Clinical trial NCT04907227
Conditions: Prostatic Neoplasms
Keywords: Programmed Cell Death 1 (PD 1, PD-1) Programmed Cell Death 1 Ligand 1 (PDL 1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL 2, PD-L2)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2020-09-23; Completion date: 2023-07-18
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy and safety of the combination of pembrolizumab (MK-3475) and docetaxel in the treatment of Chinese men with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy for mCRPC but have progressed on or are intolerant to Next Generation Hormonal Agent (NHA).

There are two primary study hypotheses.

Hypothesis 1: The combination of pembrolizumab plus docetaxel plus prednisone is superior to placebo plus docetaxel plus prednisone with respect to Overall Survival (OS).

Hypothesis 2: The combination of pembrolizumab plus docetaxel plus prednisone is superior to placebo plus docetaxel plus prednisone 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.

Detailed description:
The China extension study will include participants previously enrolled in China in the global study for MK-3475-921 (NCT03834506) plus those enrolled during the China extension enrollment period.

With Amendment 6 (effective date: 29-Sep-2022), all participants were unblinded and placebo treatment was stopped. Participants deemed to derive clinical benefit from treatment may have continued at the discretion of the investigator.

Arms: arm 1: Participants receive pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m\^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly receive dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle. arm 2: Participants receive placebo by IV infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m\^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly receive dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.
Interventions: intervention 1: Pembrolizumab intervention 2: Docetaxel intervention 3: Prednisone intervention 4: Placebo intervention 5: Dexamethasone
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion intervention 3: Oral tablets intervention 4: IV infusion intervention 5: Oral tablets

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 3, Randomized, Double-blind Study of 
Pembrolizumab (MK-3475) Plus Docetaxel Plus Prednisone 
versus Placebo Plus Docetaxel Plus Prednisone in 
Participants with Chemotherapy-naïve Metastatic Castration-
Resistant Prostate Cancer (mCRPC) who have Progressed 
on a Next Generation Hormonal Agent (NHA)(KEYNOTE-921)
NCT04907227
29-SEP-2022


