Conditions: Prostate Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 292
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess safety and efficacy of nivolumab in combination with rucaparib, docetaxel, or enzalutamide in participants with castration-resistant prostate cancer that has spread.

Detailed description:

Arms:
arm 1: Specified dose on specified days arm 2: Specified dose on specified days arm 3: Specified dose on specified days

Interventions: intervention 1: nivolumab intervention 2: docetaxel intervention 3: enzalutamide intervention 4: rucaparib intervention 5: prednisone
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 intervention 5: Specified dose on specified days

Protocol document:
Prot_000.pdf: 
Official Title of Study: 
Phase 2 Study of Nivolumab in Combination with Either Rucaparib, Docetaxel, or Enzalutamide in Men 
with Castration-resistant Metastatic Prostate Cancer (CheckMate 9KD: CHECKpoint pathway and 
nivoluMAb clinical Trial Evaluation 9KD) 
 
NCT Number: NCT03338790 
Document Date (Date in which document was last revised): August 08, 2019 


Page:
1
Protocol Number:
CA2099KD
IND Number:
135,845
EUDRACT Number:
2017-001626-17
Date:
21-Aug-2017
Revised Date:
08-Aug-2019
CLINICAL PROTOCOL CA2099KD
A Phase 2 Study of Nivolumab in Combination with Either Rucaparib, Docetaxel, or 
Enzalutamide in Men with Castration-resistant Metastatic Prostate Cancer (CheckMate 9KD: 
CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 9KD)
Revised Protocol 04
Study Director
Medical Monitor
24-hr Emergency Telephone Number
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
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 
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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 
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).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 
04
08-Aug-2019
This Global Revised Protocol 04 specifies an additional interim analysis 
(IA) in each arm, after enrollment has been completed and all treated 
patients have been followed for at least 16 weeks after first dose, in the 
event that the data from the first IA appear to be immature to support
decision-making regarding arm expansion. Additionally, it specifies an IA 
in additional participants enrolled in any expanded arm or subgroup if 
needed to determine if the data may support a regulatory filing. Lastly, it
makes minor changes to incorporate updated nivolumab clinical program 
protocol standards.
Revised Protocol 
03
31-Jan-2019
This Global Revised Protocol 03 introduces an interim analysis in each 
arm when at least 50% of planned participants have been treated with at 
least 16 weeks of follow-up from first dose. The purpose of the interim 
analysis is to generate preliminary data that will inform internal decision-
making related to external studies being planned or conducted by the 
Sponsor, as well as to determine if any of the arms should be expanded to 
generate additional data that may support regulatory filing. 
In addition, this revised protocol clarifies the timing of the final analysis 
for each arm, incorporates changes from administrative letters, 
incorporates updated nivolumab clinical program protocol standards, and 
makes minor clarifications for consistency throughout the protocol 
document.
It also clarifies text regarding prednisone in Arm B and revised language 
regarding pain intensity and added relevant thresholds. 
Administrative 
Letter 05
20-Nov-2018
To clarify how the participant allocation spots will be split across the 
different Arms within the study. Also, to clarify that super scan definition 
has been included, 
 
.
Revised Protocol 
02
10-Sep-2018
Clarifies procedure requirement in the Schedule of Activities
Clarifies requirements for inclusion and exclusion criteria
Update study design to increase the patient population
Adds language to allow plasma HRD testing and previous local results
Provides further guidance for dexamethasone and corticosteroids use
Clarifies language for rucaparib dosing
Clarifies language for enzalutamide dosing 
Adds language to clarify disease progression by PSA
Incorporates updated nivolumab clinical program protocol standards
Minor clarifications for consistency throughout document 
Revised Protocol 
01
22-Mar-2018
Clarifies content in the Schedule of Activities
Clarifies requirements for inclusion and exclusion criteria
Provides further guidance for docetaxel discontinuation criteria
Adds language to Prohibited and/or Restricted Treatments section 
Adds enzalutamide background information
Provides additional guidance for PK sampling
Incorporates updated nivolumab clinical program protocol standards
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Document
Date of Issue
Summary of Change
Updates Study Director information 
Minor clarifications for consistency throughout document
Original Protocol
21-Aug-2017
Not applicable
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OVERALL RATIONALE FOR THE REVISED PROTOCOL 04
This Global Revised Protocol 04 specifies an additional interim analysis (IA) in each arm, after 
enrollment has been completed and all treated patients have been followed for at least 16 weeks 
after first dose, in the event that the data from the first IA appear to be immature to support 
decision-making regarding arm expansion. Additionally, it specifies an IA in additional 
participants enrolled in any expanded arm or subgroup if needed to determine if the data may 
support a regulatory filing. Lastly, it makes minor changes to incorporate updated nivolumab 
clinical program protocol standards.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
Table 2-2 On-study Treatment and 
Follow-up Procedural Outline for 
Arms A or C (CA2099KD)
Table 2-3 On-study Treatment and 
Follow-up Procedural Outline for 
Arm B (CA2099KD)
6.2 Exclusion Criteria
7.1.4 Treatment of Infusion-related 
Reactions (Nivolumab or 
Docetaxel)
10.3.2 Safety Analyses
Changed NCI CTCAE v 5.0 back 
to v 4.03
For consistency through-out the 
study
Table 2-2 On-study Treatment and 
Follow-up Procedural Outline for 
Arms A or C (CA2099KD)
Table 2-3 On-study Treatment and 
Follow-up Procedural Outline for 
Arm B (CA2099KD)
For AE Assessment and 
Concomitant Medication Use, 
added columns for Safety Follow-
up and Survival Follow-up and 
added “X” for Safety Follow-up
AE and concomitant medication 
use assessment occurs for a 
minimum of 100 days after last 
dose, not continuously, and are not 
assessed during Survival Follow-up
5.1 Overall Design
Clarified that enrollment in any 
study arm may be terminated 
early due to poor accrual
Permits early termination of 
enrollment in any arm due to poor 
accrual
5.4.9 Rationale for Interim Analysis
10.3.4 Interim Analysis
Added a potential second IA after 
completion of enrollment and at 
least 16 weeks follow-up after 
first dose in each arm if first IA is 
immature, as well as IA in 
additional participants treated in 
any expanded arm or subgroup 
with at least 16 weeks of follow-
up after first dose if needed to 
support regulatory interactions
To include additional interim 
analyses that can support decisions 
regarding arm expansion and 
regulatory filing
6.1 Inclusion Criteria (3d)
Changed from 5 months to 7 
months
Corrected time that male 
participants must be willing to 
refrain from sperm donation
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
7.3 Blinding
Clarified that the immediate study 
team members will remain 
blinded to Homologous 
recombination deficiency (HRD) 
status of individual study 
participants
To maintain blinding of immediate 
study team to maintain study 
integrity
Table 9.5.2-1 Pharmacokinetic [PK] 
 Sample 
Collections (CA2099KD)
Revised text in Safety row
Revised text in footnote a to 
specify nivolumab treatment 
discontinuation
Clarification on nivolumab 
PK
 collections was made to 
the PK Table 9.5.2-1 to indicate 
that if “nivolumab” is discontinued, 
the participant should move to 
follow-up PK
 collections.
Table 10.1-1 Sample Size by 
Arm/Analysis Cohort
For ORR and RR-PSA/PFS in 
Arm A HRD subgroup, revised 
HRD status to “negative”
Updated to indicate accurate HRD 
status for the Arm A HRD-
subgroup
Appendix 2 Study Governance 
Consideration
Slightly modified definition of 
“serious breach”; provided 
additional criteria for the CSR 
Signatory Investigator; added 
publication policy
Meets current standards
Appendix 3 AEs and SAEs 
Definitions and Procedures for 
Recording, Evaluating, Follow-up, 
and Reporting
Updated definitions and 
procedures for recording, 
evaluating, follow-up, and 
reporting AEs and SAEs
Meets current standards
Appendix 4 WOCBP Definitions 
and Methods of Contraception
Moved hormonal methods of 
contraception from User 
Independent to User Dependent. 
Added additional detail
Meets current standards
Appendix 6 Management 
Algorithms for Immuno-Oncology 
Agents 
7.1.3 Management Algorithms for 
Immuno-Oncology Agents
Added algorithm on myocarditis 
and replaced all algorithms with 
version with “2019” date
Meets current standards
Appendix 8 Country Specific 
Requirements
Added relevant countries 
regarding exclusion of HIV 
positive participants where locally 
mandated
To update known countries to date
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR THE REVISED PROTOCOL 04 ............................. 
