A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) Plus Enzalutamide Versus Placebo Plus Enzalutamide in Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-641)
Phase: PHASE3
Conditions: Prostatic Neoplasms
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 3, Randomized, Double-blind Trial of 
Pembrolizumab (MK-3475) Plus Enzalutamide 
Versus Placebo Plus Enzalutamide in Participants 
With Metastatic Castration-Resistant Prostate 
Cancer (mCRPC)
NCT03834493
22-May-2023

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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, Double-blind Trial of Pembrolizumab (MK-3475) 
Plus Enzalutamide Versus Placebo Plus Enzalutamide in Participants With Metastatic 
Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-641)
Protocol Number: 641-09
Compound Number: MK-3475
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
122753
EudraCT
2018-004117-40
EU CT
2022-500785-10-00
Approval Date: 22 May 2023
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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 09
22-MAY-2023
Protocol amended consistent with recommendations of the eDMC after an 
interim review of the data;
 
Amendment 08
02-NOV-2022
To update the Statistical Analysis Plan by adding minimum follow-up time for 
the interim analyses.
Amendment 07
02-JUN-2022
Amendment 06
12-OCT-2021
 
 
Amendment 05
14-MAY-2021
To update the dose modification and toxicity management guidelines for 
immune-related adverse events (irAEs).
Amendment 04
11-DEC-2020
To revise eligibility criteria to align with the latest standard of care (NHAs given 
prior to mCRPC) and to clarify the verification of progression language.
Amendment 03
03-APR-2020
 
Amendment 02
05-SEP-2019
Corrections to the Schedule of Activities, Objectives, and Appendices, and 
minor edits throughout.
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Document
Date of Issue
Overall Rationale
Amendment 01
03-JUL-2019
Adding country-specific requirements for the United Kingdom.
Original Protocol
18-JAN-2019
N/A
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 09
Overall Rationale for the Amendments:
Protocol amended consistent with recommendations of the eDMC after an interim review of the data; specifically, to stop the study for
futility per the criteria prespecified in the sSAP.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis, Hypotheses, Objectives, 
and Endpoints
2.3 Benefit/Risk Assessment
3 Hypotheses, Objectives, and Endpoints
4.1 Overall Design
4.4.1 Clinical Criteria for Early Study 
Termination
9 Statistical Analysis Plan
Added that based on the safety and efficacy 
results of IA1, the eDMC recommended 
stopping the study for futility per the 
futility criteria prespecified in the sSAP. 
To inform of the decision to stop this 
clinical study.
1.1 Synopsis, Hypotheses, Objectives, 
and Endpoints
3 Hypotheses, Objectives, and Endpoints
4.1 Overall Design
9 Statistical Analysis Plan
9.1 Statistical Analysis Plan Summary
Added that prespecified IA2 and final 
analysis of the study described in the SAP 
will not be performed, safety analysis will 
be performed at the end of the study, and
there will be no further analyses for 
efficacy and PRO endpoints.
To inform of plans for further analyses.
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Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis, Hypotheses, Objectives, 
and Endpoints
2.3 Benefit/Risk Assessment
3 Hypotheses, Objectives, and Endpoints
4.1 Overall Design
6.3.3 Blinding
8.1.10 Participant Blinding/Unblinding
9 Statistical Analysis Plan
Added that the study has been unblinded.
To clarify status of study blind.
1.1 Synopsis, Hypotheses, Objectives, 
and Endpoints
1.3.1 Initial Treatment Phase 
(Pembrolizumab/Placebo Plus 
Enzalutamide)
3 Hypotheses, Objectives, and Endpoints
4.1 Overall Design
6.1 Study Intervention(s) Administered
9 Statistical Analysis Plan Summary
Added that all participants should be 
discontinued from study intervention; 
however, participants deriving clinical 
benefit may have the option to continue 
receiving the combination of enzalutamide 
and pembrolizumab or transition to SOC. 
In Sections 1.1, 3, 4.1, and 6.1 only, added 
that if enzalutamide as SOC is not 
accessible off-study to the participant, 
central sourcing may continue.
To clarify how participants may 
continue to receive study intervention.
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Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis, Hypotheses, Objectives, 
and Endpoints
1.3.1 Initial Treatment Phase 
(Pembrolizumab/Placebo Plus 
Enzalutamide)
3 Hypotheses, Objectives, and Endpoints
4.1 Overall Design
Added that participants still on study 
intervention will have local tumor imaging 
assessments per SOC schedule, but will no 
longer have central PSA blood samples 
collected, SSRE,
 
 or tumor response 
assessments by BICR, and Efficacy 
Follow-up and Survival Follow-up visits 
will no longer be conducted.
Given that the efficacy IA1 indicated 
futility, further tumor scans and 
response assessments by BICR, SSRE 
and PRO assessments, and collection 
of additional samples for PSA 
 
 are considered 
unnecessary.
1.1 Synopsis, Estimated Duration of 
Study
Changed the estimated duration of the 
study from approximately 
 to 
approximately 
.
To reflect new timelines based on 
updates made in Amendment 09.
1.1 Synopsis, Study Governance 
Committees
Added statement that the Executive 
Oversight Committee and DMC are no 
longer applicable.
These committees will no longer 
review the study data.
1.3.2 Second Course Phase 
(Pembrolizumab Retreatment ONLY)
4.1 Overall Design
6.6.4 Second Course
7.1 Discontinuation of Study 
Intervention
8.2.1.4 Second Course (Retreatment) 
Tumor Imaging
Added that as of Amendment 09, Second 
Course treatment is not an option.
In Section 1.3.2 only, added statement 
indicating the study will be stopped due to 
futility.
To update the status of the Second 
Course Phase of the study.
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Section # and Name
Description of Change 
Brief Rationale 
7.1 Discontinuation of Study 
Intervention
Added note to the BICR-verified 
radiographic disease progression criterion 
indicating that central tumor response 
assessments will be discontinued and tumor 
response assessments will be performed 
locally in participants who are continuing 
to receive study intervention.
To clarify that participants still on
treatment with study intervention at the 
time of Amendment 09 will be 
assessed locally for disease 
progression.
8.2.1 Tumor Imaging and Assessment of 
Disease
8.2.2 PCWG Modified RECIST 1.1 
Assessment of Disease
Added statements indicating that central 
tumor response assessments will be 
discontinued, and local tumor imaging 
should continue per SOC schedule for 
participants still on study treatment.
To clarify that participants still 
receiving study intervention will 
continue with local tumor imaging per 
SOC schedule.
8.2.3 Prostate-specific Antigen 
Assessments
Added statement indicating that PSA 
assessments will be discontinued.
PSA assessments are considered 
unnecessary given that the efficacy IA1
indicated futility.
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Section # and Name
Description of Change 
Brief Rationale 
8.4 Adverse Events (AEs), Serious 
Adverse Events (SAEs), and Other 
Reportable Safety Events
8.12.5.2 Efficacy Follow-up Visits
Added statement indicating that Efficacy 
Follow-up Visits will be discontinued.
These visits are considered 
unnecessary given that the efficacy IA1
indicated futility.
8.12.5.3 Survival Follow-up
Added statement that Survival Follow-up 
visits will be discontinued. Participants 
remaining on study intervention should 
continue to be monitored in the study 
through the AE reporting period.
Survival 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.
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Section # and Name
Description of Change 
Brief Rationale 
9.1 Statistical Analysis Plan Summary
9.7 Interim Analyses
9.8 Multiplicity
9.9 Sample Size and Power Calculations
Added statements describing the results of 
the efficacy IA that led to the determination 
to stop the study due to futility and clarified 
what analyses will be performed.
To specify which analyses will be 
conducted and which will no longer be 
performed given that the efficacy IA1
indicated futility.
9.1 Statistical Analysis Plan Summary
9.7 Interim Analyses
Added that a non-binding futility analysis 
of OS was added prior to IA1 and described 
in the sSAP.
Clarification regarding update to sSAP 
prior to IA1.
Throughout Document
Minor administrative, formatting, 
grammatical, and 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 ............................................................................................20
1.1
Synopsis.................................................................................................................20
1.2
Schema ..................................................................................................................25
1.3
Schedule of Activities (SoA)................................................................................27
1.3.1
Initial Treatment Phase (Pembrolizumab/Placebo Plus Enzalutamide).......27
1.3.2
Second Course Phase (Pembrolizumab Retreatment ONLY) .....................36
2
INTRODUCTION..........................................................................................................40
2.1
Study Rationale....................................................................................................40
2.2
Background ..........................................................................................................42
2.2.1
Pharmaceutical and Therapeutic Background .............................................42
2.2.1.1
Inhibition of PD-1 as a Target for Cancer Therapy...........................42
2.2.1.2
Overview of Prostate Cancer .............................................................43
2.2.1.3
Unmet Medical Need in Prostate Cancer...........................................43
2.2.1.4
Preclinical and Clinical Studies .........................................................45
2.2.1.5
Pembrolizumab in mCRPC................................................................45
2.2.2
Ongoing Clinical Studies.............................................................................45
2.2.2.1
Ongoing Clinical Studies in mCRPC.................................................45
2.2.3
Information on Other Study-Related Therapy .............................................46
2.2.3.1
Enzalutamide......................................................................................46
2.3
Benefit/Risk Assessment......................................................................................47
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................47
4
STUDY DESIGN............................................................................................................51
4.1
Overall Design......................................................................................................51
4.2
Scientific Rationale for Study Design.................................................................54
4.2.1
Rationale for Endpoints ...............................................................................54
4.2.1.1
Efficacy Endpoints.............................................................................54
4.2.1.2
Safety Endpoints................................................................................54
4.2.1.3
Patient-reported Outcomes (PROs)....................................................54
4.2.1.4
Planned Exploratory Biomarker Research.........................................55
4.2.1.4.1
Planned Genetic Analysis ........................................................57
4.2.2
Rationale for the Use of Comparator/Placebo .............................................57
4.3
Justification for Dose...........................................................................................57
4.3.1
Pembrolizumab ............................................................................................57
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4.3.2
Enzalutamide................................................................................................58
4.4
Beginning and End of Study Definition .............................................................58
4.4.1
Clinical Criteria for Early Study Termination .............................................58
5
STUDY POPULATION ................................................................................................59
5.1
Inclusion Criteria.................................................................................................59
5.2
Exclusion Criteria................................................................................................63
5.3
Lifestyle Considerations......................................................................................66
5.3.1
Meals and Dietary Restrictions....................................................................66
5.4
Screen Failures.....................................................................................................67
5.5
Participant Replacement Strategy......................................................................67
6
STUDY INTERVENTION............................................................................................67
6.1
Study Intervention(s) Administered...................................................................67
6.2
Preparation/Handling/Storage/Accountability .................................................69
6.2.1
Dose Preparation..........................................................................................69
6.2.2
Handling, Storage, and Accountability........................................................69
6.3
Measures to Minimize Bias: Randomization and Blinding..............................70
6.3.1
Intervention Assignment..............................................................................70
6.3.2
Stratification.................................................................................................70
6.3.3
Blinding........................................................................................................70
6.4
Study Intervention Compliance..........................................................................71
6.5
Concomitant Therapy..........................................................................................71
6.5.1
Prohibited Concomitant Therapy.................................................................71
6.5.2
Rescue Medications and Supportive Care ...................................................73
6.5.3
Radiotherapy................................................................................................74
6.6
Dose Modification (Escalation/Titration/Other)...............................................74
6.6.1
Concomitant Combination Therapy.............................................................74
6.6.2
Dose Modification for Enzalutamide...........................................................74
6.6.3
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................75
6.6.4
Second Course .............................................................................................82
6.6.5
Management of Overlapping Toxicities ......................................................83
6.7
Intervention After the End of the Study............................................................84
6.8
Clinical Supplies Disclosure................................................................................84
6.9
Standard Policies..................................................................................................84
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................84
7.1
Discontinuation of Study Intervention...............................................................84
7.2
Participant Withdrawal From the Study...........................................................86
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7.3
Lost to Follow-up .................................................................................................86
8
STUDY ASSESSMENTS AND PROCEDURES........................................................87
8.1
Administrative and General Procedures ...........................................................88
8.1.1
Informed Consent.........................................................................................88
8.1.1.1
General Informed Consent.................................................................88
8.1.2
Inclusion/Exclusion Criteria ........................................................................88
8.1.3
Participant Identification Card.....................................................................89
8.1.4
Medical History ...........................................................................................89
8.1.5
Prior and Concomitant Medications Review...............................................89
8.1.5.1
Prior Medications...............................................................................89
8.1.5.2
Concomitant Medications..................................................................89
8.1.6
Assignment of Screening Number...............................................................90
8.1.6.1
Treatment Eligibility Assessment Form ............................................90
8.1.7
Assignment of Treatment/Randomization Number.....................................90
8.1.8
Study Intervention Administration ..............................................................90
8.1.8.1
Timing of Dose Administration.........................................................90
8.1.8.1.1
Pembrolizumab/Placebo ..........................................................90
8.1.8.1.2
Enzalutamide............................................................................91
8.1.9
Discontinuation and Withdrawal .................................................................91
8.1.10
Participant Blinding/Unblinding..................................................................91
8.1.10.1
Nonemergency Unblinding................................................................92
8.1.11
Calibration of Equipment.............................................................................92
8.1.12
Tumor Tissue for Biomarker Status.............................................................93
8.2
Efficacy Assessments ...........................................................................................93
8.2.1
Tumor Imaging and Assessment of Disease................................................93
8.2.1.1
Initial Tumor Imaging........................................................................95
8.2.1.2
Tumor Imaging During the Study......................................................96
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging............................96
8.2.1.4
Second Course (Retreatment) Tumor Imaging..................................96
8.2.2
PCWG Modified RECIST 1.1 Assessment of Disease................................97
8.2.3
Prostate-specific Antigen Assessments........................................................98
8.2.4
Tumor Tissue Collection............................................................................100
8.2.5
PROs and Quality of Life Assessments.....................................................100
8.2.5.1
FACT-P............................................................................................100
8.2.5.2
BPI-SF..............................................................................................100
8.2.5.3
EQ-5D-5L ........................................................................................101
8.2.6
Patient Analgesic Log................................................................................101
8.3
Safety Assessments.............................................................................................101
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8.3.1
Physical Examinations...............................................................................102
8.3.1.1
Full Physical Examination...............................................................102
8.3.1.2
Directed Physical Examination........................................................102
8.3.2
Vital Signs..................................................................................................102
8.3.3
Electrocardiograms ....................................................................................102
8.3.4
Clinical Safety Laboratory Assessments ...................................................102
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)........................................................................................103
8.3.5
Performance Assessments..........................................................................103
8.3.5.1
Eastern Cooperative Oncology Group (ECOG) Performance 
Scale.................................................................................................103
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ..................................................................................103
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................104
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....105
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.106
8.4.4
Regulatory Reporting Requirements for SAE ...........................................106
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................106
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................107
8.4.7
Events of Clinical Interest (ECIs)..............................................................107
8.5
Treatment of Overdose......................................................................................107
8.6
Pharmacokinetics...............................................................................................108
8.7
Pharmacodynamics............................................................................................108
8.8
Future Biomedical Research Sample Collection.............................................108
8.9
Planned Genetic Analysis Sample Collection..................................................108
8.10
Biomarkers .........................................................................................................108
8.11
Medical Resource Utilization and Health Economics.....................................109
8.12
Visit Requirements.............................................................................................109
8.12.1
Screening....................................................................................................109
8.12.2
Treatment Period Visit...............................................................................110
8.12.3
Discontinuation Visit .................................................................................110
8.12.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................110
8.12.5
Post-treatment Visit ...................................................................................110
8.12.5.1
Safety Follow-up Visit.....................................................................110
8.12.5.2
Efficacy Follow-up Visits................................................................111
8.12.5.3
Survival Follow-up ..........................................................................111
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8.12.6
Vital Status.................................................................................................112
9
STATISTICAL ANALYSIS PLAN ...........................................................................112
9.1
Statistical Analysis Plan Summary...................................................................112
9.2
Responsibility for Analyses/In-house Blinding ...............................................114
9.3
Hypotheses/Estimation ......................................................................................115
9.4
Analysis Endpoints.............................................................................................115
9.4.1
Efficacy Endpoints.....................................................................................115
9.4.1.1
Primary.............................................................................................115
9.4.1.2
Key Secondary.................................................................................115
9.4.1.3
Secondary.........................................................................................115
9.4.1.4
Exploratory ......................................................................................116
9.4.2
Safety Endpoints........................................................................................116
9.4.3
PRO Endpoints...........................................................................................116
9.4.3.1
.................................................................116
9.5
Analysis Populations..........................................................................................117
9.5.1
Efficacy Analysis Populations...................................................................117
9.5.2
Safety Analysis Populations ......................................................................117
9.5.3
PRO Analysis Population ..........................................................................117
9.6
Statistical Methods.............................................................................................117
9.6.1
Statistical Methods for Efficacy Analyses.................................................118
9.6.1.1
Overall Survival...............................................................................118
9.6.1.2
Radiographic Progression-Free Survival .........................................118
9.6.1.3
TFST ................................................................................................119
9.6.1.4
Analysis Strategy for Key Efficacy Endpoints................................120
9.6.2
Statistical Methods for Safety Analyses ....................................................120
9.6.3
Analysis Methods for PRO Endpoints.......................................................122
9.6.4
Demographic and Baseline Characteristics ...............................................122
9.7
Interim Analyses ................................................................................................123
9.7.1
Efficacy Interim Analyses..........................................................................123
9.7.2
Safety Interim Analyses.............................................................................124
9.8
Multiplicity .........................................................................................................124
9.8.1
rPFS............................................................................................................125
9.8.2
OS ..............................................................................................................126
9.8.3
TFST ..........................................................................................................127
9.8.4
Safety Analyses..........................................................................................128
9.9
Sample Size and Power Calculations ...............................................................128
9.10
Subgroup Analyses.............................................................................................130
9.11
Compliance (Medication Adherence)...............................................................130
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9.12
Extent of Exposure.............................................................................................130
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................131
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......131
10.1.1
Code of Conduct for Clinical Trials...........................................................131
10.1.2
Financial Disclosure...................................................................................133
10.1.3
Data Protection...........................................................................................133
10.1.3.1
Confidentiality of Data ....................................................................134
10.1.3.2
Confidentiality of Participant Records.............................................134
10.1.3.3
Confidentiality of IRB/IEC Information..........................................134
10.1.4
Committees Structure.................................................................................134
10.1.4.1
Executive Oversight Committee......................................................134
10.1.4.2
External Data Monitoring Committee .............................................134
10.1.5
Publication Policy......................................................................................135
10.1.6
Compliance with Study Registration and Results Posting Requirements .135
10.1.7
Compliance with Law, Audit, and Debarment ..........................................135
10.1.8
Data Quality Assurance .............................................................................136
10.1.9
Source Documents .....................................................................................137
10.1.10
Study and Site Closure...............................................................................137
10.2
Appendix 2: Clinical Laboratory Tests............................................................138
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................140
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................140
10.3.2
Definition of AE ........................................................................................140
10.3.3
Definition of SAE ......................................................................................141
10.3.4
Additional Events Reported in the Same Manner as SAE.........................143
10.3.5
Recording AE and SAE .............................................................................143
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................147
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................148
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................149
10.5.1
Definitions..................................................................................................149
10.5.2
Pregnancy Testing......................................................................................149
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................150
10.7
Appendix 7: Country-specific Requirements..................................................151
10.7.1
Laboratory Testing.....................................................................................151
10.7.2
Country-specific Testing Requirements ....................................................151
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10.7.2.1
Germany...........................................................................................151
10.7.2.2
Japan ................................................................................................151
10.8
Appendix 8: Description of the Prostate Cancer Working Group (PCWG) 
Process for Assessment of Bone Lesions..........................................................152
10.8.1
Imaging Methods .......................................................................................152
10.8.2
Documentation of Bone Lesions at Baseline.............................................152
10.8.3
Assessment of Bone Response at Subsequent Imaging Time Points ........152
10.8.4
Descriptions of Bone Response Categories ...............................................153
10.8.4.1
No Evidence of Disease...................................................................153
10.8.4.2
Nonprogression (Non-PD)...............................................................153
10.8.4.3
Unconfirmed Progressive Disease (PDu) ........................................153
10.8.4.4
Progressive Disease (PD).................................................................153
10.8.4.5
Confirmation of Progression............................................................154
10.8.4.5.1
For New Lesions Within the Flare Window (<12 weeks).....154
10.8.4.5.2
For New Lesions Outside the Flare Window (>12 weeks)....154
10.8.4.6
Superscan .........................................................................................154
10.8.4.7
Management Following Confirmed PD...........................................155
10.9
Appendix 9: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................156
10.10 Appendix 10: Abbreviations .............................................................................157
10.11 Appendix 11:  Eastern Cooperative Oncology Group Performance Status.161
11
REFERENCES.............................................................................................................162
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LIST OF TABLES
Table 1
Laboratory Values for Adequate Organ Function ...........................................61
Table 2
Study Interventions..........................................................................................68
Table 3
Enzalutamide Dose Modification Guidelines for Drug-related Adverse 
Events...............................................................................................................75
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................77
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ........................................................................................................81
Table 6
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...............................................................................105
Table 7
Censoring Rules for Primary and Sensitivity Analyses of rPFS....................119
Table 8
Efficacy Analysis Methods for Key Efficacy Endpoints...............................120
Table 9
Analysis Strategy for Safety Parameters........................................................122
Table 10
Summary of Interim and Final Analyses .......................................................124
Table 11
Efficacy Boundaries and Properties for rPFS Based on Potential Alpha 
Levels to be Used for Testing........................................................................126
Table 12
Efficacy Boundaries and Properties for Overall Survival Analyses Based 
on Potential Alpha Levels to be Used for Testing.........................................127
Table 13
Efficacy Boundaries and Properties for TFST Based on Potential Alpha 
Levels to be Used for Testing........................................................................128
Table 14
Protocol-required Safety Laboratory Assessments........................................139
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LIST OF FIGURES
Figure 1
Study Schema...................................................................................................26
Figure 2
Change in Prostate-specific Antigen................................................................99
Figure 3
Multiplicity Graph for One-sided Alpha Reallocation Strategy....................125
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) 
Plus Enzalutamide Versus Placebo Plus Enzalutamide in Participants With Metastatic 
Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-641)
Short Title: Phase 3 Study of Pembrolizumab/Placebo plus Enzalutamide in mCRPC
Acronym: KEYNOTE-641
Hypotheses, Objectives, and Endpoints:
In participants with mCRPC who are abiraterone-naïve or are intolerant to/progressed on 
abiraterone acetate:
NOTE: Based on the data from an interim safety and efficacy analysis for KEYNOTE-641 
(data cutoff 12-DEC-2022), the eDMC recommended stopping the study for futility per the 
futility criteria prespecified in the sSAP. Based upon these data and the recommendation of 
the eDMC, the study has been unblinded (as of 22-FEB-2023). Prespecified IA2 and final 
analysis of the study described in the SAP will not be performed. Safety analysis will be 
performed at the end of the study; there will be no further analyses for efficacy
 
