
X
X
X
X
X
X
X
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Study Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 10
11 and 
beyond 
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-up 
Survival 
Follow-
up
Scheduling Window (Days)
-42 to -1
+3
±3 ±3
±3
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose
(+7 
days)
Q9W to 
Week 54, 
then 
Q12W (±7 
days)
Q12W
(±7 days)
Before discontinuing 
participants from therapy
(Section 7.1), submit the 
Treatment Termination & 
Disease Assessment Termination 
Form.
The Safety Follow-up is not 
needed if the Discontinuation 
Visit occurs ≥30 days after the 
last dose.
Testosterone
X
X
X
X
X
Testosterone is determined every 
4 cycles.
Procedures/Assessments: analysis performed CENTRALLY
The schedules of scans, PSA 
determinations, and CTC counts 
are calculated from the date of 
randomization and should not be 
adjusted for dose delays or cycle 
starts.
PD-L1, PSA, and CTC results 
are not reported to sites, to 
prevent early withdrawal of 
participants from study 
intervention.
Efficacy Measurements
PSA (central laboratory)
X
Q3W (± 7 days) from randomization
X
X
X
Screening PSA is determined 
within 10 days before
randomization. The window for 
other PSA sample collections is 
±7 days.
Only during screening, if the 
central laboratory PSA result is not 
expected before randomization, the 
investigator may perform this test 
locally and use the result to 
determine eligibility. The local 
laboratory may not be used in lieu 
of the central laboratory.
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Study Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 10
11 and 
beyond 
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-up 
Survival 
Follow-
up
Scheduling Window (Days)
-42 to -1
+3
±3 ±3
±3
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose
(+7 
days)
Q9W to 
Week 54, 
then 
Q12W (±7 
days)
Q12W
(±7 days)
Before discontinuing 
participants from therapy
(Section 7.1), submit the 
Treatment Termination & 
Disease Assessment Termination 
Form.
The Safety Follow-up is not 
needed if the Discontinuation 
Visit occurs ≥30 days after the 
last dose.
Tumor imaging (CT/MRI) 
and bone scan
X
Q9W (± 7 days) through Week 54, then 
Q12W (± 7 days) thereafter
X
X
Baseline CT/MRI (chest/abdomen/
pelvis) and whole-body bone scan 
must be performed within 28 days 
before randomization.
Participants who discontinue study 
intervention without BICR-
verified radiographic disease 
progression should continue to be 
monitored for disease status by 
radiologic imaging (CT/MRI and 
bone scans) until the start of new 
anticancer treatment, verified
disease progression, death, or the 
end of the study, whichever occurs 
first. If a scan was obtained within 
4 weeks before discontinuation, 
another scan at discontinuation is 
not mandatory.
Blood for CTC count 
(central laboratory)  
X
W9 (± 7 days) and W18 (± 7 days) from 
randomization
X
Collect predose on Cycle 1 Day 1. 
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Study Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 10
11 and 
beyond 
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-up 
Survival 
Follow-
up
Scheduling Window (Days)
-42 to -1
+3
±3 ±3
±3
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose
(+7 
days)
Q9W to 
Week 54, 
then 
Q12W (±7 
days)
Q12W
(±7 days)
Before discontinuing 
participants from therapy
(Section 7.1), submit the 
Treatment Termination & 
Disease Assessment Termination 
Form.
The Safety Follow-up is not 
needed if the Discontinuation 
Visit occurs ≥30 days after the 
last dose.
Tumor Tissue Collection/Correlative and Biomarker Studies (CENTRAL laboratory)
Samples should be collected 
based on the date of 
randomization, and the timing of 
assessments should not be 
adjusted for dose delays or cycle 
starts.
Tumor tissue collection 
(recent biopsy)
X
Obtained within ≤1 year of 
screening. Site required to submit 
an SCF for archived tissue >1 year.
Blood for genetic analyses 
X
Collect predose.
Blood for RNA analyses
X
W3 (±7 days) and W12 (±7 days) from 
randomization
X
Collect predose on days when 
study intervention is given. 
Blood for plasma 
biomarker analyses
X
X
Blood for serum biomarker 
analyses
X
X
Blood for ctDNA analysis
X
W9 (± 7 days) and W18 (± 7 days) from 
randomization 
X
Collect predose on days when 
study intervention is given.
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02-MAY-2022
Study Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 10
11 and 
beyond 
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-up 
Survival 
Follow-
up
Scheduling Window (Days)
-42 to -1
+3
±3 ±3
±3
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose
(+7 
days)
Q9W to 
Week 54, 
then 
Q12W (±7 
days)
Q12W
(±7 days)
Before discontinuing 
participants from therapy
(Section 7.1), submit the 
Treatment Termination & 
Disease Assessment Termination 
Form.
The Safety Follow-up is not 
needed if the Discontinuation 
Visit occurs ≥30 days after the 
last dose.
Participant-reported Outcomes
FACT-P
EQ-5D-5L
X
X
X
X
X
X
X
X
X
X
Every effort should be made to 
administer PRO questionnaires 
before dosing and before other 
assessments and procedures.
To be completed at site before
study intervention on Day 1 of 
every cycle through Cycle 8, then 
at every 2 cycles through Cycle 24, 
then at every 4 cycles thereafter 
until discontinuation, and at Safety 
Follow-up Visit.
BPI-SF
Analgesic Log
X
Q3W until W24, then Q6W until W72, and 
thereafter Q12W 
X
X
To be completed at home daily for 
any 7 consecutive days beginning 
within 10 days before
randomization.  
At each time point after 
randomization, to be completed for 
7 consecutive days (eg, Days 15 to 
21). A 3-day window will be 
permitted to begin completion of 
the BPI-SF and Analgesic Log 
before the 7 expected days.
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Study Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 to 10
11 and 
beyond 
End of 
Treatment 
Visit
Safety 
Follow-
up
Efficacy 
Follow-up 
Survival 
Follow-
up
Scheduling Window (Days)
-42 to -1
+3
±3 ±3
±3
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose
(+7 
days)
Q9W to 
Week 54, 
then 
Q12W (±7 
days)
Q12W
(±7 days)
Before discontinuing 
participants from therapy
(Section 7.1), submit the 
Treatment Termination & 
Disease Assessment Termination 
Form.
The Safety Follow-up is not 
needed if the Discontinuation 
Visit occurs ≥30 days after the 
last dose.
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; BICR=blinded independent central review; BID=twice daily; BPI-SF=Brief Pain Inventory-Short 
Form; CT=computed tomography; CTC=circulating tumor cell; ctDNA=circulating tumor deoxyribonucleic acid; discon.=discontinuation; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; EQ-5D-5L=EuroQoL 5-Dimension 5-Level Health State Utility Index; FACT-P=Functional Assessment of Cancer Therapy-
Prostate; FT3=free triiodothyronine; FT4=free thyroxine; HIV=human immunodeficiency virus; ICF=informed consent form; INR=international normalized ratio; 
IV=intravenous; MRI=magnetic resonance imaging; PD-L1=programmed cell death ligand 1; PRO=patient-reported outcome; PSA=prostate-specific antigen; PT=prothrombin 
time; PTT=partial thromboplastin time; Q3W=every 3 weeks; Q6W=every 6 weeks; Q9W=every 9 weeks; Q12W=every 12 weeks; QD=once daily; RNA=ribonucleic acid; 
SAE=serious adverse event; SCF=Sponsor Communication Form; SSRE=symptomatic skeletal-related event; T3=total triiodothyronine; TSH=thyroid-stimulating hormone; 
W=week.
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02-MAY-2022
1.3.2
Second Course Phase 
NOTE: As of Amendment 06, the study will be stopped due to futility and second course treatment is not an option for 
participants. There are currently no participants in the Second Course Phase.
Study Period
Treatment Cycles (21-day 
cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
1
2
3
4
5 and 
beyond
Discon.
Safety 
Follow-
up
Efficacy 
Follow-
up
Survival 
Follow-up
Scheduling Window (Days)
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose 
(+7 
days)
Q12W
(±7 
days)
Q12W
(±7 days)
The Safety Follow-up Visit is not needed if the 
Discontinuation Visit occurs ≥30 days after the last 
dose.
Administrative Procedures
Eligibility criteria
X
Concomitant medication review
X
X
X
X
X
X
X
Report new medications started 28 days before first 
retreatment dose and up to 30 days after last dose of 
study intervention. All medications related to reportable 
SAEs and ECIs should be recorded.
Clinical Procedures/Assessments
AE monitoring
X
X
X
X
X
X
X
X
AEs must be recorded up to 30 days after the last dose 
of study intervention. 
SAEs must be recorded up to 90 days after the last dose 
of study intervention or 30 days after cessation of study 
intervention if the participant initiates new anticancer 
treatment, whichever comes first. Treatment-related 
SAEs must be reported regardless of the time point 
when they occur.
New diagnosis of MDS or AML should be reported 
throughout the study including the follow-up phase.
Full physical examination
X
X
Directed physical examination
X
X
X
X
X
Perform as clinically indicated.
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Study Period
Treatment Cycles (21-day 
cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
1
2
3
4
5 and 
beyond
Discon.
Safety 
Follow-
up
Efficacy 
Follow-
up
Survival 
Follow-up
Scheduling Window (Days)
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose 
(+7 
days)
Q12W
(±7 
days)
Q12W
(±7 days)
The Safety Follow-up Visit is not needed if the 
Discontinuation Visit occurs ≥30 days after the last 
dose.
Vital signs and weight
X
X
X
X
X
X
Measure vital signs (temperature, blood pressure, heart 
rate, and respiratory rate) after 5 min rest, before study 
intervention administration. 
ECOG performance status
X
X
X
X
X
X
After Cycle 8, obtain at every other cycle.
Subsequent anticancer therapy status
X
X
X
The Safety Follow-up Visit must take place before the 
start of new therapy.
Survival status
X
Updated survival status may be requested by the 
Sponsor at any time during the study.
Study Intervention Administration
Pembrolizumab
X
X
X
X
X
200 mg IV Q3W
Olaparib dispensed 
X
X
X
X
X
Treatment with olaparib may be continued at the 
investigator’s discretion.
Olaparib container returned
X
X
X
X
X
Laboratory Procedures/Assessments (CENTRAL laboratory)
Perform within 10 days before the participant’s 
receiving the first retreatment infusion.
After Cycle 1, predose laboratory tests may be 
performed up to 72 hours predose. Unresolved 
abnormal results associated with drug-related AEs 
should be followed until resolution. 
PT or INR and PTT/aPTT
X
PT or INR and aPTT/PTT should be monitored more 
closely in participants receiving anticoagulants during 
study intervention and the Safety Follow-up period.
Complete blood count with differential
X
X
X
X
X
X
X
Comprehensive chemistry panel
X
X
X
X
X
X
X
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Study Period
Treatment Cycles (21-day 
cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
1
2
3
4
5 and 
beyond
Discon.
Safety 
Follow-
up
Efficacy 
Follow-
up
Survival 
Follow-up
Scheduling Window (Days)
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose 
(+7 
days)
Q12W
(±7 
days)
Q12W
(±7 days)
The Safety Follow-up Visit is not needed if the 
Discontinuation Visit occurs ≥30 days after the last 
dose.
Urinalysis
X
X
X
X
X
Urinalysis and thyroid function tests are performed 
every other cycle (Cycle 1, 3, 5, 7, etc.).
T3 or FT3, FT4, and TSH
X
X
X
X
X
Testosterone
X
X
X
X
Testosterone is determined every 4 cycles.
Procedures/Assessments
The schedules of scans and PSA determinations are 
calculated from the date of the first retreatment 
infusion. The timing of assessments should not be 
adjusted for dose delays or cycle starts.
Efficacy Measurements
PSA (central laboratory)
X
Q3W (±7 days) from 
first retreatment infusion
X
X
X
Collect samples predose on days when study 
intervention is given.
Tumor imaging (CT/MRI and bone scan)
(evaluated locally)
X
Week 9 (±7 days) after 
restart of study 
intervention, then Q12W 
(±7 days) thereafter
X
X
CT/MRI (chest/abdomen/pelvis) and whole-body bone 
scans must be performed within 28 days before the 
participant’s receiving the first retreatment infusion. If a 
scan was obtained within 4 weeks before study 
intervention discontinuation, another scan at 
discontinuation is not mandatory. Participants who 
discontinue treatment without documented disease 
progression should continue to be monitored for disease 
status by radiologic imaging (CT/MRI and bone scans) 
until the start of new anticancer treatment, documented 
disease progression, death, or the end of the study, 
whichever occurs first.
Images will be submitted to the iCRO.
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Study Period
Treatment Cycles (21-day 
cycles)
End of 
Treatment
Posttreatment Visits
Notes
Treatment Cycle/Title
1
2
3
4
5 and 
beyond
Discon.
Safety 
Follow-
up
Efficacy 
Follow-
up
Survival 
Follow-up
Scheduling Window (Days)
±3
±3
±3
±3
At time of 
discon.
30 days 
from 
last 
dose 
(+7 
days)
Q12W
(±7 
days)
Q12W
(±7 days)
The Safety Follow-up Visit is not needed if the 
Discontinuation Visit occurs ≥30 days after the last 
dose.
Abbreviations: AE=adverse event; AML=acute myeloid leukemia; aPTT=activated partial thromboplastin time; CT=computed tomography; discon.=discontinuation; ECI=event of 
clinical interest; ECOG=Eastern Cooperative Oncology Group; FT3=free triiodothyronine; FT4=free thyroxine; iCRO=imaging contract research organization; INR=international 
normalized ratio; IV=intravenous; MDS=myelodysplastic syndrome; MRI=magnetic resonance imaging; PSA=prostate-specific antigen; PT=prothrombin time; PTT=partial 
thromboplastin time; Q3W=every 3 weeks; Q12W=every 12 weeks; SAE=serious adverse event; T3=total triiodothyronine; TSH=thyroid-stimulating hormone.
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2
INTRODUCTION
Prostate cancer represents the second most common malignancy diagnosed in men 
worldwide, with an incidence of over 1,000,000 cases and >300,000 deaths annually [Ferlay, 
J., et al 2015]. In the US, approximately 1 in every 9 men will be diagnosed with prostate 
cancer in his lifetime [Siegel, R. L., et al 2018].
While many men diagnosed with locally confined disease may be treated definitively with 
radiation or surgery, those who go on to develop or are diagnosed with metastatic prostate 
cancer, an incurable entity, are typically treated first with androgen deprivation therapy 
(ADT), usually with a gonadotropin-releasing hormone (GnRH) agonist or antagonist that 
results in suppression of testosterone production in the testes. This alone often succeeds in 
controlling disease, often for many years. When prostate cancer progresses despite ADT 
alone, it is called castration-resistant. The disease at this point is known as mCRPC, and 
systemic therapies must be added to re-establish control of disease. A number of important 
systemic therapies for mCRPC now compose the current therapeutic landscape. These 
include the next-generation hormonal agents (NHAs), abiraterone acetate and enzalutamide, 
and the taxanes, docetaxel and cabazitaxel.
Abiraterone acetate is an androgen biosynthesis inhibitor that inhibits 17α hydroxylase/C17,
20-lyase (cytochrome P450 [CYP]17). This enzyme is expressed in testicular, adrenal, and 
prostatic tumor tissues and is required for androgen biosynthesis. The efficacy and safety of 
abiraterone acetate with prednisone was established in 2 Phase 3 randomized,
placebo-controlled clinical studies [Ryan, C. J., et al 2013] [Fizazi, K., et al 2012] [Ryan, C. 
J., et al 2015].
Enzalutamide is an endocrine agent currently used for treatment of mCRPC. Enzalutamide 
treatment was studied in randomized clinical trials in participants with mCRPC before 
chemotherapy and found to result in superior OS versus control therapy (placebo and 
prednisone, respectively) [Beer, T. M., et al 2014].
Docetaxel became the first systemic therapy to improve survival for men with mCRPC. A
randomized study demonstrated superior survival of median 18.9 months versus 16.5 for 
mitoxantrone [Tannock, I, et al 2004]. Cabazitaxel, a second taxane, was studied versus 
mitoxantrone in participants who had received docetaxel, and it too was found to be 
associated with superior survival (median 15.1 months versus 12.7 months for mitoxantrone) 
[de Bono, J. S., et al 2010]. However, cabazitaxel can be a toxic therapy, and 4.9% of 
participants died of various treatment-related causes, such as treatment-related neutropenia 
and treatment-related diarrhea. The cabazitaxel label contains a black box warning regarding 
risks from neutropenia, severe hypersensitivity, and other label warnings and precautions 
pertaining to diarrhea, renal failure, hepatic impairment, and prohibitive risk in patients ≥65 
years of age. Thus, an unmet need remains for patients after treatment in the mCRPC setting 
with targeted endocrine therapy and docetaxel.
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2.1
Study Rationale
Interim results from Cohort A in KEYNOTE-365 (data cutoff 27-JUL-2018), which 
evaluated the population intended for the current study, suggested promising clinical efficacy 
and potential synergistic effects in participants with mCRPC, as evidenced by a confirmed 
biochemical response (≥50% reduction in PSA from baseline) in 12.8% (95% confidence 
interval [CI] 4.3%, 27.4%) of the 39 participants with elevated PSA at baseline. In addition, 
over 50% of participants had a reduction in PSA from baseline. An OR (CR or PR) per 
RECIST 1.1 was observed in 7.1% (95% CI 0.9%, 23.5%) of the 28 participants with 
measurable disease at baseline, including 2 participants with PR and none with CR. Disease 
control rate (DCR) for all participants in this cohort was 56.1% (95% CI 39.7%, 71.5%). 
Notably, none of these participants had a known or suspected deleterious mutation in genes 
associated with HRR.
These results provide support for further evaluation of the combination of pembrolizumab 
and olaparib in patients with mCRPC unselected for HRR gene mutation.
Human cancers show genomic instability and an increased mutation rate due to underlying 
defects in DNA repair. These deficiencies render cancer cells more dependent on the 
remaining DNA repair pathways, and targeting these pathways is expected to have much 
greater impact on the survival of tumor cells than on normal cells. This study will evaluate 
the antitumor effect of olaparib, a potent polyadenosine 5' diphosphoribose (polyADP ribose) 
polymerization (PARP) inhibitor, in combination with pembrolizumab for the treatment of
mCRPC regardless of deficiencies in the HRR pathway.  
Limited data are available for patients with mCRPC who have not responded to an NHA and 
at least 1 taxane-based chemotherapy. In general, responses to treatment decrease with more 
lines of prior therapy, while differences in baseline prognostic factors still confer 
heterogeneity in response as measured by rPFS and OS. In 260 patients with mCRPC treated 
with abiraterone acetate, enzalutamide, or cabazitaxel, median OS was 10 to 15 months 
(average 11 months) for third-line treatment and 4 to 7 months (average 5 months) for 
fourth-line treatment [Caffo, O., et al 2015].  
Accordingly, there remains a high unmet medical need for an efficacious, well tolerated 
therapy for patients with mCRPC, including those who have not responded to an NHA and 
chemotherapy.
This clinical study will study the combination of the PARP inhibitor olaparib and 
pembrolizumab in the treatment of participants with mCRPC who have failed to respond to 
either abiraterone acetate or enzalutamide (but not both) and to chemotherapy. Participants 
will be randomly assigned in a 2:1 ratio to treatment with either pembrolizumab and olaparib 
or with abiraterone acetate (if previously treated with enzalutamide) or enzalutamide (if 
previously treated with abiraterone acetate).
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2.2
Background
Pembrolizumab
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies. Keytruda® (pembrolizumab) is indicated for the treatment of patients 
across a number of indications. For more details on specific indications, refer to the 
Investigator’s Brochure (IB).
Olaparib
Olaparib (AZD2281; KU-0059436) is a potent PARP inhibitor (PARP1, 2, and 3) that is 
being developed as an oral anticancer therapy, both as monotherapy (including maintenance) 
and for combination with chemotherapy and other anticancer agents.
PARP inhibition is a novel approach to targeting tumors with deficient DNA repair 
mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). 
Inhibiting PARPs leads to the persistence of SSBs, which are then converted to the more 
serious DNA double strand breaks (DSBs) during DNA replication. During cell division, 
DSBs can be efficiently repaired in normal cells by HRR. Tumors with homologous repair 
deficiency (HRD), such as ovarian cancers in patients with breast cancer susceptibility gene 
1/2 (BRCA1/2) mutations (BRCAm), 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 chemotherapy 
regimens.
Olaparib traps the inactive form of PARP on DNA at sites of SSBs, thereby preventing their 
repair [Helleday, T. 2011] [Murai, J., et al 2012]. Olaparib has demonstrated efficacy in 
ovarian, prostate, and pancreatic tumors with BRCA1 and BRCA2 mutations and has shown 
proof of concept in tumors with ataxia-telangiectasia mutated (ATM) and other indicators of 
HRD. The specificity of olaparib for binding PARP at the replication fork during DNA 
replication is believed to have applicability to tumors associated with HRR mutations.
Refer to the IB and approved labeling for detailed background information on olaparib.
2.2.1
Pharmaceutical and Therapeutic Background
Inhibition of PD-1 as a Target for Cancer Therapy
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
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prognosis in various malignancies. In particular, the presence of cluster of differentiation 
(CD)8+ T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) 
correlates with improved prognosis and long-term survival in solid malignancies, such as 
ovarian, colorectal, and pancreatic cancer, hepatocellular carcinoma, malignant melanoma, 
and renal cell carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and 
reinfused, inducing durable objective tumor responses in cancers such as melanoma [Dudley, 
M. E., et al 2005] [Hunder, N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to CD28 and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling on engagement of its ligands (PD-L1 and/or PD-L2) [Greenwald, R. J., et al 2005] 
[Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for binding 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif and an immunoreceptor tyrosine-based 
switch motif. After T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and 
SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase 
C-theta (PKCθ), and zeta chain-associated protein kinase (ZAP70), which are involved in the 
CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 2004] 
[Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
[Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in mCRPC.
Inhibition of PARP as a Target for Cancer Therapy
PARP1 and PARP2 are zinc-finger DNA-binding enzymes that play a critical role in DNA 
repair [Ame, J. C., et al 2004] by sensing DNA damage and converting it to intracellular 
signals that activate the base excision repair and SSB repair pathways. When a break in DNA 
occurs, PARP enzymes are recruited to and bind at the end of the broken DNA strands, 
initiating their enzymatic activity. PARP subsequently catalyzes the addition of long 
ADP-ribose polymers to several other proteins associated with chromatin (eg, PARP, 
histones, DNA repair proteins), resulting in chromatin relaxation, rapid recruitment of DNA 
repair proteins, and efficient repair of the break.
Under normal conditions, HRR is the preferred pathway for repairing DNA damage, as it is 
associated with a lower rate of errors compared with other forms of DNA repair [Prakash, R., 
et al 2015]. During DNA replication (S phase), pre-existing or chemotherapy-induced SSBs 
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are converted to DSBs if not adequately repaired by intracellular mechanisms [Fong, Peter 
C., et al 2009], such as HRR. Cells unable to perform HRR (eg, due to inactivation of genes 
required for homologous recombination, such as BRCA1 or BRCA2) are more likely to use 
the error-prone nonhomologous end-joining (NHEJ) or alternative (alt)-NHEJ pathways to 
repair these DSBs, and risk accumulating multiple lesions or loss of heterozygosity (LOH) 
due to an increase in deletions and accompanying genomic instability. Over time, 
accumulation of excessive DNA errors in combination with inability to complete S phase (ie, 
because of stalled replication forks due to presence of a PARP inhibitor), leads to cell death, 
showing that PARP inhibition is synthetic lethal in the context of BRCA mutations [Farmer, 
H., et al 2005] [Bryant, H. E., et al 2005]. Cells without SSBs or with intact HRR, such as 
those in somatic tissue, replicate normally in the presence of a PARP inhibitor, thereby 
minimizing toxicity.
Homologous Recombination Repair in Solid Tumors
Defects in DNA repair drive the genesis of several solid tumors, most notably ovarian and 
pancreatic. DNA strand breaks occur both as part of the recombination and replication 
process and after intercalating chemotherapy or DNA-damaging radiotherapy. HRR defective 
tumors are intrinsically sensitive to PARP inhibitors, both in tumor models in vivo 
[Rottenberg, S., et al 2008] [Hay, T., et al 2009] and in the clinic [Fong, Peter C., et al 2009] 
[Tutt, A., et al 2010] [Mateo, J., et al 2015] [Kaufman, B., et al 2015]. The main mechanism 
of action of olaparib results from trapping of inactive PARP on SSBs preventing their repair 
[Helleday, T. 2011] [Murai, J., et al 2012] and excessive conversion of SSBs to the more 
serious DSBs, which are lethal or results in incomplete/inaccurate repair of the damaged
strands, leading to LOH with subsequent aberrant protein translation and function. 
Normally, the process of HRR corrects DSBs using proteins such as BRCA1 and BRCA2. 
However, the HRR armamentarium includes proteins coded by at least 13 other genes, 
including ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, 
RAD51B, RAD51C, RAD51D, and RAD54L. For example, the protein coded by the ATM
gene also is involved in the repair of DSB. ATM is activated by DSB and phosphorylates 
diverse cellular proteins (eg, mediator of DNA damage checkpoint 1, checkpoint kinase 2) 
leading to cell cycle arrest, activates the tumor suppressor p53, contributes to chromatin 
relaxation and remodeling, and activates nuclear factor kappa light chain enhancer of 
activated B-cells (NF-κB). Defective ATM increases the risk of breast, gastrointestinal, lung, 
and lymphoid cancers. Moreover, defective ATM appears to correlate with a poor prognosis; 
however, the resulting risk has not been quantified. 
A small percentage of tumors have loss of function mutations in HRR genes, with BRCA1, 
BRCA2, and ATM the best characterized and most frequently mutated [Watkins, J. A., et al 
2014] [Marquard, A. M., et al 2015] [Choi, M., et al 2016] [Lord, C. J. 2016]. Approximately 
half the HRRm detected are germline mutations [Mateo, J., et al 2015]. While an adverse 
prognostic impact of germline BRCA2 mutations has been described in prostate cancer 
[Castro, E., et al 2015], it is less clear if other germline or somatic HRR gene mutations are 
associated with similar adverse clinical outcomes. To date, HRRm has not been associated 
with specific patient or tumor characteristics.
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Overview of Prostate Cancer
Prostate cancer represents one of the most frequently diagnosed malignancies and is the fifth
leading cause of cancer-related deaths and the second most frequently diagnosed cancer in 
men worldwide [Torre, L. A., et al 2015]. According to the Global Burden of Disease Study 
[Fitzmaurice, C., et al 2018], there were 1.4 million new prostate cancer cases and 381,000 
deaths from the disease globally in 2016. These statistics suggest the great socioeconomic 
burden prostate cancer imposes worldwide. In the US, analysts estimated that there would be 
164,690 new cases of prostate cancer (19% of all new cancer cases in males) and 29,430
deaths caused by prostate cancer (9% of all new cancer deaths in males) in 2018 [Siegel, R. 
L., et al 2018]. Since the advent of PSA screening about 3 decades ago, the prostate cancer 
death rate had been falling until it stabilized between 2013 and 2015 [Negoita, S., et al 2018]. 
However, following the US. Preventive Services Task Force’s recommendation in 2012
against routine PSA-based screening regardless of age, the incidence of late-stage disease has 
increased [Negoita, S., et al 2018]. Furthermore, it is estimated that 1 in 9 men in the US will 
be diagnosed with prostate cancer in his lifetime [Siegel, R. L., et al 2018]. Although 
identifying causes and effects is difficult, this change in the national trend in late-stage 
prostate cancer incidence may portend future increases in the number of men requiring 
treatment for advanced disease. Therefore, there is an urgent need to develop new therapeutic 
strategies, including combination therapies, for prostate cancer.
Unmet Medical Need in Prostate Cancer
Patients with mCRPC have a high unmet medical need. The prognosis for men diagnosed 
with locally confined disease is favorable, and such cases may be treated definitively with 
radiation therapy or surgery [Gray, P. J., et al 2017]. In fact, prostate cancer has been a prime 
example of an indolent cancer, with the majority of men found to have localized disease at 
diagnosis [Loeb, S., et al 2015]. For that reason, in the last decade physicians have 
increasingly adopted active surveillance as a management option for low-risk prostate cancer, 
reflecting the low rate of disease progression and enthusiasm for avoiding harm (eg, 
incontinence and impotence) associated with overtreatment [Loeb, S., et al 2015] [Resnick, 
M. J., et al 2013]. Additionally, metastatic prostate cancer evolves molecularly during 
disease progression and/or therapy through adaptive response, which may result in 
emergence of histologic variants that are biologically more aggressive and resistant to 
therapy [Vlachostergios, P. J., et al 2017].
Androgen signaling mediated through androgen receptors is a critical factor for promotion 
and growth of prostate cancer [Knudsen, K. E. 2010]. Therefore, until 2015 the SOC for 
initial first-line therapy for metastatic prostate cancer (either recurrent or de novo metastatic 
tumors, heretofore called castration-sensitive prostate cancer [CSPC]) was ADT (eg, GnRH 
agonists or antagonists). However, a great stride in treatment of CSPC was made over the last 
few years. Two randomized, controlled studies, Chemohormonal Therapy Versus Androgen 
Ablation Randomized Study for Extensive Disease in Prostate Cancer (CHAARTED 
[Sweeney, C. J., et al 2015]) and Systemic Therapy in Advancing or Metastatic Prostate 
Cancer (STAMPEDE [James, N. D., et al 2017]) demonstrated significant survival benefit 
with the addition of docetaxel to ADT.
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In a 2018 follow-up CHAARTED analysis [Kyriakopoulos, C. E., et al 2018], investigators 
extended the original median duration of follow-up from 28.9 months to 53.7 months and 
confirmed the median OS advantage in the ADT plus docetaxel group with high-volume 
disease (51.2 versus 34.4 months; hazard ratio [HR] 0.72; 95% CI 0.59, 0.89; p=0.0018). In 
the similar comparison in the STAMPEDE study, researchers recommended that docetaxel 
become part of the SOC after a 43-month follow-up found superior results with it against 
ADT in median OS (81 versus 71 months; HR 0.78; 95% CI 0.66, 0.93; p=0.006).
As part of the STAMPEDE study, participants were randomized to receive ADT and 
abiraterone acetate plus prednisolone or ADT alone. Participants in the former arm had a 
significantly higher rate of OS at 3 years (83% versus 76%; HR for death 0.63%; 95% CI 
0.52, 0.76; p<0.001) and significantly fewer treatment failure events (248 versus 535; 
HR 0.29; 95% CI 0.25, 0.34; p<0.001). Findings were similar in the LATITUDE study
[Fizazi, K., et al 2017]. At a planned IA in the LATITUDE study at 30.4 months, there was
significantly longer OS in the group receiving ADT and abiraterone than in the group 
receiving ADT and placebo (not reached versus 34.7 months; HR for death 0.62; 95% CI 
0.51, 0.76; p <0.001) [Fizazi, K., et al 2017] [Sartor, O. 2018].
While these therapies are initially effective, patients with metastatic prostate cancer 
invariably develop a lethal disease stage known as mCRPC and succumb to their disease. 
Though a number of important therapies have been approved since 2004 to treat mCRPC, no 
available guidance recommends appropriate sequencing or combining of these therapies, and 
none is curative.
Despite these recent advances, treatment options for men with mCRPC progressing after 
next-generation (second-generation) hormonal therapy and docetaxel are limited and provide 
only a modest survival benefit. In the TROPIC Phase 3 study [de Bono, J. S., et al 2010], 
investigators compared cabazitaxel, a second-generation semisynthetic tubulin-binding 
taxane, with mitoxantrone (each in combination with prednisone) for mCRPC progressing 
during or after docetaxel-based therapy, and detected a significant improvement in median 
OS in the cabazitaxel group (15.1 months [95% CI 14.1, 16.3] versus 12.7 months [95% CI 
11.6, 13.7]; HR 0.70 [95% CI 0.59, 0.83]; p<0.0001). Also, cabazitaxel maintained its 
antitumor activity after treatment with docetaxel and abiraterone or docetaxel and 
enzalutamide [Pezaro, C. J., et al 2014]. However, cabazitaxel can be a toxic therapy, and 
consequently it is not widely used. Retrospective studies suggest that either abiraterone or 
enzalutamide may be an option; however, previous therapies [Handy, C. E. 2016], potential 
for development of cross-resistance [Zhang, T., et al 2015], and potential for emergence of a 
more aggressive form of prostate cancer after prolonged treatment [Roubaud, G., et al 2017]
must be considered and could be limiting factors. Additionally, consensus guidelines, such as 
those from the National Comprehensive Cancer Network (NCCN) [National Comprehensive 
Cancer Network 2015], recommend that men with mCRPC be encouraged to participate in 
clinical studies. Thus, there remains an unmet medical need for patients with mCRPC and
disease progression after treatment with a next-generation hormonal therapy and/or 
docetaxel-based chemotherapy.
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Preclinical and Clinical Studies
Refer to the pembrolizumab and olaparib IBs for summaries of preclinical and clinical 
experience with pembrolizumab and olaparib, respectively.
Pembrolizumab in mCRPC
Participants with PD-L1 positive mCRPC were treated with pembrolizumab monotherapy in 
the Phase 1b study, KEYNOTE-028 (Cohort E3: advanced [unresectable and/or metastatic] 
prostate adenocarcinoma). The primary endpoint was objective response rate (ORR)
according to RECIST 1.1, determined by investigator review. Twenty-three participants with 
PD-L1 positive mCRPC (defined by PD-L1 expression in >1% of tumor or stromal cells) 
were enrolled and treated with pembrolizumab monotherapy. All received at least 1 prior
antineoplastic therapy, and 17 (73.9%) and 7 (30.4%) received 2 or more or 5 or more lines 
of therapy, respectively. Of the 23 participants, only 1 remained on treatment at the time of 
the last published analysis [Hansen, A. R., et al 2018]. Twenty-one participants (91.3%) had 
1 or more postbaseline PSA determinations; 5 of these participants (23.8%) had a PSA 
decline of ≥50%. There were 4 confirmed PRs according to RECIST 1.1 guidelines, for an 
ORR at the time of 17.4% (95% CI 5.0%, 38.8%). Responses were durable (median duration 
of response [DOR] 13.5 months) and treatment was well tolerated.
Ongoing Clinical Studies in mCRPC
2.2.1.8.1
Pembrolizumab
KEYNOTE-199 was designed to further evaluate the positive signal of activity seen in
KEYNOTE-028, with pembrolizumab monotherapy in participants with mCRPC who had 
previously received docetaxel-based chemotherapy and undergone abiraterone acetate or 
enzalutamide treatment. The ORR was 4.5% in participants with measurable disease by 
RECIST 1.1 and previous chemotherapy (Cohorts 1 and 2) at the IA2 with a data cutoff date 
of 13-OCT-2017. However, the DCR suggested durable responses, regardless of PD-L1 
status, that warranted further evaluation. Additionally, early unpublished results suggest a 
potential survival benefit in the advanced mCRPC population with pembrolizumab 
monotherapy [Graff, J. N., et al 2016].
Graff et al [Graff, J. N., et al 2016] initially enrolled 10 men in 2015 and 2016 with mCRPC 
and evidence of progression on enzalutamide, and subsequently enrolled a total of 28.
Because of failure of immunotherapies (nivolumab and ipilimumab) to produce objective 
responses in mCRPC in previous studies [Topalian, S. L., et al 2012] [Kwon, E. D., et al 
2014], interest in pursuing further studies waned. Nonetheless, after some success, Graff et al 
undertook the Phase 2 study, adding pembrolizumab to enzalutamide in men with mCRPC,
and reported a decline in PSA (primary endpoint) of ≥50% in 5 of 28 participants (17.9%) 
and an ORR (secondary endpoint) in 3 of 12 participants (25.0%) with measurable disease at 
baseline. At the last report, 3 of the 5 responders continued to respond (range 21.9 to 33.8 
months), and median OS was 22.2 months (95% CI 14.7, 28.4 months).
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2.2.1.8.2
Olaparib
Olaparib received an FDA breakthrough therapy designation in January 2016 as a treatment 
for patients with BRCA1/2 or ATM mCRPC who have received prior taxane-based 
chemotherapy and at least 1 targeted hormonal agent (enzalutamide or abiraterone acetate). 
This designation was based on data from the Phase 2 Trial of PARP Inhibition in Prostate 
Cancer (TOPARP-A) that demonstrated an ORR of nearly 90% for olaparib monotherapy in 
a biomarker-defined subgroup of participants with DNA repair defects [Mateo, J., et al 
2015]. Participants were considered biomarker-positive if homozygous deletions or 
deleterious mutations were identified in a gene reported to be involved either in DNA 
damage repair or sensitivity to PARP inhibition. Next-generation sequencing identified 
homozygous deletions, deleterious mutations, or both in DNA repair genes in 16 of 49 
participants (33%). Of these 16 participants, 14 (88%) had a response to olaparib, using a 
composite endpoint of RECIST 1.1 response, a decline in PSA ≥50% from baseline, or a 
reduction of circulating tumor cells (CTCs) from ≥5 cells per 7.5 mL of blood to ≤5 cells per 
7.5 mL of blood. This included all 7 participants with BRCA2 loss and 4 of 5 with ATM
aberrations. Defects in DNA repair genes were noted in 33% of the 49 evaluable participants. 
The overall prevalence of BRCA2 genomic aberrations was 6% in this cohort of unselected 
participants, and 10% of participants were found to have aberrations in the ATM gene. 
Whereas only 3% of participants without tumor genomic DNA repair alterations had a PSA 
response to olaparib, 63% of participants with tumor genomic DNA repair alterations did. In 
TOPARP-A, Grade 3 or 4 AEs were primarily anemia (20%), fatigue (12%), leukopenia 
(6%), thrombocytopenia (4%), and neutropenia (4%). Thirteen of the 50 treated participants 
(26%) required a twice daily dose reduction to 300 mg from the initial dose of 400 mg, and 3 
of these required a second dose reduction to 200 mg. Six percent of participants permanently 
discontinued olaparib because of AEs. The average delivered dose intensity was 87%.
The impressive response rate of 88% in biomarker-positive mCRPC is being further 
evaluated in the PROfound study (NCT02987543), a randomized Phase 3 study evaluating 
olaparib in participants with mCRPC and a deleterious homologous recombination DNA 
repair (HRR) aberration. The study is evaluating olaparib versus abiraterone acetate or 
enzalutamide (physician’s choice) in participants whose disease progressed when they were 
treated with a new hormonal agent. Participants are to be randomized 2:1 to olaparib or to 
enzalutamide or abiraterone, stratified based on tumor aberration (Cohort A with mutations 
in BRCA1, BRCA2, or ATM versus Cohort B with 1 or more of 12 other genes with 
aberrations). The primary endpoint of the study is rPFS in Cohort A, using RECIST 1.1 (soft 
tissue) and PCWG3 (bone) criteria. Key secondary efficacy endpoints include confirmed 
ORR, TTPP, OS (all Cohort A), and rPFS (both cohorts).
Additionally, olaparib as a treatment of mCRPC has been evaluated in combination with 
abiraterone in a randomized, double-blind, placebo-controlled Phase 2 study [Clarke, N., et al 
2018]. Investigators randomized 142 participants to olaparib and abiraterone (N=71) or 
placebo and abiraterone (N=71). They found a difference of 5.6 months in the median rPFS 
(olaparib group: rPFS 13.8 months; 95% CI 10.8 to 20.4 months; placebo group: rPFS, 
8.2 months; 95% CI 5.5 to 9.7 months) and observed an HR of 0.65 (95% CI 0.44 to 0.97; 
p=0.034), regardless of HRR mutation status. AEs of Grade 3 or higher were more frequent 
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in the olaparib group, affecting almost twice as many participants as in the placebo group (38
[54%] versus 20 [28%]), and included anemia (15 [21%] versus 0), pneumonia 
(4 [6%] versus 3 [4%]), and myocardial infarction (4 [6%] versus 0). Serious adverse events 
(SAEs) were reported by 24 participants (34%) receiving olaparib (7 events were related to 
treatment) and 13 participants (18%) receiving placebo (1 was related to treatment). One 
treatment-related death (attributed to pneumonitis) occurred in the olaparib group. A 
confirmatory Phase 3 study is under way.
For a summary of ongoing clinical study data for olaparib, refer to the IB.
2.2.2
Information on Other Study-related Therapy
The targeted endocrine therapies, abiraterone acetate and enzalutamide, are potent, orally 
available treatment options with a favorable tolerability profile that have replaced docetaxel 
as preferred first-line therapy for mCRPC [Sartor, O. 2018]. Abiraterone acetate and 
enzalutamide were investigated in randomized clinical studies in participants with mCRPC 
before chemotherapy and were found to result in superior OS versus control therapies 
(placebo and prednisone, respectively) and prolonged time to chemotherapy initiation [Ryan, 
C. J., et al 2013] [Beer, T. M., et al 2014]. Median OS was approximately 3 years with early 
initiation of abiraterone acetate or enzalutamide treatment [Ryan, C. J., et al 2013] [Beer, T. 
M., et al 2014], but this is still a greatly reduced life expectancy compared with
approximately 15 years for age-matched men (approximately 70 years of age) in the general 
US population (https://www.socialsecurity.gov/OACT/population/longevity.html). Once 
patients with mCRPC have failed to respond to abiraterone acetate or enzalutamide, the 
benefit from approved therapeutic options appears to be substantially diminished, and no 
currently approved agent has been developed for treatment of mCRPC after an NHA and 1 or 
more subsequent lines of therapy.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Pembrolizumab has been administered to a large number of cancer patients with a well 
characterized safety profile and has received regulatory approval for multiple malignancies.
Overall, pembrolizumab is well tolerated at doses up to 10 mg/kg every 2 weeks.
Pembrolizumab has also demonstrated anticancer clinical activity and efficacy in a broad 
range of cancer indications (refer to the current pembrolizumab IB).
Single-agent olaparib has been registered in the US for treatment of deleterious or suspected 
deleterious germline BRCA-mutated advanced ovarian cancer in patients who have received 
3 or more prior lines of chemotherapy for maintenance treatment of recurrent ovarian cancer 
and for deleterious or suspected deleterious germline BRCA-mutated, HER-2 negative 
metastatic breast cancer after prior chemotherapy.
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Preliminary results from Cohort A of KEYNOTE-365 (Section 2.1), in which participants 
have received a combination of pembrolizumab and olaparib show a DCR of 56.1%. In this 
cohort, >50% of participants had a reduction in PSA from baseline. Twenty-eight of 
41 participants (68.3%) experienced a Grade 3 to 5 AE, and 23 of 41 (56.1%) experienced 
SAEs.
Abiraterone acetate and enzalutamide have been approved by regulatory agencies globally 
for treatment of mCRPC and have been recommended for treatment of mCRPC in the 
guidelines of the NCCN and the European Society for Medical Oncology (ESMO) [Parker, 
C., et al 2015].
NOTE: Based on the data from an IA of safety and efficacy for KEYLYNK-010 (data cutoff 
18-JAN-2022), the eDMC recommended stopping the study for futility because it was 
extremely unlikely that the efficacy boundary for study success would be reached at the next 
(final) analysis. In addition, the eDMC indicated that continuing the trial raised the risk of 
undue toxicities (Grade 3 to 5 AEs and drug-related SAEs) to participants receiving 
investigational therapy which were greater in the investigational arm compared with control. 
Based on these data and the recommendation of the eDMC, the study was unblinded (as of 
11-MAR-2022). The prespecified final analysis of the study described in the statistical 
analysis plan (SAP) will not be performed. 
Selected analyses of safety endpoints will be performed at the end of the study. There will be 
no further analyses of efficacy and PRO endpoints.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In men with mCRPC, unselected for homologous recombination repair (HRR) gene 
mutations, whose disease has progressed during prior NHA treatment and chemotherapy:
NOTE: As of Amendment 06, participants who are still on study treatment and deriving 
clinical benefit will no longer have tumor response assessments by BICR. However, local 
tumor imaging assessments should continue per SOC schedule. In addition, ePRO
assessments will no longer be performed and biomarker samples will no longer be collected. 
Updated analyses are described in Section 9.
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Primary Objectives
Primary Endpoints

