Conditions: Prostate Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1030
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety and effectiveness of nivolumab with docetaxel in men with advanced castration resistant prostate cancer who have progressed after second-generation hormonal manipulation.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Nivolumab intervention 2: Prednisone intervention 3: Docetaxel intervention 4: Placebo
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days intervention 3: Specified dose on specified days intervention 4: Specified dose on specified days

Protocol document:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Phase 3, Randomized, Double-Blind Study of Nivolumab or Placebo in Combination With Docetaxel, 
in Men With Metastatic Castration-resistant Prostate Cancer 
NCT Number: NCT04100018 
Document Date (Date in which document was last revised): September 22, 2023 


Page:
1
Protocol Number:
CA2097DX
IND Number:
135,845
EUDRACT Number:
2019-002030-36
Date:
25-Jul-2019
Revised Date:
22-Sep-2023
CLINICAL PROTOCOL CA2097DX
A Phase 3 Randomized, Double-Blind Study of Nivolumab or Placebo in Combination with 
Docetaxel, in Men with Metastatic Castration-resistant Prostate Cancer (CheckMate 7DX: 
CHECKpoint pathway and nivoluMAB clinical Trial Evaluation 7DX)
Short Title:
A Study of Nivolumab or Placebo in Combination with Docetaxel in Men with Metastatic 
Castration-resistant Prostate Cancer
Protocol Amendment 04
Bristol-Myers Squibb Company
Bristol-Myers Squibb Company
3401 Princeton Pike 
Lawrenceville, NJ 08648 USA
Route de Perreux 1
Boudry, Switzerland
Telephone (office): 
Telephone (mobile): 
Email: 
Email: 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Company
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
1-2-1 Otematchi, Chiyoda-ku
Tokyo 100-0004, Japan
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Protocol Amendment No.: 04
Date: 22-Sep-2023
2
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
© 2023 Bristol-Myers Squibb Company
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Protocol Amendment No.: 04
Date: 22-Sep-2023
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 04
22-Sep-2023
The purpose of this protocol amendment is to formally incorporate 
guidance provided in the “Dear Investigator” letters from 27-Jul-2023 and 
10-Aug-2023, and further clarify participant management and study 
procedures as the study proceeds toward termination due to one of the 
primary efficacy endpoints not meeting the success criterion and the 
implausibility of success of the other primary endpoint. The decision to 
terminate the study was not based on any safety concerns or issues. On 
26-Jul-2023 the study independent Data Monitoring Committee convened. 
Based on a clinical data cutoff of 01-Jun-2023, the addition of nivolumab 
to docetaxel plus prednisone did not result in a statistically significant 
improvement in radiographic progression-free survival (rPFS) (hazard 
ratio 0.96; 99% confidence interval [CI] 0.77, 1.19) at final analysis and 
overall survival (OS) at the first interim analysis (hazard ratio 1.09; 
99.41% CI 0.84, 1.43) compared to placebo added to docetaxel plus 
prednisone. A Sponsor Executive Oversight Committee (EOC) requested 
to be unblinded to the study results. Further evaluation of OS results 
showed no plausible scenario of reaching OS statistical significance at 
subsequent, planned statistical analyses, including the second interim 
analysis and final analysis. Given the lack of clinical benefit from 
nivolumab added to docetaxel plus prednisone for the dual primary 
efficacy endpoints of rPFS and OS, the Sponsor EOC decided to terminate 
the study. Unblinding of study treatment assignment to full study teams 
and investigators occurred on 03-Aug-2023.
Dear Investigator 
Letter
10-Aug-2023
Study termination details and topline data.
Dear Investigator 
Letter
27-Jul-2023
Notification of study termination.
Protocol 
Amendment 03
13-Sep-2022
Major changes:

Changes to the statistical analysis section, in which the population for 
radiographic progression-free survival (rPFS) analysis has been 
changed from the first 544 participants randomized to all randomized 
and the number of events from 433 to 530 rPFS events.

Changes to clarify censoring rules for rPFS.

Increased overall survival (OS) events from 615 to 690.

Clarification of pharmacokinetic sampling at follow-up visits.

Clarification of SARS-CoV-2 serology at follow-up as optional.
Administrative 
Letter 05
20-Oct-2021
Study Personnel Updated
Administrative 
Letter 03
25-Mar-2021
Study Personnel updated
Protocol 
Amendment 02
17-Mar-2021
Major changes:
 

Removed exclusion criterion for prior radium-223 exposure.
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Protocol Amendment No.: 04
Date: 22-Sep-2023
4
Document
Date of Issue
Summary of Change

Aligned dose modification criteria and immuno-oncology (IO) agent 
management algorithms with National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 5. 

Added serologic testing for severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) status.

Incorporated additional updates in order to improve alignment 
between protocol sections and clarify remote monitoring, prior 
malignancy window, thyroid testing, and male contraception 
requirements. 
Revised Protocol 
01
06-May-2020
Major changes: 
 
 
Clarified the inclusion criteria for current evidence of metastatic 
disease and prior treatment with NAT.
Lesions that do not qualify as visceral disease clarified.
Frequency of tumor assessment revised to enhance precision of the 
radiographic progression-free survival (rPFS) endpoint, and the 
criteria for stable disease (SD) was revised based on frequency of 
tumor assessments.
The statistical section now specifies sample size for rPFS and corrects 
the number of events needed for analysis of rPFS.
Revisions 
 have been 
incorporated (France, Germany, Italy, Singapore, Czech Republic, 
US, N. Zealand).
Changes of Administrative Letters 02 and 01 now incorporated.
Administrative 
Letter 02
10-Dec-2019
Additional corrections were identified and corrected in administrative 
letter.
Administrative 
Letter 01
09-Nov-2019
Discrepancies in the protocol were corrected and clarifications to 
language were made to ensure proper alignment throughout all sections 
of the protocol. 
Original Protocol
25-Jul-2019
Not applicable.
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 04:
The purpose of this protocol amendment is to formally incorporate guidance provided in the “Dear 
Investigator” letters from 27-Jul-2023 and 10-Aug-2023, and further clarify participant 
management and study procedures as the study proceeds toward termination due to one of the 
primary efficacy endpoints not meeting the success criterion and the implausibility of success of
the other primary endpoint. The decision to terminate the study was not based on any safety 
concerns or issues. On 26-Jul-2023 the study independent Data Monitoring Committee convened. 
Based on a clinical data cutoff of 01-Jun-2023, the addition of nivolumab to docetaxel plus 
prednisone did not result in a statistically significant improvement in radiographic progression-
free survival (rPFS) (hazard ratio 0.96; 99% confidence interval [CI] 0.77, 1.19) at final analysis 
and overall survival (OS) at the first interim analysis (hazard ratio 1.09; 99.41% CI 0.84, 1.43) 
compared to placebo added to docetaxel plus prednisone. A Sponsor Executive Oversight 
Committee (EOC) requested to be unblinded to the study results. Further evaluation of OS results 
showed no plausible scenario of reaching OS statistical significance at subsequent, planned 
statistical analyses, including the second interim analysis and final analysis. Given the lack of 
clinical benefit from nivolumab added to docetaxel plus prednisone for the dual primary efficacy 
endpoints of rPFS and OS, the Sponsor EOC decided to terminate the study. Unblinding of study 
treatment assignment to full study teams and investigators occurred on 03-Aug-2023.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Title Page
Removed Clinical Scientist information.
Updated per Sponsor 
requirements.
Protocol Summary
Section 3.1: Overall 
Rationale for Protocol 
Amendment 04 and Study 
Termination
Added the following text:
“Per Protocol Amendment 04, the independent Data 
Monitoring Committee (DMC) convened on 26-Jul-2023 
for a prespecified review of all available study data based 
on a clinical data cutoff of 01-Jun-2023. After reviewing 
the final analysis of the primary efficacy endpoint of 
radiographic progression-free survival (rPFS) per Blinded 
Independent Central Review (BICR) and the first interim 
analysis of the primary efficacy endpoint of overall 
survival (OS), the DMC agreed that the study did not meet 
the prespecified boundaries for declaring statistical 
significance for either endpoint. Although the number of 
events for OS at the second interim analysis and final 
analysis of OS had not been attained, based on the first 
interim analysis results for OS, the DMC determined that 
the prespecified boundaries for declaring significance were 
unlikely to be met. No new safety concerns were 
identified. A Sponsor Executive Oversight Committee 
(EOC) requested to be unblinded to the study results and 
decided to terminate the study. Full study teams and 
investigators were unblinded to study treatment 
assignment on 03-Aug-2023.
Provide an 
explanation for study 
termination.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Protocol Amendment 04 reflects changes in study conduct. 
For participants who are deemed appropriate to continue 
on nivolumab or docetaxel therapy through  the 
CA2097DX study, re-consent will be required.”
Protocol Summary
Section 5.1: Overall 
Design
Figure 5.1-1: Study Design 
Schematic
Section 5.1.2: Treatment 
Phase
Section 7: Treatment
Table 7-1: Study 
Treatments for CA2097DX
Section 7.1: Treatments 
Administered
Table 7.1-1: Selection and 
Timing of Dose
Section 7.1.1: Nivolumab 
or Placebo Combined with 
Docetaxel
Section 7.1.2: Nivolumab 
or Placebo Dosing
Section 7.4: Dosage
Modification
Table 7.4-1: Adverse 
Event Criteria to Delay, 
Resume, or Discontinue 
Nivolumab/Placebo
Clarified that participants assigned to Arm B will no 
longer receive placebo.
Investigators and 
study teams have 
been unblinded to 
study treatment 
assignment as a result 
of study termination
due to lack of 
efficacy benefit for 
nivolumab added to 
docetaxel plus 
prednisone compared 
to placebo added to 
docetaxel plus 
prednisone.
Protocol Summary
Section 5.1.2: Treatment 
Phase
Clarified that decisions on docetaxel treatment will be 
based on the clinical judgment of the treating physician 
and on shared decision making with the participant. 
Participants who are not able to access local therapy may 
continue on study-provided docetaxel until local access is 
available. In the event that the investigator deems a 
participant is deriving clinical benefit from nivolumab 
therapy and, together with the counseled participant, 
wishes to continue treatment, this may be possible 
following discussion with the Medical Monitor to ensure a 
clinical rationale exists that justifies continuation of 
nivolumab treatment. 
Ensure that 
participants currently 
receiving study-
provided docetaxel 
do not undergo 
treatment 
interruptions.
Protocol Summary
Section 5.2: Data 
Monitoring Committee and 
Other External Committees
Noted that the Data Monitoring Committee is no longer 
applicable.
No longer relevant 
due to study 
termination.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Protocol Summary
Table 10.1-1: Sample Size 
Determination; footnote b
Section 10.3.7.1: Interim 
Analysis for OS
Clarified that the second interim analysis for OS and final 
analysis for OS will not be performed, and the first interim 
analysis will be considered as the final analysis. At the 
time of study closeout, an updated descriptive OS analysis 
will be provided to report all death events.
Study termination.
Table 2-2: On-Study 
Treatment and Follow-up 
Procedural Outline for 
Arms A and B 
(CA2097DX)
Section 5.1.2: Treatment 
Phase
Section 5.1.3: Follow-up 
Phase
Section 7.7.5: Re-
assessment Following 
Initial Assessment of 
Progression
Section 9: Study 
Assessments and 
Procedures
Section 9.1.1: Imaging 
Assessment for the Study
Section 9.1.1.2: Imaging 
and Clinical Assessment
Section 9.1.2: BICR 
Confirmation of 
Progression 
Section 9.1.3: Patient-
Reported Outcomes
Section 9.1.4: The Brief 
Pain Inventory - Short 
Form
Section 9.1.5: The 
Functional Assessment of 
Cancer Therapy - Prostate 
Cancer (FACT-P)
Section 9.1.6: The 5-Level 
EQ-5D
Section 9.2: Adverse 
Events
Section 9.2.5: Pregnancy
Section 9.2.6: Laboratory 
Test Result Abnormalities.
Provided clarification for on-treatment and follow-up 
assessments:

Safety
Only applicable to:
Participants continuing study-provided 
nivolumab.
Participants up to 100 days after their last
nivolumab infusion.
All other participants will be discontinued from 
the study and switched to local standard of care 
for metastatic castration-resistant prostate cancer, 
outside of the study.

Adverse events (AEs)
After completion of the 100-day safety follow-up 
requirement and resolution or stabilization of AEs, 
nivolumab-treated participants will be discontinued 
from the study. 

Subsequent cancer therapy is no longer applicable.

PSA is no longer applicable.

Laboratory tests
Will include local safety laboratory tests only and 
will exclude tests such as PSA, 
 and 
pharmacokinetics. In addition, the requirement 
for local safety laboratory tests will ONLY be 
applicable to:
Participants continuing study-provided 
nivolumab. 
Participants up to 100 days from their last 
nivolumab infusion.
All other participants will be discontinued from 
the study and switched to local standard of care 
for metastatic castration-resistant prostate cancer, 
outside of the study.

Efficacy is no longer applicable.

Radiographic tumor assessments per BICR and 
following Prostate Cancer Working Group 3 criteria 
are no longer applicable.
All participants receiving study treatment will 
have radiographic tumor assessments based on 
the clinical judgment of the treating investigator 
and following local imaging tumor assessment 
Study termination.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Section 9.2.7: Potential 
Drug Induced Liver Injury 
(DILI)
Section 9.2.8: Other Safety 
Considerations
Section 9.4: SafetySection 
9.4.4: Clinical Safety 
Laboratory Assessments
Section 9.5: 
PharmacokineticsSection 
 
 
 
 
 
 
 
 
Section 9.8.2: Additional 
Research Collection
Section 9.8.3: 
Immunogenicity 
Assessments
 
Section 9.9: Healthcare 
Resource Utilization and 
Health Economics 
Appendix 5: Prostate 
Cancer Working Group 3 
(PCWG3) Guidelines (with 
Modified Response 
Evaluation Criteria in Solid 
Tumors (RECIST) Criteria 
for Soft Tissue Lesion 
Assessment)
guidelines for metastatic castration-resistant 
prostate cancer. . 

Submission of tumor imaging assessments for central 
review will no longer apply.  

Collection of survival data is no longer applicable. 
 
 

Health outcomes are no longer applicable.

The Brief Pain Inventory - Short Form (BPI-SF) is no 
longer applicable.

The Functional Assessment of Cancer Therapy -
Prostate Cancer (FACT-P) is no longer applicable.

The 5-Level EQ-5D is no longer applicable.

Pregnancy is only applicable to female partners of 
male participants continuing study-provided 
nivolumab, and female partners of male participants 
up to 100 days after the last infusion of nivolumab. 

Potential DILI assessments are only applicable to 
participants continuing study-provided nivolumab, 
and participants up to 100 days after the last infusion 
of nivolumab.
 

Additional research collection is no longer applicable

Healthcare resource utilization and health economics 
are no longer applicable.

Laboratory test result abnormalities are only 
applicable to participants continuing study-provided 
nivolumab, and participants up to 100 days after the 
last infusion of nivolumab.

Overdose is only applicable to participants continuing 
study-provided nivolumab, and participants up to 100 
days after the last infusion of nivolumab.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Table 2-2: On-Study 
Treatment and Follow-up 
Procedural Outline for 
Arms A and B 
(CA2097DX)
Section 5.1.3: Follow-up 
Phase
Clarified that the follow-up phase only applies to 
participants up to 100 days after the last infusion of 
nivolumab. After 100 days of follow-up have been 
completed,  the nivolumab-treated participants will be 
permanently discontinued from the study. 
Clarified participants 
applicable to the 
follow-up phase 
following study 
termination.
Section 5.1: Study Design
Added the following text:
Per Protocol Amendment 04, full study teams and 
investigators were unblinded to study treatment 
assignment on 10-Aug-2023 and 11-Aug-2023, 
respectively, due to lack of rPFS and OS benefit from 
nivolumab added to docetaxel plus prednisone compared 
to placebo added to docetaxel plus prednisone.
Clarified unblinding 
of study teams and 
investigators due to 
study termination.
Section 5.4: End of Study 
Definition
Clarified that the first interim analysis will be considered 
the final analysis. and that the study will end when the last 
participant receiving study-provided nivolumab completes 
100 days of safety follow-up after their last nivolumab 
infusion. 
Updated the total duration of the study from the date of 
first participant treated to the final analysis of both 
primary endpoints to approximately 31 months.
Deleted the definition of the start of the study, and that the 
survival analysis may be conducted for up to 5 years after 
treatment initiation.
Clarified the end of 
study definition 
following study 
termination.
Section 7.2: Blinding
Noted that blinding is no longer applicable.
Investigators and full 
study teams have 
been unblinded to 
treatment assignment 
due to study 
termination.
Section 7.7.4: Treatment 
Beyond Progression
Noted as no longer applicable.
Study termination.
Section 7.8: Treatment 
After the End the of Study
Clarified that BMS recommends discontinuation of 
nivolumab in all participants receiving this study 
treatment. In the event that the investigator deems a 
participant is deriving clinical benefit from nivolumab 
therapy and, together with the counseled participant, 
wishes to continue nivolumab, this may be allowed 
following discussion with the Medical Monitor.
Deleted the following text:
At the conclusion of the study, participants who continue 
to demonstrate clinical benefit will be eligible to receive 
BMS supplied study treatment for the maximum treatment 
duration specified in protocol Section 5.
Clarify the potential 
continued use of 
nivolumab following 
study termination.
Protocol Amendment No.: 04
Date: 22-Sep-2023
9
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Section 8.1.2: Post Study 
Treatment - Study Follow-
up
Section 8.2: 
Discontinuation from the 
Study
Clarified that only participants who received study-
provided nivolumab and are up to 100 days after the last 
nivolumab infusion will have post-study treatment safety 
follow-up. After completion of the 100-day safety follow-
up requirement and resolution or stabilization of AEs, 
nivolumab-treated participants will be discontinued from 
the study. All other participants currently on safety or 
survival follow-up with resolution or stabilization of AEs 
will be discontinued from the study. 
Clarified the post-
study follow-up and 
discontinuation from 
the study as a result 
of study termination.
Section 8.3: Lost to 
Follow-up
Noted that this section is no longer applicable.
Study termination.
Section 10.3: Statistical 
Analyses
Section 10.3.1: Efficacy 
Analyses
Section 10.3.3: 
Pharmacokinetic Analyses
Section 10.3.4: 
Immunogenicity Analyses
Section 10.3.5: Outcomes 
Research Analyses
Noted as not applicable.
Study termination.
All
Minor formatting and edits.
These changes are 
minor and, therefore, 
have not been 
summarized.
Protocol Amendment No.: 04
Date: 22-Sep-2023
10
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Clinical Protocol
BMS-936558
CA2097DX
nivolumab
Protocol Amendment No.: 04
Date: 22-Sep-2023
11
6.0
Approved
930142083
5.0
v
Approved
1.0
v


7UHDWPHQWV$GPLQLVWHUHG
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0HWKRGRI7UHDWPHQW$VVLJQPHQW
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Clinical Protocol
BMS-936558
CA2097DX
nivolumab
Protocol Amendment No.: 04
Date: 22-Sep-2023
12
6.0
Approved
930142083
5.0
v
Approved
1.0
v


)ROORZXSRI$(VDQG6$(V
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Clinical Protocol
BMS-936558
CA2097DX
nivolumab
Protocol Amendment No.: 04
Date: 22-Sep-2023
13
6.0
Approved
930142083
5.0
v
Approved
1.0
v


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Clinical Protocol
BMS-936558
CA2097DX
nivolumab
Protocol Amendment No.: 04
Date: 22-Sep-2023
14
6.0
Approved
930142083
5.0
v
Approved
1.0
v


Clinical Protocol
CA2097DX
BMS-936558
nivolumab
1
SYNOPSIS
Protocol Title: A Phase 3 Randomized, Double-Blind Study of Nivolumab or Placebo in 
Combination with Docetaxel, in Men with Metastatic Castration-resistant Prostate Cancer 
(CheckMate 7DX: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 7DX)
Short Title:
A Study of Nivolumab or Placebo in Combination with Docetaxel in Men with Metastatic 
Castration-resistant Prostate Cancer (mCRPC)
Study Phase: 3
Rationale:
Prostate cancer tumor cells have been shown to have low tumor expression of programmed death 
ligand-1 (PD-L1), suggesting that treatments directed at the programmed death-1 (PD1)/PD-L1 
interaction are unlikely to be successful as monotherapies.1 This was confirmed by early clinical 
trials, where unselected men with mCRPC did not respond to PD-1 blockade as monotherapy.2
However, several studies show that PD-L1 expression can be up-regulated in response to 
inflammatory cytokines, a phenomenon which has been termed “adaptive immune resistance.3,4,5
This suggests that if prostate cancer treatments (ie, chemotherapy, androgen ablation) can increase 
PD-L1 expression on tumor cells by attracting infiltrating immune cells and triggering an adaptive 
immune response, there is a rationale for combining such therapies with immune check-point 
inhibitors.6,7,8,9 The rationale for combining chemotherapy and immunotherapy is based on the 
findings that cytotoxic treatments such as chemotherapy may modulate tumor/immune-system 
interactions in favor of the immune system. Chemotherapy can result in tumor cell death as part 
of its intended therapeutic effect with a resultant increase in tumor antigen delivery to antigen-
presenting cells.
These findings have led to the development of clinical trials evaluating the combination of 
docetaxel and PD1/PDL1 inhibitors which has shown promising activity in patients with mCRPC 
previously treated with second-generation hormonal therapies as described in Rationale for 
Population Section of the Protocol.
NCCN guidelines recommend to use docetaxel (category 1) as the preferred 1st line chemotherapy 
in men with symptomatic mCRPC and in patients with signs of rapid progression or visceral 
metastases despite lack of symptoms. In addition, docetaxel has a category 1 recommendation in 
second-line after prior enzalutamide/abiraterone.
The current study aims to demonstrate that treatment with docetaxel in combination with 
nivolumab will be efficacious in participants with mCRPC. Additional objectives of the study 
include characterization of safety and tolerability, as well as pharmacokinetics, 
 
 and changes in patient reported outcomes for quality of life assessments.
Per Protocol Amendment 04, the independent Data Monitoring Committee (DMC) convened 
on 26-Jul-2023 for a prespecified review of all available study data based on a clinical data 
Protocol Amendment No.: 04
Date: 22-Sep-2023
15
6.0
Approved
930142083
5.0
v
Approved
1.0
v


Clinical Protocol
CA2097DX
BMS-936558
nivolumab
cutoff of 01-Jun-2023. After reviewing the final analysis of the primary efficacy endpoint of 
radiographic progression-free survival (rPFS) per Blinded Independent Central Review 
(BICR) and the first interim analysis of the primary efficacy endpoint of overall survival 
(OS), the DMC agreed that the study did not meet the prespecified boundaries for declaring 
statistical significance for either endpoint. Although the number of events for OS at the 
second interim analysis and final analysis of OS had not been attained, based on the first 
interim analysis results for OS, the DMC determined that the prespecified boundaries for 
declaring significance were unlikely to be met. No new safety concerns were identified. A
Sponsor Executive Oversight Committee (EOC) requested to be unblinded to the study 
results and decided to terminate the study. Full study teams and investigators were 
unblinded to study treatment assignment on 03-Aug-2023.
Protocol Amendment 04 reflects changes in study conduct. For participants who are deemed 
appropriate to continue on nivolumab or docetaxel therapy through the CA2097DX study, 
re-consent will be required.
Study Population:
Male participants ages 18 or local age of majority.
Key Inclusion Criteria:

Histologic confirmation of adenocarcinoma of the prostate. Diagnosis must be stated in a 
pathology report and confirmed by the investigator

Current evidence of metastatic disease documented by either bone lesions on radionuclide bone 
scan and/or soft tissue lesions on CT/MRI. Metastases may be in regional lymph nodes (N1 
per AJCC staging criteria, 8th edition) and/or distant metastases (M1 per AJCC staging criteria, 
8th edition). 

Participants whose disease spread is limited to regional pelvic lymph nodes (N1) measuring 
at least 2 cm in short axis will be considered eligible.

Ongoing ADT with a gonadotropin-releasing hormone (GnRH) analogue or bilateral 
orchiectomy (ie, surgical or medical castration) confirmed by testosterone level ≤ 1.73 nmol/L 
(50 ng/dL) at the screening visit. Castrate levels of testosterone must be maintained by surgical 
or medical means (luteinizing hormone-releasing hormone [LHRH]/ GnRH analogues) 
throughout the conduct of the study. For participants who have not had an orchiectomy, this 
therapy must have been initiated at least 4 weeks prior to first dose of study treatment and 
treatment must be continued throughout the study

Documented prostate cancer progression as per PCWG3 criteria within 6 months prior to 
screening with at least one of the following:

PSA progression defined by a minimum of 2 rising PSA levels with an interval of 1 week 
between each determination. The PSA value at the screening visit should be 2 μg/L (2 
ng/mL).
Note: Participants who received an anti-androgen must have PSA progression after 
withdrawal (4 weeks since last flutamide administration or 6 weeks since last 
bicalutamide or nilutamide administration)
Protocol Amendment No.: 04
Date: 22-Sep-2023
16
6.0
Approved
930142083
5.0
v
Approved
1.0
v


Clinical Protocol
CA2097DX
BMS-936558
nivolumab

Radiographic disease progression in soft tissue based on RECIST 1.1 criteria. 

Radiographic disease progression in bone defined as appearance of 2 or more new bone 
lesions on bone scan

Participants who are chemotherapy- naïve for mCRPC and have received at least 1 but no more 
than 2 second-generation hormonal manipulations (also known as novel antiandrogen therapies 
[NAT] eg, including but not limited to abiraterone acetate, enzalutamide, apalutamide, and
darolutamide) in the recurrent non metastatic setting and/or the metastatic setting*(no more 
than 1 prior Novel Androgen Therapy (NAT) is allowed in the mCRPC setting), or have 
become intolerant of the drug. Patients must have progressed during or after NATs or have 
documented intolerance to the drug (ie, unacceptable toxicity in spite of comprehensive 
supportive therapy).
* If the same NAT was given more than once in the context of a different disease setting or if 
intervening therapy was administered, then these NAT will be considered as separate NAT 
regimens.

Participants already receiving agents for the management of skeletal-related events (SREs) are 
allowed to continue with anti-bone resorptive therapy (including, but not limited to,
bisphosponate or receptor activator of nuclear factor kappa ligand inhibitor) if on stable dose 
for more than 28 days prior to start of study treatment.

Prior prostate cancer vaccine therapy (eg, sipuleucel-T), radium-223, second-generation 
hormonal manipulations (eg, abiraterone acetate, enzalutamide, apalutamide, and 
darolutamide), antiandrogens (eg, flutamide), ketoconazole, and diethylstilbestrol (DES) or 
other estrogens, are allowed if treatment was completed at least 28 days prior to start of study 
treatment. Note: bicalutamide or nilutamide must be discontinued at least 6 weeks prior to the 
start of study treatment.

Participants with a history of response to an antiandrogen or adrenal androgen-production 
inhibitor and with subsequent progression while receiving that antiandrogen should be 
assessed for antiandrogen withdrawal response for 4 weeks, and must demonstrate 
progression as described in Inclusion Criterion 2e in the protocol and have stopped 
receiving the antiandrogen prior to start of study treatment.

For participants who have never responded to antiandrogens, observation for antiandrogen 
withdrawal response is not necessary.
 
 
 
 
 
 
 
 
Protocol Amendment No.: 04
Date: 22-Sep-2023
17
6.0
Approved
930142083
5.0
v
Approved
1.0
v


Clinical Protocol
CA2097DX
BMS-936558
nivolumab
 
Key Exclusion Criteria:
Medical Conditions:

Participants with active brain metastases. Participants with brain metastases are eligible to 
enroll in this study if brain metastases have been treated and there is no magnetic resonance 
imaging (MRI except where contraindicated in which case CT scan is acceptable) evidence of 
progression for at least 4 weeks after treatment is complete and within 28 days prior to first 
dose of study drug administration. Such cases should be discussed with the BMS Medical 
Monitor or designee. Previously irradiated brain lesions are not considered measurable disease.

Participants must have recovered from the effects of major surgery requiring general anesthesia 
or significant traumatic injury at least 14 days before start of study treatment.

Prior radiation therapy within 2 weeks prior to start of study treatment. Patients should have 
recovered (ie, Grade 1 or at baseline) from radiation-related toxicities.

All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have 
resolved to Grade 1 or baseline before administration of study treatment. Participants with 
toxicities attributed to prior anti-cancer therapy that are not expected to resolve and result in 
long-lasting sequelae, such as peripheral neuropathy after platinum based therapy, are 
permitted to enroll. Participants who have Grade 2 peripheral neuropathy are excluded.

Participants with an active, known, or suspected autoimmune disease. Participants with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such 
as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected 
to recur in the absence of an external trigger are permitted to enroll.

Participants who have received a live / attenuated vaccine within 30 days of first dose in the 
study.

Dementia, altered mental status, or any psychiatric condition that would prohibit the 
understanding or rendering of informed consent or completing QoL questionnaire.

Known history of a positive test for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at all sites 
in Germany and where mandated locally. (see Appendix 9).

Participants with serious or uncontrolled medical disorders that, in the opinion of the
investigator, would impair the ability of the participant to receive protocol therapy or obscure 
the interpretation of AEs, such as a condition associated with frequent diarrhea.

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
history of congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. Additionally, in 
the case of prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 
acute symptoms must have resolved and based on investigator assessment in consultation with 
the Medical Monitor, there are no sequelae that would place the participant at a higher risk of 
receiving investigational treatment (see Section 6.4.1).
Protocol Amendment No.: 04
Date: 22-Sep-2023
18
6.0
Approved
930142083
5.0
v
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab

Participants with superscan on technecium-99m radionuclide bone scans are not eligible for 
the study. Superscan is defined as a bone scan which demonstrates markedly increased skeletal 
radioisotope uptake relative to soft tissue in association with absent or faint renal activity 
(absent kidney sign).

Concurrent malignancy (present during screening) requiring treatment or history of prior 
malignancy active within the previous 2 years prior to randomization (ie participants with a 
history of prior malignancy are eligible if treatment was completed at least 2 years before 
randomization and the participant has no evidence of disease). Participants with history of prior 
early stage basal/squamous cell skin cancer or non-invasive or in situ cancers that have 
undergone definitive treatment at any time are also eligible. 
Prior/Concomitant Therapy:

Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of start 
of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg 
daily prednisone equivalent, are permitted in the absence of active autoimmune disease.

Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.

Prior treatment with docetaxel or another chemotherapy agent for metastatic castration-
resistant prostate cancer. Prior docetaxel for metastatic castration-resistant prostate cancer is 
allowed if 12 months elapsed from last dose of docetaxel.

Treatment with complementary medications (eg, herbal supplements or traditional Chinese 
medicines) to treat the disease under study within 2 weeks prior to start of study treatment.
Such medications are permitted if they are used as supportive care (refer to Section 7.7.1 for 
other prohibited therapies).

Participants currently in other interventional trials, including those for coronavirus disease 
2019 (COVID-19), may not participate in BMS clinical trials until the protocol-specific 
washout period is achieved. If a study participant has received an investigational COVID-19 
vaccine or other investigational product designed to treat or prevent COVID-19 prior to 
screening, enrollment must be delayed until the biologic impact of the vaccine or 
investigational product is stabilized, as determined by discussion between the Investigator and 
the Medical Monitor.
Objectives and Endpoints:
Objective
Endpoint
Primary

To compare the rPFS (using PCWG3) of 
nivolumab in combination with docetaxel 
to placebo in combination with docetaxel, 
in men with metastatic castration-resistant 
prostate cancer (mCRPC).

rPFS for randomized participants is the time between 
randomization and the first date of documented progression 
or death due to any cause, whichever occurs first. The 
radiographic progression will be assessed by Blinded 
Independent Central Review (BICR) per PCWG3. The 
rPFS will be censored at the last tumor assessment up to the 
start of subsequent systemic cancer therapy.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Objective
Endpoint

To compare the OS of nivolumab in 
combination with docetaxel to placebo in 
combination with docetaxel in men with 
metastatic 
castration-resistant 
prostate 
cancer (mCRPC).

OS for all randomized participants is the time between 
randomization and the date of death from any cause. For 
participants who are alive, their survival time will be 
censored at the last date that they were known to be alive. 
OS will be censored for participants at the date of 
randomization if they had no follow-up. 
Secondary

To assess the antitumor activity of 
nivolumab in combination with docetaxel.

Objective Response Rate per PCWG3 (ORR-PCWG3) is 
the proportion of participants who have a confirmed 
complete or partial best overall response (BOR) per 
PCWG3 among randomized participants who have 
measurable disease at baseline. The BOR is defined as the 
best response designation, as determined by the BICR, 
recorded between the date of randomization and the date of 
objectively documented progression per PCWG3 or the date 
of subsequent systemic cancer therapy, whichever occurs 
first. For participants without documented progression or 
subsequent systemic cancer therapy, all available response 
assessments will contribute to the BOR assessment.

Time to Response per PCWG3 (TTR-PCWG3) is the time 
from randomization to the date of the first documented CR 
or PR per PCWG3, as determined by BICR. 

Duration of Response per PCWG3 (DOR-PCWG3) is the 
time between the date of first response (CR/PR per 
PCWG3) to the date of first documented radiographic 
progression per PCWG3, as determined by BICR, or death 
due to any cause. Participants who neither progress nor die 
will be censored at the last tumor assessment up to the start 
of subsequent systemic cancer therapy.