endpoints collected from participants beyond the IA1 cutoff date.
NOTE: In alignment with the study update memo sent to investigators on 28-FEB-2023, all 
study participants should stop ongoing treatment with pembrolizumab/placebo. Exceptions 
may be requested for study participants who, in the assessment of their study physician, are 
benefitting from the combination of enzalutamide and pembrolizumab, after consulting with 
the Sponsor. All other study participants should be discontinued from the study and be 
offered SOC treatment as deemed necessary by the investigator. If enzalutamide as SOC is
not accessible off study to the participant, central sourcing may continue. As of 
Amendment 09, participants who are still on study intervention will no longer have central 
PSA blood samples collected, SSRE assessments,
 
 
 or tumor response assessments by BICR. However, local tumor imaging 
assessments should continue per SOC schedule. The last required study visit will be the 
Safety Follow-up Visit; Efficacy Follow-up and Survival Follow-up visits will no longer be 
conducted. Updated analyses are described in Section 9.
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Primary Objectives
Primary Endpoints
To compare pembrolizumab plus 
enzalutamide versus placebo plus 
enzalutamide with respect to overall 
survival (OS)
OS: the time from randomization to 
death due to any cause
Hypothesis (H1): The combination of 
pembrolizumab plus enzalutamide is 
superior to placebo plus enzalutamide with 
respect to OS
To compare pembrolizumab plus 
enzalutamide versus placebo plus 
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) where soft tissue will be 
assessed per RECIST 1.1 modified to 
follow a maximum of 10 target lesions and 
a maximum of 5 target lesions per organ, 
and bone disease will be assessed per 
PCWG criteria
rPFS: the time from randomization to 
radiographic progression, or death due 
to any cause, whichever occurs first
Hypothesis (H2): The combination of 
pembrolizumab plus enzalutamide is 
superior to placebo plus enzalutamide with 
respect to rPFS per PCWG-modified 
RECIST 1.1 as assessed by BICR
Secondary Objectives
Secondary Endpoints
To compare pembrolizumab plus 
enzalutamide versus placebo plus 
enzalutamide with respect to the time to 
initiation of the first subsequent 
anticancer therapy or death (TFST)
Hypothesis (H3): The combination of 
pembrolizumab plus enzalutamide is 
superior to placebo plus enzalutamide with 
respect to TFST
TFST: the time from randomization to
initiation of the first subsequent 
anticancer therapy or death, whichever 
occurs first
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To compare pembrolizumab plus 
enzalutamide versus placebo plus 
enzalutamide with respect to the:

Prostate-specific antigen (PSA) 
response rate

PSA undetectable rate

Objective response rate (ORR) and 
duration of response (DOR) per 
PCWG-modified RECIST 1.1 as 
assessed by BICR
PSA response: a PSA decline of ≥50% 
from baseline measured twice at least 3
weeks apart
PSA undetectable: PSA <0.2 ng/mL 
during study intervention
Objective response (OR): complete 
response (CR) or partial response (PR)
DOR: the time from the earliest date of 
the first documented evidence of CR or 
PR until earliest date of disease 
progression or death due to any cause, 
whichever occurs first
To compare pembrolizumab plus 
enzalutamide versus placebo plus 
enzalutamide with respect to the:

Time to PSA progression

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)
based on Brief Pain Inventory-Short 
Form (BPI-SF) Item 3 “worst pain in 
24 hours” and opiate analgesic use 
Analgesic Quantification Algorithm 
(AQA) score

Time to Symptomatic 
Skeletal-Related Event (SSRE)
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 radiographic soft-tissue 
progression: the time from 
randomization to radiographic soft-
tissue progression
TTPP based on BPI-SF Item 3 “worst 
pain in 24 hours” and opiate analgesic 
use (AQA score)
Time to Symptomatic Skeletal-
Related Event (SSRE): the time from 
randomization to the first SSRE, 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) 
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
occurrence of spinal cord 
compression

or tumor-related orthopedic 
surgical intervention,
whichever occurs first
To evaluate the safety and tolerability of 
pembrolizumab plus enzalutamide versus 
placebo plus enzalutamide
Adverse events (AEs) 
Study intervention discontinuation due
to AEs
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Treatment of mCRPC
Population
Participants with mCRPC
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo Control
Study Blinding
Double-blind under in-house blinding procedures
Masking
Investigator
Participant
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately
from the time the first 
participant (or their legally acceptable representative)
provides documented informed consent until the last 
participant’s last study-related contact.
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Number of Participants:
Approximately 1240 participants will be randomized in this trial. 
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose
Strength
Dose
Frequency
Route
of
Admin.
Regimen/
Treatment 
Period/
Vaccination
Regimen
Use
Arm 1:
Pembro + 
Enzalutamide
Pembrolizumab
200 mg
Q3W
IV
D1 of each 21-
day cycle for
up to 35 cycles
Test 
product
Enzalutamide
160 mg
QD
PO
Four 40-mg 
capsules/tablets 
orally QD or 
two 80-mg 
tablets orally 
QD
SOC
Arm 2:
Placebo + 
Enzalutamide
Placebo
NA
Q3W
IV
D1 of each 21-
day cycle for 
up to 35 cycles
Placebo
Enzalutamide
160 mg
QD
PO
Four 40-mg 
capsules/tablets 
orally QD or 
two 80-mg 
tablets orally 
QD
SOC
D=Day; IV=intravenous; NA=not applicable; PO=oral; Q3W=every 3 weeks; QD=once daily; 
SOC=standard of care.
Total 
Number
2 arms
Duration of 
Participation
Each participant will participate in the study from the time the participant 
provides documented informed consent through the final protocol-specified 
contact.
Each participant will be assigned to receive study intervention 
(enzalutamide combination with either pembrolizumab or placebo) until 
one of the conditions for discontinuation of study intervention is met. 
Treatment with pembrolizumab/placebo may continue for up to 35 cycles
(approximately 2 years starting with the first infusion in Cycle 1) or until 
meeting criteria for discontinuation of study intervention. Treatment with 
enzalutamide will proceed continuously from Day 1 of Cycle 1 in both 
arms, unless criteria for discontinuation of study intervention are met. 
Participants who stop pembrolizumab as a result of obtaining an 
investigator-determined confirmed CR or those subjects who stop after 
receiving 35 cycles may be eligible for an additional 17 cycles of 
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pembrolizumab (approximately 1 year) after progressive disease if they 
meet the criteria for re-treatment (Second Course Phase) and the study is 
ongoing (Section 6.6.4). Participants randomized to placebo will not be 
permitted to cross over to pembrolizumab following progression.
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.
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, start of new anticancer 
treatment, or withdrawal of consent, whichever occurs first. All participants 
will be followed up for OS until death, withdrawal of consent, or the end of 
the study.
The overall study ends when the last participant completes the last study-
related contact or visit, withdraws from the study, or is lost to follow-up (ie, 
the participant is unable to be contacted by the investigator).
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 09, 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 can be found in Appendix 10.
1.2
Schema
The study design is depicted in Figure 1.
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Figure 1
Study Schema
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1.3
Schedule of Activities (SoA)
1.3.1
Initial Treatment Phase (Pembrolizumab/Placebo Plus Enzalutamide)
Note: As of Amendment 09, study participants should stop ongoing treatment with pembrolizumab/placebo except as 
described in Section 6.1. The study participants continuing to receive enzalutamide and pembrolizumab (Arm 1) or 
enzalutamide alone (Arm 2) will follow the therapy regimen described under “Study Intervention Administration” (without
placebo) until criteria for discontinuation are met.
As of Amendment 09, participants who are still on study intervention will no longer have central PSA blood samples collected, 
SSRE assessments,
 