To compare pembrolizumab plus olaparib 
to abiraterone acetate or enzalutamide
with respect to overall survival (OS).

Hypothesis 1: The combination of 
pembrolizumab plus olaparib is superior 
to abiraterone acetate or enzalutamide 
with respect to OS.

OS: the time from randomization to 
death due to any cause.

To compare pembrolizumab plus olaparib 
to abiraterone acetate or enzalutamide 
with respect to radiographic 
progression-free survival (rPFS) per 
Prostate Cancer Working Group 
(PCWG)-modified Response Evaluation 
Criteria in Solid Tumors Version 1.1 
(RECIST 1.1) as assessed by blinded 
independent central review (BICR).

Hypothesis 2: The combination of 
pembrolizumab plus olaparib is superior 
to abiraterone acetate or enzalutamide 
with respect to rPFS per PCWG-modified 
RECIST 1.1 as assessed by BICR.

rPFS: the time from randomization to 
radiographic progression or death due to 
any cause, whichever occurs first.
Secondary Objectives
Secondary Endpoints

To compare pembrolizumab plus olaparib 
to abiraterone acetate or enzalutamide 
with respect to time to initiation of the 
first subsequent anticancer therapy 
(TFST).

Hypothesis 3: The combination of 
pembrolizumab plus olaparib is superior 
to abiraterone acetate or enzalutamide 
with respect to TFST.

TFST: the time from randomization to 
initiation of the first subsequent 
anticancer therapy or death, whichever 
occurs first.

To evaluate pembrolizumab plus olaparib 
versus abiraterone acetate or 
enzalutamide with respect to the 
objective response rate (ORR) and 
duration of response (DOR) per 
PCWG-modified RECIST 1.1 as assessed 
by BICR

Objective response (OR): complete 
response (CR) or partial response (PR)

DOR: the time from the earliest date of 
first documented evidence of confirmed 
CR or PR until the earliest date of 
disease progression or death from any 
cause, whichever comes first
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
To compare pembrolizumab plus olaparib 
to abiraterone acetate or enzalutamide 
with respect to:

Time to prostate-specific antigen (PSA)
progression
Time to first symptomatic skeletal-
related event (SSRE)
Time to radiographic soft tissue 
progression per soft tissue rules of 
PCWG-modified RECIST 1.1 as 
assessed by BICR
Time to pain progression (TTPP)

Time to PSA progression: the time from 
randomization to PSA progression. The 
PSA progression date is defined as the 
date of:

1) ≥25% increase and ≥2 ng/mL above 
the nadir, confirmed by a second value 
≥3 weeks later if there is PSA decline 
from baseline, or 2) ≥25% increase and 
≥2 ng/mL increase from baseline beyond 
12 weeks if there is no PSA decline from 
baseline.