PRODUCT: MK-3475  
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PROTOCOL/AMENDMENT NO.: 921-06
MK-3475-921-06 FINAL PROTOCOL
29-SEP-2022
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 Study of Pembrolizumab (MK-3475) 
Plus Docetaxel Plus Prednisone versus Placebo Plus Docetaxel Plus Prednisone in 
Participants with Chemotherapy-naïve Metastatic Castration-Resistant Prostate Cancer 
(mCRPC) who have Progressed on a Next Generation Hormonal Agent (NHA) (KEYNOTE-
921)
Protocol Number: 921-06
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
2018-004116-22
Approval Date: 29 September 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 06 / 
Global amendment
29-SEP-2022
The study has achieved its prespecified scientific objective to evaluate the 
combination of pembrolizumab and docetaxel in this setting, and the study will be 
closed as a result of having completed its final analysis. Added language to state 
that upon study completion, participants are discontinued from the study and may 
be enrolled in a pembrolizumab extension study, if available.
Amendment 05 / 
Global amendment
15-DEC-2021
The TEA survey was added to document the investigator’s choice to recruit 
participants for the MK-3475-921 study rather than using other available treatment 
options.
Amendment 04 / 
Global amendment
21-JUN-2021
To update the dose modification and toxicity management guidelines for irAEs.
Amendment 03 / 
Global amendment
01-SEP-2020
To add an extension portion in China to allow for the required exposure and 
number of events to investigate efficacy and safety in participants enrolled in 
China.
Amendment 02 / 
Global amendment
22-JAN-2020
Changed eligibility criteria to align with latest standard of care (SOC) (NHAs given 
prior to mCRPC), and amended stratification criteria to reflect this change.
Amendment 01
31-OCT-2019
A new version of Amendment 01 was released to fix an administrative error in the 
exclusion criteria numbering.
Amendment 01 / 
Global amendment
17-OCT-2019
Corrections to the Schedule of Activities, Objectives, and Appendices, and minor 
edits throughout.
Original Protocol
17-JAN-2019
N/A
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 06
Overall Rationale for the Amendments:
The study has achieved its prespecified scientific objective to evaluate the combination of pembrolizumab and docetaxel in this 
setting, and the study will be closed as a result of having completed its final analysis. Added language to state that upon study
completion, participants are discontinued from the study and may be enrolled in a pembrolizumab extension study, if available.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis: Hypotheses, 
Objectives, and Endpoints
Section 3 Hypotheses, 
Objectives, and Endpoints
4.1 Overall Design
Added statement:
NOTE: As of Amendment 06, participants who 
are still on study treatment and deriving clinical 
benefit will no longer have tumor response 
assessments by BICR. However, local tumor 
imaging assessments should continue per local 
SOC schedule. In addition, ePRO assessments 
will no longer be performed and biomarker 
samples will no longer be collected.
Because the final analysis of the efficacy endpoint has 
been accomplished, further tumor scans and response 
assessments by BICR, ePRO assessments, and the 
collection of additional samples for biomarker 
evaluation are considered unnecessary.
1.1 Synopsis: Estimated 
Duration of Study
The estimated duration of the study has been 
changed from approximately 28 months to 
approximately 36 months.
The actual duration of the study is approximately 36
months.
1.1 Synopsis: Study 
Governance Committees
Statement added that as of Amendment 06, 
the Executive Oversight Committee and Data 
Monitoring Committee are no longer 
applicable.
These committees will no longer review the study 
data.
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Section # and Name
Description of Change 
Brief Rationale 
1.3.1 Initial Treatment 
Phase 
(Pembrolizumab/Placebo
Plus Prednisone)
Added statement: 
NOTE: As of Amendment 06, participants 
who are still on study treatment and deriving 
clinical benefit will no longer have tumor 
response assessments by BICR. However, 
local tumor imaging assessments should 
continue per local SOC schedule. In addition, 
ePRO assessments (FACT-P, EQ-5D-5L, 
BPI-SF, Analgesic Log) will no longer be 
performed and biomarker samples (blood for: 
CTC count, genetic analysis, RNA analysis, 
plasma biomarker analysis, serum biomarker 
analysis, and ctDNA analysis) will no longer 
be collected.
As of Amendment 06, these assessments and sample 
collections are considered unnecessary.
7.1 Discontinuation of 
Study Intervention
Added the subbullet:
As of Amendment 06, central tumor response 
assessments will no longer be performed. 
However, participants still on study will be 
assessed locally by the investigator for 
disease progression per local SOC schedule.
To clarify that participants still on treatment at the 
time of Amendment 06, who are deriving clinical 
benefit, will be assessed locally for disease 
progression. Imaging scans will no longer be collected 
by vendor for central review for efficacy endpoints, as 
there will be no further efficacy analyses. Imaging will 
be performed per local SOC schedule at the treating 
physician’s discretion for patient management.
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Section # and Name
Description of Change 
Brief Rationale 
8.2.1 Tumor Imaging and 
Assessment of Disease
Added statements:
As of Amendment 06: Central tumor 
response assessments will be discontinued. 
Imaging scans will no longer be submitted to 
iCRO nor read by BICR. The subsections 
below are retained for reference. 
However, for participants who are still on 
treatment and deriving clinical benefit and 
who will continue on-study intervention until 
criteria for discontinuation are met, local 
tumor imaging should continue per local 
SOC schedule. 
As of Amendment 06, further efficacy assessments are 
considered unnecessary.
To clarify that participants still receiving treatment at 
the time of this amendment who are deriving clinical 
benefit will continue with local tumor imaging per 
local SOC schedule.
8.12.4.2 Efficacy Follow-
up Visits
Added statement: 
As of Amendment 06: Efficacy Follow-up 
will be discontinued. The section below is 
retained for reference.
As of Amendment 06, these assessments are 
considered unnecessary.
8.2.4 PROs and Quality of 
Life Assessments
Added statement: 
As of Amendment 06: ePROs and Quality of 
Life assessments will be discontinued. The 
subsections below are retained for reference.
As of Amendment 06, ePRO and Quality of Life 
assessments are considered unnecessary.
8.10 Biomarkers
Added statement: 
As of Amendment 06: Biomarker sample 
collections will be discontinued. The 
subsection below is retained for reference.
As of Amendment 06, collection of these samples is 
considered unnecessary.
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Section # and Name
Description of Change 
Brief Rationale 
8.1.6.1 Treatment 
Eligibility Assessment 
(TEA) Form
Added statement: 
As of Amendment 06: The TEA form will no 
longer be collected. The subsection below is 
retained for reference.
As of Amendment 06, this assessment is considered 
unnecessary.
1.3.2 Second Course Phase
4.1 Overall Design, 
Second Course Treatment
6.6.4 Second Course
8.2.1.4 Second Course 
(Retreatment) Tumor 
Imaging
Added statement:
NOTE: As of Amendment 06, the study will 
be closed and second course treatment is not 
an option for participants. There are currently 
no participants in the Second Course Phase.
To update the status of the Second Course Phase of 
the study.
2.3 Benefit/Risk 
Assessment
Added paragraph describing the safety and 
efficacy results of the final analysis.
Added statement:
Selected analyses of safety endpoints will be 
performed at the end of the study. There will 
be no further analyses of efficacy and PRO 
endpoints.
To inform of the decision to discontinue this clinical 
study.
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Section # and Name
Description of Change 
Brief Rationale 
6.1 Study Intervention(s) 
Administered
Added statement:
As of Amendment 06, participants currently 
still on treatment may have the option of 
continuing with study intervention, as 
appropriate, if they are deriving clinical 
benefit.
To clarify that participants may continue to receive 
treatment if deriving clinical benefit.
6.3.3 Blinding
8.1.10 Participant 
Blinding/Unblinding
Added statement: 
As of Amendment 06: All participants are to 
be unblinded. The subsections below are 
retained for reference.
As of Amendment 06, all participants are to be 
unblinded.
6.5.1 Prohibited 
Concomitant Therapy
Added “replication-incompetent” to list of 
acceptable COVID-19 vaccines.
Added to include Janssen vaccine.
6.7 Intervention After the 
End of Study 
8.1.7 Assignment of 
Treatment/Randomization 
Number
Added statement that upon study completion, 
participants are discontinued from the current 
study and may be transitioned into a 
pembrolizumab extension study, if available.
To inform that participants may be enrolled in a 
pembrolizumab extension study.
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Section # and Name
Description of Change 
Brief Rationale 
8.12.4.3 Survival Follow-
up Contacts
Added statement:
As of Amendment 06: Survival Follow-up 
visits will be discontinued. Those 
participants remaining on study at the time of 
Amendment 06 should continue to be 
monitored in the study through the AE 
reporting period (Section 8.4). The section 
below is retained for reference.
As of Amendment 06, this follow-up is only for 
participants remaining on study at the time of this 
amendment, and participants will be followed for the 
duration of the AE reporting period.
10.7.3 Japan
Added new subsection to Country-specific 
Appendix with revision to Table 2 (from 
Section 6.1 Study Intervention(s) 
Administered) stating that placebo is not 
provided by the Sponsor.
Placebo is not categorized as a “product(s) used in the 
trial” in Japan and therefore, is not supplied by the 
Sponsor.
Title Page
10.1.1 Code of Conduct for 
Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an entity 
name and address change to Merck Sharp and Dohme 
LLC, Rahway, NJ, USA. This conversion resulted 
only in an entity name change and update to the 
address.
Throughout Document
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate interpretation of the 
intent of the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................19
1.1
Synopsis.................................................................................................................19
1.2
Schema ..................................................................................................................26
1.3
Schedule of Activities (SoA)................................................................................27
1.3.1
Initial Treatment Phase (Pembrolizumab/Placebo Plus Docetaxel Plus 
Prednisone) ..................................................................................................27
1.3.2
Second Course Phase (Pembrolizumab ONLY)..........................................37
2
INTRODUCTION..........................................................................................................40
2.1
Study Rationale....................................................................................................40
2.2
Background ..........................................................................................................41
2.2.1
Pharmaceutical and Therapeutic Background .............................................41
2.2.1.1
Inhibition of PD-1 as a Target for Cancer Therapy...........................41
2.2.1.2
Overview of Prostate Cancer .............................................................42
2.2.1.3
Unmet Medical Need in Prostate Cancer...........................................42
2.2.1.4
Preclinical and Clinical Studies .........................................................44
2.2.1.5
Pembrolizumab in mCRPC................................................................44
2.2.1.6
Ongoing Clinical Trials in mCRPC...................................................44
2.2.2
Information on Other Study-related Therapy ..............................................45
2.2.2.1
Docetaxel ...........................................................................................45
2.3
Benefit/Risk Assessment......................................................................................46
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................47
4
STUDY DESIGN............................................................................................................51
4.1
Overall Design......................................................................................................51
4.2
Scientific Rationale for Study Design.................................................................53
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.................................................................54
4.2.1.4
Planned Exploratory Biomarker Research.........................................55
4.2.1.4.1
Planned Genetic Analysis ........................................................56
4.2.1.5
Future Biomedical Research..............................................................57
4.2.2
Rationale for the Use of Placebo .................................................................57
4.3
Justification for Dose...........................................................................................57
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4.3.1
Pembrolizumab ............................................................................................57
4.3.2
Docetaxel .....................................................................................................58
4.4
Beginning and End of Study Definition .............................................................59
4.4.1
Clinical Criteria for Early Study Termination .............................................59
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
5.3.2
Contraception...............................................................................................66
5.3.3
Pregnancy.....................................................................................................67
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
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................74
6.6.3
Dose Modification for Docetaxel.................................................................81
6.6.4
Second Course .............................................................................................83
6.6.5
Management of Overlapping Toxicities ......................................................84
6.7
Intervention After the End of the Study............................................................84
6.8
Clinical Supplies Disclosure................................................................................84
6.9
Standard Policies..................................................................................................85
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................85
7.1
Discontinuation of Study Intervention...............................................................85
7.2
Participant Withdrawal From the Study...........................................................86
7.3
Lost to Follow-up .................................................................................................87
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
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................89
8.1.2
Inclusion/Exclusion Criteria ........................................................................89
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..................................................................90
8.1.6
Assignment of Screening Number...............................................................90
8.1.6.1
Treatment Eligibility Assessment (TEA) Form.................................90
8.1.7
Assignment of Treatment/Randomization Number.....................................90
8.1.8
Study Intervention Administration ..............................................................91
8.1.8.1
Timing of Dose Administration.........................................................91
8.1.8.1.1
Pembrolizumab/Placebo ..........................................................91
8.1.8.1.2
Docetaxel .................................................................................91
8.1.9
Discontinuation and Withdrawal .................................................................91
8.1.9.1
Withdrawal From Future Biomedical Research ................................92
8.1.10
Participant Blinding/Unblinding..................................................................92
8.1.10.1
Non-emergency Unblinding...............................................................93
8.1.11
Calibration of Equipment.............................................................................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..................................97
8.2.2
Prostate-specific Antigen Assessments........................................................97
8.2.3
Tumor Tissue Collection..............................................................................99
8.2.4
PROs and Quality of Life Assessments.......................................................99
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8.2.4.1
EQ-5D-SL..........................................................................................99
8.2.4.2
Functional Assessment of Cancer Therapy-Prostate (FACT-P)........99
8.2.4.3
Brief Pain Inventory-Short Form (BPI-SF) and Analgesic Log ......100
8.3
Safety Assessments.............................................................................................100
8.3.1
Physical Examinations...............................................................................100
8.3.1.1
Full Physical Examination...............................................................100
8.3.1.2
Directed Physical Examination........................................................101
8.3.2
Vital Signs..................................................................................................101
8.3.3
Electrocardiograms ....................................................................................101
8.3.4
Clinical Safety Laboratory Assessments ...................................................101
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)........................................................................................102
8.3.5
Performance Assessments..........................................................................102
8.3.5.1
Eastern Cooperative Oncology Group (ECOG) Performance 
Scale.................................................................................................102
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ..................................................................................102
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................103
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.105
8.4.4
Regulatory Reporting Requirements for SAE ...........................................105
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................105
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................106
8.4.7
Events of Clinical Interest (ECIs)..............................................................106
8.5
Treatment of Overdose......................................................................................106
8.6
Pharmacokinetics...............................................................................................107
8.7
Pharmacodynamics............................................................................................107
8.8
Future Biomedical Research Sample Collection.............................................107
8.9
Planned Genetic Analysis Sample Collection..................................................107
8.10
Biomarkers .........................................................................................................107
8.11
Medical Resource Utilization and Health Economics.....................................108
8.12
Visit Requirements.............................................................................................108
8.12.1
Screening....................................................................................................108
8.12.2
Treatment Period........................................................................................108
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ........109
8.12.4
Post-treatment Visits..................................................................................109
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8.12.4.1
Safety Follow-up Visit.....................................................................109
8.12.4.2
Follow-up Visits...............................................................................109
8.12.4.3
Survival Follow-up ..........................................................................109
8.12.5
Survival Status ...........................................................................................110
9
STATISTICAL ANALYSIS PLAN ...........................................................................110
9.1
Statistical Analysis Plan Summary...................................................................110
9.2
Responsibility for Analyses/In-house Blinding ...............................................112
9.3
Hypotheses/Estimation ......................................................................................112
9.4
Analysis Endpoints.............................................................................................112
9.4.1
Efficacy Endpoints.....................................................................................113
9.4.1.1
Primary.............................................................................................113
9.4.1.2
Key Secondary.................................................................................113
9.4.1.3
Secondary.........................................................................................113
9.4.1.4
Exploratory ......................................................................................114
9.4.2
Safety Endpoints........................................................................................114
9.4.3
Patient-Reported Outcome Endpoints........................................................114
9.4.3.1
Time to Pain Progression (TTPP)....................................................114
9.5
Analysis Populations..........................................................................................114
9.5.1
Efficacy Analysis Populations...................................................................114
9.5.2
Safety Analysis Populations ......................................................................115
9.5.3
PRO Analysis Population ..........................................................................115
9.6
Statistical Methods.............................................................................................115
9.6.1
Statistical Methods for Efficacy Analyses.................................................116
9.6.1.1
Overall Survival...............................................................................116
9.6.1.2
Radiographic Progression-free Survival (rPFS) ..............................116
9.6.1.3
TFST ................................................................................................118
9.6.1.4
Analysis Strategy for Key Efficacy Endpoints................................118
9.6.2
Statistical Methods for Safety Analyses ....................................................119
9.6.3
Analysis Methods for PRO Endpoints.......................................................121
9.6.4
Demographic and Baseline Characteristics ...............................................121
9.7
Interim Analyses ................................................................................................121
9.7.1
Efficacy Interim Analyses..........................................................................122
9.7.2
Safety Interim Analyses.............................................................................122
9.8
Multiplicity .........................................................................................................122
9.8.1
Radiographic Progression-free Survival (rPFS) ........................................123
9.8.2
Overall Survival.........................................................................................124
9.8.3
TFST ..........................................................................................................125
9.8.4
Safety Analyses..........................................................................................126
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9.9
Sample Size and Power Calculations ...............................................................126
9.10
Subgroup Analyses.............................................................................................128
9.11
Compliance (Medication Adherence)...............................................................128
9.12
Extent of Exposure.............................................................................................128
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................129
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......129
10.1.1
Code of Conduct for Clinical Trials...........................................................129
10.1.2
Financial Disclosure...................................................................................131
10.1.3
Data Protection...........................................................................................131
10.1.3.1
Confidentiality of Data ....................................................................132
10.1.3.2
Confidentiality of Participant Records.............................................132
10.1.3.3
Confidentiality of IRB/IEC Information..........................................132
10.1.4
Committees Structure.................................................................................132
10.1.4.1
Executive Oversight Committee......................................................132
10.1.4.2
External Data Monitoring Committee .............................................132
10.1.5
Publication Policy......................................................................................133
10.1.6
Compliance with Study Registration and Results Posting Requirements .133
10.1.7
Compliance with Law, Audit, and Debarment ..........................................134
10.1.8
Data Quality Assurance .............................................................................134
10.1.9
Source Documents .....................................................................................135
10.1.10
Study and Site Closure...............................................................................135
10.2
Appendix 2: Clinical Laboratory Tests............................................................136
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................138
10.3.1
Definition of AE ........................................................................................138
10.3.2
Definition of SAE ......................................................................................139
10.3.3
Additional Events Reported in the Same Manner as SAE.........................140
10.3.4
Recording AE and SAE .............................................................................140
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................144
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................146
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................147
10.5.1
Definitions..................................................................................................147
10.5.2
Contraception Requirements......................................................................148
10.5.3
Pregnancy Testing......................................................................................148
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10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................149
10.7
Appendix 7: Country-specific Requirements..................................................154
10.7.1
Laboratory Testing.....................................................................................154
10.7.2
Country-specific Testing Requirements ....................................................154
10.7.2.1
Germany...........................................................................................154
10.7.2.2
China................................................................................................154
10.7.3
Japan ..........................................................................................................155
10.8
Appendix 8:  Description of the Prostate Cancer Working Group 
(PCWG) Process for Assessment of Bone Lesions..........................................156
10.8.1
Imaging Methods .......................................................................................156
10.8.2
Documentation of Bone Lesions at Baseline.............................................156
10.8.3
Assessment of Bone Response at Subsequent Imaging Time Points ........156
10.8.4
Descriptions of Bone Response Categories ...............................................157
10.8.4.1
No Evidence of Disease...................................................................157
10.8.4.2
Non-progression (Non-PD)..............................................................157
10.8.4.3
Unconfirmed Progressive Disease (PD-U) ......................................157
10.8.4.4
Progressive Disease (PD).................................................................157
10.8.4.5
Confirmation of Progression............................................................158
10.8.4.5.1
For New Lesions Within the Flare Window (<12 weeks).....158
10.8.4.5.2
For New Lesions Outside the Flare Window (>12 weeks)....158
10.8.5
Superscan ...................................................................................................158
10.8.6
Management Following Confirmed PD.....................................................159
10.9
Appendix 9: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................160
10.10 Appendix 10:  Eastern Cooperative Oncology Group Performance Status.161
10.11 Appendix 11: Abbreviations .............................................................................162
11
REFERENCES.............................................................................................................165
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LIST OF TABLES
Table 1
Laboratory Values for Adequate Organ Function .....................................61
Table 2
Study Interventions....................................................................................68
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .........................................................76
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ..................................................................................................80
Table 5
Docetaxel Dose Modification Guidelines for Drug-related Adverse 
Events.........................................................................................................82
Table 6
Docetaxel Dose Reduction Guidelines ......................................................83
Table 7
Overall Radiographic Response per PCWG-modified RECIST ...............95
Table 8
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events...............................................................104
Table 9
Censoring Rules for Primary and Sensitivity Analyses of rPFS..............117
Table 10
Efficacy Analysis Methods for Key Efficacy Endpoints.........................118
Table 11
Analysis Strategy for Safety Parameters..................................................120
Table 12
Summary of Interim and Final Analyses .................................................122
Table 13
Efficacy Boundaries and Properties for rPFS..........................................124
Table 14
Efficacy Boundaries and Properties for Overall Survival Analyses........125
Table 15
Efficacy Boundaries and Properties for TFST.........................................126
Table 16
Protocol-required Safety Laboratory Assessments..................................137
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LIST OF FIGURES
Figure 1
Study Schema.............................................................................................26
Figure 2
Change in Prostate-specific Antigen..........................................................98
Figure 3
Multiplicity Graph for One-sided Alpha Reallocation Strategy..............123
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Double-blind Study of Pembrolizumab (MK-3475) 
Plus Docetaxel Plus Prednisone versus Placebo Plus Docetaxel Plus Prednisone in 
Participants with Chemotherapy-naïve Metastatic Castration-Resistant Prostate Cancer 
(mCRPC) who have Progressed on a Next Generation Hormonal Agent (NHA) (KEYNOTE-
921)
Short Title: Phase 3 Study of Pembrolizumab plus Docetaxel in mCRPC 
Acronym: KEYNOTE-921
Hypotheses, Objectives, and Endpoints:
In participants with mCRPC who have not received chemotherapy but have progressed on or 
are intolerant to NHA:
NOTE: As of Amendment 06, all participants will be unblinded. Placebo treatment should 
stop immediately. All participants should be informed of the results of the trial as described 
in the investigator memo of 04-AUG-2022. Participants who are deemed to be deriving 
clinical benefit from treatment may continue at the discretion of the investigator. All other 
study participants should be discontinued from study and be offered SOC treatment as 
deemed necessary by the investigator. Participants who are still on treatment and deriving 
clinical benefit will no longer have tumor response assessments by BICR. However, local 
tumor imaging assessments should continue per local SOC schedule. In addition, ePRO
assessments will no longer be performed and biomarker samples will no longer be collected. 
Primary Objectives
Primary Endpoints
- To compare pembrolizumab plus 
docetaxel plus prednisone to placebo plus 
docetaxel plus prednisone with respect to 
OS
- Hypothesis 1: The combination of 
pembrolizumab plus docetaxel plus 
prednisone is superior to placebo plus 
docetaxel plus prednisone with respect to 
OS
- OS: the time from randomization to death 
due to any cause
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- To compare pembrolizumab plus 
docetaxel plus prednisone to placebo plus 
docetaxel plus prednisone with respect to 
radiographic progression-free survival 
(rPFS) per Prostate Cancer Working 
Group (PCWG)-modified Response 
Evaluation Criteria in Solid Tumors
Version 1.1 (RECIST 1.1) as assessed by 
blinded independent central review 
(BICR) 
- Hypothesis 2: The combination of 
pembrolizumab plus docetaxel plus 
prednisone is superior to placebo plus 
docetaxel plus prednisone with respect to 
rPFS per PCWG-Modified RECIST 1.1 as 
assessed by BICR
- rPFS: the time from randomization to 
radiographic progression, or death due to 
any cause, whichever occurs first
Secondary Objectives
Secondary Endpoints
- To compare pembrolizumab plus 
docetaxel plus prednisone to placebo plus 
docetaxel plus prednisone with respect to 
time to initiation of the first subsequent 
anti-cancer therapy (TFST)
- Hypothesis 3: The combination of 
pembrolizumab plus docetaxel plus 
prednisone is superior to placebo plus 
docetaxel plus prednisone with respect to 
TFST
- TFST: the time from randomization to 
initiation of the first subsequent anti-
cancer therapy or death, whichever occurs 
first
- To evaluate pembrolizumab plus docetaxel 
plus prednisone versus placebo plus 
docetaxel plus prednisone with respect to 
- PSA response 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
- ORR per PCWG-modified RECIST 1.1 as 
assessed by BICR 
- DOR: the time from the earliest date of 
first documented evidence of CR or PR 
until earliest date of disease progression or 
death from any cause, whichever occurs 
first
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- To compare pembrolizumab plus 
docetaxel plus prednisone versus placebo 
plus docetaxel plus prednisone with 
respect to the 
- Time to pain progression (TTPP) based on 
the Brief Pain Inventory-Short Form (BPI-
SF) item 3 “worst pain in 24 hours” and 
opiate analgesic use (analgesic 
quantification algorithm [AQA] score)
- Time to first symptomatic skeletal-related 
event (SSRE)
- Time to PSA progression
- TTPP: the time from randomization to 
pain progression as determined by item 3 
of the BPI-SF and AQA score
- Time to 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 non-vertebral) 
- occurrence of spinal cord compression
- or tumor-related orthopedic surgical 
intervention, whichever occurs first.
- 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.
- To compare pembrolizumab plus 
docetaxel plus prednisone versus placebo 
plus docetaxel plus prednisone with 
respect to the time to radiographic soft 
tissue progression per soft tissue rules of 
PCWG- Modified RECIST 1.1 as assessed 
by BICR
- Time to radiographic soft tissue 
progression: the time from randomization 
to radiographic soft tissue progression