PSA Response Rate (PSA-RR) is the proportion of 
randomized participants with a 50% or greater decrease in 
PSA from baseline to the lowest post-baseline PSA result. 
A second consecutive value obtained 3 or more weeks later 
is required to confirm the PSA response. PSA response will 
be calculated for all participants with PSA values at baseline 
and at least one post-baseline assessment.

Time to PSA Progression (TTP-PSA) is the time between 
randomization to the date of PSA progression per PCWG3 
in randomized participants. For participants with an initial 
PSA decline from baseline, the date of PSA progression is 
the date that an increase of 25% or more and an absolute 
increase of 2 ng/mL or more from the nadir are documented 
and confirmed by a second consecutive PSA value at least 
3 weeks later. For participants with no PSA decline from 
baseline, the date of PSA progression is the date that an 
increase of 25% or more and an absolute increase of 2 
ng/mL or more from baseline are documented beyond Week 
13. TTP-PSA will be censored at the date of last PSA 
evaluation prior to the start of subsequent systemic cancer
therapy. The time will be censored at the date of 
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Objective
Endpoint
randomization for participants with no post-baseline PSA 
evaluation.

To characterize the safety and tolerability of 
nivolumab in combination with docetaxel.

Overall safety and tolerability will be measured by the 
incidence of AEs, SAEs, AEs leading to discontinuation, 
immune-mediated AEs, select AEs, deaths, and laboratory 
abnormalities and changes from baseline.

To evaluate the progression of pain during 
treatment.

Median time to pain progression as assessed by Brief Pain 
Inventory-Short Form (BPI-SF).
Exploratory

To investigate the time to initiation of 
subsequent systemic therapy (TT-SST).

TT-SST is the time from randomization to the start of 
subsequent systemic therapy, including hormonal therapy, 
chemotherapy, immunotherapy, or investigational therapy.

To investigate the time to first symptomatic 
skeletal event (TT-SSE).

TT-SSE is the time between randomization and the date of 
first symptomatic fracture, radiation or surgery to bone, or 
spinal cord compression.

To evaluate the change in pain intensity and 
health-related cancer related symptoms and 
quality of life.

Change in mean scores as assessed by BPI-SF

Median time to deterioration and change in mean scores as 
assessed by FACT-P total score and subscales.

To assess the participant’s quality of life 
and overall health status.

Change in scores in both the EQ-5D-5L utility index and 
visual analog scale.

To investigate the time to and duration of 
PSA response.

Time to PSA response (TTR-PSA) is defined for PSA
responders as the time from randomization to the date of the 
first PSA response. Duration of PSA response (DOR-PSA)
is defined for PSA responders as the time between the date 
of first response and the date of PSA progression. 
Participants who neither progress by PSA nor die will be 
censored on the date of last PSA evaluation.

To evaluate the pharmacokinetics
of 
nivolumab 
when 
administered 
in 
combination with docetaxel. To explore 
exposure response relationships between
select exposure measures, and safety, and 
efficacy endpoints, as appropriate.

Parameter estimates from Population PK analysis and 
exposure-response analysis, if data permit.

To characterize the immunogenicity of 
nivolumab 
when 
administered 
in 
combination with docetaxel.

Immunogenicity will be determined by measurement of 
anti-drug antibody (ADA) in serum and samples with 
positive ADA response may be analyzed for neutralizing 
ADA response to nivolumab.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Objective
Endpoint

To assess the impact of SARS-CoV-2 
serologic status on participants
with 
metastatic 
castration-resistant
prostate 
cancer who are receiving nivolumab plus 
docetaxel,
 
.

Exploratory measurements of SARS-CoV-2 serology (anti-
SARS-CoV-2 total or Immunoglobulin G [IgG]), from 
serum samples collected at baseline and during the study, 
and the potential association between these measurements 
and selected endpoints related to safety, efficacy,
 
. 
Overall Design:
CA2097DX is a Phase 3 randomized, double-blinded, multi-center clinical trial comparing 
nivolumab or placebo in combination with docetaxel, in men with metastatic castration-resistant 
prostate cancer.
Randomization will be stratified according to the following baseline factors:

1 prior Novel Antiandrogen Therapy (NAT) for mCRPC vs 1 prior NAT for non-metastatic 
castration-resistant prostate cancer (nmCRPC) or metastatic castration-sensitive prostate 
cancer (mCSPC) vs 2 prior NAT

Visceral disease (Y vs N)
Visceral disease status will be assessed by investigator based on the tumor assessment performed 
during screening. Visceral disease is defined as the presence of metastatic disease in the liver, lung, 
adrenal, peritoneum, brain or other internal organs. Bone, lymph node metastases and prostate 
lesion (or bladder/rectum if from direct invasion from prostate) are not considered visceral disease.
The study design schematic is presented in Figure 1-1.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Figure 1-1:
Study Design Schematic
Per Protocol Amendment 04, participants assigned to Arm B will no longer receive placebo. 
Per Protocol Amendment 04, decisions on docetaxel treatment will be based on the clinical 
judgment of the treating physician and on shared decision making with the participant. 
Participants who are not able to access local therapy may continue on study-provided 
docetaxel until local access is available. In the event that the investigator deems a participant 
is deriving clinical benefit from nivolumab therapy and, together with the counseled 
participant, wishes to continue treatment, this may be possible following discussion with the
Medical Monitor to ensure a clinical rationale exists that justifies continuation of nivolumab 
treatment.
Number of Participants: 
Assuming a 25% screen failure rate, it is estimated that approximately 1312 participants with 
mCRPC will be enrolled in order to randomize approximately 984 participants.
The sample size determination of this study is based on a comparison of the rPFS and OS 
distribution between participants randomized to nivolumab in combination with docetaxel and 
participants randomized to placebo in combination with docetaxel. 
These endpoints will be evaluated for treatment effect using the following testing strategy: 

The analysis for rPFS will occur after enrollment for the study has completed and  
approximately 530 rPFS events are observed in all randomized global subjects. The number of 
events was estimated assuming an exponential distribution of rPFS for the Docetaxel arm (Arm 
B) and a piecewise exponential distribution with a 2-months delayed treatment effect for the 
Nivolumab + Docetaxel arm (Arm A). This number of events provides 90% power to detect 
an average HR of 0.67 (Arm A vs Arm B in all randomized global participants) with a 2-sided 
alpha of 0.01. The average HR of 0.67 resulted from an assumed targeted hazard ratio of 1 for 
the initial 2 months from randomization and a targeted hazard ratio of 0.58 for the time beyond 
2 months from randomization.

The analysis for OS has two planned interim analyses and a final analysis. The first interim 
analysis will occur at the time of rPFS analysis, the second interim analysis is planned at 
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
approximately 80% of the total events, and the final analysis is planned at approximately 690 
events among all randomized global participants. The number of events was estimated 
assuming an exponential distribution of OS for the Docetaxel arm (Arm B) and a piecewise 
exponential distribution with a 3-month delayed treatment effect for the Nivolumab + 
Docetaxel arm (Arm A). This number of events provides 92% power to detect an average HR 
of 0.76 (Arm A vs Arm B in all randomized participants) with a 2-sided alpha of 0.04. The 
average HR of 0.76 resulted from an assumed targeted hazard ratio of 1 for the initial 3 months 
from randomization and a targeted hazard ratio of 0.72 for the time beyond 3 months from 
randomization. Per Protocol Amendment 04, given the decision to terminate the study 
early, the second interim analysis for OS and final analysis for OS will no longer be 
performed, and the first interim analysis will be considered as final. At the time of study 
closeout, an updated descriptive OS analysis will be provided to report all death events.

The stopping boundaries for OS at the interim and final analyses will be based on the actual 
number of events at the time of the analysis using Lan-DeMets alpha-spending function with 
O’Brien-Fleming boundaries, taking into account any alpha that was passed from the rPFS 
analysis (if applicable).

These primary endpoints will be tested separately and if significant, the alpha allocated to each 
endpoint will be recycled to the other endpoint. For example, if rPFS is significant at the 0.01 
level, then 0.01 will be transferred to the OS analysis for testing at 0.05 level.
Treatment Arms and Duration:
Per Protocol Amendment 04, full study teams and investigators were unblinded to study
treatment assignment on 03-AUG-2023 due to lack of rPFS and OS benefit from nivolumab 
added to docetaxel plus prednisone compared to placebo added to docetaxel plus prednisone. 
Participants in the placebo arm will discontinue placebo and may be able to continue
docetaxel for up to 10 cycles through the study if the participant is in the combination phase, 
and local access to docetaxel outside the study is not available. In addition, all participants 
should receive standard of care treatment for mCRPC per local guidelines.
Arm A:

Combination Phase (maximum 10 cycles, 1 cycle is 3 weeks):

Docetaxel 75 mg/m² IV Q3W + Prednisone 5 mg PO BID + Nivo 360 mg IV Q3W

Monotherapy Phase (1 cycle is 4 weeks):

Nivolumab 480 mg IV Q4W
Arm B:
Per Protocol Amendment 04, participants assigned to Arm B will no longer receive placebo. 

Combination Phase (maximum 10 cycles, 1 cycle is 3 weeks)

Docetaxel 75 mg/m² IV Q3W + Prednisone 5 mg PO BID + Placebo IV Q3W

Monotherapy Phase (1 cycle is 4 weeks):

Placebo IV Q4W
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Study Treatment:
Selection and Timing of Dose
Study Treatment
Unit dose strength(s)/
Dosage level(s)
Dosage formulation
Frequency of Administration
Route of 
Administration
Arm A
Nivolumaba
360mg
Every 3 weeks
Intravenous
Prednisone
5mg
Twice daily (BID)
Oral
Docetaxel
75mg/m2
Every 3 weeks through cycle 10
Intravenous
Arm B
Prednisone
5mg
Twice daily (BID)
Oral
Docetaxel
75mg/m2
Every 3 weeks through cycle 10
Intravenous
Not applicable per Protocol 
Amendment 04:
Placebo
Not applicable
Every 3 weeks
Intravenous
a Nivolumab or placebo will be administered as combination therapy with docetaxel and prednisone for maximum 
10 cycles, followed by nivolumab monotherapy (480 mg Q4W) or placebo until progression, unacceptable toxicity 
or withdrawal of Consent.
Data Monitoring Committee: 
Not applicable per Protocol Amendment 04.
To provide independent oversight of safety, efficacy, and study conduct, an independent Data 
Monitoring Committee (DMC) will be established to provide oversight on safety and efficacy 
considerations. Details of the DMC responsibilities and procedures will be specified in the DMC 
charter. 
A Study Steering Committee (consisting of selected participating investigators) will meet regularly 
to advise BMS regarding study-related issues, including safety concerns.
When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation.
References:
1 Martin AM, Nirschl TR, Nirschl CJ, et al. Paucity of PD-L1 expression in prostate cancer: Innate 
and adaptive immune resistance. Prostate Cancer and Prostatic Diseases. 2015;18(4):325-332.
Protocol Amendment No.: 04
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
2 Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med. 2012;366:2443-54.
3 Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a 
potential mechanism of immune evasion. Nat Med. 2002;8:793-800.
4 Dong H, Zhu G, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell 
proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365-69.
5 Pardoll D and Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 
2012;209:201-9.
6 Gannon PO, Poisson AO, Delvoye N, et al. Characterization of the intra-prostatic immune cell 
infiltration in androgen-deprived prostate cancer patients. J Immunol Methods. 2009;348:9-17.
7 Mercader M, Bodner BK, Moser MT, et al. T cell infiltration of the prostate induced by androgen 
withdrawal in patients with prostate cancer. Proc Natl Acad Sci USA. 2001;98:14565-70.
8 Aragon-Ching JB, Williams KM, Gulley JL. Impact of androgen-deprivation therapy on the 
immune system: implications for combination therapy of prostate cancer. Front Biosci. 2007;12.
9 Drake CG. Prostate cancer as a model for tumour immunotherapy. Nature Rev Immunol. 
2010;10:580-93.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA2097DX)
Procedurea
Screening 
Visit
Notes
All windows are on calendar days.
Eligibility Assessments
Informed Consent
X
Register in Interactive Response Technology (IRT) system to obtain participant number. 
Study permits re-enrollment of a participant who has discontinued the study as a pre-
treatment failure (ie, participant has not been treated). If re-enrolled, the participant must be 
re-consented.
Inclusion/Exclusion Criteria
X
Must be confirmed prior to randomization in IRT.
Medical History
X
All medical history relevant to the disease under study.
Includes clinical stage and Gleason score at initial diagnosis.
Prior Medications/Radiation for Cancer
X
Details and dates of prior therapy including all hormonal therapies.
Body Imaging
X
Technicium-99m bone scans, contrast enhanced CT of the chest, CT/MRI of the abdomen, 
pelvis, and all other known and/or suspected sites of disease, within 28 days prior to 
randomization. Section 9.1.1 for further details.
Please refer to Appendix 5 for PCWG3 guidelines for tumor assessments.
Brain Imaging
X
MRI of the brain without and with contrast is required for participants with known or 
suspected brain metastases, unless participant has completed an imaging study of the brain 
within 28 days prior to randomization.
CT of the brain without and with contrast can be performed if MRI is contraindicated. 
See Section 9.1 for further details.
Safety Assessments
Full Physical Examination
X
Height, Weight, ECOG Performance Status (Appendix 8) within 14 days prior to 
randomization.
Vital signs (BP, heart rate, RR, temperature) to be measured at screening visit and within 
72 hours prior to first dose.
Assessment of Signs and Symptoms
X
Within 14 days prior to randomization.
Prior/Concomitant Medication Use 
X
Within 14 days prior to randomization.
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CA2097DX
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2097DX)
Procedurea
Screening 
Visit
Notes
All windows are on calendar days.
Serious Adverse Event (SAE) Assessment 
X
SAEs collected from time of consent (see Section 9.2). All AEs (SAEs or nonserious AEs) 
associated with SARS-CoV-2 infection collected from time of consent. AEs are graded per 
NCI CTCAE v. 5.0
12 lead ECG 
X
Within 14 days prior to randomization
Laboratory Tests
Clinical Laboratory Tests
CBC with differential, chemistry panel, thyroid 
testing 
X
Must be performed within 14 days prior to randomization.
Refer to Section 9.4 for list of laboratory tests to conduct 
The following must be performed up to 6 weeks prior to first dose:
PSA (See Section 6.1, inclusion criteria)
Testosterone (See Section 6.1, inclusion criteria).
Review of Pathology Report
Histologic confirmation of adenocarcinoma of the prostate. Diagnosis must be stated in a 
pathology report and confirmed by the investigator. See Section 6.1 (Inclusion Criteria).
Protocol Amendment No.: 04
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2097DX)
Procedurea
Screening 
Visit
Notes
All windows are on calendar days.
SARS-CoV-2 Serology
X
Serum collected to be used for potential future measurements of anti-SARS-CoV-2 serology 
(anti-SARS-CoV-2 total or IgG 
, central lab).
IRT
Randomization
X
Once a participant is deemed eligible for the study, the IRT system must be contacted to 
randomize the participant to a treatment group.
a Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations. If a dose is delayed, 
the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Table 2-2:
On-Study Treatment and Follow-up Procedural Outline for Arms A and B (CA2097DX)
Procedurea
Combination Phase 
Max 10 Cycles
(1 Cycle = 3 weeks)
Day 1
Monotherapy 
Phaseb
(1 Cycle = 4 weeks)
Day 1
Safety Follow-
upc
(30 days [FU1]
and 100 days
[FU2])
Survival 
Follow-
upd
Notes
Study Treatment
Dispense Study 
Treatment
X
X
First dose to be administered within 3 calendar days 
following randomization.e
Safety Assessments
Per Protocol Amendment 04, safety assessments will be applicable ONLY to:

Participants continuing study-provided nivolumab

Participants up to 100 days after their last nivolumab infusion
All other participants will be discontinued from the study and switched to local standard of care for metastatic castration-resistant prostate cancer, 
outside of the study.
Targeted Physical 
Examination and 
Vital Signs
X
X
X
Within 72 hours prior to dosing:
Weight, BP, HR, RR, and Temperature 
ECOG Performance Status.
Adverse Event and 
Serious Adverse 
Event Assessment 
Continuously
Per NCI CTCAE version 5
Record at each visit.
All AEs (SAEs or nonserious AEs), including those 
associated with SARS-CoV-2 infection, must be 
collected continuously during the treatment period
and for a minimum of 100 days following 
discontinuation of dosing.
* Beyond 100 days from the last dose of study 
therapy, participants will be followed for drug-
related AEs/SAEs until resolution, return to 
Protocol Amendment No.: 04
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Table 2-2:
On-Study Treatment and Follow-up Procedural Outline for Arms A and B (CA2097DX)
Procedurea
Combination Phase 
Max 10 Cycles
(1 Cycle = 3 weeks)
Day 1
Monotherapy 
Phaseb
(1 Cycle = 4 weeks)
Day 1
Safety Follow-
upc
(30 days [FU1]
and 100 days
[FU2])
Survival 
Follow-
upd
Notes
baseline, deemed irreversible, or participant is lost 
to follow-up or withdraws study consent.
See Section 9.2 (Adverse Events).
Concomitant 
Medication Use
X
Record at each visit.
Not applicable per 
Protocol 
Amendment 04: 
Subsequent Cancer 
Therapy
Include documentation of subsequent cancer 
therapy (ie, systemic therapy, tumor-directed 
surgery, or radiation therapy).
Laboratory Tests
Per Protocol Amendment 04, laboratory tests will include local safety laboratory tests only and will exclude tests such as PSA, 
 and 
pharmacokinetics. In addition, the requirement for local safety laboratory tests will ONLY be applicable to:

Participants continuing study-provided nivolumab 

Participants up to 100 days after their last nivolumab infusion
All other participants will be discontinued from the study and switched to local standard of care for metastatic castration-resistant prostate cancer, 
outside of the study.
Clinical Laboratory 
Tests
CBC with 
differential, 
chemistry panel, 
thyroid testing
X (see notes)
X (see notes)
X (see notes)
For the first dose visit, labs need not be repeated if 
performed within 72 hours and results are available 
and have been reviewed for eligibility.
Laboratory tests may be performed within 72 hours 
prior to dosing for each cycle.
See Section 9.4 for list of laboratory tests.
Protocol Amendment No.: 04
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Table 2-2:
On-Study Treatment and Follow-up Procedural Outline for Arms A and B (CA2097DX)
Procedurea
Combination Phase 
Max 10 Cycles
(1 Cycle = 3 weeks)
Day 1
Monotherapy 
Phaseb
(1 Cycle = 4 weeks)
Day 1
Safety Follow-
upc
(30 days [FU1]
and 100 days
[FU2])
Survival 
Follow-
upd
Notes
Specific labs required at Safety FU2 only if toxicity 
is present are noted in Section 9.4.
Not applicable per 
Protocol 
Amendment 04: 
(Local) PSA 
Perform on D1 of every cycle. Participants who 
discontinue study treatment without PSA 
progression or radiographic progression will
continue to have PSA performed at FU1, at FU2 
and every 12 weeks thereafter. PSA collection will 
continue until PSA progression, radiographic 
progression or end of study treatment, whichever 
occurs last. Additional PSA collection outside of 
this schedule is encouraged to confirm PSA 
progression as needed, during prolonged dose 
delays or if clinically indicated.
Continuous 
Assessment of 
Skeletal Events 
(SSE)
X (see notes)
Assessed from treatment initiation to first 
symptomatic fracture, radiation or surgery to bone, 
or spinal cord compression.
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Table 2-2:
On-Study Treatment and Follow-up Procedural Outline for Arms A and B (CA2097DX)
Procedurea
Combination Phase 
Max 10 Cycles
(1 Cycle = 3 weeks)
Day 1
Monotherapy 
Phaseb
(1 Cycle = 4 weeks)
Day 1
Safety Follow-
upc
(30 days [FU1]
and 100 days
[FU2])
Survival 
Follow-
upd
Notes
Efficacy Assessments
Not applicable per Protocol Amendment 04.. All participants receiving study treatment will have radiographic tumor assessments based on the 
clinical judgment of the treating investigator and following imaging tumor assessment local guidelines for mCRPC.
Body Imaging
Technicium-99m Bone Scans, Contrast enhanced 
CT of the chest, CT/MRI of the abdomen, pelvis, 
and all other known and/or suspected sites of 
disease. Tumor assessments should occur every 9 
weeks (7 days) from first dose, regardless of 
treatment schedule or dose delays for first 54 
weeks. Thereafter switch to every 12 weeks (7 
days). Imaging must continue until radiographic 
progression per PCWG3 is assessed by investigator 
and confirmed by BICR, or study treatment is 
discontinued, whichever occurs later. In case 
subsequent therapy has begun, imaging must 
continue until radiographic progression per PCWG3 
is confirmed by BICR.
See Section 9.1.1 and Section 9.1.2.
Brain Imaging 
Participants with a history of brain metastasis or 
symptoms should have a surveillance MRI study 
per standard of care (approximately every 12 
weeks), or sooner if clinically indicated. CT of the 
brain without and with contrast can be performed if 
MRI is contraindicated. Imaging must continue 
until radiographic progression per PCWG3 is 
assessed by investigator and confirmed by BICR, or
study treatment is discontinued, whichever occurs 
later. See Section 9.1.1 for further details.
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Table 2-2:
On-Study Treatment and Follow-up Procedural Outline for Arms A and B (CA2097DX)
Procedurea
Combination Phase 
Max 10 Cycles
(1 Cycle = 3 weeks)
Day 1
Monotherapy 
Phaseb
(1 Cycle = 4 weeks)
Day 1
Safety Follow-
upc
(30 days [FU1]
and 100 days
[FU2])
Survival 
Follow-
upd
Notes
Survival Status
During safety follow-up and every 3 months (clinic 
visit or by telephone) during survival phase. Include 
documentation of subsequent therapy.
Health Outcomes
Not applicable per Protocol Amendment 04.
BPI-SF
At Safety FU1 only. 
Questionnaire should be completed after 
randomization but prior to dosing or prior to safety 
labs at safety follow-up visits.
FACT-P
FACT-P PCS
For survival follow-up visits, only the Prostate 
Cancer Subscale (PCS) portion of the FACT-P 
should be administered. Can be administered by 
telephone if needed.
EQ-5D-5L
Questionnaire should be completed after 
randomization but prior to dosing or prior to safety 
labs at safety follow-up visits.
During survival follow-up visits, the questionnaire 
can be administered by phone if needed.
Healthcare Resource 
Utilization
Healthcare resource utilization data will be 
collected at each visit by study site staff using the 
case report form (CRF).
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Table 2-2:
On-Study Treatment and Follow-up Procedural Outline for Arms A and B (CA2097DX)
Procedurea
Combination Phase 
Max 10 Cycles
(1 Cycle = 3 weeks)
Day 1
Monotherapy 
Phaseb
(1 Cycle = 4 weeks)
Day 1
Safety Follow-
upc
(30 days [FU1]
and 100 days
[FU2])
Survival 
Follow-
upd
Notes
 
SARS-CoV-2 
Serology
Serum collected approximately every 6 months 
during study treatment to be used for potential 
future measurements of anti-SARS-CoV-2 serology 
(anti-SARS-CoV-2 total or IgG). 
Serum should also be collected approximately 4 
weeks after a documented or suspected SARS-CoV-
2 infection 
. If a documented or 
suspected SARS-CoV-2 infection occurs within 4 
weeks of the 6-month sampling time point, a single 
serum sample will be collected to satisfy the 
requirements for both the every 6 month and 
approximately 4 weeks after infection time points.
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Table 2-2:
On-Study Treatment and Follow-up Procedural Outline for Arms A and B (CA2097DX)
Procedurea
Combination Phase 
Max 10 Cycles
(1 Cycle = 3 weeks)
Day 1
Monotherapy 
Phaseb
(1 Cycle = 4 weeks)
Day 1
Safety Follow-
upc
(30 days [FU1]
and 100 days
[FU2])
Survival 
Follow-
upd
Notes
Pharmacokinetic (PK) and Immunogenicity (IMG) Assessments
Not applicable per Protocol Amendment 04.
Collect blood 
samples for PK/IMG
a Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations. If a dose is delayed, 
the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs.
b Monotherapy Phase will start 3 weeks 3 days from last combination dose. If a dose is delayed, the procedures scheduled for that same time point (except tumor 
scans) should also be delayed to coincide with when that time point’s dosing actually occurs. Nivolumab will be given up to a maximum duration of 24 months 
from date of first dose.
c Participants must be followed for at least 100 days after last dose of study treatment. Safety Follow-up Visit 1 (FU1) should occur 30 days from the last dose 
(7 days) or can be performed on the date of discontinuation if that date is greater than 30 days from last dose. Specific labs required at Safety FU2 only if 
toxicity is present are noted in Section 9.4. Safety Follow-up Visit #2 (FU2) occurs approximately 100 days (+ 7 days) from last dose of study drug. Both Safety 
Follow-up visits should be conducted in person.
d Per Protocol Amendment 04, the follow-up phase only applies to participants up to 100 days after the last infusion of nivolumab. After 100 days of 
follow-up has been completed, the nivolumab-treated participants will be permanently discontinued from the study.
e No dose escalation or reductions of nivolumab are allowed. For Q3W and Q4W dosing cycles, all participants may be dosed within a ± 3-day window. For the 
Q3W dosing cycle, participants may be dosed no less than 18 days after the prior dose. Refer to Section 7.1.
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3
INTRODUCTION
CA2097DX is a Phase 3, randomized, global study assessing the efficacy and safety of nivolumab 
or nivolumab placebo combined with standard of care docetaxel chemotherapy, in men with 
metastatic castration-resistant prostate cancer (mCRPC) who have progressed after second-
generation hormonal manipulation, also known as Novel Antiandrogen Therapy (NAT), and have 
not received chemotherapy for mCRPC. 
The study aims to demonstrate that treatment with nivolumab combined with docetaxel improves 
clinical efficacy in terms of overall survival (OS) or radiographic progression-free survival (rPFS), 
when compared to docetaxel alone.
A detailed description of the chemistry, pharmacology, efficacy, and safety of the study treatments 
is provided in the respective Investigator Brochures (IBs) and package inserts.
3.1
Overall Rationale for Protocol Amendment 04 and Study Termination
The independent Data Monitoring Committee (DMC) convened on 26-Jul-2023 for a prespecified 
review of all available study data based on a clinical data cutoff of 01-Jun-2023. After reviewing 
the final analysis of the primary efficacy endpoint of radiographic progression-free survival (rPFS) 
per Blinded Independent Central Review (BICR) and the first interim analysis of the primary 
efficacy endpoint of overall survival (OS), the DMC agreed that the study did not meet the 
prespecified boundaries for declaring statistical significance for either endpoint. Although the 
number of events for OS at the second interim analysis and final analysis of OS had not been 
attained, based on the first interim analysis results for OS, the DMC determined that the 
prespecified boundaries for declaring significance were unlikely to be met. No new safety concerns 
were identified. A Sponsor Executive Oversight Committee (EOC) requested to be unblinded to 
the study results and decided to terminate the study. Full study teams and investigators were 
unblinded to study treatment assignment on 03-AUG-2023.
Protocol Amendment 04 reflects changes in study conduct. For participants who are deemed 
appropriate to continue on nivolumab or docetaxel therapy through  the CA2097DX study, re-
consent will be required.
3.2
Study Rationale
Prostate cancer tumor cells have been shown to have low tumor expression of programmed death 
ligand-1 (PD-L1), suggesting that treatments directed at the programmed death (PD-1)/PD-L1 
interaction are unlikely to be successful as monotherapies.1 This was confirmed by early clinical 
trials, where unselected men with mCRPC did not respond to PD-1 blockade as monotherapy.2
However, several studies show that PD-L1 expression can be up-regulated in response to 
inflammatory cytokines, a phenomenon which has been termed “adaptive immune resistance”3,4,5
This suggests that if prostate cancer treatments (ie, chemotherapy, androgen ablation) can increase 
PD-L1 expression on tumor cells by attracting infiltrating immune cells and triggering an adaptive 
immune response, there is a rationale for combining such therapies with immune check-point 
inhibitors.6,7,8,9 The rationale for combining chemotherapy and immunotherapy is based on the 
findings that cytotoxic treatments such as chemotherapy may modulate tumor/immune-system 
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interactions in favor of the immune system. Chemotherapy can result in tumor cell death as part 
of its intended therapeutic effect with a resultant increase in tumor antigen delivery to antigen-
presenting cells.
Tumor cell death may also lead to a reduction in soluble and membrane-bound factors inhibiting 
tumor-infiltrating T-cells and disrupt immune system regulatory networks by decreasing numbers 
of T-regulatory cells. Docetaxel has been reported to increase the production of pro-inflammatory 
cytokines which may enhance the immune response. These findings have led to the development 
of several clinical trials evaluating the combination of docetaxel and PD1/PDL1 inhibitors 
(NCT03338790, NCT 03834506, NCT02861573).10 Preliminary results from Keynote-36510 have 
demonstrated promising activity with this combination in patients with mCRPC previously treated 
with NAT(s) as described in Section 5.5.1 (Rationale for Population).
The current study aims to demonstrate that treatment with docetaxel in combination with 
nivolumab will be efficacious in participants with mCRPC. Additional objectives of the study 
include characterization of safety and tolerability, as well as pharmacokinetics, 
 