Time to first SSRE: the time from 
randomization to the first symptomatic 
skeletal-related event, defined as:
1) first use of external-beam radiation 
therapy (EBRT) to prevent or relieve 
skeletal symptoms;
2) occurrence of new symptomatic 
pathologic bone fracture (vertebral or 
nonvertebral);
3) occurrence of spinal cord compression;
4) or tumor-related orthopedic surgical 
intervention,

whichever occurs first

Time to radiographic soft tissue 
progression: the time from 
randomization to radiographic soft tissue 
progression

TTPP: the time from randomization to 
pain progression as determined by Item 3 
of the Brief Pain Inventory-Short Form 
(BPI-SF) and by the Analgesic 
Quantification Algorithm (AQA) score

To evaluate the safety and tolerability of 
pembrolizumab plus olaparib versus 
abiraterone acetate or enzalutamide

Adverse events (AEs)

Study intervention discontinuations
due to AEs
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Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints

To evaluate efficacy with respect to OS, 
rPFS, ORR, and DOR in participants 
with positive PD-L1 (combined positive 
score [CPS]>1%) versus all-comers

OS, rPFS, OR, and DOR

To compare pembrolizumab plus olaparib 
to abiraterone acetate or enzalutamide 
with respect to the time to radiographic
bone progression (TTBP) per PCWG-
modified RECIST 1.1 as assessed by 
BICR

TTBP: the time from randomization to
radiographic bone progression

To compare pembrolizumab plus olaparib 
to abiraterone acetate or enzalutamide 
with respect to the change from baseline 
in disease-related symptoms and health-
related quality of life (HRQoL) using the 
BPI-SF, Functional Assessment of 
Cancer Therapy-Prostate Cancer 
(FACT-P), and EuroQoL Five-
Dimension Five-Level Health State 
Utility Index (EQ-5D-5L) 
questionnaires

BPI-SF: progression in pain severity 
domain, change in pain interference 
domain, and pain palliation

FACT-P: FACT-P total score, 
Functional Assessment of Cancer 
Therapy-General (FACT-G) total score, 
trial outcome index, functional well-
being, physical well-being, prostate 
cancer subscale, and FACT Advanced 
Prostate Symptom Index-6 (FAPSI-6)

EQ-5D-5L: mobility, self-care, usual 
activities, pain/discomfort, and 
anxiety/depression health states, and EQ-
5D-5L visual analog scale

To characterize health utilities following 
the administration of pembrolizumab plus 
olaparib versus abiraterone acetate or 
enzalutamide

EQ-5D-5L

To identify molecular (genomic, 
metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical 
response/resistance, safety, and/or the 
mechanism of action of pembrolizumab 
and other interventions

Molecular (genomic, metabolic and/or 
proteomic) determinants of response or 
resistance to treatments, using blood 
and/or tumor tissue
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4
STUDY DESIGN
4.1
Overall Design
NOTE: Based on the data from an IA of safety and efficacy for KEYLYNK-010 (data cutoff 
18-JAN-2022), the eDMC recommended stopping the study for futility because it was 
extremely unlikely that the efficacy boundary for study success would be reached at the next 
(final) analysis. In addition, the eDMC indicated that continuing the trial raised the risk of 
undue toxicities (Grade 3 to 5 AEs and drug-related SAEs) to participants receiving 
investigational therapy which were greater in the investigational arm compared to control.
This is a randomized, active-controlled, parallel-group, multi-site, open-label study of 
pembrolizumab plus olaparib versus abiraterone acetate or enzalutamide in participants with 
mCRPC.
After a screening phase of up to 42 days, approximately 780 eligible participants will be 
randomly assigned in a 2:1 ratio to 1 of the following 2 study intervention arms:
Arm 1: pembrolizumab 200 mg IV Q3W plus olaparib (as tablets) 300 mg BID
Arm 2: abiraterone acetate 1000 mg once daily (QD) plus prednisone or prednisolone 5 mg 
BID (in participants previously treated with enzalutamide) OR enzalutamide 160 mg 
QD (in participants previously treated with abiraterone acetate) 
There will be no crossover between treatment arms.
Before randomization, participants will be stratified by prior NHA treatment (abiraterone
acetate versus enzalutamide) and presence of measurable disease (yes versus no). Of 
participants randomized to the comparator arm (Arm 2), those previously treated with 
abiraterone acetate will receive enzalutamide, and those previously treated with enzalutamide 
will receive abiraterone acetate.
Participants must have had progressive disease (PD) during or after treatment with 
abiraterone acetate or enzalutamide (but not both) and 1 previous chemotherapy (docetaxel)
regimen. Prior treatment with enzalutamide or apalutamide in the hormone-sensitive setting 
is not allowed. Prior treatment with apalutamide or darolutamide is also not allowed. 
Participants must provide tumor tissue from a fresh core or excisional biopsy (obtained 
within 12 months of screening) from soft tissue not previously irradiated. Samples from 
tumors progressing at a prior site of radiation are allowed; other exceptions may be 
considered after Sponsor consultation. Participants with bone-only or bone-predominant 
disease may provide a bone biopsy sample. However, if obtaining a fresh biopsy sample is 
not feasible, participants may provide an archival tumor tissue sample after Sponsor 
consultation. Adequacy of these specimens for biomarker analysis will be evaluated by a 
central laboratory before randomization. For complete details of the eligibility criteria, refer 
to Section 5.
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Treatment with pembrolizumab may continue for up to 35 cycles (approximately 2 years 
starting with the first infusion of Cycle 1) or until a criterion for discontinuation of study 
intervention (Section 7.1) is met. Treatment with olaparib or with abiraterone acetate or 
enzalutamide will proceed continuously from Day 1 of Cycle 1, unless a criterion for 
discontinuation of study intervention (Section 7.1) is met.
In this study, an independent eDMC will monitor safety and efficacy (Section 10.1.4.2). 
Response to study intervention will be evaluated with radiologic imaging (whole-body bone
scans and computed tomography [CT]/magnetic resonance imaging [MRI] scans of the chest, 
abdomen, and pelvis) every 9 weeks for approximately 1 year (through Week 54) and every 
12 weeks thereafter. Radiographic progression will be determined according to PCWG-
modified RECIST 1.1 (Section 8.2.1).
This study will use a group-sequential design. There will be 2 planned IAs. The final OS 
analysis will take place when at least 482 OS events (target number of OS events) have been 
observed. To maintain sufficient minimal follow-up duration, the final analysis should be 
conducted at least 12 months after the last participant is randomized. There will be only 1
progression-free survival (PFS) analysis, at the time of IA1 when at least 360 rPFS events 
and 241 OS events (target number of OS events) have been observed. The results of the IAs
will be reviewed by the eDMC, which will provide recommendations for the study in 
accordance with the eDMC Charter and the SAP (Section 9).
Participants who attain an investigator-determined confirmed CR may receive up to 35 cycles
of pembrolizumab. If a participant with radiographic progression is clinically stable or 
clinically improved, an exception to continue study intervention may be considered, on
consultation with the Sponsor. Participants showing clinical benefit in the study will be 
allowed to continue study intervention regardless of any decision to stop enrollment or 
suspend the study.
AEs will be monitored throughout the study and graded in severity according to the 
guidelines outlined in the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. After the end of treatment, each participant will be 
followed for 30 days for AE monitoring. SAEs will be collected for 90 days after the end of 
treatment or 30 days after the end of treatment if the participant initiates new anticancer 
therapy, whichever is earlier. Treatment-related SAEs must be reported regardless of the time 
point when they occur. Participants who discontinue treatment for reasons other than 
radiographic disease progression will stay in the study and continue study-related disease 
assessments until radiographic disease progression, initiating a non-study cancer treatment, 
participant discontinuation from the study, or becoming lost to follow-up. All participants 
will be followed for survival. This will be performed in a variety of ways, including by 
telephone, e-mail, chart review, or review of public records, in compliance to local practices 
or regulations.
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Second Course Treatment: 
NOTE: As of Amendment 06, the study will be stopped due to futility and second 
course treatment is not an option for participants. There are currently no participants 
in the Second Course Phase.
Participants receiving pembrolizumab in combination with olaparib who stop study 
intervention with stable disease (SD) or better may be eligible for up to17 additional cycles 
(approximately 1 year) of pembrolizumab (Second Course phase) if they have BICR-verified 
PD after stopping study intervention and the study is ongoing (Section 6.6.7). The decision to 
retreat with pembrolizumab will be at the discretion of the investigator, only if no anticancer 
treatment was administered since the last dose of pembrolizumab, the participant still meets 
the safety parameters listed in the inclusion/exclusion criteria, and the study remains open.
Olaparib may be continued at the investigator’s discretion.
The risks of solid organ transplant after treatment with PD-1 inhibitor therapy have not been 
extensively studied. The timeframe for safe or appropriate solid organ transplantation after 
the last dose of pembrolizumab is unknown. Therefore, it is recommended not to perform 
solid organ transplantation within at least 120 days (5 half-lives) of stopping pembrolizumab. 
The risks and benefits of transplant should be discussed with the participant by the treating 
investigator.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This trial is a randomized open-label study. Based on interim data from Cohort A of 
KEYNOTE-365 (Section 2.1), the present study was developed to evaluate the efficacy of 
the combination of pembrolizumab and olaparib in participants who have not responded to 
abiraterone acetate or enzalutamide and to chemotherapy.
The effect of a PARP inhibitor as monotherapy is sensitive to biomarker positivity in prostate 
cancer. A case in point is the ORR of nearly 90% in a biomarker-defined subgroup of 
participants with DNA repair defects in the TOPARP-A study [Mateo, J., et al 2015]. Of 16 
participants in this subgroup, 14 (88%) had a response to olaparib, using a composite 
endpoint of OR, PSA response, or a reduction of CTCs. However, only 2 of 33(6.1%) had a 
response to olaparib in the biomarker-negative subgroup, and the median survival time in this 
subgroup was only 7.5 months. For pembrolizumab monotherapy, in KEYNOTE-199, 
although ORR was 4.5% in participants with measurable disease (Cohorts 1 and 2), survival 
data were encouraging in the first 3 cohorts whose disease progressed on 1 NHA and 1 
taxane-based chemotherapy (median OS 9.6 months). In KEYNOTE-365 Cohort A, which 
evaluated the population intended for study MK-7339-010 (none with DNA repair defects), 
DCR was 56.1% at the median follow-up of 11.4 months. The median survival time was 
approximately 13.5 months. Therefore, clinical benefit from the combination of 
pembrolizumab and olaparib is far beyond that which would be expected from either drug as 
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a single agent, especially for olaparib in patients with mCRPC unselected for DNA repair 
defects.
4.2.1
Rationale for Endpoints
Efficacy Endpoints
The dual primary endpoints of the study will be OS and rPFS. Overall survival has been 
recognized as the gold standard for demonstration of superiority of a new antineoplastic 
therapy in randomized clinical studies.
Radiographic PFS is an acceptable measure of clinical benefit for a late-stage study that 
demonstrates superiority of a new antineoplastic therapy, especially if the magnitude of the 
effect is large and the therapy has an acceptable risk/benefit profile. Radiographic PFS will 
be assessed by BICR according to PCWG-modified RECIST 1.1 (Section 8.2).
Time to initiation of the first subsequent anticancer therapy (TFST) or death will be assessed 
as a key secondary endpoint. A delay in the need to initiate the next anticancer therapy is 
clinically meaningful for patients and an important goal of any anticancer therapy. TFST is 
supportive of rPFS, as it incorporates reasons to switch therapies in addition to radiographic 
progression (eg, due to toxicity or clinical progression), thus providing a comprehensive 
measure of when an agent is considered no longer of clinical benefit.
Safety Endpoints
Safety parameters frequently used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints, including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE Version 4.0.
Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities 
as additional evidence of the risk-benefit profile of any new study intervention. In this study, 
health-related quality of life (HRQoL) and disease-related symptoms will be investigated via 
the following assessment tools: the FACT-P and BPI-SF questionnaires. Health utilities will 
be evaluated using the EQ-5D-5L PRO instrument. PRO instruments will be administered by 
trained site personnel and completed electronically by participants in the following order: 
FACT-P and EQ-5D-5L (both completed at the site), and BPI-SF (completed at home). 
These measures are not pure efficacy or safety endpoints because they are affected by both 
disease progression and treatment tolerability. The FACT-P is a disease-specific 39-item 
questionnaire included to assess HRQoL and prostate cancer-specific symptoms. It is a well-
established measure of HRQoL/health status frequently used in prostate cancer clinical 
studies. The FACT-P was developed specifically for patients with advanced prostate cancer 
and has been found to be reliable and valid in this population [Esper, P., et al 1997].
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The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. 2001]. 
This instrument has been used extensively in cancer studies and published results from these 
studies support its validity and reliability [Pickard, A. S., et al 2007].
The BPI-SF is a validated 15-item domain-specific instrument designed to assess the severity 
of pain and the impact/interference of pain on daily function [Cleeland, C. S. and Ryan, K. 
M. 1994].
The Analgesic Log will be used to capture all analgesic medication dosages and dose times. 
Both the BPI-SF and the Analgesic Log will be completed over 7 consecutive days (eg, 
Days 15 to 21) at each scheduled timepoint after randomization.
Planned Exploratory Biomarker Research
PARP inhibitors and cancer immunotherapies represent important classes of antitumor 
agents. However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these drugs in 
treating patients. Thus, to aid future patients, it is important to investigate the determinants of 
response or resistance to cancer therapy and other treatments administered, as well as 
determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/pharmacodynamic biomarkers and generate information that may better guide 
single-agent and combination therapy. To identify novel biomarkers, biospecimens (ie, blood 
components, tumor material, tissue material) will be collected to support analyses of cellular 
components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations of biomarkers that correlate with response or resistance to treatment may 
include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations. In addition to studying variation 
across the human genome, mutations in DNA damage repair genes including, but not limited 
to BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, 
PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L as well as genome scars including 
LOH may be investigated. Based on data from participants in several olaparib studies in 
multiple cancer types, known or suspected deleterious mutations in these genes and LOH 
may be predictive of a response to the combination of olaparib and pembrolizumab. Finally, 
microsatellite instability (MSI) may be evaluated as this is an important biomarker for some 
cancers (ie, colorectal cancer).
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Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to oncology drug 
development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Thus, genome-wide approaches may be used for this 
effort. Note that in order to understand tumor-specific mutations, it is necessary to compare 
the tumor genome with the germline genome. Microsatellite instability may also be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer). Circulating tumor 
DNA and/or RNA may also be evaluated from blood samples.
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment. Specific immune-related gene sets (ie, those 
capturing interferon-gamma transcriptional pathways) may be evaluated and new signatures 
may be identified. Individual genes related to the immune system may also be evaluated (eg, 
IL-10). MicroRNA profiling may also be pursued as well as exosomal profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor, tissue, and blood samples from this study may undergo proteomic analyses (eg, PD-
L1 IHC). PD-L1 protein level in tumor sections, assessed by IHC, has been shown to 
correlate with response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic 
(IVD) device has been developed for use with pembrolizumab in NSCLC. Preliminary data 
indicates that this association may also be true in additional cancer types (ie, triple negative 
breast cancer, head and neck, and gastric). Additional tumor or blood-derived proteins may 
also correlate with response to olaparib and pembrolizumab. Therefore, tumor tissue may be 
subjected to proteomic analyses using a variety of platforms that could include but are not 
limited to immunoassays and liquid chromatography/mass spectrometry. This approach could 
identify novel protein biomarkers that could aid in patient selection for olaparib (MK-7339) 
and pembrolizumab (MK-3475) therapy.
Other biomarkers
In addition to expression on the tumor tissue, other tumor derived cells, proteins and 
DNA/RNA can be shed from tumor and released into the blood. Assays such as enzyme-
linked immunoassay (ELISA) that measure proteins and assays that measure cell-free 
DNA/RNA (cfDNA/cfRNA) may also be evaluated from blood samples. Correlation of these 
biomarkers with response to treatments may identify new approaches for predictive 
biomarkers in blood, representing a major advance from today’s reliance on assessing tumor 
biomarkers. This research would serve to develop such assays for future clinical use.
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Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
4.2.1.4.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling 
(ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes, depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
FBR is to explore and identify biomarkers that inform the scientific understanding of 
diseases and/or their therapeutic treatments. The overarching goal is to use such information 
to develop safer, more effective drugs/vaccines, and/or to ensure that participants receive the 
correct dose of the correct drug/vaccine at the correct time. The details of this FBR are 
presented in Appendix 6.
4.2.2
Rationale for the Use of Comparators
There is no SOC therapy for patients with mCRPC whose disease progressed through both 
NHA and taxane-based chemotherapy. Cabazitaxel, a second taxane, can be a toxic therapy. 
Also, patients progressing during docetaxel treatment or becoming intolerant to docetaxel-
related toxicities are unlikely to receive cabazitaxel and require a different treatment 
modality. Most patients with mCRPC have bone metastases, and specifically directed 
radium-223 dichloride is not applicable for patients with visceral metastatic disease. 
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Although efficacy of a second NHA after failure of the first is limited based on retrospective 
studies, it is a reasonable therapy choice.
The effect of olaparib monotherapy is sensitive to biomarker positivity (BRCA1/2 or ATM
mutated) in prostate cancer. In the TOPARP-A study [Mateo, J., et al 2015], the response rate 
was 88% in the biomarker-positive subgroup of participants with DNA repair defects, but 
only 6.1% in the biomarker-negative subgroup. The median rPFS and OS for olaparib were 
9.8 months and 13.8 months, respectively, in the biomarker-positive subgroup. In contrast, 
the median rPFS and OS for olaparib were only 2.7 and 7.5 months, respectively, in the 
biomarker-negative subgroup. Given the current clinical evidence for efficacy of olaparib 
monotherapy in biomarker-positive mCRPC patients and the lack thereof in the 
biomarker-negative population, testing olaparib monotherapy in an unselected HRR
wild-type mCRPC population would not be ethical.
4.3
Justification for Dose
4.3.1
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab for adults across all indications and regardless of tumor type. As outlined 
below, this dose is justified by the following:

Clinical data from 8 randomized studies demonstrating flat dose- and 
exposure-efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks 
(Q2W).

Clinical data showing meaningful improvement in benefit-risk relationship, including 
OS at 200 mg Q3W across multiple indications.

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically based PK [PBPK] 
analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q3W (KEYNOTE-001 Cohort B2, KEYNOTE-001 Cohort D, KEYNOTE-002, KEYNOTE-
010, and KEYNOTE-021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B3, KN001 Cohort F2, and KEYNOTE-006). All these studies demonstrated 
flat dose- and exposure-response relationships across the doses studied, representing an 
approximate 5- to 7.5- fold difference in exposure. A dose of 2 mg/kg (or 200 mg fixed dose) 
Q3W provided similar responses to the highest doses studied. Subsequently, flat dose- and 
exposure-response relationships were observed in other tumor types, including head and neck 
cancer, bladder cancer, gastric cancer, and classical Hodgkin lymphoma, confirming 200 mg 
Q3W as the appropriate dose independent of tumor type. These findings are consistent with 
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the mechanism of action of pembrolizumab, which acts by interaction with immune cells and 
not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KEYNOTE-001 evaluating target-mediated drug disposition conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that fixed dosing 
provides similar control of PK variability to weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and the 2 mg/kg Q3W 
dose. Supported by these PK characteristics, and given that fixed dosing has advantages of 
reduced dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed 
dose was selected for evaluation across all pembrolizumab protocols.
4.3.2
Olaparib
The dose of olaparib used in this study is 300 mg BID (tablet formulation), which is the 
currently approved dose. Refer to Section 6.6.2 and the approved labeling for detailed 
information regarding dose regimen/modification.
4.3.3
Abiraterone Acetate
The recommended dose of abiraterone acetate is 1000 mg (four 250 mg tablets or two 
500 mg tablets) administered orally QD. Participants receiving abiraterone acetate will also 
take one 5 mg prednisone or prednisolone tablet BID. Refer to Section 6.6.5 and the 
approved labeling for detailed information regarding dose regimen/modification.
4.3.4
Enzalutamide
The recommended dose of enzalutamide is 160 mg (four 40 mg capsules/tablets or two 
80 mg tablets) administered orally QD. Refer to Section 6.6.6 and the approved labeling for 
detailed information regarding dose regimen/modification.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
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as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or an unacceptably high number of discontinuations or withdrawals due to administrative 
reasons.
In the event of Sponsor decision to no longer supply study interventions, ample notification
will be provided so that appropriate adjustments to participant treatment can be made.
5
STUDY POPULATION
The study population consists of male participants with mCRPC, unselected for HRR gene 
mutations, whose disease has progressed during prior NHA treatment and docetaxel 
chemotherapy. Participants must have had PD through or after prior treatment with 
abiraterone acetate or enzalutamide, but not both, and must have received and had PD during
or after no more than 1 previous docetaxel chemotherapy treatment.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
1. Have histologically or cytologically confirmed (if acceptable according to local health 
authority regulations) adenocarcinoma of the prostate without small cell histology. The 
diagnosis must be stated in a pathology report and confirmed by the investigator.
2. Have prostate cancer progression while receiving ADT (or post bilateral orchiectomy) 
within 6 months before Screening, as determined by the investigator through 1 of the 
following:

PSA progression shown by local laboratory values, as defined by a minimum of 
2 consecutive rising PSA levels with an interval of ≥1 week between each 
assessment, where PSA at screening should be ≥1 ng/mL. Refer to Section 8.2.2 
for further details.
Note: A PSA level obtained during the screening period can count as the 
confirmatory second rising PSA.

Radiographic disease progression in soft tissue based on RECIST 1.1, with or 
without PSA progression.

Radiographic disease progression in bone per PCWG, defined as the appearance 
of 2 or more new bone lesions on bone scan with or without PSA progression.
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3. Have disease progression under the following conditions if the participant received 
anti-androgen therapy before screening:

Evidence of progression >4 weeks since the last flutamide treatment.

Evidence of progression >6 weeks since the last bicalutamide or nilutamide treatment. 
4. Have current evidence of metastatic disease documented by bone lesions on bone scan 
and/or soft tissue disease shown by CT/MRI. 
5. Have received prior treatment with abiraterone acetate OR enzalutamide, but not both. 

Have disease that progressed during or after treatment with abiraterone acetate for 
either mHSPC or mCRPC or enzalutamide for mCRPC for at least 8 weeks (at least 
14 weeks for participants with bone progression).

Patients that received abiraterone acetate for mHSPC may not have received 
abiraterone acetate or enzalutamide for mCRPC.
6. Have received docetaxel chemotherapy regimen for mCRPC and have had PD during or 
after treatment with docetaxel. If docetaxel chemotherapy has been used more than once 
(eg, once for metastatic hormone-sensitive prostate cancer and once for mCRPC), it will 
be considered as 1 therapy. Prior docetaxel for mCRPC is allowed if ≥4 weeks have 
elapsed from the last dose of docetaxel before Day 1 of Cycle 1.
7. Have ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM). If the 
participant is currently being treated with luteinizing hormone-releasing hormone
(LHRH) agonists or antagonists (in participants who have not undergone orchiectomy), 
this therapy must have been initiated at least 4 weeks before the date of randomization, 
and treatment must be continued throughout the study.
8. If receiving bone resorptive therapy, including but not limited to bisphosphonates or 
denosumab, have been receiving stable doses for ≥4 weeks before the date of 
randomization. 
9. Have adequate organ function per central laboratory as defined in Table 1; all screening 
laboratory tests should be performed by the central laboratory within 10 days of the first 
dose of study intervention.
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematologic
ANCa
>1500/µL
Platelets
≥100,000/µL
Hemoglobina
≥10 g/dL or ≥6.2 mmol/L 
Renal
Estimated creatinine clearance using the Cockcroft-Gault 
equationb
≥51 mL/min
Hepatic
Serum total bilirubin
Total bilirubin ≤1.5 × ULN or direct bilirubin ≤ULN for
participants with total bilirubin >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
Coagulation
INR or PT
PTT or aPTT
≤1.5 × ULN unless participant is receiving anticoagulant 
therapy, as long as PT or PTT is within the therapeutic range 
for intended anticoagulant use 
Abbreviations: ALT=alanine aminotransferase; ANC=absolute neutrophil count; aPTT=activated partial thromboplastin 
time; AST=aspartate aminotransferase; G-CSF=granulocyte colony-stimulating factor; INR=international normalized ratio; 
PT=prothrombin time; PTT=partial thromboplastin time; SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum 
glutamic pyruvic transaminase; ULN=upper limit of normal.
a This criterion must be met without erythropoietin dependency, and without packed red blood cell transfusion or G-CSF 
administration within the last 28 days.  
b Estimated creatinine clearance using the Cockcroft-Gault equation:
(140-age [years] × weight [kg])
           serum creatinine (mg/dL) × 72
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements 
should be adapted according to local regulations and guidelines for administration of specific chemotherapies.
Demographics
10. Be male.
11. Be ≥18 years of age on the day of signing the informed consent.
Male Participants
12. Participants are eligible to participate if they agree to the following during the 
intervention period and for at least the time needed to eliminate each study intervention
after the last dose of study intervention. The length of time required to continue 
contraception after the last dose of study intervention for each study intervention is as 
follows:

Olaparib: 95 days

Abiraterone acetate: 7 days

Enzalutamide: 30 days
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
Refrain from donating sperm
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
OR

Must agree to use contraception unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause, documented from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview) as 
detailed below:

Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP (see Section 
10.5) who is not currently pregnant. Note: Male with a pregnant or 
breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile-vaginal 
penetration.