- To evaluate the safety and tolerability of 
pembrolizumab plus docetaxel plus 
prednisone versus placebo plus docetaxel 
plus prednisone
- Adverse events (AEs)
- Study intervention discontinuations due to 
AEs
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Treatment of mCRPC
Population
Participants with mCRPC who have not received 
chemotherapy but have progressed on next generation 
hormonal agent (NHA)
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo Control
Study Blinding
Double-blind with in-house blinding
Masking
Participant or Subject, Investigator, and Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 36 months from the time the first 
participant signs the informed consent until the last 
participant’s last study-related telephone call or visit.
Extension Portion in China: The Sponsor estimates that the 
study will require approximately 2 additional years 
(beyond the global study’s last participant last study-
related phone call or visit) from the time the first 
participant signs the informed consent until the last 
participant’s last study-related telephone call or visit.
Number of Participants:
Global Portion: Approximately 1000 participants will be randomized in this trial.
Extension Portion in China: Approximately 150 participants overall will be enrolled in 
China, including participants enrolled in either the global portion or the extension portion.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Regimen/ 
Treatment 
Period
Use
Arm 1
Pembrolizumab
200 mg
Q3W
IV
D1 of each 
21-day cycle 
for up to 
35 cycles
Experimental
Docetaxel
75 
mg/m2
Q3W
IV
D1 of each 
21-day cycle 
for up to 
10 cycles
SOC
Prednisone
5 mg
BID
PO
Concomitant 
with 
docetaxel
SOC
Arm 2
Placebo
NA
Q3W
IV
D1 of each 
cycle for 
35 cycles
Placebo
Docetaxel
75 
mg/m2
Q3W
IV
D1 of each 
21-day cycle 
for up to 
10 cycles
SOC
Prednisone
5 mg
BID
PO
Concomitant 
with 
docetaxel
SOC
Abbreviations: BID = twice daily; D1 = Day 1; IV = intravenous; NA = not applicable; PO = oral; 
Q3W = every 3 weeks; SOC = standard of care.
Total 
Number
2 arms
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Duration of 
Participation
Each participant may participate in the study for up to approximately 28 
months from the time the participant signs the Informed Consent Form (ICF) 
through the final contact. After a screening phase of 42 days, each participant 
will be receiving assigned intervention for approximately 2 years. After the 
end of treatment each participant will be followed up for 30 days.
Each participant will participate in the study from the time the participant 
signs the Informed Consent Form (ICF) through the final protocol-specified 
contact.
Each participant will be assigned to receive study intervention until disease 
progression is radiographically documented and , when clinically appropriate
for participants treated with pembrolizumab, unacceptable adverse event(s) 
(AEs), intercurrent illness that prevents further administration of treatment, 
investigator’s decision to discontinue the participant, noncompliance with 
study intervention or procedure requirements or administrative reasons 
requiring cessation of treatment, or until the participant has received 35 
cycles of pembrolizumab (approximately 2 years). Participants who stop 
study intervention as a result of obtaining an investigator-determined 
confirmed complete response (CR) or those subjects who stop after receiving 
35 cycles of trial treatment may be eligible for up to 17 additional cycles of 
pembrolizumab (approximately 1 year) upon experiencing disease 
progression if they meet the criteria for re-treatment (see Section 6.6.4 
Second Course) and the study is ongoing. Participants randomized to placebo 
will not be permitted to cross over to pembrolizumab following progression.
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 confirmed by the site, initiating a non-study cancer 
treatment, withdrawing consent, or becoming lost to follow-up. All 
participants will be followed up by telephone for overall survival until death, 
withdrawal of consent, or the end of the study.
Once the participant has achieved the study objective or the study has ended, 
the participant is discontinued from this study.
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).
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
As of Amendment 06, the Executive Oversight Committee and Data Monitoring Committee 
have fulfilled their responsibilities to the study and will no longer be utilized.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 11.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
Abbreviations: AE=adverse event; BID=twice daily; CTx=chemotherapy; NHA=next generation hormonal 
agent; R=randomization.* Participants who received ≥6 cycles of docetaxel for metastatic hormone-sensitive 
prostate cancer (mHSPC) and did not progress within 1 year after the last dose of docetaxel, are eligible for 
enrollment.
Study intervention will begin on Day 1 of each 3-week pembrolizumab/placebo + docetaxel dosing cycle. 
Participants should receive docetaxel (with prednisone 5 mg BID) for up to a maximum of 10 cycles, unless 
specific discontinuation criteria are met. Pembrolizumab/placebo will continue for up to 35 cycles 
(approximately 2 years) unless specific withdrawal/discontinuation criteria are met. Participants who must 
discontinue 1 of the 2 treatments due to drug-related AEs may continue with the other combination partner until 
criteria for discontinuation are met (eg, disease progression).
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1.3
Schedule of Activities (SoA)
1.3.1
Initial Treatment Phase (Pembrolizumab/Placebo Plus Docetaxel Plus Prednisone)
NOTE: As of Amendment 06, participants who are still on study treatment and deriving clinical benefit will no longer have 
tumor response assessments by BICR. However, local tumor imaging assessments should continue per local SOC schedule. In 
addition, ePRO assessments (FACT-P, EQ-5D-5L, BPI-SF, Analgesic Log) will no longer be performed and biomarker 
samples (blood for: CTC count, genetic analysis, RNA analysis, plasma biomarker analysis, serum biomarker analysis, and 
ctDNA analysis) will no longer be collected. 
Trial Period
Screening 
Phase
Treatment Cycles (21-day Cycles)
End of 
Treatment
Post-Treatment
Notes
The Safety Follow-up 
Visit is not needed if the 
Discontinuation Visit 
occurs ≥30 days after the 
last dose.
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 
to 
10
11 up to 
35
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
(+ 7days)
Q9W to 
W54, then
Q12W
(± 7 days)
Q12W
(± 7 
days)
Administrative Procedures
Informed consent
X
Obtain written consent 
prior to performing any 
protocol-specific 
procedures.  
Additional consent may be 
required after initial 
progression. 
Informed consent for 
future biomedical 
research (optional)
X
Participants can still 
participate in the study if
they decline to sign the 
Future Biomedical
Research ICF.
Inclusion/exclusion 
criteria
X
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Trial Period
Screening 
Phase
Treatment Cycles (21-day Cycles)
End of 
Treatment
Post-Treatment
Notes
The Safety Follow-up 
Visit is not needed if the 
Discontinuation Visit 
occurs ≥30 days after the 
last dose.
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 
to 
10
11 up to 
35
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
(+ 7days)
Q9W to 
W54, then
Q12W
(± 7 days)
Q12W
(± 7 
days)
Participant
identification card
X
The identification card will 
be updated at 
randomization.
Demographics and 
medical history
X
Prior and concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
Abiraterone acetate or 
enzalutamide washout 
period: ≥4 weeks; no 
prednisone washout period. 
Report medications started 
28 days prior to the first 
dose and up to 30 days after 
last dose of study 
intervention.
SSRE Evaluation
X
X
X
X
X
X
X
X
X
X
X
X
HIV, Hep B, and
Hep C status
X
No testing is required 
unless mandated by the
local health authority. Refer 
to Appendix 7 for country-
specific requirements.
Randomization
X
Telephone contact or
visit
X
Telephone contact or visit 
on C1D8 (±3 days) will 
assess participants for 
development of early 
toxicity. An unscheduled 
visit can occur at any time 
if deemed necessary by the 
investigator.
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Trial Period
Screening 
Phase
Treatment Cycles (21-day Cycles)
End of 
Treatment
Post-Treatment
Notes
The Safety Follow-up 
Visit is not needed if the 
Discontinuation Visit 
occurs ≥30 days after the 
last dose.
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 
to 
10
11 up to 
35
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
(+ 7days)
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
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 study 
intervention if the 
participant initiates new 
anticancer treatment, 
whichever comes first. 
Treatment-related SAEs 
must be reported regardless 
of the time point when they 
occur.
Full physical 
examination
X
X
Directed physical 
examination
X
X
X
X
X
X
X
X
X
Perform as clinically 
indicated.
Vital signs, height,
and weight
X
X
X
X
X
X
X
X
X
X
Vital signs (weight, 
temperature, blood 
pressure, respiratory and 
heart rate) are measured 
after 5 min rest, prior to 
study administration. 
Height will be measured at 
screening only.
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Trial Period
Screening 
Phase
Treatment Cycles (21-day Cycles)
End of 
Treatment
Post-Treatment
Notes
The Safety Follow-up 
Visit is not needed if the 
Discontinuation Visit 
occurs ≥30 days after the 
last dose.
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 
to 
10
11 up to 
35
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
(+ 7days)
Q9W to 
W54, then
Q12W
(± 7 days)
Q12W
(± 7 
days)
12-lead ECG
X
ECOG performance 
status
X
X
X
X
X
X
X
X
X
X
Obtain within 7 days of 
randomization. Obtain prior 
to dosing. After Cycle 8, 
obtain at every other cycle 
(Cycle 10, 12, 14, etc.).
Subsequent anticancer 
therapy status
X
X
X
Safety follow-up visit must 
take place before the start 
of new therapy.  
Survival status
X
Updated survival status 
may be requested by the 
Sponsor at any time during 
the course of the study.
Study Intervention Administration
Begin within 3 days of 
randomization.
Pembrolizumab/ 
placebo
X
X
X
X
X
X
X
X
Pembrolizumab/placebo IV 
infusion on Day 1 of each 
cycle Q3W up to a 
maximum 35 cycles. 
Docetaxel & 
Prednisone/
prednisolone
X
X
X
X
X
X
X
Docetaxel to be 
administered Q3W with 
prednisone/ prednisolone
(5 mg BID) for up to 
10 cycles. Docetaxel should 
begin 30 mins after the 
pembrolizumab/ placebo 
infusion.
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Trial Period
Screening 
Phase
Treatment Cycles (21-day Cycles)
End of 
Treatment
Post-Treatment
Notes
The Safety Follow-up 
Visit is not needed if the 
Discontinuation Visit 
occurs ≥30 days after the 
last dose.
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 
to 
10
11 up to 
35
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
(+ 7days)
Q9W to 
W54, then
Q12W
(± 7 days)
Q12W
(± 7 
days)
Laboratory Procedures/Assessments: analysis performed by CENTRAL laboratory
Screening labs are to be 
performed within 10 days 
of first study intervention. 
After Cycle 1, predose 
laboratory tests may be 
performed up to 72 hours 
predose. Unresolved 
abnormal laboratory 
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
X
X
X
Comprehensive 
chemistry panel
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Urinalysis and thyroid 
functions tests are
performed every other 
cycle (ie, Cycle 2, 4, 6,
etc.).
T3 or FT3, FT4, and 
TSH
X
X
X
X
X
X
X
X
Testosterone
X
X
X
X
X
Testosterone is determined 
every 4 cycles.
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Trial Period
Screening 
Phase
Treatment Cycles (21-day Cycles)
End of 
Treatment
Post-Treatment
Notes
The Safety Follow-up 
Visit is not needed if the 
Discontinuation Visit 
occurs ≥30 days after the 
last dose.
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 
to 
10
11 up to 
35
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
(+ 7days)
Q9W to 
W54, then
Q12W
(± 7 days)
Q12W
(± 7 
days)
Procedures/Assessments: analysis performed CENTRALLY
Schedule of scans, PSA, 
and CTC count are 
calculated from the date 
of randomization and 
should not be adjusted for 
dose delays or cycle 
starts.
PD-L1, PSA, and CTC 
results are not reported 
back to sites to prevent 
early withdrawal of 
participants from study 
intervention.
Efficacy Measurements
PSA by central 
laboratory
X
Q3W (± 7 days) from randomization
X
X
X
Screening PSA is 
performed within 10 days 
prior to randomization. The 
window for other PSA 
collections is ±7 days. 
Only during Screening, if 
central laboratory result for 
PSA is not expected prior 
to randomization the 
investigator may also 
perform the test locally and 
use the result to determine 
eligibility. Local laboratory 
may not be used in lieu of 
central laboratory.
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Trial Period
Screening 
Phase
Treatment Cycles (21-day Cycles)
End of 
Treatment
Post-Treatment
Notes
The Safety Follow-up 
Visit is not needed if the 
Discontinuation Visit 
occurs ≥30 days after the 
last dose.
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 
to 
10
11 up to 
35
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
(+ 7days)
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
Baseline CT/MRI
chest/abdomen/pelvis and 
whole-body bone scan must 
be performed within 
28 days prior to 
randomization. 
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. If a scan was 
obtained within 4 weeks 
prior to discontinuation, 
another scan at 
discontinuation is not 
mandatory.
Blood for CTC count 
by central laboratory
X
W9 (± 7 days) and W18 (± 7 days) from 
randomization
X
Collect predose Cycle 1 
Day 1.
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Trial Period
Screening 
Phase
Treatment Cycles (21-day Cycles)
End of 
Treatment
Post-Treatment
Notes
The Safety Follow-up 
Visit is not needed if the 
Discontinuation Visit 
occurs ≥30 days after the 
last dose.
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 
to 
10
11 up to 
35
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
(+ 7days)
Q9W to 
W54, then
Q12W
(± 7 days)
Q12W
(± 7 
days)
Tumor Tissue Collection/Correlative and Biomarker Studies performed by CENTRAL laboratory
Timing should not be 
adjusted for dose delays 
or cycle starts
Tumor tissue 
collection (recent 
biopsy)
X
Obtain within 12 months of 
screening. Site required to 
submit SCF for archived 
tissue >1 year.
Blood for genetic 
analyses
X
Collect predose.
Blood for RNA 
analyses
X
W3 (±7 days) and W12 (± 7 days) from 
randomization
X
Collect predose on days 
study intervention is given. 
Blood for plasma 
biomarker analyses
X
X
Blood for serum 
biomarker analyses
X
X
Blood for ctDNA 
analysis
X
W9 (± 7 days) and W18 (± 7 days) from 
randomization 
X
Collect predose on days 
when study intervention is 
given.
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Trial Period
Screening 
Phase
Treatment Cycles (21-day Cycles)
End of 
Treatment
Post-Treatment
Notes
The Safety Follow-up 
Visit is not needed if the 
Discontinuation Visit 
occurs ≥30 days after the 
last dose.
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 
to 
10
11 up to 
35
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
(+ 7days)
Q9W to 
W54, then
Q12W
(± 7 days)
Q12W
(± 7 
days)
Patient-reported Outcomes
FACT-P
EQ-5D-5L
X
X
X
X
X
X
X
X
X
X
Every effort should be 
made to administer PRO 
surveys prior to dosing and 
before other assessments 
and procedures.
Complete on site prior to 
study intervention on Day 1
of every cycle through 
Cycle 8, then every 2 
cycles through Cycle 24, 
then every 4 cycles 
thereafter up to 2 years or 
until discontinuation and at 
Safety Follow-up Visit.
BPI-SF 
Patient Analgesic Log
X
Q3W until W24, then Q6W until W72, thereafter 
Q12W up to 2 years 
X
X
Complete at home daily for 
any 7 consecutive days 
from Day -10 of screening.  
At each timepoint after 
randomization complete for 
7 consecutive days (eg, 
days 15 – 21). A 3-day 
window will be permitted 
to begin completing the 
BPI-SF and analgesic log 
prior to the expected 7 
days.
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Trial Period
Screening 
Phase
Treatment Cycles (21-day Cycles)
End of 
Treatment
Post-Treatment
Notes
The Safety Follow-up 
Visit is not needed if the 
Discontinuation Visit 
occurs ≥30 days after the 
last dose.
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7 
to 
10
11 up to 
35
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
(+ 7days)
Q9W to 
W54, then
Q12W
(± 7 days)
Q12W
(± 7 
days)
Abbreviations: AE= adverse event; aPTT = activated partial thromboplastin time; BPI-SF = Brief Pain Inventory-Short Form; C1D8 = Cycle 1 Day 8; CT = computed 
tomography; CTC = circulating tumor cell; ctDNA = circulating tumor deoxyribonucleic acid; Discon = discontinuation; ECG = electrocardiogram; ECI = events of clinical 
interest; ECOG = Eastern Cooperative Oncology Group; EQ-5D-5L = EuroQol 5- dimension, 5-level health state utility index; FACT-P = Functional Assessment of Cancer 
Therapy-Prostate; FBR=Future Biomedical Research; FT3 = free triiodothyronine; FT4=free thyroxine; Hep = hepatitis; HIV = human immunodeficiency virus; ICF = 
informed consent form; ICG = informed consent form; IEC=Independent Ethics Committee; INR = international normalized ratio; IRB = Institutional Review Board; 
MRI = magnetic resonance imaging; PK = pharmacokinetic; PRO = patient-reported outcome; PSA = prostate-specific antigen; PT = prothrombin time; PTT = partial 
thromboplastin time; Q3W = every 3 weeks; Q6W = every 6 weeks, Q9W = every 9 weeks; Q12W = every 12 weeks; RNA = ribonucleic acid; SAE = serious adverse event; 
SCF = Sponsor Communication Form; SSRE = symptomatic skeletal-related event; T3 = total triiodothyronine; TSH = thyroid-stimulating hormone; W = week.
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1.3.2
Second Course Phase (Pembrolizumab ONLY)
NOTE: As of Amendment 06, the study will be closed and second course treatment is not an option for participants. There are 
currently no participants in the Second Course Phase.
Trial Period
Treatment Cycles
(21-day Cycles)
End of 
Treatment
Post-Treatment
Notes
The safety follow-up is not needed if the DC visit 
occurs ≥30 days after the last dose
Treatment Cycle/Title
1
2
3
4
5 up 
to 17
Discon
Safety 
Follow-up
Follow-up 
Visits
Survival 
Follow-up
Scheduling Window (Days)
± 
3
± 
3
± 
3
± 3
At time of 
Discon
30 days 
from last 
dose 
(+ 7 days)
Q12W
(± 7 days)
Q12W
(± 7 days)
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 trial treatment. 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 study intervention if the participant 
initiates new anticancer treatment, whichever comes 
first. Treatment-related SAEs must be reported 
regardless of the time point when they occur.
Full physical examination
X
X
Directed physical examination
X
X
X
X
X
Perform as clinically indicated.
Vital signs and weight
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
After Cycle 8, conduct every other cycle.
Pembrolizumab
X
X
X
X
X
Subsequent anticancer therapy status
X
X
X
Safety Follow-up visit must occur before the start of 
the new therapy.
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Trial Period
Treatment Cycles
(21-day Cycles)
End of 
Treatment
Post-Treatment
Notes
The safety follow-up is not needed if the DC visit 
occurs ≥30 days after the last dose
Treatment Cycle/Title
1
2
3
4
5 up 
to 17
Discon
Safety 
Follow-up
Follow-up 
Visits
Survival 
Follow-up
Scheduling Window (Days)
± 
3
± 
3
± 
3
± 3
At time of 
Discon
30 days 
from last 
dose 
(+ 7 days)
Q12W
(± 7 days)
Q12W
(± 7 days)
Survival status
X
Updated survival status may be requested by the 
Sponsor at any time during the course of the study
Laboratory Procedures/Assessments: analysis performed by CENTRAL laboratory
Perform within 10 days prior to the participant’s
receiving the first retreatment infusion.
After C1, predose laboratory tests may be 
performed up to 72 hours predose. Unresolved 
abnormal laboratory 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
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. 
Comprehensive chemistry panel
X
X
X
X
X
X
X
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 to be tested every 4 cycles.
Efficacy Measurements
Schedules of PSA determinations and scans are 
calculated from the date of first re-treatment 
infusion. The timing of assessments should not be 
adjusted for dose delays or cycle starts.
PSA (central laboratory) 
X
Q3W (±7 days) 
from first 
retreatment 
infusion
X
X
X
Collect predose on study intervention days. 
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Trial Period
Treatment Cycles
(21-day Cycles)
End of 
Treatment
Post-Treatment
Notes
The safety follow-up is not needed if the DC visit 
occurs ≥30 days after the last dose
Treatment Cycle/Title
1
2
3
4
5 up 
to 17
Discon
Safety 
Follow-up
Follow-up 
Visits
Survival 
Follow-up
Scheduling Window (Days)
± 
3
± 
3
± 
3
± 3
At time of 
Discon
30 days 
from last 
dose 
(+ 7 days)
Q12W
(± 7 days)
Q12W
(± 7 days)
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 anti-cancer treatment, 
documented disease progression, death or the end of 
the study, whichever occurs first.
Images will be submitted to the central imaging 
vendor.
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; CT = computed tomography; CTC = circulating tumor cell; Discon = discontinuation; ECI =
events of clinical interest; ECOG = Eastern Cooperative Oncology Group; FBR = Future Biomedical Research; FT4 = free thyroxine; INR = international normalized ratio; MRI
= magnetic resonance imaging; PSA = prostate-specific antigen; PT = prothrombin time; PTT = partial thromboplastin time; Q12W = every 12 weeks; SAE = serious adverse 
event; T3 = total triiodothyronine; TSH = thyroid-stimulating hormone; W = week.
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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 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 agonist or antagonist that results in 
suppression of testosterone production in the testes. This alone often succeeds in controlling 
disease, often for many years. When prostate cancer progresses in spite of ADT alone it is 
referred to as castration resistant. The disease at this point is known as mCRPC and requires 
the addition of systemic therapies to re-establish control of disease. A number of important 
systemic therapies for mCRPC now comprise the current therapeutic landscape. These
include the next generation hormonal agents (NHAs), abiraterone acetate and enzalutamide, 
and the taxanes, docetaxel and cabazitaxel.
Docetaxel became the first systemic therapy to improve survival for men with mCRPC. A
randomized study demonstrated superior survival of median 18.9 months versus 16.5 for 
mitoxantrone [Tannock, I, et al 2004]. Cabazitaxel, a second taxane, was studied versus 
mitoxantrone in participants after docetaxel, and it too was found to be associated with 
superior survival (median 15.1 months versus 12.7 months with mitoxantrone) [de Bono, J. 
S., et al 2010]. However, cabazitaxel can be a toxic therapy, and 4.9% of participants died
from various treatment-related causes, such as treatment-related neutropenia and 
treatment-related diarrhea. The cabazitaxel label contains a black box warning regarding 
risks from neutropenia, severe hypersensitivity, and other label warnings and precautions 
pertaining to diarrhea, renal failure, hepatic impairment, and prohibitive risk in participants 
≥65 years of age. Thus, an unmet need remains for participants after treatment in the mCRPC 
setting with targeted endocrine therapy and docetaxel.
2.1
Study Rationale
Interim results from Cohort B of KEYNOTE-365 (data cutoff 03-APR-2018), which 
evaluated the combination of pembrolizumab and docetaxel/prednisone in the population 
intended for the current study, showed a response (at least 50% reduction in prostate-specific 
antigen [PSA] from baseline) in 26.8% (95% CI: 16.9%, 38.6%) of participants with a 
baseline PSA measurement available, and 28.8% (95% CI: 18.3%, 41.3%) in those with an 
elevated PSA at baseline. While an objective response (complete response [CR] + partial 
response [PR]) was observed in 5.6% (95% confidence interval [CI]: 1.5%, 13.6%) of 
participants, the disease control rate (DCR) for the cohort was 84.7% (95% CI: 74.3%, 
92.1%) driven primarily by the large proportion of participants who had stable disease for at 
least 24 weeks (79.2%) prior to disease progression. Approximately half of the participants 
had a reduction in tumor size, of which nearly a third had a reduction of >30%. These results 
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provide support for further evaluation of the combination of pembrolizumab and docetaxel
plus prednisone/prednisolone in patients with mCRPC.
The present study, KEYNOTE-921 (KN921), is a randomized, multicenter, double-blind, 
placebo-controlled, Phase 3 study in participants with mCRPC who have received prior 
NHA. Participants will be randomly assigned 1:1 to study intervention with either 
pembrolizumab +docetaxel + prednisone/prednisolone or with placebo + docetaxel + 
prednisone/prednisolone.
2.2
Background
Pembrolizumab is a potent humanized IgG4 monoclonal antibody (mAb) with high 
specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand
2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent 
receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety 
profile and is in clinical development as an intravenous (IV) immunotherapy for advanced 
malignancies. Keytruda® (pembrolizumab) is indicated for the treatment of patients across a 
number of indications. For more details on specific indications refer to the Investigator’s
Brochure (IB).
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 cluster of differentiation 8 
(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 
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) 
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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 United States (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 3 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 
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 
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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. 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 castration-sensitive prostate cancer [CSPC]) consisted of 
ADT (eg, a gonadotropin-releasing hormone 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 overall 
survival (OS) advantage in the ADT plus docetaxel group (57.6 vs. 47.2 months; hazard ratio 
(HR), 0.72; 95% CI, 0.50 to 0.79; p<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; HR, 0.78; 95% CI, 0.66 to 0.93; p=.006) [James, N. D., et al 
2016].
As part of the STAMPEDE study, patients were randomly assigned to receive either ADT 
and abiraterone acetate plus prednisolone or ADT alone. Patients 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 to 
0.76; p<0.001) and significantly fewer treatment failure events (248 vs. 535; HR, 0.29; 95% 
CI, 0.25 to 0.34; p<0.001). Fizazi and collaborators in the LATITUDE trial [Fizazi, K., et al 
2017] had similar findings. At a planned interim analysis 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, there is no available guidance on the appropriate sequencing or 
combination 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 only a modest survival benefit. In the 
TROPIC Phase 3 study [de Bono, J. S., et al 2010], investigators compared cabazitaxel, a 
second-generation semisynthetic tubulin-binding taxane, with mitoxantrone, (each in 
combination with prednisone) for mCRPC progressing during or after docetaxel-based 
therapy and detected a significant showed significant improvement in median OS in the 
cabazitaxel group (15.1 months [95% CI, 14.1 to 16.3] vs. 12.7 months [95% CI, 11.6 to 
13.7]; HR, 0.70 [95% CI, 0.59 to 0.83]; p<0.0001). Also, cabazitaxel maintained 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, and 
consequently it is not utilized widely. Retrospective studies suggest that either abiraterone or 
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enzalutamide may be an option; however, with previous therapies [Handy, C. E. 2016] the 
potential for developing cross-resistance [Zhang, T., et al 2015] and 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. Thus, there remains an unmet 
medical need for patients with mCRPC with disease progression following treatment with an
NHA 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 (KN028) study (Cohort E3: advanced 
[unresectable and/or metastatic] prostate adenocarcinoma). The primary end point was the 
objective response rate (ORR), according to the Response Evaluation Criteria in Solid 
Tumors version 1.1 (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 1 patient remained on treatment at the time of last published analysis. 
[Hansen, A. R., et al 2018]. Twenty-one (91.3%) had 1 or more post-baseline PSA level 
determinations; 5 of these participants (24%) had a PSA level decline of 50%. There were 
4 confirmed PRs, according to RECIST 1.1 guidelines, for an ORR at that time of 17.4% 
(95% CI, 5.0 to 38.8%). Responses were durable (median duration of response [DOR], 13.5
months), and treatment was well tolerated.
2.2.1.6
Ongoing Clinical Trials in mCRPC
KEYNOTE-199 (KN199) was designed to further evaluate the positive signal of activity seen 
in KN028 with pembrolizumab monotherapy in participants with mCRPC who previously 
received docetaxel-based chemotherapy and underwent abiraterone acetate or enzalutamide 
treatment. The ORR was 4.5% (cohorts 1 and 2) at the second interim database lock 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 to 2016 who had 
mCRPC with evidence of progression on enzalutamide, and subsequently enrolled a total of 
28. Because of 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., undertook 
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the Phase 2 study adding pembrolizumab to enzalutamide for men with mCRPC and reported 
a decline in PSA ≥50% (primary endpoint) in 5 of 28 patients (17.9%) and an ORR 
(secondary endpoint) in 3 of 12 patients (25.0%) who had measurable disease at baseline. At 
last report, 3 of the 5 responders continued to respond (range, 21.9 to 33.8 months), and 
median OS was 22.2 months (95% CI, 14.7 to 28.4 months).  
KN365, a Phase 2 umbrella study evaluating pembrolizumab combination therapies in 
mCRPC participants, included a cohort for the evaluation of pembrolizumab in combination 
with up to 10 cycles of docetaxel (Cohort B). Participants in this cohort were required to 
have had previously received either abiraterone acetate or enzalutamide. 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 3 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 of pembrolizumab are being conducted in multiple additional tumor 
types. For study details, please refer to the pembrolizumab IB.
2.2.2
Information on Other Study-related Therapy
2.2.2.1
Docetaxel
Docetaxel is a microtubule inhibitor indicated for locally advanced or metastatic breast 
cancer, non-small cell lung cancer (NSCLC), mCRPC, gastric adenocarcinoma, and 
squamous cell carcinoma of the head and neck. Docetaxel is an antineoplastic agent that acts 
by disrupting the microtubular network in cells that is essential for mitotic and interphase 
cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into 
stable microtubules while simultaneously inhibiting their disassembly. This leads to the 
production of microtubule bundles without normal function and to the stabilization of 
microtubules, which results in the inhibition of mitosis in cells. The binding of docetaxel to 
microtubules does not alter the number of protofilaments in the bound microtubules, a feature 
which differs from most spindle poisons currently in clinical use.
The safety and efficacy of docetaxel in combination with prednisone in participants with 
mCRPC were evaluated in a randomized, multicenter, active control trial [Tannock, I, et al 
2004]. A total of 1006 participants with Karnofsky Performance Status ≥60 were randomized 
to the following treatment groups:
•
Docetaxel 75 mg/m2 every 3 weeks (Q3W) for 10 cycles
•
Docetaxel 30 mg/m2 administered weekly for the first 5 weeks in a 6-week cycle for 
5 cycles
•
Mitoxantrone 12 mg/m2 Q3W for 10 cycles
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All 3 regimens were administered in combination with prednisone 5 mg twice daily (BID), 
continuously. In the docetaxel Q3W arm, a statistically significant OS advantage was 
demonstrated compared to mitoxantrone. Median OS was 18.9 months (95% CI, 17.0 to 21.2 
months) versus 16.5 months (95% CI, 14.4 to 18.6 months) in the docetaxel and 
mitoxantrone arms, respectively. In the docetaxel weekly arm, no OS advantage was 
demonstrated compared to the mitoxantrone control arm.
Refer to the approved labeling for detailed background information on docetaxel.
Concomitant treatment with prednisone prior to and during docetaxel treatments is 
recommended per docetaxel labeling. Corticosteroids provide palliation and tumor responses 
in prostate cancer patients [Montgomery, B., et al 2014]. Docetaxel was approved in the US 
in combination with prednisone as the first treatment shown to prolong survival in men with 
mCRPC.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from study 
intervention 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 multiple malignancies. 
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).
Docetaxel has been approved by regulatory agencies globally for the treatment of mCRPC 
and have been recommended for treatment for mCRPC by NCCN and European Society for 
Medical Oncology guidelines [Parker, C., et al 2015].
Preliminary results from Cohort B of KEYNOTE-365 (see Section 2.1), in which participants 
have been treated with a combination of pembrolizumab and docetaxel, show a modest 
objective response, although the DCR for the cohort was 84.7% with a large proportion of 
participants with stable disease for at least 24 weeks (79.2%) prior to disease progression. 
Two thirds of the participants had a reduction in tumor size, of which nearly a third had a 
reduction of >30%. Participants in this cohort reported Grade 3 to 5 AEs in 42 of 72 (58.3%)
participants, and SAEs in 30 of 72 (41.7%).
NOTE: At the final analysis, the combination of pembrolizumab and docetaxel plus 
prednisone did not demonstrate a benefit in OS, one of the study’s dual primary endpoints, 
compared to placebo and docetaxel plus prednisone. The study’s other dual primary 
endpoint, rPFS, was evaluated at an earlier interim analysis and did not demonstrate 
improvement compared to the control arm. There were trends toward an improvement in both 
OS and rPFS for participants who received pembrolizumab plus chemotherapy compared 
with chemotherapy alone; however, these results did not meet statistical significance per the 
prespecified statistical plan.
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The combination was associated with a slightly higher incidence of AEs compared to 
docetaxel alone, however the safety profile of pembrolizumab in combination with docetaxel 
in this study appears consistent with that observed in previously reported studies for the 
individual therapies.
Selected analyses of safety endpoints will be performed at the end of the study. There will be 
no further analyses of efficacy and PRO endpoints.
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 have not received chemotherapy but have progressed on or 
are intolerant to NHA:
NOTE: As of Amendment 06, all participants will be unblinded. Placebo treatment should 
stop immediately. All participants should be informed of the results of the trial as described 
in the investigator memo of 04-AUG-2022. Participants who are deemed to be deriving 
clinical benefit from treatment may continue at the discretion of the investigator. All other 
study participants should be discontinued from study and be offered SOC treatment as 
deemed necessary by the investigator. Participants who are still on treatment and deriving 
clinical benefit will no longer have tumor response assessments by BICR. However, local 
tumor imaging assessments should continue per local SOC schedule. In addition, ePRO
assessments will no longer be performed and biomarker samples will no longer be collected. 
Objectives
Endpoints
Primary
To compare pembrolizumab plus 
docetaxel plus prednisone to placebo 
plus docetaxel plus prednisone with 
respect to overall survival (OS)
Hypothesis 1: The combination of 
pembrolizumab plus docetaxel plus 
prednisone is superior to placebo plus 
docetaxel plus prednisone with respect 
to OS
OS: the time from randomization to death 
due to any cause
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Objectives
Endpoints
To compare pembrolizumab plus 
docetaxel plus prednisone to placebo 
plus docetaxel plus prednisone with 
respect to radiographic progression-
free survival (rPFS) per Prostate 
Cancer Working Group (PCWG)-
modified Response Evaluation Criteria 
in Solid Tumors Version 1.1 (RECIST 
1.1) as assessed by blinded independent 
central review (BICR) 
Hypothesis 2: The combination of 
pembrolizumab plus docetaxel plus 
prednisone is superior to placebo plus 
docetaxel plus prednisone with respect 
to rPFS per PCWG-Modified RECIST 
1.1 as assessed by BICR
rPFS: the time from randomization to 
radiographic progression, or death due to 
any cause, whichever occurs first
Secondary