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04............................ 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
3.1 Study Rationale ................................................................................................. 
3.1.1 Research Hypothesis ................................................................................ 
3.2 Background ....................................................................................................... 
3.2.1 Indication Background ............................................................................. 
3.2.2 Nivolumab Mechanism of Action ............................................................. 
3.2.3 Mechanism of Action of Co-administered Therapeutic Agents ............... 
3.2.3.1 Rucaparib ........................................................................................ 
3.2.3.2 Docetaxel ........................................................................................ 
3.2.3.3 Enzalutamide................................................................................... 
3.3 Benefit/Risk Assessment .................................................................................. 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Data Monitoring Committee and Other External Committees ................ 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
5.4 Scientific Rationale for Study Design............................................................... 
5.4.1 Rationale for Immunotherapy in mCRPC ................................................ 
5.4.2 Rationale for Co-administration of Nivolumab with Selected Therapeutic 
Agents in mCRPC ....................................................................................... 
5.4.2.1 Nivolumab plus Rucaparib ............................................................. 
5.4.2.2 Nivolumab plus Docetaxel .............................................................. 
5.4.2.3 Nivolumab plus Enzalutamide ........................................................ 
5.4.3 Rationale for Sample Size Determination ................................................ 
5.4.4 Rationale for Evaluating Asymptomatic or Minimally Symptomatic 
Metastatic CPRC Participants (ARM A2 and ARM C subjects) ................. 
5.4.5 Rationale for Treatment Beyond PSA Elevation ...................................... 
5.4.6 Rationale for Duration of Treatment ....................................................... 
5.4.7 Rationale for Nivolumab 30-Minute Infusion .......................................... 
5.4.9 Rationale for Interim Analysis ................................................................. 
5.5 Justification for Dose ........................................................................................ 
5.5.1 Dose Justification for Nivolumab ............................................................ 
5.5.1.1 Dose Justification for Nivolumab 480 mg IV Q4W ........................ 
5.5.1.2 Dose Justification for Nivolumab 360 mg IV Q3W ........................ 
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5.5.2 Dose Justification for Nivolumab 480 mg IV Q4W and Rucaparib 600 mg 
PO BID........................................................................................................ 
6 STUDY POPULATION ............................................................................................ 
6.1 Inclusion Criteria .............................................................................................. 
6.2 Exclusion Criteria ............................................................................................. 
6.3 Lifestyle Restrictions ........................................................................................ 
6.4 Screen Failures .................................................................................................. 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
7 TREATMENT ........................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.1.1 Dose Delay Criteria ................................................................................. 
7.1.1.1 Nivolumab ....................................................................................... 
7.1.1.2 Rucaparib ........................................................................................ 
7.1.1.3 Docetaxel ........................................................................................ 
7.1.1.4 Enzalutamide................................................................................... 
7.1.2 Criteria to Resume Study Treatment ........................................................ 
7.1.2.1 Nivolumab ....................................................................................... 
7.1.2.2 Rucaparib ........................................................................................ 
7.1.2.3 Docetaxel ........................................................................................ 
7.1.2.4 Enzalutamide................................................................................... 
7.1.3 Management Algorithms for Immuno-Oncology Agents ......................... 
7.1.4 Treatment of Infusion-related Reactions (Nivolumab or Docetaxel) ...... 
7.1.5 Treatment of Hypersensitivity or Allergic Reactions (Rucaparib or 
Enzalutamide) ............................................................................................. 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dosage Modification ......................................................................................... 
7.4.1 Nivolumab ................................................................................................ 
7.4.2 Rucaparib ................................................................................................. 
7.4.3 Docetaxel ................................................................................................. 
7.4.4 Enzalutamide............................................................................................ 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
7.6 Treatment Compliance ...................................................................................... 
7.7 Concomitant Therapy........................................................................................ 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.2 Other Restrictions and Precautions ......................................................... 
7.7.2.1 Imaging Restriction and Precautions ............................................. 
7.7.3 Permitted Therapy ................................................................................... 
7.7.3.1 Palliative Local Therapy................................................................. 
7.8 Treatment After the End of the Study ............................................................... 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Nivolumab Dose Discontinuation ............................................................ 
8.1.2 Rucaparib Discontinuation ...................................................................... 
8.1.3 Docetaxel Discontinuation....................................................................... 
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8.1.4 Enzalutamide Discontinuation ................................................................. 
8.1.5 Nivolumab Treatment Beyond Disease Progression ............................... 
8.1.6 Post Study Treatment Follow-up ............................................................. 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-Up ............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Imaging Assessment for the Study............................................................ 
9.1.2 Disease Response Evaluation .................................................................. 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.8 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Clinical Safety Laboratory Assessments .................................................. 
9.4.2 Imaging Safety Assessment ...................................................................... 
9.5 Pharmacokinetics .............................................................................................. 
9.5.1 Background .............................................................................................. 
9.5.2 Pharmacokinetics Assessments ................................................................ 
9.8.2 Tumor Tissue Specimens .......................................................................... 
10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
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10.3.2 Safety Analyses....................................................................................... 
10.3.4 Interim Analyses ..................................................................................... 
11 REFERENCES ........................................................................................................ 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 5 PCWG3 GUIDELINES (WITH MODIFIED RECIST V1.1 CRITERIA 
FOR SOFT TISSUE LESION ASSESSMENT) .................................................... 
APPENDIX 6 MANAGEMENT ALGORITHMS ....................................................... 
APPENDIX 7 PERFORMANCE STATUS SCALES - ECOG ................................... 
APPENDIX 8 COUNTRY SPECIFIC REQUIREMENTS ......................................... 
APPENDIX 9 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
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1
SYNOPSIS
Protocol Title: A Phase 2 Study of Nivolumab in Combination with Either Rucaparib, Docetaxel, 
or Enzalutamide in Men with Castration-resistant Metastatic Prostate Cancer (CheckMate 9KD: 
CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 9KD)
Study Phase: 2
Rationale:
Prostate cancer tumor cells have been shown to have low tumor expression of PD-L1, suggesting 
that treatments directed at the PD-1 / PD-L1 interaction are unlikely to be successful as 
monotherapies. This was confirmed by early clinical trials, where men with castration-resistant 
metastatic prostate cancer (mCRPC) did not respond to PD-1 blockade as monotherapy. 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”. This suggests
that, if prostate cancer treatments (ie, androgen ablation, chemotherapy, or PARP inhibitors) can 
increase PD-L1 expression on tumor cells by attracting infiltrating immune cells and triggering an 
adaptive immune response, then there is a rationale for combining such therapies with immune 
check-point inhibitors.
This study aims to demonstrate that treatment with nivolumab combined with rucaparib (Arm A), 
docetaxel (Arm B) or enzalutamide (Arm C) will have clinical activity in participants with 
mCRPC. Additional objectives of the study include further characterization of efficacy, safety and 
tolerability
 
as well as pharmacokinetics
. 
Response to study treatment and disease progression will be assessed using Prostate Cancer 
Clinical Trials Working Group 3 (PCWG3) criteria.
Study Population: The study population consists of participants 18 years of age or older with 
mCRPC (ie, histologically confirmed adenocarcinoma of the prostate with evidence of M1 
metastatic disease, ongoing androgen deprivation therapy [ADT] or bilateral orchiectomy, and 
documented prostate cancer progression per PCWG3 criteria).
Key Inclusion Criteria:
Histologic confirmation of adenocarcinoma of the prostate. Diagnosis must be stated in a 
pathology report and confirmed by the investigator.
•
Evidence of stage IV disease (as defined by the American Joint Committee on Cancer [AJCC]
cancer staging criteria) on previous bone, CT, and/or MRI scan
•
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 subjects 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.
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•
Documented prostate cancer progression as per PCWG3 criteria with at least one of the 
following:
−
PSA progression* defined by a minimum of two rising PSA levels with an interval of 
≥1 week between each determination The prostate-specific antigen (PSA) value at the 
screening visit should be ≥2 μg/L (2 ng/mL). 
* Participants who received an anti-androgen must have progression after withdrawal
(≥4 weeks since last flutamide administration or ≥6 weeks since last bicalutamide or 
nilutamide administration).
−
Radiographic disease progression in soft tissue based on RECIST 1.1 criteria. Participants 
whose disease spread is limited to regional pelvic lymph nodes (N1) measuring at least 2 
cm in short axis will be considered eligible.