Contraceptive use by men should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical 
studies. If the contraception requirements in the local label for any of the 
study interventions is more stringent than the requirements above, the local 
label requirements are to be followed.
Informed Consent
13. The participant (or legally acceptable representative if applicable) provides written 
informed consent/assent for the study. The participant may also provide consent/assent
for FBR. However, the participant may participate in the main study without participating 
in FBR.
Additional Categories
14. Have provided tumor tissue from a fresh core or excisional biopsy (obtained within 
12 months of screening) from soft tissue not previously irradiated. Samples from tumors 
progressing at a prior site of radiation are allowed; other exceptions may be considered 
after Sponsor consultation. Participants with bone-only or bone-predominant disease may 
provide a bone biopsy sample. However, if obtaining a fresh biopsy is not feasible, 
participants may provide an archival tumor tissue sample after Sponsor consultation 
(Sponsor Communication Form [SCF] submission). Formalin-fixed, paraffin embedded
tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
Note: Details pertaining to tumor tissue submission are in the Procedures Manual.
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15. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 
assessed within 7 days of randomization. 
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a known additional malignancy that is progressing or has required active treatment in 
the last 3 years. Participants with basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, or carcinoma in situ who have undergone potentially curative 
therapy are not excluded.
2. Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or features 
suggestive of MDS/AML.
3. Has persistent toxicities (CTCAE Grade ≥2) caused by previous cancer therapy, 
excluding alopecia and neuropathy.
4. Has received colony-stimulating factors (eg, granulocyte colony-stimulating factor 
[G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], or recombinant 
erythropoietin) within 28 days before the date of randomization.
5. Is considered a high medical risk due to a serious uncontrolled medical disorder, 
nonmalignant systemic disease, or active uncontrolled infection. Examples include, but 
are not limited to, uncontrolled ventricular arrhythmia, recent myocardial infarction, 
uncontrolled major seizure disorder, unstable spinal cord compression, superior vena 
cava syndrome, extensive interstitial bilateral lung disease on high-resolution CT scan, or 
any psychiatric disorder that prohibits obtaining informed consent.
6. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the study.
7. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.
8. Has a gastrointestinal disorder affecting absorption (eg, gastrectomy, active peptic ulcer 
disease within the last 3 months).
Note: Participants with rare hereditary problems of galactose intolerance, the lapp lactase 
deficiency, or glucose-galactose malabsorption are also excluded.
9. Is unable to swallow capsules/tablets.
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10. Has a history of (noninfectious) pneumonitis requiring steroids, or has current 
pneumonitis.
11. Has an active infection, including tuberculosis, requiring systemic therapy.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s participation 
for the full duration of the study, or indicate that participation in the study is not in the 
best interest of the participant, in the opinion of the treating investigator.
13. Has known active human immunodeficiency virus (HIV), hepatitis B virus (eg, hepatitis 
B surface antigen reactive) or hepatitis C virus (HCV) infection (eg, HCV RNA 
[qualitative] is detected). Testing is not required unless mandated by the local health 
authority. Refer to Appendix 7 for country-specific testing requirements.
14. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least 4 weeks before
the date of randomization) and any neurologic symptoms have returned to baseline), have 
no evidence of new or enlarging brain metastases, and do not use steroids for at least 7 
days before the date of randomization. This exception does not include carcinomatous 
meningitis, which is excluded regardless of clinical stability.
15. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (at 
doses exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days before the date of randomization.
16. Has (Grade ≥3) hypersensitivity to pembrolizumab and/or any of its excipients.
17. Has known hypersensitivity to the components or excipients in olaparib, abiraterone 
acetate, prednisone or prednisolone, or enzalutamide.
18. Has CTCAE Grade ≥2 peripheral neuropathy, except when due to trauma.
19. Has ascites or clinically significant pleural effusion.
20. Has had a seizure or seizures within 6 months of signing the informed consent or has any 
condition that may predispose to seizures, including but not limited to prior 
cerebrovascular accident, transient ischemic attack, or brain arteriovenous malformation, 
or intracranial mass such as a schwannoma or meningioma that is causing edema or mass 
effect.
21. Has a history of loss of consciousness within 12 months of the screening visit.
22. Has symptomatic congestive heart failure (New York Heart Association Class III or IV 
heart disease).
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23. Has had a myocardial infarction or uncontrolled angina within 6 months before the date 
of randomization.
Note: Participants with a recent history of revascularization for acute coronary syndrome 
within 3 months before the date of randomization will be included.
24. Has a history of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, 
ventricular fibrillation, or torsade de pointes).
25. Has a history of Mobitz II second-degree or third-degree heart block without a pacemaker 
in place.
26. Has hypotension as indicated by systolic blood pressure (BP) <86 mm Hg at the 
screening visit.
27. Has bradycardia as indicated by heart rate <50 beats/minute on the screening 
electrocardiogram (ECG).
28. Has uncontrolled hypertension as indicated by systolic BP >170 mm Hg or diastolic BP 
>105 mm Hg at the screening visit.
Prior/Concomitant Therapy
29. Has received an anticancer mAb within 4 weeks before the date of randomization, or has 
not recovered (ie, Grade ≤1 or baseline) from AEs due to mAbs administered more than 4 
weeks before the date of randomization.
Note: Treatment with denosumab as SOC for bone metastases is permitted.
30. Has received prior treatment with olaparib or any other PARP inhibitor.
31. Has received prior treatment with apalutamide or darolutamide.
32. Has received prior treatment with enzalutamide or apalutamide for metastatic hormone-
sensitive prostate cancer.
33. Has undergone major surgery, including local prostate intervention (except prostate 
biopsy), within 28 days before the date of randomization, and has not recovered from the 
toxicities and/or complications.
34. Has used herbal products that may have hormonal antiprostate cancer activity and/or are 
known to decrease PSA (eg, saw palmetto) within 4 weeks before the date of 
randomization.
35. Has received prior treatment with radium or other therapeutic radiopharmaceuticals for 
prostate cancer.
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36. Has received prior radiotherapy within 2 weeks of the date of randomization. Participants 
must have recovered from all radiation-related toxicities, must not require corticosteroids, 
and must not have had radiation pneumonitis. A 1-week washout is permitted for 
palliative radiation (≤2 weeks of radiotherapy) for non-CNS disease.
37. Has received prior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with 
an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, 
OX-40, or CD137).
38. Has received prior targeted small molecule therapy within 4 weeks before the date of 
randomization or has not recovered (ie, Grade ≤1 or at baseline) from AEs due to a 
previously administered agent, with the exception of Grade ≤2 alopecia.
39. Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, 
protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, 
boceprevir, or telaprevir) or moderate (eg, ciprofloxacin, erythromycin, diltiazem, 
fluconazole, or verapamil) inhibitors of CYP3A4 that cannot be discontinued for the 
duration of the study. The required washout period before starting olaparib is 2 weeks.
40. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, nevirapine, or St John’s wort) or moderate (eg,
bosentan, efavirenz, or modafinil) inducers of CYP3A4 that cannot be discontinued for 
the duration of the study. The required washout period before starting olaparib is 5 weeks 
for phenobarbital and 3 weeks for other agents.
Note: A current list of strong/moderate inhibitors and inducers of CYP3A4 can be found 
at the following website: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm
41. Is currently being treated with CYP450-inducing antiepileptic drugs for seizures. Use of 
antiepileptic drugs for pain control is allowed in participants without seizures, unless 
these drugs are excluded due to CYP450 induction (eg, phenytoin, carbamazepine, and
phenobarbital).
42. Has received 5α reductase inhibitors (eg, finasteride or dutasteride), estrogens, or 
cyproterone within 4 weeks before the date of randomization.
43. Has received a previous allogenic bone marrow transplant or double umbilical cord 
transplantation (dUCBT) or a solid organ transplant.
44. Has received a whole blood transfusion in the last 120 days before the date of 
randomization. Packed red blood cells and platelet transfusions are acceptable if not 
given within 28 days of the date of randomization.
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45. Has received a live vaccine within 30 days before the date of randomization. Examples of 
live vaccines include, but are not limited to, measles, mumps, rubella, varicella/zoster 
(chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed.
Prior/Concurrent Clinical Study Experience
46. Is currently participating in or has participated in a study of an investigational agent, or 
has used an investigational device, within 4 weeks before the date of randomization.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
47. Has a resting ECG indicating uncontrolled, potentially reversible cardiac conditions as 
judged by the investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, 
congestive heart failure, Fridericia-corrected QC interval [QTcF] prolongation 
>500 msec, electrolyte disturbances, etc.), or has congenital long QT syndrome.
48. Has a bone “superscan,” defined as intense symmetric activity in bones and diminished 
renal parenchymal activity on the baseline bone scan, such that the presence of additional 
metastases in the future cannot be evaluated.
Other Exclusions
49. Is expecting to father children within the projected duration of the study, starting with the 
screening visit through the duration (days) after the last dose of study intervention listed 
in inclusion criterion #12.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants receiving pembrolizumab in combination with olaparib should avoid grapefruit, 
grapefruit juice, Seville oranges, Seville orange juice, and St John’s wort (tablet or tea) while 
receiving study intervention. Otherwise, participants should maintain a normal diet unless 
modifications are required to manage an AE such as diarrhea, nausea, or vomiting.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. 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 (CONSORT) publishing requirements and to 
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respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who is discontinued from study intervention OR withdraws from the study will 
not be replaced.
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 study protocol.
Clinical supplies (study interventions provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
As of Amendment 06, the study is being stopped for futility. However, participants currently 
still on study treatment may have the option of continuing with study intervention or SOC 
treatment, as appropriate, if they are deriving clinical benefit. 
The study interventions to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen
Use
IMP/
NIMP
Sourcing
Arm 1
Experimental
Olaparib
Drug
Tablet
150 mg
100 mg
600 mg
Oral
Two 150 mg 
tablets BID
Experimental
IMP
Central
Arm 1
Experimental
Pembrolizumab
Biological/
Vaccine
Solution for 
Infusion
25 mg/mL
200 mg
IV Infusion
Day 1 of each 
21-day cycle
Experimental
IMP
Central
Arm 2
Active 
Comparator
Abiraterone acetate (a) Drug
Tablet
500 mg
250 mg
1000 mg
Oral
Two 500 mg 
tablets QD 
or
Four 250 mg 
tablets QD
SOC
IMP
Central/
Local(e)
Arm 2
Active 
Comparator
Prednisone or 
prednisolone (a) (b)
Drug
Tablet
5 mg
10 mg
Oral
One 5 mg tablet 
BID
SOC
NIMP
Local
Arm 2
Active 
Comparator
Enzalutamide (c) (d)
Drug
Capsule/Tablet
40 mg/80 
mg
160 mg
Oral
Four 40 mg 
capsules/tablets
QD
or
Two 80 mg 
tablets QD
SOC
IMP
Central
Definition of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European Commission. Regional 
and/or country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
Abbreviations: BID=twice daily; IV=intravenous; QD=once daily; SOC=standard of care.
a Participants previously treated with enzalutamide
b Prednisone is the preferred steroid for use in the study. Prednisolone should only be used when prednisone is unavailable and requires Sponsor consultation.
c Participants previously treated with abiraterone acetate
d Participants will take either enzalutamide capsules or enzalutamide tablets.
e The 250 mg dosage strength will be sourced locally where available. The 500 mg dosage strength will be sourced centrally depending on local regulations. 
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All study interventions will be administered on an outpatient basis.
All products indicated in Table 2 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details of preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. 
Olaparib, abiraterone acetate, prednisone or prednisolone, and enzalutamide do not require 
preparation.
6.2.2
Handling, Storage, and Accountability
The investigator or designee 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.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
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).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
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investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will take place centrally using an interactive response technology
(IRT) system. There are 2 study intervention arms. Participants will be randomly assigned in 
a 2:1 ratio to pembrolizumab in combination with olaparib or to abiraterone acetate or
enzalutamide, respectively.
6.3.2
Stratification
Participants will be stratified according to the following factors:

Prior NHA treatment: abiraterone acetate versus enzalutamide

Measurable disease at baseline: yes versus no
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the treatment administered. Imaging data for the primary analysis will be centrally reviewed 
by an independent radiologist(s) without knowledge of participants’ treatment assignment.
PD-L1, PSA, and CTC results are not reported to sites, to prevent early withdrawal of 
participants from study intervention.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan for more than 12 weeks between 
pembrolizumab doses for nondrug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
For study interventions taken at home, the site will validate compliance with study 
intervention at each site visit according to its SOP.
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6.5
Concomitant Therapy
6.5.1
Prohibited Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study OR during time periods specified by this protocol for that 
medication or vaccination. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from [study intervention or vaccination] may be 
required. The investigator is to discuss prohibited medication/vaccination with the Sponsor's 
Clinical Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.

Based on in vitro data, olaparib may increase exposure to substrates of CYP3A4, organic 
anion-transporting polypeptide 1B1, organic cation transporter 1/2/3, and multidrug and 
toxic compound extrusion 1/2, and reduce exposure to substrates of CYP2B6. Caution 
should be observed if substrates of these isoenzymes or transporter proteins are co-
administered, including statins (eg, lovastatin, simvastatin, etc.). A current list of 
substrates can be found at the following website:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm

Listed below are specific concomitant therapies or vaccinations prohibited during the 
study:

Anticancer hormonal therapy (eg, anti-estrogens).
Note: Hormonal replacement therapy and ADT with LHRH agonists (eg, leuprolide) 
and LHRH antagonists (eg, degarelix) are allowed.

Strong and moderate inhibitors or inducers of CYP3A4.
Note: A current list of strong and moderate inhibitors/inducers of CYP3A4 can be 
found at the following website: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/D
rugInteractionsLabeling/ucm093664.htm
Refer to Section 6.6.2.5 for exceptions.

Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 
inducer. Concomitant use of enzalutamide with narrow therapeutic index drugs 
metabolized by CYP3A4 (eg, alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus), CYP2C9 (eg, 
phenytoin and warfarin), and CYP2C19 (eg, [S]-mephenytoin and clopidogrel) 
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should be avoided if possible, as enzalutamide may decrease their exposure. If 
coadministration with warfarin cannot be avoided, perform additional INR 
monitoring.

Abiraterone is an inhibitor of CYP2D6. Dose reduction should be considered for 
medicinal products that are metabolized by CYP2D6 and have a narrow therapeutic 
index to prolong the QT interval (ie, pimozide, sertindole, droperidol, haloperidol, 
thioridazine).

Strong inhibitors of CYP2C8.

Antineoplastic systemic chemotherapy or biologic therapy, except denosumab and 
bisphosphonates for bone metastases as SOC (the participant must have been 
receiving stable doses for ≥4 weeks before randomization).

Immunotherapy not specified in this protocol.

Chemotherapy not specified in this protocol.

Targeted therapy not specified in this protocol.

Administration of radium-223 while on study and for at least 5 days after the last 
administration of abiraterone in combination with prednisone/prednisolone.
The clinical efficacy and safety of concurrent therapy of abiraterone acetate plus 
prednisone/prednisolone and radium-223 were evaluated in a Phase 3, randomized, 
placebo-controlled, multicenter study in patients with asymptomatic or mildly 
symptomatic castration-resistant prostate cancer with bone metastases. Increased 
incidences of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) were 
observed in patients who received abiraterone plus prednisone/prednisolone in 
combination with radium-223 compared to patients who received placebo in 
combination with abiraterone acetate plus prednisone/prednisolone [Smith, M., et al 
2019]. Therefore, the combination of abiraterone and prednisone/prednisolone with 
radium-223 is contraindicated. Additionally, subsequent treatment with radium-223 
should not be initiated for at least 5 days after the last administration of abiraterone in 
combination with prednisone/prednisolone. 

Initiation of bone resorptive therapy including, but not limited to, bisphosphonates or 
denosumab (unless approved by Sponsor consultation).

Any second-generation androgen receptor inhibitor, except enzalutamide in 
participants randomized to abiraterone acetate or enzalutamide arm.

Investigational agents other than pembrolizumab or olaparib.
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
Herbal products that may have hormonal antiprostate cancer activity and/or are 
known to decrease PSA (e.g., saw palmetto).

Radiation therapy.

Note: Palliative localized radiation therapy to a site of pre-existing disease may be 
permitted during the study after consultation with the Sponsor. The radiation 
treatment field may not include a target or measurable lesion per RECIST 1.1.

Live vaccines within 30 days before the date of randomization and while participating 
in the study. Examples of live vaccines include, but are not limited to, measles, 
mumps, rubella, chicken pox, yellow fever, intranasal seasonal influenza, rabies, 
BCG, and oral typhoid vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed.
Note: If precluded by local regulations, live vaccines should not be given for 90 days 
after the last dose of study intervention. (See Appendix 7 for country-specific 
requirements).

Systemic glucocorticoids for any purpose other than for administration to participants 
receiving abiraterone acetate, or to modulate symptoms from an AE that is suspected 
to have an immunologic etiology. The use of physiologic doses of corticosteroids 
may be approved after consultation with the Sponsor.
Note: The following uses of corticosteroids are permitted without Sponsor 
consultation:

Inhaled steroids for management of asthma.

Prophylactic corticosteroids to avoid allergic reactions (eg, reactions to IV 
contrast material).

Palliative prednisone or prednisolone up to 10 mg daily or corticosteroid 
equivalent as used to treat men with prostate cancer.

Physiologic doses of corticosteroids for adrenal insufficiency.

Intranasal steroids for management of allergies.

Disease-modifying agents or immunosuppressive drugs.

5α reductase inhibitors (eg, finasteride or dutasteride), estrogens, or cyproterone.
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
In addition to the medications listed here, site staff should refer to the local approved 
product labels for permitted and prohibited medications, as well as drug-drug 
interactions, for each intervention used in this study. Caution should be used if 
participants receiving enzalutamide are receiving concomitant medications that may 
lower the seizure threshold.
The exclusion criteria (Section 5.2) describe other medications prohibited in this study.
Participants who, in the assessment of the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, over-the-counter (OTC) products, herbal supplements, and IV medications and 
fluids. If changes occur during the study period, documentation of drug dosage, frequency, 
route, and date should also be included on the eCRF.
All concomitant medications received within 28 days prior to the date of randomization and 
up to 30 days after the last dose of study intervention should be recorded. Concomitant 
medications administered 30 days after the last dose of study intervention should be recorded 
for SAEs and events of clinical interest (ECIs) as defined in Section 8.4.7.
6.5.2
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6.3.1, Table 7. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 7 in Section 
6.6.3.1 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
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6.5.3
Radiotherapy
Sites must consult the Sponsor before the use of radiotherapy or surgical intervention while a 
participant is in the study, and the intervention must be recorded in the study database.
Localized palliative radiation therapy to a site of pre-existing disease may be permitted while 
a participant is in the study. However, if the participant develops a new lesion or a definite 
increase in the size of existing bone or visceral lesions, with or without extension into soft 
tissue, that meets the criteria for disease progression according to PCWG [Scher, H. I., et al 
2016], study intervention must be discontinued for PD regardless of whether radiation 
therapy is initiated.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Concomitant Combination Therapy
If either pembrolizumab is interrupted for >12 weeks for an immune-related AE (irAE) or for 
administrative reasons, or olaparib is interrupted for 28 consecutive days, the site must gain 
approval via an SCF to continue the other study intervention. Participants who must 
discontinue 1 of the 2 interventions due to drug-related AEs may continue with the other
intervention after consultation with the Sponsor until a criterion for study intervention 
discontinuation (e.g., disease progression) is met.
6.6.2
Dose Modification for Olaparib
The dose of olaparib can be reduced to 250 mg BID initially and then to 200 mg BID as 
needed. If the 200 mg BID dose is not tolerable, no further dose reduction is allowed, and 
olaparib should be discontinued. Once the dose has been reduced, escalation is not permitted, 
except after concomitant treatment with CYP3A4 inhibitors (Table 6).
The reason for the dose interruption or reduction should be captured on the appropriate 
electronic case report form (eCRF).
Management of Hematologic Toxicities
Any hematologic toxicity observed during the study could be managed by a brief interruption 
of olaparib dosing or a reduction of the olaparib dose (Table 3 and Table 4). Repeated 
interruptions, not exceeding 4 weeks (28 days), are allowed as required. If the interruption is 
any longer, the Sponsor must be informed.
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Table 3
Management of Anemia
Toxicity
NCI CTCAE Grade
Action Taken
Hemoglobin (Hb)
Grade 2
(<10 but ≥8 g/dL)
First Occurrence:
Give appropriate supportive treatment and 
investigate causality.

Investigator judgment to either continue 
olaparib with supportive treatment (eg, 
transfusion) or interrupt olaparib dosing for 
a maximum of 4 weeks (28 days). Treatment 
can be restarted if Hb has recovered to >9 
g/dL.
Subsequent Recurrence:

Hb <10 but ≥9 g/dL: Investigator judgment 
to either continue olaparib with supportive 
treatment (eg, transfusion) or interrupt 
olaparib dosing for a maximum of 4 weeks 
(28 days). On recovery, a dose reduction to 
250 mg BID as a first step or 200 mg BID as 
a second step may be considered.

Hb <9 but ≥8 g/dL: Interrupt olaparib for a 
maximum of 4 weeks (28 days) until Hb 
improves to >9 g/dL. On recovery, reduce 
the dose of olaparib to 250 mg BID. A
second dose reduction to 200 mg BID may 
be considered if additional decreases in Hb 
occur.
Grade 3
(<8 g/dL)
Give appropriate supportive treatment (eg,
transfusion) and investigate causality.

Interrupt olaparib for a maximum of 
4 weeks (28 days), until Hb improves to 
≥9 g/dL.

On recovery, reduce the dose of olaparib to 
250 mg BID. A second dose reduction to 
200 mg BID may be considered if additional 
decreases in Hb occur.
Abbreviations: BID=twice daily; CTCAE=Common Terminology Criteria for Adverse Events; 
Hb=hemoglobin; NCI=National Cancer Institute.
Note: 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. Management of prolonged hematologic toxicities is detailed in Section 6.6.2.2.
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Table 4
Management of Neutropenia, Leukopenia, and Thrombocytopenia
Toxicity
NCI CTCAE Grade
Action Taken
Neutropenia, 
leukopenia, or 
thrombocytopenia
Grade 1 or 2
Investigator judgment to either continue olaparib 
or interrupt dosing for a maximum of 4 weeks 
(28 days). Give appropriate supportive treatment 
and investigate causality.
Grade 3 or 4

Interrupt olaparib for a maximum of 
4 weeks (28 days), until event recovers to 
≤Grade 1.

Repeated incidence: reduce the dose of 
olaparib to 250 mg BID. A second dose 
reduction to 200 mg BID may be considered 
if additional Grade 3 or 4 events occur.
Abbreviations: AEs=adverse events; BID=twice daily; CTCAE=Common Terminology Criteria for Adverse 
Events; G-CSF=granulocyte colony-stimulating factor; NCI=National Cancer Institute.
AEs of neutropenia and leukopenia should be managed as deemed appropriate by the investigator with close 
follow-up and interruption of study intervention if CTCAE Grade 3 or worse neutropenia occurs.
Primary prophylaxis with G-CSF is not recommended; however, if a participant develops febrile neutropenia, 
study intervention should be stopped and appropriate management including G-CSF should be given 
according to local hospital guidelines. Please note that G-CSF should not be used within at least 24 hours (7 
days for pegylated G-CSF) of the last dose of study intervention unless absolutely necessary.
Platelet transfusions, if indicated, should be performed according to local hospital guidelines.
Management of prolonged hematologic toxicities is detailed in Section 6.6.2.2.
Management of Prolonged Hematologic Toxicities
If a participant develops prolonged hematologic toxicity, such as:

≥2-week interruption/delay of olaparib dosing due to NCI CTCAE Grade 3 or worse 
anemia and/or development of blood transfusion dependence,

≥2-week interruption/delay of olaparib dosing due to NCI CTCAE Grade 3 or worse 
neutropenia (absolute neutrophil count <1 × 109/L), or