To compare pembrolizumab plus 
docetaxel plus prednisone to placebo 
plus docetaxel plus prednisone with 
respect to time to initiation of the first 
subsequent anti-cancer therapy 
(TFST)

Hypothesis 3: The combination of 
pembrolizumab plus docetaxel plus 
prednisone is superior to placebo plus 
docetaxel plus prednisone with respect 
to TFST
TFST: the time from randomization to 
initiation of the first subsequent anti-cancer 
therapy or death, whichever occurs first

To evaluate pembrolizumab plus 
docetaxel plus prednisone versus 
placebo plus docetaxel plus 
prednisone with respect to 
o
PSA response rate
o
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
ORR per PCWG-modified RECIST 1.1 as 
assessed by BICR
DOR: the time from the earliest date of 
first documented evidence of CR or PR 
until earliest date of disease progression or 
death from any cause, whichever occurs
first
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Objectives
Endpoints

To compare pembrolizumab plus 
docetaxel plus prednisone versus 
placebo plus docetaxel plus 
prednisone with respect to the 
o
Time to pain progression 
(TTPP) based on the Brief Pain 
Inventory-Short Form (BPI-SF) 
item 3 “worst pain in 24 hours” 
and opiate analgesic use (analgesic 
quantification algorithm [AQA] 
score)
o
Time to first symptomatic 
skeletal-related event (SSRE)
o
Time to PSA progression

TTPP: the time from randomization to 
pain progression as determined by item 3 
of the BPI-SF and AQA score

Time to SSRE: the time from 
randomization to the first SSRE, defined 
as  
1) first use of external-beam radiation 
therapy (EBRT) to prevent or relieve 
skeletal symptoms 
2) occurrence of new symptomatic 
pathologic bone fracture (vertebral or 
non-vertebral) 
3) occurrence of spinal cord compression
4) or tumor-related orthopedic surgical 
intervention whichever occurs first.

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.

To compare pembrolizumab plus 
docetaxel plus prednisone versus 
placebo plus docetaxel plus 
prednisone with respect to the time to 
radiographic soft tissue progression
per soft tissue rules of PCWG-
Modified RECIST 1.1 as assessed by 
BICR

Time to radiographic soft tissue 
progression: the time from randomization 
to radiographic soft tissue progression

To evaluate the safety and tolerability 
of pembrolizumab plus docetaxel plus 
prednisone versus placebo plus 
docetaxel plus prednisone

Adverse events (AEs)

Study intervention discontinuations due to 
AEs
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Objectives
Endpoints
Tertiary/Exploratory

To evaluate efficacy with respect to 
OS, rPFS, ORR and DOR in 
participants with positive PD-L1 
(combined positive score >1%) versus 
all- comers

OS, rPFS, OR, DOR

To compare pembrolizumab plus 
docetaxel plus prednisone versus 
placebo plus docetaxel plus 
prednisone with respect to the time to 
radiographic bone progression 
(TTBP) per PCWG-Modified 
RECIST 1.1, as assessed by BICR 

TTBP: the time from randomization to 
radiographic bone progression 

To assess the effect of the 
combination of pembrolizumab plus 
docetaxel plus prednisone versus 
placebo plus docetaxel plus 
prednisone on disease-related 
symptoms and health-related quality 
of life (HRQoL) using BPI-SF, 
Functional Assessment of Cancer 
Therapy (FACT) - Prostate Cancer 
(FACT-P) and EuroQoL Five-
Dimension Five-Level Health State 
Utility Index (EQ-5D-5L)
questionnaires in patients with 
mCRPC

BPI-SF: progression in pain severity 
domain, change in pain interference 
domain, and pain palliation

FACT-P total score, FACT-G total score, 
trial outcome index, functional well-
being, physical well-being, prostate 
cancer subscale, and FACT Advanced 
Prostate Symptom Index 6 (FAPSI6)

EQ-5D-5L: mobility, self-care, usual 
activities, pain/discomfort, and 
anxiety/depression health states and EQ-
5D-5L visual analog scale

To characterize health utilities in 
participants following administration 
of pembrolizumab plus docetaxel plus 
prednisone versus placebo plus 
docetaxel plus prednisone

EQ-5D-5L

To identify molecular (genomic, 
metabolic, and/or proteomic) 
biomarkers that may be indicative of 
clinical response/resistance, safety, 
and/or the mechanism of action of 
pembrolizumab and other treatments

Molecular (genomic, metabolic and/or 
proteomic) determinants of response or 
resistance to study interventions, using 
blood and/or tumor tissue
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4
STUDY DESIGN
4.1
Overall Design
NOTE: As the study has completed its final analysis, the study has achieved its prespecified 
scientific objective to evaluate the combination of pembrolizumab and docetaxel in this 
setting, and the study will be closed.
All participants will be unblinded. Placebo treatment should stop immediately. Investigators 
should inform all participants of the study results as described in the investigator memo of 
04-AUG-2022; participants who are deemed to be deriving clinical benefit from treatment 
may continue at the discretion of the investigator. All other study participants should be 
discontinued from study and be offered SOC treatment as deemed necessary by the 
investigator. Upon study completion, participants are discontinued from the current study and 
may be transitioned into a pembrolizumab extension study, if available.
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind/mask study 
of pembrolizumab/placebo plus docetaxel plus prednisone in participants with mCRPC.
After a screening phase of up to 42 days, approximately 1000 eligible participants will be 
randomly assigned in a 1:1 ratio to 1 of the following 2 study intervention arms:
•
Arm 1: pembrolizumab plus docetaxel plus prednisone/prednisolone
•
Arm 2: placebo plus docetaxel plus prednisone/prednisolone 
Participants must have previously received treatment with a NHA (but not more than one)
and failed treatment or become intolerant of the drug. Participants who progressed must have 
received at least 8 weeks (minimum 14 weeks for those with bone progression) of treatment. 
Participants who became intolerant of NHA must have had a minimum of 4 weeks exposure.
Prior docetaxel chemotherapy in the hormone-sensitive setting is allowed. 
Participants must provide tumor tissue from a new core or excisional biopsy 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). For participants
with bone only or bone predominant disease may provide a bone biopsy sample
(decalcification not allowed). However, if obtaining a new 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 entrance criteria, please see Section 5.1 –
Inclusion Criteria.
Prior to randomization, participants will be stratified by prior NHA treatment (abiraterone:
Yes vs. No) and metastases (bone only vs. liver vs. other). Pembrolizumab/placebo 
administration will occur on Day 1 of each 3-week dosing cycle and will continue for a 
maximum of 35 cycles (approximately 2 years starting with the first infusion in Cycle 1) or 
until specific withdrawal/discontinuation criteria are met (Section 7.1). Participants should 
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receive a maximum of 10 cycles of docetaxel Q3W with prednisone/prednisolone BID; a
minimum of 6 cycles of docetaxel is recommended, unless specific withdrawal/study 
intervention discontinuation criteria are met. Prior to docetaxel treatments, participants may
be premedicated with dexamethasone or per local standard of care, and will be treated 
concomitantly with prednisone/prednisolone per docetaxel labeling. Participants who must 
discontinue either pembrolizumab/placebo or docetaxel due to drug-related AEs, may 
continue with the other combination partner following consultation with the Sponsor until 
criteria for discontinuation of study intervention are met (eg, disease progression). After
cessation of docetaxel treatment, prednisone/prednisolone should be discontinued (tapering is 
acceptable).
This trial will use an independent, external Data Monitoring Committee (eDMC) to monitor 
safety and efficacy (Section 10.1.4.2). Response to study intervention will be evaluated with 
radiologic imaging (whole body bone scans and computed tomography [CT] scans of the 
chest, abdomen, and pelvis) every 9 weeks for approximately 1 year (through Week 54) and 
every 12 weeks thereafter.  
Participants will be evaluated with radiologic imaging to assess response to treatment at 
regular intervals during the study (Section 8.2.1). 
Participants who attain an investigator-determined confirmed complete response (CR) may 
receive up to 35 cycles of pembrolizumab/placebo. If a participant with radiographic 
progression is clinically stable or clinically improved, an exception may be considered to 
continue study intervention upon consultation with the Sponsor. Participants showing clinical 
benefit in the trial will be allowed to continue study intervention per protocol regardless of 
any decision to stop enrollment or suspend the study.
Adverse events (AEs) will be monitored throughout the trial and graded in severity according 
to the guidelines outlined in the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. After the end of the study intervention, 
each participant will be followed for 30 days for AE monitoring (all serious AEs [SAEs] will 
be collected for 90 days after the end of study intervention or 30 days after the end of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier). 
Treatment-related SAEs must be reported regardless of when they occur. Participants who 
discontinue study intervention for reasons other than radiographic disease progression will 
stay on study and continue study-related disease assessments until radiographic disease 
progression, initiation of a non-study cancer treatment, participant discontinuation from the 
trial, or if the participant becomes lost to follow-up. All participants will be followed up for 
survival. This may be done in a variety of ways including phone, email, chart review, or 
review of public records in compliance with local practices or regulations.
Second Course Treatment:
NOTE: As of Amendment 06, second course treatment is not an option for participants. 
There are currently no participants in the Second Course Phase.
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Participants who stop study intervention as a result of obtaining an investigator-determined 
confirmed CR or those participants who stop after receiving 35 cycles may be eligible, at the 
discretion of the investigator, for an additional 17 cycles (approximately 1 year) of 
pembrolizumab after BICR-verified progressive disease if they meet the criteria for re-
treatment (see 6.6.4 Second Course) and the study is ongoing. Participants who receive 
pembrolizumab after progression as described above will not receive further treatment with 
docetaxel plus prednisone/prednisolone. The decision to retreat with pembrolizumab will be 
at the discretion of the investigator only if no cancer 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 trial remains open.
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 eDMC to monitor safety 
and efficacy during the course of the study. There will be 2 planned interim analyses 
conducted. The final OS analysis will be conducted when approximately 549 OS events 
(target number of OS events) have been observed. There will be only 1 PFS analysis 
conducted, which is at the time of first interim analysis (IA1) when at least 468 rPFS events 
have been observed. The results of the interim analyses will be reviewed by the eDMC, 
which will provide recommendations for the study in accordance with the eDMC Charter and 
the Statistical Analysis Plan (SAP) described in detail in Section 9.0 - Statistical Analysis
Plan.
Extension Portion in China:
Approximately 150 participants in China will be randomized overall in the global portion and
the China Extension Portion of the study. After enrollment of the global portion is closed, 
participants in China will continue to be enrolled and randomized in a 1:1 ratio in the
Extension Portion designed to meet local regulatory requirements. The Extension Portion
will be identical to the global portion (eg, double-blinded, with identical inclusion and 
exclusion criteria, study endpoints, primary and secondary objectives, and study procedures), 
with the exception of an additional supplemental statistical analysis plan (sSAP) section for 
participants enrolled in China. Details of the analysis will be provided in the sSAP.
4.2
Scientific Rationale for Study Design
This study is a randomized, placebo-controlled, double-blind study, a design selected to 
eliminate potential bias.  
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4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The dual primary endpoints of the study are OS and rPFS. Overall survival 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. Radiographic 
progression for soft tissue lesions will be determined as assessed by BICR according to 
PCWG-Modified RECIST 1.1 (Section 8.2).  
Time to initiation of the first subsequent anti-cancer therapy or death (TFST) will be assessed 
as a key secondary endpoint. A delay in the need to initiate the next anti-cancer therapy is 
clinically meaningful for patients and an important goal of any anti-cancer 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
The EuroQoL-5D (EQ-5D-SL), BPI-SF, and FACT-P patient-reported outcomes (PROs) are 
not pure efficacy or safety endpoints because they are affected by both disease progression 
and study intervention tolerability.
The EQ-5D-SL is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001]. This instrument has been used extensively in cancer studies and published 
results from these studies support its validity and reliability [Pickard, A. S., et al 2007].  
The FACT-P is a disease-specific 39-item questionnaire included for the purpose of assessing 
HRQoL and prostate cancer-specific symptoms. It is a well-established measure of 
HRQoL/health status commonly used in prostate cancer clinical studies. The FACT-P was 
developed specifically for patients with advanced prostate cancer and has been found to be 
reliable and valid in this population [Esper, P., et al 1997].  
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The BPI-SF is a validated, 15-item domain-specific instrument designed to assess the 
severity of pain and the impact/interference of pain on daily functions [Cleeland, C. S. and 
Ryan, K. M. 1994].
The Patient Analgesic Log will be used to capture all analgesic medication dosages and dose 
times. Both the BPI-SF and Patient Analgesic Log will be used over a 7-day period each 
treatment cycle.
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).
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.
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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.
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.
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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.
4.2.1.5
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Placebo
Normal saline or dextrose infusion Q3W will be used as placebo for pembrolizumab. The use 
of saline or dextrose placebo in combination with chemotherapy will ensure the objectivity of
the investigator. The use of a placebo-controlled trial will allow for testing the hypotheses 
that OS for participants treated with pembrolizumab and chemotherapy is superior to the 
combination of placebo and chemotherapy 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 and regardless of tumor type. As outlined 
below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg Q2W,
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
Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg 
Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically based PK 
[PBPK] analysis) at 200 mg Q3W.
Among the 8 randomized, dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and 
KN006). All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5- to 7.5- fold difference in exposure. 
The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses 
studied. Subsequently, flat dose-exposure-response relationships were also observed in other 
tumor types including head and neck cancer, bladder cancer, gastric cancer, and classical 
Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the 
tumor type. These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
4.3.2
Docetaxel
The recommended dose of docetaxel for mCRPC is 75 mg/m2 Q3W as a 1-hour IV infusion 
for a maximum of 10 cycles. The recommended premedication with dexamethasone is 8 mg 
PO at 12 hours, 3 hours, and 1 hour before the start of the docetaxel infusion. Steroid 
pretreatment prior to docetaxel administration as per local standard of care is allowed.
Prednisone/prednisolone 5 mg PO BID is administered continuously according to the 
docetaxel prescribing information for the treatment of mCRPC. After cessation of docetaxel 
treatment, prednisone/prednisolone should be discontinued. 
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Refer to Section 6.6.3 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 signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone call or visit, withdraws 
consent, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or an unacceptably high number of discontinuations or withdrawals due to administrative 
reasons.
In the event of Sponsor decision to no longer supply study interventions, ample notification 
will be provided so that appropriate adjustments to participant treatment can be made.
5
STUDY POPULATION
Male participants with mCRPC in the pre-chemotherapy state who have been previously 
treated with an NHA and have failed treatment or become intolerant of the drug and meet the 
following inclusion criteria will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
1. Have histologically- or cytologically-confirmed (if acceptable according to local health 
authority regulations) adenocarcinoma of the prostate without small cell histology. 
Diagnosis must be stated in a pathology report and confirmed by the investigator.
2. Have prostate cancer progression while on androgen deprivation therapy (or post bilateral 
orchiectomy) within 6 months prior to screening, 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 
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where the PSA value at screening should be ≥1 ng/mL – See Section 8.2.2 –
Prostate-specific Antigen Assessment for further details.
Note: A PSA level obtained during the Screening Period can count as the 
confirmatory second rising PSA.
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.
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 received prior treatment with one (but not more than one) NHA (eg, abiraterone 
acetate, enzalutamide, apalutamide, or darolutamide) for mHSPC or CRPC and either:
a) progressed through treatment after a minimum of 8 weeks treatment (minimum 
14 weeks for those with bone progression).
OR
b) have become intolerant of the drug (minimum 4 weeks treatment).
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 the 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
ANC
>1,500/µL
Plateletsa
≥100,000/µL
Hemoglobina
≥9.0 g/dL or ≥5.6 mmol/L 
Renal
Serum creatinine OR
Measured or calculatedb creatinine 
clearance
(GFR can also be used in place of 
creatinine or creatinine clearance)
≤1.5 × ULN OR
≥60.0 mL/min for participant with creatinine 
levels >1.5 × ULN
Hepatic
Serum total bilirubin
Total bilirubin ≤ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN; (≤5 × ULN for participants 
with liver metastases)
Coagulation
INR or PT
PTT or aPTT
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT 
is within therapeutic range of intended use of 
anticoagulants
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT 
is within therapeutic range of intended use of 
anticoagulants
a. Hemoglobin and platelet requirements cannot be met by use of recent transfusion or growth factor support (GCSF or 
erythropoietin) within 28 days prior to treatment randomization.
b. Creatinine clearance should be calculated per institutional standard.
Abbreviations: ALT=alanine aminotransferase; ANC=absolute neutrophil count; aPTT=activated partial thromboplastin 
time; AST=aspartate aminotransferase; GCSF=granulocyte colony-stimulating factor; GFR=glomerular filtration rate; 
INR=international normalized ratio; PT=prothrombin time; PTT=partial thromboplastin time; SGOT=serum glutamic 
oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase; ULN=upper limit of normal.
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 informed consent.
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Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods
of contraception for those participating in clinical studies.
11. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 120 days after the last dose of pembrolizumab or 180 
days after the last dose of docetaxel, whichever is longer:

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 [Appendix 5]) as detailed below:

Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a woman of childbearing potential 
(WOCBP) who is not currently pregnant. Note: Men 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.
12. Male participants must agree to use male condom when engaging in any activity that 
allows for passage of ejaculate to another person of any sex.
Female Participants
Not applicable.
Informed Consent
13. The participant (or legally acceptable representative if applicable) provides written 
informed consent/assent for the study. The participant may also provide consent/assent 
for future biomedical research. However, the participant may participate in the main 
study without participating in future biomedical research.
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 
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bone biopsy sample. However, if obtaining a fresh biopsy is not feasible, then 
participants may provide an archival tumor tissue sample after Sponsor consultation 
(SCF). Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. 
Newly obtained biopsies are preferred to archive tissue.
Note: If submitting unstained cut slides, newly cut slides should be submitted to the 
testing laboratory within 14 days from the date slides are cut (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:
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 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 trial, interfere with the participant’s participation 
for the full duration of the trial, or is not in the best interest of the participant, in the 
opinion of the treating investigator.
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 the last 3 months).
7. Is unable to swallow tablets/capsules.
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8. Has an active infection (including tuberculosis) requiring systemic therapy.
9. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
10. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the trial.
11. Has known active human immunodeficiency virus (HIV), hepatitis B virus (eg, hepatitis
B surface antigen reactive) or hepatitis C virus (HCV) (eg, HCV RNA [qualitative] is 
detected). Testing at screening is not required unless mandated by local regulations. Refer 
to Appendix 7 for country-specific testing requirements.
12. 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.
13. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
14. Has CTCAE Grade ≥2 peripheral neuropathy, except when due to trauma.
15. Has ascites and/or clinically significant pleural effusion.
16. Has symptomatic congestive heart failure (New York Heart Association Class III or IV 
heart disease).
Prior/Concomitant Therapy
17. Has received a whole blood transfusion in the last 120 days prior to entry into the 
study. Packed red blood cells and platelet transfusions are acceptable if not given within 
28 days of the first dose of study intervention.
18. Has received colony-stimulating factors (eg, granulocyte colony-stimulating factor [G 
CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], or recombinant 
erythropoietin) within 28 days prior to the first dose of study intervention.
19. Has had a prior anticancer mAb within 4 weeks prior to randomization or who 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 if 
the participant has been on a stable dose for ≥4 weeks prior to randomization.
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20. Has used herbal products that may have hormonal anti-prostate cancer activity and/or are 
known to decrease PSA levels (eg, saw palmetto) within 4 weeks prior to treatment 
randomization.
21. Has received prior treatment with radium or other therapeutic radiopharmaceuticals for 
prostate cancer.
22. 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 co-inhibitory T-cell receptor (eg, CTLA-4, 
OX-40, CD137).
23. Has received prior treatment with docetaxel or another chemotherapy agent for metastatic 
prostate cancer. NOTE: Participants who received docetaxel for mHSPC are permitted
provided they received ≥6 cycles and did not progress within 1 year after the last dose of 
docetaxel.
24. Has hypersensitivity to docetaxel or polysorbate 80.
25. Participant is currently receiving either strong or moderate inhibitors of cytochrome P450 
(CYP)3A4 that cannot be discontinued for the duration of the study.  
Note: a current list of strong/moderate inhibitors of CYP3A4 can be found at the 
following website:  https://www.fda.gov/Drugs/DevelopmentApprovalProcess/
DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#table2-2
26. Has received prior targeted small molecule therapy or abiraterone acetate, enzalutamide, 
apalutamide or darolutamide within 4 weeks prior to the first dose of study intervention, 
or has not recovered (ie, Grade ≤1 or at baseline) from AEs due to a previously 
administered agent.
Note: Participants with Grade ≤2 alopecia may be eligible.
27. Has received prior radiotherapy within 2 weeks of start of study intervention. 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.
28. Has received a live vaccine within 30 days prior to randomization. Examples of live 
vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.
Note: Refer to Section 6.5 for information on COVID-19 vaccines.
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29. Has received treatment with 5α reductase inhibitors (eg, finasteride or dutasteride), 
estrogens, and/or cyproterone within 4 weeks prior to randomization.
30. Has received prior treatment with ketoconazole for prostate cancer.
Prior/Concurrent Clinical Study Experience
31. 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 the first dose of study 
intervention.
Note: Participants who have entered the non-treatment 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
32. 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
33. Is expecting to conceive or father children within the projected duration of the study, 
starting with the screening visit through 120 days after the last dose of study intervention.
34. 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.
5.3.2
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Refer to Appendix 5 for 
approved methods of contraception.
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, participants with a partner of childbearing potential must adhere to the 
contraception requirement (Appendix 5) from the day of study medication initiation (or 14 
days prior to the initiation of study medication for oral contraception) throughout the study 
period up to 120 days after the last dose of pembrolizumab/placebo or 180 days after the last 
dose of docetaxel, whichever is longer. If there is any question that a participant with a 
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partner of childbearing potential will not reliably comply with the requirements for 
contraception, that participant should not be entered into the study.
5.3.3
Pregnancy
If a participant impregnates his female partner, the study personnel at the site must be 
informed immediately, and the pregnancy must be reported to the Sponsor and followed up 
as described in Section 8.4.
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 the study intervention or withdraws consent 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 will be packaged to support enrollment. When a replacement participant is 
required, the Sponsor or designee needs to be contacted prior to dosing the replacement 
supplies. Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
6.1
Study Intervention(s) Administered
As of Amendment 06, placebo treatment should stop immediately. Investigators should 
inform all participants of the study results; participants who are deemed to be deriving 
clinical benefit from treatment may continue at the discretion of the investigator. All other
study participants should be discontinued from study and be offered SOC treatment as 
deemed necessary by the investigator. The study intervention(s) to be used in this study are
outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Arm 1
Experi-
mental
pembrolizumab
Biological/
Vaccine
Solution for 
Infusion
25 mg/mL
200 mg
IV Infusion
Day 1 of each 
21-day cycle
Experimental
IMP
Central or 
Local
Arm 1, 
Arm 2
Other
docetaxel
Drug
Solution for 
Infusion
10 or 20 
mg/mLa
75 mg/m2
IV Infusion
Day 1 of each 
21-day cycle
Standard of 
Care
NIMP
Central or 
local
Arm 1, 
Arm 2
Other
prednisone 
(or equivalent 
dose of 
prednisoloneb)
Drug
Tablet
5 mg
5 mg
Oral
BID
Standard of 
Care
NIMP
Local
Arm 1, 
Arm 2
Other
Recommended 
dexamethasone 
(or equivalent 
dose of another 
corticosteroidc) 
premedication.
Local SOC 
premedication 
allowed
Drug
Tablet
8 mg
8 mg
Oral
12, 3, and 1 
hour prior to 
docetaxel 
administration
Standard of 
Care
NIMP
Local
Arm 2
Placebo
Normal saline 
or dextrosed
Other
Solution for 
Infusion
N/A
N/A
IV infusion
Day 1 of each 
21-day cycle
Placebo
IMP
Local
BID= twice daily; IMP = Investigational Medicinal Product; IV = intravenous; NIMP = Non-Investigational Medicinal Product; SOC = Standard of care.
Note: Definition IMP and NIMP is based on guidance issued by the European Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
a When locally supplied, docetaxel unit vial strength is based on region.
b Prednisone is the preferred steroid to be used in the study. Prednisolone should only be used when prednisone is unavailable. 
c Dexamethasone, or the equivalent dose of another steroid, is the preferred corticosteroid to be used in the study. Local standard of care premedication prior to docetaxel infusion
is allowed
d Normal saline is the primary diluent/placebo for pembrolizumab; use dextrose only if saline is not available.
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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/placebo are provided in the 
Pharmacy Manual. Concomitant chemotherapeutic agents will be prepared and administered 
as per the approved product labels.
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.
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.
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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 + docetaxel study intervention and placebo + docetaxel study 
intervention, respectively.
6.3.2
Stratification
Participants will be stratified according to the following factors:

Prior NHA treatment: abiraterone (Yes vs. No)

Metastases: bone only versus liver versus other
NOTE: for metastases, if there are only bone metastases, it will be categorized as bone only; 
otherwise (ie, not bone only), if there are liver metastases, then participants will be 
categorized as liver. All other participants will be categorized as other. 
6.3.3
Blinding
As of Amendment 06: all participants will be unblinded. The subsections below are 
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 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 study intervention identity of docetaxel and prednisone/prednisolone will be open-label; 
the identity of those study interventions 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.
PD-L1, PSA, and CTC results are not reported back to sites to prevent early withdrawal of 
participants from study intervention.
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6.4
Study Intervention Compliance
Administration of study medication(s) will be monitored by the investigator and/or study 
staff. 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 prednisone/prednisolone taken at home, the site will validate compliance with study 
intervention at each site visit according to their standard operating procedure.
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.
In addition, the following concomitant medications/vaccinations are not permitted:

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

Granulocyte-macrophage colony stimulating factor

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 inhibitors apalutamide or darolutamide

Investigational agents other than pembrolizumab
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
Herbal products that may have hormonal anti-prostate cancer activity or that 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 or measurable lesion by RECIST 1.1.

Live vaccines within 30 days prior to randomization and while participating in the study. 
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed.

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 (i.e., those not licensed or approved for Emergency Use) 
are not allowed.
Note: If precluded by local regulations, live vaccines should not be given for 120 days after 
the last dose of pembrolizumab is administered.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE
that is suspected to have an immunologic etiology or that are listed as permitted below. 
The use of physiologic doses of corticosteroids may be approved after consultation with 
the Sponsor.  
Note: The following uses of systemic glucocorticoids are permitted without Sponsor 
consultation: 

Concomitant prednisone/prednisolone 5 mg PO BID during treatment with 
docetaxel.

Standard dexamethasone (or equivalent) premedication prior to administration of 
docetaxel.

Inhaled steroids for management of asthma.

Intranasal steroids for allergies.

Use of prophylactic corticosteroids to avoid allergic reactions (eg, IV contract dye).

Treatment with palliative prednisone up to 10 mg daily or corticosteroid equivalent 
in the manner used to treat men with prostate cancer.
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
Physiologic doses of corticosteroids for adrenal insufficiency.

Strong or moderate inhibitors of cytochrome CYP3A4.  
Note: a current list of strong/moderate inhibitors of CYP3A4 can be found at the following 
website:  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/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 
docetaxel and prednisone.
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. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
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 6.6.2, Table 3. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 3 in 
Section 6.6.2 for guidelines regarding dose modification and supportive care.
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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, the site must gain approval via 
Sponsor consultation form (SCF) to continue the other study intervention. Participants who 
must discontinue 1 of the 2 interventions due to drug-related AEs may continue with the 
other following consultation with the Sponsor until criteria for discontinuation of treatment 
are met (eg, disease progression). A maximum of 10 cycles of docetaxel + 
prednisone/prednisolone is allowed. It is recommended that participants receive a minimum 
of 6 cycles of docetaxel, unless specific withdrawal/treatment discontinuation criteria are 
met.
In response to AEs that occur during combination therapy, refer to the approved labeling for 
docetaxel for more detailed information regarding dose regimen/modification, and refer to
Table 3 for pembrolizumab dose modification. Additionally, refer to the respective product 
information/labeling for additional information about avoidance of concomitant medications 
or foods that may affect the metabolism of these drugs.
6.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
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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 3.
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Table 3
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
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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
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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
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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
Hypophysitis
Grade 2
Withhold
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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
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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
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 
diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs
(eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions 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 4.
Table 4
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/Placebo
Pembrolizumab/placebo may be interrupted for situations other than treatment-related AEs 
such as medical / surgical events or logistical reasons not related to study therapy. 
Participants should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should 
be documented in the participant's study record.
6.6.3
Dose Modification for Docetaxel
Adverse events due to docetaxel will be managed as shown in Table 5.
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Table 5
Docetaxel Dose Modification Guidelines for Drug-related Adverse Events
Toxicity
Hold Treatment
Docetaxel Timing for 
Restarting Treatment
Action
Diarrhea/Colitis
Grade 2 or 3
Toxicity resolves to 
Grade 0 or 1
Reduce subsequent 
doses
Grade 4
Discontinue docetaxel
Discontinue docetaxel
AST (SGOT), ALT 
(SGPT)
Grade 2
Toxicity resolves to 
Grade 0 or 1
Reduce subsequent 
doses 
Grade 3 or 4
Discontinue docetaxel
Discontinue docetaxel
Bilirubin
>ULN
<ULN
Reduce subsequent 
doses
ANC
<1500
>1500
See footnotea
Febrile neutropenia
Grade 3 with feverb 
See footnotec 
Reduce dose
Platelet count
<100,000
>100,000
See footnoted
Peripheral 
neuropathy
Grade 2
Grade ≤1
Reduce subsequent 
doses
Grade ≥3
Discontinue docetaxel
Discontinue docetaxel
Other grade ≥3 
toxicities attributed 
to docetaxel except 
for Grade 3 
lymphopenia
Grade ≥3
Grade ≤1 or baseline
Reduce subsequent 
doses
a If on Day 1 of the next cycle, the ANC is <1500, hold docetaxel. Recheck ANC weekly. Hold docetaxel until recovery 
to ANC 1500. If neutrophil count is <500 cells/mm3 for a sustained period of at least 1 week from the preceding cycle, 
the dose of docetaxel should be reduced in successive cycles. If the ANC does not recover to >1500 in 3 weeks from 
the previously scheduled Day 1, discontinue docetaxel and continue with pembrolizumab monotherapy.
b Grade 3 neutropenia associated with fever (one reading of oral temperature of >38.5 or 3 readings of oral temperature 
>38.0 in a 24-hour period.
c For retreatment, fever must have resolved and infection be adequately treated and clinically resolved before next dose. 
If bacteremia blood cultures must be negative on recheck.
d If on Day 1 of the next cycle the platelet count is less than 100,000, hold docetaxel. Recheck platelet count weekly. 
Hold docetaxel until recovery to platelet count 100,000. Reduce dose of docetaxel in successive cycles. If the platelet 
count does not recover to >100,000 in 3 weeks from the previously scheduled Day 1, discontinue docetaxel and 
continue with pembrolizumab monotherapy.
Abbreviations: ALT= alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate aminotransferase; 
SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase; ULN=upper limit of 
normal.
After resolution of the toxicity, the subject can resume treatment with docetaxel with a dose 
reduction according to Table 6. Once the dose has been reduced, it may not be escalated up 
to a previous dose level. 
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Table 6
Docetaxel Dose Reduction Guidelines
Drug
Dose/Potency
Regimen
Initial docetaxel dose
75 mg/m2
Every 3 weeks
Dose reduction
60 mg/m2
Every 3 weeks
If a scheduled docetaxel dose must be delayed for 3 consecutive weeks, docetaxel must be 
discontinued.
Other Allowed Dose Interruption for Docetaxel
Docetaxel may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant's study record.
6.6.4
Second Course
NOTE: As of Amendment 06, second course treatment is not an option for participants. 
There are currently no participants in the Second Course Phase.
All participants who received pembrolizumab who stop study intervention with SD or better 
may be eligible for up to an additional 17 cycles (approximately 1 year) of pembrolizumab 
monotherapy treatment if they progress after stopping study intervention from the initial 
treatment phase. This retreatment is termed the Second Course Phase of this study and is only 
available if the study remains open and the participant meets the following conditions:
Either
Stopped initial study intervention after attaining an investigator determined confirmed CR 
based on RECIST 1.1, and
Was treated with at least 8 cycles of study intervention before discontinuing treatment, 
and
Received at least 2 cycles with pembrolizumab beyond the date when the initial CR was 
declared
OR
Had SD, PR, or CR and stopped study intervention after completion of 35 cycles 
(approximately 2 years) of study intervention for reasons other than disease progression or 
intolerability
AND
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Experienced BICR-verified radiographic disease progression by RECIST 1.1 after 
stopping initial treatment, and
Upon unblinding at the time of centrally verified disease progression were found to have 
received pembrolizumab, and
No new anticancer treatment was administered after the last dose of study intervention, 
and
The participant meets all of the safety parameters listed in the inclusion criteria and none 
of the safety parameters listed in the exclusion criteria, and
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 docetaxel, certain treatment-
related AEs are uniquely associated with one drug versus the other. For example, 
neutropenia, anemia, thrombocytopenia, peripheral neuropathy, alopecia, nail disorders, and 
fluid retention are known risks for docetaxel treatment, while irAEs are risks for 
pembrolizumab treatment. However, certain AEs, such as such as skin reactions, infusion-
related reactions and liver enzyme elevation, may be initially considered attributable to either 
study drug. Therefore, evaluation of attribution is important for determining the study drug 
most likely related to the AE, or an alternative etiology, and subsequently proper clinical 
management. 
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 treatment with 
a corticosteroid and other supportive care should be taken promptly.
6.7
Intervention After the End of the Study
Upon study completion, participants are to be discontinued and may be enrolled in an 
extension study using pembrolizumab monotherapy, if available.
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 intervention allocation/randomization system (IRT) should be used to 
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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 
treatment 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. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9. Participants 
should be placed back on study therapy within 3 weeks of any scheduled interruption, unless 
otherwise discussed with the Sponsor.
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 study intervention administration for more than 12 consecutive 
weeks of pembrolizumab or has missed 2 consecutive cycles of docetaxel.
NOTE: Interruptions from the protocol-specified treatment plan for more than 12 weeks 
between pembrolizumab doses or 6 weeks between docetaxel 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.
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
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.