or tumor response assessments by BICR. However, local tumor imaging assessments 
should continue per SOC schedule. The last required study visit will be the Safety Follow-up visit; Efficacy Follow-up and 
Survival Follow-up visits will no longer be conducted. The full SoA table below is retained for reference.
Trial Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Post-Treatment
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
Follow-up 
Visits
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 
W54 then 
Q12W
(± 7 days)
Q12W
(± 7 days)
Administrative Procedures
Informed consent
X
Inclusion/exclusion 
criteria
X
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Trial Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Post-Treatment
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
Follow-up 
Visits
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 
W54 then 
Q12W
(± 7 days)
Q12W
(± 7 days)
Participant 
identification card
X
Demographics and 
medical history
X
Prior and 
concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
SSRE Evaluation
X
X
X
X
X
X
X
X
X
X
X
X
HIV, Hep B, and 
Hep C status
X
Randomization
X
Telephone contact
or visit
X
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Trial Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Post-Treatment
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
Follow-up 
Visits
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 
W54 then 
Q12W
(± 7 days)
Q12W
(± 7 days)
Clinical Procedures/Assessments
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
Full physical 
examination
X
X
Directed physical 
examination
X
X
X
X
X
X
X
X
X
Vital signs, height, 
and weight
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
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Trial Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Post-Treatment
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
Follow-up 
Visits
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 
W54 then 
Q12W
(± 7 days)
Q12W
(± 7 days)
ECOG performance 
status
X
X
X
X
X
X
X
X
X
X
Subsequent 
anticancer therapy 
status
X
X
X
Vital status
---------------------------------------------------------------------------------------------------
X
Study Intervention Administration
Pembrolizumab/ 
placebo
X
X
X
X
X
X
X
X
Enzalutamide 
X
X
X
X
X
X
X
X
Enzalutamide 
container returned
X
X
X
X
X
X
X
X
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Trial Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Post-Treatment
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
Follow-up 
Visits
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 
W54 then 
Q12W
(± 7 days)
Q12W
(± 7 days)
Laboratory Procedures/Assessments: analysis performed by central laboratory
PT or INR and 
PTT/aPTT
X
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
T3 or FT3, FT4, and 
TSH
X
X
X
X
X
X
X
X
Testosterone
X
X
X
X
X
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Trial Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Post-Treatment
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
Follow-up 
Visits
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 
W54 then 
Q12W
(± 7 days)
Q12W
(± 7 days)
Procedures/Assessments: analysis performed CENTRALLY
Efficacy Measurements
PSA by central 
laboratory
X
Q3W (± 7 days) from randomization
X
X
X
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Trial Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Post-Treatment
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
Follow-up 
Visits
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 
W54 then 
Q12W
(± 7 days)
Q12W
(± 7 days)
Tumor imaging 
(CT/MRI) and bone 
scan
X
Q9W (± 7 days) through Week 54, then Q12W
(± 7 days) thereafter
X
X
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Trial Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Post-Treatment
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
Follow-up 
Visits
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 
W54 then 
Q12W
(± 7 days)
Q12W
(± 7 days)
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Trial Period
Screening 
Phase
Treatment Cycles (21-day cycles)
End of 
Treatment
Post-Treatment
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
Follow-up 
Visits
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 
W54 then 
Q12W
(± 7 days)
Q12W
(± 7 days)
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; 
; BICR=blinded independent central review; 
 CT=computed tomography; 
; DC=discontinuation; 
; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; 
; FT3=free 
triiodothyronine; FT4=free thyroxine; Hep=hepatitis; HIV=human immunodeficiency virus; ICF=informed consent form; INR=international normalized ratio; IRB=Institutional Review Board; 
IV=intravenous; MRI=magnetic resonance imaging; PD=progressive disease; PD-L1=programmed cell death ligand 1; PRO=patient-reported outcome; PSA=prostate-specific antigen; 
PT=prothrombin time; PTT=partial thromboplastin time; Q9W=every 9 weeks; Q12W=every 12 weeks; 
; SAE=serious adverse event; SCF=Sponsor Communication Form; 
T3=total triiodothyronine; TSH=thyroid-stimulating hormone; W=week.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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1.3.2
Second Course Phase (Pembrolizumab Retreatment ONLY)
NOTE: As of Amendment 09, the study will be stopped due to futility. Second Course treatment is not an option for 
participants.
Trial Period
Treatment Cycles (21-day cycles)
End of 
Treatment
Post-Treatment
Notes
Treatment Cycle/Title
1
2
3
4
Cycle 5 
to 17
End of 
Treatment 
Visit
Safety 
Follow-up
Follow-up 
Visits
Survival 
Follow-up
The safety follow-up is not needed 
if the Discontinuation Visit occurs 
>30 days after the last dose
Scheduling Window
(Days)
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
from last 
dose
(+ 7 days)
Q12W 
(± 7 days)
Q12W
(± 7 days)
Administrative Procedures
Eligibility criteria
X
Concomitant medication 
review
X
X
X
X
X
X
X
Report new medications started 
28 days prior to the 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 last dose of study intervention.
SAEs must be recorded up to 90 
days after the last dose of study 
intervention or 30 days following 
cessation of treatment if the 
participant initiates new anticancer 
treatment, whichever comes first. 
Treatment-related SAEs must be 
reported regardless of the time point 
when they occur.
Full physical examination
X
X
Directed physical 
examination
X
X
X
X
X
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Trial Period
Treatment Cycles (21-day cycles)
End of 
Treatment
Post-Treatment
Notes
Treatment Cycle/Title
1
2
3
4
Cycle 5 
to 17
End of 
Treatment 
Visit
Safety 
Follow-up
Follow-up 
Visits
Survival 
Follow-up
The safety follow-up is not needed 
if the Discontinuation Visit occurs 
>30 days after the last dose
Scheduling Window
(Days)
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
from last 
dose
(+ 7 days)
Q12W 
(± 7 days)
Q12W
(± 7 days)
Vital signs and weight
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
X
After Cycle 8, perform every other 
cycle.
Subsequent anticancer 
therapy status
X
X
X
Safety Follow-up visit must occur 
before the start of the new therapy.
Survival status
---------------------------------------------------------------------------------------------------
X
Updated survival status may be 
requested by the Sponsor at any 
time during the course of the study.
Study Intervention Administration
Pembrolizumab
X
X
X
X
X
200 mg IV Q3W
Laboratory Procedures/Assessments: analysis performed by CENTRAL laboratory
Perform within 10 days prior to 
participant receiving first 
retreatment infusion. After Cycle 
1, predose laboratory procedures 
may be conducted up to 72 hours 
predose. Unresolved abnormal 
lab 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 anticoagulant 
therapy during treatment and 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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Trial Period
Treatment Cycles (21-day cycles)
End of 
Treatment
Post-Treatment
Notes
Treatment Cycle/Title
1
2
3
4
Cycle 5 
to 17
End of 
Treatment 
Visit
Safety 
Follow-up
Follow-up 
Visits
Survival 
Follow-up
The safety follow-up is not needed 
if the Discontinuation Visit occurs 
>30 days after the last dose
Scheduling Window
(Days)
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
from last 
dose
(+ 7 days)
Q12W 
(± 7 days)
Q12W
(± 7 days)
Urinalysis
X
X
X
X
X
Urinalysis and thyroid function tests
are performed every other cycle (ie, 
Cycle 5, 7, 9, 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: 
Schedule of scans and PSA are 
calculated from the first 
retreatment infusion. The timing 
of assessments should not be 
adjusted for dose delays or cycle 
starts.
Efficacy Measurements
PSA by central laboratory
X
------------------------------------------
Q3W (±7 days) from first retreatment 
infusion
X
X
X
Collect predose on days 
pembrolizumab is given.
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Trial Period
Treatment Cycles (21-day cycles)
End of 
Treatment
Post-Treatment
Notes
Treatment Cycle/Title
1
2
3
4
Cycle 5 
to 17
End of 
Treatment 
Visit
Safety 
Follow-up
Follow-up 
Visits
Survival 
Follow-up
The safety follow-up is not needed 
if the Discontinuation Visit occurs 
>30 days after the last dose
Scheduling Window
(Days)
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
from last 
dose
(+ 7 days)
Q12W 
(± 7 days)
Q12W
(± 7 days)
Tumor imaging
(CT/MRI) and bone scan
(evaluated locally)
X
------------------------------------------
W9 (± 7 days) after restart of treatment, 
then Q12W (± 7 days) thereafter.
X
X
CT/MRI chest/abdomen/pelvis and 
whole-body bone scans must be 
performed within 28 days prior to 
the participant receiving first 
retreatment infusion. If a scan was 
obtained within 4 weeks prior to 
treatment discontinuation, then 
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 imaging 
Contract Research Organization 
(iCRO).
Abbreviations:  AE=adverse event; aPTT=activated partial thromboplastin time; CT=computed tomography; DC=discontinuation; ECI=events of clinical interest; ECOG=Eastern Cooperative 
Oncology Group; FT3=free triiodothyronine; FT4=free thyroxine; INR=international normalized ratio; MRI=magnetic resonance imaging; PSA=prostate-specific antigen; PT=prothrombin time; 
PTT=partial thromboplastin time; Q9W=every 9 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 estimated annual incidence of over 1 million and an expected 300,000 
plus deaths annually [Ferlay, J., et al 2015]. In the United States (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, men 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 for some time, years in many cases. However, prostate cancer progresses 
invariably and requires additional systemic therapies to re-establish control of disease. The 
point at which metastatic prostate cancer progresses in spite of ADT alone is referred to as 
castration resistance, and the disease at this point is known as mCRPC.
A number of important systemic therapies have been developed to treat mCRPC, have 
received regulatory approval, and now comprise the current therapeutic landscape. This 
includes the next generation hormonal agents (NHA) abiraterone acetate and enzalutamide, 
and the taxanes docetaxel and cabazitaxel.
Abiraterone acetate is an androgen biosynthesis inhibitor that inhibits 17 α-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 two Phase 3 randomized 
placebo-controlled clinical studies [Fizazi, K., et al 2012] [Ryan, C. J., et al 2015].
Enzalutamide is an endocrine therapy currently used for the treatment of mCRPC. 
Enzalutamide was examined in randomized clinical studies in participants with mCRPC 
before treatment with chemotherapy and found to have superior OS versus control therapy 
(placebo and prednisone, respectively) [Ryan, C. J., et al 2013] [Beer, T. M., et al 2014].
2.1
Study Rationale
The NHAs enzalutamide and abiraterone acetate were examined in randomized clinical 
studies in participants with mCRPC before treatment with chemotherapy and found to have
superior OS versus control therapy (placebo and prednisone, respectively) [Ryan, C. J., et al 
2013] [Beer, T. M., et al 2014].
The efficacy and safety of enzalutamide in participants with mCRPC were demonstrated in 
2 randomized, placebo-controlled, multicenter Phase 3 clinical trials. In one study, a total of 
1199 participants who had received prior docetaxel-based chemotherapy were randomized 
2:1 to receive either enzalutamide orally at a dose of 160 mg once daily (N = 800) or placebo 
orally once daily (N = 399) [Scher, H. I., et al 2012]. A statistically significant improvement 
in OS was demonstrated at the prespecified IA at the time of 520 deaths in participants in the 
enzalutamide arm compared to participants in the placebo arm. Median survival was 18.4 
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months (95% CI, 17.3 months to “not reached”) versus 13.6 months (95% CI, 11.3 to 15.8 
months) in the enzalutamide and placebo arms, respectively [Scher, H. I., et al 2012]. In the 
other study, 1717 chemotherapy-naïve participants were randomized 1:1 to receive either 
enzalutamide orally at a dose of 160 mg once daily (N = 872) or placebo orally once daily 
(N = 845). A statistically significant improvement in OS was demonstrated at the 
prespecified IA, conducted after 540 deaths in participants in the enzalutamide arm compared 
to participants in the placebo arm. Median survival was 32.4 months (95% CI, 30.1 months 
to “not reached”) versus 30.2 months (95% CI, 28.0 months to “not reached”) in the 
enzalutamide and placebo arms, respectively. Forty percent of enzalutamide-treated 
participants and 70% of placebo-treated participants received subsequent therapies for 
mCRPC that may prolong OS [Beer, T. M., et al 2014]. An updated survival analysis was 
conducted when 784 deaths were observed, and results from this analysis were consistent 
with those from the prespecified IA. Median survival was 35.3 months (95% CI, 32.2 months 
to “not reached”) versus 31.3 months (95% CI, 28.8 to 34.2 months) in the enzalutamide and 
placebo arms, respectively [Beer, T. M., et al 2017].
Bishop et al. demonstrated in a mouse xenograft model that enzalutamide-resistant tumors 
express significantly increased levels of tumor intrinsic programmed cell death ligand 1 (PD-
L1) compared to non-enzalutamide resistant tumors [Bishop, J. L., et al 2015]. Additionally, 
in a small cohort of participants, it was noted that those who progressed while on 
enzalutamide had a significantly increased number of PD-L1/programmed cell death ligand 2 
(PD-L2)-positive dendritic cells in their blood compared to treatment-naïve participants or 
participants who were responding to enzalutamide. Thus, by blocking the programmed cell 
death 1 (PD-1) receptor, pembrolizumab treatment may increase the immune response to 
enzalutamide-resistant cells that emerge in response to treatment with enzalutamide.
The PSA response rate of participants treated with enzalutamide after abiraterone acetate 
may be modest, as judged by a retrospective study of mCRPC in participants who received 
various prior sequences of abiraterone acetate, docetaxel, and enzalutamide. The study found 
that the group that received enzalutamide after abiraterone acetate (N = 79) demonstrated a 
50% or greater PSA decline in 18% of participants. The median OS was reached only for 
participants in the prior abiraterone acetate + docetaxel group and was 12.2 months [Cheng, 
H. H., et al 2015]. However, in another retrospective study evaluating the PSA response of 
enzalutamide or docetaxel treatment after abiraterone acetate, the enzalutamide arm (N = 30) 
demonstrated a 50% or greater PSA decline in 34% of participants. The median PSA 
progression-free survival (PFS) was 4.1 months and the median PFS was 4.7 months. OS was 
not described [Suzman, D. L., et al 2014]. It is hoped that the present study of the 
pembrolizumab + enzalutamide combination will provide data to evaluate the efficacy of this 
combination in this setting where there is a need for data from prospectively designed studies 
to demonstrate improved response.
KEYNOTE-365, a Phase 2 umbrella study evaluating pembrolizumab combination therapies 
in mCRPC participants, included a Cohort C for the evaluation of pembrolizumab in 
combination with enzalutamide in participants who have received prior abiraterone acetate in 
the prechemotherapy mCRPC state. Interim results from Cohort C in KN365 (data cutoff 
03-APR-2018), which evaluated the population intended for the current study, showed a 
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response (at least 50% reduction in PSA from baseline) in 23.9% (95% CI: 14.3%, 35.9%) of 
participants with a baseline PSA value available (n = 67), and 29.6% (95% CI: 18.0%, 
43.6%) in those with an elevated PSA at baseline (n = 54). While an OR (CR + PR) was 
observed in 20.0% (95% CI: 6.8%, 40.7%) of participants with RECIST-measurable disease 
at baseline (n = 25), the DCR for the cohort was 50.7% (95% CI: 38.4%, 63.0%) driven 
primarily by the proportion of participants who had SD for at least 24 weeks (43.5%) prior to 
disease progression. Half of the participants had a reduction in tumor size, of which nearly a 
third had a reduction of more than 30%. These results provide support for further evaluation 
of the combination of pembrolizumab and enzalutamide in patients with mCRPC.
The present trial, KEYNOTE-641, will be a randomized, multicenter, double-blind, placebo-
controlled, Phase 3 trial in participants with mCRPC in the prechemotherapy mCRPC state. 
Participants will be randomly assigned 1:1 to treatment with either pembrolizumab + 
enzalutamide or placebo + enzalutamide. 
2.2
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction 
with PD-L1 and 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).
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
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 
prognosis in various malignancies. In particular, the presence of CD8+ 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 cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
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regulate antigen receptor signaling upon 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 the binding of 
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. Following 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 the 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.
2.2.1.2
Overview of Prostate Cancer
Prostate cancer represents one of the most commonly diagnosed cancer malignancies and the 
second leading cause of cancer-related deaths in men worldwide [Center, M. M., et al 2012] 
[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 highlight the socioeconomic burden prostate cancer 
poses worldwide. In the US, analysts estimated that there will be 164,690 new cases of 
prostate cancer (19% of all new cases in males) and 29,430 deaths caused by prostate cancer 
(9% of all new deaths of males) in 2018 [Siegel, R. L., et al 2018]. Since the advent of PSA 
screening about three decades ago, the prostate cancer death rate had been falling until it 
stabilized between 2013 and 2015 [Negoita, S., et al 2018]. Additionally, following the US 
Preventive Services Task Force’s recommendation against routine PSA-based screening 
regardless of age in 2012, incidence of late-stage disease has increased [Negoita, S., et al 
2018]. Although identifying cause and effect 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.
2.2.1.3
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 harms associated 
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with overtreatment (eg, incontinence and impotence) [Loeb, S., et al 2015] [Resnick, M. J., et 
al 2013]. Additionally, metastatic prostate cancer evolves molecularly during disease 
progression and/or therapy through an 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 the androgen receptor is a critical factor for promotion 
and growth of prostate cancer [Knudsen, K. E. and Penning, T. M. 2010]. Therefore, until 
2015 the standard of care for initial first-line therapy for metastatic prostate cancer (either 
recurrent or de novo metastatic tumors, heretofore called CSPC) consisted of ADT (eg, 
GnRH agonist or antagonist). However, a great stride in treatment of CSPC was made over 
the last few years. The Chemohormonal Therapy Versus Androgen Ablation Randomized 
Trial for Extensive Disease in Prostate Cancer (CHAARTED [Sweeney, C. J., et al 2015] 
[James, N. D., et al 2016]) study demonstrated significant survival benefit with the addition 
of docetaxel to ADT. In a 2018 follow-up 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 (57.6 vs. 
47.2 months; HR, 0.72; 95% CI, 0.50-0.79; p<0.001). In a similar comparison from the 
STAMPEDE study [James, N. D., et al 2017], researchers recommended docetaxel become 
part of the standard of care after a 43-month follow-up found superior results with it against 
ADT in median OS (81 vs 71 months; 0.78; 95% CI, 0.66-0.93; p=.006) [James, N. D., et al 
2016].
As part of the STAMPEDE study, participants were randomly assigned to receive either 
ADT and abiraterone acetate plus prednisolone or ADT alone. Participants in the former arm 
had a significantly higher OS rate at 3 years (83% vs 76%; HR for death, 0.63%; 95% CI, 
0.52-0.76; p<0.001) and significantly fewer treatment failure events (248 vs. 535; HR, 0.29; 
95% CI, 0.25-0.34; p<0.001). Fizazi and collaborators in the LATITUDE trial [Fizazi, K., et 
al 2017] had similar findings. At a planned IA at 30.4 months, they reported significantly 
longer OS in the group receiving abiraterone acetate along with ADT than in the group 
receiving ADT and placebo (not reached vs 34.7 months; HR for death, 0.62; 95% CI, 0.51-
0.76; p<0.001). While these therapies are initially effective, patients with metastatic prostate 
cancer invariably develop a lethal stage of the disease known as mCRPC and succumb to 
their disease. Though, a number of important therapies have been approved since 2004 to 
treat mCRPC, including chemotherapy (docetaxel and cabazitaxel), NHAs that target the 
androgen-receptor axis (abiraterone acetate and enzalutamide), immunotherapy 
(sipuleucel-T), and a bone-specific radionuclide (radium-223), no available guidance 
recommends appropriate sequencing or combining of these therapies, and none are curative.
In spite of these recent advances, treatment options for men with mCRPC progressing after 
NHA therapy and docetaxel are limited and provide limited 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] vs 12.7 months [95% CI, 11.6-13.7]; HR, 0.70 [95% CI, 0.59–0.83]; 
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p<0.0001). Also, cabazitaxel retained its antitumor activity following treatment with 
docetaxel and abiraterone or docetaxel and enzalutamide [Pezaro, C. J., et al 2014]. 
However, cabazitaxel can be a toxic therapy. Deaths have occurred on study after the onset 
of treatment-related neutropenia or treatment-related diarrhea. Furthermore, the cabazitaxel 
label contains a black box warning regarding risks from neutropenia and severe 
hypersensitivity [U.S. Prescribing Information 2018]. Other label warnings and precautions 
pertain to diarrhea, renal failure, prohibitive risk in elderly patients (patients ≥65 years of 
age), and hepatic impairment. Consequently, cabazitaxel is not utilized widely. Retrospective 
studies suggest that either abiraterone or enzalutamide may be an option; however, previous 
therapies [Handy, C. E. and Antonarakis, E. S. 2016], the potential for developing cross-
resistance [Zhang, T., et al 2015], and potential for the emergence of a more aggressive form 
of prostate cancer following 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 diagnosed with 
mCRPC with disease progression following treatment with an NHA therapy and/or 
docetaxel-based chemotherapy.
2.2.1.4
Preclinical and Clinical Studies
Refer to the pembrolizumab IB for a summary of the preclinical and clinical experience with 
pembrolizumab.
2.2.1.5
Pembrolizumab in mCRPC
Participants with PD-L1 positive mCRPC have been treated with pembrolizumab 
monotherapy in the Phase 1b KEYNOTE-028 study (Cohort E3: advanced [unresectable 
and/or metastatic] prostate adenocarcinoma). The primary endpoint was the ORR, according 
to the RECIST 1.1, which was determined by investigator review. Participants with PD-L1 
positive (defined by PD-L1 expression in >1% tumor or stroma cells) mCRPC were enrolled 
and treated with pembrolizumab monotherapy. All had treatment with at least 1 prior 
antineoplastic therapy, and 17 of 23 (73.9%) and 7 of 23 (30%) had been treated with 2 or 
more or 5 or more lines of therapy, respectively. Of the 23 participants, only one patient 
remained on treatment at the time of last published analysis [Hansen, A. R., et al 2018].
Twenty-one (91.3%) had one or more post-baseline PSA level determinations; five of these 
participants (24%) had a ≥PSA level decline of 50%. There were 4 confirmed partial 
responses, according to RECIST 1.1 guidelines, for an ORR at that time of 17.4% (95% CI, 
5.0-38.8%). Responses were durable (median DOR, 13.5 months), and treatment was well 
tolerated.
2.2.2
Ongoing Clinical Studies
2.2.2.1
Ongoing Clinical Studies in mCRPC
KEYNOTE-199 was designed to further evaluate the positive signal of activity seen in 
KEYNOTE-028 with pembrolizumab monotherapy in participants with mCRPC who 
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previously received docetaxel-based chemotherapy and underwent abiraterone acetate or 
enzalutamide treatment. The ORR was 4.5% (Cohorts 1 and 2) at the second IA (IA2) with a 
data cutoff date of 13-OCT-2017. However, the DCR suggested a durable response and 
potential OS benefit, regardless of PD-L1 status, that warranted further evaluation. 
Additionally, early unpublished results from Graff et al 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 2015-2016 who had mCRPC 
with evidence of progression on enzalutamide, and subsequently enrolled a total of 28. 
Because previous immunotherapies (nivolumab, ipilimumab) had failed to produce an 
objective response in mCRPC [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 [Graff, J. N., 
et al 2018], undertook the Phase 2 study adding pembrolizumab to enzalutamide for men 
with mCRPC progressing on enzalutamide and reported a decline in PSA ≥50% (primary 
endpoint) in 5 of 28 participants (17.9%) and an OR (secondary endpoint) in 3 of 
12 participants (25.0%) who had measurable disease at baseline. At last report, 3 of the 5
responders continued to respond (range, 21.9-33.8 months), and median OS was 22.2 months 
(95% CI, 14.7-28.4 months).
KEYNOTE-365, a Phase 2 umbrella study evaluating pembrolizumab combination therapies 
in mCRPC participants, included a cohort for the evaluation of pembrolizumab in 
combination with enzalutamide (Cohort C). Participants in this cohort were required to have 
had previously received abiraterone acetate. The primary endpoint is the percentage of 
participants with a decrease in PSA level of ≥50%. In a recent amendment of the protocol, 
ORR based on RECIST 1.1 by BICR was changed from a secondary endpoint to a (dual) 
primary endpoint. Additionally, the target enrollment in each of the three cohorts was 
expanded to 100, and a new cohort for pembrolizumab in combination with abiraterone 
acetate with target enrollment of 100 mCRPC participants was added. See Section 2.1 for a 
summary of interim results.
Ongoing clinical trials are being conducted in multiple additional tumor types. For study 
details, please refer to the pembrolizumab IB.
2.2.3
Information on Other Study-Related Therapy
2.2.3.1
Enzalutamide
Enzalutamide (Xtandi®) is an androgen-receptor inhibitor indicated for the treatment of 
patients with mCRPC. Enzalutamide acts on different steps in the androgen-receptor 
signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding 
to androgen receptors and inhibit androgen-receptor nuclear translocation and interaction 
with deoxyribonucleic acid (DNA). A major metabolite, N-desmethyl enzalutamide, 
exhibited similar in vitro activity to enzalutamide. Enzalutamide decreased proliferation and 
induced cell death of prostate cancer cells in vitro and decreased tumor volume in a mouse 
prostate cancer xenograft model. Refer to the approved labeling for detailed background 
information on enzalutamide.
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For additional information on enzalutamide, refer to the approved product label.
2.3
Benefit/Risk Assessment
NOTE: Based on the data from an interim safety and efficacy analysis for KEYNOTE-641 
(data cutoff 12-DEC-2022), the eDMC recommended stopping the study for futility per the 
futility criteria prespecified in the sSAP. Based upon these data and the recommendation of 
the eDMC, the study has been unblinded (as of 22-FEB-2023).
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 in a large number of cancer participants with a well 
characterized safety profile and has received regulatory approval for advanced melanoma and 
non-small cell lung cancer (NSCLC). Overall, pembrolizumab is well tolerated at doses up to 
10 mg/kg every 2 weeks (Q2W). Pembrolizumab has also demonstrated anticancer clinical 
activity and efficacy in a broad range of cancer indications (see the pembrolizumab IB).
Enzalutamide has been approved by regulatory agencies globally for the treatment of 
mCRPC and has been recommended for treatment for mCRPC by NCCN and ESMO 
guidelines [Torre, L. A., et al 2016].
Preliminary results from Cohort C of KEYNOTE-365 (Section 2.1), in which participants 
have been treated with a combination of pembrolizumab and enzalutamide, showed a modest 
OR although the DCR was 50.7%, driven primarily by the proportion of participants who had 
SD for at least 24 weeks (43.5%) prior to disease progression. Half of the participants had a 
reduction in tumor size, of which nearly a third had a reduction of more than 30%. The safety 
profile of the combination of pembrolizumab with other therapies is being characterized in 
KEYNOTE-365, a Phase 2 umbrella study in mCRPC. Pembrolizumab combination 
therapies have not been associated with new safety signals. In Cohort C, 37 of 69 (53.6%) 
participants reported Grade 3 to 5 AEs, and 24 of 69 (34.8%) participants experienced
serious adverse events (SAEs).
Additional details regarding specific benefits and risks for participants participating in this
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In participants with mCRPC who are abiraterone-naïve or are intolerant to/progressed on 
abiraterone acetate:
NOTE: Based on the data from an interim safety and efficacy analysis for KEYNOTE-641 
(data cutoff 12-DEC-2022), the eDMC recommended stopping the study for futility per the 
futility criteria prespecified in the sSAP. Based upon these data and the recommendation of 
the eDMC, the study has been unblinded (as of 22-FEB-2023). Prespecified IA2 and final 
analysis of the study described in the SAP will not be performed. Safety analysis will be 
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performed at the end of the study; there will be no further analyses for efficacy 
 