−
Radiographic disease progression in bone defined as appearance of 2 or more new bone 
lesions on bone scan.
NOTE: Radiographs must be collected and transmitted to the central imaging vendor at 
study entry
•
ECOG Performance Status of 0-1
•
mCRPC participants will be assigned to a study arm as follows:
−
Arm A: Participants must meet either of the following criteria: 
♦Arm A1: Participants who have received at least 1 but no more than 2 prior taxane-
based regimens for castration-resistant disease. If docetaxel chemotherapy is used more 
than once, this will be considered as one regimen. Up to 2 second generation hormonal 
manipulations for castration-resistant disease are allowed.
♦Arm A2: Participants who are chemotherapy-naive for mCRPC who have received 
prior treatment with abiraterone acetate and/or enzalutamide/apalutamide
for 
castration-resistant disease up to 28 days prior to study arm assignment and are not 
candidates for or refuse immediate chemotherapy 
−
Arm B: Participants who are chemotherapy-naive for mCRPC who are candidates to 
receive docetaxel chemotherapy. Up to 2 second-generation hormonal manipulations (eg, 
abiraterone acetate and/or enzalutamide/apalutamide) for castration-resistant disease are 
allowed up to 28 days prior to study arm assignment.
−
Arm C: Participants who are chemotherapy-naive for mCRPC who have received prior 
treatment with abiraterone acetate for castration-resistant disease up to 28 days prior to 
study arm assignment without prior enzalutamide/apalutamide, and are not candidates for 
or refuse immediate chemotherapy.
•
For Arm A2 and Arm C, asymptomatic or minimally symptomatic according to BPI-SF 
performed during screening
•
Sufficient plasma and, fresh or archival tumor tissue obtained within 5 years prior to 
enrollment from a metastatic tumor lesion or from a primary tumor lesion that has not been 
previously irradiated (formalin-fixed paraffin-embedded block or unstained tumor tissue 
sections). Tumor sample may be from core biopsy, punch biopsy, excisional biopsy, or surgical 
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specimen). Fine needle aspiration is unacceptable for submission. Central laboratory must 
confirm receipt of plasma and tumor samples prior to IRT treatment arm assignment.
Results of homologous recombination deficiency (HRD) testing by the central laboratory 
must be available to IRT prior to treatment arm assignment. If local HRD test results
obtained prior to enrollment are provided to Sponsor, they should be confirmed to be 
acceptable for treatment assignment, and results will be transmitted to IRT prior treatment 
arm assignment. 
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 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 must be discussed with the BMS Medical 
Monitor or designee. Previously irradiated brain lesions are not considered measurable disease. 
•
Less than 1 year since resolution of ≥Grade 2 toxicity related to pelvic-targeted therapy 
(eg, radiation enteritis)
•
All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have 
resolved to Grade 1 (NCI CTCAE version 5) 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.
•
The following exclusion criteria apply to Arm A only: 
−
Participants with myelodysplastic syndrome/acute myeloid leukemia.
−
Gastrointestinal disorders likely to interfere with absorption of the study medication
•
The following exclusion criterion applies to Arm B only: 
−
Participants who have ≥Grade 2 peripheral neuropathy (NCI CTCAE version 5)
•
The following exclusion criteria apply to Arm C only: 
−
History of seizure or any condition that may have a predisposition to seizure. Also, history 
of loss of consciousness or transient ischemic attack within 12 months of enrollment (Day 1 
visit)
−
History of prostate cancer progression on ketoconazole
−
Gastrointestinal disorders likely to interfere with absorption of the study medication
−
History of Mobitz II second degree or third degree heart block without a permanent 
pacemaker in place
−
Hypotension as indicated by systolic blood pressure < 86 mm Hg at the screening visit
−
Bradycardia as indicated by a heart rate of < 50 beats per minute on the screening ECG
−
Uncontrolled hypertension as indicated by systolic blood pressure > 170 mm Hg or 
diastolic blood pressure > 105 mm Hg at the screening visit
Revised Protocol No.: 04
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CA2099KD
BMS-936558
nivolumab
•
Participants with  superscan on Technecium-99m radionuclide bone scans are not eligible for 
the study 
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.
•
Radiotherapy to the pelvic region within 3 months prior to treatment arm assignment 
•
Radiotherapy to symptomatic bone lesions within 14 days prior to treatment arm assignment.
•
The following exclusion criteria apply to Arm A only: 
−
Prior PARP inhibitor treatment, mitoxantrone, cyclophosphamide, or platinum-based 
chemotherapy
−
Arm A2 only: Prior chemotherapy for mCRPC. Prior docetaxel for metastatic hormone-
sensitive prostate cancer is allowed if ≥12 months elapsed from last dose of docetaxel
•
The following exclusion criterion applies to Arm B only: 
−
Prior treatment with docetaxel or another chemotherapy agent for metastatic castration-
resistant prostate cancer. Prior docetaxel for metastatic hormone-sensitive prostate cancer 
is allowed if ≥ 12 months elapsed from last dose of docetaxel.
•
The following exclusion criteria apply to Arm C only: 
−
Prior chemotherapy for mCRPC. Prior docetaxel for metastatic hormone-sensitive prostate 
cancer is allowed if ≥12 months elapsed from last dose of docetaxel.
−
Prior treatment with enzalutamide, apalutamide , or other novel androgen receptor 
inhibitor.
−
Treatment with 5-α reductase inhibitors (eg, finasteride, dutasteride), estrogens, and/or 
cyproterone within 4 weeks prior to treatment arm assignment
Objectives and Endpoints:
Objective
Endpoint
Co-Primary
•
To evaluate the objective 
response rate per PCWG3
(ORR-PCWG3) in HRD+ 
participants and in all 
treated participants 
•
ORR-PCWG3 is the proportion of participants who have a confirmed 
complete or partial best overall response (BOR) per PCWG3 among 
treated participants who have measurable disease. The BOR will be 
assessed by the investigator per PCWG3 and is recorded between 
treatment initiation 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.
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CA2099KD
BMS-936558
nivolumab
Objective
Endpoint
•
To evaluate PSA response 
rate (RR-PSA) in HRD+ 
participants and in all 
treated participants
•
RR-PSA is the proportion of treated 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.
Secondary
To evaluate radiographic 
progression-free survival 
(rPFS) in HRD+ 
participants and in all 
treated participants
•
rPFS is the time between treatment initiation and the first date of 
documented progression or death due to any cause, whichever occurs first. 
The radiographic progression will be assessed by the investigator per 
PCWG3. The rPFS will be censored at the last tumor assessment up to the 
start of subsequent systemic cancer therapy.
•
To evaluate time to 
response (TTR) and 
duration of response (DOR) 
per PCWG3 (TTR-PCWG3 
and DOR-PCWG3) in 
HRD+ participants and in 
all treated participants
•
TTR-PCWG3 is the time from treatment initiation to the date of the first 
documented CR or PR 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 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 cancer therapy.
•
To estimate time to PSA 
progression (TTP-PSA) in 
HRD+ participants and in 
all treated participants
•
TTP-PSA is the time between treatment initiation to the date of PSA 
progression per PCWG3 in treated participants. For participants with 
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.  TTP- PSA will be 
censored at the date of last PSA evaluation prior to start of subsequent 
systemic cancer therapy. The time will be censored at the date of treatment 
initiation for participants with no post- baseline PSA evaluation.
•
To assess overall survival 
(OS) in HRD+ participants 
and in all treated 
participants
•
OS is the time between treatment initiation 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 treatment initiation if they had no follow-up.
•
To evaluate overall safety 
and tolerability
•
Overall safety and tolerability will be measured by the incidence of AEs, 
SAEs, AEs leading to discontinuation, immune-mediated AEs, deaths, and 
laboratory abnormalities and changes from baseline
Overall Design:
This is an open-label Phase 2 study of nivolumab in combination with rucaparib (Arm A), 
docetaxel (Arm B), or enzalutamide (Arm C) in men with mCRPC. Arm A is split into 
2 sub-groups according to whether participants have received prior chemotherapy (Arm A1) or are 
chemotherapy-naive for mCRPC (Arm A2) (Figure 1-1:). The study is not randomized, and 
treatment arm assignment will depend on prior systemic treatment history. Treatment arm 
assignment will also depend on 2 clinical variables: 1) the presence or absence of measurable 
disease on the baseline tumor assessment per investigator review; and 2) the presence or absence 
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CA2099KD
BMS-936558
nivolumab
of HRD based on testing of a submitted tumor tissue sample by the central laboratory. Within each 
treatment arm, 60% of the available spots will be designated for participants that have measurable 
disease and 40% of the available spots will be designated for those who do not have measurable 
disease. In the entire study, 50% of the available spots will be designated for participants who are 
HRD positive and 50% will be designated for participants who are HRD negative or HRD not 
evaluable. However, the number of HRD+ versus HRD- or HRD-not evaluable spots will vary in 
each arm as follows: 100 HRD+ and 80 HRD- or not evaluable in Arm A; 25 HRD+ and 60 HRD-
or not evaluable in Arm B; 25 HRD+ and 40 HRD- or not evaluable in Arm C. The Interactive 
Response Technology (IRT) system will be used for treatment arm assignment. IRT will assign 
each participant to a treatment arm based on prior treatment history, measurable disease status, 
and HRD status.