 and changes in patient reported outcomes for quality of life assessments.
3.2.1
Research Hypothesis
1) The administration of nivolumab in combination with docetaxel will improve radiographic 
progression-free survival (PFS) assessed by BICR compared with docetaxel in participants
with mCRPC
2) The administration of nivolumab in combination with docetaxel will improve overall survival 
(OS) compared with docetaxel in participants with mCRPC
3.3
Background
3.3.1
Background Indication and Treatment Landscape
Prostate cancer is a leading cause of cancer mortality in men worldwide,11 with an estimated 
incidence of 1,276,106 new cases and 358,989 deaths globally12 and 164,690 new cases and 
29,430 deaths in US in 2018.13 Prostate cancer is the most frequently diagnosed cancer and second 
most frequent cause of cancer deaths in US males. In the US, prostate cancer accounted for almost 
1 in 5 new diagnoses of cancer in men in 2018. In Europe, prostate cancer was the most common 
primary sites in men in 2018 (21.8% of the total), with 450,000 new cases and 107,000 deaths 
from prostate cancer being reported in that year.14
In 1941, Huggins and Hodges first noted the beneficial effects of castration and injection of 
estrogens in participants with metastatic prostate cancer. Over time, androgen deprivation therapy 
(ADT), defined as medical castration when it is administered as neoadjuvant, concomitant or 
adjuvant therapy in combination with radiation, became the cornerstone of treatment for patients 
with metastatic disease, as well as for patients with localized or locally advanced prostate cancers. 
ADT results in disease remission in 90% of metastatic prostate cancer participants, evidenced by 
a decline in levels of prostate-specific antigen (PSA). Nevertheless, most participants become 
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resistant, with disease progression occurring within a median of 18 to 24 months of continuous 
hormonal manipulation.
In 1996, mitoxantrone plus prednisone was approved for the treatment of patients with mCRPC 
based on improvement in pain palliation. Docetaxel became the first chemotherapeutic agent to 
show an OS benefit in mCRPC in two randomized controlled clinical trials (TAX 32715 and 
SWOG 99-1616), and was approved in combination with prednisone for this indication in the US 
in 2004. Since 2010, 6 new therapeutic agents with diverse mechanisms of action have been added 
to the therapeutic armamentarium, 5 of which (sipuleucel-T, cabazitaxel, abiraterone, 
enzalutamide, and radium-223) have been approved for the treatment of mCRPC based on 
improvement in median overall survival (OS). 
Cabazitaxel is another taxane-based chemotherapy that was approved by the FDA, in 2010, in 
patients with mCRPC previously treated with docetaxel.17 In the FIRSTANA trial,18 which studied 
cabazitaxel vs docetaxel as first-line therapy in chemotherapy-naïve mCRPC, different dosages of 
cabazitaxel did not show superiority over docetaxel. 
Sipuleucel-T19 was the first immunotherapy to receive FDA approval in men with asymptomatic 
mCRPC based on the Phase III IMPACT trial which showed a median survival of 25.8 months vs 
21.7 months (placebo arm). Two androgen-directed therapies, abiraterone acetate and 
enzalutamide, were approved by the FDA for post chemotherapy20,21 and chemotherapy-naïve22,23
mCRPC patients. Furthermore, bone targeting alpha-emitting radionuclide radium-223 chloride 
(radium-223)24 was approved in men with symptomatic bone metastases but no visceral disease, 
based on data from the ALSYMPCA trial which showed a median OS benefit (HR, 0.7; 14.9 vs 
11.3 months; P < 0.001). However, cross-resistance has been observed between some of these 
agents (ie, enzalutamide and abiraterone; abiraterone and docetaxel) and a lack of consensus 
currently exists on optimal sequencing of these therapies in mCRPC. 
The use of some of these agents has now expanded into earlier stages of the disease, with 
docetaxel25 and abiraterone26,27 demonstrating a significant OS improvement in metastatic 
cstration-sensitive prostate cancer (mCSPC) which led to their approval in this setting. 
Enzalutamide has also been tested in in men with mCSPC 28 and recently showed to significantly 
improve rPFS and other efficacy endpoints compared to ADT alone. Furthermore, both 
enzalutamide29 and apalutamide30, another second-generation antiandrogen that is an irreversible 
AR antagonist, showed improved metastasis-free survival in non-metastatic CRPC and were 
approved in 2018. More recently, darolutamide31, an AR antagonist related to enzalutamide and 
apalutamide, but with a high affinity for AR and low affinity for GABA receptors, has 
demonstrated a significant improvement of metastasis-free survival (MFS) in M0 CRPC (HR 0.41; 
40.4 months with darolutamide vs 18.4 months with placebo; P < 0.0001). It is unknown if using 
chemotherapy and AR-directed agent therapy for the upfront treatment of mCSPC and in 
non-metastatic CRPC will alter disease biology, clinical course, and sequencing of these agents in 
the mCRPC setting.
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Significant progress has been made in the last few years in the treatment and understanding of the 
biology of CRPC and molecular classification is likely to guide future treatment strategies. 
Olaparib and rucaparib are two examples of PARP inhibitors that are being investigated in a 
molecularly defined mCRPC subgroup and received FDA breakthrough therapy designation in 
2016 and in 2018, respectively. Olaparib as a treatment for BRCA1/2 or ATM-mutated mCRPC 
in patients who have received a prior taxane-based chemotherapy and at least one hormonal agent, 
either enzalutamide or abiraterone based on the initial results of Phase 2 TOPARP-A32 trial, which 
found that 88% of participants with DNA-repair defects (DRD) (n=16) had a response (composite 
response endpoint including PSA response, objective response, and CTC conversion) to olaparib 
vs 6% of patient without DRD. Rucaparib as a treatment for BRCA1/2-positive mCRPC following 
at least 1 androgen receptor–directed therapy and taxane-based chemotherapy based on the 
ongoing TRITON-233 Phase II study, which showed that 44.0% (11/25) of patients with a 
BRCA1/2 alteration had a confirmed radiographic response. Recently, findings of TOPARP-B,34
the second stage of the trial where 98 patients were pre-selected based on the detection of DNA 
repair defects, showed a response rate (combined primary endpoint) of 54% overall in the 400 mg 
olaparib cohort and 37% in the 300 mg cohort. Radiographic responses based on specific genomic 
alterations were 42.4% in patients with a BRCA1/2, PALB2 – 33.3%, ATM – 8.3%, and no 
responses in CDK12 or other genomic alterations. 
While the availability of these new treatment options allows for tailoring therapy to patient 
characteristics such as presence or absence of symptoms, prior treatments, patient preferences, and 
life expectancy, none of these therapies result in durable clinical responses. Despite high initial 
response rates, remissions following second-generation hormone therapies are temporary due to 
the occurrence of resistance mechanisms, including androgen receptor (AR) reactivation. At this 
time, with judicious sequencing and use of available new therapies, participants with established 
mCRPC have a life expectancy in the range of 12 to 35 months. Thus mCRPC remains a disease 
with a lethal outcome with the urgent need for treatment options that will provide durable disease 
control and long term survival.
3.3.2
Nivolumab Mechanism of Action
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses.35,36,37
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by mechanisms such as introducing cancer antigens by therapeutic 
vaccination or by modulating regulatory checkpoints of the immune system. T-cell stimulation is 
a complex process involving the integration of numerous positive as well as negative co-
stimulatory signals in addition to antigen recognition by the T-cell receptor (TCR).38 Collectively, 
these signals govern the balance between T-cell activation and tolerance.
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PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA 4, ICOS, and BTLA.39 PD-1 signaling has been shown to inhibit CD28-mediated 
upregulation of interleukin (IL)-2, IL-10, IL-13, interferon-gamma (IFN-γ) and Bcl-xL. PD-1 
expression has also been noted to inhibit T-cell activation, and expansion of previously activated 
cells. Evidence for a negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, 
which develop a variety of autoimmune phenotypes.40 These results suggest that PD-1 blockade 
has the potential to activate anti-self T-cell responses, but these responses are variable and 
dependent upon various host genetic factors. Thus, PD-1 deficiency or inhibition is not 
accompanied by a universal loss of tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39 - 2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA 
4 and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement 
of both proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). Using a 
cytomegalovirus (CMV) re-stimulation assay with human peripheral blood mononuclear cells 
(PBMC), the effect of nivolumab on antigen specific recall response indicates that nivolumab 
augmented IFN-γ secretion from CMV specific memory T cells in a dose-dependent manner versus 
isotype-matched control. In vivo blockade of PD-1 by a murine analog of nivolumab enhances the 
anti-tumor immune response and result in tumor rejection in several immunocompetent mouse 
tumor models (MC38, SA1/N, and PAN02).41
3.3.3
Docetaxel Mechanism of Action
Docetaxel is an anti-neoplastic chemotherapeutic agent which acts by disrupting the microtubular 
network that is essential for mitotic and interphase cellular functions. See the current prescribing 
information for docetaxel (SmPC, USPI, or country-specific label) for more information.42
3.4
Benefit/Risk Assessment
Although multiple new agents have been approved for mCRPC over the last decade, benefits 
remain modest and the median survival of patients with mCRPC is unsatisfactory at approximately 
12 to 35 months.43,44,45,46,47 It is clear that there is an urgent need for new therapeutic options that 
offer further improvement in cancer control and overall survival.
Nivolumab has demonstrated significant clinical benefit in the treatment of advanced solid 
(eg, melanoma, renal cell carcinoma [RCC], and non-small cell lung cancer [NSCLC]) and 
hematologic (eg, classical Hodgkin Lymphoma [cHL]) malignancies as monotherapy or in 
combination with other agents such as ipilimumab, depending on the malignancy. Details of the 
clinical activity in these various malignancies are provided in the USPI48 and SmPC49.
Overall, the safety profile of nivolumab is manageable and generally consistent across completed 
and ongoing clinical trials with no maximum tolerated dose (MTD) reached at any dose tested up 
to 10 mg/kg. Most adverse events (AEs) were low-grade (Grade 1 to 2) with relatively few related 
high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or causality of AEs 
with respect to nivolumab dose level.
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A pattern of immune-mediated adverse events (IMAEs) associated with nivolumab has been 
defined, for which management algorithms have been developed; these are provided in Appendix 
6. Most high-grade events were manageable with the use of corticosteroids or hormone 
replacement therapy (in the case of endocrinopathy) as instructed in these algorithms. 
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the nivolumab IB.
Notwithstanding that there have been several immunotherapy failures in prostate cancer, the 
approval of cancer vaccine sipuleucel-T in the US, together with the promising activity shown by 
the recent early phase trials of PD-1 inhibitors in combination with anti-CTLA-4 inhibitors or,
with other non-immunotherapy agents (ie, docetaxel, enzalutamide and olaparib) have provided 
support for further exploring the use of immune therapies in prostate cancer.50,51,52,53 As outlined 
in Section 5.5.2 the purpose of combination immune therapies is to enhance anti-tumor T-cell 
responses and several lines of evidence support combination of immune therapies with 
chemotherapy in men with mCRPC. 
Docetaxel has a well-characterized AE profile as a cytotoxic chemotherapy, including the potential 
of pancytopenia, fluid retention, peripheral neuropathies, diarrhea, nausea and vomiting. 
Preliminary data from a NSCLC study suggest that nivolumab in combination with platinum 
doublet chemotherapy has additive anti-tumor activity in participants regardless of PD-L1 
expression, but with a numerically higher ORR observed in non-squamous NSCLC.54 The safety 
profile of nivolumab plus platinum-doublet chemotherapy reflected additive toxicities of the 
individual agents, which were manageable using established safety guidelines. In addition, the 
safety and tolerability of docetaxel in combination with pembrolizumab in patients with mCRPC 
appeared to be acceptable.55 Grade 3-5 treatment-related AEs occurred in 27 (38%) pts, including 
2 deaths from treatment-related AEs (pneumonitis). The most commonly reported grade 
3 treatment-related AEs were febrile neutropenia (12%), decreased neutrophil count (6%), colitis 
(4%), and pneumonitis (4%). Most immune-mediated AEs were low grade with the most common 
being infusion-related reactions (11%) and colitis (10%).55 Docetaxel is being tested in 
combination with nivolumab in Arm B of the ongoing Phase 2 CA209-9KD study 
(NCT03338790). Enrollment has been completed (n = 84) and preliminary results from the interim 
analysis have demonstrated promising anti-tumor activity with no new safety concerns and as 
described in Section 5.5.2 (Rationale for Immunotherapy in mCRPC).
To assure an ongoing favorable risk/benefit assessment for participants enrolled into the present 
study, the following safety measures will be employed throughout the conduct of the study:

Institution of a Data Monitoring Committee (DMC) to provide independent oversight of safety, 
study conduct and efficacy of nivolumab in combination with docetaxel. In addition, a Study 
Steering Committee (consisting of selected participating investigators) will meet regularly to 
advise BMS regarding study-related issues, including safety concerns.

Rigorous safety monitoring by BMS to ensure participants’ safety including regular and 
systematic review of safety data, close follow-up of reported safety events, and intensive site 
and study investigator training/education on the implementation of the nivolumab toxicity 
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management algorithms and toxicity management of docetaxel. A BMS Safety Management 
Team will review and evaluate all emerging data across the program for potential safety signal
assessment in a timely manner. 

Risks will be further minimized by adherence to inclusion and exclusion selection criteria (see 
Section 6), avoidance of prohibited medication (see Section 7.7.1), close safety monitoring 
(see Section 9.2 Adverse Events and Section 9.4 Safety), and dose adjustment guidelines (see 
Section 7.4 Dose Modifications). These will also be clearly discussed and highlighted during 
site visits.
In conclusion, treatment of nivolumab in combination with docetaxel in men with mCRPC is 
expected to be tolerable, and toxicities of the treatment are expected to be manageable and 
reversible upon dose reduction, treatment interruption, or discontinuation. The overall risk-benefit 
of the combination is deemed acceptable.
Detailed information about the known and expected benefits and risks and reasonably anticipated 
AEs of nivolumab may be found in their respective IBs. Similar information is provided for 
docetaxel in the associated Patient Information Leaflet, USPI, country-specific label, Development 
Safety Update Report, or SmPC.
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objective
Endpoint
Primary

To compare the rPFS (using 
PCWG3) 
of 
nivolumab 
in 
combination with docetaxel to 
placebo 
in 
combination 
with 
docetaxel, in men with metastatic 
castration resistant prostate cancer 
(mCRPC).

rPFS for randomized
participants is the time between 
randomization and the first date of documented progression or death 
due to any cause, whichever occurs first. The radiographic 
progression will be assessed by Blinded Independent Central 
Review (BICR) per PCWG3. The rPFS will be censored at the last 
tumor assessment up to the start of subsequent systemic cancer 
therapy.

To compare the OS of nivolumab in 
combination with docetaxel to
placebo 
in 
combination 
with 
docetaxel, in men with metastatic 
castration resistant prostate cancer 
(mCRPC).

OS for all randomized participants is the time between 
randomization and the date of death from any cause. For 
participants who are alive, their survival time will be censored at 
the last date that they were known to be alive. OS will be censored 
for participants at the date of randomization if they had no follow-
up.
Secondary

To assess the antitumor activity of 
nivolumab in combination with 
docetaxel.

Objective Response Rate per PCWG3 (ORR-PCWG3) is the 
proportion of participants who have a confirmed complete or partial 
best overall response (BOR) per PCWG3 among randomized
participants who have measurable disease at baseline. The BOR is 
defined as the best response designation, as determined by the 
BICR, recorded between the date of randomization and the date of 
objectively documented progression per PCWG3 or the date of 
subsequent systemic cancer therapy, whichever occurs first. For 
participants without documented progression or subsequent 
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Table 4-1:
Objectives and Endpoints
Objective
Endpoint
systemic cancer therapy, all available response assessments will 
contribute to the BOR assessment.

Time to Response per PCWG3 (TTR-PCWG3) is the time from 
randomization to the date of the first documented CR or PR per 
PCWG3, as determined by BICR. 

Duration of Response per PCWG3 (DOR-PCWG3) is the time
between the date of first response (CR/PR per PCWG3) to the date 
of first documented radiographic progression per PCWG3, as 
determined by BICR, or death due to any cause. Participants who 
neither progress nor die will be censored at the last tumor 
assessment up to the start of subsequent systemic cancer therapy.

PSA Response Rate (PSA-RR) is the proportion of randomized 
participants with a 50% or greater decrease in PSA from baseline to 
the lowest post-baseline PSA result. A second consecutive value 
obtained 3 or more weeks later is required to confirm the PSA 
response. PSA response will be calculated for all participants with 
PSA values at baseline and at least one post-baseline assessment.

Time to PSA Progression (TTP-PSA) is the time between 
randomization to the date of PSA progression per PCWG3 in 
randomized participants. For participants with an initial PSA 
decline from baseline, the date of PSA progression is the date that 
an increase of 25% or more and an absolute increase of 2 ng/mL or 
more from the nadir are documented and confirmed by a second 
consecutive PSA value at least 3 weeks later. For participants with 
no PSA decline from baseline, the date of PSA progression is the
date that an increase of 25% or more and an absolute increase of 2
ng/mL or more from baseline are documented beyond Week 13.
TTP-PSA will be censored at the date of last PSA evaluation prior 
to the start of subsequent systemic cancer therapy. The time will be 
censored at the date of randomization for participants with no post-
baseline PSA evaluation.

To characterize the safety and 
tolerability
of 
nivolumab 
in 
combination with docetaxel.

Overall safety and tolerability will be measured by the incidence of
AEs, SAEs, AEs leading to discontinuation, immune-mediated 
AEs, select AEs, deaths, and laboratory abnormalities and changes 
from baseline.

To evaluate the progression of pain 
during treatment.

Median time to pain progression as assessed by Brief Pain 
Inventory-Short Form (BPI-SF).
Exploratory

To investigate the time to initiation 
of subsequent systemic therapy 
(TT-SST).

TT-SST is the time from randomization to the start of subsequent 
systemic therapy, including hormonal therapy, chemotherapy,
immunotherapy, or investigational therapy.

To investigate the time to first
symptomatic skeletal event (TT-
SSE).

TT-SSE is the time between randomization and the date of first
symptomatic fracture, radiation or surgery to bone, or spinal cord
compression.

To evaluate the change in pain 
intensity and health-related cancer 

Change in mean scores as assessed by BPI-SF.
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Table 4-1:
Objectives and Endpoints
Objective
Endpoint
related symptoms and quality of 
life.

Median time to deterioration and change in mean scores as assessed 
by FACT-P total score and subscales.

To assess the participant’s quality 
of life and overall health status.

Change in scores in both the EQ-5D-5L utility index and visual 
analog scale.

To investigate the time to and 
duration of PSA response.

Time to PSA response (TTR-PSA) is defined for PSA responders 
as the time from randomization to the date of the first PSA response. 
Duration of PSA response (DOR-PSA) is defined for PSA 
responders as the time between the date of first response and the 
date of PSA progression. Participants who neither progress by PSA 
nor die will be censored on the date of last PSA evaluation.

To evaluate the pharmacokinetics 
of nivolumab when administered in 
combination with docetaxel. To 
explore 
exposure
response 
relationships 
between 
select 
exposure measures, and safety, and 
efficacy endpoints, as appropriate.

Parameter estimates from Population PK analysis and exposure-
response analysis, if data permit.

To 
characterize 
the 
immunogenicity 
of 
nivolumab 
when administered in combination
with docetaxel.

Immunogenicity will be determined by measurement of anti-drug
antibody (ADA) in serum and samples with positive ADA response
may be analyzed for neutralizing ADA response to nivolumab.

To assess the impact of SARS-
CoV-2 
serologic 
status 
on 
participants 
with 
metastatic 
castration-resistant prostate cancer 
who are receiving study treatment
 

Exploratory measurements of SARS-CoV-2 serology (anti-SARS-
CoV-2 total or IgG), from serum samples collected at baseline and 
during the study, and the potential association between these 
measurements and selected endpoints related to safety, efficacy, 
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5
STUDY DESIGN
5.1
Overall Design
The study design schematic is presented in Figure 5.1-1.
CA2097DX is a Phase 3 randomized, double-blinded, multi-center clinical trial comparing 
nivolumab or placebo in combination with docetaxel, in men with metastatic castration-resistant 
prostate cancer.
The study will randomize up to approximately 984 participants 1:1 into 1 of the 2 treatment arms 
(nivolumab combined with docetaxel or docetaxel combined with placebo). The primary endpoints 
of the study are rPFS and OS, as described in Section 4.
Per Protocol Amendment 04, full study teams and investigators were unblinded to study 
treatment assignment on 03-AUG-2023 due to the lack of rPFS and OS benefit from 
nivolumab added to docetaxel plus prednisone compared to placebo added to docetaxel plus 
prednisone. 
Arm A:

Combination Phase (maximum 10 cycles, 1 cycle is 3 weeks):

Docetaxel 75 mg/m² IV Q3W + Prednisone 5 mg PO BID + Nivo 360 mg IV Q3W

Monotherapy Phase (1 cycle is 4 weeks):

Nivolumab 480 mg IV Q4W
Arm B:
Per Protocol Amendment 04, participants assigned to Arm B will no longer receive placebo. 

Combination Phase (maximum 10 cycles, 1 cycle is 3 weeks)

Docetaxel 75 mg/m² IV Q3W + Prednisone 5 mg PO BID + Placebo IV Q3W

Monotherapy Phase (1 cycle is 4 weeks):

Placebo IV Q4W
Randomization will be stratified according to the following baseline factors:

1 prior Novel Antiandrogen Therapy (NAT) for mCRPC vs 1 prior NAT for non-metastatic 
castration-resistant prostate cancer (nmCRPC) or metastatic castration-sensitive prostate 
cancer (mCSPC) vs 2 prior NAT

Visceral disease (Y vs N)
Visceral disease status will be assessed by investigator based on the tumor assessment performed 
during screening. Visceral disease is defined as the presence of metastatic disease in the liver, lung, 
adrenal, peritoneum, brain or other internal organs. Bone, lymph node metastases and prostate 
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Cli nical Pr ot oc ol
C A 2 0 9 7 D X
B M S - 9 3 6 5 5 8
ni v ol u ma b
lesio ns ( or bla d der/rect u m if fr o m direct i n vasi on fr om
pr ostate) are n ot c o nsi dere d viscera l 
di sease.
Fi g ure 5. 1 - 1:
St u d y Desi g n Sc he m atic
Per Pr ot oc ol A me n d me nt 0 4, p artici p a nts assi g ne d t o Ar m B will n o l o n ger recei ve pl ace b o. 
T his st u d y  will c o ns ist of t hree p hases: Scree ni n g, Treat me nt, a n d F ol l ow- u p. F or a c o m plete list  
of  st u d y r e q uire d pr oce d ures, please refer t o  Sectio n 2 .
5. 1. 1
S cr e e ni n g P h a s e
P arti cipa nt s will pr o vi de wri tte n i nf or me d c o nse nt t o partici pate i n t he st u d y befor e c o mpleti n g 
a n y pr ot oc ol -s pecifie d pr oce d ures or e val uat i ons n ot c o nsi dere d t o be part of  the partici pa nts’ 
sta n dar d of care (refer t o Secti o n 2 Sc he d ule of A cti vities f or details). After sig ni n g t he i nf or me d 
c o nse nt f or m (I C F), partici pa nts will be e val uate d f or e ntr y crit eria d uri n g t he scree ni n g p eri o d 
bef ore a d mi nistrati o n of  st u d y dr u g(s). Re -e nr oll me nt aft er scree n fail ure will be allo we d a n d 
la bs/ pr oce d ures ma y be reteste d (see Secti o n 6. 4. 1 ( Retesti n g D uri n g Scree ni n g or Lea d -I n 
P eri o d).
T u m o r i ma gi n g is re q uire d withi n 2 8 da ys of ra n d o mizat i on.
5. 1. 2
Tr e at m e nt P h a s e
Per Pr ot oc ol A me n d me nt 0 4 a n d t he decisi o n t o ter mi n ate t he st u d y d ue t o a l ac k of effic ac y, 
t he f ull st u d y te a ms a n d i n vesti g at ors h a ve bee n u n bli n de d t o tre at me nt assi g n me nts. 
P arti ci p a nts i n t he pl ace b o ar m will disc o nti n ue pl ace b o a n d m a y be a ble t o c o nti n ue
d ocet a xel f or u p t o 1 0 c ycles t hr o u g h t he st u d y if t hey are i n t he c o m bi n ati o n p h ase, a n d l oc al 
access t o d ocet a xel o utsi de t he st u d y is n ot a v ail a ble. I n a d diti o n, all p artici p a nts s h o ul d 
recei ve st a n d ar d of c are tre at me nt f or m C R P C per l oc al g ui deli nes. 
Pr ot oc ol A me n d me nt N o.: 0 4
Date: 2 2- Se p- 2 0 2 3
4 7
6 . 0
A p p r o v e d
9 3 0 1 4 2 0 8 3
5 . 0
v
P PI
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nivolumab
Following confirmation of eligibility, participants will be randomized to receive nivolumab or 
placebo in combination with docetaxel.
The treatment period will consist of a combination phase (nivolumab or placebo in combination 
with docetaxel for up to 10 cycles) and a monotherapy phase (nivolumab or placebo) as described 
above in Section 5.1. Treatment with nivolumab will be given for a maximum of 24 months from 
date of first dose in the absence of disease progression, unacceptable toxicity or other reasons 
specified in the protocol. See Section 7.1 (Treatments administered) for details of treatments. 
Not applicable per Protocol Amendment 04: PK samples and immunogenicity samples will be 
collected according to schedules in Table 9.5-1
Not applicable per Protocol Amendment 04: Tumor assessments should occur every 9 weeks 
(7 days) from first dose, regardless of treatment schedule or dose delays, for first 54 weeks. 
Thereafter switch to every 12 weeks (7 days). Imaging must continue until radiographic 
progression per PCWG3 is assessed by investigator, and confirmed by BICR, or treatment is 
discontinued, whichever occurs later. See Section 9.1.1 (Imaging Assessment for the Study) and 
Section 9.1.2 (BICR Confirmation of Progression). Per Protocol Amendment 04, all 
participants receiving study treatment will have radiographic tumor assessments based on 
the clinical judgment of the treating investigator and following imaging tumor assessment 
local guidelines for mCRPC.
Per Protocol Amendment 04, decisions on docetaxel treatment will be based on the clinical 
judgment of the treating physician and on shared decision making with the participant. 
Participants who are not able to access local therapy may continue on study-provided 
docetaxel until local access is available. In the event that the investigator deems a participant 
is deriving clinical benefit from nivolumab therapy and, together with the counseled 
participant, wishes to continue treatment, this may be possible following discussion with the 
Medical Monitor to ensure a clinical rationale exists that justifies continuation of nivolumab 
treatment.
Not applicable per Protocol Amendment 04: In certain circumstances, participants with 
progressive disease (PD) per PCWG3, but with otherwise stable or improved performance and 
clinical status, may continue to be treated in the event of a perceived benefit per investigator; see 
Section 7.7.4 for treatment beyond progression criteria.
This phase ends when the participant is discontinued from study therapy.
5.1.3
Follow-up Phase
Per Protocol Amendment 04, the follow-up phase only applies to participants up to 100 days 
after their last infusion of nivolumab. After 100 days of follow-up have been completed, the 
nivolumab-treated participants will be permanently discontinued from the study. 
Begins when the decision to discontinue a participant from study therapy is made (no further 
treatment with study therapy). Not applicable per Protocol Amendment 04: Every effort should 
be made to continue tumor assessments for participants who discontinue treatment for reasons 
other than disease progression or consent withdrawal, according to the schedule in Table 2-2 until 
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progression. Not applicable per Protocol Amendment 04: After completion of the first two 
safety follow-up visits, participants will be followed every 3 months for survival, and include 
documentation of subsequent therapy.
Not applicable per Protocol Amendment 04: BMS may request that survival data be collected 
on all treated participants outside of the protocol defined window as detailed in the Schedule of 
Activities in Section 2. At the time of this request, each participant will be contacted to determine 
their survival status unless the participant has withdrawn consent for all contact.
5.2
Data Monitoring Committee and Other External Committees
Not applicable per Protocol Amendment 04 due to study termination.
To provide independent oversight of safety, efficacy, and study conduct, an independent Data 
Monitoring Committee (DMC) will be established to provide oversight on safety and efficacy 
considerations. Details of the DMC responsibilities and procedures will be specified in the DMC 
charter. 
A Study Steering Committee (consisting of selected participating investigators) will meet regularly 
to advise BMS regarding study-related issues, including safety concerns.
When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation.
5.3
Number of Participants
Assuming a 25% screen failure rate, it is estimated that approximately 1,312 participants with 
mCRPC, will be enrolled in order to randomize approximately 984 participants. See Section 10.1
for a description of the sample size calculation. Recruitment was completed globally as of 13-Jun-
2022. China region will continue enrolling until required number of participants to satisfy 
regulatory requirements is achieved (approximately 15% of the global participants).
5.4
End of Study Definition
Per Protocol Amendment 04, the study will be terminated, and the first interim analysis will 
be considered the final analysis. The end of the trial is defined as when the last participant 
receiving study-provided nivolumab completes 100 days of safety follow-up after their last 
nivolumab infusion. Study completion is defined as the final date on which data for the primary 
endpoint was or is expected to be collected, if this is not the same.
The total duration of the study from the date of first participant treated to the final analysis of both 
primary endpoints is expected to be approximately 31 months. 
5.5
Scientific Rationale for Study Design
5.5.1
Rationale for Population
Men with metastatic CRPC who have progressed after 1 or 2 NATs and have not received 
chemotherapy for mCRPC will be included in this study. Although most patients without 
symptoms are not treated with chemotherapy, the survival benefit reported with docetaxel applies 
to those with or without symptoms. NCCN guidelines recommends to use docetaxel (category 1) 
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as the preferred 1st line chemotherapy in men with symptomatic mCRPC and in patients with signs 
of rapid progression or visceral metastases despite lack of symptoms. Docetaxel also has a category 
1 recommendation in second-line after prior enzalutamide/abiraterone. Clinical data from a 
number of small retrospective cohort studies suggests that once participants with mCRPC progress 
response rates to abiraterone after enzalutamide and conversely enzalutamide after abiraterone are 
low and no robust criteria exist clinically to select one drug rather than the other.56
Given that abiraterone and enzalutamide are the preferred 1st line option for men with 
asymptomatic, chemotherapy-naïve mCRPC and the recent approvals of next generation hormonal 
therapies in mCSPC and M0 CRPC settings, it is expected that most patients will have received 
one of these agents when they develop mCRPC. Therefore, the current study will include chemo-
naïve mCRPC patients who are post-1 or 2 prior lines of second-generation hormonal therapies. 
No more than 1 prior NAT is allowed in the mCRPC setting. The study will stratify by prior NAT 
(1 prior NAT for mCRPC vs 1 prior NAT for nmCRPC/mCSPC vs 2 prior NAT) in order to 
account for potential differences in survival outcomes.
Significant progress made over the last few years in understanding the biology and molecular 
classification of CRPC, with Olaparib and rucaparib being two examples of PARP inhibitors that 
are being investigated in a molecularly defined mCRPC subgroup, namely patients with mutations 
in specific HRD genes, such as BRCA1/2 and ATM. Data from the Phase 2 Check-Mate 650 study 
(NIVO1+IPI3) presented at ASCO-GU in Feb-201957 demonstrated clinical activity in mCRPC, 
with ORR of 10% and 25% in chemotherapy-pretreated and chemotherapy-naïve patients, 
respectively, and preliminary evidence of tumor mutational burden (TMB) as a biomarker for 
immuno-oncology (IO) activity in a subgroup of patients with tumor samples evaluable for whole 
exome sequencing. However, little published data are available on the efficacy of chemotherapy 
by biomarker status in advanced prostate cancer as several older trials did not include next-
generation sequencing of tumor samples. 
 