endpoints collected from participants beyond the IA1 cutoff date.
NOTE: In alignment with the study update memo sent to investigators on 28-FEB-2023, all 
study participants should stop ongoing treatment with pembrolizumab/placebo. Exceptions 
may be requested for study participants who, in the assessment of their study physician, are 
benefitting from the combination of enzalutamide and pembrolizumab, after consulting with 
the Sponsor. All other study participants should be discontinued from the study and be 
offered SOC treatment as deemed necessary by the investigator. If enzalutamide as SOC is 
not accessible off study to the participant, central sourcing may continue. As of 
Amendment 09, participants who are still on study intervention will no longer have central 
PSA blood samples collected, SSRE assessments,
 
 
, or tumor response assessments by BICR. However, local tumor imaging 
assessments should continue per SOC schedule. The last required study visit will be the 
Safety Follow-up Visit; Efficacy Follow-up and Survival Follow-up visits will no longer be 
conducted. Updated analyses are described in Section 9.
Objectives
Endpoints
Primary
To compare pembrolizumab plus 
enzalutamide versus placebo plus 
enzalutamide with respect to OS
Hypothesis (H1): The combination of 
pembrolizumab plus enzalutamide is 
superior to placebo plus enzalutamide with 
respect to OS
OS: the time from randomization to death 
due to any cause
To compare pembrolizumab plus 
enzalutamide versus placebo plus 
enzalutamide with respect to rPFS per 
PCWG-modified RECIST 1.1 as assessed 
by BICR where soft-tissue will be assessed
per RECIST 1.1 modified to follow a 
maximum of 10 target lesions and a 
maximum of 5 target lesions per organ and 
bone disease will be assessed per PCWG 
criteria
Hypothesis (H2): The combination of 
pembrolizumab plus enzalutamide is 
superior to placebo plus 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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Objectives
Endpoints
Secondary
To compare pembrolizumab plus 
enzalutamide versus placebo plus 
enzalutamide with respect to TFST
Hypothesis 3: The combination of 
pembrolizumab plus enzalutamide is 
superior to placebo plus enzalutamide with 
respect to TFST
TFST: the time from randomization to
initiation of the first subsequent anticancer 
therapy or death, whichever occurs first
To compare pembrolizumab plus 
enzalutamide versus placebo plus 
enzalutamide with respect to the:

PSA response rate

PSA undetectable rate

ORR and DOR per PCWG-modified 
RECIST 1.1 as assessed by BICR
PSA response: a PSA decline of ≥50% 
from baseline measured twice at least 
3 weeks apart
PSA undetectable: PSA < 0.2 ng/mL 
during study intervention
OR: CR or PR
DOR: the time from the earliest date of the 
first documented evidence of CR or PR 
until earliest date of disease progression or 
death due to any cause, whichever occurs 
first

To compare pembrolizumab plus 
enzalutamide versus placebo plus 
enzalutamide with respect to the:

Time to PSA progression

Time to radiographic soft-tissue 
progression per soft-tissue rules of 
PCWG-modified RECIST 1.1, as 
assessed by BICR

TTPP based on BPI-SF Item 3 “worst 
pain in 24 hours” and opiate analgesic 
use (AQA score)

Time to SSRE
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 radiographic soft-tissue 
progression: the time from randomization
to radiographic soft-tissue progression
TTPP based on BPI-SF Item 3 “worst pain 
in 24 hours” and opiate analgesic use (AQA 
score)
Time to SSRE: the time from 
randomization to the first SSRE, defined as  
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Objectives
Endpoints

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

or tumor-related orthopedic surgical 
intervention,
whichever occurs first
To evaluate the safety and tolerability of 
pembrolizumab plus enzalutamide versus 
placebo plus enzalutamide
AEs
Study intervention discontinuation due to 
AEs
Tertiary/Exploratory
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Objectives
Endpoints
4
STUDY DESIGN
4.1
Overall Design
NOTE: Based on the data from an interim safety and efficacy analysis for KEYNOTE-641 
(data cutoff 12-DEC-2022), the eDMC recommended stopping the study for futility per the 
futility criteria prespecified in the sSAP. Based upon these data and the recommendation of 
the eDMC, the study has been unblinded (as of 22-FEB-2023). Prespecified IA2 and final 
analysis of the study described in the SAP will not be performed. Safety analysis will be 
performed at the end of the study; there will be no further analyses for efficacy 
 
endpoints collected from participants beyond the IA1 cutoff date.
NOTE: In alignment with the study update memo sent to investigators on 28-FEB-2023, all 
study participants should stop ongoing treatment with pembrolizumab/placebo. Exceptions 
may be requested for study participants who, in the assessment of their study physician, are 
benefitting from the combination of enzalutamide and pembrolizumab, after consulting with 
the Sponsor. All other study participants should be discontinued from study and be offered 
SOC treatment as deemed necessary by the investigator. If enzalutamide as SOC is not 
accessible off study to the participant, central sourcing may continue. As of Amendment 09, 
participants who are still on study intervention will no longer have central PSA blood 
samples collected, SSRE assessments,
), 
or tumor response assessments by BICR. However, local tumor imaging assessments should 
continue per SOC schedule. The last required study visit will be the Safety Follow-up Visit; 
Efficacy Follow-up and Survival Follow-up visits will no longer be conducted. Updated 
analyses are described in Section 9.
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This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind/mask study 
of pembrolizumab plus enzalutamide versus placebo plus enzalutamide in participants with
mCRPC.
Approximately 1240 participants will be randomly assigned in a 1:1 ratio to 1 of 2 treatment 
arms following a screening period of up to 42 days. There will be no crossover between
treatment arms.
Arm 1: pembrolizumab 200 mg every 3 weeks (Q3W) plus enzalutamide 160 mg once 
daily (QD)
Arm 2: placebo Q3W plus enzalutamide 160 mg QD
 