The study will consist of 3 phases: screening, treatment, and follow-up. Study visits and endpoint 
measurements will occur as indicated in the procedural outlines (Schedule of Activities) in 
Section 2 of the protocol.
Number of Participants: 
Approximately 330 participants are planned to be enrolled and treated in 1 of 3 parallel treatment 
arms as follows:
•
Arm A: 180 participants to receive nivolumab plus rucaparib
−
Arm A1 = 80
−
Arm A2 = 100
•
Arm B: 85 participants to receive nivolumab plus docetaxel plus prednisone plus 
dexamethasone
•
Arm C: 65 participants to receive nivolumab plus enzalutamide
The sample size is calculated using the precision approach for the co-primary endpoints, ie, ORR 
as assessed by the investigator per PCWG3, among treated participants with measurable disease 
at baseline in an analysis cohort, and RR-PSA among treated participants in an analysis cohort.
The precision for potential response rates is detailed in Section 10.1 of the protocol. 
Treatment Arms and Duration:
Study Treatment: 
Study Drug for CA2099KD
Medication
Potency
IMP/Non-IMP
BMS-936558-01
(Nivolumab) Solution for Injection
100 mg (10 mg/mL)
IMP
Rucaparib
200 mg/250 mg/300 mg
IMP
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Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Study Drug for CA2099KD
Medication
Potency
IMP/Non-IMP
Immediate Release Tablets
Docetaxel
80 mg
IMP
Prednisone
5 mg
Non-IMP
Dexamethasone
4 mg
Non-IMP
Xtandi®
(enzalutamide)
40 mg
IMP
Abbreviations: IMP = Investigational Medicinal Product
The study design schematic is presented in Figure 1-1:. The decision tree guiding treatment 
assignment is provided in Figure 1-2:.
Figure 1-1:
Study Design Schematic
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CA2099KD
BMS-936558
nivolumab
Figure 1-2:
Decision Tree Guiding Treatment Arm Assignment
Treatment arm assignment will also depend on 2 clinical variables: 1) the presence or absence of 
measurable disease on the baseline tumor assessment per investigator review; and 2) the presence 
or absence of HRD based on testing of a blood plasma and/or tumor tissue sample by the central 
laboratory during screening or by local laboratory prior to enrollment. 
A participant is considered HRD+ if they have a deleterious genomic alteration (protein truncating 
or splice site mutation, homozygous deletion, large protein truncating rearrangement, or 
deleterious missense mutation) in plasma and/or tumor sample in at least one of the following HR 
genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, 
RAD51, RAD51B, RAD51C, RAD51D, or RAD54L. HRD status will be determined by central 
laboratory testing of a submitted blood plasma and/or tumor sample during screening or by local 
laboratory testing performed prior to enrollment. If local HRD testing has been performed prior to 
enrollment, the local HRD test results must be documented in the participant’s medical records 
and local HRD laboratory report must be provided to the Sponsor.  The local HRD laboratory 
report must clearly document the presence of a pathogenic or deleterious mutation in one of the 
HR genes noted above in order for it to be acceptable for assignment to an HRD+ spot. If the 
records do not clearly indicate the patient’s HRD status, the local testing results must be submitted 
to the sponsor for further interpretation of the HRD status.
During the treatment phase, participants will receive:
•
In Arm A: Nivolumab 480 mg IV Q4W for a maximum of 24 months from date of first dose 
and rucaparib 600 mg PO BID.
•
In Arm B: Nivolumab 360 mg IV Q3W and docetaxel 75 mg/m2 IV Q3W plus prednisone 
5 mg PO BID and dexamethasone 8 mg PO as premedication at 12 hours, 3 hours, and 1 hour 
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BMS-936558
nivolumab
before docetaxel infusion. Nivolumab will be administered for a maximum of 24 months from 
date of first dose, and docetaxel will be administered for a maximum of 10 cycles. After the 
completion of 10 cycles, nivolumab 480 mg IV Q4W will continue to be given alone as 
maintenance therapy. The total treatment duration for nivolumab (in combination with 
docetaxel or as monotherapy after completion of 10 cycles of docetaxel) is a maximum of 
24 months from date of first dose.
•
In Arm C: Nivolumab 480 mg IV Q4W for a maximum of 24 months from date of first dose
and enzalutamide 160 mg PO QD.
Tumor Assessments:
Tumor assessments are scheduled to be performed every 8 weeks (± 7 days) for 24 weeks following 
treatment initiation and thereafter every 12 weeks (± 7 days) until radiographic progression or 
discontinuation of study treatment (whichever occurs later). Tumor assessments should be 
performed at these time points regardless of treatment schedule or dose delays.
Dose delays for all 4 investigational products are permitted for toxicity and other protocol-
specified criteria. Dose reductions are permitted for rucaparib, docetaxel, and enzalutamide but 
not for nivolumab. The criteria for discontinuation due to toxicities are discussed in Section 8.1 of 
the protocol. The assessment for delay or discontinuation should be made separately for each study 
drug in the combination. Treatment may be prematurely discontinued due to withdrawal of 
consent, unacceptable toxicity, disease progression, completion of treatment cycles, or termination 
of the study, whichever occurs first. 
A Data Monitoring Committee (DMC) will provide independent oversight of safety, study conduct 
and efficacy of nivolumab in combination with rucaparib, docetaxel or enzalutamide.
Duration:
The duration for accrual is approximately 15 months based on a monthly enrollment rate of 
20 participants and the follow-up period will be 12 months. The final analysis of the co-primary 
endpoints of ORR and RR-PSA will occur approximately 2.5 years after the first participant is 
treated. This will allow sufficient follow up for a stable estimate of best overall response and 
duration and adequate safety assessment. Additional survival analyses may be conducted for up to 
5 years after treatment initiation following the updated analysis of the co-primary endpoints.
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CA2099KD
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA2099KD)
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 treatment arm assignment in IRT
BPI-SF
X
To be completed for all participants and must be performed to establish eligibility in Arm A2 
and Arm C. (See Section 6.1, inclusion criterion 2.i)
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
Blood plasma and Tumor Tissue Sample
X
Mandatory submission during screening. See Section 6.1 and Section 9.8.2 for specifications.
Central HRD testing must be performed on submitted blood plasma and archival/fresh tumor 
sample unless local HRD test results obtained prior to enrollment are provided to Sponsor 
and confirmed to be acceptable for treatment arm assignment (see Section 5.1). Results from 
central or local HRD testing must be available to IRT prior to treatment arm assignment.
Baseline Tumor Assessments
X
Imaging should be done within 28 days prior to first dose.
Bone lesions should be assessed with Technecium-99m radionuclide bone scans.
CT/MRI scan of chest, abdomen, pelvis, and any suspected/known sites of soft tissue lesions.
CT/MRI of the brain without and with contrast is required in participants with known or 
suspected brain metastases. 
Images will be collected and held centrally for potential future independent review. 
Please refer to Appendix 5 for PCWG3 guidelines for tumor assessments.
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CA2099KD
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2099KD)
Procedurea
Screening 
Visit
Notes
All windows are on calendar days.
Safety Assessments
Full Physical Examination, Measurements and
Vital Signs
X
Height, Weight, ECOG Performance Status (Appendix 7) within 14 days prior to treatment 
arm assignment
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 treatment arm assignment in IRT
Prior/Concomitant Medication Use 
X
Within 14 days prior to treatment arm assignment in IRT
Vaccine use must be collected within 30 days prior to treatment arm assignment.
Serious Adverse Event (SAE) Assessment 
X
SAEs from time of consent. See Section 9.2.2.