≥2-week interruption/delay of olaparib dosing due to NCI CTCAE Grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (platelets <50 × 
109/L),
differential blood count, including reticulocytes and peripheral blood smear, should be 
checked weekly. If any blood parameters remain clinically abnormal after olaparib dosing 
has been interrupted for ≥4 weeks (≥28 days), the participant should be referred to a 
hematologist for further investigations. Bone marrow analysis and/or blood cytogenetic 
analysis should be considered, according to local regulations and/or standard institutional 
hematologic practice. Olaparib should be discontinued if blood counts do not recover to NCI 
CTCAE Grade 1 or better within 4 weeks (28 days) of dose interruption.
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Development of confirmed MDS or other clonal blood disorder should be reported as an 
SAE, and full reports must be provided by the investigator to the Sponsor as outlined in 
Section 8.4.4. Olaparib should be discontinued for confirmed MDS and/or AML 
(Section 7.1).
Management of Nonhematologic Toxicity
Repeated dose interruptions, not exceeding 4 weeks (28 days), are allowed as required. If 
toxicity recurs after rechallenge with olaparib, and where further dose interruptions are 
considered inadequate for management of toxicity, either a dose reduction should be 
considered (Section 6.6.2) or the participant must permanently discontinue olaparib.
Olaparib dosing must be interrupted if any NCI CTCAE Grade 3 or 4 AE occurs that the 
investigator considers to be related to olaparib administration.
6.6.2.3.1
Management of New or Worsening Pulmonary Symptoms
If new or worsening pulmonary symptoms (eg, dyspnea) or radiologic abnormalities occur in 
the absence of a clear diagnosis, an interruption of olaparib dosing is recommended, and 
further diagnostic workup (including a high-resolution CT scan) should be performed to 
exclude pneumonitis.
After investigation, if no evidence of abnormality is observed on CT imaging and symptoms 
resolve, olaparib can be restarted if deemed appropriate by the investigator. If significant 
pulmonary abnormalities are identified, these need to be discussed with the Sponsor.
6.6.2.3.2
Management of Nausea and Vomiting
Events of nausea and vomiting are known to be associated with olaparib administration. 
These events are generally mild to moderate in severity (NCI CTCAE Grade 1 or 2), 
intermittent, and manageable with continued treatment. The first onset generally occurs in the 
first month of olaparib dosing for nausea and within the first 6 months of olaparib dosing for 
vomiting. For nausea, the incidence generally plateaus at around 9 months, and for vomiting 
at around 6 to 7 months.
No routine prophylactic antiemetic treatment is required at the start of olaparib treatment; 
however, participants should receive appropriate antiemetic treatment at the first onset of 
nausea or vomiting and as required thereafter, in accordance with local regulations or 
institutional guidelines. Alternatively, olaparib tablets can be taken with a light meal/snack 
(ie, 2 pieces of toast or a couple of crackers).
Per international guidance on antiemetic use in cancer patients (ESMO; NCCN), generally a 
single-agent antiemetic should be considered (eg, a dopamine receptor antagonist, 
antihistamines, or dexamethasone).
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6.6.2.3.3
Management of Renal Impairment
If, after study entry and/or while still receiving olaparib, a participant’s estimated creatinine 
clearance (CrCl) falls below the threshold for study inclusion (≥51 mL/min), retesting should 
be performed promptly.
A dose reduction is recommended for participants who develop moderate renal impairment 
(calculated CrCl 31 to 50 mL/min, either as calculated with the Cockcroft-Gault equation or 
based on a 24-hour urine test) for any reason during the study.
Table 5
Olaparib Dose Reduction to Manage Moderate Renal Impairment
Initial Dose
Moderate Renal Impairmenta
300 mg BID
200 mg BID
Abbreviation: BID=twice daily.
a Creatinine clearance 31 to 50 mL/min as calculated with the Cockcroft-Gault equation or based on a 24-hour urine test
Because CrCl determination is only an estimate of renal function, in instances where CrCl 
falls to 31 to 50 mL/min the investigator should use his or her discretion in determining 
whether a dose change or discontinuation of olaparib is warranted.
Olaparib has not been studied in participants with severe renal impairment 
(CrCl ≤30 mL/min) or end-stage renal disease. If participants develop severe renal 
impairment or end-stage renal disease, it is recommended that olaparib be discontinued.
Interruptions for Intercurrent Nontoxicity-related Events
Olaparib dose interruption for conditions other than toxicity resolution should be kept as 
short as possible. If a participant cannot restart olaparib within 4 weeks (28 days) for 
resolution of intercurrent conditions not related to disease progression or toxicity, the case 
should be discussed with the Sponsor and approved via an SCF.
All dose reductions and interruptions (including any missed doses) and the reasons for the 
reductions/interruptions are to be recorded in the eCRF. 
Olaparib should be stopped at least 3 days before planned surgery and can be restarted when 
the wound has healed. It is not required to stop olaparib for any needle biopsy procedure.
Localized palliative radiation therapy to a site of pre-existing disease may be permitted while 
a participant is in the study. Olaparib should be discontinued for a minimum of 3 days before 
radiation therapy and should be restarted within 4 weeks (28 days), as long as any bone 
marrow toxicity has recovered.
Because 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.
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Dose Reductions for Concurrent CYP3A4 Inhibitor Use
Strong or moderate CYP3A inhibitors should not be taken with olaparib. If there is no 
suitable alternative concomitant medication, the dose of olaparib should be reduced for the 
period of concomitant administration as described in Table 6. After washout of the inhibitor 
is complete (Section 5.2), the olaparib dose can be re-escalated. The olaparib dose reduction 
should be recorded in the eCRF, with the reason documented as concomitant CYP3A4 
inhibitor use.
Table 6
Olaparib Dose Reduction with a Strong or Moderate CYP3A4 Inhibitor
Initial Dose
Strong CYP3A Inhibitor
Moderate CYP3A Inhibitor
300 mg BID
100 mg BID
150 mg BID
Abbreviation: BID=twice daily.
6.6.3
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs 
Associated with Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 7.
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Table 7
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2. Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose 
is not ≤10 mg/day within 12 weeks of the last treatment. 
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4. If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for signs and symptoms of 
pneumonitis

Evaluate participants with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid 
treatment

Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)

Participants with ≥Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis

Participants with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient oral 
fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold

Administer 
corticosteroids (initial 
dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a

Initiate insulin 
replacement therapy for 
participants with T1DM

Administer anti-
hyperglycemic in 
participants with 
hyperglycemia

Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated

Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue

Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate

Monitor for signs and symptoms of thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue

Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyronine) per 
standard of care

Monitor for signs and symptoms of thyroid disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold

Administer 
corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper

Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold

Based on severity of AE 
administer 
corticosteroids

Ensure adequate evaluation to confirm etiology and/or 
exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold

Based on severity of AE 
administer 
corticosteroids

Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 
diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs (eg, 
vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions 
Associated with Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines for pembrolizumab-associated 
infusion reactions are provided in Table 8.
Table 8
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of the 
investigator
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs
Stop Infusion
Additional appropriate medical therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of the 
investigator.
If symptoms resolve within 1 hour of stopping drug infusion, 
the infusion may be restarted at 50% of the original infusion 
rate (eg, from 100 mL/hr to 50 mL/hr). Otherwise dosing will 
be held until symptoms resolve and the participant should be 
premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug intervention.
Participant may be 
premedicated 1.5 h (±30 
minutes) before infusion 
with:
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine).
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
analgesic).
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms after
initial improvement; 
hospitalization indicated for 
other clinical sequelae (eg, 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may include but is not 
limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of the 
investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used 
immediately.
Participant is permanently discontinued from further study drug 
intervention.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of
drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Abbreviations: NCI=National Cancer Institute; NSAID=nonsteroidal anti-inflammatory drug; IV=intravenous; po=orally.
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 3 weeks for Q3W (21 days) of the 
originally scheduled dose and within 42 days of the previously administered dose, unless 
otherwise discussed with the Sponsor. The reason for study intervention interruption is to be 
documented in the participant’s study record.
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6.6.4
Management of Overlapping Toxicities
Based on the known toxicity profiles of pembrolizumab and olaparib, certain 
treatment-related AEs are uniquely associated with one drug versus the other. For example, 
anemia is a known risk of olaparib treatment, while immune-related/immune-mediated AEs 
are risks of pembrolizumab treatment. However, certain AEs, such as diarrhea, pneumonitis,
and increased creatinine, may be initially considered attributable to either study drug. 
Therefore, evaluation of attribution is important for determining the study drug most likely 
related to the AE, or an alternative etiology, and subsequently for proper clinical 
management. The following should be considered: 
1. Timing of AE Onset
Since olaparib is dosed daily and continuously due to a relatively short half-life (11.9 hours) 
and pembrolizumab is dosed Q3W due to a long half-life, olaparib can be interrupted to 
assess whether an AE improves/resolves with dechallenge (ie, interruption of treatment) 
based on the following 2 scenarios:

If an AE is identified during a treatment cycle (ie, between 2 pembrolizumab doses), only 
olaparib dose interruption is needed. 

If an AE is identified at the beginning of a treatment cycle, olaparib can be interrupted 
and pembrolizumab dosing should be held.
If the participant recovers from an AE in response to olaparib interruption (ie, positive 
dechallenge), the event is more likely to be related to olaparib. Otherwise, after excluding 
other alternative explanations, an irAE should be considered.
2. Severity of AE
If an AE is suspected to be treatment-related and is severe/life-threatening at the time of 
onset or rapidly worsens, action, including interrupting both drugs and initiating treatment 
with a corticosteroid (with the exception of hypothyroidism and type 1 diabetes mellitus 
[T1DM]) and other supportive care, should be promptly taken.
6.6.5
Dose Modification for Abiraterone Acetate
Dose modification guidelines for abiraterone acetate are given in Table 9. The dose 
regimen/modification should be adopted according to the efficacy and safety risk information 
according to local regulations and guidelines for administration of abiraterone acetate. Once 
the dose has been reduced, it may not be escalated to a previous dose level.
Management of Hepatotoxicity
In participants who develop hepatotoxicity during treatment with abiraterone acetate ALT 
and/or AST >5 × ULN or total bilirubin >3 × ULN), interrupt treatment. Treatment may be 
restarted at a reduced dose of 750 mg QD after return of liver function test results to baseline 
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or to AST and ALT ≤2.5 × ULN and total bilirubin ≤1.5 × ULN. If hepatotoxicity recurs at 
the dose of 750 mg QD, treatment may be restarted at a reduced dose of 500 mg QD after
return of liver function test results to baseline or to AST and ALT ≤2.5 × ULN and total 
bilirubin ≤1.5 × ULN. If hepatotoxicity recurs at the reduced dose of 500 mg QD, treatment 
with abiraterone acetate is to be discontinued.
Abiraterone acetate is to be permanently discontinued in participants who develop a 
concurrent elevation of ALT >3 × ULN and total bilirubin >2 × ULN in the absence of 
biliary obstruction or other causes responsible for this concurrent elevation. 
Participants who develop AST or ALT ≥20 × ULN and/or bilirubin ≥10 × ULN should be 
discontinued from treatment with abiraterone acetate.
Management of Hypokalemia 
Correct hypokalemia before and during treatment. For Grade 1 or 2 hypokalemia, initiate oral 
potassium supplementation, and titrate to maintain serum potassium ≥3.5 mEq/L and ≤5.0 
mEq/L (maintenance at ≥4.0mEq/L is recommended). Treatment without dose reduction can 
continue after hypokalemia is corrected to Grade 0.
If a participant develops Grade 3 hypokalemia (serum potassium <3.0 mEq/L to 2.5 mEq/L 
[NCI CTCAE Version 4.0]) or life-threatening hypokalemia with serum potassium 
<2.5 mEq/L (Grade 4 hypokalemia [NCI CTCAE Version 4.0]), abiraterone acetate should 
be withheld and the participant hospitalized for IV potassium replacement and cardiac 
monitoring. Re-initiation of abiraterone acetate after normalization (Grade 0) of serum 
potassium must be discussed with and approved by the Sponsor.
Management of Hypertension
For Grade 1 to 2 hypertension, continue abiraterone acetate without dose reduction. 
Management of hypertension is per the investigator.
For Grade 3 to 4 hypertension, withhold abiraterone acetate. Adjust or add medications to 
mitigate the toxicity, and/or consider a specific mineralocorticoid receptor blocker such as 
eplerenone. When hypertension resolves to Grade ≤1, resume abiraterone acetate at the full 
dose.
If Grade 3 to 4 hypertension recurs, withhold abiraterone acetate and adjust or add 
medications to mitigate the toxicity. When hypertension is resolved to Grade ≤1, resume 
abiraterone acetate at 750 mg QD.
If Grade 3 to 4 hypertension recurs again, withhold abiraterone acetate and adjust or add 
medications to mitigate the toxicity. When hypertension is resolved to Grade ≤1, resume 
abiraterone acetate at 500 mg QD.
If Grade 3 to 4 hypertension recurs despite optimal medical management and 2 dose 
reductions, discontinue abiraterone acetate. 
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Management of Edema and Fluid Retention
Supportive management of pedal edema is per the investigator. Dose reduction of abiraterone 
acetate is not necessary.
If anasarca and/or pulmonary edema requiring supplemental oxygen occurs, withhold 
abiraterone acetate. Adjust or add medications to mitigate the toxicity, and/or consider a 
specific mineralocorticoid receptor blocker such as eplerenone. When anasarca and/or 
pulmonary edema resolves to Grade ≤1, resume abiraterone acetate at the full dose.
If anasarca and/or pulmonary edema recurs, withhold abiraterone acetate and adjust or add 
medications to mitigate the toxicity. When anasarca and/or pulmonary edema is resolved to 
Grade ≤1, resume abiraterone acetate at 750 mg QD.
If anasarca and/or pulmonary edema recurs again, withhold abiraterone acetate and adjust or 
add medications to mitigate the toxicity. When anasarca and/or pulmonary edema is resolved 
to Grade ≤1, resume abiraterone acetate at 500 mg QD.
If anasarca and/or pulmonary edema recurs despite optimal medical management and 2 dose 
reductions, discontinue abiraterone acetate.
Management of Other AEs Believed to be Related to Abiraterone Acetate
For Grade 1 to 2 toxicities, give supportive care per institutional guidelines. Dose reduction
of abiraterone acetate is not necessary.
For Grade 3 to 4 toxicities, withhold abiraterone acetate. Adjust or add medications to 
mitigate the toxicity, and/or consider a specific mineralocorticoid receptor blocker such as 
eplerenone. When the toxicity is resolved to Grade ≤1, resume abiraterone acetate at the full 
dose.
If the toxicity recurs, withhold abiraterone acetate and adjust or add medications to mitigate 
the toxicity. When the toxicity is resolved to Grade ≤1, resume abiraterone acetate at 750 mg 
QD.
If the toxicity recurs again, withhold abiraterone acetate and adjust or add medications to 
mitigate the toxicity. When the toxicity is resolved to Grade ≤1, resume abiraterone acetate at 
500 mg QD.
If the toxicity recurs despite optimal medical management and 2 dose level reductions, 
discontinue abiraterone acetate.
Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions 
associated with mineralocorticoid excess seen in participants treated with abiraterone acetate. 
If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical 
insufficiency. Increased corticosteroid dosage may be indicated before, during, and after 
stressful situations. Monitor the participant for symptoms and signs of adrenocortical 
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insufficiency. If stress doses of corticosteroids are necessary, withhold abiraterone acetate 
and contact the Sponsor to discuss when to restart abiraterone acetate.
Table 9
Abiraterone Acetate Dose Modification Guidelines for Drug-related Adverse 
Events
Dose
Regimen
Initial abiraterone acetate dose
1000 mg
Two 500 mg tablets PO QD
First dose reduction
750 mg
One 500 mg tablet and one 250 mg tablet PO QD
Second dose reduction
500 mg
One 500 mg tablet PO QD
Abbreviations: PO=orally; QD=once daily.
Note: Table 9 is in accordance with the US FDA drug label. The dose regimen/modification 
should be adopted according to the efficacy and safety risk information according to local 
regulations and guidelines for administration of abiraterone acetate.
6.6.6
Dose Modification for Enzalutamide
If a participant experiences any Grade ≥3 toxicity related to enzalutamide, the drug should be 
withheld until the toxicity decreases to Grade ≤2. Enzalutamide can then be resumed at a 
reduced dose of 120 mg QD. If Grade ≥3 toxicity recurs, enzalutamide can again be withheld 
until toxicity decreases to Grade ≤2 and resumed at a reduced dose of 80 mg QD. Dose 
reduction below 80 mg QD is not permitted.
Once the dose has been reduced, it may not be escalated to a previous dose level.
Enzalutamide should be permanently discontinued in participants who experience a seizure 
during treatment.
Posterior reversible encephalopathy syndrome (PRES) has been observed in participants 
treated with enzalutamide. This syndrome may present with rapidly evolving symptoms of 
seizure, lethargy, headache, confusion, blindness or visual disturbances, or other neurologic 
symptoms. Hypertension may or may not be present. PRES is diagnosed by brain imaging 
(preferably MRI). Enzalutamide must be permanently discontinued in participants who 
develop PRES during treatment.
Participants taking enzalutamide should promptly report the development of rash, regardless 
of severity, to the investigator. These participants should be promptly treated with steroids 
and dose interruption per protocol and monitored closely for worsening of rash, which may 
require additional treatment. 
After resolution of toxicity, enzalutamide can be resumed with dose reduction according to
Table 10.
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Table 10
Enzalutamide Dose Modification Guidelines for Drug-related Adverse Events
Dose
Regimen
Initial enzalutamide dose
160 mg
Four 40 mg capsules/tablets PO QD
or
Two 80 mg tablets PO QD
First dose reduction
120 mg
Three 40 mg capsules/tablets PO QD
or
One 80 mg tablet and one 40 mg tablet PO QD
Second dose reduction
80 mg
Two 40 mg capsules/tablets PO QD
or
One 80 mg tablet PO QD
Abbreviations: PO=orally; QD=once daily.
Note: Table 10 is in accordance with the US FDA drug label. The dose regimen/modification 
should be adopted according to the efficacy and safety risk information according to local 
regulations and guidelines for administration of enzalutamide.
6.6.7
Second Course
NOTE: As of Amendment 06, the study will be stopped due to futility and second 
course treatment is not an option for participants. There are currently no participants 
in the Second Course Phase.
All participants receiving pembrolizumab in combination with olaparib who stop study 
intervention with SD or better may be eligible for up to 17 additional cycles (approximately 
1 year) of pembrolizumab treatment if their disease progresses after stopping study 
intervention in the initial treatment phase. Olaparib may be continued at the investigator’s 
discretion. This retreatment is termed the Second Course phase of this study, and is only 
available if the study remains open and the participant meets the following conditions:
Either

The participant stopped initial study intervention after attaining a BICR-verified CR 
based on PCWG-modified RECIST 1.1, and

The participant was treated with at least 8 cycles of study intervention before 
discontinuing treatment, and

The participant received at least 2 treatments with pembrolizumab beyond the date when 
the initial CR was declared.
OR
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
The participant had SD, PR, or CR and stopped study intervention after completion of 35 
cycles (approximately 2 years) of study intervention for reasons other than disease 
progression or intolerability.
AND

The participant experienced BICR-verified radiographic disease progression per PCWG-
modified RECIST 1.1 after stopping initial treatment.

No new anticancer treatment was administered after the last dose of study intervention.

The participant meets all safety parameters listed in the inclusion criteria and none of the 
safety parameters listed in the exclusion criteria.

The study is ongoing.
An OR disease progression occurring during the Second Course phase will not be counted as 
an event for the primary analysis of either endpoint in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
Not applicable
6.9
Standard Policies
Study site personnel will have access to a central electronic IRT system to allocate 
participants, to assign study intervention to participants, and to manage the distribution of 
clinical supplies. Each person accessing the IRT system must be assigned an individual 
unique personal identification number (PIN). They must use only their assigned PIN to 
access the system, and they must not share their assigned PIN with anyone.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified study 
intervention period will still continue to participate in the study as specified in Section 1.3 
and Section 8.12.3.
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Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Participants should be placed back on study 
intervention within 3 weeks of any scheduled interruption, unless otherwise discussed with 
the Sponsor. Specific details regarding procedures to be performed at study intervention 
discontinuation are provided in Section 8.1.9. Before discontinuing participants from study 
intervention, submit the Treatment Termination and Disease Assessment Termination Form.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:

The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.

Bone marrow findings consistent with MDS or AML.

The participant interrupts pembrolizumab administration for >12 consecutive weeks for 
an irAE, or >12 weeks for administrative reasons, without Sponsor consultation.

The participant interrupts olaparib administration for more than 28 consecutive days 
without Sponsor consultation.

The participant interrupts abiraterone acetate or enzalutamide administration for more 
than 28 consecutive days without Sponsor consultation.

The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of study intervention.

The participant has a clinical indication for any medication or vaccination specifically 
prohibited in this study (Section 6.5.1).

BICR-verified radiographic disease progression as outlined in Section 8.2.1 (except if the 
Sponsor approves study intervention continuation).
o
As of Amendment 06, central tumor response assessments will no longer be 
performed. However, participants still on study treatment and deriving clinical 
benefit and are continuing to receive study intervention or SOC, will be assessed 
locally by the investigator for disease progression per SOC schedule.

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.

Recurrent Grade 2 pneumonitis.
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
Recurrent Grade 3 colitis/diarrhea.

Completion of 35 cycles (approximately 2 years) of pembrolizumab treatment.

Intercurrent illness that prevents further administration of study intervention.

Noncompliance with study intervention or procedure requirements.

Administrative reasons requiring cessation of study intervention.

Note: The number of treatments is calculated starting with the first dose. Participants who 
stop pembrolizumab + olaparib or pembrolizumab after 35 cycles may be eligible for 
retreatment if their disease progresses after stopping study intervention, provided they 
meet the requirements detailed in Section 6.6.7. Participants may be retreated in the 
Second Course phase (retreatment) for up to 17 additional cycles of pembrolizumab
(approximately 1 year). Olaparib may be continued at the investigator’s discretion.

Discontinuation of treatment may be considered for participants randomized to 
pembrolizumab + olaparib who have attained a confirmed CR and been treated for at 
least 8 cycles (at least 24 weeks), receiving 2 cycles of pembrolizumab and olaparib
including 2 doses of pembrolizumab and at least 80% of the planned doses of olaparib,
beyond the date when the initial CR was declared. These participants may be eligible for 
Second Course treatment as described in Section 6.6.7.
For participants who are discontinued from study intervention but continue to be 
monitored in the study, all visits and procedures, as outlined in the SoA, should be 
completed.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. 
The procedures to be performed should a participant repeatedly fail to return for scheduled 
visits and/or if the study site is unable to contact the participant are outlined in Section 7.3.
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of maintaining 
the protocol-specified visit schedule.
The investigator or designee must make every effort to regain contact with the participant at 
each missed visit (eg, telephone calls and/or a certified letter to the participant’s last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
The investigator is responsible for ensuring that procedures are conducted by appropriately 
qualified (by education, training, and experience) staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or equivalent).
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
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 ICF may be utilized for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations may 
require that additional informed consent be obtained from the participant. In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
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The maximum amount of blood collected from each participant over the duration of the study 
is provided in the Procedures Manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate consent is in place.
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
The participant or his legally acceptable representative will be asked to sign consent at the 
point of initial radiographic disease progression.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, answer all of his questions, and obtain written informed consent before 
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performing any procedure related to the FBR. A copy of the informed consent will be given 
to the participant.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 10 
years that the investigator considers to be clinically important. In addition, significant and 
potentially relevant conditions that occurred >10 years previously should be collected.
Details regarding the disease for which the participant has enrolled in this study will be 
recorded separately and not listed as medical history.
8.1.5
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before the date of randomization. Treatment for the disease for which the 
participant has enrolled in this study will be recorded separately and not listed as a prior 
medication.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit. All medications related to reportable 
SAEs and ECIs should be recorded as defined in Section 8.4.1. In addition, new medications 
started during the Second Course phase through the Second Course Safety Follow-up Visit 
should be recorded.
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8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a treatment 
/randomization number. The treatment/randomization number identifies the participant for all 
procedures occurring after treatment randomization. Once a treatment/randomization number 
is assigned to a participant, it can never be reassigned to another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Administration of pembrolizumab will be monitored by the investigator and/or study staff.
Administration of olaparib, abiraterone acetate and prednisone or prednisolone, or 
enzalutamide will be administered by the investigator and/or study staff according to the 
specifications within the Pharmacy Manual, at the Cycle 1 Day 1 clinic visit. Participants will 
then self-administer olaparib, abiraterone acetate and prednisone or prednisolone, or 
enzalutamide orally on a continuous daily dosing schedule.
On Day 1 of subsequent cycles, pembrolizumab should be administered after all procedures 
and assessments have been completed. Study intervention can be administered within 
±3 days of the targeted Day 1 for each cycle except Cycle 1, when intervention can only be 
administered within +3 days of the targeted Day 1.
Timing of Dose Administration
8.1.8.1.1
Pembrolizumab
Pembrolizumab treatments will begin on Day 1 of each cycle after all predose study 
procedures and assessments have been completed as detailed in the SoA.
Pembrolizumab will be administered at a fixed dose of 200 mg, as a 30-minute IV infusion 
Q3W. Sites should make every effort to target infusion time to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes -5 min/+10 min).
The Pharmacy Manual contains specific instructions for pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration.
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8.1.8.1.2
Olaparib
Olaparib will be administered at a dose of 300 mg (two 150 mg tablets) po BID for a total 
daily dose of 600 mg.
At the Cycle 1 Day 1 clinic visit, the first dose of olaparib will be administered after all 
predose assessments and procedures and pembrolizumab infusion have been completed. 
Participants will be instructed to self-administer olaparib. Olaparib tablets should be taken 
BID with 1 glass of water at the same time each day, approximately 12 hours between doses. 
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 olaparib tablets are swallowed, the dose should only be 
replaced if all the intact tablets can be seen and counted. Should any participant enrolled in
the study miss a scheduled dose for any reason (eg, because of forgetting to take the tablets 
or vomiting), the participant will be allowed to take the scheduled dose up to a maximum of 
2 hours after that scheduled dose time. If it is more than 2 hours after the scheduled dose 
time, the missed dose is not to be taken, and the participant should take his allotted dose at 
the next scheduled time.
Participants must be instructed that if they miss a dose or vomit at any time after taking a 
dose, they should take their next dose at its scheduled time. The site will validate compliance 
with study intervention (including missed or vomited doses) at each site visit according to its 
SOP. If doses are missed or vomited, this must be indicated in the source documents and 
CRFs.
8.1.8.1.3
Abiraterone Acetate + Prednisone or Prednisolone
Abiraterone acetate will be administered at a dose of 1000 mg (two 500 mg tablets or four 
250 mg tablets) PO QD. Participants taking abiraterone acetate must also take prednisone or 
prednisolone (one 5 mg tablet PO BID).
Abiraterone acetate will be taken at approximately the same time each day on a continuous 
daily dosing schedule and must be taken on an empty stomach. No food should be consumed 
for at least 1 hour after the dose of abiraterone acetate. The tablets should be swallowed 
whole with water and not crushed or chewed.
Participants must be instructed that if they miss a dose or vomit at any time after taking a 
dose, they should take their next dose at its scheduled time. The site will validate compliance 
with study intervention (including missed or vomited doses) at each site visit according to its
SOP. If doses are missed or vomited, this must be indicated in the source documents and 
CRFs.
Detailed information regarding the dose regimen/modification is in the approved labeling for 
abiraterone acetate.
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8.1.8.1.4
Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (four 40 mg capsules/tablets or two 
80 mg tablets PO QD).
Enzalutamide will be taken at approximately the same time each day on a continuous daily 
dosing schedule and can be taken with or without food. Capsules/tablets must be swallowed 
whole and should not be chewed, dissolved, or opened.
Participants must be instructed that if they miss a dose or vomit at any time after taking a 
dose, they should take their next dose at its scheduled time. The site will validate compliance 
with study intervention (including missed or vomited doses) at each site visit according to its
SOP. If doses are missed or vomited, this must be indicated in the source documents and 
CRFs.
Detailed information regarding the dose regimen/modification is in the approved labeling for 
enzalutamide.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the study intervention 
period should be encouraged to continue to be followed for all remaining study visits as 
outlined in the SoA and Section 8.12.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the end of treatment visit should be performed (at the time of withdrawal). Any 
AEs that are present at the time of withdrawal should be followed in accordance with the 
safety requirements outlined in Section 8.4 and Section 8.12.4.
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
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8.1.10
Participant Blinding/Unblinding
Not applicable
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
As of Amendment 06: Central tumor response assessments will be discontinued.
Imaging scans will no longer be submitted to iCRO nor read by BICR. The subsections 
below are retained for reference.
However, for participants who are still on study treatment and deriving clinical benefit and 
will continue on study intervention or SOC treatment until criteria for discontinuation are
met, local tumor imaging should continue per SOC schedule.
The process for image collection and transmission to the central imaging vendor is given in 
the Site Imaging Manual.