 
Participants are allowed to have previously received and progressed on or become intolerant 
to abiraterone acetate in the prechemotherapy mHSPC or mCRPC state. Prior docetaxel for 
mHSPC is allowed if more than 4 weeks have elapsed from the last dose of docetaxel. Prior 
treatment with second-generation androgen-receptor inhibitor or CYP17 inhibitor other than 
abiraterone acetate is not allowed. Participants must provide a 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 in 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 (decalcification not allowed). 
However, if obtaining a fresh biopsy is not feasible, then 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 prior to randomization. For 
complete details about eligibility criteria, refer to Section 5.
Treatment with pembrolizumab/placebo may continue for up to 35 cycles (approximately 2 
years starting with the first infusion in Cycle 1) or until meeting criteria for discontinuation 
of study intervention (Section 7.1). Treatment with enzalutamide will proceed continuously 
from Day 1 of Cycle 1 in both arms, unless criteria for discontinuation of study intervention 
are met (Section 7.1).
Participants will be evaluated with radiologic imaging to assess response to treatment at 
regular intervals during the study (Section 8.2.2). 
If a participant with radiographic progression is clinically stable or clinically improved, after 
obtaining documented informed consent addendum and Sponsor communication, the 
investigator may elect to continue treatment following radiographic disease progression
confirmed by central vendor. Participants showing clinical benefit in the study will be 
allowed to continue treatment regardless of any decision to stop enrollment or suspend the 
study.
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AEs will be monitored throughout the study and graded in severity according to the 
guidelines outlined in the NCI 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 on study and continue study-
related disease assessments until radiographic disease progression, initiating a nonstudy 
cancer treatment, participant discontinuation from the study, or becoming lost to follow-up. 
All participants will be followed for survival. This will be done in a variety of ways 
including phone, email, chart review, or review of public records in compliance to local 
practices or regulations.
Second Course Treatment: As of Amendment 09, Second Course treatment is not an option 
for participants.
Participants who stop study intervention as a result of obtaining an investigator-determined 
confirmed CR or those subjects who stop after receiving 35 cycles may be eligible for an 
additional 17 cycles (approximately 1 year) of pembrolizumab after BICR-verified 
progressive disease if they meet the criteria for re-treatment (Second Course Phase) and the 
study is ongoing (Section 6.6.4). Enzalutamide may be continued at the investigator’s 
discretion during the Second Course treatment. 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/placebo, the participant still meets the safety 
parameters listed in the Inclusion/Exclusion criteria, and the study remains open.
The risks of solid organ transplant following 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.
This study will use a group sequential design, using an independent, external Data
Monitoring Committee (eDMC) to monitor safety and efficacy during the course of the
study. 
 The final OS analysis will be
conducted when approximately 784 OS events (target number of OS events) have been 
observed. 
 
 
 
 
 
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4.2
Scientific Rationale for Study Design
This study is a randomized, double-blind, placebo-controlled study, a design selected to 
eliminate potential bias.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The dual primary endpoints of the study will be OS and rPFS. OS has been recognized as the 
gold standard for the 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. The rPFS will be 
assessed by BICR according to PCWG-modified RECIST 1.1 (Section 8.2). Time-to-
progression endpoints, including DOR and rPFS, will be measured until PD per PCWG-
modified RECIST 1.1.
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 participants 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.
4.2.1.2
Safety Endpoints
Safety parameters commonly 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.
4.2.1.3
Patient-reported Outcomes (PROs)
 
 
 
 
 
 
 
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4.2.1.4
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class 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 new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations 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. 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 immuno-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 with pembrolizumab or other immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype. 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 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 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 pembrolizumab (MK-3475) therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as enzyme-linked immunoassay 
(ELISA) measure such proteins in serum. Correlation of expression with response to 
pembrolizumab therapy 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.
4.2.2
Rationale for the Use of Comparator/Placebo
Normal saline or dextrose infusion Q3W will be used as placebo for pembrolizumab. The use 
of saline or dextrose placebo in combination with enzalutamide will ensure the objectivity of 
the investigator. Normal saline is the primary diluent/placebo for pembrolizumab; use 
dextrose only if saline is not available. The use of a placebo will allow for testing the 
hypotheses that OS for participants treated with pembrolizumab and enzalutamide is superior
to the combination of placebo and enzalutamide in participants with mCRPC to be tested.
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. As outlined below, this dose is justified 
by the following:

Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg Q2W representing an approximate 5- to 7.5-fold exposure range (refer to IB)
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
Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W 

Clinical data showing meaningful improvement in benefit-risk 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 PBPK analysis) at 200 mg Q3W
4.3.2
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 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).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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 
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.
NOTE: Based on the data from an interim safety and efficacy analysis for KEYNOTE-641 
(data cutoff 12-DEC-2022), the eDMC recommended stopping the study for futility per the 
futility criteria prespecified in the sSAP.
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5
STUDY POPULATION
Male participants with mCRPC in the prechemotherapy mCRPC state who have not received 
abiraterone acetate or who were previously treated with abiraterone acetate (without prior 
enzalutamide) and have progressed on treatment or became intolerant of the drug. Prior 
docetaxel for mHSPC is allowed if more than 4 weeks have elapsed from the last dose of 
docetaxel. Prior treatment with abiraterone acetate for mHSPC is allowed if the participant 
received more than 4 weeks of treatment and as long as there was no progression on this 
agent.
As stated in the Code of Conduct for Clinical Trials (Section 10.1.1), our studies include 
people of varying age, race, ethnicity, and sex. The collection and use of these demographic 
data is to follow all local laws and guidelines in keeping with the needs for participant 
confidentiality while supporting the study of the disease, its related factors, and the IMP 
under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant meets the following 
criteria:
1. Have histologically- or cytologically-confirmed (if acceptable according to local health 
authority regulations) adenocarcinoma of the prostate without small cell histology. 
Diagnosis must be stated in a pathology report and confirmed by the investigator.
2. Have prostate cancer progression while on ADT (or post bilateral orchiectomy) within 6 
months prior to randomization, as determined by the investigator, by means of one of the 
following:
a.
PSA progression using local laboratory values as defined by a minimum of 
2 consecutive rising PSA levels with an interval of ≥1 week between each assessment 
where the PSA value at screening should be ≥1 ng/mL. See Section 8.2.3 –
Prostate-specific Antigen Assessment for further details.
b. Radiographic disease progression in soft tissue based on RECIST 1.1 criteria with or 
without PSA progression.
c.
Radiographic disease progression in bone based on 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 progression under the following conditions if the participant received anti-androgen 
therapy prior to enrollment:
a.
Evidence of progression >4 weeks since last flutamide treatment.
b. Evidence of progression >6 weeks since last bicalutamide or nilutamide treatment.
4. Have current evidence of metastatic disease documented by either bone lesions on bone 
scan and/or soft-tissue disease by CT/MRI. Participants whose disease spread is limited 
to regional pelvic lymph nodes are not eligible.
5. Have met one of the following criteria with regard to abiraterone acetate exposure:
a.
Not received prior abiraterone acetate (ie, abiraterone-naïve) 
b. Received prior abiraterone acetate for the treatment of mHSPC or mCRPC, for a 
minimum of 4 weeks and must not have progressed while on treatment.
c.
Received prior abiraterone acetate for the treatment of mHSPC or mCRPC and
progressed on treatment after a minimum of 8 weeks treatment (minimum 14 weeks 
for those with bone progression).
6. 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 
agonists or antagonists (participants who have not undergone an orchiectomy), this 
therapy must have been initiated at least 4 weeks prior to randomization, and treatment 
must be continued throughout the study.
7. Participants receiving bone resorptive therapy (including, but not limited to, 
bisphosphonate or denosumab) must have been on stable doses for ≥4 weeks prior to
randomization. 
8. Demonstrate adequate organ function as defined in Table 1; all screening labs should be 
performed in central laboratory within 10 days of the first dose of study intervention.
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Table 1
Laboratory Values for Adequate Organ Function
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100,000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥50 mL/min for participant with creatinine 
levels >1.5 × ULN
Hepatic
Total bilirubin
≤1.5 × ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT) 
or PTT
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
ALT (SGPT) = alanine aminotransferase (serum glutamic-pyruvic transaminase); AST (SGOT) = aspartate 
aminotransferase (serum glutamic-oxaloacetic transaminase); GFR = glomerular filtration rate; ULN = upper 
limit of normal.
a Hemoglobin and platelet requirements cannot be met by use of recent transfusion or growth factor support 
(GCSF or erythropoietin) within 2 weeks prior to randomization.
b Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
Demographics
9. Participant is male.
10. Participant is ≥18 years of age on day of signing the informed consent.
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Contraception
11. Participants are eligible to participate if they agree to the following during the 
intervention period and for at least 90 days after the last dose of enzalutamide:
•
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 participants 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.
12. Removed.    
Informed Consent
13. The participant (or legally acceptable representative if applicable) provides documented
informed consent for the study.
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Additional Categories
14. Have provided newly obtained core or excisional biopsy (obtained within 12 months of 
screening) from soft tissue not previously irradiated (samples from tumors progressing in 
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, then 
participants may provide an archival tumor tissue sample after Sponsor consultation and 
completion of an SCF. FFPE tissue blocks are preferred to slides. Newly obtained 
biopsies are preferred to archive tissue.  
Note: Details pertaining to tumor tissue submission can be found in the Procedures 
Manual.
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 meets any of the following 
criteria:
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 that have undergone potentially curative 
therapy are not excluded.
2. Has an active autoimmune disease that has required systemic treatment in 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.
3. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study intervention.
4. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study or interfere with the participant’s 
participation for the full duration of the study, such that it is not in the best interest of the 
participant to participate, in the opinion of the treating investigator.
Note: Refer to Appendix 7 for additional country-specific conditions that require 
participant exclusion.
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5. Has undergone major surgery, including local prostate intervention (excluding prostate 
biopsy), within 28 days prior to randomization and not recovered adequately from the 
toxicities and/or complications.
6. Has a gastrointestinal disorder affecting absorption (eg, gastrectomy, active peptic ulcer 
disease within last 3 months).
7. Is unable to swallow tablets/capsules.
8. Has an active infection (including tuberculosis) requiring systemic therapy.
9. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
10. Has known active HIV, concurrent active hepatitis B (defined as HBsAg positive reactive 
and/or detectable HBV DNA) or known active hepatitis C virus (defined as anti-HCV Ab 
positive and detectable HCV RNA infection).
Note: Hepatitis B and C screening tests are not required unless:
- Known history of HBV and HCV infection.
- As mandated by local health authority.
11. 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 prior to 
randomization and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases, and are not using steroids for at least 7 
days prior to randomization. This exception does not include carcinomatous meningitis, 
which is excluded regardless of clinical stability.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the study.
13. Has a history of seizure or any condition that may predispose to seizure (including, but 
not limited to prior cerebrovascular accident, transient ischemic attack, or brain 
arteriovenous malformation; or intracranial masses such as a schwannoma or 
meningioma that is causing edema or mass effect).
14. Has a history of loss of consciousness within 12 months of the Screening Visit.
15. Has had myocardial infarction or uncontrolled angina within 6 months prior to 
randomization.
Note: Participants with recent history of revascularization for acute coronary syndrome
within 3 months prior to randomization are included.
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16. Has a history of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, 
ventricular fibrillation, torsades de pointes).
17. Has a history of Mobitz II second degree or third-degree heart block without a permanent 
pacemaker in place.
18. Has hypotension as indicated by systolic blood pressure <86 mmHg at the Screening 
Visit.
19. Has bradycardia as indicated by a heart rate of <50 beats per minute on the Screening 
electrocardiogram (ECG).
20. Has uncontrolled hypertension as indicated by systolic blood pressure >170 mmHg or 
diastolic blood pressure >105 mmHg at the Screening Visit.
21. Has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their
excipients.
Prior/Concomitant Therapy
22. Has history of prostate cancer progression on ketoconazole.
23. Has had prior treatment with second-generation androgen-receptor inhibitor (eg, 
enzalutamide, apalutamide, darolutamide) or CYP17 inhibitor other than abiraterone 
acetate.
24. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-
40, CD137).
25. Has received prior treatment with radium or other therapeutic radiopharmaceuticals for 
prostate cancer.
26. Has had prior chemotherapy for mCRPC. Prior docetaxel for mHSPC is allowed if more 
than 4 weeks have elapsed from the last dose of docetaxel.
27. Has received prior targeted small molecule therapy or abiraterone treatment within 4 
weeks prior to randomization or who has not recovered (ie, Grade ≤1 or at baseline), with 
the exception of Grade ≤2 neuropathy or Grade ≤2 alopecia from AEs due to a previously 
administered agent.
28. Has received an anticancer mAb within 4 weeks prior to randomization or has not 
recovered (ie, Grade ≤1 or at baseline) from AEs due to mAbs administered more than 4 
weeks prior to randomization.
Note: Treatment with denosumab as standard of care for bone metastases is permitted. 
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29. Has used herbal products that may have hormonal antiprostate cancer activity and/or are 
known to decrease PSA levels (eg, saw palmetto) within 4 weeks prior to randomization.
30. Has received treatment with 5-α reductase inhibitors (eg, finasteride, dutasteride), 
estrogens, and/or cyproterone within 4 weeks prior to randomization.
31. Has received a live or live attenuated vaccine within 30 days prior to randomization. 
Administration of killed vaccines is allowed.
Refer to Section 6.5 for information on COVID-19 vaccines.
32. Has received prior radiotherapy within 2 weeks of randomization. Participants must have 
recovered from all radiation-related toxicities, not require corticosteroids, and not have 
had radiation pneumonitis. A 1-week washout is permitted for palliative radiation 
(≤2 weeks of radiotherapy) to non-CNS disease.
Prior/Concurrent Clinical Study Experience
33. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to randomization.
Note: Participants who have entered the nontreatment 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
34. Has a “superscan” bone scan. This is defined as an intense symmetric activity in the 
bones and diminished renal parenchymal activity on baseline bone scan such that the 
presence of additional metastases in the future could not be evaluated.
Other Exclusions
35. Is to father children within the projected duration of the study, starting with the screening 
visit through 90 days after the last dose of study intervention.
36. Has had an allogenic tissue/solid organ transplant.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
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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 
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
NOTE: In alignment with the study update memo sent to investigators on 28-FEB-2023, all 
study participants should stop ongoing treatment with pembrolizumab/placebo. Exceptions 
may be requested for study participants who, in the assessment of their study physician, are 
benefitting from the combination of enzalutamide and pembrolizumab, after consulting with 
the Sponsor. All other study participants should be discontinued from the study and be 
offered SOC treatment as deemed necessary by the investigator. If enzalutamide as SOC is 
not accessible off study to the participant, central sourcing may continue.
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 
Admin-
istration
Regimen/
Treatment Period/
Vaccination 
Regimen
Use
IMP or
NIMP/
AxMP
Sourcing
Arm 1
Experimental
pembrolizumab
Biologi
cal/Vac
cine
Solution for 
Infusion
25 mg/mL
200 mg
IV Infusion
Day 1 of each 21-day 
cycle
Test Product
IMP
Central
Arm 1
Experimental
enzalutamide
Drug
Capsule/Tablet
40 mg/80 mg
160 mg
Oral
Four 40-mg 
capsules/tablets
orally per day/two 
80-mg tablets orally 
per day
Test Product
IMP
Central 
Arm 2
Comparator
enzalutamide
Drug
Capsule/Tablet
40 mg/80 mg
160 mg
Oral
Four 40-mg 
capsules/tablets
orally per day/two 
80-mg tablets orally 
per day
Comparator
IMP
Central 
Arm 2
Comparator
Normal saline 
or dextrose
Drug
Solution for 
infusion
0 mg
0 mg
IV Infusion
Day 1 of each 21-day 
cycle
Placebo
IMP
Local
IMP=investigational medicinal product; IV=intravenous; NIMP/AxMP=noninvestigational/auxiliary medicinal product.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the European Economic Area (EEA). Country 
differences with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
In this protocol, placebo for pembrolizumab is diluent alone (normal saline and/or dextrose); diluent is used for blinding purposes and does not contain active ingredients.
Please see Appendix 7 for country-specific requirements.
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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.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab or placebo are provided in the 
Pharmacy Manual. 
Specific calculations or evaluations are not required to administer the proper dose of 
enzalutamide to each participant. The rationale for selection of doses to be used in this study 
is provided in Section 4.3.
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 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
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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 occur centrally using an interactive response technology 
(IRT) system. There are 2 study intervention arms. Participants will be randomly assigned in 
a 1:1 ratio to pembrolizumab + enzalutamide or placebo + enzalutamide, respectively.
6.3.2
Stratification
Randomization will be stratified according to the following factors:
6.3.3
Blinding
As of IA1, the study has been unblinded. The subsection below is retained for reference.
A double-blinding technique with in-house blinding will be used. Pembrolizumab and 
placebo will be prepared and/or dispensed in a blinded fashion by an unblinded pharmacist or 
qualified site personnel so that the blind is maintained. The participant, the investigator, and 
Sponsor personnel or delegate(s) who are involved in the study intervention administration or 
clinical evaluation of the participants are unaware of the intervention assignments.
The treatment identity of enzalutamide will be open-label; the identity of those treatments 
will be known by the participant, the investigator, the Sponsor, and delegate(s) who are 
involved in study intervention administration or the clinical evaluation of participants.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study should such action be warranted.
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PD-L1, PSA, CTC, and AR-V7 results are not reported back to sites to prevent early 
withdrawal of participants from study intervention.
6.4
Study Intervention Compliance
The total volume of study medication infused will be compared with the total volume 
prepared to determine compliance with each dose administered.
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 enzalutamide, the site will validate compliance with study intervention at each site visit 
according to their standard operating procedure. If doses are missed or vomited, this must be 
indicated in the source documents and CRFs.
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. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study therapy or vaccination may be required. 
The investigator should discuss any questions regarding this 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.
The following medications and vaccinations are prohibited during the study:
•
Antineoplastic systemic chemotherapy or biological therapy (except denosumab and 
bisphosphonate for bone metastases as standard of care if on stable doses ≥4 weeks prior 
to randomization)
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Targeted therapy not specified in this protocol
•
Initiation of bone resorptive therapy including but not limited to bisphosphonate or 
denosumab (unless approved by Sponsor consultation)
•
Second-generation androgen-receptor inhibitor except enzalutamide
•
Investigational agents other than pembrolizumab
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•
Herbal products that may have hormonal antiprostate cancer activity and/or are known to 
decrease PSA levels (eg, saw palmetto)
•
Radiation therapy
Note: Palliative localized radiation therapy to a site of pre-existing disease may be 
permitted while on study after consultation with Sponsor. The radiation treatment field 
may not include a target lesion by RECIST 1.1.
•
Live or live attenuated vaccines within 30 days prior to randomization and while 
participating in the study. 
Note: If precluded by local regulations, live vaccines should not be given for 120 days 
after the last dose of pembrolizumab is administered.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be 
treated just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
•
Systemic glucocorticoids except when used for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology
-
For the prevention of emesis
-
To premedicate for IV contrast allergies
-
To treat asthma or COPD exacerbations (only short-term oral or IV use in doses 
>10 mg/day prednisone equivalent)
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
•
Other glucocorticoid use except when used for the following purposes:
-
For topical use or ocular use
-
Intraarticular joint use
-
For inhalation in the management of asthma or chronic obstructive pulmonary disease
•
5-α reductase inhibitors (eg, finasteride, dutasteride), estrogens, and/or cyproterone
•
Strong CYP2C8 inhibitors or strong CYP3A4 inducers should be avoided. However, if 
these medications are necessary and cannot be avoided then enzalutamide dose should be 
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adjusted as indicated in the approved product label. Enzalutamide is a strong CYP3A4 
inducer and a moderate CYP2C9 and CYP2C19 inducer. Concomitant use of 
enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4 (eg, 
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus), CYP2C9 (eg, phenytoin, warfarin), and CYP2C19 (eg, 
S-mephenytoin, clopidogrel) should be avoided if possible as enzalutamide may decrease 
their exposure. If coadministration with warfarin cannot be avoided, conduct additional 
INR monitoring.
Note: a list of strong/moderate inducers of CYP3A4 can be found at the following 
website: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm#table2-2.
In addition to the medications listed here, site staff should refer to the local approved product 
label for permitted and prohibited medications, as well as drug-drug interactions for
enzalutamide. Caution should be used if participants are receiving concomitant medications 
that may lower the seizure threshold.
The exclusion criteria describe other medications which are 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 first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. If 
participants experience an SAE or ECI, all concomitant medications administered 30 days 
after the last dose of study intervention are to be recorded 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, Table 4. 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 
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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 4 in Section 
6.6 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.
6.5.3
Radiotherapy
Sites must consult with the Sponsor prior to the use of radiotherapy or surgical intervention 
while a participant is on 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 
on 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 the soft tissue that meets 
the criteria for disease progression according to PCWG3 [Scher, H. I., et al 2016], treatment 
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/placebo is interrupted for >12 weeks (immune-related AE) or >12 
consecutive weeks for administrative reasons or enzalutamide is interrupted for 
28 consecutive days, the site must gain approval from the Sponsor to continue the other 
partner drug. Participants who must discontinue 1 of the 2 drugs in the combination due to 
drug-related AEs may continue with the other combination partner following consultation 
with the Sponsor until criteria for discontinuation of treatment are met. 
In response to AEs that occur in either treatment group refer to the approved labeling for 
enzalutamide for more detailed information regarding dose regimen/modification and refer to
Table 4 for pembrolizumab/placebo dose modification. Additionally, refer to the approved 
enzalutamide label for additional information about avoidance of concomitant medications or 
foods that may affect the metabolism of these drugs.
6.6.2
Dose Modification for Enzalutamide
If a participant experiences any Grade ≥3 toxicity related to enzalutamide treatment, the drug 
should be withheld until the toxicity decreases to Grade ≤2. Enzalutamide can then be 
resumed at the reduced dose of 120 mg daily. For repeat Grade ≥3 toxicity, it can again be 
held until toxicity decrease to Grade ≤2 and resumed at the reduced dose of 80 mg daily.
Reduction below 80 mg is not allowed.
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Once the dose has been reduced, it may not be escalated up to a previous dose level. 
Enzalutamide should be permanently discontinued in participants who develop a seizure 
while on treatment.
PRES has been observed in patients treated with enzalutamide. This 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. 
Posterior reversible encephalopathy syndrome is diagnosed by brain imaging (preferably 
MRI). Discontinue enzalutamide treatment if the participant develops PRES. Enzalutamide 
must be permanently discontinued in participants who develop seizures or PRES on 
treatment. Pembrolizumab/placebo may be resumed in these participants after consultation 
with the Sponsor.
Participants should be directed to report the development of rash, regardless of severity,
promptly to investigators. Participants with rash should be treated promptly with steroids,
dose interruption per protocol, and monitored closely for worsening of rash, which may 
require additional treatment. 
After resolution of the toxicity, the participant can resume treatment with enzalutamide with 
a dose reduction according to Table 3.
Table 3
Enzalutamide Dose Modification Guidelines for Drug-related Adverse Events
Drug
Dose/Potency
Dose Frequency
Regimen
Initial enzalutamide 
dose
160 mg
QD
Four 40-mg 
capsules/tablets or two 80-
mg tablets
First dose reduction
120 mg
QD
Three 40-mg 
capsules/tabletsa
Second dose reduction
80 mg
QD
Two 40-mg 
capsules/tablets or one 80-
mg tablet
QD=every day
a.
This dose level is not applicable for 80 mg tablets.
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. 
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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 4.
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Table 4
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)
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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
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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.
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
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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
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
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
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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
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 Related to 
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 on pembrolizumab associated 
infusion reaction are provided in [Table 5].
Table 5
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) prior to infusion 
of pembrolizumab 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 
following 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
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab/placebo 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 (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.
6.6.4
Second Course
NOTE: As of Amendment 09, Second Course treatment is not an option for participants. 
All participants who have completed the first course of the pembrolizumab plus enzalutamide 
arm or stopped for confirmed CR may be eligible for up to an additional 17 cycles of 
pembrolizumab, with or without enzalutamide, at the investigator’s discretion, if there is 
investigator-determined progressive disease by RECIST 1.1 after initial treatment. This 
retreatment is the Second Course of this study.
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Participants may enter the Second Course if all of the following criteria are met:
1. The participant received pembrolizumab, determined on unblinding if applicable
2. No new anticancer treatment was administered after the last dose of study intervention
3. The participant meets all of the inclusion criteria and none of the exclusion criteria
4. The study is ongoing
An objective response or disease progression that occurs during the Second Course Phase for 
a participant will not be counted as an event for the primary analysis of either endpoint in this
study.
6.6.5
Management of Overlapping Toxicities
Based on the known toxicity profiles of pembrolizumab and enzalutamide, certain treatment-
related AEs are uniquely associated with one drug versus the other. For example, seizure is a 
known risk for enzalutamide treatment, while immune-related AEs are risks for 
pembrolizumab treatment. However, certain AEs, such as diarrhea, may be initially 
considered attributable to either study intervention. Therefore, evaluation of attribution is 
important for determining the study intervention most likely related to the AE, or an 
alternative etiology, and subsequently proper clinical management. The following aspects 
should be considered: 
1. Timing of AE onset: 
Since enzalutamide is dosed daily and continuously due to a relatively short half-life (5.8
days), and pembrolizumab is dosed Q3W due to a long half-life, enzalutamide 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 enzalutamide dose interruption is needed. 