12 lead ECG 
X
Within 14 days prior to treatment arm assignment
Laboratory Tests
CBC with differential, Chemistry, Endocrine, 
Viral, PSA
X
Must be performed within 14 days prior to treatment arm assignment.
Refer to Section 9.4.1 for list of laboratory tests to conduct.
The following must be performed up to 6 weeks prior to first dose:
1.
PSA (See Section 6.1, inclusion criterion 2.d.1)
2.
Testosterone (See Section 6.1, inclusion criterion 2.c)
IRT
Treatment Arm Assignment
X
Treatment arm assignment via IRT will be based on prior treatment history, presence or 
absence of measurable disease, and HRD status per Section 7.2.
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.
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CA2099KD
BMS-936558
nivolumab
Table 2-2:
On-study Treatment and Follow-up Procedural Outline for Arms A or C (CA2099KD)
Procedurea
C1b (Cycle 
Duration = 
4 weeks)
Days 1 and 15
C2 and Subsequent 
Cyclesc (Cycle 
Duration = 4 weeks)
Day 1
Safety 
Follow-upd
Survival 
Follow-upe
Notes
Study Treatment
Dispense Study Treatment
X
X
First dose to be administered within 
3 calendar days following treatment arm 
assignment. 
Safety Assessments
Targeted Physical Examination and 
Vital Signs
X
X
X
Weight, BP, heart rate, RR, Temperature 
and ECOG Performance Status; within 72 
hours prior to dosing.
AEs Assessment (including SAEs)
Continuously
X
Per NCI CTCAE v. 4.03. Record at each 
visit
Concomitant Medication Use
Continuously
X
Record at each visit
Laboratory Tests
CBC with differential, Chemistry 
panel, Thyroid testing
X*
X
X01-yes
X02 - if
toxicities are
present
*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.
See Section 9.4.1 for list of laboratory 
tests.
PSA (Local) 
X
X
See notes
See notes
Perform on D1 of C1 to C4, then D1 of 
every even-numbered cycle (C6, C8, C10, 
etc.). Participants who discontinue study 
treatment without documented 
radiographic progression will continue to 
have PSA performed every 8 weeks 
(± 7 days) until radiographic progression 
or the start of subsequent systemic cancer 
therapy, whichever occurs later. PSA 
evaluation beyond radiographic
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CA2099KD
BMS-936558
nivolumab
Table 2-2:
On-study Treatment and Follow-up Procedural Outline for Arms A or C (CA2099KD)
Procedurea
C1b (Cycle 
Duration = 
4 weeks)
Days 1 and 15
C2 and Subsequent 
Cyclesc (Cycle 
Duration = 4 weeks)
Day 1
Safety 
Follow-upd
Survival 
Follow-upe
Notes
progression or the start of subsequent 
systemic cancer therapy to confirm PSA 
response or PSA progression should be 
performed as needed.
PSA should be performed by the same 
lab throughout the treatment period to 
avoid variations in results between cycles
Efficacy Assessments
CT/MRI of chest, abdomen, pelvis, and 
all known or suspected areas of disease
X
[X if 
progression is 
not 
documented 
prior to 
discontinuatio
n of study 
treatment]
See notes
Every 8 weeks (± 7 days) from first dose,
regardless of treatment schedule or dose 
delays for first 24 weeks. Following this, 
switch to every 12 weeks (± 7 days).
CT/MRI must continue until disease 
progression is documented or treatment is 
discontinued (whichever occurs later). 
See Section 9.1.
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CA2099KD
BMS-936558
nivolumab
Table 2-2:
On-study Treatment and Follow-up Procedural Outline for Arms A or C (CA2099KD)
Procedurea
C1b (Cycle 
Duration = 
4 weeks)
Days 1 and 15
C2 and Subsequent 
Cyclesc (Cycle 
Duration = 4 weeks)
Day 1
Safety 
Follow-upd
Survival 
Follow-upe
Notes
Radionuclide Bone Scan
X
[X if 
progression is 
not 
documented 
prior to 
discontinuatio
n of study 
treatment]
See notes
Every 8 weeks (± 7 days) from first dose, 
regardless of treatment schedule or dose 
delays for first 24 weeks. Following this, 
switch to every 12 weeks (± 7 days).
Bone scans must continue until disease 
progression is confirmed or treatment is 
discontinued (whichever occurs later).
See Section 9.1.
Survival Status
X
X
During safety follow-up and every 3 
months (clinic visit or by telephone) 
during survival phase. Include 
documentation of subsequent therapy.
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Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Table 2-2:
On-study Treatment and Follow-up Procedural Outline for Arms A or C (CA2099KD)
Procedurea
C1b (Cycle 
Duration = 
4 weeks)
Days 1 and 15
C2 and Subsequent 
Cyclesc (Cycle 
Duration = 4 weeks)
Day 1
Safety 
Follow-upd
Survival 
Follow-upe
Notes
Pharmacokinetic (PK) 
 Assessments
Collect blood samples for PK
Refer to Sampling Schedule Table 9.5.2-1
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 There is no nivolumab infusion at the Day 15 visit. Safety assessments are to be performed on Day 15.
c 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.
d Participants must be followed for a minimum of 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 42 days from last dose. 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.
e Survival Follow-up visits to occur every 3 months (± 14 days) from Safety Follow-up Visit 2. Survival Follow-up visits may be conducted in person or by 
telephone. BMS may request that survival data be collected on all treated participants outside of the 3 month specified window. 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.
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Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Table 2-3:
On-study Treatment and Follow-up Procedural Outline for Arm B (CA2099KD)
Procedurea
C1b (Cycle 
Duration = 
3 weeks)
Days 1 and 15
C2-C10 c
(Cycle 
Duration = 
3 weeks)
Day 1
C11 and 
Subsequent 
Cycles c,d
(Cycle 
Duration = 
4 weeks)
Day 1
Safety 
Follow-upe
Survival 
Follow-upf
Notes
Study Treatment
Dispense Study treatment
X
Xg
X
First dose to be administered within 
3 calendar days following treatment arm 
assignment. 
Safety Assessments
Targeted Physical 
Examination and Vital Signs 
X
X
X
X
Weight, BP, heart rate, RR, Temperature and 
ECOG Performance Status; within 72 hours 
prior to dosing.
Adverse Event (AE) 
Assessment
Continuously
X
Per NCI CTCAE v. 4.03. Record at each visit
Concomitant Medication Use
Continuously
X
Record at each visit
Laboratory Tests
CBC with differential, 
Chemistry, Thyroid testing
X*
X
X
X01-yes
X02 - if 
toxicities are 
present
*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.
See Section 9.4.1 for list of laboratory tests.
PSA (Local)
X
X
X
Perform on D1 of C1 to C5, then D1 of every 
other cycle starting with C7. Participants 
who discontinue study treatment without 
documented radiographic progression will 
continue to have PSA performed every 
8weeks (± 7 days) until radiographic 
progression or the start of subsequent 
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CA2099KD
BMS-936558
nivolumab
Table 2-3:
On-study Treatment and Follow-up Procedural Outline for Arm B (CA2099KD)
Procedurea
C1b (Cycle 
Duration = 
3 weeks)
Days 1 and 15
C2-C10 c
(Cycle 
Duration = 
3 weeks)
Day 1
C11 and 
Subsequent 
Cycles c,d
(Cycle 
Duration = 
4 weeks)
Day 1
Safety 
Follow-upe
Survival 
Follow-upf
Notes
systemic cancer therapy, whichever occurs 
later. PSA evaluation beyond radiographic 
progression or the start of subsequent 
systemic cancer therapy to confirm PSA 
response or PSA progression should be 
performed as needed
Efficacy Assessments
CT/MRI of chest, abdomen, 
pelvis, and all known or 
suspected areas of disease
X
X
[X if 
progression 
is not 
documented 
prior to 
discontinuati
on of study 
treatment]
Every 8 weeks (± 7 days) from first dose, 
regardless of treatment schedule or dose 
delays for first 24 weeks. Following this, 
switch to every 12 weeks (± 7 days). 
CT/MRI must continue until disease 
progression is documented or treatment is 
discontinued (whichever occurs later). See 
Section 9.1.