5.5.2
Rationale for Immunotherapy in mCRPC
Like most types of cancer, prostate cancer develops in an immune-competent environment. 
Immune responses against prostate tumors are noted in the form of intratumoral leukocyte 
infiltration and inflammatory pathway activation.58 Evidence from animal models and human 
prostate cancer suggests that, despite the presence of immune effector cells that recognize tumor 
antigens, these cells are actively tolerized and become incapable of mediating tumor destruction.59
The induction of regulatory or suppressor T cells60 with increased CD4+CD25+ and CD8+Foxp3+ 
regulatory T cells (Treg), detected both within prostate glands and in the peripheral blood of 
prostate cancer subjects, suggests the presence of active immune suppression of antitumor 
immunity.61,62
An analysis of the prognostic significance of PD-1 and/or PD-L1 expression in a cohort of 
535 prostate cancer tumors showed that a high density of PD-1+ lymphocytes independently 
predicted shorter clinical failure-free survival.63 This may indicate that tumor immune escape, and 
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thus tumor immune elimination, are important mechanisms in prostate cancer and the association 
of pathway molecules with poor prognosis makes them attractive targets for inhibition. These lines 
of evidence support targeting the immune system itself, via activation of T cells and overcoming 
T-cell tolerance, to result in durable antitumor activity in prostate cancer.
Two Phase 3 Studies (CA184043 and CA184095) carried out subsequently have failed to show a 
clear-cut survival advantage for ipilimumab (10 mg/kg) over placebo, although some patients 
achieved sustained complete responses and treatment with ipilimumab was associated with longer 
median PFS and higher PSA response rate.64,65 More recently, the approval of cancer vaccine 
sipuleucel-T in the US, together with the promising activity shown by the recent early phase trials 
of immune checkpoint inhibitors66,10,52,53,57 have provided support for further exploring the use of 
immune therapies in prostate cancer.
The IMPACT study evaluated sipuleucel-T (Provenge, Dendreon Corp., Seattle, WA), an 
autologous therapeutic vaccine, vs placebo in chemotherapy-naïve CRPC participants and reported 
a 
4.1-month 
survival 
improvement 
in 
asymptomatic 
or 
minimally 
symptomatic 
CRPC participants.67 While these data show little overall impact on delaying progression of 
disease, the reported benefits in OS may be considered “proof of concept” that immunotherapeutic 
agents can play an important role in treating advanced prostate cancer.68
Prostate cancer has been shown to have low tumor expression of PD-L12 and single-agents anti-
programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapies have shown 
limited clinical success in prostate cancer patients, particularly when compared to other cancer 
types such as melanoma and non-small cell lung cancers. In a cohort of 17 subjects with mCRPC,
nivolumab 10 mg/kg showed no objective responses.69 One out of 10 subjects evaluable for PSA 
response demonstrated a PSA reduction 50% from baseline. Prostate tumor samples were 
available in 2 subjects with mCRPC, and tumor PD-L1 expression was 0% in both subjects.
Atezolizumab monotherapy was evaluated in a Phase 1a study, including 15 heavily pretreated 
subjects with mCRPC.70 There were no objective responses per RECIST 1.1, although 1 subject 
had a PR per immune-related response criteria (irRC). Pembrolizumab was recently evaluated in 
a Phase 2 study of mCRPC patients previously treated with docetaxel.71 Among those with 
measurable disease, ORR was 3% and 5% in PD-L1 negative (n = 66) and positive (n = 133) 
patients, respectively. PSA responses were observed in 11% of evaluable patients (n = 193). 
Among 19 patients with somatic aberrations in BRCA1/2 or ATM, ORR was 11%, suggesting that 
DNA repair defects may be associated with anti-tumor activity.
However, immunotherapy-based combinations could potentially result in increasing immune-
mediated anti-tumor activity in subjects with prostate cancer. Nivolumab plus ipilimumab
demonstrated antitumor activity in patients with mCRPC and further evaluation of the clinical 
activity of this combination, as well as the potential association between biomarkers is currently 
ongoing in study CA209650.57 In addition to this study, an open-label Phase 2 trial of nivolumab 
combined with rucaparib, docetaxel, or enzalutamide in patients with mCRPC (NCT03338790) is 
ongoing.
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Other clinical trials are underway evaluating the role of PD-1/PDL1 inhibitors in combination with 
other agents that work via varied mechanisms of action and are potentially synergistic 
(NCT02861573, 
NCT03834506, 
NCT03834519, 
NCT03834493, 
NCT03016312, 
NCT02814669). The addition of pembrolizumab upon enzalutamide failure was evaluated in a 
single-arm, Phase 2 study.66 The study demonstrated meaningful clinical activity to PD-1 blockade 
in men with mCRPC and no unexpected AEs. Furthermore, recent results from other early phase 
studies combining permbrolizumab with olaparib, docetaxel or enzalutamide have shown 
acceptable safety profile and promising anti-tumor activity, supporting further evaluation of these 
combinations 
in 
the 
ongoing 
Phase 
3 
studies
(NCT03834506, 
NCT03834519, 
NCT03834493).10,52,53
ADT, which has been shown to alter the immune environment in prostate cancer, plays a central 
role in the treatment of high-risk early PCa and recurrent or metastatic disease. Therefore, it is 
crucial that immune-based therapies are compatible and, preferably, show synergistic activity.8
For example, neoadjuvant ADT of prostate cancer patients results in increased numbers of 
infiltrating CD4 T-cells, CD8 T-cells, natural killer (NK) cells, and macrophages in prostate 
tissues.6,7 Similarly, there is growing evidence that chemotherapy can induce immuno-modulatory 
effects that could facilitate the induction of antitumor immunity.
Nivolumab in combination with Docetaxel
Docetaxel, a second-generation semisynthetic taxane analog, became the first chemotherapeutic 
agent to show an OS benefit in mCRPC in two randomized controlled clinical trials (TAX 327 and 
SWOG 99-16), and was approved in combination with prednisone for this indication in the US in 
2004.15,16 In the landmark TAX 327 Phase 3 trial, 1006 participants with mCRPC were 
randomized to receive daily prednisone and either mitoxantrone 12 mg/m2 Q3W, docetaxel 
75 mg/m2 Q3W, or docetaxel 30 mg/m2 QW for 5 of every 6 weeks.15 Participants who received 
docetaxel Q3W had a median survival of 19.2 months, compared to 16.3 months in the 
mitoxantrone Q3W and 17.8 months in the docetaxel QW arms. The hazard ratio for the docetaxel 
Q3W arm was 0.76 (95% confidence interval [CI], 0.62 to 0.94; P = 0.009). It is hypothesized that 
chemotherapy may modify the immune response to tumors by influencing multiple mechanisms, 
including inducing immunogenic cell death, stimulating release of tumor antigens and/or depleting 
immuno-suppressive Tregs. Chemotherapies (docetaxel, cabazitaxel) can have profound effects 
on the immune system, including acute reductions in NK, T, and B cells. Paradoxically, while 
treatment with docetaxel may induce lymphocytopenia in patients,72 upon regeneration of immune 
cell populations, an enhanced anti-tumor immune response can occur through a reduction of 
immunosuppressive cell types, including myeloid-derived suppressor cell (MDSC) suppression73
and the selective depletion of Treg cells.74 In mouse models, the administration of docetaxel after 
vaccine-based immunotherapy increased the response compared to either treatment alone,75
potentially as a result of increased T cell response and neoantigen presentation.76 Docetaxel has 
been reported to increase the production of proinflammatory cytokines which may enhance the 
immune response.77 In patient studies, evaluating immune response to taxanes in breast cancer, 
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increased T-Cell and natural killer (NK) activation is also correlated with the use of docetaxel.78
These findings indicate that use of immunotherapy may augment the enhanced immune response 
seen following the use of standard-of-care chemotherapy and have led to the development of 
clinical trials evaluating the combination of docetaxel and various immune therapy approaches.
Nivolumab has been combined with docetaxel and other taxane agents, such as paclitaxel, and also 
with other cytotoxic agents. The combination of nivolumab with platinum-based doublet 
chemotherapy has shown promising activity and limited added toxicity in a Phase 1 study in 
NSCLC.79 In this study, 14 participants were treated with nivolumab 5 mg/kg (equivalent to a 
360 mg flat dose), 200 mg/m2 paclitaxel, and carboplatin Q3W for 4 cycles, followed by 
nivolumab alone until disease progression or unacceptable toxicity. The most common toxicities 
reported with the combination were those expected for chemotherapy alone and included fatigue, 
nausea, and decreased appetite. Treatment-related select AEs (those AEs with an immunological 
etiology) were slightly higher than seen with nivolumab monotherapy. Select AEs of skin rash 
occurred in 5 participants (36%, with 1 Grade 3-4 AE), diarrhea in 3 participants (21%, Grade 1-2), 
acute renal failure in 2 participants (14%, Grade 3-4), and pneumonitis in 2 participants (with 1 
Grade 3-4). All select AEs were effectively managed with corticosteroids, and none resulted in 
death. Compared to historical controls, the activity of the combination, even in such a small cohort, 
was encouraging. The ORR was 43%, with 6 participants achieving a partial response (PR). The 
median DOR was 19.6 months, the median PFS was 7.1 months, and the 6-month PFS rate was 
51%. Median OS had not been reached at the time of the database lock, but 1-year and 2-year OS 
rates were 86% and 62%, respectively. 
In a Phase 1, open-label, uncontrolled study of nivolumab in combination with chemotherapy in 
participants with Stage IIIB/IV or recurrent NSCLC (ONO-4538-04, see the current IB for 
nivolumab for more information), nivolumab 10 mg/kg was administered in combination with 
docetaxel in 6 Japanese participants. The most common drug-related AEs reported in at least 
2 participants were neutrophil count decreased, white blood cell count decreased, lymphocyte 
count decreased and alopecia. AEs leading to nivolumab discontinuation were observed in 
3 participants (hypothyroidism, lung infection, and infusion-related reaction); hypothyroidism and 
infusion-related reaction were considered possibly related to nivolumab.
In mCRPC, docetaxel is being tested in combination with nivolumab in Arm B of the ongoing 
Phase 2 CA209-9KD study (NCT03338790) in patients who had received up to two prior second-
generation hormonal manipulation in the pre-chemotherapy setting. Enrollment has been 
completed (n = 84) and an interim analysis was conducted in 41 patients with at least 16 weeks of 
follow-up (Database lock date 09-May-2019). The safety of the combination was consistent with 
the profiles of individual agents, with 49% of patients experiencing Grade 3-4 treatment-related 
adverse events. Preliminary antitumor activity appeared promising, with ORR being 37%, PSA-
RR 47% and rPFS 8.2 months.
In addition, the combination of pembrolizumab and docetaxel was tested in 72 pts with mCRPC 
who progressed after either abiraterone or enzalutamide.10 The preliminary results showed that the 
combination was generally well tolerated with promising anti-tumor activity (ORR 14%; PSA-RR 
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31%; time to PSA progression 5.5 and 7 months for patients with measurable and non-measurable 
disease, respectively; rPFS 8 months; OS NR [12.9 to NR]), and potential benefit vs docetaxel 
alone.
Given the well characterized AE profile of docetaxel (ie, pancytopenia, fluid retention, peripheral 
neuropathies, diarrhea, nausea, and vomiting) and the evidence from combination studies showing 
that the safety profile of nivolumab plus chemotherapy can be managed using established safety 
guidelines, the proposed combination of nivolumab and docetaxel is expected to bring clinical 
benefits with manageable safety to men with mCRPC.
5.5.3
Rationale for Choice of Endpoints
OS is easily measured, unambiguous, objective, and unaffected by the timing of assessment. It is 
considered the gold standard among efficacy endpoints (clinically and regulatory accepted), and 
an appropriate measure of treatment benefit for immune checkpoint inhibitors. However, given the 
availability of effective systemic therapies to treat mCRPC patients in the post-docetaxel setting 
(eg, abiraterone, enzalutamide, cabazitaxel, radium-223), rPFS has been chosen as a second 
primary endpoint as it will not be confounded by subsequent treatments.
5.5.4
Rationale for Sample Size Determination
The sample size of the study accounts for the two primary endpoints: rPFS and OS. The 
assumptions of rPFS and OS were derived from the following studies:

two Phase 3 studies that led to docetaxel approval (TAX32715: OS 19.9 mo; 
SWOG991616: rPFS 6.3 mo; OS 17.5 mo).

two 
retrospective 
docetaxel 
studies 
conducted 
in 
the
post-abiraterone 
setting 
(Azad 201480: rPFS 4 mo, OS 11.6 mo; Mezynski 201281: OS 12.5 mo).
Since the pivotal Phase 3 studies were conducted approximately 15 years ago prior to novel 
antiandrogen therapies approval and survival outcomes have improved since then, a more recent 
study evaluating 1st line docetaxel vs cabazitaxel (Firstana: rPFS 12. 1 mo derived from composite 
PFS endpoint) was also used for rPFS assumptions.82
Therefore, the expected rPFS and OS with docetaxel monotherapy in the chosen population are 6 
months and 15 months, respectively.
Delayed separation of KM curves is included in the alternative hypotheses for rPFS and OS 
because a delayed immunotherapy effect was observed in various tumors.83 84 85 86
See Section 10.1 (Sample Size Determination) for a description of the sample size determination.
5.5.5
Rationale for Duration of Study Treatment
5.5.5.1
Nivolumab
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Clinical trials across different tumors types in the nivolumab and ipilimumab development 
program indicate that most of the responses occur early, with a median time to response of 2 to 4 
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months,87,88,89,90,91 and emerging data suggest that benefit can be maintained in the absence of 
continued treatment. A recent analysis in a melanoma study suggests the majority of patients who 
discontinue nivolumab and/or ipilimumab for toxicity maintain disease control in the absence of 
further treatment.92 Furthermore, a limited duration of ipilimumab, including only 4 induction 
doses, resulted in long term survival in patients with metastatic melanoma, with a sustained plateau 
in survival starting around 2 years after the start of treatment.93
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 subjects with NSCLC), specified a maximum treatment duration of 2 years. Among 
16 subjects with NSCLC who discontinued nivolumab after completing 2 years of treatment, 
12 subjects were alive > 5 years and remained progression-free without any subsequent therapy. 
In the CA209003 NSCLC cohort, the OS curve begins to plateau after 2 years, with an OS rate of 
25% at 2 years and 18% at 3 years.94 These survival outcomes are similar to Phase 3 studies in 
previously treated NSCLC, in which nivolumab treatment was continued until progression or 
unacceptable toxicity (2 year OS rates of 23% and 29%, and 3 year OS rates of 16% to18% for 
squamous and non-squamous NSCLC, respectively).95
Similar results have been reported in clinical studies of pembrolizumab, another PD-1 inhibitor. 
Keynote-010 was a randomized Phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg 
every 3 weeks) versus docetaxel in subjects with previously treated, PD-L1-positive, advanced 
NSCLC which specified a maximum treatment duration of 2 years for pembrolizumab. OS was 
significantly longer with both pembrolizumab 2 mg/kg (HR 0.72, P = 0.00017) and 
pembrolizumab 10 mg/kg (HR 0.60, P < 0.00001) compared to docetaxel, with an OS plateau 
developing beyond 2 years in both pembrolizumab arms. Among 690 patients who received 
pembrolizumab, 47 patients completed 2 years of pembrolizumab and stopped treatment. Most
were able to maintain their response, including those with stable disease, with only 2 patients (4%) 
having confirmed progression after stopping at 2 years.96
Keynote-006 was a randomized Phase 3 study of pembrolizumab versus ipilimumab in patients 
with advanced melanoma, which also specified a maximum 2 year duration of pembrolizumab 
treatment. 104 (19%) of 556 patients randomized to pembrolizumab completed 2 years of 
treatment. With a median follow-up of 9 months after completion of pembrolizumab, the estimated 
risk of progression or death was 9% in these patients.97
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 
2 years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed 
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
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of retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
progression-free survival (PFS) compared to those who were randomized to stop treatment, with 
median PFS (post-randomization) not reached vs 10.3 months, respectively; HR = 0.42 (95% CI, 
0.25 to 0.71). With a median follow-up of 14.9 months post-randomization, there also was a trend 
for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33 to 1.20]). Of note, 
the PFS curves in both groups plateau approximately 1 year after randomization (ie, 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years.98
Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O 
treatment beyond 2 years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer term treatment. Therefore, in 
this study, treatment will be given for a maximum of 2 years from the start of study treatment.
5.5.5.2
Docetaxel
The duration of treatment for docetaxel, should be based on the assessment of benefit and 
toxicities. In a pivotal trial establishing the survival advantage of docetaxel chemotherapy, 
participants received up to 10 cycles of treatment.15 Administering more than 10 cycles of 
docetaxel has not demonstrated any further improvement in survival and is associated with more 
adverse effects.99,100 Therefore, in the present study, docetaxel will be administered for a 
maximum of 10 cycles, or until disease progression, unacceptable toxicity, withdrawal of 
participant consent, or the end of the study, whichever occurs sooner.
Please consult the current prescribing information for docetaxel for further details concerning 
administration. 
5.5.6
Rationale for Nivolumab 30-Minute Infusion
Long infusion times place a burden on participants and treatment centers. Nivolumab was 
originally approved in the US with a 60-minute infusion using 3 mg/kg Q2W body weight-based 
dosing and is now approved in the US using a 30 minute infusion for the 240 mg Q2W and 480 mg 
Q4W flat doses. Previous clinical studies show that nivolumab has been administered safely over 
60 minutes at doses ranging up to 10 mg/kg over long treatment durations. In Study CA209010 
(a Phase 2, randomized, double-blind, dose-ranging study of nivolumab in participants with 
advanced/metastatic clear cell RCC), a dose association was observed for infusion site reactions 
and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg, and 18.5% at 10 mg/kg). All 
the events were Grade 1-2 and were manageable. An infusion duration of 30 minutes for 360 mg 
or 480 mg doses of nivolumab is not expected to present safety concerns compared to the prior 
experience at 10-mg/kg nivolumab dose infused over a 60-minute duration. Nivolumab 480 mg 
Q4W and nivolumab 360 mg Q3W infused over 30 minutes are also being investigated in several 
ongoing clinical studies. Overall, preliminary safety analysis suggests that the safety profile of 
nivolumab administered IV over 30 minutes at 480 mg Q4W or 360 mg Q3W is consistent with 
nivolumab 240 mg Q2W or 3 mg/kg Q2W administered IV over 30 or 60 minutes across multiple 
tumor types with respect to Grade 3-4 AEs, serious adverse events (SAEs), AEs leading to 
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discontinuation, and immune-mediated AEs (IMAEs) including hypersensitivity/infusion reaction 
IMAEs. There were no new safety concerns identified. For study CA2099KD (a Phase 2 study of 
nivolumab in combination with either rucaparib, docetaxel or enzalutamide in men with mCRPC), 
the protocol specifies monitoring and management of safety events including nivolumab-related 
infusion reactions. In summary, nivolumab 360 mg Q3W or nivolumab 480 mg Q4W infused over 
30 minutes is expected to provide a comparable safety profile to that seen with a 60-minute 
infusion, and is not expected to present additional safety concerns.
 
 
 
 
 
 
 
 
5.6
Justification for Dose
5.6.1
Justification for Nivolumab Dose
Nivolumab will be administered as a flat dose of 360 mg once every 3 weeks (Q3W) in 
combination with docetaxel for a maximum of 10 cycles, in order to maintain synchronized dosing 
of both agents on the same day and then switch to a nivolumab dose of 480 mg given every 4 
weeks (Q4W) for dosing convenience. 
Nivolumab PK has been extensively studied in multiple tumor types, including melanoma, 
NSCLC, RCC, cHL, SCCHN, CRC and urothelial carcinoma and has been safely administered at 
doses up to 10 mg/kg Q2W. Nivolumab monotherapy was originally approved as a body-weight 
based dose of 3 mg/kg Q2W, and was recently updated to 240 mg Q2W or 480 mg Q4W in multiple 
indications.101,102 Nivolumab 360 mg Q3W is also under evaluation in monotherapy and in 
combination therapy studies. Less frequent 360 mg Q3W and 480 mg Q4W dosing regimens can 
reduce the burden to patients of frequent, lengthy IV treatments and allow combination of 
nivolumab with other agents using alternative dosing regimens. 
The benefit-risk profiles of nivolumab 240 mg Q2W, 360 mg Q3W and 480 mg Q4W are predicted 
to be comparable to 3 mg/kg Q2W. This assessment is based on a comprehensive characterization 
of nivolumab PK, safety, efficacy, and exposure-response relationships across indications. 
Population PK (PPK) analyses have shown that the PK of nivolumab is linear with proportional 
exposures over a dose range of 0.1 to 10 mg/kg; no clinically meaningful differences in PK across 
ethnicities and tumor types were observed. Using the PPK model, the exposures following 
administration of several dosing regimens of nivolumab administered as a flat dose were 
simulated, including 240 mg Q2W, 360 mg Q3W and 480 mg Q4W. The simulated average serum 
concentration at steady state [Cavgss] following administration of nivolumab 360 mg Q3W and 
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480 mg Q4W are predicted to be similar to those following administration of nivolumab 240 mg 
Q2W and nivolumab 3 mg/kg Q2W administered to participants over a wide body weight range 
(34 to 180 kg) across tumor types.
Extensive exposure-response (E-R) analyses of multiple PK measures (maximum serum 
concentration at Day 1 [Cmax1], average serum concentration at Day 28 [Cavg28], and trough 
serum concentration at Day 28 [Cmin28]) and efficacy and safety endpoints indicated that the 
efficacy of the flat-dose 480 mg IV regimen are similar to that of 3 mg/kg Q2W IV regimen. In 
E-R efficacy analyses for OS and ORR conducted in melanoma, RCC, and NSCLC using Cavg28 
as the exposure measure, probabilities of achieving a response and survival probabilities at 1 year 
and 2 years for IV 480 mg Q4W were similar to that of IV 3 mg/kg Q2W. In E-R safety analyses, 
it was demonstrated that the exposure margins for safety are maintained following nivolumab 
480 mg Q4W, and the predicted risks of discontinuations due to AEs or death, AE Grade 3+, and 
immune-mediated AEs (IMAEs) Grade 2+ are similar following nivolumab 480 mg Q4W relative 
to nivolumab 3 mg/kg Q2W across tumor types. In addition, nivolumab exposures with 240 mg 
Q2W, 360 mg Q3W, and 480 mg Q4W flat-dose IV regimens across tumor types are maintained 
well below the corresponding exposures observed with the well-tolerated 10 mg/kg IV nivolumab 
Q2W dose regimen.
Additional details on nivolumab posologies and risk-benefit can be found in the investigator 
brochure.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants or their legally acceptable representative (see Appendix 2), must have signed 
and dated an IRB/IEC approved written informed consent form in accordance with 
regulatory and institutional guidelines. This must be obtained before the performance of 
any protocol-related procedures that are not part of normal patient care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study.
2) Type of Participant and Target Disease Characteristics
a) Histologic confirmation of adenocarcinoma of the prostate without small cell features. 
Diagnosis must be stated in a pathology report and confirmed by the investigator
b)
Current evidence of metastatic disease documented by either bone lesions on radionuclide 
bone scan and/or soft tissue lesions on CT/MRI. Metastases may be in regional lymph 
nodes (N1 per AJCC staging criteria, 8th edition) and/or distant metastases (M1 per AJCC 
staging criteria, 8th edition).
i)
Participants whose disease spread is limited to regional pelvic lymph nodes (N1) 
measuring at least 2 cm in short axis will be considered eligible.
c) ECOG performance status 0-1
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d) Ongoing androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone 
(GnRH) analogue or bilateral orchiectomy (ie, surgical or medical castration) confirmed 
by testosterone level 1.73 nmol/L (50 ng/dL) at the screening visit. Castrate levels of 
testosterone must be maintained by surgical or medical means (luteinizing hormone-
releasing hormone [LHRH]/ GnRH analogues) throughout the conduct of the study. For 
participants who have not had an orchiectomy, this therapy must have been initiated at least 
4 weeks prior to first dose of study treatment and treatment must be continued throughout 
the study
e) Documented prostate cancer progression as per PCWG3 criteria within 6 months prior to 
screening with at least one of the following:
i)
PSA progression* defined by a minimum of 2 rising PSA levels with an interval of 
1 week between each determination. The PSA value at the screening visit should be 
2 g/L (2 ng/mL).
Note: *Participants who received an anti-androgen must have PSA progression after 
withdrawal (4 weeks since last flutamide administration or 6 weeks since last 
bicalutamide or nilutamide administration)
ii) Radiographic disease progression in soft tissue based on RECIST 1.1 criteria. 
iii) Radiographic disease progression in bone defined as appearance of 2 or more new bone 
lesions on bone scan
f)
Participants who are chemotherapy- naïve for mCRPC and have received at least 1 but no 
more than 2 second-generation hormonal manipulations (also known as novel antiandrogen 
therapies [NAT] eg, including but not limited to abiraterone acetate, enzalutamide, 
apalutamide, and darolutamide) in the recurrent non-metastatic setting and/or the 
metastatic setting (no more than 1 prior Novel Androgen Therapy (NAT) is allowed in the 
mCRPC setting*), or have become intolerant of the drug. Patients must have progressed 
during or after NATs or have documented intolerance to the drug (ie, unacceptable toxicity 
in spite of comprehensive supportive therapy).
* If the same NAT was given more than once in the context of a different disease setting or 
if intervening therapy was administered, then these NAT will be considered as separate 
NAT regimens.
g) Participants already receiving agents for the management of skeletal-related events (SREs) 
are allowed to continue with anti-bone resorptive therapy (including, but not limited to 
bisphosponate or receptor activator of nuclear factor kappa ligand inhibitor) if on stable 
dose for more than 28 days prior to start of study treatment.
 
 
 
 
 
 
i)
Prior prostate cancer vaccine therapy (eg, sipuleucel-T), radium-223, second-generation 
hormonal manipulations (eg, abiraterone acetate, enzalutamide, apalutamide, and 
darolutamide), antiandrogens (eg, flutamide), ketoconazole, and diethylstilbestrol (DES) 
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or other estrogens, are allowed if treatment was completed at least 28 days prior to start of 
study treatment. Note: bicalutamide or nilutamide must be discontinued at least 6 weeks 
prior to the start of study treatment.
i)
Participants with a history of response to an anti-androgen or adrenal androgen-
production inhibitor and with subsequent progression while receiving that antiandrogen 
should be assessed for antiandrogen withdrawal response for 4 weeks, and must 
demonstrate progression as described in Inclusion Criterion 2e and have stopped 
receiving the antiandrogen prior to start of study treatment.
ii) For participants who have never responded to antiandrogens, observation for 
antiandrogen withdrawal response is not necessary.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3) Age and Reproductive Status
a) Males, ages 18 or local age of majority
b) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with docetaxel plus 5 half-lives of 
the study treatment plus 90 days (duration of sperm turnover) for a total of 6 months after 
the last dose of docetaxel. In addition, male participants must be willing to refrain from 
sperm donation during this time.
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Investigators shall counsel male participants who are sexually active with WOCBP on the 
importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise male participants who are sexually active with WOCBP on the use 
of highly effective methods of contraception (Appendix 4). Highly effective methods of 
contraception have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) Not applicable per Protocol Amendment 02 (see new criterion m) below): Prior 
malignancy active within the previous 3 years (ie participants with a history of prior 
malignancy are eligible if treatment was completed at least 3 years before enrollment) 
except for locally curable cancers that have been apparently cured, such as basal or 
squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the breast.
b) Participants with active brain metastases. Participants with brain metastases are eligible to 
enroll in this study if brain metastases have been treated and there is no magnetic resonance 
imaging (MRI except where contraindicated in which case CT scan is acceptable) evidence 
of progression for at least 4 weeks after treatment is complete and within 28 days prior to 
first dose of study drug administration. Such cases should be discussed with the BMS 
Medical Monitor or designee. Previously irradiated brain lesions are not considered 
measurable disease. Participants must have recovered from the effects of major surgery 
requiring general anesthesia or significant traumatic injury at least 14 days before start of 
study disease.
c) Participants must have recovered from the effects of major surgery requiring general 
anesthesia or significant traumatic injury at least 14 days before start of study treatment.
d)
Prior radiation therapy within 2 weeks prior to start of study treatment. Patients should 
have recovered (ie, Grade 1 or at baseline) from radiation-related toxicities. 
e) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 or baseline before administration of study treatment. Participants 
with toxicities attributed to prior anti-cancer therapy that are not expected to resolve and 
result in long-lasting sequelae, such as peripheral neuropathy after platinum based therapy, 
are permitted to enroll. Participants who have Grade 2 peripheral neuropathy are 
excluded.
f)
Participants with an active, known or suspected autoimmune disease. Participants with type 
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
g) Participants who have received a live/attenuated vaccine within 30 days of first dose in the 
study.
h) Dementia, altered mental status, or any psychiatric condition that would prohibit the 
understanding or rendering of informed consent or completing QoL questionnaire.
i)
Known history of a positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at all sites in Germany and where mandated locally (see Appendix 9).
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j)
Participants with serious or uncontrolled medical disorders that, in the opinion of the 
investigator, would impair the ability of the participant to receive protocol therapy or 
obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
k) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
history of congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.
Additionally, in the case of prior severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) infection, acute symptoms must have resolved and based on investigator 
assessment in consultation with the Medical Monitor, there are no sequelae that would 
place the participant at a higher risk of receiving investigational treatment (see Section 
6.4.1).
l)
Participants with superscan on technecium-99m radionuclide bone scans are not eligible 
for the study. Superscan is defined as a bone scan which demonstrates markedly increased 
skeletal radioisotope uptake relative to soft tissue in association with absent or faint renal 
activity (absent kidney sign).
m) Concurrent malignancy (present during screening) requiring treatment or history of prior 
malignancy active within the previous 2 years prior to randomization (ie, participants with 
a history of prior malignancy are eligible if treatment was completed at least 2 years before 
randomization and the patient has no evidence of disease). Participants with history of prior 
early stage basal/squamous cell skin cancer or non-invasive or in situ cancers that have 
undergone definitive treatment at any time are also eligible.
2) Prior/Concomitant Therapy
a) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement 
steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
b) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways
c) Prior treatment with docetaxel or another chemotherapy agent for metastatic castration-
resistant prostate cancer. Prior docetaxel for metastatic castration-sensitive prostate cancer 
is allowed if 12 months elapsed from last dose of docetaxel.
d) Not applicable per Protocol Amendment 02: Prior treatment with radium-223 or other 
therapeutic radiopharmaceuticals for prostate cancer.
e) Treatment with complementary medications (eg, herbal supplements or traditional Chinese 
medicines) to treat the disease under study within 2 weeks prior to start of study treatment. 
Such medications are permitted if they are used as supportive care. Refer to Section 7.7.1
for other prohibited therapies.
f)
Participants currently in other interventional trials, including those for coronavirus disease 
2019 (COVID-19), may not participate in BMS clinical trials until the protocol-specific 
washout period is achieved. If a study participant has received an investigational COVID-
19 vaccine or other investigational product designed to treat or prevent COVID-19 prior to 
screening, enrollment must be delayed until the biologic impact of the vaccine or 
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investigational product is stabilized, as determined by discussion between the investigator 
and the Medical Monitor.
3) Physical and Laboratory Test Findings
a) WBC < 2000/L
b) Neutrophils < 1500/L
c) Platelets < 100*103/L
d) Hemoglobin < 9.0 g/dL
e) Serum creatinine > 1.5 x upper limit of normal (ULN), unless creatinine clearance 40 
mL/min (measured or calculated using the Cockroft-Gault formula)
f)
AST/ALT > 3.0 x ULN
g) Total bilirubin > 1.0 x ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0 x ULN)
h) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative)
i)
AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. 
Note: Testing for asymptomatic SARS-CoV-2 infection, eg, by reverse transcription polymerase 
chain reaction (RT-PCR) or viral antigen is not required. However, some participants may develop 
suspected or confirmed symptomatic SARS-CoV-2 infection, or be discovered to have 
asymptomatic SARS-CoV-2 infection during the screening period. In such cases, participants may 
be considered eligible for the study after meeting all inclusion/exclusion criteria related to active 
infection, and after meeting the following criteria: 

At least 10 days (20 days for severe/critical illness) have passed since symptoms first 
appeared or positive RT-PCR or viral antigen test result, and

At least 24 hours have passed since last fever without the use of fever-reducing 
medications, and

Acute symptoms (eg, cough, shortness of breath) have resolved, and

In the opinion of the investigator, there are no COVID-19-related sequelae that may place 
the participant at a higher risk of receiving investigational treatment, and 

Negative follow-up SARS-CoV-2 RT-PCR or viral antigen test based on institutional, 
local, or regional guidelines.
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
b) History of hypersensitivity to docetaxel or polysorbate 80
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances and only in countries where local regulations permit, a person who has 
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been imprisoned may be included or permitted to continue as a participant. Strict 
conditions apply and Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Participants receiving docetaxel should be advised to use appropriate sun protection due to the 
potential risk of photosensitivity which may cause sunburn with minimal sun exposure.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized in the study/included in the analysis population. 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, as applicable, and to respond to queries from regulatory authorities. Minimal 
information includes date of consent, demography, screen failure details, eligibility criteria, and 
any serious AEs.
6.4.1
Retesting During Screening 
This study permits the re-enrollment of a participant who has discontinued the study as a pre-
treatment failure (ie, participant has not been treated). If re-enrolled, the participant must be 
re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening or
Lead-in period will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1 Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor/designee may be needed to identify whether repeat testing of any 
particular parameter is clinically relevant.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
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assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
Per Protocol Amendment 04, due to lack of rPFS benefit at the final analysis and OS benefit 
at the first interim analysis for nivolumab added to docetaxel plus prednisone compared to 
placebo added to docetaxel plus prednisone, on 26-Jul-2023, a BMS EOC decided to 
terminate the study. The decision to terminate the study was not based on any safety 
concerns or issues. Full study teams and investigators were unblinded to study treatment 
assignment on 03-Aug-2023; therefore, no participant receiving study treatment will receive 
placebo.
In this protocol, the following are considered Investigational [Medicinal] Product (IP/IMP):

Nivolumab (BMS-936558)

Docetaxel

Not applicable per Protocol Amendment 04: Nivolumab-Placebo (0.9% Sodium Chloride 
Injection, USP, or 5% Dextrose Injection)
Solutions used as placebo (ie, 0.9% Sodium Chloride Injection or 5% Dextrose Injection) or as
diluent should be sourced by investigative sites.
In this protocol, the following is considered as a Non-investigational [Medicinal] Product (Non-
IP/Non-IMP):

Prednisone
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nivolumab
Table 7-1:
Study Treatments for CA2097DX
Product 
Description/Class and 
Dosage Form
Potency
IP/Non-IMP
Blinded or Open 
Label
Packaging / 
Appearance
Storage Conditions
(per label)
BMS-936558-01 
(Nivolumab) Solution 
for Injectiona
100mg (10mg/mL)
IMP
Open Labelb
Vial (multiple vials per 
carton)
Store at 2o – 8oC.
Protect from light and 
freezing.
0.9% Sodium Chloride
for Injection
N/A
IMP
Open-Labelb
Various (local
commercial product)
As per package insert
5% Dextrose for 
Injection
N/A
IMP
Open-Labelb
Various (local
commercial product)
As per package insert
Docetaxel
80mg
IMP
Open Label
Vial in various 
packaging 
configurations
Refer to storage 
conditions on container 
label.
Prednisone
5mg 
Non-IMP
Open Label
Tablets in various 
packaging 
configurations.
Refer to storage 
conditions on container 
label.
a May be labeled as “BMS-936558-01” or “Nivolumab.
b The term “open label” refers to the medication as it is upon receipt at the pharmacy. Not applicable per Protocol Amendment 04: Unblinded pharmacy staff 
at the sites will prepare blinded Nivolumab-placebo.
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BMS-936558
nivolumab
7.1
Treatments Administered
Per Protocol Amendment 04, due to lack of rPFS benefit at the final analysis and OS benefit 
at the first interim analysis for nivolumab added to docetaxel plus prednisone compared to 
placebo added to docetaxel plus prednisone, on 26-Jul-2023, a BMS EOC decided to 
terminate the study. The decision to terminate the study was not based on any safety 
concerns or issues. Study teams and investigators were unblinded to study treatment 
assignment on 03-Aug-2023 and, therefore, no participant receiving study treatment will 
receive placebo.
The selection and timing of dose for each participant, based on allocation to an arm, is presented 
in Table 7.1-1. Duration of treatment per arm is discussed in the sections below the table.
The selection and timing of dose for each participant is as follows:
Table 7.1-1:
Selection and Timing of Dose
Per Protocol Amendment 04, investigators and study teams were unblinded to study treatment assignment; 
therefore, no participant receiving study treatment will receive placebo.
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage formulation
Frequency of Administration
Route of 
Administration
Arm A
Nivolumaba
360 mg
Every 3 weeks
Intravenous
Prednisone
5 mg
Twice daily (BID)
Oral
Docetaxel
75 mg/m2
Every 3 weeks through cycle 10
Intravenous
Arm B
Prednisone
5 mg
Twice daily (BID)
Oral
Docetaxel
75 mg/m2
Every 3 weeks through cycle 10
Intravenous
Not applicable per Protocol 
Amendment 04: Placebo
Not applicable
Every 3 weeks
Intravenous
a Nivolumab or placebo will be administered as combination therapy with docetaxel and prednisone for maximum 
10 cycles, followed by nivolumab monotherapy (480 mg Q4W) or placebo until progression, unacceptable toxicity 
or withdrawal of Consent.
Nivolumab:
There will be no dose escalations or reductions of nivolumab allowed. For Q3W and Q4W dosing 
cycles, all participants may be dosed within a 3 day window. For the Q3W dosing cycle, 
participants may be dosed no less than 18 days after the prior dose. Premedications are not 
recommended for the first dose of nivolumab.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed.
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nivolumab
For nivolumab, refer to the current version of the Investigator Brochure and/or Pharmacy Manual 
for complete storage, handling, dispensing, and infusion information.
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles. 
7.1.1
Nivolumab or Placebo Combined with Docetaxel 
Per Protocol Amendment 04, due to lack of rPFS benefit at the final analysis and OS benefit 
at the first interim analysis for nivolumab added to docetaxel plus prednisone compared to 
placebo added to docetaxel plus prednisone, on 26-Jul-2023, a BMS EOC decided to 
terminate the study. The decision to terminate the study was not based on any safety 
concerns or issues. Full study teams and investigators and study teams were unblinded to 
study treatment assignment on 03-Aug-2023; therefore, no participant receiving study 
treatment will receive placebo.
Participants will receive nivolumab or placebo IV at a flat dose of 360 mg as a 30-minute infusion 
in combination with docetaxel IV at 75 mg/m2 as a 1-hour infusion Q3W and prednisone 
(or prednisolone) 5 mg orally twice daily continuously. Oral dexamethasone 8 mg (or equivalent 
dose of another corticosteroid) to be administered at 12 hours, 3 hours, and 1 hour before the 
docetaxel infusion. Other schedules and routes of administration are also acceptable according to 
local standards
After the nivolumab or placebo infusion, there is a 30-minute delay before the start of the docetaxel 
infusion to monitor the participant for signs of possible infusion reactions and differentiate any 
such reaction from one related to the subsequent docetaxel infusion. Dosing of docetaxel and 
prednisone (or prednisolone) will continue for a maximum of 10 cycles every 3 weeks (± 3 days), 
until progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever 
occurs first.
Dosing calculations of docetaxel should be based on the body weight assessed at baseline. It is not 
necessary to re-calculate subsequent doses if the participant weight is within 10% of the weight 
used to calculate the previous dose. All doses should be rounded up or to the nearest milligram per 
institutional standard.
Participants should begin study treatment within 3 calendar days of start of randomization.
7.1.2
Nivolumab or Placebo Dosing
Per Protocol Amendment 04, due to lack of rPFS benefit at the final analysis and OS benefit 
at the first interim analysis for nivolumab added to docetaxel plus prednisone compared to 
placebo added to docetaxel plus prednisone, on 26-Jul-2023, a BMS EOC decided to 
terminate the study. The decision to terminate the study was not based on any safety 
concerns or issues. Full study teams and investigators were unblinded to study treatment 
assignment on 03-Aug-2023; therefore, no participant receiving study treatment will receive 
placebo.
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nivolumab
After the completion of maximum 10 cycles of combination treatment, nivolumab dosing will 
change to 480 mg. Nivolumab 480 mg or placebo IV will continue to be given alone as a 30-minute 
infusion as maintenance therapy Q4W (s 3 days). The treatment with nivolumab or placebo will 
be given until progression, unacceptable toxicity, completion of 24 months of treatment, 
withdrawal of consent, or the study ends, whichever occurs first.
There will be no dose escalations or reductions of nivolumab or placebo allowed. For Q4W dosing 
cycles, all participants may be dosed within a ± 3 day window. 
Doses of nivolumab or placebo may be interrupted, delayed, or discontinued depending on how 
well the participant tolerates the treatment. Dosing visits are not skipped, only delayed.
For nivolumab, refer to the current version of the Investigator Brochure and/or Pharmacy Manual 
for complete storage, handling, dispensing, and infusion information.
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles.
Premedication:
Premedications are not recommended for the first dose of nivolumab or placebo.
For docetaxel, given the concurrent use of prednisone, the recommended premedication regimen 
is oral dexamethasone 8 mg (or equivalent dose of another corticosteroid) to be administered at 
12 hours, 3 hours, and 1 hour before the docetaxel infusion, however other corticosteroids and/or 
schedules and routes of administration are also acceptable according to local standards. Antiemetic 
premedication will be administered according to local standards. 
If one of the study drugs is discontinued, the other study drug may be continued for the remainder 
of the cycles. 
Participants should be carefully monitored for infusion reactions during nivolumab and docetaxel 
administration. If an acute infusion reaction is noted, participants should be managed according to 
Section 7.4.6 and Section 7.4.7.
7.2
Blinding 
Not applicable per Protocol Amendment 04.Due to lack of rPFS and OS benefit from 
nivolumab added to docetaxel plus prednisone compared to placebo added to docetaxel plus 
prednisone, on 26-Jul-2023 a BMS EOC decided to terminate the study. The decision to 
terminate the study was not based on any safety concerns or issues. Full study teams and 
investigators were unblinded to study treatment assignment on 03-Aug-2023.
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual participant in which knowledge of the 
investigational product is critical to the participant's management, the blind for that participant 
may be broken by the investigator. The participant’s safety takes priority over any other 
considerations in determining if a treatment assignment should be unblinded.
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nivolumab
Before breaking the blind of an individual participant's treatment, the investigator should 
determine that the unblinded information is necessary, ie, that it will alter the participant's 
immediate management. In many cases, particularly when the emergency is clearly not related to 
the investigational product, the problem may be properly managed by assuming that the participant 
is receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The actual TASK of unblinding can be delegated by the investigator to a 
designee assigned the task on the Delegation of Authority. The Principal Investigator or appointed 
designee should only call in for emergency unblinding AFTER the decision to unblind the 
participant has been documented.
For this study, the method of unblinding for emergency purposes is through the IRT. For 
information on how to unblind for emergency, please consult the IRT manual.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind. Any request to unblind a participant for non-emergency purposes should be 
discussed with the Medical Monitor. Scientist in the Bioanalytical Science department of BMS 
(and/or a designee in the external bioanalytical laboratory) will be unblinded to the randomized 
treatment assignments in order to minimize unnecessary bioanalytical analysis of samples. Any 
results shared by the Bioanalytical Science group with the sponsor’s study team will be blinded to 
ensure integrity of the study. The independent central review is blinded to the study therapy 
administrated as well.
7.3
Method of Treatment Assignment
All participants will be centrally randomized using an Interactive Response Technology (IRT). 
Before the study is initiated, each user will receive log in information and directions on how to 
access the IRT.
Study treatment will be dispensed at the study visits as listed in Section 2 (Schedule of Activities).
Within each panel, participants will be randomized in a 1:1 ratio to receive either Docetaxel + 
Nivolumab arm (Arm A) or Docetaxel + Placebo arm (Arm B) according to a computer-generated 
randomization scheme prepared by a Randomization Coordinator within the Drug Supply 
Management Department of BMS Research and Development. Randomization will be stratified 
by the following factors:

1 prior Novel Antiandrogen Therapy (NAT) for mCRPC vs 1 prior NAT for nmCRPC/mCSPC 
vs 2 prior NAT

Visceral disease (Y vs N)
Visceral disease status will be assessed by investigator based on the tumor assessment performed 
during screening. Visceral disease is defined as the presence of metastatic disease in the liver, lung, 
adrenal, peritoneum, brain or other internal organs. Bone, lymph node metastases and prostate 
lesions (or bladder/rectum if from direct invasion from prostate) are not considered visceral 
disease.
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BMS-936558
nivolumab
Enrolled participants, including those not dosed, will be assigned sequential participant numbers 
starting with 
. Sequential numbering may restart at 
 for each participating site as the distinct patient identification number (PID) will ultimately 
be comprised of the site number and participant number
. Those enrolled 
participants meeting inclusion and exclusion criteria will be eligible to be randomized. 
Randomization numbers will be assigned prior to dosing.
7.4
Dosage Modification
Per Protocol Amendment 04, full study teams and investigators were unblinded to study 
treatment assignment on 03-Aug-2023; therefore, no participant receiving study treatment 
will receive placebo.
Table 7.4-1 shows AE criteria to delay, resume, or discontinue nivolumab/placebo. Table 7.4-2
shows AE criteria to delay, reduce, resume, or discontinue docetaxel.
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BMS-936558
nivolumab
Table 7.4-1:
Adverse Event Criteria to Delay, Resume, or Discontinue Nivolumab/Placebo
Per Protocol Amendment 04, full study teams and investigators were unblinded to study treatment assignment; therefore, no participant receiving 
study treatment will receive placebo.
Drug-Related Adverse Event 
(AE) per NCI CTCAE v.5.0
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Gastrointestinal
Colitis or diarrhea
Grade 2 
Delay dose
Dosing may resume when AE resolves to baseline. 
Grade 3 
Delay dose
Dosing may resume when AE resolves to baseline. If Grade 
3 diarrhea or colitis recurs while on nivolumab, 
permanently discontinue. 
Grade 4 
Permanently discontinue
N/A
Renal
Serum creatinine increased
Grade 2 or 3 
Delay dose
Dosing may resume when AE resolves to Grade ≤ 1 or 
baseline value.
Grade 4 
Permanently discontinue
N/A
Pulmonary
Pneumonitis
Grade 2 
Delay dose
Dosing may resume after pneumonitis has resolved to 
≤Grade 1
Grade 3 or 4 
Permanently discontinue
N/A
Hepatic
Aspartate aminotransferase 
(AST), alanine aminotransferase 
(ALT), or total bilirubin (T.bili) 
increased
AST or ALT > 3x and ≤5 x 
upper limit of normal (ULN) 
or T.bili > 1.5 x and ≤ 3 x 
ULN, regardless of baseline 
value
Delay dose
Dosing may resume when laboratory values return to 
baseline.
AST or ALT > 5 x ULN or 
T.bili > 3 x ULN, regardless 
of baseline value
Permanently discontinue 
In most cases of AST or ALT > 5 x ULN, study treatment 
will be permanently discontinued. If the investigator 
determines a possible favorable benefit/risk ratio that 
warrants continuation of study treatment, a discussion 
between the investigator and the Medical Monitor/designee 
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BMS-936558
nivolumab
Table 7.4-1:
Adverse Event Criteria to Delay, Resume, or Discontinue Nivolumab/Placebo
Per Protocol Amendment 04, full study teams and investigators were unblinded to study treatment assignment; therefore, no participant receiving 
study treatment will receive placebo.
Drug-Related Adverse Event 
(AE) per NCI CTCAE v.5.0
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
must occur and approval must be obtained from the Medical 
Monitor prior to resuming therapy.
Concurrent AST or ALT > 3 x 
ULN and T.bili > 2 x ULN, 
regardless of baseline value
Permanently discontinue 
N/A
Endocrinopathy
Adrenal insufficiency
Grade 2 adrenal insufficiency
Delay dose
Dosing may resume after adequately controlled with 
hormone replacement.
Grade 3 or 4 adrenal 
insufficiency or adrenal crisis
Delay dose or 
permanently discontinue
Mandatory discussion with and approval from the Medical 
Monitor needed prior to resuming therapy. If adrenal 
insufficiency resolves or is adequately controlled with 
physiologic hormone replacement, participant may not 
require discontinuation of study drug.
Hyperglycemia
Hyperglycemia requiring 
initiation or change in daily 
management (Grade 2 or 3)
Delay dose
Dosing may resume if hyperglycemia resolves to Grade ≤ 1 
or baseline value, or is adequately controlled with glucose-
controlling agents.
Grade 4
Delay dose or 
permanently discontinue
Mandatory discussion with and approval from the Medical 
Monitor needed prior to resuming therapy. If 
hyperglycemia resolves, or is adequately controlled with 
glucose-controlling agents, participant may not require 
discontinuation of study drug.
Hypophysitis or hypopituitarism 
Symptomatic Grade 1-3 that is 
also associated with 
corresponding abnormal lab 
and/or pituitary scan
Delay dose 
Dosing may resume if endocrinopathy resolves to be 
asymptomatic, or is adequately controlled with only 
physiologic hormone replacement.
Grade 4
Delay dose or 
permanently discontinue
Mandatory discussion with and approval from the Medical 
Monitor needed prior to resuming therapy. If 
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CA2097DX
BMS-936558
nivolumab
Table 7.4-1:
Adverse Event Criteria to Delay, Resume, or Discontinue Nivolumab/Placebo
Per Protocol Amendment 04, full study teams and investigators were unblinded to study treatment assignment; therefore, no participant receiving 
study treatment will receive placebo.
Drug-Related Adverse Event 
(AE) per NCI CTCAE v.5.0
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
endocrinopathy resolves or is adequately controlled with 
physiologic hormone replacement, participant may not 
require discontinuation of study drug.
Hyperthyroidism or 
hypothyroidism
Grade 2 or 3
Delay dose
Dosing may resume if endocrinopathy resolves to be 
asymptomatic, or is adequately controlled with only 
physiologic hormone replacement or other medical 
management.
Grade 4
Delay dose or 
permanently discontinue
Mandatory discussion with and approval from the Medical 
Monitor needed prior to resuming therapy. If 
endocrinopathy resolves or is adequately controlled with 
physiologic hormone replacement or other medical 
management, participant may not require discontinuation of 
study drug.
Skin
Rash
Grade 2 rash covering >30% 
body surface area or Grade 3 
rash 
Delay dose 
Dosing may resume when rash reduces to ≤ 10% body 
surface area. 
Suspected Stevens-Johnson 
syndrome (SJS), toxic 
epidermal necrolysis (TEN), 
or drug reaction with 
eosinophilia and systemic 
symptoms (DRESS)
Delay dose
Dosing may resume if SJS, TEN, or DRESS is ruled out 
and rash reduces to is ≤10% body surface area.
Grade 4 rash or confirmed 
SJS, TEN, or DRESS
Permanently discontinue
N/A
Neurological
Guillain-Barré Syndrome (GBS)
Any Grade
Permanently discontinue
N/A
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BMS-936558
nivolumab
Table 7.4-1:
Adverse Event Criteria to Delay, Resume, or Discontinue Nivolumab/Placebo
Per Protocol Amendment 04, full study teams and investigators were unblinded to study treatment assignment; therefore, no participant receiving 
study treatment will receive placebo.
Drug-Related Adverse Event 
(AE) per NCI CTCAE v.5.0
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Myasthenia gravis (MG)
Any Grade
Permanently discontinue
N/A
Encephalitis
Any Grade encephalitis
Delay dose 
After workup for differential diagnosis (ie, infection, tumor-
related), if encephalitis is not drug related, then dosing may 
resume when AE resolves. 
Any Grade drug-related 
encephalitis 
Permanently discontinue
N/A
Myelitis
Any Grade myelitis
Delay dose
After workup for differential diagnosis (ie, infection, tumor-
related), if myelitis is not drug related, then dosing may 
resume when AE resolves. 
Any Grade drug-related 
myelitis
Permanently discontinue
N/A
Neurological (other than GBS, 
MG, encephalitis, or myelitis)
Grade 2
Delay dose
Dosing may resume when AE resolves to baseline. 
Grade 3 or 4
Permanently discontinue
N/A
Myocarditis
Myocarditis
Symptoms induced from mild 
to moderate activity or 
exertion
Delay dose
Dosing may resume after myocarditis has resolved.
Severe or life-threatening, 
with symptoms at rest or with 
minimal activity or exertion, 
and/or where intervention 
indicated.
Permanently discontinue
N/A
Other Clinical AE
Pancreatitis: 
Grade 3 with symptoms
Delay dose
Note: Grade 3 increased amylase or lipase without signs or 
symptoms of pancreatitis does not require dose delay. 
Dosing may resume when patient becomes asymptomatic.
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CA2097DX
BMS-936558
nivolumab
Table 7.4-1:
Adverse Event Criteria to Delay, Resume, or Discontinue Nivolumab/Placebo
Per Protocol Amendment 04, full study teams and investigators were unblinded to study treatment assignment; therefore, no participant receiving 
study treatment will receive placebo.
Drug-Related Adverse Event 
(AE) per NCI CTCAE v.5.0
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Amylase or lipase increased
Grade 4
Permanently discontinue
N/A
Uveitis
Grade 2 uveitis
Delay dose
Dosing may resume if uveitis responds to topical therapy 
(eye drops) and after uveitis resolves to Grade ≤ 1 or 
baseline. If patient requires oral steroids for uveitis, then 
permanently discontinue study drug. 
Grade 3 or 4 uveitis
Permanently discontinue
N/A
Other drug-related AE (not listed 
above)
Grade 2 non-skin AE, except 
fatigue
Delay dose
Dosing may resume when AE resolves to Grade ≤ 1 or 
baseline value.
Grade 3 AE - First occurrence 
lasting ≤ 7 days
Delay dose
Dosing may resume when AE resolves to Grade ≤ 1 or 
baseline value.
Grade 3 AE- First occurrence 
lasting > 7 days
Permanently discontinue
N/A
Recurrence of Grade 3 AE of 
any duration
Permanently discontinue
N/A
Grade 4 or Life-threatening 
adverse reaction
Permanently discontinue
N/A
Other Laboratory Abnormalities 
Other drug-related laboratory 
abnormality (not listed above)
Grade 3
Delay dose
Exceptions:
No delay required for: Grade 3 lymphopenia. 
Permanent discontinuation for: Grade 3 thrombocytopenia 
> 7 days or associated with bleeding. 
Grade 4
Permanently discontinue
Exceptions: The following events do not require 
discontinuation of study drug: 

Grade 4 neutropenia ≤ 7 days
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CA2097DX
BMS-936558
nivolumab
Table 7.4-1:
Adverse Event Criteria to Delay, Resume, or Discontinue Nivolumab/Placebo
Per Protocol Amendment 04, full study teams and investigators were unblinded to study treatment assignment; therefore, no participant receiving 
study treatment will receive placebo.
Drug-Related Adverse Event 
(AE) per NCI CTCAE v.5.0
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria

Grade 4 lymphopenia or leukopenia
Grade 4 isolated electrolyte imbalances/abnormalities that 
are not associated with clinical sequelae and are responding 
to supplementation/appropriate management within 72 
hours of their onset.
Infusion Reactions (manifested by fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension, hypertension, bronchospasm, or other 
allergic-like reactions.)
Hypersensitivity reaction or 
infusion reaction
Grade 3 or 4
Permanently discontinue
Refer to Section 7.4.6 on Treatment of Related Infusion 
Reactions. 
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Table 7.4-2:
Adverse Event Criteria to Delay, Resume, Reduce or Discontinue Docetaxel
Drug-Related Adverse Event 
(AE) per NCI CTCAE v.5.0
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Hematological
Neutropenia
Grade 2
Delay dose/reduce dosea
If not recovered on the day of administration, delay next 
infusion until neutrophil counts ≥ 1.5 x 109/ L.

1st episode: no dose reduction is required.

2nd episode: consider dose reduction by 1 dose levela.
Granulocyte colony-stimulating factor (G-CSF) may be 
administered at the discretion of the investigator and 
following local guidelines.
Grade 3 or Grade 4
Delay dose/reduce dosea or 
permanently discontinue 
Delay next infusion until neutrophil counts ≥1.5 x 109/ L.
No dose reduction if isolated and duration £ 7 days. 
If duration > than 7 days or not recovered on D21:

1st 
episode: 
consider 
prophylactic 
G-CSF 
in 
subsequent cycles.

2nd episode or 1st episode despite prophylactic G-CSF: 
Reduce dose by 1 dose levela.

3rd episode or 2nd episode despite prophylactic G-
CSF:  permanently discontinue.
Febrile neutropenia or
neutropenic infection
Grade 3 or Grade 4
Delay dose/reduce dosea or 
permanently discontinue
Delay next infusion until neutrophil counts ≥1.5 x 109/ L. 

1st episode: reduce the dosea and consider prophylactic 
G-CSF in subsequent cycles.

2nd episode: permanently discontinue.
Thrombocytopenia
Grade 2
Delay dose
Dosing may resume when AE resolves to Grade ≤1 or 
baseline. 
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Table 7.4-2:
Adverse Event Criteria to Delay, Resume, Reduce or Discontinue Docetaxel
Drug-Related Adverse Event 
(AE) per NCI CTCAE v.5.0
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
No dose reduction required.
Grade 3 or Grade 4
Delay dose/reduce dosea or 
permanently discontinue
Dosing may resume when AE resolves to Grade ≤1 or 
baseline.
If Grade 3 without delay, no dose reduction required.
If Grade 4, or Grade 3 with delay.

1st episode: reduce dose by 1 dose levela.

2nd episode: permanently discontinue.
Permanent discontinuation for: Grade 3 thrombocytopenia 
> 7 days or associated with bleeding.
Gastrointestinal
Diarrhea
Grade 2
Delay dose
Dosing may resume when AE resolves to baseline.
Grade 3
Delay dose/reduce dosea or 
permanently discontinue
1st episode: reduce dose by 1 dose levela. 
2nd episode: permanently discontinue. 
Grade 4
Permanently discontinue
N/A
Colitis or enterocolitis
Grade 2
Delay dose
Dosing may resume when AE resolves to baseline.
Grade 3
Permanently discontinue 
Rare cases of gastrointestinal events, gastrointestinal 
perforation, ischaemic colitis, colitis, neutropenic 
enterocolitis, ileus, and intestinal obstruction have been 
reported with docetaxel.
Participants with obvious signs of enterocolitis or 
peritoneal irritation should be referred urgently to the 
appropriate specialist (ie, gastroenterologist) for 
assessment, and full details of the participant’s exposure to 
docetaxel should be provided.
Grade 4 
Permanently discontinue
Oral mucositis
Grade 2
Delay dose
Dosing may resume when AE resolves to baseline. 
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Table 7.4-2:
Adverse Event Criteria to Delay, Resume, Reduce or Discontinue Docetaxel
Drug-Related Adverse Event 
(AE) per NCI CTCAE v.5.0
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Grade 3 or Grade 4
Delay dose/reduce dosea or 
permanently discontinue
Dosing may resume when AE resolves to Grade ≤1 or 
baseline. 

1st episode: reduce dose by 1 dose levela. 

2nd episode: permanently discontinue. 
Skin
Rash
Grade 2 rash covering <30% 
body surface area 
Delay dose
Dosing may resume when AE resolves to Grade ≤ 1 or 
baseline.
Dosing may resume when rash reduces to ≤ 10% body 
surface area 
Grade 2 rash covering >30% 
body surface area or Grade 3 
rash
Delay dose/reduce dosea or 
permanently discontinue
Dosing may resume when AE resolves to Grade ≤1 or 
baseline.

1st episode: reduce dose by 1 dose levela. 

2nd episode: permanently discontinue. 
Grade 4
Permanently discontinue
N/A
Renal
Creatinine increase
Grade 2 or Grade 3
Delay dose/reduce dosea
Dosing may resume when AE resolves to Grade ≤1 or 
baseline.
Dose reduction may be considered for Grade 3 events at 
the discretion of the investigator and following local 
guidelines.
Grade 4
Permanently discontinue
N/A
Neurological
Neurological toxicity
Grade 2
Reduce dosea
Reduce dose by 1 dose levela.
Grade 3 or Grade 4
Permanently discontinue
N/A
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Table 7.4-2:
Adverse Event Criteria to Delay, Resume, Reduce or Discontinue Docetaxel
Drug-Related Adverse Event 
(AE) per NCI CTCAE v.5.0
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Hepatic
Aspartate aminotransferase 
(AST), alanine 
aminotransferase (ALT), or 
total bilirubin (T.bili) 
increased with or without 
alkaline phosphatase increase
AST or ALT > 3 x and ≤5 x 
upper limit of normal (ULN) or 
T.bili > 1.5 x and ≤3 x ULN, 
regardless of baseline value
or 
T.bili > ULN and/or AST/ALT 
> 1.5 x ULN associated with 
alkaline phosphatase > 2.5 x 
ULN
Delay dose/reduce dosea
Dose reduction may be considered at the discretion of the 
investigator and following local guidelinesa. 
Dosing may resume when laboratory values return to 
baseline. 
AST or ALT > 5 x ULN or 
T.bili > 3 x ULN, regardless of 
baseline value or 
T.bili > ULN and/or ALT and 
AST > 3.5 x ULN associated 
with alkaline phosphatase > 6 x 
ULN
Permanently discontinue 
N/A
Concurrent AST or ALT > 3 x 
ULN and T.bili > 2 x ULN, 
regardless of baseline value
Permanently discontinue 
N/A
Infusion Reactions (manifested by fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension, hypertension, bronchospasm, or other 
allergic-like reactions.)
Hypersensitivity reaction or 
infusion reaction
Grade 3 or 4
Permanently discontinue
Refer to Section 7.4.7: Docetaxel-related Hypersensitivity 
Reactions. 
Other Clinical AE
Cystoid macular oedema 
(CMO)  diagnosed by 
ophthalmologic examination 
Any Grade
Permanently discontinue 
docetaxel
CMO has been reported in participants treated with 
docetaxel. Participants with impaired vision should 
undergo a prompt and complete ophthalmologic 
examination. In case CMO is diagnosed, docetaxel 
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Table 7.4-2:
Adverse Event Criteria to Delay, Resume, Reduce or Discontinue Docetaxel
Drug-Related Adverse Event 
(AE) per NCI CTCAE v.5.0
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
treatment should be discontinued and appropriate 
treatment initiated.
Other drug-related AE (not 
listed above)
Grade 2 non-skin AE, except 
fatigue
Delay dose
Dosing may resume when AE resolves to Grade ≤ 1 or 
baseline value.
Grade 3 AE 
Delay dose/reduce dosea or 
permanently discontinue 
Dosing may resume when AE resolves to Grade ≤ 1 or 
baseline value.

1st episode: dose reduction may be considered at the 
discretion of the investigatora. 

2nd episode: permanently discontinue.
Grade 4 or life-threatening 
adverse reaction 
Permanently discontinue
N/A
Other Laboratory Abnormalities
Other drug-related laboratory 
abnormality (not listed 
above)
Grade 3
Delay dose or reduce dosea  
Dose reduction may be considered at the discretion of the 
investigator and following local guidelinesa. 
Exceptions:
No delay required for: Grade 3 lymphopenia.
Grade 4
Permanently discontinue
Exceptions: The following events do not require 
discontinuation of study drug: 

Grade 4 lymphopenia or leukopenia.

Grade 4 isolated electrolyte imbalances/abnormalities 
that are not associated with clinical sequelae and are 
responding 
to 
supplementation/appropriate 
management within 72 hours of their onset.
Participants receiving docetaxel may receive growth factors (including G-CSF and erythropoietin) at the discretion of the investigator and following local 
guidelines.
a Please refer to section 7.4.2 for instructions on docetaxel dose reduction.
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7.4.1
Nivolumab or Placebo
There will be no dose modifications permitted for nivolumab or placebo
7.4.2
Docetaxel Dose Reduction
Dose reductions of docetaxel may be required and will be performed according to Table 7.4.2-1.
Table 7.4.2-1:
Dose Reductions for Docetaxel
Dose Level
Docetaxel
Starting dose
75 mg/m²
First dose reduction
60 mg/m²
Second dose reduction
Discontinue docetaxel
Docetaxel dose can be reduced when necessary as described in Table 7.4.2-1. The dose which has 
been reduced for toxicity must not be re-escalated. Up to a maximum of 1 dose reduction will be 
allowed per participant. If a second dose reduction is required per the modifications above, the 
patient should discontinue study treatment.
Prednisone (or prednisolone) 
Prednisone or prednisolone doses should not be delayed or modified or stopped (unless there is a 
contraindication to continue, the decision will be left to the investigator’s discretion).
If prednisone or prednisolone is stopped, the participant will continue docetaxel treatment in the 
absence of major toxicity, disease progression or any other discontinuation criteria as defined in 
Section 8.
7.4.3
Dose Delay Criteria
Dose delay criteria apply for all drug-related AEs regardless of whether the event is attributed to 
nivolumab/placebo or docetaxel or both. Delay administration of both nivolumab/placebo and 
docetaxel if any of the delay criteria in Table 7.4-1 and Table 7.4-2 are met. Delay 
nivolumab/placebo and docetaxel dosing for any adverse event, laboratory abnormality, or 
intercurrent illness which, in the judgment of the investigator, warrants delaying the dose of study 
medication. Delay administration of all drugs if SARS-CoV-2 infection either confirmed or 
suspected. 
For participants who require delay of nivolumab/placebo and docetaxel, re-evaluate weekly, or 
more frequently, if clinically indicated and resume dosing when criteria to resume treatment are 
met (see Section 7.4.4). Continue tumor assessments per protocol even if dosing is delayed.
If treatment is delayed > 8 weeks (Q3W cycle) or > 10 weeks (Q4W cycle), nivolumab/placebo
treatment must be permanently discontinued, except as specified in Section 8. Prior to re-initiating 
treatment in a participant with a dosing delay lasting > 8 weeks (Q3W cycle) or > 10 weeks (Q4W 
cycle), the Medical Monitor (or designee) must be consulted.
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7.4.4
Criteria to Resume Study Treatment
Participants may resume dosing when resuming criteria for BOTH nivolumab and docetaxel are 
met if they have completed AE management (ie, corticosteroid taper) or are on ≤ 10 mg prednisone 
or equivalent, and meet the requirements per Table 7.4-1 and Table 7.4-2. That is, nivolumab or 
placebo and docetaxel must be administered together until completion of Cycle 10 or until one or 
both agents are discontinued. The only exception is immune-related toxicities that require 
prolonged nivolumab delay (ie, toxicities treated with a prolonged corticosteroid taper). In such 
cases, dosing with docetaxel may resume prior to nivolumab, when the criteria to resume dosing 
for docetaxel have been met. Nivolumab or placebo dosing may be resumed later, after completion 
of the corticosteroid taper and when criteria to resume nivolumab or placebo dosing have been 
met. It is allowed to administer either nivolumab/placebo or docetaxel if the other is discontinued 
because of toxicity if, in the opinion of the treating investigator, it is in the best interest of the 
participant.
Prior to re-initiating treatment in a participant with a dosing delay lasting > 8 weeks (Q3W cycle) 
or > 10 weeks (Q4W cycle), the Medical Monitor (or designee) must be consulted. Continue tumor 
assessments per protocol even if dosing is delayed. Continue periodic study visits to assess safety 
and laboratory studies as clinically indicated during such dosing delays. 
Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume treatment 
after all of the following criteria are met: 1) at least 10 days (20 days for severe/critical illness) 
have passed since symptoms first appeared or positive test result (eg, RT-PCR or viral antigen);
2) resolution of acute symptoms (including at least 24 hours have passed since last fever without 
fever-reducing medications); 3) evaluation by the investigator with confirmation that there are no 
sequelae that would place the participant at a higher risk of receiving investigational treatment;
and 4) consultation with the Medical Monitor. For suspected cases, treatment may also resume if 
SARS-CoV-2 infection is ruled-out and other criteria to resume treatment are met.
7.4.5
Management Algorithms for Nivolumab 
Immuno-oncology (IO) agents are associated with AEs that can differ in severity and duration 
from AEs caused by other therapeutic classes. Nivolumab is considered an IO agent, and the 
management algorithms in Appendix 6 provide guidance on assessing and managing the following 
groups of AEs:

Gastrointestinal

Renal

Pulmonary

Hepatic

Endocrinopathy

Skin

Neurological

Myocarditis
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7.4.6
Treatment of Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. Report all Grade 3 or 4 
infusion reactions as SAEs (if they meet the criteria) within 24 hours of onset. 
Treatment recommendations are provided below based on National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 5. Grading definitions and may 
be modified based on local treatment standards and guidelines, as appropriate:
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated):

Remain at bedside and monitor participant until recovery from symptoms. The following
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administrations.
For Grade 2 symptoms: (Therapy or infusion interruption indicated but responds promptly to
symptomatic treatment (eg, antihistamines, nonsteroidal anti-inflammatory drugs [NSAIDS], 
narcotics, IV fluids); prophylactic medications indicated for ≤ 24 hrs):

Stop the study drug infusion, begin an IV infusion of normal saline, and treat the participant 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor participant until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor participant closely. If symptoms recur, 
then no further study medication will be administered at that visit.

For future infusions, the following prophylactic premedications are recommended:
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
administered at least 30 minutes before nivolumab infusions. If necessary, corticosteroids (up 
to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for clinical sequelae. Grade 4: Life-threatening 
consequences; urgent intervention indicated):

Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline and 
treat the participant as follows: Recommend bronchodilators: epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration;
and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Monitor participant until the 
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investigator judges that the symptoms will not recur. Study drug will be permanently 
discontinued. Follow institutional guidelines for the treatment of anaphylaxis. Remain at 
bedside and monitor participant until symptoms resolve.
In case of late-occurring hypersensitivity symptoms (eg, appearance of localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.4.7
Docetaxel-related Hypersensitivity Reactions
Patients should be observed closely for hypersensitivity reactions especially during the first and 
second infusions. Hypersensitivity reactions may occur within a few minutes following the 
initiation of the infusion of docetaxel, thus facilities for the treatment of hypotension and 
bronchospasm should be available. If hypersensitivity reactions occur, minor symptoms such as 
flushing or localized cutaneous reactions do not require interruption of therapy. However, severe 
reactions (≥ Grade 3), such as severe hypotension, bronchospasm or generalized rash/erythema 
require immediate discontinuation of docetaxel and appropriate therapy. Patients who have 
developed severe hypersensitivity reactions should not be re-challenged with docetaxel. Patients 
who have previously experienced a hypersensitivity reaction to paclitaxel may be at risk to develop 
hypersensitivity reaction to docetaxel, including more severe hypersensitivity reaction. These 
patients should be closely monitored during initiation of docetaxel therapy.
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
For nivolumab, refer to the current version of the Investigator Brochure and/or Pharmacy Manual 
for complete storage, handling, dispensing and infusion information.
For docetaxel and prednisone, refer to the current prescribing information for the complete storage, 
handling, dispensing and administration information.
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Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2 and Study Reference Manual.
7.5.1
Retained Samples for Bioavailability/Bioequivalence/Biocomparability
Not applicable
7.6
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the participant’s 
medical record and eCRF.
7.7
Concomitant Therapy
Drug-drug interactions (DDI) between nivolumab and co-administered medications are unlikely. 
See the recent nivolumab IB for information concerning DDI studies conducted with nivolumab.
7.7.1
Prohibited and/or Restricted Treatments
7.7.1.1
All Participants
For both treatment arms, the following medications are prohibited during the study (unless utilized 
to treat a drug-related AE):

Immunosuppressive agents and immunosuppressive doses of systemic corticosteroids (except 
as stated in Section 7.7.2) are prohibited during the treatment with nivolumab

Any concurrent non-protocol-specified anti-neoplastic therapy (ie, chemotherapy, hormonal 
therapy other than ADT, immunotherapy, extensive, non-palliative radiation therapy, standard 
or investigational agents for treatment of mCRPC)

Any non-palliative radiation therapy (unless specified per protocol). Limited radiation therapy 
administered with palliative intent (ie, for pain, bleeding, spinal cord compression, brain 
metastasis, new or impending pathologic fracture, superior vena-cava syndrome, or 
obstruction) is permitted  

Any complementary medications (eg, herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study. Such medications are permitted if they are used as 
supportive care.

Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella [MMR]) during treatment and until 100 days post last dose.