If an AE is identified at the beginning of a treatment cycle, enzalutamide can be 
interrupted and dosing of pembrolizumab should be held.
If the participant recovers from an AE in response to enzalutamide interruption (ie,
positive dechallenge), the event is more likely to be related to enzalutamide. Otherwise, 
after excluding other alternative explanations, an immune-related AE 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 is rapidly worsened, action including interrupting both drugs and initiating 
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treatment with a corticosteroid (with exception of hypothyroidism, Type 1 diabetes 
mellitus) and other supportive care should be taken promptly.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic IRT should be used to unblind participants and to unmask study 
intervention identity. The Sponsor will not provide random code/disclosure envelopes or lists 
with the clinical supplies.
6.9
Standard Policies
Trial site personnel will have access to the IRT system to allocate participants, to assign 
intervention to participants and to manage the distribution of clinical supplies. Each person 
accessing the IRT system must be assigned an individual unique 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 treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.12.3.
Participants may discontinue study intervention at any time for any reason or be dropped 
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 
therapy 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.
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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.
•
The participant interrupts pembrolizumab or placebo administration for more than 
12 consecutive weeks for an irAE or >12 consecutive weeks for administrative reasons 
without Sponsor consultation.
•
The participant has missed 28 consecutive days of enzalutamide without Sponsor 
consultation.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed 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 outlined in Section 8.2.2 (exception if the 
Sponsor approves treatment continuation with enzalutamide)
Note: As of Amendment 09, central tumor response assessments will no longer be 
performed. Participants on study treatment will be assessed locally by the investigator for 
disease progression per SOC schedule. Participants with PD per local investigator 
assessment should be discontinued (exception if the Sponsor approves treatment 
continuation with enzalutamide following PD).
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
•
Completion of 35 cycles (approximately 2 years) with pembrolizumab/placebo (does not 
apply to enzalutamide)
Note: The number of treatments is calculated starting with the first dose. Participants who 
stop the combination or pembrolizumab after receiving 35 doses may be eligible for 
retreatment if they progress after stopping study intervention provided they meet the 
requirements detailed in Section 6.6.4. Participants may be retreated in the Second 
Course Phase (Retreatment) for up to an additional 17 cycles (approximately 1 year).
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Discontinuation of pembrolizumab/placebo may be considered for participants who have 
attained a confirmed CR and have been treated for at least 8 cycles (at least 24 weeks), 
receiving 2 cycles of pembrolizumab or placebo beyond the date when the initial CR was 
declared. These participants may be eligible for second course treatment described in 
Section 6.6.4.
Note: As of Amendment 09, second course treatment is not an option for participants.
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
It has been well documented that a higher rate of withdrawal can render a study 
uninterpretable; therefore, unnecessary withdrawal of participants should be avoided. 
As clinical event data are important study endpoints, participants who discontinue study 
intervention prior to completion of the treatment period should be encouraged to continue all 
remaining study visits for follow-up and vital status assessment as outlined in the SoA and 
Section 8.12.3.
If a participant repeatedly fails to return for scheduled visits and/or if the study site is unable 
to contact the participant after multiple attempts (ie, is lost to follow-up), the procedures to 
be performed are outlined in Section 7.3.
If a participant decides not to continue receiving study intervention, the participant is to be 
encouraged to continue visits in the study for follow-up, imaging, and vital status assessment.
Participants who withdraw consent during the study
If the participant or participant’s legally acceptable representative withdraws consent, the 
participant must be withdrawn from the study.
Any AEs that are present at the time of withdrawal should be followed in accordance with 
the safety requirements outlined in Section 8.4.
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.
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•
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.
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.
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8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study. 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 documented 
informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the 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 or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
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.
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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 documented 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.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout, or run-in treatment including placebo run-in).
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
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 prior to 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.
8.1.5.2
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.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.12.1.
8.1.6.1
Treatment Eligibility Assessment Form
A TEA form is included in this study to document the investigator assessment of participant 
suitability for potential treatment with enzalutamide, and the rationale. These data may be 
required to support reimbursement efforts for pembrolizumab plus enzalutamide.
The investigator must complete this form and provide rationale to document the choice of
enzalutamide before randomization.
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 re-assigned to another 
participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Administration of pembrolizumab/placebo will be monitored by the investigator and/or study 
staff.
On Day 1 of each cycle, study intervention should be administered after all procedures and 
assessments have been completed. Study intervention can be administered ±3 days of the 
targeted Day 1 for each cycle, except Cycle 1 where treatment can only be administered 
+3 days of the targeted Day 1.
8.1.8.1
Timing of Dose Administration
8.1.8.1.1
Pembrolizumab/Placebo
Pembrolizumab/placebo treatments will begin on Day 1 of each cycle after all predose study 
procedures and assessments have been completed as detailed in the SoA. 
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Pembrolizumab will be administered as a fixed-dose of 200 mg using a 30-minute IV 
infusion Q3W. Sites should make every effort to target infusion timing 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).
8.1.8.1.2
Enzalutamide
Enzalutamide will be administered at a dose of 160 mg (four 40-mg capsules/tablets or two 
80-mg tablets) orally QD. Enzalutamide treatment should begin on the same day as Cycle 1, 
Day 1 of pembrolizumab/placebo treatment, with the first dose administered after the end of 
the pembrolizumab/placebo IV infusion.
Subsequent enzalutamide treatments will be taken PO QD at approximately the same time 
each day on a continuous daily dosing schedule. Capsules/tablets 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 
their standard operating procedure. If doses are missed or vomited, this must be indicated in 
the source documents and CRFs.
Detailed information regarding dose regimen/modification can be found in the approved 
labeling for enzalutamide.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment 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 final study 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.
8.1.10
Participant Blinding/Unblinding
As of IA1, the study has been unblinded. The subsections below are retained for reference.
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNBLINDED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
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dosage administered, he/ she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
toxicity grade of the AEs observed, the relation to study drug, the reason thereof, etc., in the 
medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date,
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
8.1.10.1
Nonemergency Unblinding
In the event of PD, there may be a need to unblind the participant’s treatment assignment 
prior to initiating second course treatment (Section 6.6.4). In this circumstance, unblinding to 
pembrolizumab versus placebo administration may occur on an individual basis and only 
after consultation with the Sponsor Clinical Director. Every effort should be made not to 
unblind the participant unless necessary.
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.
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8.1.12
Tumor Tissue for Biomarker Status
During the screening period, a tissue sample is required for each participant consisting of:

A newly obtained core or excisional biopsy of a tumor lesion, which was not previously 
irradiated.
Or

An archival tumor tissue sample if a new biopsy is unavailable.
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
Details pertaining to tumor tissue submission can be found in the Procedures Manual.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
As of Amendment 09: Central tumor response assessments will be discontinued. 
Imaging scans will no longer be submitted to iCRO nor read by BICR. Local tumor imaging 
should continue per SOC schedule for participants still on study treatment. The subsections 
below are retained for reference.
The process for image collection and transmission to the central imaging vendor can be 
found in the SIM.