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Table 2-3:
On-study Treatment and Follow-up Procedural Outline for Arm B (CA2099KD)
Procedurea
C1b (Cycle 
Duration = 
3 weeks)
Days 1 and 15
C2-C10 c
(Cycle 
Duration = 
3 weeks)
Day 1
C11 and 
Subsequent 
Cycles c,d
(Cycle 
Duration = 
4 weeks)
Day 1
Safety 
Follow-upe
Survival 
Follow-upf
Notes
Radionuclide Bone Scan
X
X
[X if 
progression 
is not 
confirmed 
prior to 
discontinuati
on of study 
treatment]
Every 8 weeks (± 7 days) from first dose, 
regardless of treatment schedule or dose 
delays for first 24 weeks. Following this, 
switch to every 12 weeks (± 7 days).
Bone scans must continue until disease 
progression is confirmed or treatment is 
discontinued (whichever occurs later). See 
Section 9.1
Survival Status
X
X
During safety follow-up and every 3 months 
(clinic visit or by telephone) during survival 
phase. Include documentation of subsequent 
therapy.
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Table 2-3:
On-study Treatment and Follow-up Procedural Outline for Arm B (CA2099KD)
Procedurea
C1b (Cycle 
Duration = 
3 weeks)
Days 1 and 15
C2-C10 c
(Cycle 
Duration = 
3 weeks)
Day 1
C11 and 
Subsequent 
Cycles c,d
(Cycle 
Duration = 
4 weeks)
Day 1
Safety 
Follow-upe
Survival 
Follow-upf
Notes
Pharmacokinetic 
 Assessments
Collect blood samples for 
PK
Refer to Sampling Schedule Table 9.5.2-1
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 There is no nivolumab infusion at the Day 15 visit. Only safety assessments are to be performed on Day 15.
c 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.
d Three weeks after Cycle 10, nivolumab 480 mg Q4W monotherapy will be administered at Cycle 11 (± 3 days) and continue until completion of 24 months of 
treatment, disease progression, or unacceptable toxicity, whichever occurs first.
e Participants must be followed for a minimum of 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 42 days from last dose. 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.
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f Survival Follow-up visits to occur every 3 months (±14 days) from Safety Follow-up Visit 2. Survival visit may be conducted in person or by telephone. BMS 
may request that survival data be collected on all treated participants outside of the 3 month specified window. 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.
g Docetaxel may be given for a maximum of 10 cycles. If docetaxel is discontinued prior to Cycle 10, nivolumab 360 mg Q3W should be continued alone until 
Cycle 10.
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3
INTRODUCTION
CA2099KD is a Phase 2, open-label study of nivolumab in combination with either rucaparib, 
docetaxel or enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC).
mCRPC is defined as castrate resistant prostate cancer and M1 metastatic disease on bone, CT 
and/or MRI scan, per the American Joint Committee on Cancer (AJCC) cancer staging manual1.
Participants in this study will be evaluated in 3 parallel arms as follows: 
•
Arm A (nivolumab plus rucaparib): 
−
Arm A1: Participants who have received at least one but no more than 2 prior taxane-based 
regimens for castration-resistant disease. If docetaxel chemotherapy is used more than 
once, this will be considered as one regimen. Up to 2 second generation hormonal 
manipulations for castration-resistant disease are allowed.
−
Arm A2: Participants who are chemotherapy-naive for mCRPC and have received prior 
treatment with abiraterone acetate and/or enzalutamide for castration-resistant disease up 
to 28 days prior to study arm assignment and are not candidates for or refuse immediate 
chemotherapy
•
Arm B (nivolumab plus docetaxel): Participants who are chemotherapy-naive for mCRPC and
are candidates to receive docetaxel chemotherapy. Up to 2 second-generation hormonal 
manipulations (eg, abiraterone acetate and/or enzalutamide) in the mCRPC setting are allowed 
up to 28 days prior to study arm assignment.
•
Arm C (nivolumab plus enzalutamide): Participants who are chemotherapy-naive for mCRPC 
and have received prior treatment with abiraterone acetate in the mCRPC setting up to 28 days 
prior to study arm assignment without prior enzalutamide, and are not candidates for or refuse 
immediate chemotherapy.
Please refer to the Investigator Brochures (IBs) for nivolumab and rucaparib and the current 
prescribing information for enzalutamide for information not presented in this protocol. For 
docetaxel, the current prescribing information and local standards of practice should be considered.
3.1
Study Rationale
Prostate cancer tumor cells have been shown to have low tumor expression of PD-L1, suggesting 
that treatments directed at the PD-1 / PD-L1 interaction are unlikely to be successful as 
monotherapies.2 This was confirmed by early clinical trials, where men with mCRPC did not 
respond to PD-1 blockade as monotherapy.3 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”.4,5,6 This suggests that, if prostate cancer treatments (ie, poly [ADP 
ribose] polymerase [PARP] inhibitors, chemotherapy, or androgen ablation) can increase PD-L1 
expression on tumor cells by attracting infiltrating immune cells and triggering an adaptive 
immune response, then there is a rationale for combining such therapies with immune check-point 
inhibitors.7,8,9,10
This study aims to demonstrate that treatment with nivolumab combined with rucaparib, docetaxel 
or enzalutamide will have clinical activity in participants with mCRPC. Additional objectives of 
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the study include further characterization of efficacy, safety and tolerability
 
 as well as 
pharmacokinetics
. Response to study 
treatment and disease progression will be assessed using Prostate Cancer Clinical Trials Working 
Group 3 (PCWG3) criteria (Appendix 5).
3.1.1
Research Hypothesis
Nivolumab in combination with rucaparib, docetaxel, or enzalutamide can be given safely and will 
demonstrate meaningful clinical activity in participants with mCRPC.
3.2
Background
The attainment of meaningful, durable clinical response to treatment of mCRPC presents a 
daunting challenge, given the disease’s ability to acquire resistance to standard of care (SOC) 
options. Study treatment combinations with nivolumab that are investigated in the present study 
could represent viable additions to the current therapeutic armamentarium in this area of unmet 
medical need.
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of nivolumab and 
rucaparib are provided in the respective current Investigator Brochures (IBs). Similar details for 
docetaxel and enzalutamide can be found in the current prescribing information (ie, United States 
Prescribing Information [USPI], Summary of Product Characteristics [SmPC], and/or country-
specific product labels).
3.2.1
Indication Background
Prostate cancer is a leading cause of cancer mortality in men worldwide.11 With an estimated 
incidence of 161,360 new cases and 26,730 deaths in 2017, prostate cancer is the most frequently 
diagnosed cancer and third most frequent cause of cancer deaths in US males.12 In the US, 1 in 
every 7 men is diagnosed with prostate cancer.13 In Europe, prostate cancer was the third most 
common cancer in 2012, with 417,000 new cases and 92,000 deaths from prostate cancer being 
reported in that year.
In 1941, Huggins and Hodges first noted the beneficial effects of castration and injection of 
estrogens in participants with metastatic prostate cancer. 14 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).15 Nevertheless, most participants become 
resistant, with disease progression occurring within a median of 18 to 24 months of continuous 
hormonal manipulation.16
In 1996, mitoxantrone plus prednisone was approved for the treatment of patients with mCRPC 
based on improvement in pain palliation. 17 In 2004, two Phase 3 studies (TAX327 and 
SWOG S9916) demonstrated that docetaxel-based regimens can improve overall survival of 
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patients with mCRPC. 18,19 However, docetaxel-based treatment is associated with clinically 
significant toxicities that greatly limit its use in the management of lower risk, asymptomatic or 
minimally symptomatic mCRPC participants without visceral metastases. 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). 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 temporary20 due to the occurrence of resistance mechanisms, including androgen 
receptor (AR) reactivation.21 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.22 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.
3.2.2
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.23,24,25
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either 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).26 Collectively, these signals govern 
the balance between T-cell activation and tolerance.
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA-4, ICOS, and BTLA. 27 PD-1 signaling has been shown to inhibit CD-28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ), and Bcl-xL. PD-1 expression 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.28 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 
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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 CMV 
re-stimulation assay with human 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). 29 See the 
nivolumab IB for more information on the clinical pharmacology of this agent.
3.2.3
Mechanism of Action of Co-administered Therapeutic Agents
3.2.3.1
Rucaparib
Rucaparib is an inhibitor of PARP enzymes, including PARP-1, PARP-2, and PARP-3, which play 
a role in DNA repair. In vitro studies have shown that rucaparib-induced cytotoxicity may involve 
inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes 
resulting in DNA damage, apoptosis, and cell death. Increased rucaparib-induced cytotoxicity was 
observed in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Rucaparib 
has been shown to decrease tumor growth in mouse xenograft models of human cancer with or 
without deficiencies in BRCA. See the rucaparib IB for more information.