Initiation or dose adjustment of approved bone targeting agents is prohibited within 28 days 
prior to start of study treatment. Initiation of these agents is allowed during study treatment, if 
clinically indicated, and should not result in study treatment discontinuation.
7.7.1.2
Nivolumab Combined with Docetaxel
Strong CYP3A4 inhibitors and inducers should be avoided during the treatment with docetaxel. 
Please refer to Appendix 7 for a list of common strong CYP3A4 inhibitors and inducers.
7.7.1.3
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history, and renal status), the appropriate imaging modality and 
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contrast regimen per imaging study. Imaging contraindications and contrast risks are to be 
considered in this assessment. Participants with renal insufficiency are to be assessed as to whether 
or not they should receive contrast and if so, which contrast agent and dose is appropriate. Specific 
to MRI, participants with severe renal insufficiency (ie, estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis, therefore MRI 
contrast is contraindicated. In addition, participants may be excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc. This will be outlined in the image acquisition manual.
Gentle hydration before and after IV contrast should follow local standard of care. The ultimate 
decision to perform MRI in an individual participant in this study rests with the site radiologist, 
the investigator, and standards set by the local Ethics Committee.
7.7.2
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-
type hypersensitivity reaction caused by a contact allergen) is permitted.
7.7.3
Palliative Local Therapy 
Palliative local therapy, including palliative radiotherapy and palliative surgical resection, to 
symptomatic tumor lesions is permitted. Participants requiring palliative local therapy should be 
evaluated (by CT/MRI and bone scan if clinically indicated) for objective evidence of disease 
progression prior to the initiation of such therapy, particularly if the most recent tumor assessment 
was more than 4 weeks prior to the planned start of local therapy. If progression per PCWG3 is 
identified prior to the initiation of palliative local therapy, then participants must either discontinue 
study treatment or they must meet criteria to continue treatment beyond progression (Section 7.7.4)
in order to resume study treatment after the completion of palliative local therapy.
In cases where palliative radiotherapy is required, nivolumab dosing should be withheld for at least 
1 week before, during, and 1 week after radiotherapy. Participants should be closely monitored for 
any potential toxicity during and after receiving radiotherapy, and AEs should resolved to 
Grade 1 prior to resuming nivolumab.
For docetaxel local standard of care guidelines should be followed. 
7.7.4
Treatment Beyond Progression 
Not applicable per Protocol Amendment 04.
Participants will be permitted to continue treatment beyond initial PCWG3-defined PD, as 
assessed by the investigator, up to a maximum of 24 months from date of first dose, as long as the 
following criteria are considered:

Investigator-assessed clinical benefit

Tolerance of study drug

Stable performance status
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
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)

Participant provides written informed consent prior to receiving additional treatment with the 
study drug regimen. All other elements of the main consent including description of reasonably 
foreseeable risks or discomforts, or other alternative treatment options will still apply.
7.7.5
Re-assessment Following Initial Assessment of Progression
Not applicable per Protocol Amendment 04. Radiographic tumor assessments by BICR 
following PCWG3 criteria will no longer apply. All participants receiving study treatment 
will have radiographic tumor assessments based on the clinical judgment of the treating 
investigator and following local imaging tumor assessment guidelines for mCRPC. 
Submission of tumor imaging assessments for central review will no longer apply.
Radiographic assessment/scan(s) should continue in accordance with Section 2 (Schedule of 
Activities) for the duration of the treatment beyond progression and should be submitted to the 
central imaging vendor. This assessment will allow determination of whether there has been a 
decrease in the tumor size or continued PD. The assessment of clinical benefit should be balanced 
by clinical judgment as to whether the participant is clinically deteriorating and unlikely to receive 
any benefit from continued treatment with nivolumab.
For the participants who continue study therapy beyond progression, further progression is defined
as follows: 
Further disease progression of soft tissue is defined as an additional 10% increase in tumor burden 
with a minimum 5 mm absolute increase from time of initial PD. This includes an increase in the 
sum of diameters of all target lesions and/or the diameters of new measurable lesions compared to 
the time of initial PD.
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least
15 mm). Any new lesion considered non-measurable at the time of initial progression may become 
measurable and therefore included in the tumor burden if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes, which must have a short axis of at least 15 mm). In 
situations where the relative increase in total tumor burden by 10% is solely due to inclusion of 
new lesions, which become measurable, these new lesions must demonstrate an absolute increase 
of at least 5 mm.
Further bone disease progression is defined as additional two or more new bone lesions noted on
bone scans compared to the time of PCWG3-defined progression of bone disease.
Study treatment should be discontinued permanently upon documentation of any further 
progression as described above. Confirmed PSA progression alone is not necessarily an indication 
to stop treatment.
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7.8
Treatment After the End of the Study
Per Protocol Amendment 04, due to lack of rPFS benefit at the final analysis and OS benefit 
at the first interim analysis for nivolumab added to docetaxel plus prednisone compared to 
placebo added to docetaxel plus prednisone, on 26-Jul-2023, a BMS EOC decided to 
terminate the study. The decision to terminate the study was not based on any safety 
concerns or issues. Based on these results, BMS recommends discontinuation of nivolumab 
in all participants receiving this study treatment. In the event that the investigator deems a 
participant is deriving clinical benefit from nivolumab therapy and, together with the 
counseled participant, wishes to continue nivolumab, this may be allowed following 
discussion with the Medical Monitor to ensure a clinical rationale exists that justifies 
continuation of nivolumab treatment. 
Study treatment will be provided via an extension of the study, a rollover study requiring approval 
by responsible health authority and ethics committee or through another mechanism at the 
discretion of BMS.
BMS reserves the right to terminate access to BMS supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) development is terminated for other 
reasons, including but not limited to lack of efficacy and/or not meeting the study objectives; c) the 
participant can obtain medication from a government sponsored or private health program. In all 
cases BMS will follow local regulations.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol-specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant

Termination of the study by Bristol-Myers Squibb (BMS) for reasons including but not limited 
to the following: safety concerns, termination of drug development, lack of efficacy, and lack
of meeting study objectives/endpoints.

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required.)
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
Participant meets criteria for radiographic progression per PCWG3 criteria (as defined in 
Appendix 5) unless criteria for treatment beyond progression have been met (see 
Section 7.7.4). PSA progression alone is not an indication to discontinue study treatment (see 
Section 9.1.2).
Refer to Section 2 (Schedule of Activities) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
All participants who discontinue study treatment should comply with protocol-specified follow-
up procedures as outlined in Section 2 (Schedule of Activities). The only exception to this 
requirement is when a participant withdraws consent for all study procedures including post-
treatment study follow-up or loses the ability to consent freely (ie, is imprisoned or involuntarily 
incarcerated for the treatment of either a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
8.1.1
Discontinuation of Specific Study Treatments
The assessment for discontinuation of nivolumab and docetaxel should be made separately for 
each study drug. Although there is overlap among the discontinuation criteria, if discontinuation 
criteria are met for one study treatment but not the other, it may be acceptable to continue treatment 
with the study treatment that is not felt to be related to the toxicity. If the investigator considers 
the toxicity to be related to both study treatments or is unable to determine which study treatment 
is the cause of toxicity, then both study treatments should be discontinued, and the 
recommendations for management of toxicity related to both study treatments should be promptly 
initiated.
Nivolumab and/or docetaxel treatment must be permanently discontinued per criteria in Table 7.4-
1 and Table 7.4-2.
Discontinue nivolumab and/or docetaxel for any adverse event, laboratory abnormality, or 
intercurrent illness which, in the judgment of the investigator, presents a substantial clinical risk 
to the participant with continued nivolumab and/or docetaxel dosing. 
Any event that leads to delay in dosing lasting > 8 weeks (Q3W cycle) or > 10 weeks (Q4W cycle), 
from the previous dose requires discontinuation of study drug, with the following exceptions:

Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events are 
allowed. 

Dosing delays lasting > 8 weeks (Q3W cycle) or > 10 weeks (Q4W cycle) from the previous 
dose that occur for non-drug-related reasons may be allowed if approved by the Medical 
Monitor (or designee).
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8.1.2
Post Study Treatment - Study Follow-up
Not applicable per Protocol Amendment 04. Only participants who received study provided 
nivolumab and are up to 100 days after their last nivolumab infusion will have post-study 
treatment safety follow-up. After completion of the 100-day safety follow-up requirement 
and resolution or stabilization of AEs, nivolumab-treated participants will be discontinued 
from the study. All other participants currently on safety or survival follow-up with 
resolution or stabilization of AEs will be discontinued from the study. 
In this study, overall survival is a key endpoint of the study. Post study follow-up is of critical 
importance and is essential to preserving participant safety and the integrity of the study. 
Participants who discontinue study treatment must continue to be followed (in this study or a 
rollover study) for collection of outcome and/or survival follow-up data as required and in line 
with Section 5 until death or the conclusion of the study.
BMS may request that survival data be collected for all treated participants outside the protocol-
defined window (as detailed in the Schedule of Activities in Section 2). At the time of this request, 
each participant will be contacted to determine his or her survival status, unless the participant has 
withdrawn consent for all contact or is lost to follow-up.
8.2
Discontinuation from the Study
Not applicable per Protocol Amendment 04. Only participants continuing study-provided 
nivolumab and are up to 100 days after their last nivolumab infusion will have post-study 
treatment safety follow-up. After completion of the 100-day safety follow-up requirement 
and resolution or stabilization of AEs, nivolumab-treated participants will be discontinued 
from the study. All other participants currently on safety or survival follow-up with 
resolution or stabilization of AEs will be discontinued from the study. 
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol-specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 

Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.

The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.

In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
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8.3
Lost to Follow-Up
Not applicable per Protocol Amendment 04. 

All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.

Lost to follow-up is defined by the inability to reach the participant after a minimum of three 
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.

If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.

If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 

The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.

If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES

Per Protocol Amendment 04:

Participants continuing study-provided nivolumab and deriving treatment benefit 
per investigator assessment, as well as participants up to 100 days after the last 
infusion of nivolumab, will continue study participation. All other participants will 
be discontinued from the study.

Safety clinical and laboratory assessments will apply only to participants continuing 
study-provided nivolumab, and participants up to 100 days after their last nivolumab 
infusion.

Radiographic tumor assessments will be performed based on the clinical judgment of 
the treating investigator and following local imaging tumor assessment guidelines for 
mCRPC. The same applies for PSA collection.

Study procedures and timing are summarized in Section 2 (Schedule of Activities).

Protocol waivers or exemptions are not allowed.

All immediate safety concerns must be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.

Adherence to the study design requirements, including those specified in Section 2 (Schedule 
of Activities), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
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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 informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.

Perform additional measures, including non-study required laboratory tests, as clinically 
indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug-
induced liver enzyme evaluations) will be monitored during the follow-up phase via on-
site/local labs until all study drug-related toxicities resolve, return to baseline, or are deemed 
irreversible.

Evaluate participant immediately to rule out cardiac or pulmonary toxicity if participant shows 
cardiac or pulmonary-related signs (hypoxia, abnormal heart rate, or changes from baseline) 
or symptoms (eg, dyspnea, cough, chest pain, fatigue, palpitations).

Some of the assessments referred to in this section may not be captured as data in the eCRF. 
They are intended to be used as safety monitoring by the treating physician. Additional testing 
or assessments may be performed as clinically necessary or where required by institutional or 
local regulations.
9.1
Efficacy Assessments
9.1.1
Imaging Assessment for the Study
Not applicable per Protocol Amendment 04: Radiographic tumor assessments by BICR 
following PCWG3 criteria will no longer apply. Moving forward from Protocol Amendment 
04, all participants receiving study treatment will have radiographic tumor assessments 
based on the clinical judgment of the treating investigator and following local imaging tumor 
assessment guidelines for mCRPC. Submission of tumor imaging assessments for central 
review will no longer apply.  
Images will be submitted to a central imaging vendor for BICR during the study. Prior to scanning 
first participant, sites should be qualified and understand the image acquisition guidelines and 
submission process as outlined in the CA2097DX Imaging Manual provided by the central 
imaging.
Screening and on study images should be acquired as outlined in Section 2 (Schedule of Activities).
Tumor assessments at other timepoints may be performed if clinically indicated and should be 
submitted to the central imaging vendor as soon as possible. Unscheduled bone scans, CT/MRI 
should be submitted to central imaging vendor. X-rays that clearly demonstrate interval 
progression of disease, for example most commonly as unequivocal lesions that are unmistakably 
new since the prior CT/MRI, should be submitted to central imaging vendor. Otherwise, they do 
not need to be submitted centrally.
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9.1.1.1
Methods of Measurement
Bone lesions, including those with soft tissue component, will be assessed using technetium-99m 
(Tc-99m) based radionuclide bone scans. 
Contrast-enhanced CT of the, chest, abdomen, pelvis, and all other known and/or suspected sites 
of disease should be performed for tumor assessments. Bone lesions, including those with or 
without a soft tissue component, will be assessed by radionuclide bone scans and not by CT or 
MRI. Images should be acquired with slice thickness of 5 mm or less with no intervening gap 
(contiguous). Every attempt should be made to image each participant using an identical 
acquisition protocol on the same scanner for all imaging timepoints. Tumor measurements should 
be made by the same investigator or radiologist for each assessment, whenever possible. Change 
in tumor measurements and tumor response to guide ongoing study treatment decisions will be 
assessed by the investigator using the PCWG3 criteria.
If a participant has a contraindication for CT intravenous contrast, then a non-contrast CT of the 
chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained. 
If a participant has a contraindication for both MR and CT intravenous contrasts, then a noncontrast 
CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other known/suspected sites 
of disease should be obtained. 
If a participant has a contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, then a non-contrast CT of the chest, abdomen, pelvis, 
and other known/suspected sites of disease is acceptable.
MRI of brain (without and with contrast) should be acquired as outlined in Section 2 (Schedule of 
Activities). CT of the Brain (without and with contrast) can be performed if MRI is 
contraindicated.
9.1.1.2
Imaging and Clinical Assessment
Not applicable per Protocol Amendment 04: Radiographic tumor assessments will no longer 
apply. Moving forward from protocol Amendment 04, all participants receiving study 
treatment will have radiographic tumor assessments based on the clinical judgment of the 
treating investigator and following local imaging tumor assessment guidelines for mCRPC. 
Submission of tumor imaging assessments for central review will no longer apply.
Tumor assessments should continue even if dosing is delayed or discontinued. Changes in tumor 
measurements and tumor responses will be assessed by the same investigator or designee using 
PCWG3 criteria. Assessments of PR and CR must be confirmed at least 4 weeks (28 days) after 
initial response. A Best Overall Response (BOR) of SD requires a minimum of 56 days on study 
from date of first dose to the date of the first imaging assessment.
9.1.2
BICR Confirmation of Progression 
Not applicable per Protocol Amendment 04. Moving forward from Protocol Amendment 04, 
all participants receiving study treatment will have radiographic tumor assessments by 
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BICR following PCWG3 criteria based on the clinical judgment of the treating investigator 
and following local imaging tumor assessment guidelines for mCRPC. Submission of tumor 
imaging assessments for central review will no longer apply.
Sites should submit all scans to the central imaging vendor on a rolling basis, throughout the 
duration of the study. BICR of scans will occur on a rolling basis, blinded to treatment arm, clinical 
data, and investigator assessment of submitted scans. When progression per PCWG3 criteria is 
assessed by the investigator, the site will inform the central imaging vendor, in order for BICR 
assessment of progression to be performed. The BICR will be completed and the results provided 
to the site as specified in the imaging vendor documents, provided there are no pending imaging 
queries to the site. All details on the timelines and associated process requirements will be outlined 
in the Imaging Manual.
Participants whose progression is not confirmed by the BICR will be required to continue tumor 
assessments (if clinically feasible) according to the protocol-specified schedule, or sooner if 
clinically indicated. Also, if participants discontinue treatment without radiographic progression, 
tumor assessments will continue according to the protocol-specified schedule, as noted in 
Section 2 (Schedule of Activities) until progression has been confirmed by BICR. In case 
subsequent therapy has begun, imaging must continue until radiographic progression per PCWG3 
is confirmed by BICR.
All study treatment decisions will be based on the investigator’s assessment of tumor images and 
not on the BICR assessment.
Disease Progression Criteria
Radiographic Progression in soft tissue lesions (Target lesions, Non-target [non-bone] lesions) and 
bone lesions is described in Table 9.1.2-1. See Appendix 6 for more information.
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Table 9.1.2-1:
Definition of Radiographic Progression
Parameter
Progression
Date of Progression
Soft tissue lesions 
(target, non-target 
lesions with CT or 
MRI)
Progression of soft tissue lesions (target, non-target, new 
lesions with CT or MRI)
Date of first unequivocal 
progression of soft tissue 
lesion (target, non-target, or 
new lesions) as per PCWG3a
Bone lesions on 
radionuclide bone 
scan per PCWG3
At least 2 new lesions on the first post-treatment bone 
scan, with at least 2 additional lesions on the next scan 
(performed at least 6 weeks later) as compared to the first 
post-treatment bone scan.
Date of first post-treatment 
scan
For scans after the first post-treatment scan, at least 2 
new lesions relative to the first post treatment scan AND 
confirmed on a subsequent scan (performed at least 6 
weeks later)
Date of progression is the 
date of the scan that first 
documents at least 2 new 
lesions relative to the first 
post-treatment scan
a RECIST v1.1 criteria are modified for assessing soft tissue lesions per PCWG3. See Appendix 5.
Disease progression by PSA (PSA Progression): For participants with an initial PSA decline
from baseline, the date of PSA progression is the date that an increase of 25% or more and an 
absolute increase of 2 ng/mL or more from the nadir are documented and confirmed by a second 
consecutive PSA value at least 3 weeks later. For participants with no PSA decline from baseline, 
the date of PSA progression is the date that an increase of 25% or more and an absolute increase 
of 2 ng/mL or more from baseline are documented at or beyond Week 13.
PSA progression alone is not an indication to stop treatment. Rather, participants must discontinue 
study treatment upon radiographic progression criteria per PCWG3 for measurable disease and/or 
bone disease (Table 9.1.2-1 above). Participants who discontinue treatment without PSA 
progression or radiographic progression will continue to have PSA at FU1, FU2, and every 12 
weeks thereafter (or sooner if needed to confirm PSA progression or if clinically indicated. PSA 
collection will continue until PSA progression, radiographic progression or end of study treatment, 
whichever occurs last.
9.1.3
Patient-Reported Outcomes
Not applicable per Protocol Amendment 04. 
The evaluation of patient-reported outcomes is an increasingly important aspect of clinical efficacy 
in oncology trials. Such data provide an understanding of the impact of treatment from the 
participant’s perspective and offer insights into patient experience that may not be captured 
through physician reporting. Additionally, generic health-related quality of life measures provide 
data needed for calculating utility values to inform health economic models.
Participants will be asked to complete the Brief Pain Inventory - Short Form (BPI-SF), The 
Functional Assessment Of Cancer Therapy - Prostate Cancer (FACT-P), and the 5-level version 
of the EuroQol Group’s EQ-5D (EQ-5D-5L) in the participant’s preferred language when 
available.  The assessments will be given before any clinical activities are performed during on-
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treatment dosing visits and at safety follow-up visits. Additionally, the EQ-5D-5L and the Prostate 
Cancer Subscale (PCS) from the FACT-P will be administered at survival follow-up visits by 
telephone. A standardized guide can be used the EQ-5D-5L by telephone. A similar guide does 
not exist for the PCS. Participants will be provided with a hard copy of the PCS to take home and 
use as a visual aid during telephone interviews. See Section 2 (Schedule of Activities) for more 
information on timing of assessments. If exceptional circumstances preclude the continued 
administration of measures using planned modalities, alternate administration methods may be 
required.
9.1.4
The Brief Pain Inventory - Short Form
Not applicable per Protocol Amendment 04. 
The BPI-SF103 measures both pain severity and functional interference caused by pain through the 
use of a numerical rating scale. Participants rate the severity of their pain at its “worst,” “least,” 
and “average” in the last 24 hours using an 11-point numerical rating scale with anchors of “no 
pain” and “pain as bad as you can imagine.” They are also asked to rate their pain at the time they 
complete the BPI-SF. Using an 11 point numerical rating scale with anchors of “does not interfere” 
and “completely interferes,” the BPI-SF similarly assesses to what extent pain interferes with 
mood, walking, general activity, work, relations with others, sleep, and enjoyment of life. The 
BPI-SF also asks participants to mark the location of their pain on a body drawing and includes 
additional questions regarding pain treatment and the extent of pain relief. The original instrument 
on which the BPI-SF is based, The Wisconsin Brief Pain Questionnaire, was developed and 
validated in oncology patients with the following four tumor types: breast, prostate, colorectal, and 
gynecological.104 The BPI-SF has been validated in cancer patients in several countries with 
psychometrically validated translations in over 25 countries.
9.1.5
The Functional Assessment of Cancer Therapy - Prostate Cancer 
(FACT-P)
Not applicable per Protocol Amendment 04. 
The FACT-P is a multidimensional, self-report instrument specifically designed for use with 
prostate cancer patients.105 The FACT-P includes the 27-item FACT-General (FACT-G), a generic 
cancer-related core, to assess physical well-being (PWB; seven items), social/family well-being 
(SWB; seven items), emotional well-being (EWB; six items), and functional well-being (FWB; 
seven items). In addition, the FACT-P includes a 12-item disease-specific Prostate Cancer 
Subscale that assesses prostate-related symptoms. Each of the 39 items is rated on a 0 (Not at all) 
to 4 (Very much) Likert-type scale, then combined to produce subscale scores for each domain, a 
Trial Outcome Index (TOI) based on the Physical and Functional well-being scales and the PCS 
as well as a total score which ranges from 0 to 156. Higher scores represent better QoL. The FACT-
P uses a recall period of the past 7 days.
9.1.6
The 5-Level EQ-5D
Not applicable per Protocol Amendment 04. 
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The EQ-5D-5L is a standardized instrument used to measure self-reports of general health 
status.106 The instrument has two components, a descriptive system, and a visual analogue scale 
(VAS). The descriptive system consists of 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has five levels, reflecting no problems, 
slight problems, moderate problems, severe problems, and extreme problems. A dimension for 
which there are no problems is said to be at level 1, while a dimension for which there are extreme 
problems is said to be at level 5. Thus, the vectors 11111 and 55555 represent the best health state 
and the worst health state, respectively. Altogether, the instrument describes 3,125 different health 
states. Empirically-derived weights can be applied to an individual’s responses to the EQ-5D-5L 
descriptive system to generate a utility index measuring the value to society of his or her current 
health.107
The EQ-5D-5L VAS allows participants to rate their own current health on a 0 to 100 point scale 
ranging from “the worst health you can imagine” to the “best health you can imagine,” 
respectively.
The EQ-5D-5L uses a recall period of “today.”
9.2
Adverse Events
Per Protocol Amendment 04, AE assessments will only be applicable to participants 
continuing study-provided nivolumab, and participants up to 100 days after their last 
infusion of nivolumab. After completion of the 100-day safety follow-up requirement and 
resolution or stabilization of AEs, nivolumab-treated participants will be discontinued from 
the study. All other participants will be discontinued from the study.
The definitions of an AE or serious adverse event (SAE) are classified according to NCI CTCAE 
version 5 and can be found in Appendix 3.
AEs 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 and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
Contacts for SAE reporting specified in Appendix 3
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
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All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures and within 100 days of discontinuation of dosing.
For participants assigned to treatment and never treated with study drug, SAEs should be collected 
for 30 days from the date of treatment assignment.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure, (eg, a follow-up skin biopsy), Medical 
occurrences that begin before the start of study treatment but after obtaining informed consent will 
be recorded on the appropriate section of the CRF module.

All SAEs will be recorded and reported to sponsor or designee within 24 hours, as indicated in 
Appendix 3.

The investigator will submit any updated SAE data to the sponsor or designee within 24 hours
of updated information being available.
All nonserious AEs (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment.
All SAEs, and all AEs (SAEs and nonserious AEs) associated with confirmed or suspected SARS-
CoV-2 infection must be collected from the date of the participant’s written consent until 100 days 
following discontinuation of dosing.
Investigators are not obligated to actively seek AEs or SAEs 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 reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgment in 
the context of known adverse events, when appropriate for the program or protocol.
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the participant’s case report form.
9.2.3
Follow-up of AEs and SAEs

Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).

Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
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
All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, nonserious AEs of special interest (as defined in 
Section 9.1.3 Adverse Events), and AEs (SAEs and nonserious AEs) associated with confirmed or 
suspected SARS-CoV-2 infection will be followed until resolution; until the condition stabilizes;
until the event is otherwise explained; the event is deemed irreversible; until the participant is lost 
to follow-up (as defined in Section 8.3); or, for suspected cases, until SARS-CoV-2 infection is 
ruled out.
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.

An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will file it along with 
the Investigator Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
Per Protocol Amendment 04, only applicable to female partners of male participants
continuing study-provided nivolumab, and female partners of male participants up to 100 
days after their last infusion of nivolumab. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
sponsor or designee. In order for sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
In cases where a study drug can be present in seminal fluid, at exposures sufficient to potentially 
cause fetal toxicity, and if any sexual activity (eg, vaginal, anal, oral) has occurred between a male 
participant and a pregnant WOCBP partner(s), the information should be reported to the sponsor 
or designee, even if the male participant has undergone a successful vasectomy. In order for 
sponsor or designee to collect any pregnancy surveillance information from the female partner, the 
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female partner(s) must sign an informed consent form for disclosure of this information. 
Information on the pregnancy will be collected on the Pregnancy Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
Per Protocol Amendment 04, only applicable to participants continuing study-provided 
nivolumab, and participants up to 100 days after their last infusion of nivolumab, as required 
in Table 2-2.
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted

Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (DILI)
Per Protocol Amendment 04, only applicable to participants continuing study-provided 
nivolumab, and participants up to 100 days after their last infusion of nivolumab.
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2.1 and Appendix 3 for reporting 
details).
Potential drug induced liver injury is defined as:
1) AT (ALT or AST) elevation > 3 X upper limit of normal (ULN)
AND
2) Total bilirubin > 2 X ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8
Other Safety Considerations
Per Protocol Amendment 04, only applicable to participants continuing study-provided 
nivolumab, and participants up to 100 days after their last infusion of nivolumab.
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Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
Per Protocol Amendment 04, only applicable to participants continuing study-provided 
nivolumab, and participants up to 100 days after their last infusion of nivolumab.
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Overdoses that meet the regulatory 
definition of SAE will be reported as an SAE (refer to Appendix 3).
All instances of accidental overdose and/or dosing errors should be reported on the Dosage 
Administration Record eCRF.
There are a few reports of docetaxel overdose. There is no known antidote for docetaxel overdose.
In case of overdose, the participant should be kept in a specialized unit and vital functions closely 
monitored. In cases of overdose, exacerbation of AEs may be expected. The primary anticipated 
complications of overdose would consist of bone marrow suppression, peripheral neurotoxicity 
and mucositis. Participants should receive therapeutic G-CSF as soon as possible after discovery 
of overdose. Other appropriate symptomatic measures should be taken, as needed.
9.4
Safety
Per Protocol Amendment 04, only applicable to participants continuing study-provided 
nivolumab, and participants up to 100 days after their last infusion of nivolumab.
Planned time points for all safety assessments are listed in Section 2 (Schedule of Activities).
9.4.1
Physical Examinations
Refer to Schedule of Activities (Section 2).
9.4.2
Vital signs
Refer to Schedule of Activities (Section 2).
9.4.3
Electrocardiograms
Refer to Schedule of Activities (Section 2).
9.4.4
Clinical Safety Laboratory Assessments
Per Protocol Amendment 04, laboratory tests will include local safety laboratory tests only 
and will exclude tests such as PSA, 
 and pharmacokinetics. In addition, the 
requirement for local safety laboratory tests will ONLY be applicable to participants 
continuing study-provided nivolumab and participants up to 100 days after their last 
nivolumab infusion. All other participants will be discontinued from the study and switched 
to local standard of care for metastatic castration-resistant prostate cancer outside of the 
study.
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Investigators must document their review of each laboratory safety report.
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)**
Creatinine**
Blood Urea Nitrogen (BUN) or Serum Urea
Fasting glucose**
TSH, Free T3 (fT3), Free T4 (fT4)** 
(screening)
TSH with reflexive fT3*** and fT4 if TSH is 
abnormal on treatment
Albumin* 
Sodium
Potassium
Chloride
Calcium
Phosphorus**
Magnesium**
Creatinine clearance (CLcr)- screening only 
(Cockcroft-Gault method)
Serology
Serum for hepatitis C antibody, hepatitis B surface antigen, HIV-1 and -2 antibody (screening 
only) Note: Testing for HIV must be performed at sites where mandated locally (see Appendix 
9).
Other Analyses
Prostate Specific Antigen (PSA) (PSA should be performed by the same lab throughout the 
treatment period to avoid variations in results between cycles)
Testosterone (at screening only)
*Screening only.
**Assess as indicated in Table 2-1 and Table 2-2. Assess at Safety FU2 only if toxicities are 
present.
***Total T3 may be obtained when free T3 is not available. 
9.4.5
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
9.5
Pharmacokinetics
 
 
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 All on treatment PK time points 
are intended to align with days on which study treatment is administered. If it is known that a dose 
is going to be delayed, then the predose sample should be collected just prior to the delayed dose. 
However, if a predose sample is collected but the dose is subsequently delayed, an additional 
predose sample should not be collected. 
Serum concentration analyses for nivolumab will be performed by validated bioanalytical method. 
Further details of sample collection, processing, and shipment will be provided in the laboratory 
procedures manual. Bioanalytical samples designated for assessments (eg, immunogenicity, PK, 
) from the same collection time point may be used interchangeably for analyses, if 
required (eg, insufficient volume for complete assessment, to follow-up on suspected 
immunogenicity related AE, etc.).
Additionally, residual bioanalytical samples will be archived and may be used for potential 
exploratory bioanalysis (including but not limited to: analysis of drug-ADA immune complexes, 
metabolite analyses, etc.) and or for additional method purposes (including, but not limited to, 
cross-validation, ADA/PK selectivity, cut point, etc.).
Table 9.5-1:
Pharmacokinetic Sampling Schedule for all Arms
Study Day of Sample Collectiona
Combination Phase (max 10 cycles):
1 Cycle = 3 weeks
Monotherapy Phase: (1 Cycle = 4 weeks)
Event
Time Relative to 
Nivolumab/Placebo 
Dose
Hour: Min
Nivolumab 
PK Serum 
Sample
Nivolumab 
IMG Serum 
Sample
Cycle 1 Day 1
Predoseb
00:00
X
X
EOIc
00:30
X
Cycle 2 Day 1
Predoseb
00:00
X
X
Cycle 4 Day 1
Predoseb
00:00
X
X
Cycle 6 Day 1
Predoseb
00:00
X
X
Cycle 10 Day 1d
Predoseb
00:00
X
X
EOIc
00:30
X
Every 4 Cycles (D1) starting at first cycle 
of Monotherapy Phase Day 1 until 2 years
(e.g. C11, C15, C19, C23)
Predoseb
00:00
X
X
Follow Up Period
Follow Up 30 Days
Note: from the last dose of nivolumab 
during treatment period
X
X
Follow Up 100 Days
Note: from the last dose of nivolumab 
during treatment period
X
X
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a If a participant discontinues study drug treatment during the treatment/sampling period, they will move to sampling 
at the follow-up visits. See notes.
b Predose samples should be collected just before the administration of the drug (preferably within 30 minutes prior 
to the start of infusion). If it is known that a dose is going to be delayed, then the predose sample should be collected 
just prior to the delayed dose. However, if a predose sample is collected but the dose is subsequently delayed, an
additional predose sample should not be collected.
c Since the end of infusion pharmacokinetic (EOI-PK) sample is drawn with the intent of accurately estimating the 
maximum concentration (Cmax) of the drug, draw the EOI-PK sample when all of the study drug has been infused. 
If the site infuses drug without a flush, then collect the EOI-PK sample within approximately 5 minutes after end 
of infusion. If a flush is administered to clear the IV lines of the drug and to ensure delivery of the entire drug dose, 
then draw the EOI-PK sample within approximately 5 minutes after end of the flush. Do not draw EOI-PK samples 
from the same IV access through which that the drug was administered.
d If combination therapy ends before 10 cycles, switch directly to the monotherapy phase sampling schedule starting 
at Cycle 11.
9.6
Pharmacodynamics
9.7
Pharmacogenomics
Not applicable
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9.8.2
Additional Research Collection
 
This protocol will include residual sample storage for additional research.
This protocol will include both sample collection and residual sample storage for additional 
research (AR).
For All US sites:
Additional research participation is required for all investigational sites in the US.
If the IRB and investigative site agree to the mandatory additional research retention and/or 
collection, then the study participant must agree to the mandatory additional research collection as 
a requirement for participation in the study.
For non-US Sites:
Additional research is optional for all study participants, except where retention is prohibited by 
local laws or regulations, ethics committees, or institutional requirements. 
This additional research is intended to expand the translational R&D capability at Bristol-Myers 
Squibb, and will support as yet undefined research aims that will advance our understanding of 
disease and options for treatment. It may also be used to support health authority requests for 
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analysis, and advancement of pharmacodiagnostic development to better target drugs to the right 
patients. This may also include 
 aimed at exploring disease 
 
progression and response to treatment etc. 
Sample Collection and Storage:
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the sponsor’s senior leaders in R&D to ensure the research supports appropriate and 
well-defined scientific research activities. 
 