Chest, abdomen, and pelvis scans are required for all participants at screening and on 
study. CT with IV and oral contrast is preferred or non-contrast CT of the chest and MRI 
of the abdomen and pelvis with IV gadolinium for participants in whom iodinated 
contrast is contraindicated, or when mandated by local practice.

Bone scans (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) cannot be a substitute for the 
bone scan.

Additional imaging acquired as per standard of care or as clinically indicated, used to
support radiographic disease progression or efficacy assessments, should be sent to the 
iCRO.
Note: Radiographic disease progression is per PCWG Modified RECIST 1.1.
Note: For the purposes of assessing tumor imaging, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility.
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Participant eligibility will be determined using local assessment (investigator assessment) 
based on PCWG-modified RECIST 1.1. All scheduled images for all study participants from 
the sites will be submitted to the central imaging vendor. In addition, images (including via 
other modalities) that are obtained at an unscheduled time point to determine disease 
progression, as well as imaging obtained for other reasons, but which demonstrates 
radiologic progression, should also be submitted to the central imaging vendor.
When the investigator identifies radiographic progression, the central imaging vendor will 
perform expedited verification of radiologic PD and communicate the results to the study site 
and Sponsor. Treatment should continue until PD has been verified. Images should continue 
to be submitted to the central imaging vendor.
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 (eg,
discontinuation of study intervention) will be PCWG-modified RECIST 1.1.
Assessment of treatment response in the soft tissues will be according to 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.
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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
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. 
*If the bone scan is entirely missing or was not done, and bone lesions were present at baseline, then the overall 
response is nonevaluable.
Initial tumor imaging showing site-assessed PD should be submitted immediately for BICR 
verification of PD. The site will be notified if the BICR verifies PD using PCWG-modified 
RECIST 1.1.     
8.2.1.1
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
randomization. Tumor imaging by CT (or MRI) and radionuclide bone scan is required at 
screening.
Scans performed as part of routine clinical management are acceptable for use as the 
screening scans if they are of diagnostic quality and performed within 28 days prior to the 
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date of randomization. Scans are required to be sent to the central imaging vendor prior to 
enrollment; however, central imaging assessment is not required prior to enrollment.
At screening, all soft-tissue lesions seen by CT (or MRI) and all bone lesions seen by 
radionuclide bone scan will be documented. In determining response to treatment or 
progression, investigators must evaluate all target and nontarget lesions and search for new 
lesions at each imaging time point.
8.2.1.2
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 
remain on treatment beyond Week 54 will have imaging performed every 12 weeks (84 days 
± 7 days). All supplemental imaging must be submitted to the central imaging vendor.
Timing of imaging should follow calendar days from 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 radiographic evidence of disease progression.
8.2.1.3
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 prior to the date of discontinuation, then 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 using 
the same imaging schedule used while on treatment (every 9 weeks in Year 1 or 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.
8.2.1.4
Second Course (Retreatment) Tumor Imaging
As of Amendment 09, Second Course treatment is not an option for participants. The section 
below is retained for reference.
Tumor imaging must be performed within 28 days prior to restarting treatment with 
pembrolizumab. Local reading (investigator assessment with site radiology reading) will be 
used to determine eligibility. All second course imaging should be submitted to the central 
imaging vendor for quality control, storage, and possible retrospective review.
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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 prior to the date of discontinuation, then 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 either the start of a new 
anticancer treatment, disease progression, death, or the end of the study, whichever occurs 
first.
8.2.2
PCWG Modified RECIST 1.1 Assessment of Disease
As of Amendment 09: Central tumor response assessments will be discontinued. 
Imaging scans will no longer be submitted to iCRO nor read by BICR. The section below is
retained for reference.
Local tumor imaging should continue per SOC schedule for participants still on study 
treatment.
PCWG Modified RECIST 1.1 will be used by BICR as the primary measure for assessment 
of tumor response, date of disease progression, and as a basis for all protocol guidelines 
related to disease status (eg, discontinuation of study intervention).
Upon 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 email 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 (≥4 weeks to next scan)
-
Send scans to iCRO
-
Continue local assessment
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-
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 addendum must be signed
Note: the reconsent addendum may be signed any time after investigator-assessed 
progression is identified but must be signed prior to 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
-
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.
8.2.3
Prostate-specific Antigen Assessments
As of Amendment 09: PSA assessments will be discontinued. The section below is retained 
for reference.
There are 2 components required for defining trial eligibility by PSA, 1) a rising PSA as 
determined by local laboratory and 2) a PSA >1 ng/mL as defined by central laboratory. PSA 
determination by central laboratory has to be performed within 10 days prior to 
randomization (refer to Section 1.3.1). If central laboratory result for PSA is not expected to 
be available to the site prior to randomization, the investigator may also perform the test 
locally and if >1 ng/mL, use that result to determine eligibility. However, a sample must still 
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be collected within 10 days prior to randomization for submission to central laboratory. 
During the remainder of the study, local laboratory may not be used in lieu of central 
laboratory.
For defining rising PSA, the reference value to use (No. 1) is the last PSA 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 compared to a prior single increased PSA value. If a PSA value obtained
during screening is used as the second data point to confirm a rising PSA and it does not 
confirm the PSA increase, but is still greater than the reference point, the PSA determination
should be repeated by the local laboratory in 1 week to prove that there is a sequence of 
rising PSA. 
If there are 2 consecutive rising PSA test results before screening, but the value obtained is 
less than the previous value (but still above the reference value), the participant is still 
eligible for the study.
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 PSAs are needed to ensure that 
PSA is rising.
Central laboratory PSA assessment must occur every 3 weeks (±7 days) from the date of 
randomization while the participant is on study intervention. PSA timing should follow 
calendar days from the date of randomization and should not be adjusted for delays in cycle 
starts.
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In participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring their disease status by PSA assessments 
until: (1) the start of new anticancer treatment, (2) disease progression, (3) death or (4) the 
end of the study, whichever occurs first. In these participants, PSA will be measured by a 
central laboratory at the same time points as imaging.
Sample collection, storage, and shipment instructions will be in the Procedures Manual. The 
window for PSA collections is ±7 days.
8.2.4
Tumor Tissue Collection
Baseline tumor tissue for biomarker analysis must be sent to the testing laboratory and 
analyzed for adequacy prior to enrollment.
8.2.5
PROs and Quality of Life Assessments
 
 
 
 
 
 
 
8.2.5.1
FACT-P
 
 
 
8.2.5.2
BPI-SF 
 
 
CCI
CCI
CCI
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8.2.5.3
EQ-5D-5L
 
 
 
8.2.6
Patient Analgesic Log
 
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. 
Planned time points for all safety assessments are provided in the SoA.
CCI
CCI
CCI
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8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical exam during the 
Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 1.3. After the first 
dose of study intervention, new clinically significant abnormal findings should be recorded 
as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical exam as defined in Section 1.3, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
study intervention administration. New clinically significant abnormal findings should be 
recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
Vital signs will be measured in a sitting, semirecumbent or supine position after 5 minutes 
rest and will include weight, temperature, systolic and diastolic blood pressure, heart, and 
respiratory rate. Record vital signs prior to study intervention administration at treatment 
visits. Height will be measured at screening only.
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.
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•
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.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Study 
Procedures Manual. Refer to the Study Flow Chart (Section 1.3) for the timing of laboratory 
assessments.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.5
Performance Assessments
8.3.5.1
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (Appendix 11) at screening
and prior to the administration of each dose of study intervention as specified in the SoA 
(Section 1.3).
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.
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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. Investigators need to document if an SAE was associated 
with a medication error, misuse, or abuse.
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 participant provides 
documented informed consent, 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 causes 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.
•
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 the time required to eliminate systemic exposure after
cessation of study intervention as described in Sections 5.1 and 8.4.5, or 30 days after
cessation of study intervention if the participant initiates new anticancer therapy must be 
reported by the investigator.
•
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 6].
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Table 6
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 (ECI) (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 and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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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 
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.
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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.
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 upon 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: 

An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.

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).
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.
An enzalutamide overdose 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 drug should be stopped 
and general supportive measures initiated, taking into consideration the half-life is 5.8 days 
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for enzalutamide. Participants may be at increased risk of seizures following 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 drug overdose.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
Not applicable.
8.9
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be obtained predose on Day 1 but may be 
collected at the next scheduled blood draw, if needed. Sample collection, storage, and 
shipment instructions for planned genetic analysis samples will be provided in the Procedures 
Manual.
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 
local IRB/IEC does not approve) sample collection for these purposes, then such samples 
should not be collected at the corresponding sites.
8.10
Biomarkers
 
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8.11
Medical Resource Utilization and Health Economics
 
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.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed prior to the participant 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 prior to 
randomization except for the following:
•
Laboratory tests are to be performed within 10 days prior to the first dose of study 
intervention. An exception is HIV and hepatitis testing which may be done up to 42 days 
prior to randomization if required by local regulations. Refer to Appendix 7 for country-
specific requirements.
•
Evaluation of ECOG status is to be performed within 7 days prior to randomization.
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•
Tumor tissue from a fresh core or excisional biopsy obtained within 12 months of 
screening. Archival tumor tissue sample (>12 months) can be submitted after Sponsor 
consultation. 
•
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
randomization.
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 met. Participants who are rescreened will retain their original 
screening number.
8.12.2
Treatment Period Visit
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
8.12.3
Discontinuation Visit
The Discontinuation Visit should occur at the time 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 Section 1.3 – Schedule of Activities. Specific procedure-related 
details are provided above in Section 8 – Study Assessments and Procedures. Prior to 
discontinuing participants from therapy, submit the Treatment Termination & Disease 
Assessment Termination Form.
8.12.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Prior to discontinuing participants from therapy, submit the Treatment Termination & 
Disease Assessment Termination Form.
8.12.5
Post-treatment Visit
8.12.5.1
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 occurs first.
Participants who are eligible for retreatment with pembrolizumab may have up to 2 safety 
follow-up visits, 1 after the Initial Treatment or First Course and 1 after the Second Course.
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8.12.5.2
Efficacy Follow-up Visits
NOTE: As of Amendment 09: Efficacy Follow-up visits will be discontinued. The section 
below is retained for reference.
Participants who discontinue study intervention for a reason other than BICR-verified 
radiographic disease progression will move into Follow-up. Follow-up visits will be 
scheduled every 9 weeks (63 days ± 7 days) through Week 54 and then every 12 weeks (84 
days ± 7 days) thereafter, from the date of randomization, to coincide with the imaging 
schedule the participant was on at the time of discontinuation from treatment. Participants 
who discontinue study intervention without documented disease progression (including 
confirmation of bone progression) should continue monitoring disease status by radiologic 
imaging (CT/MRI and bone scans) and PSA according to the schedule that the participant 
was on 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, end of study (or if the participant begins retreatment with pembrolizumab
as detailed in Section 6.6.4). Information regarding poststudy anticancer treatment will be 
collected if new treatment is initiated.
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 6.6.4 will move from Follow-up to Second Course when they experience 
disease progression. Details are provided in the SoA (Section 1.3) for retreatment with 
pembrolizumab.
8.12.5.3
Survival Follow-up
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8.12.6
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the course of the study by the 
Sponsor. For example, updated survival status may be requested prior to but not limited to an 
external Data Monitoring Committee (eDMC) review, interim and/or final analysis. Upon 
Sponsor notification, all participants who do not/will not have a scheduled study visit or 
study contact during the Sponsor defined time period will be contacted.
9
STATISTICAL ANALYSIS PLAN
As of Amendment 09: The Statistical Analysis Plan is amended as follows.
NOTE: Based on the data from an interim safety and efficacy analysis for KEYNOTE-641 
(data cutoff 12-DEC-2022), the eDMC recommended stopping the study for futility per the 
futility criteria prespecified in the sSAP. Based upon these data and the recommendation of 
the eDMC, the study has been unblinded (as of 22-FEB-2023). Prespecified IA2 and final 
analysis of the study described in the SAP will not be performed. Safety analysis will be 
performed at the end of the study. There will be no further analyses for efficacy 
 
endpoints collected from participants beyond the IA1 cutoff date.
This section outlines the statistical analysis strategy and procedures for the study.  The study 
has been unblinded as of 22-FEB-2023. Changes made to primary and/or key secondary 
hypotheses, or the statistical methods related to those hypotheses that occurred prior to 
Amendment 09 were documented in previous protocol amendments(s) and sSAP (consistent 
with ICH Guideline E-9). Changes to exploratory or other nonconfirmatory analyses made 
after the protocol has been finalized, but prior to unblinding/final data base lock, will be 
documented in a sSAP and referenced in the Clinical Study Report (CSR) for the study. Post 
hoc exploratory analyses will be clearly identified in the CSR.
 
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12. As of Amendment 09, prespecified IA2 and final 
analysis of the study described in the SAP will not be performed. Safety analysis will be 
performed at the end of the study; there will be no further analyses of efficacy
 
endpoints collected from participants beyond the IA1 cutoff date. The SAP summary has 
been updated accordingly.
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Study Design Overview
A Phase 3, Randomized, Double-blind Study of Pembrolizumab 
(MK-3475) Plus Enzalutamide versus Placebo Plus Enzalutamide in 
Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Treatment Assignment
Approximately 1240 eligible participants will be randomized in a 1:1 
ratio to one of the following 2 treatment arms:

Arm 1: pembrolizumab plus enzalutamide

Arm 2: placebo plus enzalutamide
In alignment with the study update memo sent to investigators on 
28-FEB-2023, all study participants should stop ongoing treatment with 
pembrolizumab/placebo.
Analysis Populations
Efficacy: Intent-to-Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
1.
Overall survival (OS)
2.
Radiographic progression-free survival (rPFS)
Key Secondary Endpoints
1.
Time to initiation of the first subsequent anticancer therapy (TFST)
or death
Statistical Methods for Key 
Efficacy Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab 
plus enzalutamide arm to placebo plus enzalutamide arm with respect to 
OS, rPFS, and TFST using a stratified log-rank test. The hazard ratio 
will be estimated using a Cox regression model. Event rates over time 
will be estimated within each treatment 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 events in this study. 
Tier 2 parameters will be assessed via point estimates with 95% 
confidence interval (CIs) provided for between-group comparison; only 
point estimates by treatment group are provided for Tier 3 safety 
parameters. The 95% CIs for the between-treatment differences in 
percentages will be provided using the Miettinen & Nurminen method.
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Interim Analyses
Multiplicity
Sample Size and Power 
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.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
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.
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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
9.4.1.1
Primary
Overall Survival
OS is defined as the time from randomization to death due to any cause.  
Radiographic Progression-free Survival – 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.
9.4.1.2
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, whichever occurs first. 
9.4.1.3
Secondary
PSA response rate is defined as the proportion of participants in the analysis population 
with PSA decline of ≥50% from baseline measured twice at least 3 weeks apart. 
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 - 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 until earliest date of 
disease progression or death from any cause, whichever occurs 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 that 1) ≥25% increase and ≥2 ng/mL above the 
nadir, and which is confirmed by a second value ≥3 weeks later if there is PSA decline from 
baseline 2) or ≥25% increase and ≥2 ng/mL increase from baseline beyond 12 weeks if there 
is no PSA decline from baseline.
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PSA undetectable rate is defined as the proportion of participants in the analysis population 
with PSA < 0.2 ng/mL during study intervention.
Time to first symptomatic skeletal-related event is defined as the time from randomization 
to the first symptomatic skeletal-related event, which is defined as to the 
1) first use of EBRT to prevent or relieve skeletal symptoms, 
2) the 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 – soft-tissue rule of PCWG-modified 
RECIST 1.1 by BICR is defined as the time from randomization to radiographic soft-tissue 
progression.
9.4.1.4
Exploratory
 
  
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 
adverse events, laboratory values and vital signs.
9.4.3
PRO Endpoints
9.4.3.1
 
 
 
 
 
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
 
 
 
9.5.2
Safety Analysis Populations
 
 
 
 
 
9.5.3
PRO Analysis Population
 
9.6
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 9.6.2. 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, Multiplicity. 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. In the event that 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 stratum. Details regarding the 
combining of strata will be specified in the sSAP prior to database lock based on a blinded 
review of response counts by stratum.
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9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and key secondary 
objectives. 
9.6.1.1
Overall Survival
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, the hazard ratio). 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.
 