3.2.3.2
Docetaxel
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.
3.2.3.3
Enzalutamide
Enzalutamide is an AR inhibitor that acts on different steps in the AR signaling pathway. See the 
current prescribing information for enzalutamide (SmPC, USPI, or country-specific label) for more 
information.
3.3
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.22,30,31,32,33,34 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. 
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 
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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.
A pattern of immune-related 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 35,36, have provided support for further exploring 
the use of immune therapies in prostate cancer. Currently, clinical trials are underway evaluating 
the role of PD-1 inhibitor pembrolizumab, either alone or in combination with other immune 
therapies such as vaccines or cryosurgery, in hormone sensitive metastatic prostate cancer (HSPC)
and mCRPC (NCT02312557, NCT02499835, NCT02489357, NCT02787005). Nivolumab is 
currently being evaluated in mCRPC in combination with ipilimumab in study CA209650. 37
As outlined in Section 5.4.1, several lines of evidence support combination of immune therapies 
with chemotherapy, hormonal therapy and targeted therapy in men with mCRPC. The purpose of 
combination immune therapies is to enhance anti-tumor T-cell responses. There are robust clinical 
data suggesting the potential improvement in clinical outcomes in mCRPC with the combinations 
chosen in this study.
•
Recently published early phase studies evaluating the combination of immune checkpoint 
blockade and PARP inhibitors demonstrated preliminary evidence of durable activity and a 
good safety profile in an unselected population with mCRPC38, as well as in advanced solid 
tumors.39,40 The majority of AEs, primarily hematologic toxicities, were manageable with 
supportive care, and no new AEs were noted.39 To date, PARP inhibitors administered as 
monotherapy have been most extensively studied in the ovarian cancer population. Those 
PARP inhibitors furthest along in clinical development have demonstrated clinical activity and 
a manageable safety profile.,41,42,43,44,45,46 Arm A of this study will evaluate nivolumab in 
combination with the PARP inhibitor rucaparib. Homologous recombination deficiency 
(HRD) status will be assessed in all participants. Given the hypothesis that increased DNA 
damage by PARP inhibition will increase the number of tumor neoantigens, thereby creating 
a more antigenic environment in which to stimulate the immune microenvironment, and the 
promising anti-tumor activity of similar combinations in patients without germline or somatic 
mutations in BRCA or other homologous recombination (HR) genes39, both HRD-positive 
(HRD+) and HRD-negative (HRD-) participants will be enrolled (2:1 ratio).
•
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 
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PD-L1 expression, but with a numerically higher ORR observed in non-squamous NSCLC.47
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, ongoing internal and external studies of PD-L1 inhibitors in combination with 
chemotherapy suggest that this type of combination is tolerable and manageable, with no new 
safety signals being detected. 
•
In light of its immunomodulatory capacity, enzalutamide is an attractive combination agent 
with other immune treatments. Meaningful clinical activity and no unexpected AEs were seen 
when the combination of PD-1 inhibitor pembrolizumab and enzalutamide was evaluated in 
men with mCRPC.48
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 rucaparib, docetaxel or 
enzalutamide
•
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 
management algorithms and toxicity management of the coadministered agents. In addition, a 
Study Steering Committee (consisting of selected participating investigators) will meet 
regularly to advise BMS regarding study-related issues, including safety concerns.
•
Open-label drug administration of study treatments to allow for prompt and accurate 
assessment of the unique toxicities associated with study treatments
In conclusion, the overall risk-benefit of nivolumab in combination with rucaparib, docetaxel or 
enzalutamide in men with mCRPC is deemed acceptable.
Detailed information about the known and expected benefits and risks and reasonably anticipated 
AEs of nivolumab and rucaparib may be found in their respective IBs. Similar information is 
provided for docetaxel and enzalutamide in the associated Patient Information Leaflet, USPI, 
country-specific label, Development Safety Update Report, or SmPC.
4
OBJECTIVES AND ENDPOINTS
The following are the objectives and associated endpoints in this study of nivolumab combined 
with either rucaparib, docetaxel, or enzalutamide in participants with mCRPC and measureable 
disease at baseline:
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoint
Co-Primary
To evaluate the objective response rate 
per PCWG3 (ORR-PCWG3) in HRD+ 
participants and in all treated 
participants 
ORR-PCWG3 is the proportion of participants who have a confirmed 
complete or partial best overall response (BOR) per PCWG3 among 
treated participants who have measurable disease. The BOR will be 
assessed by the investigator per PCWG3 and is recorded between 
treatment initiation 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.
To evaluate PSA response rate (RR-
PSA) in HRD+ participants and in all 
treated participants
RR-PSA is the proportion of treated 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.
Secondary
To evaluate radiographic progression-
free survival (rPFS) in HRD+ 
participants and in all treated 
participants
rPFS is the time between treatment initiation and the first date of 
documented progression or death due to any cause, whichever occurs 
first. The radiographic progression will be assessed by the investigator
per PCWG3. The rPFS will be censored at the last tumor assessment 
up to the start of subsequent systemic cancer therapy for those without 
progression/death.
To evaluate time to response (TTR) and 
duration of response (DOR) per 
PCWG3 (TTR-PCWG3 and DOR-
PCWG3) in HRD+ participants and in 
all treated participants
TTR-PCWG3 is the time from treatment initiation to the date of the 
first documented CR or PR 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 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.
To estimate time to PSA progression 
(TTP-PSA) in HRD+ participants and 
in all treated participants
TTP-PSA is the time between treatment initiation to the date of PSA 
progression per PCWG3 in treated 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 at or 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 treatment initiation for participants with no 
post-baseline PSA evaluation.
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoint
To assess overall survival (OS) in 
HRD+ participants and in all treated 
participants
OS is the time between treatment initiation 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 treatment initiation if they had 
no follow-up.
To evaluate overall safety and 
tolerability
Overall safety and tolerability will be measured by the incidence of 
AEs, SAEs, AEs leading to discontinuation, immune-mediated AEs, 
deaths, and laboratory abnormalities and changes from baseline
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoint
5
STUDY DESIGN
5.1
Overall Design
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
This is an open-label Phase 2 study of nivolumab in combination with rucaparib (Arm A), 
docetaxel (Arm B), or enzalutamide (Arm C) in men with mCRPC. Arm A is split into 
2 sub-groups according to whether participants have received prior chemotherapy (Arm A1) or are 
chemotherapy naive (Arm A2). The study is not randomized, and treatment arm assignment will 
depend on prior systemic treatment history, as specified in protocol Section 6.1 and as illustrated 
in the decision tree provided in Figure 5.1-2.
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Figure 5.1-2:
Decision Tree Guiding Treatment Arm Assignment
Treatment arm assignment will also depend on 2 clinical variables: 1) the presence or absence of 
measurable disease on the baseline tumor assessment per investigator review; and 2) the presence 
or absence of HRD based on testing of a blood plasma and/or tumor tissue sample by the central 
laboratory during screening or by local laboratory prior to enrollment. 
A participant is considered HRD+ if they have a deleterious genomic alteration (protein truncating 
or splice site mutation, homozygous deletion, large protein truncating rearrangement, or 
deleterious missense mutation) in plasma and/or tumor sample in at least one of the following HR 
genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, 
RAD51, RAD51B, RAD51C, RAD51D, or RAD54L. HRD status will be determined by central 
laboratory testing of a submitted blood plasma and/or tumor sample during screening or by local 
laboratory testing performed prior to enrollment. If local HRD testing has been performed prior to 
enrollment, the local HRD test results must be documented in the participant’s medical records 
and local HRD laboratory report must be provided to the Sponsor. The local HRD laboratory report 
must clearly document the presence of a pathogenic or deleterious mutation in one of the HR genes 
noted above in order for it to be acceptable for assignment to an HRD+ spot. If the records do not 
clearly indicate the patient’s HRD status, the local testing results must be submitted to the sponsor 
for further interpretation of the HRD status.
Within each treatment arm, 60% of the available spots will be designated for participants who have 
measurable disease and 40% of the available spots will be designated for those who do not have 
measurable disease. In the entire study, approximately 45% of the available spots will be 
designated for participants who are HRD positive and approximately 55% will be designated for 
participants who are HRD negative or HRD not evaluable. However, the number of HRD+ versus 
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HRD- or HRD-not evaluable spots will vary in each arm as follows: 100 HRD+ and 80 HRD- or 
not evaluable in Arm A; 25 HRD+ and 60 HRD- or not evaluable in Arm B; 25 HRD+ and 
40 HRD- or not evaluable in Arm C. Since the estimated prevalence of HRD+ status in this patient
population is approximately 20%, it is anticipated that the HRD- or not evaluable spots will be 
filled before HRD+ spots, and the rate of accrual of HRD+ participants will largely determine the 
duration of the enrollment period. Enrollment in any of the study arms may be terminated early 
due to poor accrual.  