Recurrent Grade 3 colitis/diarrhea.

Confirmed BICR-verified radiographic disease progression outlined in Appendix 8
(exception if the Sponsor approves treatment continuation).
-
As of Amendment 06, central tumor response assessments will no longer be 
performed. However, participants still on study will be assessed by the investigator 
for disease progression per local SOC schedule.

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment

Recurrent Grade 2 pneumonitis

Completion of 35 cycles (approximately 2 years) with pembrolizumab
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).

Discontinuation of treatment 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 the combination including 2 doses of pembrolizumab or placebo and at least 
80% of the planned doses of docetaxel beyond the date when the initial CR was declared. 
These participants may be eligible for second course treatment described in Section 6.6.4.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:

The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).

All study-related medical decisions must be made by an investigator who is a qualified 
physician.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
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The maximum amount of blood collected from each participant over the duration of the study
is provided in the procedures manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research.If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
The participant or his/her legally acceptable representative will be asked to sign consent at 
the point of initial radiographic disease progression.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
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8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to future biomedical research. A copy of the 
informed consent will be given to the participant.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior
10 years that the investigator considers to be clinically significant. In addition, significant 
and potentially relevant conditions that occurred >10 years should also be collected. Details 
regarding the disease for which the participant has enrolled in this study will be recorded 
separately and not listed as medical history.
8.1.5
Prior and Concomitant Medications Review
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.
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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 8.4.2. In addition, new medications 
started during the Second Course Phase through the Second Course Safety Follow-up visit 
should be recorded.
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 (TEA) Form
As of Amendment 06: The TEA form will no longer be collected. The subsection below is 
retained for reference.
A TEA form is included in this study to document the investigator assessment of participant 
suitability for potential treatment with docetaxel and the rationale. These data may be 
required to support reimbursement efforts for pembrolizumab plus docetaxel.
The investigator must complete this form and provide rationale to document the choice of 
docetaxel 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.
Upon study completion, participants are discontinued from the current study and may be 
transitioned into a pembrolizumab extension study, if available. All participants in the 
extension study will be allocated by non-random assignment and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation. This number will be 
unique from the treatment/randomization number in the parent study.
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8.1.8
Study Intervention Administration
Administration of study medication 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 treatment 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 or placebo will be administered as a 30-minute IV infusion on Day 1 of each 
cycle. Pembrolizumab or placebo will be administered prior to docetaxel. 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).
The Pharmacy Manual contains specific instructions for pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration.
8.1.8.1.2
Docetaxel
Docetaxel, at a dose of 75 mg/m2, will be administered as an IV infusion on Day 1 of each 
cycle for up to 10 cycles. Docetaxel administration should begin 30 minutes after the end of 
the pembrolizumab IV infusion per local practice and product label. The recommended 
premedication with dexamethasone is 8 mg at 12 hours, 3 hours, and 1 hours prior to 
docetaxel infusion. Steroid pretreatment prior to docetaxel administration as per local 
standard of care is allowed. Participants should be treated concomitantly with 
prednisone/prednisolone (5 mg BID) according to the approved product label and/or standard 
of practice. After cessation of docetaxel treatment, prednisone/prednisolone should be 
discontinued (tapering is acceptable per standard of care).
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 End-of-treatment Visit should be performed (at the time of withdrawal). 
Any AEs that are present at the time of withdrawal should be followed in accordance with 
the safety requirements outlined in Section 8.4 and Section 8.12.4 .
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8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
8.1.10
Participant Blinding/Unblinding
As of Amendment 06: all participants will be 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 
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.
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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
Non-emergency 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.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
As of Amendment 06: Central tumor response assessments will be discontinued. 
Imaging scans will no longer be submitted to iCRO nor read by BICR. The subsections 
below are retained for reference.
However, for participants who are still on study treatment and deriving clinical benefit and 
will continue on study treatment until criteria for discontinuation are met, tumor imaging 
should continue per local SOC schedule.
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual. 
Tumor imaging should be to be acquired by computed tomography (CT is strongly preferred)
and radionuclide bone scan. For the abdomen and pelvis, contrast-enhanced magnetic 
resonance imaging (MRI) may be used when CT with iodinated contrast is contraindicated, 
or when mandated by local practice. Magnetic resonance imaging is the strongly preferred 
modality for imaging the brain. The same imaging technique regarding modality, ideally the 
same scanner, and the use of contrast should be used in a participant throughout the study to 
optimize the reproducibility of the assessment of existing and new tumor burden and improve 
the accuracy of the assessment of response or progression based on imaging. Tumor imaging 
by both CT (or MRI) chest, abdomen, pelvis and whole-body radionuclide bone scan is 
required at every scheduled imaging time point. MRI (or CT) brain imaging is only as
clinically indicated at baseline and on study.   
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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.
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. Once disease 
progression is verified centrally, subsequent imaging (if acquired) should not be submitted to 
the iCRO.
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 soft tissues will be according to soft tissue rules of 
PCWG-Modified RECIST 1.1, modified to follow a maximum of 10 target 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 rules, as described in 
Appendix 8.
Soft tissue and bone response assessments will be combined to produce an overall 
radiographic response, as shown in Table 7.
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Table 7
Overall Radiographic Response per PCWG-modified RECIST
Soft Tissue Response
Bone Scan Result
PCWG-modified RECIST 1.1 
Time Point Response Entered 
into CRF
PD
Any
PD
Any
PD
PD
Any (except PD)
PDu
PDu
NE
Non-PD, NED or NE
NE
NED
NE
NE
NED
Non-PD
Non-CR/Non-PD
NED
NED
NED
SD
Non-PD, NED, or NE*
SD
Non-CR/Non-PD 
Non-PD, NED, or NE*
Non CR/Non-PD
PR
Non-PD, NED or NE*
PR
CR
Non-PD or NE*
PR
(if target lesions were present 
at baseline)
Non-CR/Non-PD
(if no target lesions at baseline)
CR
NED
CR
Abbreviations: CR = complete response; CRF = case report form; NE = nonevaluable; NED = no evidence of 
disease; PCWG = Prostate Cancer Working Group; PD = progressive disease; PDu = progressive disease 
unconfirmed; PR= partial response; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 
1.1. 
* If the bone scan is entirely missing or was not done, and bone lesions were present at baseline, then the 
overall response is NE.
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 
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.
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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 non-target lesions and search for new 
lesions at each imaging time point. 
MRI of the brain at screening should be performed only if clinically indicated.
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). Imaging should continue to be performed until disease progression is 
identified by the investigator and verified by the BICR, the start of new anticancer treatment, 
withdrawal of consent, or death, whichever occurs first. 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 radiologic evidence of progression is initially observed.
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.
Scans are to be continued until one of the following conditions are met:
•
Disease progression as defined by PCWG Modified RECIST 1.1 as verified by BICR. 
•
The start of a new anticancer treatment
•
Death
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•
Withdrawal of consent
•
The end of the study
8.2.1.4
Second Course (Retreatment) Tumor Imaging
NOTE: As of Amendment 06, second course treatment is not an option for participants. 
There are currently no participants in the Second Course Phase.
Tumor imaging must be performed within 28 days 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 performed locally.
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.
The only Second Course scan to be provided to the iCRO is the baseline scan if it is the final 
scan for the Initial Treatment or First Course.
8.2.2
Prostate-specific Antigen Assessments
There are 2 components required for defining trial eligibility by PSA, 1) a rising PSA as 
determined by local lab and 2) a PSA >1 ng/mL as determined by central lab. PSA 
determination by central lab must be performed within 10 days prior to randomization (refer 
to Section 1.3.1). If that 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 be collected 
within 10 days prior to randomization for submission to central laboratory. During the 
remainder of the trial local laboratory may not be used in lieu of central laboratory results.
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For defining rising PSA, the reference value to use (No. 1) is the last PSA before a sequence 
of PSA increases. (See Figure 2 from Prostate Cancer Working Group 2).
Figure 2
Change in Prostate-specific Antigen
The screening value performed during the Screening Period can count as the confirmatory 
second rising PSA compared to a prior single increased PSA value. If a PSA value during 
screening is used as the second data point to confirm rising PSA and it does not confirm the 
PSA rise, but is still greater than the reference point, PSA determination should be repeated 
by the local laboratory in 1 week to prove that there is a sequence of rising PSA. 
If there are 2 consecutive rising PSA test results before screening, but the local laboratory 
value obtained is less than the previous one (but still above the reference value), the 
participant is still eligible for the study.
If a local lab 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.
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 
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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. 
8.2.3
Tumor Tissue Collection
Baseline tumor tissue for biomarker analysis must be sent to the testing laboratory and 
analyzed for adequacy prior to enrollment. (Details pertaining to tumor tissue submission can 
be found in the Procedures Manual.)
8.2.4
PROs and Quality of Life Assessments
As of Amendment 06: PROs and Quality of Life assessments will be discontinued. The 
subsections below are retained for reference. 
The EuroQoL EQ-5D-SL, FACT-P, and the BPI-SF and analgesic questionnaires should be 
administered per the SoA in Section 1.3. Both the EQ-5D-SL and the FACT-P will be 
administered at the site, while the BPI-SF and analgesic questionnaires will be completed by 
the participant at home. It is best practice and strongly recommended that electronic patient-
reported outcomes (ePROs) are administered to randomized participants prior to drug 
administration, AE evaluation, and disease status notification. If the participant does not 
complete the ePROs at a scheduled time point, the MISSMODE form must be completed to 
capture the reason the assessment was not performed. Site staff must not read, administer or 
complete the PRO questionnaires on behalf of the participant. If the participant is unable to 
read the questionnaire (eg, is blind or illiterate), that participant may still participate in the 
study, but is exempted from completing PRO questionnaires, including the Analgesic Log. 
Participants exempted in this regard should be flagged appropriately by the site staff.
8.2.4.1
EQ-5D-SL
The 5 health state dimensions in the EQ-5D-SL include the following: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 
5-point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ-5D-SL also 
includes a graded (0 to 100) vertical visual analog scale on which the participant rates his or 
her general state of health at the time of the assessment. 
8.2.4.2
Functional Assessment of Cancer Therapy-Prostate (FACT-P)
FACT-P was developed as a disease-specific adjunct to the FACT measurement system and 
consists of FACT-G (general) which contains a 27-item self-report questionnaire measuring 
general health-related quality of life in 4 domains (physical, social, emotional, and functional 
well-being) and 12 prostate cancer-specific items. FACT-P (version 4) is self–administered 
and requires approximately 8 to 10 minutes to complete.
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8.2.4.3
Brief Pain Inventory-Short Form (BPI-SF) and Analgesic Log
BPI-SF
The BPI-SF is provided on an ePRO device and will be completed by the participant daily for 
7 consecutive days at the time points specified in the SoA (Section 1.3). It does not have to 
be completed at the site.  
The BPI-SF has 15 items that are rate on a 0 to 10 numeric rating scale, with 0=No Pain and 
10=Worst Pain Imaginable. This instrument consists of 2 domains: pain severity and pain 
interference. The pain severity domain consists of 4 items (Items 3, 4, 5, and 6) which assess 
pain at its “worst,” “least,” “average,” and “now” (current pain) respectively on the 11-point 
scale. In this study, the “worst pain” (item 3) will be used as a single item in assessing pain 
progression. A composite pain severity score from all the 4 items will also be evaluated as 
“pain severity progression”. A ≥2 point change in the average pain severity or in “worst 
pain” item is considered clinically meaningful.
The pain interference domain score is a mean of 7 items: general activity (item #9A), mood 
(item #9B), walking ability (item #9C), normal work (item #9D), relations with other people 
(item #9E), sleep (item #9F), and enjoyment of life (item #9G), each scored on an 11-point 
scale from 0 (Does not interfere) to 10 (Completely interferes). Based on the BPI-SF scoring 
manual [Cleeland, C. S. 2009], the following items are not used in scoring pain severity or 
pain interference domains: items #1, #2, #7 and #8. Item #7 (a free text field) describing pain 
medication use is captured separately in more detail using the Analgesic Log.
Patient Analgesic Log
The analgesic log is a paper form that will be completed by the participant, daily for 7 
consecutive days per the SoA (Section 1.3). Participants will record all analgesic medication 
dosages and dosage times. All medications captured in ePRO database will be reconciled 
periodically with the concomitant medications data to address any discrepancies. The 
Analgesic Log is study specific (not generic).
8.3
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
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.
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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 with the participant in a sitting, semi-recumbent, or supine 
position after 5 minutes of rest and will include weight, temperature, systolic and diastolic 
blood pressure, heart rate, 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.

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).
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
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 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 at screening (within 7 days of 
randomization) and prior to dosing during the treatment period, 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.
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.
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before intervention allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.

All AEs from the time of intervention allocation/randomization through 30 days 
following cessation of study intervention must be reported by the investigator.

All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 days following cessation of study intervention or 30 days following cessation 
of study intervention if the participant initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator.

All pregnancies and exposure during breastfeeding, from the time of intervention
allocation/randomization through 120 days following cessation of study intervention, or 
30 days following cessation of study intervention if the participant initiates new 
anticancer therapy must be reported by the investigator.

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 8.
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Table 8
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential drug-
induced liver 
injury (DILI)
- require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
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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.
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
All reported pregnancies of participants’ female partner 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: 
1. An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
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.
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8.6
Pharmacokinetics
Not applicable.
8.7
Pharmacodynamics
Not applicable.
8.8
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA

Leftover tumor 

Leftover RNA

Leftover plasma and serum from biomarker analyses

Leftover plasma or derivative for ctDNA
8.9
Planned Genetic Analysis Sample Collection
Samples should be collected for planned analysis of associations between genetic variants in 
germline/tumor DNA and drug response. If a documented law or regulation prohibits (or 
local IRB/Independent Ethics Committee [IEC] does not approve) sample collection for these 
purposes, then such samples should not be collected at the corresponding sites. Leftover 
DNA extracted from planned genetic analysis samples will be stored for future biomedical 
research only if participant signs the Future Biomedical Research consent.
8.10
Biomarkers
As of Amendment 06: Biomarker sample collections will be discontinued. The section 
below is retained for reference.
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA (Section 1.3):

Newly obtained tumor tissue

Blood for Genetic Analysis

Blood for RNA analyses

Blood for Serum and Plasma biomarker analyses
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
Blood for ctDNA
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the Procedures Manual.
8.11
Medical Resource Utilization and Health Economics
Health Economics and Medical Resource Utilization are not evaluated in this study.
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
Written consent must be obtained prior to 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 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 28 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.

Imaging for screening assessments is to be performed within 28 days prior to 
randomization.

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.