 
 
9.6.1.2
Radiographic Progression-Free Survival
The nonparametric Kaplan-Meier method will be used to estimate the rPFS curve in each 
treatment 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, hazard ratio) between the 
treatment arms. The hazard ratio 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 (see Section 6.3.2) will be applied to both the 
stratified log-rank test and the stratified Cox model.
 
 
 
 
 
 
 
 
 
 
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9.6.1.3
TFST
The nonparametric Kaplan-Meier method will be used to estimate the TFST curve in each 
treatment group. 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, hazard ratio) between the 
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treatment arms. The hazard ratio and its 95% confidence interval 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 (See 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.
9.6.1.4
Analysis Strategy for Key Efficacy Endpoints
Table 8 summarizes the primary analysis approach for key efficacy endpoints.
Table 8
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 7
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
BICR=blinded independent central review; ITT=intention-to-treat; OS=overall survival; PCWG=Prostate Cancer 
Working Group; RECIST 1.1= Response Evaluation Criteria in Solid Tumors Version 1.1; rPFS=radiographic 
progression-free survival; TFST=Time to initiation of the first subsequent anticancer therapy or death; 
a Statistical 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 prior to the analysis.
 
 
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences, laboratory tests, vital signs, and ECG measurements. 
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The analysis of safety results will follow a tiered approach (Table 9). 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 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 subject to inferential testing for statistical significance.
AEs 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. The combination of 
pembrolizumab and enzalutamide has not been associated with any new safety signals. 
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% confidence intervals 
provided for between-treatment differences in the proportion of participants with events. 
Membership in Tier 2 requires that at least 
 of participants in any treatment group exhibit 
the event; all other AEs and predefined limits of change will belong to Tier 3. The threshold 
of at least 
 of participants was chosen for Tier 2 events because the population enrolled 
in this study are in critical conditions and usually experience various AEs of similar types 
regardless of treatment; events reported less frequently than 
 of participants would 
obscure the assessment of the overall safety profile and add little to the interpretation of 
potentially meaningful treatment differences. 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.
In addition, the broad AE categories consisting of the proportion of participants with any AE, 
a drug-related AE, a Grade 3 to 5 AE, an AE that is both Grade 3 to 5 and drug-related, an 
SAE, an AE which is both serious and drug-related, a dose modification due to an AE, a 
discontinuation due to an AE, and death will be considered Tier 2 endpoints.
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.
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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 treatment group in table format.  
Table 9
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE 
 
X
X
Any Grade 3 to 5 AE 
 
X
X
Any serious AE
 
X
X
Tier 3
Any AE
X
Change from baseline results (laboratory test toxicity 
grade, vital signs, ECGs)
X
AE=adverse event; CI=confidence interval; ECG=electrocardiogram; X=results will be provided.
9.6.3
Analysis Methods for PRO Endpoints
 
 
 
 
 
 
 
9.6.4
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of 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 
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diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.7.1
Efficacy Interim Analyses
 
 
 
 
 
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9.7.2
Safety Interim Analyses
 
9.8
Multiplicity
 
 
 
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9.8.1
rPFS
 
 
 
 
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9.8.2
OS
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.8.3
TFST
 
 
 
 
 
 
 
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9.8.4
Safety Analyses
9.9
Sample Size and Power Calculations
NOTE: As of Amendment 09, prespecified IA2 and 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 dual primary endpoints of rPFS and OS. 
A total of approximately 1240 participants will be randomized in a 1:1 ratio to the 
pembrolizumab plus enzalutamide group and the placebo plus enzalutamide group, 
(approximately 600 participants per group) respectively.
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With 
, the study has approximately 
power to demonstrate males 
treated with pembrolizumab + enzalutamide has a longer median 
 than males treated with 
enzalutamide 
if the underlying constant HR
is 
. Sample size and power calculations are based on the following assumptions: (1) an 
HR of 
where the
follows 
 distribution with a median of 
 in 
the pembrolizumab + enzalutamide group and a median of 
 in the enzalutamide 
group
 
 
 (2) 
 (3) an 
enrollment duration of 
under an average enrollment rate of 
participants per 
month 
; and (4) a monthly drop-out rate of 
 will be conducted 
 when approximately
 events are 
observed. Approximately 
 events are expected to be observed at that time. 
With 
, the study has approximately 
 power to demonstrate that males 
treated with pembrolizumab + enzalutamide have a longer median 
than males treated 
with enzalutamide at a one- sided significance level of 
if the underlying constant HR is 
. These calculations are based on the following assumptions: (1) a hazard ratio of 
where
follows 
 distribution with a median of 
 in the 
pembrolizumab + enzalutamide group and a median of 
 in the enzalutamide group
 
 
 (3) an 
enrollment duration of 
under an average enrollment rate of 
participants per 
month 
 and (4) an approximately monthly drop-out rate of 
 will be conducted
 when approximately
 events are 
observed. Approximately 
events are expected to be observed at that time. With 
, the study has approximately 
 power to demonstrate males treated 
with pembrolizumab + enzalutamide have a longer median 
than males treated with 
enzalutamide at a one-sided significance level of 
 if the underlying constant 
. 
These calculations are based on the following assumptions: (1) a hazard ratio of 
where 
follows 
 distribution with a median of 
 in the pembrolizumab 
+ enzalutamide group and a median of 
 in the enzalutamide group
 
 
 
 (2) interim analyses for efficacy evaluation as outlined in 
Section 9.7; (3) an enrollment duration of 
under an average enrollment rate of
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participants per month 
and (4) an approximately 
The sample size and power calculations for rPFS, TFST, and OS were performed 
 
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:
In addition, a Forest plot will be produced, which provides the estimated point estimates and 
confidence intervals for the treatment effect across the categories of subgroups listed above.
In the event that 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 stratum. Details regarding the combining of strata will be specified in the sSAP prior 
to 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 enzalutamide will be summarized as duration of treatment in days. 
The extent of exposure for pembrolizumab/placebo will be summarized as duration of 
treatment in cycles. Dose interruption for each drug, dose reduction or dose increase for 
enzalutamide will be summarized. Summary statistics will be provided on 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 
are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
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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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10.1.3.1
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.
10.1.3.2
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.
10.1.3.3
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
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the DMC regarding the study.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC 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 DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
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study results, consider the overall risk and benefit to study participants (Section 9.7 Interim 
Analysis) 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 DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC 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 participants’ documented informed consent, 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 14 will be performed by the central laboratory.
•
Results of predose laboratory procedures must be reviewed by the investigator or 
qualified designee and found to be acceptable prior to each dose of trial treatment. During 
initial treatment, local laboratory results are permitted in the event that the central 
laboratory results are not available in time for either study intervention administration 
and/or response evaluation. If a local sample is used, it is important that the sample for 
central analysis is obtained in parallel. Additionally, if the use of local laboratory test
results in 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.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 of the protocol, respectively.
•
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, CTC and AR-V7 results are not reported back to sites to prevent early 
withdrawal of participants from study intervention.
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Table 14
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
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose (Indicate if 
fasting, or 
nonfasting)
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, (bilirubin, urobilinogen, nitrite, leukocyte 
esterase)
•
Microscopic examination (if blood or protein is abnormal)
Other Tests
•
Testosterone
•
Thyroid function tests
•
PT or INR and PTT/aPTT
ALT=alanine aminotransferase; ANC=absolute neutrophil count; aPTT=activated partial thromboplastin time; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; MCH=mean corpuscular hemoglobin; MCV=mean 
corpuscular volume; PT/INR=prothrombin time/international normalized ratio; PTT=partial thromboplastin time; 
RBC=red blood cell; SGOT= serum glutamic-oxaloacetic transaminase; SGPT=serum glutamate pyruvate transaminase; 
WBC=white blood cell.
The investigator (or medically qualified designee) must document their 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
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
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, or are 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.
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•
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.
•
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.
10.3.3
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:
Results in death
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.
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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.
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.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
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.
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10.3.4
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
10.3.5
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.
•
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.
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•
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 
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.
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-
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?
•
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.
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•
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.
10.3.6
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 and Pregnancy Testing
10.5.1
Definitions
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.
10.5.2
Pregnancy Testing
Not applicable.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not Applicable.
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10.7
Appendix 7: Country-specific Requirements
CCI
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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 PCWG 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 the radionuclide (Tc-99m) bone scintigraphy. 
Other modalities, including 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 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 timepoints, 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.
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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, but is 
updated to PD during analysis by MSD.
Non-PD
Nonprogressive disease: 
At least one 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
10.8.4
Descriptions of Bone Response Categories
10.8.4.1
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.
10.8.4.2
Nonprogression (Non-PD)
At least one 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 two new lesions present.
10.8.4.3
Unconfirmed Progressive Disease (PDu)
At least two 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.
10.8.4.4
Progressive Disease (PD)
At least two 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 one new lesion appears at 
visit N, and another new lesion at visit N+1, visit N+1 is considered to represent progressive 
disease.
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10.8.4.5
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.
10.8.4.5.1
For 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 two 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 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 two 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

The bone lesions seen within the flare window are ignored for the purposes of 
counting new lesions at later timepoints, since they were not new. This may be 
referred to as “re-baselining”.
10.8.4.5.2
For 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 re-baselining of lesions will occur in 
this scenario.
10.8.4.6
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 increase 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 patient’s 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. 
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10.8.4.7
Management Following 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 the 
participant is achieving a clinically meaningful benefit, an exception to continue study 
intervention may be considered following 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
ADT
androgen deprivation therapy
AE
adverse event 
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
aPTT
activated partial thromboplastin time
AQA
analgesic quantification algorithm
AR
androgen receptor
AR-V7
androgen-receptor splice variant 7
AST
aspartate aminotransferase
BCG
Bacillus Calmette–Guérin
BICR
blinded independent central review
BPI-SF
Brief Pain Inventory-Short Form
CD28
cluster of differentiation 28
CD3 ζ
cluster of differentiation 3 zeta
CHAARTED
Chemohormonal Therapy Versus Androgen Ablation Randomized 
Trial for Extensive Disease
CI
confidence interval
cLDA
constrained longitudinal data analysis
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
CPS
combined (tumor and immune cells) positive score
CR
complete response
CRF
case report form 
CSPC
castration-sensitive prostate cancer
CSR
Clinical Study Report
CT
computed tomography
CTC
circulating tumor cell
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor deoxyribonucleic acid
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTx
chemotherapy
DCR
disease control rate
DNA
deoxyribonucleic acid 
DOR
duration of response
EBRT
external-beam radiation therapy
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
eDMC
external Data Monitoring Committee
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Abbreviation
Expanded Term
EEA
European Economic Area
ELISA
enzyme-linked immunoassay
EOC
Executive Oversight Committee
ePRO
electronic PRO
EQ-5D-5L
EuroQoL 5- dimension, 5-level health state utility
ESMO
European Society for Medical Oncology
EU CTR
European Union Clinical Trials Regulation
EWB
Emotional Well-Being
FACT-P
Functional Assessment of Cancer Therapy-Prostate
FAPSI6
FACT Advanced Prostate Symptom Index 6
FAS
full analysis set
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose
FFPE
formalin-fixed, paraffin embedded
FSH
follicle stimulating hormone
FWB
Functional Well-Being
GCP
Good Clinical Practice 
GnRH
gonadotropin-releasing hormone
H
hypothesis
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life
IA
interim analysis
IA1
first interim analysis
IA2
second interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
iCRO
Imaging Contract Research Organization
IEC
Independent Ethics Committee
Ig
immunoglobulin
IHC
immunohistochemistry
IL
interleukin
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
irAE
Immune-related adverse event
IRB
Institutional Review Board 
IRT
interactive response technology
ITT
Intent-to-Treat
IV
intravenous
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Abbreviation
Expanded Term
IVD
in vitro diagnostic
IVRS
Integrated Voice Response System
IWRS
Integrated Web Response System
mAb
monoclonal antibody
mCRPC
metastatic castration-resistant prostate cancer
mHSPC
metastatic hormone-sensitive prostate cancer
MID
minimum important difference
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MSI
microsatellite instability
N
number
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NE
nonevaluable
NED
no evidence of disease
NHA
next generation hormonal agents
NIMP
Non-Investigational Medicinal Product
Non-PD
nonprogression
NRS
numeric rating scale
NSCLC
Non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PBPK
physiologically-based pharmacokinetic
PCS
Prostate Cancer Subscale
PCWG
Prostate Cancer Working Group
PD
progressive disease
PDu
unconfirmed progressive disease 
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography
PFS
progression-free survival
PIN
personal identification number
PK
pharmacokinetic
PKCθ
protein kinase C-theta
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PRO
patient-reported outcome
PSA
prostate-specific antigen
PSMA
prostate-specific membrane antigen
PT
prothrombin time
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Abbreviation
Expanded Term
PTT
partial thromboplastin time
PWB
Physical Well-Being
Q2W
every 2 weeks
Q3W
every 3 weeks
QD
every day
QTc
corrected QT interval
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RMST
Restricted Mean Survival Time
RNA
ribonucleic acid
rPFS
radiographic progression-free survival
RPSFT
Rank Preserving Structural Failure Time
SAE
serious adverse event 
SCF
Sponsor Communication Form
SD
stable disease
SIM
Site Imaging Manual
SLAB
supplemental laboratory
SNP
single nucleotide polymorphism
SoA
schedule of activities
SOC
standard of care
SPECT
single photon emission computerized tomography
sSAP
supplemental Statistical Analysis Plan
SSRE
Symptomatic Skeletal-related Event
SUSAR
suspected unexpected serious adverse reaction
SWB
Social Well-Being
TB
tuberculosis
TEA
treatment eligibility assessment
TFST
time to initiation of the first subsequent anticancer therapy
TMDD
target-mediated drug disposition
TOI
Trial Outcome Index
TTBP
time to bone progression
TTPP
time to pain progression
US
United States
VOP
verification of progression
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 pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed 
or chair
5
Dead
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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08BH8M

PRODUCT:  MK-3475  
170
PROTOCOL/AMENDMENT NO.:  641-09
MK-3475-641-09 FINAL PROTOCOL
22-MAY-2023
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08BH8M

PRODUCT:  MK-3475  
171
PROTOCOL/AMENDMENT NO.:  641-09
MK-3475-641-09 FINAL PROTOCOL
22-MAY-2023
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