 
Samples kept for future research will be stored at the BMS Biorepository in 
 USA or an 
independent, BMS-approved storage vendor.
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than fifteen (15) 
years after the end of the study or the maximum allowed by applicable law.
Transfers of samples by research sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
9.8.3
Immunogenicity Assessments 
 
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Blood samples for immunogenicity analysis will be collected according to the schedule given in
Section 9.5 (Pharmacokinetics and Immunogenicity). Samples collected will be evaluated for 
development of Anti-Drug Antibody (ADA) by a validated electrochemiluminescent (ECL) 
immunoassay. Samples may also be analyzed for neutralizing antibodies and PK samples may be 
used for ADA analysis in the event of insufficient volume, to complete immunogenicity 
assessment, or to follow up on suspected immunogenicity-related AEs. 
 
 
 
 
9.9
Healthcare Resource Utilization and Health Economics
Not applicable per Protocol Amendment 04. 
Healthcare resource utilization data, associated with medical encounters, will be collected in the 
CRF by the investigator and study-site personnel for all participants throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded. 
The data collected may be used to conduct exploratory economic analyses and will include:

Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient)

Duration of hospitalization (total days length of stay, including duration by wards; eg, intensive 
care unit)

Number and character of diagnostic and therapeutic tests and procedures

Outpatient medical encounters and treatments (including physician or emergency room visits, 
tests and procedures, and medications)].
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
The primary objectives of this study are to compare rPFS and OS between treatment groups in all 
randomized participants. The primary endpoints, rPFS and OS comprise the primary endpoint 
family and will be compared at the 0.01 level and 0.04 level respectively, ensuring family-wise 
control of the Type I error rate. These endpoints will be tested separately and if significant, the 
alpha allocated to each endpoint will be recycled to the other endpoint. For example, if rPFS is 
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significant at the 0.01 level, then 0.01 will be transferred to the OS analysis for testing at 0.05 
level. Sample size estimation is conducted using EAST 6.4 and further verified in Solara.
Approximately 984 participants will be randomized in a 1:1 ratio to Arm A and Arm B. Sample 
size is calculated assuming exponential distribution for time-to-event endpoints. See Table 10.1-1
for a summary of the sample size assumptions.
Sample size justification for rPFS endpoint
The number of events was estimated assuming an exponential distribution of rPFS for the
Docetaxel arm (Arm B) and a piecewise exponential distribution with a 2 months delayed 
treatment effect for the Nivolumab + Docetaxel arm (Arm A). Approximately 530 rPFS events, 
observed among the 984 randomized participants, provides 90% power to detect an average hazard 
ratio (HR) of 0.67 with a type 1 error of 0.01 (two-sided). The average HR of 0.67 resulted from 
an assumed targeted hazard ratio of 1 for the initial 2 months from randomization and a targeted 
hazard ratio of 0.58 for the time beyond 2-months from randomization. 
Sample size justification for OS endpoint
The number of events was estimated assuming an exponential distribution of OS for the Docetaxel 
arm (Arm B) and a piecewise exponential distribution with a 3-months delayed treatment effect 
for the Nivolumab + Docetaxel arm (Arm A). Approximately 690 OS events, observed among the 
984 randomized participants, provides 92% power to detect an average hazard ratio of 0.76 with a 
type 1 error of 0.04 (two-sided). The average hazard ratio of 0.76 resulted from an assumed 
targeted hazard ratio of 1 for the initial 3 months from randomization and a targeted hazard ratio 
of 0.72 for the time beyond 3-months from randomization. 
For all randomized participants, two interim OS analyses are planned. The two interim OS analyses 
are planned at approximately 47% and 80% of the total events observed at final analysis, 
respectively. The first interim analysis will occur at the time of rPFS analysis. The stopping 
boundaries at the interim and final analyses will be based on the actual number of OS events at the 
time of the analysis using Lan-DeMets alpha-spending function with O’Brien-Fleming boundaries, 
taking into account any alpha that was passed from the rPFS analysis (if applicable). Details of the 
interim analysis will be included in Section 10.3.6 (Interim Analysis).
Assuming an average enrollment rate of 2, 20, 45, and 70 participants randomized per month
during months 1 to 7, 8 to 15, 16 to 21, and 22 to 29, respectively, with a 29-month accrual period, 
it will take approximately 51 months from the date of randomization of the first participant to 
observe the required number of events for OS analyses in all randomized population. The number 
of events needed for the analyses will be monitored by the unblinded independent statistician 
supporting the IDMC. 
Table 10.1-1:
Sample Size Determination
Endpoint
rPFS
Hypothesized median survival time (month)
Arm A= 9: Arm B = 6
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Table 10.1-1:
Sample Size Determination
Endpoint
rPFS
Target Hazard Ratio
HR=1 for t < 2m; Hazard Ratio =0.58 for t ≥2 months
Average Hazard Ratio =0.67
Critical Hazard Ratio
0.80
2-Sided Alpha 
0.01
Sample Size
984
Accrual Duration
29 months
Power
90%
Expected Number of Events
530 eventsa
Expected Timing of rPFS Final Analysis (from 
randomization of first participant)
31 months
Endpoint
OS
Hypothesized median survival time (month)
Arm A= 19.7 : Arm B = 15
Target Hazard Ratio
HR=1 for t < 3m; HR=0.72 for t≥3 months
Average Hazard Ratio =0.76
Critical Hazard Ratio
   The 1st IA 
0.70
   The 2nd IAb
0.82
Final Analysis
0.85
2-Sided Alpha
0.040 (full allocation)
   The 1st IA 
0.0014
   The 2nd IAb
0.018
   Final Analysisb
0.034 (nominal)
Sample Size
984
Accrual Duration
29 months
Power
92%
Expected Number of Events for 
   The 1st IA 
326 events
   The 2nd IAb
552 events
   Final Analysisb
690 events
Expected Timing of OS Analysis (from randomization 
of first participant) 
   The 1st IA 
31 months
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Table 10.1-1:
Sample Size Determination
Endpoint
rPFS
   The 2nd IAb
42 months
   Final Analysisb
51 months
Abbreviations: HR = hazard ratio; IA = Interim Analysis; OS = overall survival.
a rPFS analysis is performed after enrollment completes and observing 530 events in all randomized subjects.
b Per Protocol Amendment 04, the second IA for OS and final analysis for OS will not be performed, and the 
first IA will be considered as the final analysis. At the time of study closeout, an updated descriptive OS 
analysis will be provided to report all death events.
10.2
Populations for Analyses
Table 10.2-1:
Populations for Analyses
Population
Description
Enrolled
All participants who signed an informed consent and were registered into 
the IRT.
Randomized
All participants who were randomized to either treatment arm in the 
study. Primary efficacy analysis, demography, protocol deviations, and 
baseline characteristics will be performed on this population.
All Treated
All treated participants who receive any dose of study drug. Participants 
are grouped within the all treated population according to the treatment 
they actually receive. This is the analysis set for all safety analyses and 
study drug administration.
All Response Evaluable Population
All randomized participants who have measurable disease at baseline as 
assessed by investigator per PCWG3.
PK
All treated participants with available serum concentration data for 
nivolumab.
Immunogenicity
All treated participants with baseline and at least 1 pre-infusion 
immunogenicity assessment.
10.3
Statistical Analyses
Not applicable per Protocol Amendment 04.
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe the selection of participants to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary and secondary endpoints.
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A description of the participant population will be included in a statistical output report, including 
subgroups of age and race.
10.3.1
Efficacy Analyses
Not applicable per Protocol Amendment 04.
Statistical analyses for efficacy are shown in Table 10.3.1-1.
Table 10.3.1-1:
Efficacy Statistical Analyses
Endpoint
Statistical Analysis Methods
Primary
rPFS is defined as the time from randomization
initiation to the first date ofdocumented radiographic
progressions per PCWG3 or death due to any cause,
whichever occurs first. The rPFS will be censored at 
the last tumor assessment up to the start of subsequent 
systemic cancer therapy. It will also be censored at the 
date of last tumor assessment prior to the missed tumor 
assessments for participants who had progressive 
disease (PD) or death immediately after more than one 
consecutive missed tumor assessments.
The following radiographic progressive diseases will 
be collected and documented as assessed by BICR.

Soft tissue disease progression per PCWG3.
Date of first unequivocal progression of soft
tissue lesion will be recorded per BICR 
assessment.

Bone disease progression per PCWG3. Date
of bone progression will be recorded per 
BICR assessments.
rPFS in all randomized participants will be compared 
using a stratified 2-sided log rank test with 
alpha=0.01. The log-rank test p-value will be reported.
The hazard ratio and the corresponding 2-sided 99% 
CI will be estimated in a stratified Cox proportional 
hazard model using the randomized arm as a single 
covariate.
The rPFS function for each treatment arm will be 
estimated using the KM product limit method and will 
be displayed graphically. A 2-sided 95% CI for median 
rPFS in each arm will be estimated via the log-log 
transformation method (primary comparison where 0.01 
alpha will be spent). In addition, descriptive estimates 
for 6 months and 12-months rPFS rates will be 
presented along with their associated 95% CIs.
OS is the time from randomization initiation to the date
of death from any cause.
The OS for all randomized participants will be 
compared using a stratified 2-sided log rank test with 
adjusted alpha at each interim analysis and final 
analysis (alpha will be recycled from rPFS to OS if 
rPFS test is significant). The log-rank test p-value will 
be reported. The hazard ratio and the corresponding 2-
sided (1-adjusted alpha)*100% CI will be estimated in 
a stratified Cox proportional hazard model using the 
randomized arm as a single covariate.
The OS function for each treatment arm will be 
estimated using the KM product limit method and will 
be displayed graphically. A 2-sided 95% CI for median 
OS in each arm will be estimated via the log-log 
transformation method (primary comparison where up 
to 0.04 alpha will be spent). In addition, descriptive
estimates for 12-months and 24-months OS rate will be 
presented along with their associated 95% CIs. 
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Table 10.3.1-1:
Efficacy Statistical Analyses
Endpoint
Statistical Analysis Methods
Secondary
Objective response rate (ORR) per PCWG3 assessed 
by BICR 
ORRs per PCWG3 and corresponding 2-sided exact
95% CIs will be calculated using the Clopper-Pearson
method for all Response Evaluable participants by 
treatment arm.
PSA response rate (PSA-RR)
PSA-RRs per PCWG3 and corresponding 2-sided
exact 95% CIs will be calculated using the Clopper-
Pearson method for all randomized participants with 
PSA values at baseline and at least one post baseline 
assessment by treatment arm.
Time to response (TTR) and duration of response 
(DOR) per PCWG3 assessed by BICR
Summary statistics of time to objective response
(TTR) will be provided for all randomized
participants with a BOR of CR or PR by each
treatment arm.
Duration of response (DOR) will be summarized for 
participants with a BOR of PR or CR per BICR using 
the Kaplan-Meier methodology. Median values, along 
with 2-sided 95% CIs will also be calculated.
Time to PSA progression
Kaplan-Meier plots of time to PSA progression will be
presented for all randomized participants by treatment 
arm. The estimates of the median and corresponding
log-log transformed 2-sided 95% CIs will be
calculated. The rates at months 6 and 12 and 
corresponding 95% CIs will be estimated via the 
Kaplan-Meier methodology.
10.3.2
Safety Analyses
Statistical analyses for efficacy are shown in Table 10.3.2-1
Table 10.3.2-1:
Safety Statistical Analyses
Secondary
Statistical Analysis Methods
Incidence of AE, SAE, AE leading to 
discontinuation, immune-related AEs, 
deaths, and laboratory abnormalities
Descriptive statistics of safety will be presented using NCI CTCAE 
v5.0 by treatment arm. All on-study AEs, treatment-related AEs, 
SAEs, and treatment-related SAEs will be tabulated using worst 
grade per NCI CTCAE v5.0 criteria by system organ class and 
preferred term. On-study laboratory parameters including 
hematology, chemistry, liver function, and renal function will be 
summarized using worst grade NCI CTCAE v5.0 criteria.
10.3.3
Pharmacokinetic Analyses
Not applicable per Protocol Amendment 04.
The nivolumab concentration data obtained in this study may be combined with data from other 
studies in the clinical development program to develop population PK models.
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These models may be used to evaluate the effects of intrinsic and extrinsic covariates on the PK 
of nivolumab and to determine measures of individual exposure (such as steady state peak, trough 
and time averaged concentration). Model determined exposures may be used for exposure-
response analyses of selected efficacy and safety endpoints. If the analyses are conducted, the 
results of population PK and exposure response analyses will be reported separately.
10.3.4
Immunogenicity Analyses
Not applicable per Protocol Amendment 04.
Methodology for analysis of immunogenicity will be described in the statistical analysis plan.
10.3.5
Outcomes Research Analyses
Not applicable per Protocol Amendment 04.
Analyses of BPI-SF, FACT-P, and EQ-5D-5L data will be performed by treatment arm in all 
treated participants who have an assessment at baseline (Day 1, assessment prior to administration 
of drug on day of first dose) Change from baseline analyses also require at least 1 other assessment 
post-baseline. Questionnaire completion rate, defined as the proportion of questionnaires actually 
received out of the expected number, will be calculated and summarized at each assessment point.
Further details will be provided in the Statistical Analysis Plan.
Thresholds for change scores judged to be important to patients are summarized in Table 10.3.5-1
Table 10.3.5-1:
Thresholds Values for Change Scores Judged to be Important to 
Patients
Instruments and Domains
Thresholds reported in the 
literature
Main analyses thresholds
BPI-SF110
2
2
FACT-P
Total Score111
6-10
8
Total Outcome Index (TOI)112
5-9
7
Prostate Cancer Scale (PCS)112
2-3
3
Emotional Well Being Score113
2-3
3
Functional Well Being Score114
2-3
3
Physical Well Being Score114
2-3
3
Social Well Being Score114
2-3
3
EQ-5D-5L VAS110
7
7
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10.3.5.1
BPI-SF
Time to Pain Progression
The participant’s assessment of pain with BPI-SF Item #3 (pain symptoms at their worst over the 
last 24 hours) will form the basis for the analysis of median time to pain progression.112 Pain 
progression will be considered to have occurred,114 if an increase in the worst pain intensity of 2 
points is observed from baseline and maintained over 2 consecutive time periods. Participants who 
die without a reported pain progression will be considered to have progressed on the date of their 
death. Those who neither progress nor die will be censored at the time of their last BPI-SF 
assessment prior to subsequent therapy, while those who neither die nor have any BPI-SF 
assessments after randomization will be censored on the date of randomization. Time to pain 
progression for all randomized participants will be summarized and plotted using the Kaplan-
Meier methodology. Median values, along with two-sided 95% CIs will also be calculated. The 
rate of pain progression at select timepoints and corresponding 95% CIs will also be estimated.
Change in Pain Intensity
The mean value of least pain (Item #4), average pain (Item #5), and current pain (Item #6), along 
with Item #3, will also be analyzed as a composite assessment of change in pain intensity.110
Summary statistics at each assessment point will be provided for each treatment group. The mean 
change from baseline will also be reported at each post-baseline assessment point.
10.3.5.2
FACT-P
Time to Deterioration in Cancer-Related Symptoms and Quality of Life
The analysis of FACT-P will be performed for the total score and all subscales. Participants who 
die without a reported deterioration will be considered to have deteriorated on the date of their 
death. Those who neither deteriorate nor die will be censored at the time of their last FACT-P 
assessment, while those who neither die nor have any FACT-P assessments after randomization 
will be censored on the date of randomization.
Change in Cancer-Related Symptoms and Quality of Life
For FACT-P total scores and all subscales, summary statistics at each assessment point will be 
provided for each treatment group. The mean change from baseline will also be reported at each 
post-baseline assessment point.
10.3.5.3
EQ-5D-5L
Summary statistics for health status and health utility using EQ-5D-5L data at each assessment 
point will be provided for each treatment group. The mean change from baseline will also be 
reported at each post-baseline assessment point.
10.3.6
Other Analyses
Methodology for analysis of other exploratory objectives 
 will be described 
in the statistical analysis plan.
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10.3.7
Interim Analyses 
The Statistical Analysis Plan will further describe the planned interim analyses.
10.3.7.1
Interim Analysis for OS
For the randomized population, two interim OS analyses and one final analysis is planned using 
an alpha of 0.04 if rPFS is not significant and 0.05 if rPFS is significant (0.01 alpha passed). The 
two interim OS analyses are planned at approximately 47% and 80% of the total events observed 
at final analysis, respectively. The stopping boundaries at the interim and final analyses will be 
based on the actual number of OS events at the time of the analysis using Lan-DeMets alpha-
spending function with O’Brien-Fleming boundaries, taking into account any alpha that was 
passed from the rPFS analysis (if applicable). If the interim analyses are performed exactly at 326
and 552 events, respectively, and the rPFS was not significant, the study could be stopped for OS 
superiority if the p-values are 0.0014 and 0.018, respectively. The nominal significance level for 
the final look of OS in all randomized participants after 690 events would then be 0.034.
An independent statistician external to BMS will perform interim analysis.
Per Protocol Amendment 04 and the decision to terminate the study early, the second interim 
analysis for OS and final analysis for OS will no longer be performed, and the first interim 
analysis will be considered as final. At the time of study closeout, an updated descriptive OS 
analysis will be provided to report all death events.
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11
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28 Armstrong A, Smulewitz RZ, Petrylak DP, et al: Phase 3 study of androgen deprivation therapy 
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42 TAXOTERE (docetaxel) prescribing information. Sanofi-Aventis U.S. RSI-SmPC-EMA, 
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50 Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients 
with metastatic castration-resistant prostate cancer that had progressed after docetaxel 
chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet 
Oncol. 2014;15(7):700-12.
51 Beer TM, Kwon ED, Drake CG et al. Randomized, double-blind, Phase III trial of ipilimumab 
versus placebo in asymptomatic or minimally symptomatic patients with metastatic 
chemotherapy- naïve castration-resistant prostate cancer. J Clin Oncol. 2017,35(1):40-47.
52 Yu EY, Massard C, Retz M, et al. Pembrolizumab (pembro) plus olaparib in docetaxel-
pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC): Cohort A 
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54 Rizvi N, Hellmann M, Brahmer J, et al. Nivolumab in combination with platinum-based
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64 Kwon ED, Drake CG, Scher Hi, et al. Ipilimumab versus placebo after radiotherapy in patients 
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chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet 
Oncol. 2014;15(7):700-12
65 Beer TM, Kwon ED, Drake CG et al. Randomized, double-blind, Phase III trial of ipilimumab 
versus placebo in asymptomatic or minimally symptomatic patients with metastatic 
chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol. 2017;35(1):40-47.
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66 Graff JN, Alumkal JJ, Thompson RF, et al. Pembrolizumab (Pembro) plus enzalutamide (Enz) 
in metastatic castration resistant prostate cancer (mCRPC): Extended follow up. J Clin Oncol 
36;no. 15_suppl (May 20 2018) 5047-5047.
67 Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant 
prostate cancer. N Engl J Med. 2010;363:411-22.
68 Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled Phase III trial of 
immunologic therapy with Sipuleucel-T (APC8015) in subjects with metastatic, asymptomatic 
hormone refractory prostate cancer. J Clin Oncol 2006;24:3089-94.
69
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-
1 antibody in cancer.N Engl J Med 2012;366(26):2443-54. 
70 Kim JW, Shaffer DR, Massard C, et al. A phase Ia study of safety and clinical activity of 
atezolizumab (atezo) in patients(pts) with metastatic castration-resistant prostate cancer 
(mCRPC) J Clin Oncol 36, no. 6_suppl (February 2018);187-187.
71 Antonarakis ES, Goh JC, Gross-Goupil M, et al. Pembrolizumab for metastatic castration-
resistant prostate cancer (mCRPC) previously treated with docetaxel: Updated analysis of 
KEYNOTE-199. J Clin Oncol 37; no. 7_suppl (March 1 2019):216-216.
72 Kotsakis, A.; Sarra, E.; Peraki, M.; Koukourakis, M.; Apostolaki, S.; Souglakos, J.; 
Mavromanomakis, E.;Vlachonikolis, J.; Georgoulias, V. Docetaxel-induced lymphopenia in 
patients with solid tumors: A prospective phenotypic analysis. Cancer 2000,89: 1380-6.
73 Kodumudi, KN, Woan, K; Gilvary, DL, Sahakian, E.; Wei, S.; Djeu, J.Y. A novel 
chemoimmunomodulating property of docetaxel: Suppression of myeloid-derived suppressor 
cells in tumor bearers. Clin. Cancer Res 2010;6:4583-94.
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79 Rizvi N, Hellmann M, Brahmer J, et al. Nivolumab in combination with platinum-based 
doublet chemotherapy for first-line treatment of advanced non–small-cell lung cancer. Clin 
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80 Azad AA, Leibowitz-Amit R, Eigl BJ, et al. A retrospective, canadian multi-center study 
examining the impact of prior response to abiraterone acetate on efficacy of docetaxel in 
metastatic castration-resistant prostate cancer. Prostate 2014;74:1544–50.
81 Mezynski J, Pezaro C, Bianchini D, et al. Antitumour activity of docetaxel following treatment 
with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Ann Oncol 
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patients with metastatic castration-resistant prostate cancer: A randomized phase III trial-
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83 Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with 
two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an 
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84 Doki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal 
Squamous-Cell Carcinoma. N Engl J Med. 2022;386(5):449-462.
85 Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus 
chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal 
adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 
2021;398(10294):27-40.
86 Fizazi K, Drake CG, Beer TM, et al. Final Analysis of the Ipilimumab Versus Placebo 
Following Radiotherapy Phase III Trial in Postdocetaxel Metastatic Castration-resistant 
Prostate Cancer Identifies an Excess of Long-term Survivors. Eur Urol. 2020;78(6):822-830.
87 Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-
cell non–small-cell lung cancer. N Engl J Med 2015;373:123-35.
88 Borghaei H, Luis Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced 
nonsquamous non–small-cell lung cancer. N Engl J Med 2015; 373:1627-39.
89 Hellmann, MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line 
treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, 
phase 1, multicohort study. Lancet Oncol 2017;18(1):31-41.
90 Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or 
monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.
91 Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-
cell carcinoma. N Engl J Med. 2015;373(19):1803-13.
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92 Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and quality of life outcomes in patients 
with advanced melanoma (MEL) who discontinued treatment with nivolumab (NIVO) plus 
ipilimumab (IPI) due to toxicity in a phase III trial (CheckMate 067). 2016 Annual Meeting of 
the European Association of Dermato-Oncology; August 31-September 3, 2016; Vienna, 
Austria.
93 Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from 
Phase II and Phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin 
Oncol 2015;33:1889-94.
94 Brahmer J, Horn L, Jackman D et al. Five-year follow-up from the CA209-003 study of 
nivolumab in previously treated advanced non-small cell lung cancer: clinical characteristics 
of long-term survivors. Oral presentation presented at: American Association for Cancer 
Research (AACR) Annual Meeting; April 1-5, 2017; Washington, DC, USA.
95 Felip E, Gettinger SN, Burgio MA et al. Three-year follow-up from Checkmate 017/057: 
Nivolumab versus docetaxel in patients with previously treated advanced non-small lung 
cancer (NSCLC). Poster discussion presentation at the European Society of Medical Oncology 
Annual Meeting. September 8-12, 2017;Madrid, Spain. Poster 1301PD.
96 Herbst RS, Garon E, Kim DW et al. KEYNOTE-010: Durable clinical benefit in patients with 
previously treated, PD-L1-expressing NSCLC who completed pembrolizumab. Poster 
presentation at the World Conference on Lung Cancer ;December 4-7,2016;Vienna, Austria.
97 Robert C, Long GV, Schachter J et al. Long-term outcomes in patients with ipilimumab-naive 
advanced melanoma in the phase 3 KEYNOTE-006 study who completed pembrolizumab 
treatment.J Clin Oncol 2017;35(15_suppl):9504-9504.
98 Spigel DR, McLeod M, Hussein MA et al. Randomized results of continuous vs 1-year fixed-
duration in patients with advanced non-small cell lung cancer. Oral presentation at the 
European Society of Medical Oncology Annual Meeting; Sep 8-12, 2017;Madrid, Spain.
99 Shen YC, Chiang PH, Luo HL, et al. Determine of the optimal number of cycles of docetaxel 
in the treatment of metastatic castration-resistant prostate cancer. Kaohsiung J Med Sci. 
2016;32(9):458-63.
100 Pond GR, Armstrong AJ, Wood BA, et al. Evaluating the value of number of cycles of 
docetaxel and prednisone in men with metastatic castration-resistant prostate cancer. Eur Urol. 
201261:363-9.
101 Nivolumab (Opdivo) US Prescribing Information. Bristol-Myers Squibb Company; Revised
January 2018.
102 Medicines.org.uk. OPDIVO 10 mg/mL Concentrate for Solution for Infusion - Summary of
Product Characteristics - (eMC). Bristol-Myers Squibb Pharmaceuticals, Ltd; Updated July 
2019.Available from: URL: https://www.medicines.org.uk/emc/product/6888/smpc. Accessed 
July 1, 2019.
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103 Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad 
Med Singapore 1994;23(2):129-38.
104 Cleeland CS. The measurement of pain from metastatic bone disease: capturing the patient's 
experience. Clin Cancer Res 2006;12(20 Pt 2):6236s-42s.
105 Esper P, Mo F, Chodak G, et al. Measuring quality of life in men with prostate cancer using 
the functional assessment of cancer therapy-prostate instrument. Urology. 1997;50:920-8
106 Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. 
Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). 
Qual Life Res 2011,20(10):1727-36.
107 Van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, Lloyd A, Scalone 
L, Kind P, Pickard AS. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-
3L value sets. Value  Health. 2012,15(5):708-15.
 
 
 
110 Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ-5D 
utility and VAS scores in cancer. Health and quality of life outcomes 2007;5(1):70
111 Cella D, Nichol MB, Eton D, et al. Estimating clinically meaningful changes for the functional
assessment of cancer therapy--prostate: Results from a clinical trial of patients with metastatic 
hormone-refractory prostate cancer. Value Health. 2009:12(1):124-9. 
112 Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: 
IMMPACT recommendations. Pain 2005,113: 9-19.
113 Cella D, Hahn E, Dineen K. Meaningful change in cancer-specific quality of life scores: 
Differences between improvement and worsening. Qual Life Res. 2002;11:207-21. 
114 Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes 
in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 
2001;94(2):149-58.
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
ADA
anti-drug antibody
ADT
androgen deprivation therapy
AE
adverse event
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
BID, bid
bis in die, twice daily
BICR
Blinded Independent Central Review
BMS
Bristol-Myers Squibb
BP
blood pressure
BPI-SF
brief pain inventory short form
BUN
blood urea nitrogen
C
Celsius
CBC
complete blood count
CFR
Code of Federal Regulations 
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Term
Definition
CI
confidence interval
CLcr
creatinine clearance
cm
centimeter
Cmax, CMAX
maximum observed concentration
CMO
cystoid macular oedema
CNS
central nervous system
COVID-19
coronavirus disease 2019
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
CTAg
Clinical Trial Agreement
CTC
circulating tumor cells
CYP
cytochrome p-450
dL
deciliter
DMC
Data monitoring committee
DRESS
drug reaction with eosinophilia and systemic symptoms
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
EOC
Executive Oversight Committee
EOI-PK
end of infusion pharmacokinetic
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Term
Definition
FACT-P
Functional Assessment of Cancer Therapy-Prostate
FACT-P-PCS
Functional Assessment of Cancer Therapy-Prostate Prostate Cancer 
Subscale
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
GBS
Guillain-Barré syndrome
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate
IA
Interim Analysis
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IHC
immunohistochemistry
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Term
Definition
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IO
immuno-oncology
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
kg
kilogram
L
liter
LDH
lactate dehydrogenase
MDSC
myeloid-derived suppressor cell
mg
milligram
MG
myasthenia gravis
min
minute
mCRPC
metastatic castration-resistant prostate cancer
mCSPC
metastatic castration-sensitive prostate cancer
mL
milliliter
MR
medical research
MTD
maximum tolerated dose
nmCRPC
non-metastatic castration-resistant prostate cancer
g
microgram
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Term
Definition
N
number of subjects or observations
NAT
Novel antiandrogen therapy
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
ng
nanogram
NK
natural killer
OS
overall survival
PCWG3
Prostate Cancer Working Group
PD
pharmacodynamics
PD-1
programmed death-1
PD-L1
programmed death ligand 1
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PSA
Prostate-specific antigen
rPFS
radiographic progressive free survival
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2 
SD
standard deviation
SJS
Stevens-Johnson syndrome
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Term
Definition
t
temperature
T
time
T.bili
total bilirubin
TEN
toxic epidermal necrolysis 
ULN
upper limit of normal
WBC
white blood cell
WOCBP
women of childbearing potential
WNOCBP
women not of childbearing potential
x g
times gravity
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the CRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:

Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines Good Clinical Practice (GCP), 

as defined by the International Council on Harmonisation (ICH)

in accordance with the ethical principles underlying European Union Directive 2001/20/EC

United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 

applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree one or more of the following:  (1) the physical, safety or mental 
integrity of one or more subjects/participants; (2) the scientific value of the trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP Regulation(s) or 
Trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects/participants. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or 
product labeling information to be provided to subjects/participants and any updates. 
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The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects/participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as soon 
as possible to:

IRB/IEC

Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
subjects/participants currently enrolled in the study if they are affected by the amendment; and (3) 
the new form must be used to obtain consent from new subjects/participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects/participants are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they volunteer 
to participate. 
In situations where consent cannot be given by subjects/participants, their legally acceptable 
representatives (as per country guidelines) are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which the participant 
volunteers to participate. 
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Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:

Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 

Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.

Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects/participants, prior to the beginning of 
the study, and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects’/participants’ signed ICF and, in the US, the subjects’/participants’ signed HIPAA 
Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
The rights, safety, and well-being of the study subjects/participants are the most important 
considerations and should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
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devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable regulations 
and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each 
participant, including unique participant identifiers

amount transferred to another area/site for 
dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for 
bioavailability/bioequivalence/biocomparability, if 
applicable 

dates and initials of person responsible for 
Investigational Product dispensing/accountability, as 
per the Delegation of Authority Form.
Sourced by site, and not supplied by 
BMS or its vendors (examples 
include IP sourced from the sites 
stock or commercial supply, or a 
specialty pharmacy)
The investigator or designee accepts responsibility for 
documenting traceability and study treatment integrity in 
accordance with requirements applicable under law and 
the SOPs/standards of the sourcing pharmacy.
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BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. They will review study records and directly compare them with 
source documents, discuss the conduct of the study with the investigator, and verify that the 
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facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents:
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator)
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety, 
or to meet local regulations (eg, cytotoxics or 
biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
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It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:

External Principal Investigator designated at protocol development

Study Steering Committee chair or their designee

Participant recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or country)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
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Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.  
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.  
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from 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. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.

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. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
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).
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.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as 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)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE:
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)

admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.3.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see Section 9.3.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

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 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 Sponsor.

The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE

SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.

SAEs must be recorded on the SAE Report Form.

The required method for SAE data reporting is through the eCRF.

The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
When paper forms are used, the original paper forms are to remain on site

Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
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
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 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF
CHILDBEARING POTENTIAL DURING TREATMENT WITH DOCETAXEL
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during treatment with docetaxel and until the end of relevant systemic 
exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure, defined as 6 months after the end of study treatment with docetaxel.

Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 6 months after the end of 
treatment with docetaxel in the male participant.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 6 months after the end of study treatment with docetaxel. 
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Refrain from donating sperm for the duration of the study treatment and until 6 months after 
the end of study treatment with docetaxel.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.3.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.
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APPENDIX 5
PROSTATE CANCER WORKING GROUP 3 (PCWG3)
GUIDELINES (WITH MODIFIED RESPONSE EVALUATION 
CRITERIA IN SOLID TUMORS (RECIST) CRITERIA FOR SOFT 
TISSUE LESION ASSESSMENT)
Not applicable per Protocol Amendment 04.
1
EVALUATION OF LESIONS
Bone lesions should be evaluated with Technecium-99m based radionuclide bone scan as per 
PCWG31.
At baseline, soft tissue lesions/lymph nodes will be categorized as measurable or non-measurable 
as follows. 
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or 2x slice thickness if 
greater than 5 mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be 15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of
15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis 10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other soft tissue lesions are considered non-measurable, including small lesions (longest 
diameter < 10mm or pathological lymph nodes with 10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
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disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.3
Special considerations regarding bone lesions
Bone lesions will be assessed (as non-target lesions) with Technecium-99m based radionuclide 
bone scans as per PCWG3.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
20 lesions total (and a maximum of 5 lesions per organ system) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline.
Note: A maximum of 5 lesions can be selected per organ system. For example, a maximum of 
5 lung lesions can be selected. A maximum of 5 lymph nodes can be selected at baseline, as the 
lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Pelvic lymph nodes and extrapelvic 
lymph nodes (retroperitoneal, mediastinal, thoracic and other) may be reported separately, per 
PCWG3. Measurements are not required and these lesions should be followed as ‘present’, 
‘absent’, or in rare cases ‘unequivocal progression’ (more details to follow). In addition, it is 
possible to record multiple non-target lesions involving the same organ as a single item on the case 
record form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).
2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions,
taking as reference the baseline sum diameters.
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
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.

Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD, and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
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2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.

Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 

Non-CR/Non-PD: Persistence of one or more non-target lesion(s)

Progressive Disease (PD): Unequivocal progression (see below) of existing non-target 
lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy (see examples in Appendix 2 and further details below). A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. Pleural effusions, pericardial effusions and ascites will not be 
followed as target or non-target lesions and will not contribute to response or progression. The 
designation of overall progression solely on the basis of change in non-target disease in the face 
of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
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increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
2.2.2
New Lesions
New bone lesions
New bone lesions should be evaluated as per PCWG3 criteria. Bone lesions will be assessed by 
radionuclide bone scan only. Radiographic progression on bone scan is defined by the following 
criteria:

At least 2 new lesions on the first post-treatment bone scan, with at least two additional lesions
on the next scan (performed at least 6 weeks later)as compared to the first post-treatment bone 
scan. Date of progression is then the date of first post-treatment scan.