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 is met. Participants who are rescreened will 
retain their original screening number.
8.12.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
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8.12.3
Discontinued Participants Continuing to be Monitored in the Study
The Discontinuation Visit should occur at the time study treatment is discontinued. If the
Discontinuation Visit occurs 30 after the last dose of study treatment, 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. Prior to discontinuing participants from 
therapy, submit the Treatment Termination & Disease Assessment Termination Form.
8.12.4
Post-treatment Visits
8.12.4.1
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 comes first.
Participants who are eligible for retreatment with pembrolizumab may have up to 2 safety 
follow-up visits, 1 after the Initial Treatment Period and 1 after the Second Course 
Treatment.
8.12.4.2
Follow-up Visits
As of Amendment 06: Efficacy Follow-up will be discontinued. The section below is 
retained for reference.
Participants who discontinue study intervention for a reason other than BICR-verified PD 
will move into the Follow-up Phase. Follow-up visits will be scheduled occur 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 confirmed disease 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 anti-
cancer 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 the Follow-up Phase to the Second Course Phase 
when they experience disease progression. Details are provided in the SoA (Section 1.3) for 
retreatment with pembrolizumab.
8.12.4.3
Survival Follow-up
As of Amendment 06: Survival Follow-up visits will be discontinued. Those participants 
remaining on study at the time of Amendment 06, should continue to be monitored in 
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the study through the AE reporting period (Section 8.4). The section below is retained for 
reference.
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-up Phase and should be contacted approximately every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the 
study, whichever occurs first.  
8.12.5
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival 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 for their survival status (excluding 
participants that have a previously recorded death event in the collection tool).
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after the
study has begun, but prior to any unblinding/final database lock, changes are made to primary 
and/or key secondary hypotheses, or the statistical methods related to those hypotheses, then 
the protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory 
or other non-confirmatory analyses made after the protocol has been finalized, but prior to 
unblinding/final database lock, will be documented in a sSAP and referenced in the Clinical 
Study Report for the study. Post hoc exploratory analyses will be clearly identified in the 
Clinical Study Report.  Other planned analyses (ie, those specific to the analysis of PK data, 
patient-reported outcomes, and future biomedical research) are beyond the scope of this 
document or will be documented in separate analysis plans.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.  
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Study Design Overview
A Phase 3, Randomized, Double-blind Treatment Study of Pembrolizumab 
(MK-3475) Plus Docetaxel versus Placebo Plus Docetaxel in Participants 
with Chemotherapy-naïve Metastatic Castration-Resistant Prostate Cancer 
(mCRPC) who have Progressed on Next Generation Hormonal Therapy
Treatment Assignment
Approximately 1000 eligible participants will be randomized in a 1:1 ratio 
to one of the following 2 treatment arms:
• Arm 1: pembrolizumab plus docetaxel plus prednisone/prednisolone
• Arm 2: placebo plus docetaxel plus prednisone/prednisolone
Randomization stratification factors are:
• Prior NHA treatment: abiraterone (Yes vs. No)
• Metastases: bone only versus liver versus other
Analysis Populations
Efficacy: Intent to Treat (ITT)
Safety: All Participant 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 anti-cancer therapy or death 
(TFST)
Statistical Methods for Key 
Efficacy Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab plus 
docetaxel plus prednisone/prednisolone with placebo plus docetaxel plus 
prednisone/prednisolone arm with respect to OS, TFST, and rPFS 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% 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 
and Nurminen method.
Interim Analyses
Two interim analyses (IAs) will be performed in this study. Results will be 
reviewed by an external data monitoring committee. These interim analyses 
are summarized below. Details are provided in Section 9.7.
Interim Analysis 1: 
◦
Timing: To be performed when at least 468 rPFS events and 
approximately 302 OS events (target number of OS events) are 
observed (approximately 18 months after the first participant is 
randomized).
◦
Testing: final analysis for rPFS, final analysis for TFST, and interim 
analysis for OS
Interim Analysis 2: 
◦
Timing: To be performed when approximately 439 OS events 
(target number of OS events) are observed (approximately 23 
months after the first participant is randomized).  
◦
Testing: interim analysis for OS
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Multiplicity
The Type-I error rate over the multiple endpoints tested, as well as for the 
multiple analyses planned, will be strongly controlled at 2.5% (one-sided) 
by sequential interim monitoring and the methods of Maurer and Bretz
[Maurer, W. and Bretz, F. 2013]. A total of 2.0% Type I error rate is 
initially allocated to test OS superiority between 2 arms and a total of 0.5% 
Type I error rate is initially allocated to test rPFS superiority between 2
arms.
Sample Size and Power 
The planned sample size is approximately 1000 participants. For rPFS, the 
trial has approximately 93% power to demonstrate that pembrolizumab plus 
docetaxel plus prednisone/prednisolone is superior to placebo plus 
docetaxel plus prednisone/prednisolone (HR: 0.70) at an overall 1-sided 0. 
5% alpha-level. For OS, the trial has about 90% power to demonstrate that 
pembrolizumab plus docetaxel plus prednisone/prednisolone is superior to 
placebo plus docetaxel plus prednisone/prednisolone (HR: 0.75) at an initial 
overall 1-sided 2.0% alpha-level.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
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(s) for study intervention assignment for this protocol, and the randomization will be 
implemented in an interactive response technology by a study vendor. 
Extension Portion in China:
For all participants in China, including participants randomized in the global portion and the
extension portion, participant level treatment randomization information will be blinded to 
the statistician(s)/programmer(s) responsible for the analysis of the Extension Portion in 
China until the extension portion database lock is achieved. The extent to which individuals 
are unblinded to the results will be limited. Blinded and unblinded members will be clearly
documented.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and between-treatment 
differences are listed below.
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9.4.1
Efficacy Endpoints
9.4.1.1
Primary
Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause.  
Radiographic Progression-free survival (rPFS) – PCWG-Modified RECIST 1.1 by BICR 
is defined as the time from randomization to the first documented disease progression or 
death due to any cause, whichever occurs first.
9.4.1.2
Key Secondary
Time to initiation of the first subsequent anti-cancer therapy or death (TFST) is defined 
as the time from randomization to initiation of the first subsequent anti-cancer 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 who 
have a 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 (DOR) – PCWG-Modified RECIST 1.1 by BICR is defined as the
time from the earliest date of first documented evidence of confirmed CR or PR until the 
earliest date of disease progression or death from any cause, whichever occurs first.
Time to first symptomatic skeletal-related event (SSRE) is defined as the time from 
randomization to the first symptomatic skeletal-related event, which is defined as the 
1) first use of EBRT to prevent or relieve skeletal symptoms, 
2) the occurrence of new symptomatic pathologic bone fracture (vertebral or non-vertebral), 
3) occurrence of spinal cord compression
4) a 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.
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 
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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.
9.4.1.4
Exploratory 
Time to radiographic bone progression – PCWG-Modified RECIST 1.1 by BICR is 
defined as the time from randomization to radiographic bone progression.  
Additional details of the efficacy measurements are described in Section 4.2.1.1.
9.4.2
Safety Endpoints
Safety measurements are described in Section 4.2.1.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events, laboratory values and vital signs.
9.4.3
Patient-Reported Outcome Endpoints
9.4.3.1
Time to Pain Progression (TTPP)
Time to pain progression is defined as the time from randomization to pain progression based 
on the BPI SF Item 3 “worst pain in 24 hours” and opiate analgesic use (AQA score). Pain 
progression is defined as follows: 1) for participants who are asymptomatic at baseline, a ≥2 
point change from baseline in the average (4 to 7 days) BPI SF Item 3 score OR initiation of 
opioid use for pain; 2) for participants who are symptomatic at baseline (average BPI SF 
Item 3 score >0 and/or currently taking opioids), a ≥2 point change from baseline in the 
average BPI SF Item 3 score and an average worst pain score ≥4, and no decrease in average 
opioid use (≥1-point decrease in AQA score from a starting value of 2 or higher) OR any 
increase in opioid use (eg, 1 point change in AQA score) at 2 consecutive follow-up visits. 
Any participant who has more than 2 consecutive visits that are not evaluable for pain 
progression will be censored at the last evaluable assessment.
Details of exploratory PRO endpoints will be included in the sSAP.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The ITT population will serve as the primary population for the analysis of efficacy data in 
this study. All randomized participants will be included in this population. Participants will 
be included in the treatment group to which they are randomized for the analysis of efficacy 
data using the ITT population.
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Extension Portion in China:
After enrollment of the global portion is closed, the study will continue to randomize
participants in China until the sample size for participants in China reaches approximately
150. The participants in China who are randomized in the extension portion will not be
included in the primary efficacy analysis population for the global portion. The China ITT
population, including all participants in China randomized in the global portion and the
extension portion, will be analyzed separately.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received at least one dose of study 
intervention. Participants will be included in the treatment group corresponding to the study 
intervention they actually received for the analysis of safety data using the APaT population. 
This will be the treatment group to which they are randomized except for participants who 
take incorrect study intervention for the entire treatment period; such participants will be 
included in the treatment group corresponding to the study intervention actually received.
At least 1 laboratory, vital sign, or ECG measurement obtained subsequent to at least 1 dose 
of study intervention is required for inclusion in the analysis of the respective safety 
parameter. To assess change from baseline, a baseline measurement is also required.
Extension Portion in China:
The participants in China randomized and treated in the extension portion after completion of
the global enrollment will not be included in the primary safety analysis population for the
global portion. The China APaT population, including all participants in China randomized 
in the global portion and the extension portion who received at least 1 dose of study 
treatment, will be analyzed separately.
9.5.3
PRO Analysis Population
The PRO analyses are based on the PRO full analysis set population, defined as participants 
who have at least 1 PRO assessment available and have received at least 1 dose of study 
intervention.
9.6
Statistical Methods
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 
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combining of strata will be specified in the sSAP prior to database lock based on a blinded 
review of response counts by stratum.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and key secondary 
objectives. Methods related to other objectives will be described in the sSAP.
9.6.1.1
Overall Survival
The non-parametric 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 HR). The HR and its 95% CI from the stratified Cox model with a single 
treatment covariate will be reported. The stratification factors used for randomization 
(Section 6.3.2) will be applied to both the stratified log-rank test and the stratified Cox 
model. 
Participants without documented death at the time of analysis will be censored at the date of 
last known contact. Restricted Mean Survival Time method proposed by Uno et al. [Uno, H., 
et al 2014] may be conducted for OS to account for the possible non-proportional hazards 
effect.
9.6.1.2
Radiographic Progression-free Survival (rPFS)
The non-parametric 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, HR) between the treatment arms. 
The HR 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.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. The true date of disease progression will be approximated by the date of the 
first assessment at which PD is objectively documented per PCWG-Modified RECIST 1.1 by 
BICR. Death is always considered as a confirmed PD event. Participants who do not 
experience a rPFS event will be censored at the last disease assessment. Sensitivity analyses 
will be performed for comparison of rPFS based on investigator's assessment. 
In order to evaluate the robustness of the rPFS endpoint, 1 primary and 2 sensitivity analyses 
with a different set of censoring rules will be performed. For the primary analysis, if the 
events (PD or death) are immediately after more than 1 missed disease assessment, the data 
are censored at the last disease assessment prior to missing visits. Also, data after new anti-
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cancer therapy are censored at the last disease assessment prior to the initiation of new anti-
cancer therapy. The first sensitivity analysis follows the intention-to-treat principle. That is, 
PDs/deaths are counted as events regardless of missed study visits or initiation of new anti-
cancer therapy. The second sensitivity analysis considers discontinuation of treatment or 
initiation of an anti-cancer treatment subsequent to discontinuation of study-specified 
treatments due to reasons other than complete response, whichever occurs later, to be a PD 
event for participants without documented PD or death. If a participant meets multiple 
criteria for censoring, the censoring criterion that occurs earliest will be applied. The 
censoring rules for primary and sensitivity analyses are summarized in Table 9.
Table 9
Censoring Rules for Primary and Sensitivity Analyses of rPFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death 
documented after ≤1 
missed disease 
assessment, and before 
new anti-cancer 
therapy, if any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
Death or progression 
immediately after ≥2 
consecutive missed 
disease assessments, or 
after new anti-cancer 
therapy
Censored at last disease 
assessment prior to 
the earlier date of ≥2 
consecutive missed disease 
assessment and new anti-
cancer therapy, if any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
No PD and no death; 
and new anticancer 
treatment is not initiated
Censored at last disease 
assessment 
Censored at last 
disease assessment 
Progressed at treatment 
discontinuation due to 
reasons other than 
complete response; 
otherwise censored at last 
disease assessment if still 
on study treatment or 
completed study 
treatment.
No PD and no death; 
new anticancer 
treatment is initiated
Censored at last disease 
assessment before new 
anticancer treatment 
Censored at last 
disease assessment
Progressed at date of new 
anticancer treatment
In case the proportional hazards assumption is not valid, supportive analyses using Restricted 
Mean Survival Time method may be conducted for rPFS to account for the possible non-
proportional hazards effect.
Further details of sensitivity analyses will be described in sSAP as needed.
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9.6.1.3
TFST
The non-parametric 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, HR) between the treatment arms. 
The HR 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 sSAP.
9.6.1.4
Analysis Strategy for Key Efficacy Endpoints
Table 10 summarizes the primary analysis approach for key efficacy endpoints.
Table 10
Efficacy Analysis Methods for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method †
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 9
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 
anti-cancer therapy
Abbreviations: BICR=blinded independent central review; ITT=Intent to treat; OS=Overall survival; PCWG=Prostate 
Cancer Working Group; rPFS= radiographic progression-free survival; TFST=Time to initiation of the first subsequent 
anti-cancer therapy or death.   
† 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.
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The strategy to address multiplicity issues with regard to multiple efficacy endpoints, and 
interim analyses is described in Section 9.7 - Interim Analyses and in Section 9.8 -
Multiplicity.
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. 
The analysis of safety results will follow a tiered approach (Table 11). 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 pre-specified 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. Similarly, the combination
of pembrolizumab and docetaxel has not been associated with any new safety signals. 
Finally, there are no known AEs associated with participants with prostate for which 
determination of a p value is expected to impact the safety assessment. Therefore, there are 
no Tier 1 events for this protocol.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 10% 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 10% 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 10% 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 adverse events and safety parameters that 
meet predefined limits of change.
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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, a 
serious AE, 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 (Table 11).
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 11
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
Any Drug-Related AE
X
X
Any Drug-Related and Serious AE
X
X
Any Drug-Related and Grade 3-5 AE
X
X
Discontinuation due to AE
X
X
Dose modification due to AE
X
X
Death
X
X
Specific AEs, SOCs, or PDLCs‡ (incidence ≥10% of 
participants in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs† (incidence <10% of 
participants in all of the treatment groups)
X
Change from baseline results (laboratory test toxicity 
grade, vital signs, ECGs)
X
† Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints.
‡ Indicates broad AE category of the number of participants reporting any adverse event
Abbreviations: AE = adverse event; CI = confidence interval; ECG=electrocardiogram; PDLC=Pre-Defined 
Limit of Change; SOC=System Organ Class; X = results will be provided.
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9.6.3
Analysis Methods for PRO Endpoints
For time to pain progression, the Kaplan Meier method will be used to estimate the survival 
curves for TTPP, separately, in each treatment arm. In addition, corresponding survival 
curves will be estimated by treatment arm. Stratified Cox proportional hazards models with 
Efron's method of tie handling will be used to assess the magnitude of the treatment 
difference. Stratification factors used for randomization will be used in the stratified Cox 
proportional hazards models. The HR, 95% CI, and nominal p value will be reported.
Details of additional PRO analyses will be included in the sSAP.
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 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
Blinding to treatment assignment will be maintained at all investigational sites. The results of 
interim analyses will not be shared with the investigators prior to the completion of the study. 
Participant-level unblinding will be restricted to an external unblinded statistician and 
scientific programmer performing the interim analysis, who will have no other 
responsibilities associated with the study.
An eDMC will serve as the primary reviewer of the results of the interim analysis (analyses)
of the study and will make recommendations for discontinuation of the study or protocol 
modifications to an executive oversight committee (EOC) of the Sponsor. If the eDMC
recommends modifications to the design of the protocol or discontinuation of the study, this 
executive oversight committee (and potentially other limited Sponsor personnel) may be 
unblinded to results at the participant level in order to act on these recommendations. The 
extent to which individuals are unblinded with respect to results of interim analyses will be 
documented by the external unblinded statistician. Additional logistical details will be 
provided in the DMC Charter. 
Treatment-level results from the interim analysis will be provided to the eDMC by the 
external unblinded statistician. Prior to final study unblinding, the external unblinded 
statistician will not be involved in any discussions regarding modifications to the protocol, 
statistical methods, identification of protocol deviations, or data validation efforts after the 
interim analyses.
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9.7.1
Efficacy Interim Analyses
Two interim analyses and a final analysis are planned for this study. There is no plan to stop 
the study before superiority hypotheses for OS have been adequately evaluated. However, 
earlier positive findings may form the basis for earlier regulatory submission based on the 
recommendation of the eDMC. Final analysis is to be performed approximately 28 months 
after the first participant is randomized. 
The analyses planned, endpoints evaluated, and drivers of the timing are summarized in 
Table 12. Type I error control for the efficacy analyses as well as efficacy bounds are 
described in Section 9.8 – Multiplicity.
Table 12
Summary of Interim and Final Analyses
Analysis
Endpoint(s)
Criteria for Conduct of Analysis
Estimated Time 
after First 
Participant 
Randomized
Primary 
Purpose of 
Analysis
IA 1: Final 
rPFS and TFST 
Analyses, 
interim OS 
analysis
rPFS, TFST, 
OS
Enrollment is complete
At least 468 rPFS events to achieve 
90% power
Approximate 302 OS events (target 
number of OS events)
~18 months
rPFS FA, 
TFST FA
OS IA
IA 2: Interim 
OS analysis
  OS
Approximately 439 OS events (target 
number of OS events)
~23 months
OS IA
FA: Final OS 
analysis
OS
Approximately 549 OS events (target 
number of OS events) and at least 12 
months after the last participant is 
randomized
~28 months
OS FA
Abbreviations: rPFS = FA = final analysis; IA = interim analysis; OS = overall survival; radiographic progression-free 
survival; TFST = Time to initiation of the first subsequent anti-cancer therapy or death.
9.7.2
Safety Interim Analyses
The eDMC will conduct regular safety interim analyses. The timing of these safety interim 
analyses will be specified in the eDMC charter.
9.8
Multiplicity
The study uses the graphical method of Maurer and Bretz [Maurer, W. and Bretz, F. 2013] to 
strongly control multiplicity for multiple hypotheses as well as interim analyses. Figure 3
shows the initial 1-sided α allocation for each hypothesis in the ellipse representing the 
hypothesis. The weights for reallocation from each hypothesis to the others are represented in 
the boxes on the lines connecting hypotheses.
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Figure 3
Multiplicity Graph for One-sided Alpha Reallocation Strategy
9.8.1
Radiographic Progression-free Survival (rPFS)
This study initially allocates one-sided α = 0.005 for superiority test of rPFS between 
2 treatment groups. If OS null hypothesis has been rejected, then rPFS hypothesis will be 
tested at a Type I error level of =0.025.
Table 13 shows the boundary properties for the rPFS. Note that the final row indicates the 
total power to reject the null hypothesis for rPFS superiority. In addition, if the testing of 
rPFS is not positive at IA1 but the testing of OS is positive at IA2 or FA, then re-testing of 
rPFS at IA1 will be conducted.
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Table 13
Efficacy Boundaries and Properties for rPFS
Analysis 
Value 
α =0.005
α =0.025
IA 1: 
N: 1000
Events: 468
Month: 16
Z 
2.5760
1.9600
p (1-sided) §
0.0050
0.0250
HR at bound
0.7881
0.8343
P(Cross) if HR=1†
0.0050
0.0250
P(Cross) if HR=0.70#
0.9000
0.9710
IA 1: 
N: 1000
Events: 516
Month: 18
Z 
2.5760
1.9600
p (1-sided)§
0.0050
0.0250
HR at bound
0.7970
0.8420
P(Cross) if HR=1†
0.0050
0.0250
P(Cross) if HR=0.70#
0.9300
0.9820
§p (1-sided) is the nominal alpha for testing.
HR at bound is the approximate HR required to reach an efficacy bound
†P(Cross if HR=1) is the cumulative probability of crossing a bound  under the null hypothesis
#P(Cross if HR=0.70) is the cumulative probability of crossing a bound  under the alternative hypothesis
9.8.2
Overall Survival
This study initially allocates one-sided α = 0.020 for superiority test of OS between 
2 treatment groups. If both the rPFS and TFST null hypotheses have been rejected, then OS 
hypothesis will be tested at a Type I error level of =0.025.
Table 14 shows the boundary properties for the interim analyses and the final OS analysis 
which were derived using a Lan-DeMets O'Brien-Fleming approximation spending function. 
Note that the final row indicates the total power to reject the null hypothesis for OS
superiority. If the actual number of OS events differs from that specified in the table, the 
bounds will be adjusted using the Lan-DeMets O’Brien-Fleming alpha-spending function 
accordingly. Cumulative alpha spent in the interim analysis will not exceed the pre-specified 
level based on the projected number of events as shown in below table. That is, if the number 
of observed events exceeds the pre-specified number of events in the interim analysis, then 
the pre-specified cumulative alpha spent in the interim analysis based on the projected 
number of events will be used. Otherwise, cumulative alpha based on the observed number of 
events will be used. The boundary thresholds at final analysis will be updated using the 
actual observed number of events at previous interim analyses and final analysis.
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Table 14
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis 
Value 
α =0.020
α =0.025
IA 1: 55%*
N: 1000
Events: 302
Month: 18
Z
2.9276
2.8059
p (1-sided) §
0.0017
0.0025
HR at bound
0.7138
0.7239
P(Cross) if HR=1†
0.0017
0.0025
P(Cross) if HR=0.75#
0.3338
0.3791
IA 2: 80%*
N: 1000
Events: 439
Month: 23
Z
2.3758
2.2759
p (1-sided) §
0.0088
0.0114
HR at bound
0.7970
0.8047
P(Cross) if HR=1†
0.0093
0.0122
P(Cross) if HR=0.75#
0.7412
0.7728
Final 
N: 1000
Events: 549
Month: 28 
Z
2.1172
2.0291
p (1-sided) §
0.0171
0.0212
HR at bound
0.8346
0.8409
P(Cross) if HR=1†
0.0200
0.0250
P(Cross) if HR=0.75#
0.9000
0.9150
*Percentage of expected number of events at final analysis
§p (1-sided) is the nominal alpha for testing.
HR at bound is the approximate HR required to reach an efficacy bound
†P(Cross if HR=1) is the cumulative probability of crossing a bound  under the null hypothesis
#P(Cross if HR=0.75) is the cumulative probability of crossing a bound  under the alternative hypothesis
9.8.3
TFST
The testing of the key secondary TFST hypothesis will be conducted at the time of the first 
IA. The TFST hypothesis is initially allocated a Type I error =0% and thus, cannot be tested 
unless rPFS null hypothesis has been rejected. If rPFS null hypothesis has been rejected and 
OS null hypothesis has not been rejected, then TFST hypothesis will be tested at a Type I 
error of 0.5%. If both rPFS and OS null hypotheses have been rejected, then TFST 
hypothesis will be tested at a Type I error level of =2.5%.
Table 15 shows the boundary properties for the TFST. Note that the final row indicates the 
total power to reject the null hypothesis for TFST superiority. In addition, if the testing of 
TFST is not positive at IA1 but if the retesting of rPFS at IA1 is positive, then re-testing of 
TFST at IA1 will be conducted.
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Table 15
Efficacy Boundaries and Properties for TFST
Analysis
Value
α =0.005
α =0.025
IA 1: 
N: 1000
Events: 516
Month: 18
Z 
2.5760
1.9600
p (1-sided)§
0.0050
0.0250
HR at bound
0.7970
0.8420
P(Cross) if HR=1†
0.0050
0.0250
P(Cross) if HR=0.70#
0.9300
0.9820
§p (1-sided) is the nominal alpha for testing.
HR at bound is the approximate HR required to reach an efficacy bound
†P(Cross if HR=1) is the cumulative probability of crossing a bound under the null hypothesis
#P(Cross if HR=0.70) is the cumulative probability of crossing a bound under the alternative hypothesis
9.8.4
Safety Analyses
The eDMC has responsibility for assessment of overall risk:benefit. When prompted by
safety concerns, the eDMC can request corresponding efficacy data. External DMC review of
efficacy data to assess the overall risk:benefit to study participants will not require a
multiplicity adjustment typically associated with a planned efficacy interim analysis.
However, to account for any multiplicity concerns raised by the eDMC review of unplanned
efficacy data prompted by safety concerns, a sensitivity analysis for efficacy endpoints
adopting a conservative multiplicity adjustment will be prespecified in the sSAP. This
analysis will be performed if requested by the eDMC.
9.9
Sample Size and Power Calculations
The sample size is estimated based on the primary endpoint OS. 
A total of approximately 1000 participants will be randomized in a 1:1 ratio to 
pembrolizumab plus docetaxel plus prednisone/prednisolone group and placebo plus 
docetaxel plus prednisone/prednisolone group (approximately 500 participants per group).
The final analysis of OS is event-driven and will be conducted after approximately 549
events (target number of OS events) have been observed between 2 treatment groups and at 
least 12 months after the last participant is randomized unless OS is proven at an earlier 
interim analysis. It is expected to occur around 28 months after the first participant is 
randomized (depending on enrollment rate and event accumulation rate). 
With 549 OS events, the study has approximately 90% (91.5%) power to demonstrate that 
males treated with pembrolizumab + docetaxel have a longer median OS than males treated 
with docetaxel at a one-sided significance level of 0.020 (0.025) if the underlying constant 
HR between treatment groups is 0.75. Sample size and power calculations are based on the 
following assumptions: 1) a HR of 0.75 where the OS follows an exponential distribution 
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with 18 months in the pembrolizumab + docetaxel group and a median of 13.5 months in the 
docetaxel group; 2) interim analyses for efficacy evaluation as outlined in Table 14; 3) an 
enrollment rate of 80 participants per month with a 6-month ramp up time; and 4) an
approximately monthly drop-out rate of 0.2%.
The final analysis of rPFS will be conducted when 1) enrollment is complete; 2) At least 468
rPFS events are observed; 3) approximately 302 OS events (target number of OS events) are 
observed. It is expected to occur around 18 months after the first participant is randomized 
(depending on enrollment rate and event accumulation rate) with about 516 rPFS events. 
With 516 rPFS events, the study has approximately 93% (98.2%) power to demonstrate that 
males treated with pembrolizumab + docetaxel have a longer median rPFS than males treated 
with docetaxel at a one-sided significance level of 0.005 (0.025) if the underlying constant 
HR between treatment groups is 0.70. These calculations are based on the following 
assumptions: 1) a HR of 0.70 where rPFS follows an exponential distribution with a median 
of 7 months in the pembrolizumab + docetaxel group and a median of 5 months in the control 
arm; 2) interim analyses for efficacy evaluation as outlined in Table 14; 3) an enrollment rate 
of 80 participants per month with a 6-month ramp up time; and 4) an approximately monthly 
drop-out rate of 5%.
The final analysis of TFST will be conducted at IA1 and approximately 516 TFST are 
expected. With 516 TFST events, the study has approximately 90% power to demonstrate 
males treated with pembrolizumab + docetaxel has a longer median TFST than males treated 
with docetaxel at a one-sided significance level of 0.005 if the underlying constant HR is 
0.70. These calculations are based on the following assumptions: 1) a HR of 0.70 where 
TFST follows an exponential distribution with a median of 7 months in the pembrolizumab + 
docetaxel group and a median of 5 months in the docetaxel group; 2) IAs for efficacy 
evaluation as outlined in Section 9.7; 3) an enrollment rate of 80 participants per month with 
a 6-month ramp up time; and 4) an approximately monthly drop-out rate of 5%.
The sample size and power calculations for rPFS, TFST, and OS were performed in the 
software R (package “gsDesign”) and EAST 6.4.
Extension Portion in China:
To evaluate the consistency of efficacy and safety in the population in China compared with
the global population, after completion of global portion enrollment, participants in China 
will continue to be randomized in a 1:1 ratio into the pembrolizumab plus docetaxel plus 
prednisone/prednisolone arm and the placebo plus docetaxel plus prednisone/prednisolone
arm until the planned sample size of approximately 150 participants in China is reached. 
Participants in China randomized after completion of enrollment in the global portion will 
not be included in the analysis of the global portion.
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9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoints will be estimated and plotted within each category of the following classification 
variables:

Age group: <65 years vs ≥65 years

Race: white vs non-white

ECOG status: 0 vs 1

Prior NHA treatment: abiraterone (Yes vs. No)

Metastases: bone only vs liver vs other
In addition, a Forest plot will be produced, which provides the estimated point estimates and 
CIs for the treatment effect across the categories of subgroups listed above.
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 pembrolizumab and docetaxel will be summarized as duration of 
treatment in cycles. Dose interruption for each drug and dose reduction or dose increase for 
docetaxel will be summarized. Summary statistics will be provided on Extent of 
Exposure for 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 Executive Oversight Committee (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.
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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 
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.
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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
(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.
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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 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 16 will be performed by the central laboratory during the 
initial treatment and during the Second Course phase.

Results of pre-dose 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 tests 
result 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, and CTC results are not reported back to sites to prevent early withdrawal 
of participants from study intervention.
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Table 16
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 
ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ 
Serum Glutamic-
Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose 
(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/INR and PTT/aPTT
NOTES: 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
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
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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.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. 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.
c.
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.
d. 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, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.

Is a new cancer (that is not a condition of the study)

Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
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
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.

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.
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•
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.
-
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.)
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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.

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.
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
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.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
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
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)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 120 days after the last dose of pembrolizumab/placebo or 
180 days after the last dose of docetaxel, whichever is longer:

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) 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 who is not currently pregnant. Note: 
Men 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.

Male participants must also agree to use male condom when engaging in any activity that 
allows for passage of ejaculate to another person of any sex.
10.5.3
Pregnancy Testing
Not applicable.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 will be used 
in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways with which drugs/vaccines may interact
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations with 
the greatest need. All specimens will be used by the Sponsor or those working for or with the 
Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Laboratory Testing
HIV Status
While the protocol does not require specific testing for HIV at Screening, it does require 
testing if required by the local health authority. Sites should check with their local health 
authority to inquire if country-specific guidance regarding mandatory HIV testing at 
Screening is required. This can also be performed per the discretion of the investigator, if 
desired.
Hepatitis B/C Status
While the protocol does not require specific testing for hepatitis B/C at Screening, it does 
require testing if required by the local health authority. Sites should check with their local 
health authority to inquire if country-specific guidance regarding mandatory hepatitis B/C 
testing at Screening is required. This can also be performed per the discretion of the 
investigator, if desired.
10.7.2
Country-specific Testing Requirements
10.7.2.1
Germany
HIV testing and hepatitis B/C screening are required evaluations for study entry and need to 
be performed in order to evaluate eligibility. This testing can be performed at any time during 
the Screening Period.
10.7.2.2
China
Biomarker sample collection and analysis including tumor tissue collection, blood for genetic 
analyses, blood for RNA analyses, blood for serum/plasma analyses, and blood for ctDNA 
analysis, for participants enrolled in China will be dependent on approval by the Human 
Genetic Resources Administration of China (HGRAC).
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10.7.3
Japan
Section 6.1 Study Interventions Administered
Table 2
Study Interventions
Arm 
Name
Arm 
Type
Intervention Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Arm 1
Experi-
mental
pembrolizumab
Biological/
Vaccine
Solution for 
Infusion
25 mg/mL
200 mg
IV 
Infusion
Day 1 of each 
21-day cycle
Experimental
IMP
Central or 
Local
Arm 1, 
Arm 2
Other
docetaxel
Drug
Solution for 
Infusion
10 or 20 
mg/mLa
75 
mg/m2
IV 
Infusion
Day 1 of each 
21-day cycle
Standard of 
Care
NIMP
Central or 
local
Arm 1, 
Arm 2
Other
prednisone (or 
equivalent dose of 
prednisoloneb)
Drug
Tablet
5 mg
5 mg
Oral
BID
Standard of 
Care
NIMP
Local
Arm 1, 
Arm 2
Other
Recommended 
dexamethasone (or 
equivalent dose of 
another corticosteroidc) 
premedication. Local 
SOC premedication 
allowed
Drug
Tablet
8 mg
8 mg
Oral 
12, 3, and 1 hour 
prior to 
docetaxel 
administration
Standard of 
Care
NIMP
Local
Arm 2
Placebo
Normal saline or 
dextrosed
Other
Solution for 
Infusion
N/A
N/A
IV 
infusion
Day 1 of each 
21-day cycle
Placebo
IMP
Locale
BID= twice daily; IMP = Investigational Medicinal Product; IV = intravenous; NIMP = Non-Investigational Medicinal Product; SOC = Standard of care.
Note: Definition IMP and NIMP is based on guidance issued by the European Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In 
these circumstances, local legislation is followed.
a When locally supplied, docetaxel unit vial strength is based on region.
b Prednisone is the preferred steroid to be used in the study. Prednisolone should only be used when prednisone is unavailable.
c Dexamethasone, or the equivalent dose of another steroid, is the preferred corticosteroid to be used in the study. Local standard of care premedication prior to docetaxel infusion 
is allowed 
d Normal saline is the primary diluent/placebo for pembrolizumab; use dextrose only if saline is not available.
eIntravenous solution, not provided by the Sponsor, as placebo for infusion in this protocol is not categorized as “product(s) used in the clinical trial” in Japan.
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10.8
Appendix 8:  Description of the Prostate Cancer Working Group (PCWG) 
Process for Assessment of Bone Lesions
The rules for evaluation of response and progression based on bone lesions were created by 
the Prostate Cancer Working Group, and published as part of both PCWG2 and PCWG3 
[Scher, H. I., et al 2016]. All bone lesions are evaluated according to these rules, including 
assessment at screening/baseline and evaluation of response.
10.8.1
Imaging Methods
The PCWG rules were designed based on 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 non-malignant 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 non-target lesions only, and the 
number of bone lesions should be noted.
10.8.3
Assessment of Bone Response at Subsequent Imaging Time Points
At all follow-up time points, bone disease will be classified as PD (progressive disease), PDu
(progressive disease unconfirmed), Non-PD (no progressive disease), NED (no evidence of 
disease), or NE (non-evaluable). 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 Sponsor.
Non-PD
Non progressive disease: 
At least 1 bone lesion present, but not enough to trigger PD
NE
Non-evaluable: 
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
Non-progression (Non-PD)
At least 1 bone lesion is present on the scan at this visit, but the conditions for progression 
have not been met, because there are not at least 2 new lesions present.
10.8.4.3
Unconfirmed Progressive Disease (PD-U)
At least 2 new bone lesions are present, but an additional scan is required for confirmation. 
This response category is meant as a placeholder that reflects temporary uncertainty and is 
updated to PD or non-PD once a subsequent bone scan is available.
10.8.4.4
Progressive Disease (PD)
At least 2 new bone lesions are present, which have been confirmed to not represent flare or 
any other confounder (see below), and which are persistent for at least 6 weeks. The new 
bone lesions do not all have to appear at the same time. Thus, if 1 new lesion appears at visit 
N, and another new lesion at visit N+1, visit N+1 is considered to represent progressive 
disease.
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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 PD-U, 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 2 additional new bone lesions (in addition to the new 
lesions seen on the prior scan), the initial progression is considered confirmed, and the bone 
scan response updated to PD. Because this requires at least 2 new lesions, followed by 
another 2 new lesions, this is known as the “2+2 rule”.
If the next bone scan outside the flare window does not show at least 2 additional new bone 
lesions, the lesions seen on the prior scan within the flare window are considered to be pre-
existing lesions that became more visible because of the tumor flare phenomenon.

The bone response at the prior visit is updated to non-PD

The bone lesions seen within the flare window are ignored for the purposes of counting 
new lesions at later time points, since they were not new. This may be 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 non-malignant in nature. No re-baselining of lesions will occur in 
this scenario.
10.8.5
Superscan
A “superscan” occurs when there is diffuse skeletal involvement by tumor, such that 
individual bone lesions are not distinguishable. The bone scan may initially appear normal, 
because the 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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10.8.6
Management Following Confirmed PD
If repeat imaging does confirm PD, participants will be discontinued from study treatment.
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 
treatment may be considered following consultation with the Sponsor. In this case, if study 
treatment is continued, tumor imaging should continue.
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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:  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 housework, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% 
of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed 
or chair
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of 
the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55.  http://ecog-acrin.org/resources/ecog-
performance-status
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ABI
abiraterone acetate
ADL
activities of daily living  
ADT
androgen-deprivation therapy
AE
adverse event 
APaT
All Participants as Treated
aPTT
activated partial thromboplastin time
AQA
analgesic quantification algorithm
BDS
blood drug screen
BICR
blinded independent central review
BID
twice daily
BPI-SF
Brief Pain Inventory – Short Form
C1D1
Cycle 1 Day 1
CAC
Clinical Adjudication Committee
CD8
cluster of differentiation 8
CD28
cluster of differentiation 28
CI
confidence interval
CNS
central nervous system 
CR
complete response
CRF
Case Report Form 
CRU
clinical research unit
CSPC
castration-sensitive prostate cancer
C-SSRS
Columbia-Suicide Severity Rating Scale 
CT
computed tomography
CTC
circulating tumor cell
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor deoxyribonucleic acid
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTx
chemotherapy
DC
discontinuation
D1
Day 1
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
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
EDC
electronic data collection 
EMA
European Medicines Agency
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Abbreviation
Expanded Term
ENZA
enzalutamide
EOC
Executive Oversight Committee 
ePRO
Electronic patient-reported outcome
EQ-5D-5L
EuroQol 5- dimension, 5-level health state utility index
FACT-P, FACT-G
Functional Assessment of Cancer Therapy – Prostate; -General
FAPS16
FACT Advanced Prostate Symptom Index 6
FBR
Future Biomedical Research
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle stimulating hormone 
FT3
free triiodothyronine
FT4
free thyroxine
GCP
Good Clinical Practice 
GCSF
granulocyte colony-stimulating factor
HGRAC
Human Genetic Resources Administration of China
HR
hazard ratio
HRQoL
health-related quality of life
IA
interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference for Harmonisation
IEC
Independent Ethics Committee
Ig
immunoglobulin
IND
Investigational New Drug 
INR
international normalized ratio
irAE
Immune-related Adverse Event
iRECIST
Modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics
IRB
Institutional Review Board 
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
mCRPC
metastatic castration-resistant prostate cancer
mHSPC
metastatic hormone-sensitive prostate cancer
MRI
magnetic resonance imaging
MTD
maximum tolerated dose 
NA
not applicable
NCCN
National Comprehensive Cancer Network
NSCLC
non-small cell lung cancer
NDA
New Drug Application 
NHA
next generation hormonal agent
NOAEL
no observed adverse effect level 
ORR
objective response rate
OS
overall survival
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Abbreviation
Expanded Term
PCWG
Prostate Cancer Working Group
PD
progressive disease
PD-1
programmed cell death 1 receptor
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PK
pharmacokinetic
PO
by mouth
PR
partial response
PRO
patient-reported outcome
PSA
prostate-specific antigen
PT
prothrombin time
PTT
partial thromboplastin time
Q3W
every 3 weeks
QP2
department of quantitative pharmacology and pharmacometrics
RECIST 1.1
Response Evaluation Criteria in Solid Tumors 1.1 
RNA
ribonucleic acid
rPFS
radiographic progression-free survival
SAE
serious adverse event 
SCF
Sponsor consultation form
SD
stable disease
SOC
standard of care
SoA
schedule of activities
sSAP
supplemental statistical analysis plan
SSRE
symptomatic skeletal-related event
SUSAR
suspected unexpected serious adverse reaction
T3
total triiodothyronine
TEA
Treatment Eligibility Assessment
TFST
the first subsequent anti-cancer therapy
TSH
thyroid-stimulating hormone
TTBP
time-to bone progression
TTPP
time to pain progression
WOCBP
woman/women of childbearing potential 
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11
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