Chest, abdomen, and pelvis scans are required for all participants at screening and on-
study. CT with IV and oral contrast is preferred or noncontrast CT of the chest and MRI 
of the abdomen and pelvis with IV gadolinium for participants in whom iodinated 
contrast is contraindicated.

Bone scans (eg, bone scintigraphy, bone scan, radionuclide bone scan, etc.) are required 
for all participants at screening and on-study.

Other modalities (eg, (FDG-PET, PSMA PET, MRI, SPECT, etc) cannot be a substitute 
for the bone scan.

Additional imaging acquired as per SOC or as clinically indicated, used to support 
radiographic disease progression or efficacy assessments, should be sent to the iCRO.
Note: For the purposes of assessing tumor imaging, the term “investigator” refers to the 
local investigator at the site and/or the radiologic reviewer at the site or at an offsite 
facility.
Participant eligibility will be determined using local assessment (investigator assessment) 
based on PCWG-modified RECIST 1.1. All scheduled images for all participants from the 
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sites will be submitted to the iCRO. In addition, images (including via other modalities)
obtained at an unscheduled time point to determine disease progression, as well as imaging 
obtained for other reasons, but which demonstrates radiologic progression, should be 
submitted to the iCRO.
On investigator-assessed disease progression, the indicative scans are to be submitted 
immediately to iCRO for BICR verification of progression. After submission of scans, the 
iCRO will e-mail the assessment to the site and Sponsor.
If disease progression is not verified, the process continues as follows:

If participant is clinically stable, continue study intervention per protocol
-
Resume imaging per protocol schedule 
-
Send scans to iCRO
-
Continue local assessment
-
Do not change investigator assessment of progression
-
If subsequent scan(s) indicate progression, submit scans to iCRO to request 
verification

If the participant is not clinically stable, best medical practice is to be applied
Before stopping study intervention or imaging or starting new anticancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required.
If disease progression is verified, the process continues as follows:

Investigator judgment will determine action

If the participant is clinically stable and study intervention is to continue, communication 
with the Sponsor is required and a reconsent must be signed
Note: the reconsent may be signed any time after investigator-assessed progression is 
identified but must be signed before starting study intervention after verification of 
disease progression is provided by the iCRO.

Obtain scans locally per original protocol schedule

Do not send scans to iCRO

For the purpose of this decision process, lack of clinical stability is defined as:
-
Unacceptable toxicity
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-
Clinical signs or symptoms indicating clinically significant disease progression
-
Decline in performance status
-
Rapid disease progression or threat to vital organs or critical anatomical sites (eg, 
CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression) requiring urgent alternative medical intervention.
The primary measure used by BICR for assessment of tumor response, date of disease 
progression, and as a basis for all protocol guidelines related to disease status (e.g., 
discontinuation of study intervention) will be PCWG-modified RECIST 1.1. PCWG PDu is 
not considered radiographic PD.
Assessment of treatment response in soft tissue will be according to the soft tissue rules of 
PCWG-modified RECIST 1.1, modified to follow a maximum of 10 target soft tissue lesions 
and a maximum of 5 target lesions per organ. Assessment of treatment response in bone will 
be according to the bone lesion rules of PCWG-modified RECIST 1.1, as described in 
Appendix 8.
Soft tissue and bone response assessments will be combined to produce an overall 
radiographic response, as follows:
Soft Tissue Response
Bone Scan Result
PCWG-modified RECIST 1.1 Time 
Point Response Entered into CRF
PD
Any
PD
Any
PD
PD
Any (except PD)
PDu
PDu
NE
Non-PD, NED, or NE
NE
NED
NE
NE
NED
Non-PD
Non-CR/Non-PD
NED
NED
NED
SD
Non-PD, NED, or NE*
SD
Non-CR/Non-PD
Non-PD, NED, or NE*
Non-CR/Non-PD
PR
Non-PD, NED, or NE*
PR
CR
Non-PD or NE*
PR (if target lesions were present at 
baseline)
Non-CR/Non-PD
(if no target lesions at baseline)
CR
NED
CR
Abbreviations: CR=complete response; CRF=case report form; NE=nonevaluable; NED=no evidence of 
disease; PCWG=Prostate Cancer Working Group; PD=progressive disease; PDu=progressive disease 
unconfirmed; PR=partial response; RECIST 1.1=Response Evaluation Criteria in Solid Tumors Version 1.1; 
SD=stable disease.
*If the bone scan is entirely missing or was not performed and bone lesions were present at 
baseline, the overall response is nonevaluable.
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Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days before the date of 
randomization. Tumor imaging by CT (or MRI) and radionuclide bone scanning is required 
at screening.
Scans performed as part of routine clinical management are acceptable as screening scans if 
they are of diagnostic quality and performed within 28 days before the date of randomization. 
Scans are required to be sent to the iCRO before enrollment; however, central imaging 
assessment is not required before enrollment.
At screening, all soft tissue lesions seen with CT (or MRI) and all bone lesions seen with
radionuclide bone scanning will be documented. In determining response to study 
intervention or progression, investigators must evaluate all target and nontarget lesions and 
search for new lesions at each imaging time point.
Tumor Imaging During the Study
In the first year, on-study imaging assessments must be performed every 9 weeks (63 days ± 
7 days) from the date of randomization (through Week 54). Participants who continue 
receiving study intervention beyond Week 54 will have imaging performed every 12 weeks 
(84 days ± 7 days). All supplemental imaging must be submitted to the iCRO.
Timing of imaging should follow calendar days from the date of randomization and should 
not be adjusted for delays in cycle starts.
Response must be confirmed at least 4 weeks later to be considered for best overall response.
Radiographic progression will be determined according to PCWG-modified RECIST 1.1. 
Disease progression in bone lesions should be confirmed by another bone scan ≥6 weeks 
after site-assessed first radiologic evidence of progression is initially observed.
End of Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4-week window). If previous imaging was obtained 
within 4 weeks before the date of discontinuation, imaging at treatment discontinuation is not 
mandatory.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging with the 
same schedule used while on treatment (every 9 weeks in Year 1 or every 12 weeks after 
Year 1) until the start of a new anticancer treatment, disease progression, death, withdrawal 
of consent, or the end of the study, whichever occurs first.
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Scans are to be continued until one of the following conditions are met:

disease progression as defined by PCWG-modified RECIST 1.1 verified by BICR

the start of a new anticancer treatment

death

withdrawal of consent

the end of the study
Second Course (Retreatment) Tumor Imaging
NOTE: As of Amendment 06, the study will be stopped due to futility and second 
course treatment is not an option for participants. There are currently no participants 
in the Second Course Phase.
Tumor imaging must be performed within 28 days before restarting treatment with 
pembrolizumab. Local reading (investigator assessment with site radiology reading) will be 
used to determine eligibility. 
Response assessments and progressive disease are determined by investigator assessment. 
The only Second Course scan to be provided to the iCRO is the baseline scan if it is the final 
scan for the Initial Treatment or First Course.
The first on-study imaging assessment should be performed at 9 weeks (63 days ±7 days) 
after the restart of treatment. Subsequent tumor imaging should be performed every 12 weeks 
(84 days ±7 days) or more frequently, if clinically indicated.
Imaging should continue to be performed until disease progression, the start of a new 
anticancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first.
For participants who discontinue Second Course study intervention, tumor imaging should be 
performed at the time of intervention discontinuation (±4-week window). If previous imaging 
was obtained within 4 weeks before the date of discontinuation, imaging at intervention 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
documented disease progression, this is the final required tumor imaging.
For participants who discontinue Second Course study intervention without documented 
disease progression, every effort should be made to continue monitoring their disease status 
by radiologic imaging every 12 weeks (84 days ±7 days) until the start of a new anticancer 
treatment, disease progression, death, or the end of the study, whichever occurs first.
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8.2.2
Prostate-specific Antigen Assessments
Two components are required for defining trial eligibility in terms of PSA: 1) rising PSA as 
determined by the local laboratory and 2) PSA ≥1 ng/mL as determined by the central 
laboratory. PSA determination by the central laboratory must be performed within 10 days 
before randomization (Section 1.3.1). If this central laboratory result for PSA is not expected 
to be available to the site before randomization, the investigator may also perform the test 
locally, and, if PSA is ≥1 ng/mL, may use that result to determine eligibility. However, a 
sample must still be collected within 10 days before randomization for submission to the 
central laboratory. During the remainder of the study, the local laboratory may not be used in 
lieu of central laboratory results.
For defining rising PSA, the reference value to use (#1) is the last PSA value before a
sequence of PSA increases (see Figure 2 below from Prostate Cancer Working Group 2).
Figure 2
Change in Prostate-specific Antigen
The screening value obtained during the screening period can count as the confirmatory 
second rising PSA value compared with a prior single increased PSA value. If a PSA value 
during screening is used as the second data point to confirm rising PSA and does not confirm 
the PSA rise but is still greater than the reference point, PSA determination should be 
repeated by the local laboratory in 1 week to prove that there is a sequence of rising PSA 
values.
If there are 2 consecutive rising PSA values before screening but the local laboratory value is 
less than the previous value (but still above the reference value), the participant is still 
eligible for the study.
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If a local laboratory PSA value obtained during screening is less than the reference point, this 
constitutes a new PSA nadir, and another sequence of 2 rising PSA values is needed to 
ensure that PSA is rising.
8.2.3
Tumor Tissue Collection
Baseline tumor tissue for biomarker analysis must be sent to the testing laboratory and 
analyzed for adequacy before enrollment. Details of tumor tissue submission are in the 
Procedures Manual.
8.2.4
PROs and Quality of Life Assessments
As of Amendment 06: PROs and Quality of Life assessments will be discontinued. The 
subsections below are retained for reference. 
The FACT-P, EuroQoL EQ-5D-5L, and BPI-SF questionnaires and the Analgesic Log 
should be administered per the SoA in Section 1.3.1. Both the FACT-P and the EQ-5D-5L
will be administered at the site, while the BPI-SF and Analgesic Log will be completed by 
the participant at home. It is best practice and strongly recommended that electronic 
patient-reported outcomes (ePROs) are administered to randomized participants before study 
intervention administration, AE evaluation, and disease status notification. If the participant 
does not complete the ePROs at a scheduled time point, the MISS_MODE form must be 
completed to capture the reason that the assessment was not performed. Site staff must not 
read, administer, or complete the PRO questionnaires for the participant. If the participant is 
unable to read the questionnaire (eg, is blind or illiterate), that participant may still participate
in the study, but is exempted from completing PRO questionnaires, including the Analgesic 
Log. Participants exempted in this regard should be flagged appropriately by the site staff.
Functional Assessment of Cancer Therapy-Prostate (FACT-P)
FACT-P was developed as a disease-specific adjunct to the FACT measurement system, and
consists of FACT-G (general), which is a 27-item self-report questionnaire measuring 
general HRQoL in 4 domains (physical, social, emotional, and functional well-being), and 
12 prostate cancer-specific items. FACT-P (version 4) is self–administered and requires 
approximately 8 to 10 minutes to complete.
EQ-5D-5L
The 5 health state dimensions in the EQ-5D-5L include mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension is rated on a 5-point scale from 
1 (no problem) to 5 (unable to/extreme problems). The EQ-5D-5L also includes a graded 
(0 to 100) vertical visual analog scale on which the participant rates his general state of 
health at the time of the assessment.
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Brief Pain Inventory-Short Form (BPI-SF) and Analgesic Log
BPI-SF
The BPI-SF is provided on an ePRO device and will be completed by the participant daily for 
7 consecutive days at the time points specified in the SoA (Section 1.3.1). It does not have to 
be completed at the site.
The BPI-SF has 15 items that are rated on a 0 to 10 numeric rating scale, with 0=No Pain and 
10=Worst Pain Imaginable. This instrument consists of 2 domains, pain severity and pain 
interference. The pain severity domain includes 4 items (Items 3, 4, 5, and 6), which assess 
pain at its “worst,” “least,” “average,” and “now” (current pain) respectively on an 11-point 
scale. In this study, the “worst pain” (Item 3) will be used as a single item in assessing pain 
progression. A composite pain severity score from all 4 items will also be evaluated as “pain 
severity progression”. A ≥2-point change in the average pain severity or in “worst pain” item 
is considered clinically meaningful.
The pain interference domain score is a mean of 7 items: general activity (Item 9A), mood 
(Item 9B), walking ability (Item 9C), normal work (Item 9D), relations with other people 
(Item 9E), sleep (Item 9F), and enjoyment of life (Item 9G), each scored on an 11-point scale 
from 0 (does not interfere) to 10 (completely interferes). Based on the BPI-SF scoring 
manual [Cleeland, C. S. 2009], the following items are not used in scoring pain severity or 
pain interference domains: Items 1, 2, 7, and 8. Item 7 (a free text field) describing pain 
medication use is captured separately in more detail, using the Analgesic Log.
Analgesic Log
The Analgesic Log is a paper form that will be completed by the participant daily for 
7 consecutive days per the SoA (Section 1.3.1). Participants will record all analgesic 
medication dosages and dose times. The Analgesic Log is study-specific (not generic). All 
medications captured in the paper log will be reconciled at every visit with the concomitant 
medications data to address any discrepancies.
8.3
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical examinations are given in Section 1.3.1. After the 
first dose of study intervention, new clinically significant abnormal findings should be 
recorded as AEs.
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Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Directed Physical Examination
In cycles that do not required a full physical examination as defined in Section 1.3.1, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated before study intervention administration. New, clinically significant abnormal 
findings should be recorded as Aes.
8.3.2
Vital Signs

Vital signs will be measured with the participant in a sitting, semirecumbent, or supine 
position after 5 minutes of rest, and will include temperature, systolic and diastolic BP, 
heart rate, and respiratory rate. Record vital signs before study intervention 
administration at treatment visits.
8.3.3
Electrocardiograms

A standard 12-lead ECG will be performed once at the screening visit using local 
standard procedures. Clinically significant abnormal findings should be recorded as 
medical history.
8.3.4
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.

The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).

For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
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Details regarding specific laboratory assessments to be performed in this study are provided 
below. The total amount of blood to be drawn over the course of the study (from prestudy to 
poststudy visits), including approximate blood volumes drawn by visit and by sample type 
per participant, are in the Study Procedures Manual. Refer to Section 1.3 for the timing of 
laboratory assessments.
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.5
Performance Assessments
Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG performance status (Appendix 11) 
at screening (within 7 days of randomization) and before dosing during the study intervention
period as specified in the SoA (Section 1.3.1).
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety 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, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before intervention allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.
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
All AEs from the time of intervention allocation/randomization through 30 days 
following cessation of study intervention must be reported by the investigator.

All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 days following cessation of study intervention or 30 days following cessation 
of study intervention if the participant initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator.

All pregnancies and exposure during breastfeeding, from the time of intervention
allocation/randomization through 120 days following cessation of study intervention, or 
30 days following cessation of study intervention if the participant initiates new 
anticancer therapy must be reported by the investigator.

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 the 
Sponsor regardless of investigator’s assessment of causality or knowledge of the 
treatment arm. Investigators will be asked during the regular follow up for OS if the 
participant has developed MDS/AML or a new primary malignancy and prompted to 
report any such cases.

Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 11.
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Table 11
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time Period:
After the Protocol-
specified Follow-up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
Nonserious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE) including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical Interest 
(require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential drug-
induced liver injury 
(DILI)
- require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical Interest 
(do not require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting Aes and/or SAEs and other 
reportable safety events. Open-ended, nonleading verbal questioning of the participant is the 
preferred method of inquiring about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events 
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including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of 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 and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered Aes, any 
pregnancy or infant exposure during breastfeeding in a participant’s female partner 
(spontaneously reported to the investigator or their designee) that occurs during the study are 
reportable to the Sponsor.
All reported pregnancies of participants’ female partners must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage, and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
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The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that on review is 
not progression of the cancer under study will be forwarded to Global Pharmacovigilance as 
an SAE within 24 hours of determination that the event is not progression of the cancer under 
study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
3. Any event of MDS/AML, new primary malignancy, or pneumonitis should be reported 
whether it is considered a non-serious AE (eg non-melanoma skin cancer) or SAE and 
regardless of investigator’s assessment of causality.
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater (≥5 times the indicated dose).
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
Olaparib must only be used in accordance with the dosing recommendations in this protocol.
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol 
should be reported as an overdose.
No specific information is available on the treatment of overdose of olaparib. In the event of 
overdose, the study intervention should be discontinued, and the participant should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated.
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Abiraterone acetate 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.
No specific information is available on the treatment of overdose of abiraterone acetate. In 
the event of overdose, the study intervention should be discontinued, and the participant 
should be observed closely for signs of toxicity. Appropriate supportive treatment should be 
provided if clinically indicated.
An overdose of enzalutamide is defined as at least 2 daily doses of study intervention taken 
the same calendar day. In the event of an overdose, treatment with study intervention should 
be stopped and general supportive measures initiated, taking into consideration the half-life 
of 5.8 days for enzalutamide. Participants may be at an increased risk of seizures after an 
overdose of enzalutamide. Neither the effects of overdose of enzalutamide nor an antidote to 
overdose are known.
The medical monitor must be contacted in the event of a study intervention overdose.
8.6
Pharmacokinetics
Not applicable
8.7
Pharmacodynamics
Not applicable
8.8
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of FBR:

Leftover DNA

Leftover tumor 

Leftover RNA

Leftover plasma and serum from biomarker analyses

Leftover plasma or derivative for ctDNA
8.9
Planned Genetic Analysis Sample Collection
Samples should be collected for planned analysis of associations between genetic variants in 
germline/tumor DNA and drug response. If a documented law or regulation prohibits (or the
local IRB/IEC does not approve) sample collection for these purposes, then such samples 
should not be collected at the corresponding sites. Leftover DNA extracted from planned 
genetic analysis samples will be stored for FBR only if the participant signs the FBR consent.
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Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the Procedures Manual.
8.10
Biomarkers
As of Amendment 06: Biomarker sample collections will be discontinued. The section 
below is retained for reference.
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (e.g., protein, RNA, DNA, and metabolites) and other circulating 
molecules will be collected from all participants as specified in the SoA (Section 1.3):

Newly obtained tumor tissue

Blood for genetic analysis

Blood for RNA analyses

Blood for serum and plasma biomarker analyses

Blood for ctDNA analysis
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the Procedures Manual.
8.11
Medical Resource Utilization and Health Economics
As of Amendment 06: Medical Resource Utilization and Health Economics data 
collection will be discontinued. The section below is retained for reference. 
Medical resource utilization and health economics data associated with medical encounters
will be collected in the CRF by the investigator and study site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses and will include:
•
All-cause hospitalizations and emergency room visits from the time of treatment 
randomization through 90 days after cessation of study treatment or 30 days after
cessation of study treatment, if the participant initiates new anticancer therapy, whichever 
is earlier.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
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8.12.1
Screening
Written consent must be obtained before performing any protocol-specific procedure. Results 
of a test performed before the participant’s signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 42 days before the date of 
randomization except for the following:

Laboratory tests are to be performed within 10 days before the first dose of study 
intervention. An exception is HIV and hepatitis testing, which may be performed up to 
42 days before the date of randomization if required by local regulations. Refer to 
Appendix 7 for country-specific requirements.

Evaluation of ECOG performance status is to be performed within 7 days of 
randomization.

Initial tumor imaging at screening assessments must be performed within 28 days before
the date of randomization.

Tumor tissue from a fresh core or excisional biopsy must be obtained within 12 months 
of screening. An archival tumor tissue sample (>12 months) can be submitted after 
Sponsor consultation.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame, and the corresponding
inclusion/exclusion criteria are met. Participants who are rescreened will retain their original 
screening number.
8.12.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.
8.12.3
Discontinuation Visit
The Discontinuation Visit should occur at the time when study intervention is discontinued. 
If the Discontinuation Visit occurs 30 days after the last dose of study intervention, at the 
time of the mandatory Safety Follow-up Visit, procedures do not need to be repeated. Visit 
requirements are outlined in the SoA (Section 1.3). Specific procedure-related details are 
provided in Section 8. Before discontinuing participants from study intervention submit the 
Treatment Termination and Disease Assessment Termination Form.
8.12.4
Discontinued Participants Continuing to be Monitored in the Study
Before discontinuing participants from therapy, submit the Treatment Termination & Disease 
Assessment Termination Form.
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8.12.5
Posttreatment Visits
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
Participants who are eligible for retreatment with pembrolizumab may have up to 2 Safety 
Follow-up Visits, 1 after the initial treatment period and 1 after Second Course treatment.
Efficacy Follow-up Visits
As of Amendment 06: Efficacy Follow-up Visits will be discontinued. The section below 
is retained for reference.
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than BICR-verified radiographic PD will 
move into the Efficacy Follow-up Phase. Follow-up visits will be scheduled every 9 weeks 
(63 days ± 7 days) through Week 54 and every 12 weeks (84 days ± 7 days) thereafter, from 
the date of randomization, to coincide with the imaging schedule at the time of 
discontinuation from study intervention. Participants who discontinue study intervention 
without documented confirmed disease progression should continue monitoring of disease 
status by radiologic imaging (CT/MRI and bone scans) and PSA determinations according to 
the imaging schedule at the time of discontinuation (every 9 or 12 weeks). Every effort 
should be made to collect information regarding disease status until the start of new 
anticancer therapy, disease progression, death, or the end of the study, or if the participant 
begins retreatment with pembrolizumab as detailed in Section 6.6.7. Information regarding 
poststudy anticancer treatment will be collected if new treatment is initiated. Participants 
who completed all efficacy assessments and/or will not have further efficacy assessments 
must enter the Survival Follow-up Phase.
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 6.6.7 will move from the Efficacy Follow-up Phase to the Second Course 
phase when they experience disease progression. Details are provided in the SoA (Section 
1.3.2) for retreatment with pembrolizumab.
Survival Follow-up Contacts
As of Amendment 06: Survival Follow-up visits will be discontinued. Those participants 
remaining on study treatment at the time of Amendment 06, should continue to be 
monitored in the study through the AE reporting period (Section 8.4). The section below 
is retained for reference.
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-up Phase and should be contacted approximately every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the 
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study, whichever occurs first. Investigators will be asked during the regular follow-up for OS 
if the participant has developed MDS/AML or a new primary malignancy and prompted to 
report any such cases.
The first survival follow-up assessment should be scheduled as described below: 

For participants who discontinue treatment intervention and who will not enter the 
Efficacy Follow-up Phase, the first survival follow-up assessment will be scheduled 
12 weeks after the Discontinuation Visit and/or Safety Follow-up Visit (whichever is 
last). 