For scans after the first post-treatment scan, at least 2 new lesions relative to the first post-
treatment scan AND confirmed on a subsequent scan (performed at least 6 weeks later). Date 
of progression is the date of the scan that first documents at least 2 new lesions relative to the 
first post-treatment scan.
New soft tissue lesions
The appearance of new malignant soft tissue lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging modality 
or findings thought to represent something other than tumor. This is particularly important when 
the patient’s baseline lesions show partial or complete response. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan.
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2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression per PCWG3 criteria, or the last response recorded, taking into account any 
requirement for confirmation and censoring rules regarding subsequent therapy. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions. Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol-specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 2.3.2-2:
Time Point Response
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
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a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol-specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study). If the subject is not on-study for 
at least this amount of time, any tumor assessment indicating stable disease before this time period 
will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR&PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BEST Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
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CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR 
(eg, CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of 
a previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
REFERENCES
1
Scher HI, Morris MJ, Stadler WM et al. Trial design and objectives for castration-resistant 
prostate cancer: Updated recommendations from the Prostate Cancer Clinical Trials Working 
Group 3. J Clin Oncol 2016, 34(12):1402-18.
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APPENDIX 6
MANAGEMENT ALGORITHMS FOR STUDIES UNDER NCI 
CTCAE VERSION 5
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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6HS
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6HS
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6HS
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6HS
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6HS
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APPENDIX 7
CYP3A4 STRONG INHIBITOR AND INDUCER GUIDANCE
The lists below are not meant to be all inclusive. Please consult individual drug labels for further 
information. Additional information is also available at:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm
Table 7-1:
Representative examples of Drugs that are strong CYP3A4 
Inhibitors or Inducers
CYP Enzyme
Strong Inhibitorsa
5 fold Increase in AUC
Or > 80% Decrease in CL
Strong Inducers 
80% Decrease in AUC
CYP3A
Boceprevir, clarithromycin, conivaptan, 
grapefruit juiceb, indinavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, mibefradilc, 
nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, voriconazole
Avasimibed, carbamazepine, phenytoin, 
rifampin, St. Johns Worte
Abbreviations: AUC = area under the concentration time curve; ; CL = clearance; CYP = cytochrome P450
a A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for that CYP 
by equal or more than 5-fold.
b The effect of grapefruit juice varies widely among brands and is concentration, dose, and preparation dependent. 
Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used 
(eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (eg, low 
dose, single strength).
c Withdrawn from the United States market because of safety reasons.
d Not a marketed Drug.
e The effect of St John’s Wort varies widely and is preparation dependent.
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APPENDIX 8
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUSa
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
a Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
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APPENDIX 9
COUNTRY SPECIFIC AMENDMENTS: HIV TESTING
Criteria for exclusion of HIV-positive subjects in Argentina, Czech Republic, Germany, and any 
other countries where exclusion of HIV-positive participants is locally mandated:
Table 2-1 Screening Procedural Outline 
(CA2097DX)
Add ͆HIV testing͇ to list of laboratory tests.
Section 6.2 Exclusion Criteria, 1) 
Medical Conditions i)
Replace 
͆Known 
history 
of 
a
positive
test
for 
human 
immunodeficiency virus (HIV) or known acquired immunodeficiency 
syndrome (AIDS). Note: Testing for HIV must be performed at all sites 
in Germany and where mandated by locally” with “Positive test for 
HIV”
Section 9.6.1 Clinical Safety 
Laboratory Assessments
Replace ͆Testing for HIV must be performed at sites where mandated
locally” with “Testing for HIV must be performed.͇
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APPENDIX 10
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
Overall Rationale for the Protocol Amendment 03, 13-Sep-2022
Protocol Amendment 03 includes changes to expand the radiographic progression-free survival 
(rPFS) analysis population and clarify censoring rules for rPFS
 
, and clarification of pharmacokinetic (PK) sampling at follow-up visits, and 
clarification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology at 
follow-up as optional. 
Main changes have been included in the statistical analysis section, in which the population for the 
number of rPFS analysis has been changed from the first 544 randomized participants to all 
randomized
 for expansion to Intention-to-treat (ITT). By incorporating the 
delayed treatment effect, the number of rPFS events has been increased from 433 to 530, the 
number of and the number of overall survival (OS) events has been increased from 615 to 690 for 
final analysis. Additional revisions in the statistical analysis section have been added to align and 
clarify the populations for analysis.  
Additional revisions, including to sections of the Synopsis, have been made to align the protocol 
with respect to these changes. This protocol amendment applies to all participants.
Summary of key changes for Protocol Amendment 03
Section Number & Title
Description of Change
Brief Rationale
Title Page
Changed one of the 
 
Medical Monitor from
 
to
.
Changed 
 from 
 
 to 
.
To reflect updated personnel
Section 4 Objectives and 
Endpoints. Table 4-1
Added clarification of the censoring rules 
for rPFS
Section 5.3 Number of 
Participants
Added wording regarding global 
recruitment completion and China 
continuation of enrollment
To clarify recruitment status at the 
moment of the global amendment 
Section 9.6 
Pharmacokinetics. Table 
9.6-1: Pharmacokinetic 
Sampling Schedule for All 
Arms
Notes added to collection follow-up to 
clarify this is 30 or 100 days from the 
discontinuation of nivolumab
To clarify PK collection when 
nivolumab is discontinued during the 
treatment period but not docetaxel, 
making clear that PK collection is 
always related to nivolumab infusion
Section 10.1 Sample Size
Determination, and Table 
10.1-1
Expanded rPFS analysis population from 
first 544 to all global randomized, and 
changed the number of target rPFS events 
from 433 to 530. OS events increased from 
615 to 690. Updated enrollment rate.
 rPFS analysis was
expanded to the entire Intention-to-
treat (ITT) population. Another 
rationale for this change that is based 
on the curent observed event rate, it 
is not feasible to observe 433 events 
in the first 544 randomized 
participants. Based on previous 
observed delayed effect of nivolumab 
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Summary of key changes for Protocol Amendment 03
Section Number & Title
Description of Change
Brief Rationale
and ipilimumab across tumors, 
implementation of delayed treatment 
effect was applied for both rPFS and 
OS resulting in modification to the 
number of target events. Enrollment 
rate was updated because current 
enrollment rate significantly deviates 
from that of the previous protocol.
Table 10.3.1-1 Efficacy 
Statistical Analyses 
Updated statistical analysis method to 
increase population for rPFS analysis from 
first 544 to all randomized  Updated rPFS 
censoring rule to include censoring at the 
date of last tumor assessment prior to the 
missed tumor assessments for participants 
who had progressive disease (PD) or death 
immediately after more than one 
consecutive missed tumor assessments.
Updated to stay consistent with 
changes made in Table 10.1-1
Section 10.3.7.1 Interim 
Analysis for OS 
Reduced % OS events estimated for the 
first interim analysis from  59% to 47%
Updated to stay consistent with 
changes made in Table 10.1-1
All
Minor formatting and typographical 
corrections
To correct minor errors
Overall Rationale for the Protocol Amendment 02, 17-Mar-2021
Protocol Amendment 02 includes changes 
 
 
to allow inclusion of patients who have received prior radium-223. 
Dose modification criteria and immuno-oncology (IO) agent management algorithms have been 
aligned with National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) version 5. Serologic testing for severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) status has been added. Additional updates have been incorporated in order to improve 
alignment between protocol sections and clarify remote monitoring, prior malignancy window, 
thyroid testing, and male contraception requirements. 
Additional revisions, including to sections of the Synopsis, have been made to align the protocol 
with respect to these changes. This protocol amendment applies to all participants.
Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Title Page
Updated contact information.
To reflect changes in study personnel 
and align with changes in the BMS 
protocol model document.
Synopsis
Updated synopsis to align with changes to 
protocol.
To align with changes to protocol.
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Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Section 2: Schedule of 
Activities 
Table 2-1 and Table 2-2: Updated notes for 
AE/SAE assessment to include SARS-
CoV-2.
Tables 2-1 and Table 2-2: Added SARS 
CoV-2 serology procedure.
Serum and AE/SAE collection in the 
context of SARS-CoV-2 was added 
in the event that coronavirus disease 
2019 (COVID-19) sequelae may 
increase toxicity or impact 
interpretation of study events/results.
Table 2-2: Included Subsequent Cancer 
Therapy row. 
To clarify requirements for reporting 
subsequent systemic therapies.
Table 2-2: Updated notes for Brain 
Imaging.
To clarify timing of brain MRI.
Table 2-2: Updated health outcome 
questionnaire requirements.
To clarify timing of questionnaire 
completion.
Section 2: Schedule of 
Activities
Added minor clarifications and references 
to the notes across Tables 2-1 and 
Table 2-2.
To improve understanding of the 
procedures.
Section 3.3: Benefit/Risk 
Assessment
Updated source information for nivolumab 
clinical activity in various malignancies.
To clarify source information of 
clinical activity for nivolumab. 
Section 4: Objectives and 
Endpoints
Table 4-1: Objectives and 
Endpoints
Table 4-1: Added SARS-CoV-2 
exploratory objective and endpoint.
 
related to SARS-CoV-2.
Section 5.1.1: Screening 
Phase
 
Section 6.1: Inclusion 
Criteria
Updated criterion 2i to specify allowed 
prior cancer vaccine therapy (eg, 
sipuleucel-T), and radium-223 therapy, 
and clarify the time required between the 
To provide examples of prior prostate 
cancer vaccine therapy allowed in the 
study.
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Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
2) Type of Participant and 
Target Disease 
Characteristics
prior therapy and the beginning of the 
study treatment.
 
 
Section 6.1: Inclusion 
Criteria
3)
Age and Reproductive 
Status
Updated criterion 3b to reflect 
contraception requirements for males 
treated with docetaxel (ie, 6 months after 
the last dose of docetaxel).
To update contraceptive requirements 
based on current safety information.
Section 6.2: Exclusion 
Criteria
1)
Medical Conditions
Removed criterion 1a, as not applicable 
per Protocol Amendment 02, and replaced 
with criterion 1m, which clarifies study 
eligibility based on prior and/or concurrent 
malignancies. 
To update requirements for inclusion 
of patients with concurrent or prior 
malignancies and prior SARS-CoV-2 
infection.
Updated criterion 1k to include eligibility 
condition for participants with prior 
SARS-CoV-2 infection.
To clarify of eligibility condition for 
participants with prior SARS-CoV-2 
infection.
Section 6.2: Exclusion 
Criteria
2)
Prior/Concomitant 
Therapy
Removed criterion 2d, as not applicable 
per Protocol Amendment 02.
To allow inclusion of patients who 
have received prior radium-223 or 
other radiopharmaceuticals, as data 
suggest that prior treatment with 
these agents does not affect safety of 
subsequent docetaxel treatment.
Updated criterion 2e to clarify use of 
complementary medications.
To clarify use of complementary 
medications.
Added criterion 2f, which clarifies 
eligibility of participants who received 
products designed to treat or prevent 
COVID-19. 
To clarify eligibility of participants 
currently in other interventional 
trials, including those for COVID-19.
Section 6.2: Exclusion 
Criteria
3) Physical and Laboratory 
Test Findings
Added clarification for eligibility of 
participants with symptomatic or 
asymptomatic SARS-CoV-2 infection.
Included language to clarify 
expectations for eligibility and 
retesting for participants with 
suspected or confirmed symptomatic 
COVID-19.
Section 7.4: Dosage 
Modification 
Tables 7.4-1 and 
Table 7.4-2 
Added Table 7.4-1: Adverse Event Criteria 
to Delay, Resume, or Discontinue 
Nivolumab/Placebo and Table 7.4-2:
Adverse Event Criteria to Delay, Reduce, 
Resume, or Discontinue Docetaxel. 
To align with NCI CTCAE version 5. 
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Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Updated entire section to align with new 
tables and remove redundant content. 
Section 7.4.2: Docetaxel 
Dose Reduction
Section 7.4.3: Dose Delay 
Criteria
Section 7.4.4: Criteria to 
Resume Study Treatment
Section 7.4.5: Management 
Algorithms for Nivolumab
Section 7.4.6: Treatment of 
Related Infusion Reactions
Removed redundant content, updated 
section title, aligned content with CTCAE 
version 5, added SARS-CoV-2 language, 
and renumbered sections as needed.
Updated Section 7.4.2 to include one 
allowed dose reduction.
Updated Section 7.4.3 to align with Table
7.4-1 and Table 7.4-2.
Updated Section 7.4.4 to align with Table 
7.4-1 and to provide criteria for resuming 
treatment after SARS-CoV-2 infection.
Updated Section 7.4.6 title to align with 
Table 7.4-1
To align with NCI CTCAE version 5 
and include SARS-CoV-2 language. 
Section 7.6.2: Other 
Restrictions and 
Precautions
Section 7.7: Concomitant 
Therapy
Removed redundant content.
Revised to align with NCI CTCAE 
version 5. 
Section 7.7.1: Prohibited 
and/or Restricted 
Treatments
Updated to clarify use of complementary 
medications.
To clarify use of complementary 
medications.
Section 7.7.4: Treatment 
Beyond Progression
Updated to specify permitted treatment up 
to a maximum of 24 months from date of 
first dose.
To clarify treatment beyond 
progression.
Section 8.1.1: 
Discontinuation of Specific 
Study Treatments
Updated to align with Table 7.4-1 and 
Table 7.4-2.
To align with Table 7.4-1 and Table 
7.4-2.
Section 8.1.2: Post Study 
Treatment  - Study Follow-
up
Updated to clarify collection of survival 
data.
To align with Section 5.1.3.
Section 9: Study 
Assessments and 
Procedures
Added clarification for additional 
measures and procedures.
Included language for AE/SAE 
follow-up in the context of SARS-
CoV-2 in the event that COVID-19 
sequelae may increase toxicity or 
impact interpretation of study 
events/results.
Section 9.1.3: Patient-
Reported Outcomes
Added clarification for alternative 
administration methods.
To clarify alternative administration 
methods. 
Section 9.2.1: The 5-Level 
EQ-5D
Made necessary clarifications and 
corrections.
To clarify content.
Section 9.3: Adverse 
Events
Made necessary clarifications and 
corrections.
To clarify content. 
Protocol Amendment No.: 04
Date: 22-Sep-2023
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CA2097DX
BMS-936558
nivolumab
Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Section 9.3.1: Time Period 
and Frequency for 
Collecting AE and SAE 
Information
Section 9.3.3: Follow-up of 
AEs and SAEs
Updated to include details related to 
follow-up of SAEs and nonserious AEs 
associated with confirmed or suspected 
SARS-CoV-2 infection.
Included language for AE/SAE 
follow-up in the context of SARS-
CoV-2 in the event that COVID-19 
sequelae may increase toxicity or 
impact interpretation of study 
events/results.
Table 9.6-1 
Pharmacokinetic Sampling 
Schedule for all Arms
Updated footnote c to provide detailed 
instructions for PK blood sampling at the 
end of nivolumab infusion.
To align with EPE version 6.
Section 9.6.1: Clinical 
Safety Laboratory 
Assessments
Updated table and footnotes to clarify T3
sampling requirements.
To allow total T3 when free T3 is not 
available.
Section 11: References 
Updated references to reflect changes in 
the content.
To align with updated protocol 
content. 
Appendix 1: Abbreviations 
and Trademarks 
Updated abbreviations to reflect changes in 
the content.
To align with updated protocol 
content.
Appendix 2: Study 
Governance 
Considerations 
Made necessary clarifications and 
corrections.
To clarify content. 
Appendix 4: Childbearing 
Potential Definitions and 
Methods of Contraception
Updated contraception guidance for male 
participants with partners of childbearing 
potential to reflect requirements for 
participants treated with docetaxel. 
Changed definition of relevant systemic 
To align methods of contraception 
with updates made to male 
contraceptive requirements in 
Section 6.1.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Summary of key changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
exposure to 6 months after end of 
docetaxel treatment. 
Appendix 6: Management 
Algorithms for Studies 
Under NCI CTCAE 
version 5
Updated title to include NCI. Replaced IO 
agent management algorithms with those 
aligned with NCI CTCAE version 5.
Updated management algorithms for 
immune-mediated AEs to align with 
NCI CTCAE version 5 and 
nivolumab Investigator Brochure.
All
Minor formatting, typographical and style 
corrections. 
These changes are minor and 
therefore have not been summarized. 
Overall Rationale for the Revised Protocol 01, 06-May-2020
Revised Protocol 01 includes changes 
 
 
to clarify the inclusion criteria for current evidence of metastatic 
disease and prior treatment with NAT, and to clarify lesions that do not qualify as visceral disease.
Frequency of tumor assessment was revised to enhance precision of the radiographic 
progression-free survival (rPFS) endpoint and the criteria for stable disease (SD) was revised based 
on frequency of tumor assessments. The statistical section now specifies sample size for rPFS.
In addition Revised Protocol 01 includes revisions made 
 
. These include providing guidance on treatment of infusion reactions for nivolumab 
and docetaxel, clarifying the purpose of 30-minute observation period between nivolumab and 
docetaxel, mandating discontinuation of docetaxel for cystoid macular oedema (CMO) and for 
Grade 3 hypersensitivity reaction, and modifying the rules for dose reduction of docetaxel to 
align with docetaxel labeling. In addition to changes made for clarity and alignment with 
nivolumab program-wide standards, changes were also made to explicitly state the time period for 
collection for all non-serious adverse events and to exclude participants with HIV, as described 
below.
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Title page
BMS Research and 
Development address changed. 
Administrative correction. 

Synopsis Key Inclusion 
Criteria

Section 2: Schedule of 
Activities: Table 2-1, 
Screening Procedural 
Outline (CA2097DX); 
Eligibility Assessments: 
 
Update of text that specifies 
required evidence of metastatic 
disease 
Added specification that if the 
same NAT is given more than 
once in the context of a different 
disease setting, these NAT will 
Clarified patient eligibility
 
 
 
 
 
 
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
 

Section 6.1 Inclusion 
Criteria 2) Type of 
Participant and Target 
Disease Characteristics 
b), f), h) and j).
be considered as separate NAT 
regimens
 
 
 
 
 
 

Synopsis Key Inclusion 
Criteria

Section 6.1 Inclusion 
Criteria 2) Type of 
Participant and Target 
Disease Characteristics b) 
and e) 
The criterion presented below is 
now moved (synopsis) and 
numbered separately (Section
6.1) as 2) b  i and deleted from 
criterion 2 e) ii
Participants whose disease 
spread is limited to regional 
pelvic lymph nodes (N1) 
measuring at least 2 cm in short 
axis will be considered eligible
Revised for clarity. 

Synopsis Key Inclusion 
Criteria

Section 6.1 Inclusion 
Criteria 2) Type of 
Participant and Target 
Disease Characteristics i) 
Added to criterion: second-
generation hormonal 
manipulations (eg, abiraterone 
acetate, enzalutamide, 
apalutamide, and darolutamide).
Radiation therapy, previously 
included in this criterion is 
moved to and clarified in Section 
6.2: Exclusion Criteria Medical 
Conditions 1) d)
Clarification.

Synopsis Key Exclusion 
Criteria

Section 6.2: Exclusion 
Criteria Medical 
Conditions 1) a)
Added the following 
clarification to prior malignancy 
active within the previous 3 
years: (i.e. participants with a 
history of prior malignancy are 
eligible if treatment was 
Clarification
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
completed at least 3 years before 
enrollment)

Synopsis Key Exclusion 
Criteria

Section 6.2: Exclusion 
Criteria Medical 
Conditions 1) d) 
Revised to: Prior radiation 
therapy must be completed prior 
to 2 weeks before start of study 
treatment and patients should 
have recovered (Grade 1) from 
radiation-related toxicities
Clarification of exclusion 
for prior radiation therapy 
and recovery from 
radiation-related toxicities. 

Synopsis Key Exclusion 
Criteria

Section 6.2: Exclusion 
Criteria, 1) Medical 
Conditions i) 

Section 9.4.4 Clinical 
Safety Laboratory 
Assessments 
Reference to Appendix 9 added
Appendix 9 specifies 
modifications in specific 
protocol sections regarding 
exclusion of HIV-positive 
subjects in countries where 
exclusion of HIV-positive 
participants is locally 
mandated.

Synopsis: 
Prior/Concomitant 
Therapy

Section 6.2: Exclusion 
Criteria, 2) 
Prior/Concomitant 
Therapy
Botanical preparations intended 
for general health have been 
removed from exclusion 
criterion.
Adjustment in program 
standard.

Synopsis: Overall Design

Section 5.1 Overall 
Design

Section 7.3 Method of 
Treatment Assignment
In addition to bone and lymph 
node metastases,  prostate lesion 
(or bladder/rectum if from direct 
invasion from prostate) are 
specified as not to be considered 
as visceral disease. 
To clarify lesions that do 
not qualify as visceral
disease.

Synopsis: Number of 
Participants

Section 10.1 Sample Size 
Determination

Table 10.1-1: Sample 
Size Determination
Text/table data added to state 
that rPFS analysis will be based 
on the first 544 randomized
participants only. In addition, the 
number of rPFS events for the 
rPFS analysis was changed from
372 to 433.
To clarify the number of 
subjects for the rPFS 
analysis and correct the 
number of events needed 
for rPFS analysis.

Synopsis: Objectives and 
Endpoints
Minor changes in endpoint text 
for rPFS.
Aligned with specification 
that rPFS analysis will be 
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale

Section 4. Objectives and 
Endpoints Table 4-1 
Objectives and Endpoints
based on the first 544 
randomized participants.
Section 2: Schedule of 
Activities  
Table 2-1, Screening 
Procedural Outline 
(CA2097DX): Eligibility 
Assessments: Brain Imaging 
and Body Imaging
MRI brain imaging for eligibility 
is required as part of screening, 
unless the participant has 
completed an imaging study of 
the brain now within 28 days of 
randomization, rather than from
the beginning of study drug 
administration  
To clarify timing of 
screening MRI brain.

IRT 
Note specifies that once a 
participant is eligible for the 
study, IRT must be contacted to 
randomize the participant.
Clarification.

Section 2: Schedule of 
Activities 
Table 2-1, Screening 
Procedural Outline 
(CA2097DX): 
Laboratory Tests 

Section 2: Schedule of 
Activities Table 2-2: On-
Study Treatment and 
Follow-up Procedural 
Outline for Arms A and 
B (CA2097DX); 
Laboratory Tests

Section 9.4.4 Clinical 
Safety Laboratory 
Assessments
Removed urinalysis from 
laboratory tests to be conducted 
at screening or on treatment. 
Alignment with specified 
program-wide laboratory 
tests.
Section 2: Schedule of 
Activities
Footnote added to specify that 
no dose escalation or reductions 
Clarification.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Table 2-2: On-Study 
Treatment and Follow-up 
Procedural Outline for Arms 
A and B (CA2097DX)

Study Treatment: 
Dispense Study 
Treatment
for nivolumab are allowed. 
Additional details for Q3W and 
Q4W dosing are also included.

Safety: Assessment: AEs 
Assessment

Safety: Assessments: 
SAE Assessment
The row was updated and text 
was added to the note for AE 
assessment to state that all non-
serious adverse events (not only 
those deemed to be treatment-
related) should be collected 
continuously during the 
treatment period and for a 
minimum of 100 days following 
discontinuation of study 
treatment.
In addition to the existing row 
for AE assessment, a separate 
row was added for SAE 
assessment during treatment and 
follow-up periods
To explicitly state the time 
period for collection for 
non-serious AEs and SAEs.
Section 2: Schedule of 
Activities 
Table 2-2: On-Study 
Treatment and Follow-up 
Procedural Outline for Arms 
A and B (CA2097DX)
Assessment of concomitant 
medication use has been 
removed as an assessment during 
survival follow-up.
Aligned to program 
standard.

Section 2: Schedule of 
Activities: Table 2-2:
On-Study Treatment and 
Follow-up Procedural 
Outline for Arms A and 
B (CA2097DX)
Laboratory Tests: 
Clinical Laboratory Tests 
Note added to allow for labs to 
be conducted 72 hours prior to 
dosing for each cycle.
Clarifies window to 
perform labs prior to each 
cycle.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Efficacy Assessments: 
Body Imaging 
Section 5.1.2 Treatment 
Phase
Section 9.1.2, BICR 
Confirmation of 
Progression
(clarification on imaging 
and subsequent therapy 
only) 
Tumor assessments should occur 
every 9 weeks (7 days) from 
first dose, regardless of 
treatment schedule or dose 
delays for first 54 weeks, rather 
than for the first 28 weeks.
In addition, clarified that 
imaging must continue until 
radiographic progression per 
PCWG3 is confirmed by BICR, 
even in cases where subsequent 
therapy has begun. 
 
frequency of tumor 
assessment was revised to 
enhance precision of the 
rPFS endpoint.
Clarification. 
Section 2: Schedule of 
Activities 
Table 2-2: On-Study 
Treatment and Follow-up 
Procedural Outline for Arms 
A and B (CA2097DX)

Footnote c [follow-up] 
Notes for Clinical 
Laboratory Tests 
Section 9.4.4. Clinical 
Safety Laboratory 
Assessments
In Footnote c, Safety Follow-up 
Visit 1 (FU1) can be performed 
on the date of discontinuation if 
that date is greater than 30 days
rather than 42 days from last 
dose. 
In addition, text or footnote 
added to indicate specific tests to 
be performed at FU2 only if 
toxicities are present.
Revised in conjunction 
with nivolumab standards.
Clarification for study 
sites.
Section 2: Schedule of 
Activities 
Table 2-2: On-Study 
Treatment and Follow-up 
Procedural Outline for Arms 
Text added to indicate 
assessments to be performed 
only at safety FU1
Clarification for study 
sites.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
A and B (CA2097DX): 
Notes for the following 
assessments BPI-SF. FACT-
P, FACT-P PCS
Section 6.2 Exclusion 
Criteria 3) Physical and 
Laboratory Test Findings i)
Added as new exclusion 
criterion: AST and/ or ALT > 
1.5 x ULN concomitant with 
alkaline phosphatase > 2.5 x 
ULN
Aligned with criteria in 
docetaxel labeling.
Section 7 Treatment Table 7-
1, Study Treatments for 
CA2097DX
Study medications have each 
been defined in-text as 
investigational product or non-
investigational product
To more clearly define 
study treatments.
Placebos (0.9% sodium chloride 
and 5% dextrose for injection) 
added to Table 7-1
To more clearly define 
study treatments.
Section 7.1.1 Nivolumab or 
Placebo Combined with 
Docetaxel
Text describing nivolumab 
monotherapy or placebo dosing 
removed
Text describing monitoring for 
docetaxel infusion reactions 
added.
To better organize the 
information in Section 
7.1.1 to focus on Q3W 
nivolumab or placebo 
dosing in combination with 
docetaxel and to add 
additional information on 
the purpose of 30-minute 
observation period between 
the end of nivolumab or 
placebo infusion and the 
start of docetaxel infusion.

Section 7.1.1 Nivolumab 
or Placebo Combined 
with Docetaxel.
Specification of 8 mg dose and 
clarification of dexamethasone 
administration schedule.
To align with 
dexamethasone 
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale

Section 7.1.2 Nivolumab 
or Placebo Dosing
premedication specified in 
docetaxel product label.
Section 7.1.2 Nivolumab or 
Placebo Dosing
Text describing nivolumab 
monotherapy or placebo dosing 
from Section 7.1.1 added
Text describing Q3W dosing 
removed.
To better organize the 
information in Section 
7.1.2 to focus on Q4W
nivolumab monotherapy or 
placebo dosing.

Section 7.4.2 Docetaxel 
Dose Reduction 

Table 7.4.2-1:
Dose 
Reductions for Docetaxel
Second dose reduction of 
docetaxel removed from text and 
from Table 7.4.2-1. If a second 
dose reduction is required, the 
protocol now indicates that the 
participant should discontinue 
docetaxel treatment.
Reference to Section 8.1.1.2 
Docetaxel Discontinuation added
To align with docetaxel 
product label.
For clarity.
Section 7.4.3.2 Docetaxel 
Dose Delay
Bulleted list reformatted
Clarification.

Section 7.4.3.2 Docetaxel 
Dose Delay

Section 8.1.1.2 Docetaxel 
Discontinuation
Addition of information on 
impaired vision and cystoid 
macular oedema (CMO) to the list 
of events for which docetaxel dose 
delay or permanently discontinued 
should be considered.
Added to align with 
docetaxel label.
Section 7.4.6 Treatment of 
Nivolumab-related Infusion 
Reactions
Addition of information for 
treatment of infusion reactions 
related to nivolumab
Alignment with standards 
for studies with nivolumab. 
Section 7.4.7 Docetaxel-
related Infusion Reactions
New section added
Updated to align with the 
EU SmPC for docetaxel.
Section 7.7.1 Prohibited
and/or Restricted 
Treatments: 7.7.1.1 All 
Participants
Specification added for 
restriction/allowance of non-
palliative and palliative 
radiation.
Restriction of botanical 
preparations to provide 
supportive care has been 
removed from this section.
Adjustment in program 
standard.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Section 8.1 Discontinuation
from Study Treatment
The following text added:
Termination of the study by 
Bristol-Myers Squibb (BMS) for 
reasons including but not limited 
to the following: safety 
concerns, termination of drug 
development, lack of efficacy, 
and lack of meeting study 
objectives/endpoints.
To clarify reasons for 
sponsor-mandated 
discontinuation.
Clinical progression has been 
deleted from criteria for 
discontinuation from  study 
treatment. 
For consistency with the 
protocol: discontinuation is 
only mandated for 
radiographic progression

Section 8.1 
Discontinuation from 
Study Treatment

Section 9.1.2, BICR 
Confirmation of 
Progression
Text added to clarify that PSA 
progression alone is not an 
indication to stop treatment. 
Discontinuation from study 
treatment is only mandated for 
radiographic progression per 
PCWGS criteria for measurable 
disease and/or bone disease.
Clarification. 
Section 8.1.1.2 Docetaxel 
Discontinuation
Permanent discontinuation for 
any Grade 3 drug-related 
hypersensitivity reaction added.
Updated to align with the 
EU SmPC for docetaxel. 
Section 9.1.1.2 Imaging and 
Clinical Assessment
A Best Overall Response (BOR) 
of SD requires a minimum of 56 
days rather than 49 days on 
study from date of first dose to 
the date of the first imaging 
assessment
Clarification of minimum 
criteria for SD based on 
frequency of tumor 
assessments.
Section 9.2 Adverse Events
Paragraph added:
Immune-mediated adverse 
events are AEs consistent with 
an immune-mediated mechanism 
or immune-mediated component 
for which non-inflammatory 
etiologies (eg, infection or tumor 
progression) have been ruled 
out. IMAEs can include events 
with an alternate etiology which 
Alignment with nivolumab 
standards.
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
were exacerbated by the 
induction of autoimmunity. 
Information supporting the 
assessment will be collected on 
the participant’s case report 
form.
Section 9.2.1
Time Period and Frequency 
for Collecting AE and SAE 
Information
Text added. For participants 
assigned to treatment and never 
treated with study drug, SAEs 
should be collected for 30 days 
from the date of treatment 
assignment.
Text was added to state that all 
non-serious adverse events (not 
only those deemed to be 
treatment-related) should be 
collected continuously during 
the treatment period and for a 
minimum of 100 days following 
discontinuation of study 
treatment.
Alignment with nivolumab 
standards.
To explicitly state the time 
period for collection for 
non-serious adverse events.
Section 9.2.2, Method of 
Detecting AEs and SAEs
Paragraph added.
Every adverse event must be 
assessed by the investigator with 
regard to whether it is 
considered immune-mediated. 
For events which are potentially 
immune-mediated, additional 
information will be collected on 
the participant’s case report 
form.
Alignment with nivolumab 
program standard.
Section 9.4.4 Clinical Safety 
Laboratory Assessments
BUN or Serum Urea
Uric acid, creatine kinase, total 
protein, and direct bilirubin 
removed from lab assessments. 
Revised to align with the 
most recent language for 
BMS studies and to align 
with specified program-
wide laboratory 
assessments. 
Protocol Amendment No.: 04
Date: 22-Sep-2023
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Clinical Protocol
CA2097DX
BMS-936558
nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Section 11. References
References added.
New references added in 
support of changes 
 
Appendix 1 Abbreviations
and Trademarks 
Addition of terms to align with 
protocol content
Updated for clarity.
Appendix 5 APPENDIX 5:
Prostate Cancer Working 
Group 3 (PCWG3) 
Guidelines (With Modified 
Response Evaluation Criteria 
In Solid Tumors (RECIST) 
Criteria For Soft Tissue 
Lesion Assessment)
Section 1.3 Special 
considerations regarding 
bone lesions
Added text to specify that bone 
lesions will be assessed as non-
target lesions.
Clarification.
Appendix 9 Country Specific 
Amendments: HIV Testing
New Appendix added that 
describes procedures for HIV 
testing to be performed in 
Germany and any other site 
where exclusion of HIV-positive 
participants is mandated
Appendix 9 specifies 
modifications in specified 
protocol sections regarding 
exclusion of HIV-positive 
subjects in countries where 
exclusion of HIV-positive 
participants is locally 
mandated.
Protocol Amendment No.: 04
Date: 22-Sep-2023
187
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