For participants who completed assessments in the Efficacy Follow-up Phase, the first 
survival follow-up assessment will be scheduled 12 weeks after the last efficacy 
assessment follow-up visit has been performed.
8.12.6
Survival Status
To ensure that current and complete survival data are available at the time of database locks, 
updated survival status may be requested during the study by the Sponsor. For example, 
updated survival status may be requested before but not limited to an eDMC review, interim,
and/or final analysis. On Sponsor notification, all participants who do not/will not have a 
scheduled study visit or study contact during the Sponsor-defined period will be contacted 
for their survival status (excluding participants with a previously recorded death event in the 
collection tool).
9
STATISTICAL ANALYSIS PLAN
As of Amendment 06: The Statistical Analysis Plan is amended as follows.
NOTE: Based on the data from an interim safety and efficacy for KEYLYNK-010 (data 
cutoff 18-JAN-2022), eDMC recommended stopping the study for futility because it was 
extremely unlikely that the efficacy boundary for study success would be reached at the next 
(final) analysis. In addition, the eDMC indicated that continuing the trial raised the risk of 
undue toxicities (Grade 3 to 5 AEs and drug-related SAEs) to patients receiving 
investigational therapy which were greater in the investigational arm compared to control.
Based upon these data and the recommendation of the eDMC, the study was unblinded (as of 
11-MAR-2022). The prespecified final analysis of the study described in the SAP will not be 
performed. Selected analyses of safety endpoints will be performed at the end of the study; 
there will be no further analyses of efficacy and PRO endpoints. 
This section outlines the statistical analysis strategy and procedures for the study. The study 
has been unblinded (as of 11-MAR-2022). Changes made to primary and/or key secondary 
hypotheses or the statistical methods related to those hypotheses that occurred prior to 
Amendment 06 were documented in previous protocol amendments(s) (consistent with 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use Guideline [ICH] E9). Changes to exploratory or other nonconfirmatory analyses 
made after the protocol has been finalized, but before the final database lock, will be 
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documented in a supplemental Statistical Analysis Plan (sSAP) and referenced in the clinical 
study report (CSR) for the study. Post hoc exploratory analyses will be clearly identified in 
the CSR. Other planned analyses (ie, those specific to the analysis of PROs and FBR) are 
beyond the scope of this document or will be documented in separate analysis plans.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized here. The comprehensive plan is provided in 
Sections 9.2 through 9.12. As of Amendment 06, the prespecified final analysis of the study 
described in the SAP will not be performed. Selected analyses of safety endpoints will be 
performed at the end of the study; there will be no further analyses of efficacy and PRO 
endpoints. The SAP summary has been updated accordingly. 
Study Design Overview
A Phase 3 Randomized Open-label Study of Pembrolizumab (MK-3475) Plus 
Olaparib versus Abiraterone Acetate or Enzalutamide in Participants with 
Metastatic Castration-resistant Prostate Cancer (mCRPC) Who are Unselected for 
Homologous Recombination Repair Defects and Have Failed Prior Treatment 
with One Next-generation Hormonal Agent (NHA) and Chemotherapy
(KEYLYNK-010)
Treatment Assignment
Approximately 780 eligible participants will be randomized in a 2:1 ratio to one of 
the following 2 study intervention arms:

Arm 1: pembrolizumab plus olaparib

Arm 2: abiraterone acetate or enzalutamide
Randomization stratification factors are:

Measurable disease at baseline: yes versus no

Prior NHA treatment: abiraterone acetate versus enzalutamide
As of Amendment 06, all ongoing participants may have the option to continue 
receiving study intervention or SOC, until criteria for discontinuation are met, if 
they are deriving clinical benefit.
Analysis Populations
Efficacy: Intent to Treat (ITT)
Safety: All Participant as Treated (APaT)
Primary Endpoints
1.
Overall survival (OS)
2.
Radiographic progression-free survival (rPFS)
Key Secondary Endpoint
Time to initiation of the first subsequent anticancer therapy or death (TFST)
Statistical Methods for
Key Efficacy Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab plus 
olaparib to abiraterone acetate or enzalutamide with respect to rPFS, TFST, and 
OS using a stratified log-rank test. The hazard ratio will be estimated using a 
stratified Cox regression model. Event rates over time will be estimated within 
each study intervention group using the Kaplan-Meier method.
Statistical Methods for
Key Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ with 
respect to the analyses that will be performed. There are no events of interest that 
warrant elevation to Tier 1 in this study. Tier 2 parameters will be assessed via 
point estimates with 95% CIs provided for between-group comparison; only point 
estimates by study intervention group are provided for Tier 3 safety parameters.
The 95% CIs for the between-treatment differences in percentages will be provided 
using the Miettinen and Nurminen method.
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Interim Analyses
As of Amendment 06, the prespecified final analysis of the study described in the 
SAP will not be performed. 
Two IAs will be performed in this study. Results will be reviewed by an eDMC. 
These IAs are summarized below. Details are provided in Section 9.7.

IA1: 
o
Timing: To be performed when at least 360 rPFS events and at least 
241 OS events (target number of OS events) are observed 
(approximately 17 months after the first participant is randomized). If 
rPFS event number achieves but OS event number does not achieve, 
IA1 may be delayed for up to 3 months as long as the enrollment is 
complete.
o
Testing: primary analysis for rPFS, primary analysis for TFST, and IA
for OS.

IA2: 
o
Timing: To be performed when at least 386 OS events (target number 
of OS events) are observed (approximately 23 months after the first 
participant is randomized). IA2 should be conducted at least 6 months 
after the last participant is randomized.
o
Testing: IA for OS.
Multiplicity
The Type I error rate over the multiple endpoints tested, as well as for the multiple 
analyses planned, will be strongly controlled at 2.5% (one-sided) by sequential 
interim monitoring and the methods of Maurer and Bretz [Maurer, W. 2013]. A
total of 2.0% Type I error rate is initially allocated to test OS superiority between 
2 arms, and a total of 0.5% Type I error rate is initially allocated to test rPFS 
superiority between 2 arms.
Sample Size and Power
As of Amendment 06, no final analysis of the study will be performed.
The planned sample size is approximately 780 participants, with approximately 
520 and 260 in the pembrolizumab and olaparib and abiraterone/enzalutamide 
arms, respectively. For rPFS, with 432 rPFS events, the study has approximately 
95% power to demonstrate that pembrolizumab + olaparib is superior to 
abiraterone/enzalutamide (HR: 0.65) at an overall 1-sided 0.5% α level. For OS, 
with 482 OS events, the study has about 90% power to demonstrate that 
pembrolizumab and olaparib is superior to abiraterone/enzalutamide (HR: 0.725) 
at an initial overall 1-sided 2.0% α level.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Clinical Biostatistics department of the Sponsor will generate the randomized allocation 
schedule for study intervention assignment for this protocol, and the randomization will be 
implemented in an IRT by a study vendor.
This study will be conducted as an unblinded, open-label study (ie, participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned). Although the study is open-label, 
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analyses or summaries generated by randomized treatment assignment or actual treatment 
received will be limited and documented.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
9.4.1
Efficacy Endpoints
Primary
Overall survival (OS) is defined as the time from randomization to death due to any cause.
Radiographic progression-free survival (rPFS) (PCWG-modified RECIST 1.1 by BICR)
is defined as the time from randomization to the first documented disease progression or 
death due to any cause, whichever occurs first.
Key Secondary
Time to initiation of the first subsequent anticancer therapy or death (TFST) is defined as the 
time from randomization to initiation of the first subsequent anticancer therapy or death.
Secondary
Objective response rate (PCWG-modified RECIST 1.1 by BICR) is defined as the 
proportion of participants in the analysis population who have a best overall response of 
either confirmed CR or PR.
Duration of response (DOR) (PCWG-modified RECIST 1.1 by BICR) is defined as the 
time from the earliest date of first documented evidence of confirmed CR or PR to the
earliest date of disease progression or death from any cause, whichever comes first.
Time to PSA progression is defined as the time from randomization to PSA progression. 
Participants without PSA progression will be censored at the last PSA assessment date. The 
PSA progression date is defined as the date of 1) ≥25% increase and ≥2 ng/mL above the 
nadir, confirmed by a second value ≥3 weeks later if there is PSA decline from baseline, or 
2) ≥25% increase and ≥2 ng/mL increase from baseline beyond 12 weeks if there is no PSA 
decline from baseline.
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Time to initiation of first skeletal-related event is defined as the time from randomization 
to the first symptomatic skeletal-related event, defined as:

first use of EBRT to prevent or relieve skeletal symptoms

occurrence of new symptomatic pathologic bone fracture (vertebral or nonvertebral)

occurrence of spinal cord compression

tumor-related orthopedic surgical intervention whichever comes first.
Time to radiographic soft tissue progression (soft tissue rule of PCWG-modified
RECIST 1.1 by BICR) is defined as the time from randomization to radiographic soft tissue 
progression.
Exploratory
Time to radiographic bone progression (PCWG-modified RECIST 1.1 by BICR) is 
defined as the time from randomization to radiographic bone progression.
Additional details of the efficacy measurements are described in Section 4.2.1.1.
9.4.2
Safety Endpoints
Safety measurements are described in Section 4.2.1.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters,
including AEs, laboratory values, and vital signs.
9.4.3
PRO Endpoints
Time to Pain Progression
TTPP is defined as the time from randomization to pain progression based on the BPI-SF 
Item 3 “worst pain in 24 hours” and opiate analgesic use (AQA score). Pain progression is 
defined as follows: 1) for participants who are asymptomatic at baseline, a ≥2-point change 
from baseline in the average (4-7 days) BPI-SF Item 3 score OR initiation of opioid use for 
pain; 2) for participants who are symptomatic at baseline (average BPI-SF Item 3 score >0 
and/or currently taking opioids), a ≥2-point change from baseline in the average BPI-SF Item 
3 score and an average worst pain score ≥4 and no decrease in average opioid use (≥1-point 
decrease in AQA score from a starting value of 2 or higher) OR any increase in opioid use 
(eg, 1-point change in AQA score) at 2 consecutive follow-up visits. Any participant who has 
more than 2 consecutive visits that are not evaluable for pain progression will be censored at 
the last evaluable assessment.
Details of exploratory PRO endpoints will be included in the sSAP.
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The ITT population will serve as the primary population for the analysis of efficacy data in 
this study. All randomized participants will be included in this population. Participants will 
be included in the treatment group to which they were randomized for the analysis of 
efficacy data using the ITT population.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of study intervention. Participants will be included 
in the study intervention group corresponding to the study intervention they actually received 
for the analysis of safety data using the APaT population. This will be the study intervention
group to which they were randomized except for participants who take incorrect study 
intervention for the entire treatment period; such participants will be included in the study 
intervention group corresponding to the study intervention actually received.
At least 1 laboratory, vital sign, or ECG measurement obtained after at least 1 dose of study 
intervention is required for inclusion in the analysis of the respective safety parameter. To 
assess change from baseline, a baseline measurement is also required.
Details of the approach to handling safety analyses are provided in Section 9.6.2.
9.5.3
PRO Analysis Population
The PRO analyses are based on the PRO full analysis set (FAS) population, defined as 
participants who have at least 1 PRO assessment available and have received at least 1 dose 
of study intervention.
9.6
Statistical Methods
NOTE: As of Amendment 06, the prespecified final analysis of the study described in the 
SAP will not be performed. Selected analyses of safety endpoints will be performed at end of 
study; there will be no further analyses of efficacy and PRO endpoints. The subsections 
below are retained for reference.
Statistical testing and inference for safety analyses are described in Section 9.6.2. Methods 
related to exploratory objectives will be described in the sSAP. Efficacy results that will be 
deemed to be statistically significant after consideration of the Type I error control strategy 
are described in Section 9.8. Nominal p-values may be computed for other efficacy analyses, 
but should be interpreted with caution due to potential issues of multiplicity, sample size, etc. 
Unless otherwise stated, all statistical tests will be conducted at the α=0.05 (2-sided) level. If
there are a small number of responses/events in one or more strata, for the purpose of 
analysis strata will be combined to ensure sufficient number of responses/events in each 
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stratum. Details regarding the combining of strata will be specified in the sSAP before
database lock based on a blinded review of response counts by stratum.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and key secondary
objectives. Methods related to other objectives will be described in the sSAP.
OS
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test (based on the 
stratification factors defined in Section 6.3.2). A stratified Cox proportional hazard model 
with Efron’s method of tie handling will be used to assess the magnitude of the treatment 
difference (ie, HR). The HR and its 95% CI from the stratified Cox model with a single 
treatment covariate will be reported. The stratification factors used for randomization 
(Section 6.3.2) will be applied to both the stratified log-rank test and the stratified Cox 
model. 
Participants without documented death at the time of analysis will be censored at the date of 
last known contact. The restricted mean survival time (RMST) method proposed by Uno et al
[Uno, H., et al 2014] may be used for OS to account for the possible nonproportional hazards 
effect.
rPFS
The nonparametric Kaplan-Meier method will be used to estimate the rPFS curve in each 
study intervention group. The treatment difference in rPFS will be assessed by the stratified 
log-rank test. A stratified Cox proportional hazard model with Efron’s method of tie handling 
will be used to assess the magnitude of the treatment difference (ie, HR) between the study 
intervention arms. The HR and its 95% CI from the stratified Cox model with Efron’s 
method of tie handling and with a single treatment covariate will be reported. The 
stratification factors used for randomization (Section 6.3.2) will be applied to both the 
stratified log-rank test and the stratified Cox model.
Since disease progression is assessed periodically, PD can occur any time between the last 
assessment where PD was not documented and the assessment when PD is documented. The 
true date of disease progression will be approximated by the date of the first assessment at 
which PD is objectively documented per PCWG-modified RECIST 1.1 by BICR. Death is 
always considered as a confirmed PD event. Participants who do not experience an rPFS 
event will be censored at the last disease assessment. Sensitivity analyses will be performed 
for comparison of rPFS based on the investigator’s assessment. 
To evaluate the robustness of the rPFS endpoint, 1 primary and 2 sensitivity analyses with a 
different set of censoring rules will be performed. For the primary analysis, if the events (PD 
or death) are immediately after more than 1 missed disease assessment, the data are censored 
at the last disease assessment before missing visits. In addition, data after new anticancer 
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therapy are censored at the last disease assessment before the initiation of new anticancer 
therapy.
The first sensitivity analysis follows the ITT principle; PDs/deaths are counted as events 
regardless of missed study visits or initiation of new anticancer therapy. The second 
sensitivity analysis considers discontinuation of study intervention or initiation of an 
anticancer treatment after discontinuation of study intervention due to reasons other than CR, 
whichever occurs later, to be a PD event for participants without documented PD or death. If 
a participant meets multiple criteria for censoring, the censoring criterion that occurs earliest 
will be applied. The censoring rules for primary and sensitivity analyses are summarized in
Table 12.
Table 12
Censoring Rules for Primary and Sensitivity Analyses of rPFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death documented 
after ≤1 missed disease 
assessment, and before 
new anticancer therapy, if 
any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
Death or progression 
after ≥ 2 consecutively
missed disease 
assessments without 
further valid non-PD 
disease assessments, or 
after new anticancer 
therapy
Censored at last disease 
assessment before
the earlier date of ≥2 
consecutive missed disease 
assessment and new 
anticancer therapy, if any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
No PD and no death; and 
new anticancer treatment 
is not initiated
Censored at last disease 
assessment 
Censored at last 
disease assessment 
Progressed at treatment 
discontinuation due to 
reasons other than CR; 
otherwise censored at last 
disease assessment if still 
on study treatment or 
completed study 
treatment.
No PD and no death; new 
anticancer treatment is 
initiated
Censored at last disease 
assessment before new 
anticancer treatment 
Censored at last 
disease assessment
Progressed at date of new 
anticancer treatment
Abbreviations: PD=progressive disease; rPFS=radiographic progression-free survival.
In case the proportional hazards assumption is not valid, supportive analyses using the RMST 
method may be conducted for rPFS to account for the possible nonproportional hazards 
effect.
Further details of sensitivity analyses will be described in the sSAP as needed.
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TFST
The nonparametric Kaplan-Meier method will be used to estimate the TFST curve in each 
treatment arm. The treatment difference in TFST will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (ie, HR) between the treatment arms. 
The HR and its 95% CI from the stratified Cox model with Efron’s method of tie handling 
and with a single treatment covariate will be reported. The stratification factors used for 
randomization (Section 6.3.2) will be applied to both the stratified log-rank test and the 
stratified Cox model.
Details of efficacy analyses for other endpoints will be provided in the sSAP.
Analysis Strategy for Key Efficacy Endpoints
Table 13 summarizes the primary analysis approach for key efficacy endpoints.
Table 13
Efficacy Analysis Methods for Key Efficacy Endpoints
Endpoint/Variable
Statistical Methoda
Analysis 
Population
Missing Data Approach
Primary Analyses
OS
Testing: Stratified Log-rank Test
Estimation: Stratified Cox model 
with Efron’s tie handling method
ITT
Censored at last known alive date
rPFS per PCWG-
modified 
RECIST 1.1 as 
assessed by BICR
Testing: Stratified Log-rank Test
Estimation: Stratified Cox model 
with Efron’s tie handling method
ITT
Censored according to rules in 
Table 12
Key Secondary Analysis
TFST
Testing: Stratified Log-rank Test
Estimation: Stratified Cox model 
with Efron’s tie handling method
ITT
Censored at the last known time to 
have not received subsequent new 
anticancer therapy
Abbreviations: BICR=blinded independent central review; ITT=intention to treat; TFST=time to initiation of 
the first subsequent anticancer therapy or death; OS=overall survival; PCWG=Prostate Cancer Working 
Group; rPFS=radiographic progression-free survival.
aStatistical models are described in further detail in the text. For stratified analyses, the stratification factors 
used for randomization (Section 6.3.2) will be applied to the analysis. Small strata will be combined in a way 
specified by a blinded statistician before the analysis.
The strategy to address multiplicity issues regarding multiple efficacy endpoints and IAs is 
described in Sections 9.7 and 9.8.
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9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements. 
The analysis of safety results will follow a tiered approach (Table 14). The tiers differ with 
respect to the analyses that will be performed. Adverse experiences (specific terms as well as 
system organ class terms) and events that meet predefined limits of change in laboratory and 
vital signs and ECG parameters are either prespecified as Tier 1 endpoints or will be 
classified as belonging to Tier 2 or Tier 3, based on the observed proportions of participants 
with an event.
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute Tier 1 safety 
endpoints that will be participant to inferential testing for statistical significance.
AEs of special interest that are immune-mediated or potentially immune-mediated are well
documented and will be evaluated separately; however, these events have been characterized 
consistently throughout the pembrolizumab clinical development program and determination 
of statistical significance is not expected to add value to the safety evaluation. Finally, there 
are no known AEs associated with participants with prostate cancer for which determination 
of a p-value is expected to impact the safety assessment. Therefore, there are no Tier 1 events 
for this protocol.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [Miettinen, O. 1985].
Membership in Tier 2 requires that at least 10% of participants in any study intervention
group show the event; all other AEs and predefined limits of change will belong to Tier 3. 
The threshold of at least 10% of participants was chosen for Tier 2 events because the 
population enrolled in this study are in critical condition and usually experience various AEs 
of similar types regardless of treatment; events reported less frequently than 10% of 
participants would obscure assessment of the overall safety profile and add little to the 
interpretation of potentially meaningful treatment differences. In addition, Grade 3 to 5 AEs 
(≥5% of participants in 1 of the treatment groups) and SAEs (≥5% of participants in 1 of the 
treatment groups) will be considered Tier 2 endpoints. Because many 95% CIs may be 
provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in safety review, not a formal method for assessing the 
statistical significance of the between-group differences in AEs and safety parameters that 
meet predefined limits of change.
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Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG
parameters, summary statistics for baseline, on treatment, and change from baseline values 
will be provided by study intervention group in table format.
Table 14
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE (≥10% of participants in one of the treatment 
groups)
X
X
Any Grade 3 to 5 AE (≥5% of participants in one of the 
treatment groups)
X
X
Any serious AE (≥5% of participants in one of the 
treatment groups)
X
X
Tier 3
Any AE
X
Change from baseline results (laboratory test toxicity 
grade, vital signs, ECGs)
X
Abbreviations: AE=adverse event; CI=confidence interval; ECG=electrocardiogram; X=results will be 
provided.
9.6.3
Analysis Methods for PRO Endpoints
For TTPP, the Kaplan-Meier method will be used to estimate the survival curves for TTPP, 
separately, in each study intervention arm. In addition, corresponding survival curves will be 
estimated by study intervention arm. Stratified Cox proportional hazards models with Efron’s 
method of tie handling will be used to assess the magnitude of the treatment difference. 
Stratification factors used for randomization will be used in the stratified Cox proportional 
hazards models. The HR, 95% CI, and nominal p-value will be reported.
Details of additional PRO analyses will be included in the sSAP.
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9.6.4
Demographic and Baseline Characteristics
The comparability of the study intervention groups for each relevant demographic and 
baseline characteristic will be assessed using tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reason for screening failure and discontinuation 
will be displayed. Demographic variables, baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by study intervention
either by descriptive statistics or categorical tables.
9.7
Interim Analyses
NOTE: As of Amendment 06, the prespecified final analysis of the study described in the 
SAP will not be performed. This section is retained for reference. 
An eDMC will serve as the primary reviewer of the results of the IAs and will make 
recommendations for discontinuation of the study or protocol modifications to an Executive 
Oversight Committee (EOC) of the Sponsor. Depending on the recommendation of the 
eDMC, the Sponsor may prepare a regulatory submission. Additional logistic details, 
revisions to the above plan, and data monitoring guidance will be provided in the eDMC 
Charter.
9.7.1
Efficacy Interim Analyses
Two IAs and a final analysis are planned for this study. There is no plan to stop the study 
before superiority hypotheses for OS have been adequately evaluated. However, earlier 
positive findings may form the basis for earlier regulatory submission based on the 
recommendation of the eDMC. The final analysis is to be performed approximately 
29 months after the first participant is randomized.
The analyses planned, endpoints evaluated, and drivers of the timing are summarized in
Table 15. Type I error control for the efficacy analyses, as well as efficacy bounds, are 
described in Section 9.8.
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Table 15
Summary of Interim and Final Analyses
Analysis
Endpoint(s)
Criteria for Conduct of 
Analysis
Estimated Time After 
First Participant 
Randomized
Primary Purpose 
of Analysis
IA 1: final rPFS
and TFST
analyses; interim 
OS analysis
rPFS, TFST, 
OS
Enrollment is complete
At least 360 rPFS events
At least 241 OS events
(target number of OS 
events)
If rPFS event number
achieves but OS event 
number does not achieve, 
IA1 may be delayed for up 
to 3 months.
~17 months
rPFS final 
analysis
TFST final 
analysis
OS IA
IA 2: interim OS 
analysis
OS
At least 386 OS events
(target number of OS 
events)
At least 6 months after the 
last participant is
randomized.
~23 months
OS IA
Final analysis: 
final OS analysis
OS
At least 482 OS events
(target number of OS 
events)
At least 12 months after 
the last participant is 
randomized.
~29 months
OS final 
analysis
Abbreviations: IA=interim analysis; OS=overall survival; rPFS=radiographic progression-free survival; 
TFST=time to initiation of the first subsequent anticancer therapy or death.
9.7.2
Safety Interim Analyses
The eDMC conducted regular safety IAs. The timing of these safety IAs was specified in the 
eDMC charter. No further analysis is warranted.
9.8
Multiplicity
NOTE: As of Amendment 06, the prespecified final analysis of the study described in the 
SAP will not be performed. This section is retained for reference. 
The study uses the graphical method of Maurer and Bretz [Maurer, W. 2013] to strongly 
control multiplicity for multiple hypotheses as well as IAs. Figure 3 shows the initial one-
sided α allocation for each hypothesis in the ellipse representing the hypothesis. The weights 
for reallocation from each hypothesis to the others are represented in the boxes on the lines 
connecting the hypotheses.
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Figure 3
Multiplicity Graph for One-sided Alpha Reallocation Strategy
9.8.1
rPFS
This study initially allocates 1-sided α=0.005 for superiority testing of rPFS between 2 study 
intervention arms. If the OS null hypothesis has been rejected, the rPFS hypothesis will be 
tested at a Type I error level of =0.025.
Table 16 shows the boundary properties for rPFS. Note that the final row indicates the total 
power to reject the null hypothesis for rPFS superiority. In addition, if testing of rPFS is not 
positive at IA1 but testing of OS is positive at IA2 or final analysis, then rPFS at IA1 will be
retested.
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Table 16
Efficacy Boundaries and Properties for rPFS
Analysis
Value
α=0.005
α=0.025
IA1:
N: 780
Events: 432a
Month: 16.7
Z
2.576
1.96
p (1-sided)c
0.005
0.025
HR at boundd
0.769
0.819
P(Cross) if HR=1e
0.005
0.025
P(Cross) if HR=0.65f
95%
98.8%
IA1:
N: 780
Events: 360b
(Required rPFS events)
Z 
2.576
1.96
p (1-sided)c
0.005
0.025
HR at boundd
0.75
0.803
P(Cross) if HR=1e
0.005
0.025
P(Cross) if HR=0.65f
90%
97.1%
Abbreviations: HR=hazard ratio; IA=interim analysis; rPFS=radiographic progression-free survival.
aProjected rPFS events
bRequired rPFS events
cp (1-sided) is the nominal α for testing.
dHR at bound is the approximate HR required to reach an efficacy bound.
eP(Cross if HR=1) is the cumulative probability of crossing a bound under the null hypothesis.
fP(Cross if HR=0.725) is the cumulative probability of crossing a bound under the alternative hypothesis.
9.8.2
OS
This study initially allocates 1-sided α=0.020 for superiority testing of OS between the 
2 treatment arms. If both the rPFS and TFST null hypotheses have been rejected, then the OS 
hypothesis will be tested at a Type I error level of =0.025.
Table 17 shows the boundary properties for the IAs and the final OS analysis, which were 
derived using a Lan-DeMets O’Brien-Fleming approximation spending function. Note that 
the final row indicates the total power to reject the null hypothesis for OS superiority. If the 
actual number of OS events differs from that specified in Table 17, the bounds will be 
adjusted using the Lan-DeMets O’Brien-Fleming α spending function accordingly. The 
cumulative α spent in the IA will not exceed the prespecified level based on the projected 
number of events as shown in Table 17 (ie, if the number of events exceeds the prespecified 
event number in the IA, the prespecified cumulative α spent in the IA based on the projected 
number of events will be used). Otherwise, cumulative α based on the observed number of 
events will be used. The boundary thresholds at final analysis will be updated using the 
actual observed number of events at previous IAs and final analysis.
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Table 17
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Value
α=0.020
α=0.025
IA1: 50%
N: 780
Events: 241
Month: 16.7
Z
3.0896
2.9626 
p (1-sided)a
0.0010
0.0015 
HR at boundb
0.6554
0.6667 
P(Cross) if HR=1c
0.0010
0.0015 
P(Cross) if HR=0.725d
0.2393
0.2804 
IA2: 80%
N: 780
Events: 386
Month: 22.7
Z
2.3668
2.2662 
p (1-sided)a
0.0090
0.0117 
HR at boundb
0.7743
0.7826 
P(Cross) if HR=1c
0.0093
0.0122 
P(Cross) if HR=0.725d
0.7423
0.7740 
Final analysis
N: 780
Events: 482
Month: 28.3
Z
2.1160
2.0277 
p (1-sided)a
0.0172
0.0213 
HR at boundb
0.8150
0.8219 
P(Cross) if HR=1c
0.0200
0.0250 
P(Cross) if HR=0.725d
0.9000
0.9150 
Abbreviations: HR=hazard ratio; IA=interim analysis.
*Percentage of expected number of events at final analysis.
a p (1-sided) is the nominal α for testing.
b HR at bound is the approximate HR required to reach an efficacy bound.
c P(Cross if HR=1) is the cumulative probability of crossing a bound under the null hypothesis.
d P(Cross if HR=0.725) is the cumulative probability of crossing a bound under the alternative hypothesis.
9.8.3
TFST
The key secondary TFST hypothesis will be tested at the time of IA1. The TFST hypothesis 
is initially allocated a Type I error =0% and thus cannot be tested unless the rPFS null 
hypothesis has been rejected. If the rPFS null hypothesis has been rejected and the OS null 
hypothesis has not been rejected, then the TFST hypothesis will be tested at a Type I error of 
0.5%. If both the rPFS and OS null hypotheses have been rejected, then the TFST hypothesis 
will be tested at a Type I error level of α=2.5%.
Table 18 shows the boundary properties for TFST. Note that the final row indicates the total 
power to reject the null hypothesis for TFST superiority. In addition, if testing of TFST is not 
positive at IA1 but retesting of rPFS at IA1 is positive, then TFST at IA1 will be retested. 
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Table 18
Efficacy Boundaries and Properties for TFST
Analysis
Value
α=0.005
α=0.025
IA1:
N: 780
Events: 432a
Month: 16.7
Z 
2.576
1.96
p (1-sided)b
0.005
0.025
HR at boundc
0.769
0.819
P(Cross) if HR=1d
0.005
0.025
P(Cross) if HR=0.65e
95%
98.8%
Abbreviations: HR=hazard ratio; IA=interim analysis; TFST=time to initiation of the first subsequent 
anticancer therapy or death.
a Projected TFST events.
b p (1-sided) is the nominal α for testing.
c HR at bound is the approximate HR required to reach an efficacy bound.
d P(Cross if HR=1) is the cumulative probability of crossing a bound under the null hypothesis.
e P(Cross if HR=0.725) is the cumulative probability of crossing a bound under the alternative hypothesis.
9.8.4
Safety Analyses
The eDMC has responsibility for assessment of overall risk/benefit. When prompted by
safety concerns, the eDMC can request corresponding efficacy data. External DMC review of
efficacy data to assess the overall risk/benefit to study participants will not require a
multiplicity adjustment typically associated with a planned efficacy IA. However, to account 
for any multiplicity concerns raised by the eDMC review of unplanned efficacy data 
prompted by safety concerns, a sensitivity analysis for efficacy endpoints adopting a 
conservative multiplicity adjustment will be prespecified in the sSAP. This analysis will be 
performed if requested by the eDMC.
9.9
Sample Size and Power Calculations
NOTE: As of Amendment 06, the prespecified final analysis of the study described in the 
SAP will not be performed. This section is retained for reference.
The sample size is estimated based on the primary endpoint OS. 
A total of approximately 780 participants will be randomized in a 2:1 ratio to the 
pembrolizumab and olaparib arm and the abiraterone/enzalutamide arm; approximately 
520 and 260 participants, respectively.
The final analysis of OS is event-driven and will be conducted after at least 482 OS events 
(target number of OS events) have been observed between the 2 treatment arms unless OS is 
proven at an earlier IA. It is expected to occur around 29 months after the first participant is 
randomized (depending on enrollment rate and event accumulation rate). The final analysis 
should be conducted at least 12 months after the last participant is randomized to maintain 
sufficient minimal follow-up duration.
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With 482 OS events, the study has approximately 90% (91.5%) power to demonstrate that 
men treated with pembrolizumab and olaparib have a longer median OS than do those treated 
with abiraterone acetate or enzalutamide at a 1-sided significance level of 0.020 (0.025) if the 
underlying constant HR is 0.725. Sample size and power calculations are based on the 
following assumptions: 1) an HR of 0.725 where OS follows an exponential distribution with 
a median of 14.5 months in the pembrolizumab and olaparib arm and a median of 10.5
months in the control arm; 2) IAs for efficacy evaluation as outlined in Section 9.7, 3) an 
enrollment rate of 60 participants per month with a 6-month ramp-up time; and 4) an 
approximately monthly dropout rate of 0.2%.
The final analysis of rPFS will be conducted when (1) enrollment is complete, (2) at least 
360 rPFS events are observed, and (3) at least 241 OS events (target number of OS events) 
are observed. If rPFS event number achieves but OS event number does not achieve, IA1 
may be delayed for up to 3 months. It is expected to occur around 17 months after the first 
participant is randomized (depending on enrollment rate and event accumulation rate), with 
about 432 rPFS events. 
With 432 rPFS events, the study has approximately 95% (98%) power to demonstrate that 
men treated with pembrolizumab + olaparib have a longer median rPFS than do those treated 
with abiraterone or enzalutamide at a 1-sided significance level of 0.005 (0.025) if the 
underlying constant HR is 0.65. These calculations are based on the following assumptions: 
1) an HR of 0.65 where rPFS follows an exponential distribution with a median of 
4.6 months in the pembrolizumab and olaparib arm and a median of 3 months in the control 
group, 2) IAs for efficacy evaluation as outlined in Section 9.7, 3) an enrollment rate of 60 
participants per month with a 6-month ramp-up time; and 4) a monthly dropout rate of 5%.
The final analysis of TFST will be conducted at IA1, and approximately 432 TFST events are 
expected. With 432 TFST events, the study has approximately 95% (98%) power to 
demonstrate that men treated with pembrolizumab and olaparib have a longer median TFST
than do those treated with abiraterone or enzalutamide at a 1-sided significance level of 0.005 
(0.025) if the underlying constant HR is 0.65. These calculations are based on the following 
assumptions: 1) an HR of 0.65 where TFST follows an exponential distribution with a 
median of 4.6 months in the pembrolizumab and olaparib arm and a median of 3 months in 
the control arm, 2) IAs for efficacy evaluation as outlined in Section 9.7, 3) an enrollment 
rate of 60 participants per month with a 6-month ramp-up time; and 4) a monthly dropout 
rate of 5%.
The sample size and power calculations for rPFS, TFST, and OS were performed using
software R (package “gsDesign”) and EAST 6.4.
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9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoints will be estimated and plotted within each category of the following classification 
variables:

Age group: <65 years versus ≥65 years

Race: white versus nonwhite

ECOG performance status: 0 versus 1

Measurable disease at baseline: yes versus no

Prior NHA treatment: abiraterone acetate versus enzalutamide
In addition, a forest plot will be produced, which provides the estimated point estimates and 
CIs for the treatment effect across the categories of subgroups listed above.
If there are a small number of responses/events in one or more strata, then, for analysis, strata 
will be combined to ensure a sufficient number of responses/events in each stratum. Details 
regarding the combining of strata will be specified in the sSAP before database lock based on 
a blinded review of response counts by stratum.
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure for olaparib, abiraterone, and enzalutamide will be summarized as 
duration of treatment in days. The extent of exposure for pembrolizumab will be summarized 
as duration of treatment in cycles. Dose interruption for each drug and dose reduction or dose 
increase for olaparib will be summarized. Summary statistics will be provided for extent of 
exposure for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
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 that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her 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.
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Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
Executive Oversight Committee
The EOC is composed of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an eDMC will monitor
the interim data from this study. The voting members of the committee are external to the 
Sponsor. The members of the eDMC must not be involved with the study in any other way 
(eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The eDMC will make recommendations to the EOC regarding steps to ensure both 
participant safety and the continued ethical integrity of the study. Also, the eDMC will 
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review interim study results, consider the overall risk and benefit to study participants 
(Section 9.7) and recommend to the EOC whether the study should continue in accordance 
with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of eDMC reports, minutes, and recommendations will be described in the eDMC charter that 
is reviewed and approved by all eDMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. 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 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, 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.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
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(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
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requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site 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 ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF 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/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 19 will be performed by the central laboratory.

Results of predose laboratory procedures must be reviewed by the investigator or 
qualified designee and found acceptable before each dose of study intervention. Local 
laboratory results are permitted if the central laboratory results are not available in time 
for study intervention administration and/or response evaluation. If a sample for local 
analysis is used, it is important that the sample for central analysis is obtained in parallel. 
Additionally, if the use of local laboratory tests results in a change in participant 
management or is considered clinically significant by the investigator (eg, SAE, AE, or 
dose modification), the results must be recorded in the appropriate CRF.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.

PD-L1, PSA, and CTC results are not reported to sites, to prevent early withdrawal of 
participants from study intervention.
Table 19
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count 
RBC indices:
MCV
MCH
% reticulocytes
WBC count with differential:
Neutrophils (ANC)
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC count
Hemoglobin
Hematocrit
Chemistry
Blood urea 
nitrogen 
(BUN)
Potassium
Aspartate aminotransferase
(AST)/serum glutamic 
oxaloacetic transaminase 
(SGOT)
Total bilirubin (and direct 
bilirubin if total bilirubin is 
elevated above the upper limit 
of normal)
Albumin
Bicarbonate
Chloride
Phosphorus
Creatinine
Sodium
Alanine aminotransferase 
(ALT)/serum glutamic 
pyruvic transaminase 
(SGPT)
Total Protein
Glucose 
(fasting or 
nonfasting)
Calcium
Alkaline phosphatase
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Laboratory 
Assessments
Parameters
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, (bilirubin, urobilinogen, nitrite, leukocyte esterase) 

Microscopic examination (if blood or protein is abnormal)
Other tests
Serology (HIV antibody, hepatitis B surface antigen, and hepatitis C virus antibody), if 
required by local regulations

Testosterone

Thyroid function tests

PT or INR and PTT/aPTT
The investigator (or medically qualified designee) must document his or her review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
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
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
1. Results in death
2. Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
3. Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
4. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
5. Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis.
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6. Other important medical events

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.

Is a new cancer (that is not a condition of the study)

Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
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
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.

The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 4.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality

Did the Sponsor’s product cause the AE?

The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.

The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
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count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.

Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
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
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.

Use the following scale of criteria as guidance (not all criteria must be present to be
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor's product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the AE 
onset relative to administration of the Sponsor’s product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product. (Also 
entered for a participant with overdose without an associated AE.)

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.

For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
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
New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.

Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.

Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable
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10.5
Appendix 5: Contraceptive Guidance
Definition
Women of Childbearing Potential (WOCBP) Nonparticipant Only
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):

Women in the following categories are not considered WOCBP:
-
Premenarchal
-
Premenopausal female with 1 of the following:
-
Hysterectomy
-
Bilateral salpingectomy
-
Bilateral oophorectomy
-
Permanent infertility due to an alternate medical cause other than the above (eg, 
Mullerian agenesis, androgen insensitivity.
-
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways drugs/vaccines may interact with
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research.
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research 
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in the FBR. FBR specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
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to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1.
National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.
International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3.
Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4.
Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Laboratory Testing
HIV Status
While the protocol does not require specific testing for HIV at screening, it does require 
testing if required by the local health authority. Sites should check with their local health 
authority to inquire if country-specific guidance regarding mandatory HIV testing at 
screening is required. This can also be performed per the discretion of the investigator, if 
desired. Perform this testing locally if required.
Hepatitis B/C Status
While the protocol does not require specific testing for hepatitis B/C at screening, it does 
require testing if required by the local health authority. Sites should check with their local 
health authority to inquire if country-specific guidance regarding mandatory hepatitis B/C 
testing at screening is required. This can also be performed per the discretion of the 
investigator, if desired. Perform this testing locally if required.
10.7.2
Country-specific Requirements
Germany
Section 5.2: Exclusion Criteria
HIV testing and hepatitis B/C screening are required evaluations for study entry and must be 
performed to evaluate eligibility. This testing can be performed at any time during the 
screening period. Perform this testing locally if required.
Section 6.5.1: Rescue Medications and Supportive Care
Live vaccines should not be administered to participants for 90 days after the last dose of 
study intervention is administered.
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10.8
Appendix 8: Description of the Prostate Cancer Working Group (PCWG) 
Process for Assessment of Bone Lesions
The rules for evaluation of response and progression based on bone lesions were created by 
the Prostate Cancer Working Group and published as part of both PCWG2 and PCWG3 
[Scher, H. I., et al 2016]. All bone lesions are evaluated according to these rules, including 
assessment at screening/baseline and evaluation of response.
10.8.1
Imaging Methods
The PCWG rules were designed based on radionuclide (99mTc) bone scintigraphy. Other 
modalities, including fluorodeoxyglucose positron emission tomography (FDG-PET), 
sodium fluoride PET, bone MRI, etc. may have individual advantages, but the PCWG rules 
were not created with the performance characteristics of these methods in mind, and these 
methods should not be used instead of radionuclide bone scan. 
Only bone lesions seen by bone scan may be followed for assessment of tumor treatment 
response. Bone disease seen by CT only (not visible on bone scan) is presumed not to 
represent active disease and should not be documented as a bone lesion (sclerotic lesions 
seen on CT may represent healed disease or nonmalignant confounders such as bone infarcts 
or other benign findings).
10.8.2
Documentation of Bone Lesions at Baseline
At baseline, individual bone lesions may be recorded as nontarget lesions only, and the 
number of bone lesions should be noted.
10.8.3
Assessment of Bone Response at Subsequent Imaging Time Points
At all follow-up time points, bone disease will be classified as PD (progressive disease), PDu 
(progressive disease unconfirmed), Non-PD (no progressive disease), NED (no evidence of 
disease), or NE (nonevaluable). The definitions are summarized in the following table and 
described in more detail below.
Bone Response
Definition
PD
Progressive disease: 
2 new lesions, not flare, persistent
PDu
Progressive disease unconfirmed: 
Temporary marker of possible PD, to be updated to PD or non-PD once a subsequent 
scan is available. 
If this is the final visit, the visit response will remain PDu
Non-PD
Nonprogressive disease: 
At least 1 bone lesion present, but not enough to trigger PD
NE
Nonevaluable: 
Status of bone lesions cannot be determined (scan quality, scan missing, etc.)
NED
No evidence of disease: 
No lesions seen on bone scan
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10.8.4
Descriptions of Bone Response Categories
No Evidence of Disease
No lesions seen on bone scan at this visit. Either none were seen at baseline, or all 
completely resolved on subsequent imaging.
Nonprogression (Non-PD)
At least 1 bone lesion is present on the scan at this visit but the conditions for progression 
have not been met, because there are not at least 2 new lesions present.
Unconfirmed Progressive Disease (PDu)
At least 2 new bone lesions are present, but an additional scan is required for confirmation. 
This response category is meant as a placeholder that reflects temporary uncertainty and is 
updated to PD or non-PD once a subsequent bone scan is available.
Progressive Disease (PD)
At least 2 new bone lesions are present, which have been confirmed to not represent flare or 
any other confounder (see below), and which are persistent for at least 6 weeks. The new 
bone lesions do not all have to appear at the same time. Thus, if 1 new lesion appears at visit 
N, and another new lesion at visit N+1, visit N+1 is considered to represent progressive 
disease.
Confirmation of Progression
Radiographic progression of bone lesions is defined as the appearance of ≥2 new bone 
lesions on radionuclide bone scan. When ≥2 new bone lesions are first observed this is 
classified as PDu, which marks the possibility of progression that will be resolved by the next 
scan.
New Lesions Within the Flare Window (<12 Weeks)
After a scan classified as PDu within the first 12 weeks of treatment, if the next bone scan 
outside the flare window shows at least 2 additional new bone lesions in addition to the new
lesions seen on the prior scan, the initial progression is considered confirmed, and the bone 
scan response is updated to PD. Because this requires at least 2 new lesions followed by 
another 2 new lesions, this is known as the “2+2 rule”.
If the next bone scan outside the flare window does not show at least 2 additional new bone 
lesions, the lesions seen on the prior scan within the flare window are considered to be 
pre-existing lesions that became more visible because of the tumor flare phenomenon.

The bone response at the prior visit is updated to non-PD.
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
The bone lesions seen within the flare window are ignored for the purposes of counting 
new lesions at later time points, since they were not new. This may be called
“rebaselining”.
New Lesions Outside the Flare Window (>12 Weeks)
After a scan classified as PDu after the first 12 weeks of treatment, if at least 2 of the new 
lesions seen on that scan persist on the next bone scan performed at least 6 weeks later, this 
confirms the initial progression. The prior response is then updated to PD. If the new lesions 
have disappeared on this later scan, the prior response is updated to non-PD because these 
lesions are presumed to be nonmalignant in nature. No rebaselining of lesions will occur in 
this scenario.
10.8.5
Superscan
A “superscan” occurs when there is diffuse skeletal involvement by tumor, such that 
individual bone lesions are not distinguishable. The bone scan may initially appear normal 
because the increased bone uptake may be uniform, but can be distinguished by the faint or 
absent activity in the kidneys and urinary tract.
If there is a true superscan at baseline, identifying individual new bone lesions and 
determining progression based on bone lesions may be impossible. 
If a superscan occurs after baseline, the bone response will be recorded as PD. No subsequent 
imaging will be required for confirmation, because a superscan is extremely unlikely to be 
caused by benign conditions or tumor flare.
10.8.6
Management After Confirmed PD
If repeat imaging does confirm PD, participants will be discontinued from study intervention.
Note: If a participant has confirmed radiographic progression as defined above but is 
achieving a clinically meaningful benefit, an exception to continue study intervention may be 
considered after consultation with the Sponsor. In this case, if study intervention is 
continued, tumor imaging should continue (See Section 8.2).
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10.9
Appendix 9: Description of the iRECIST Process for Assessment of Disease 
Progression
Not applicable
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
ABI
abiraterone acetate
ADP
adenosine diphosphate
ADT
androgen deprivation therapy
AE
adverse event 
ALT
alanine aminotransferase
AML
acute myeloid leukemia
APaT
all participants as treated
AQA
Analgesic Quantification Algorithm
AST
aspartate aminotransferase
ATM
ataxia-telangiectasia mutated
BICR
blinded independent central review
BID
twice daily
BP
blood pressure
BPI-SF
Brief Pain Inventory-Short Form
BRCAm
breast cancer susceptibility gene 1/2 mutations
CD28
cluster of differentiation 28
CD3 ζ
cluster of differentiation 3 zeta
CI
confidence interval
CNS
central nervous system 
CR
complete response
CrCl
creatinine clearance
CRF
case report form 
CT
computed tomography
CTC
circulating tumor cell
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor cell deoxyribonucleic acid
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CYP
cytochrome P450
DCR
disease control rate
DNA
deoxyribonucleic acid 
DOR
duration of response
DSB
double strand break
EBRT
external-beam radiation therapy
ECG
electrocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data collection
eDMC
external Data Monitoring Committee
EMA
European Medicines Agency
EOC
Executive Oversight Committee
ePRO
electronic patient-reported outcome
EQ-5D-5L
EuroQoL 5- dimension, 5-level health state utility
ESMO
European Society for Medical Oncology
FAS
final analysis set
FACT-G
Functional Assessment of Cancer Therapy-General
FACT-P
Functional Assessment of Cancer Therapy-Prostate
FDAAA
Food and Drug Administration Amendments Act
FT3
free triiodothyronine
FT4
free thyroxine
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Abbreviation
Expanded Term
GCP
Good Clinical Practice 
G-CSF
granulocyte colony-stimulating factor
GnRH
gonadotropin-releasing hormone
HIV
human immunodeficiency virus
HR
hazard ratio
HRD
homologous repair deficiency
HRQoL
health-related quality of life
HRR
homologous recombination repair
IA
interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
iCRO
imaging contract research organization
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IMP
investigational medicinal product
irAE
immune-related adverse event
IRB
Institutional Review Board 
IRT
interactive response technology
ITT
intent to treat
IV
intravenous(ly)
KN
Keynote
LHRH
luteinizing hormone-releasing hormone
LOH
loss of heterozygosity
mAb
monoclonal antibody
mCRPC
metastatic castration-resistant prostate cancer
MDS
myelodysplastic syndrome
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NE
nonevaluable
NED
no evidence of disease
NF-κB
nuclear factor kappa light chain enhancer of activated B-cells
NHA
next-generation hormonal agent
NHEJ
nonhomologous end-joining
NIMP
noninvestigational medicinal product
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PARP
polyadenosine 5’ diphosphoribose (polyADP ribose) polymerization
PBPK
physiologically based pharmacokinetics
PCWG
Prostate Cancer Working Group
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PDu
progressive disease unconfirmed
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Abbreviation
Expanded Term
PET
positron emission tomography
PFS
progression-free survival
PIN
personal identification number
PK
pharmacokinetics
PKCθ
protein kinase C-theta
PO
oral(ly)
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PRO
patient-reported outcome
PSA
prostate-specific antigen
Q2W
every 2 weeks
Q3W
every 3 weeks
Q9W
every 9 weeks
Q12W
every 12 weeks
QD
once daily
RBC
red blood cell
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RMST
Restricted Mean Survival Time
RNA
ribonucleic acid
rPFS
radiologic progression-free survival
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SCF
Sponsor Communication Form
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SoA
schedule of activities
SOC
standard of care
SOP
standard operating procedure
sSAP
sSupplemental Statistical Analysis Plan
SSB
single strand break
SSRE
symptomatic skeletal-related event
STAMPEDE
Systemic Therapy in Advancing or Metastatic Prostate Cancer
T1DM
type 1 diabetes mellitus
TFST
time to initiation of the first subsequent anticancer therapy
TOPARP-A
Trial of PARP Inhibition in Prostate Cancer
TTPP
time to pain progression
ULN
upper limit of normal
US
United States
WBC
white blood cell
WOCBP
woman/women of childbearing potential
ZAP70
zeta chain-associated protein kinase
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10.11 Appendix 11: Eastern Cooperative Oncology Group Performance Status
Grade
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the
Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55. http://ecog-acrin.org/resources/ecog-performance-
status
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11
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