The Interactive Response Technology (IRT) system will be used for treatment arm assignment. 
IRT will assign each participant to a treatment arm based on prior treatment history, measurable 
disease status, and HRD status. Additional details are specified in Section 7.2.The study will 
consist of 3 phases: screening, treatment, and follow-up.
Screening Phase:
•
Begins by participant signing of the informed consent form (ICF) and establishing the 
participant’s initial eligibility 
•
Participant is enrolled using the Interactive Response Technology (IRT). 
•
Obtain mandatory pre-treatment blood plasma and archival or fresh tumor tissue specimen.
Central lab must provide IRT with the results of HRD testing on a submitted blood plasma 
and/or tumor sample prior to treatment assignment unless local lab HRD results obtained prior 
to enrollment are provided to the Sponsor and confirmed to be acceptable for treatment 
assignment.( Additional details can be found in Section 9.8.2.)
Tumor assessments must be performed within 28 days of treatment arm assignment.
Treatment Phase:
•
Begins with the treatment arm assignment using the IRT
•
Within 3 calendar days from treatment arm assignment the participant must receive the first 
dose of study medication (Day 1 of Cycle 1). See Section 7.1 for details on treatment 
administration.
−
Arm A dosing: nivolumab 480 mg IV Q4W plus rucaparib 600 mg PO BID
−
Arm B dosing: nivolumab 360 mg IV Q3W plus docetaxel 75 mg/m2 IV Q3W plus 
prednisone 5 mg PO BID co-administered with docetaxel plus dexamethasone 8 mg PO 
administered in 3 doses prior to docetaxel infusion
−
Arm C dosing: nivolumab 480 mg IV Q4W plus enzalutamide 160 mg PO QD
•
During the first cycle, a Day 15 study visit will occur. No study treatment will be administered.
•
On-study laboratory assessments should be drawn within 72 hours prior to dosing.
•
AE assessments should be documented at each clinic visit.
•
PK samples 
 samples will be collected according to schedules in 
Section 9.5.
•
Study drug dosing may be delayed for toxicity as described in Section 7.1.1.
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•
Each cycle during the treatment phase is expected to last 4 weeks for Treatment Arms A and 
C, through to PD or unacceptable toxicity, unless there are delays. For Arm B only, each cycle 
will last 3 weeks up to and through Cycle 10, at which point, cycle duration will change to 
4 weeks and nivolumab 480 mg will be administered as monotherapy.
•
Tumor assessments are scheduled to be performed every 8 weeks (± 7 days) for 24 weeks
following treatment initiation and thereafter every 12 weeks (± 7 days) until radiographic 
progression or discontinuation of study treatment (whichever occurs later). Tumor assessments 
should be performed at these time points regardless of treatment schedule or dose delays.
This phase ends when the participant is discontinued from study therapy. 
Follow-Up Phase:
•
Begins when the decision to discontinue a participant from study therapy is made (no further 
treatment with study therapy)
•
If biopsy or surgical resection is performed at progression, a tumor sample (block or slides) 
should be submitted to the central laboratory
•
Two safety follow-up visits will be conducted which include collection of PK
 
samples.
•
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 and Table 2-3 until progression.
•
Participants will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All AEs will be documented for a minimum of 100 days 
after last dose.
•
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
The procedures specified in each phase can be found in Section 2.
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
5.1.1
Data Monitoring Committee and Other External Committees
To provide independent oversight of safety, efficacy, and study conduct, a DMC will be instituted. 
The DMC will meet regularly to ensure that participant safety is carefully monitored. The DMC 
will convene additional ad hoc meetings if necessary. Following each meeting, the DMC will 
recommend continuation, modification, or discontinuation of the study based on observed 
toxicities and efficacy. A separate DMC charter will describe the activities of this committee in 
more detail. 
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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. 
Regarding external committees, no prospective Blinded Independent Central Review (BICR) is 
planned. The study will collect and hold images for future BICR assessments, as needed, per the 
Sponsor.
5.2
Number of Participants
Approximately 330 participants are planned to be enrolled and assigned treatment in 1 of 3 parallel 
treatment arms as follows:
•
Arm A: 180 participants to receive nivolumab plus rucaparib
−
Arm A1 = 80
−
Arm A2 = 100
•
Arm B: 85 participants to receive nivolumab plus docetaxel plus prednisone and 
dexamethasone
•
Arm C: 65 participants to receive nivolumab plus enzalutamide
See Section 10.1 for a description of the sample size calculation.
5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant treated. End of trial is defined 
as the last visit or scheduled procedure shown in the Schedule of Activities for the last participant.
Study completion is defined as the final date on which data for the co-primary endpoints are
expected to be collected.
The total duration of the study from the date of first participant treated to final analysis of 
co-primary endpoints is expected to be approximately 2.5 years. In addition, survival analysis may 
be conducted for up to 5 years after treatment initiation following the analysis of the co-primary 
endpoints.
5.4
Scientific Rationale for Study Design
5.4.1
Rationale for Immunotherapy in mCRPC
Immunotherapy agents represent a promising approach for the management of asymptomatic and 
minimally symptomatic CRPC participants.
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.49 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.50
The induction of regulatory or suppressor T cells51 with increased CD4+CD25+ and CD8+Foxp3+ 
regulatory T cells (Treg), detected both within prostate glands and in the peripheral blood of 
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prostate cancer subjects, suggests the presence of active immune suppression of antitumor 
immunity.52,53
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.54 This may indicate that tumor immune escape, and 
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. 
•
The inherent characteristics of prostate cancer make it an ideal target for immunotherapy. 
Prostate cancer is generally considered a slow growing tumor, which may allow adequate time 
for an immunotherapy agent to activate the immune system. Prostate cancer has many well-
described tumor-associated antigens (TAAs), which may be ideal targets for immunotherapy,
such as vaccines because they are specific to the cancer. Examples of TAAs for prostate cancer 
include PSA, prostatic acid phosphatase (PAP), and prostate-specific membrane antigen 
(PSMA). Targeting TAAs has led to the evaluation of therapeutic cancer vaccines designed to 
break immune tolerance55 and are currently being explored in participants with early CRPC, 
ie, before chemotherapy, with vaccines of autologous origin 56 , poxvirus 57 , and PSA 
TRICOM.58
Prostvac®
(developed by the National Cancer Institute and licensed to BN 
Immunotherapeutics, Mountain View, CA), is a therapeutic prostate cancer vaccine, consisting 
of a recombinant vaccinia vector, as a primary vaccination engineered to express PSA and a 
triad of human T-cell costimulatory molecules (designated TRICOM). A multicenter 
randomized Phase 2 study that randomized minimally symptomatic mCRPC participants to 
Prostvac vs placebo showed preliminary evidence of improved overall survival. 59 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.22 While these preliminary 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. 60
While antigen-specific therapies such as vaccines have shown evidence of potential for benefit 
in the clinic, this approach has many limitations10,61,62,63, underscoring the need to explore 
immunotherapy that does not rely mainly on the expression of a specific antigen. 
•
Prostate cancer has been shown to have low tumor expression of PD-L1.3 In a Phase 1 study 
targeting PD-1, treatment with nivolumab was ineffective in unselected participants with 
CRPC (0/17 responses). However, immunotherapy agents in conjunction with SOC therapy 
could potentially result in increasing immune-mediated anti-tumor activity in subjects with 
prostate cancer as outlined in Section 5.4.2. Androgen-deprivation therapy (ADT), a mainstay 
of treatment for both high-risk early prostate cancer and recurrent and/or metastatic disease, 
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has been shown to alter the immune environment in prostate cancer.9 For example, neoadjuvant 
ADT of prostate cancer patients results in increased numbers of infiltrating CD4 T-cells, CD8
T-cells, natural killer cells, and macrophages in prostate tissues.7,8 Similarly, there is growing 
evidence that chemotherapy and PARP inhibitors can induce immuno-modulatory effects that 
could facilitate the induction of antitumor immunity.
Taken together, these lines of evidence strongly support the continued investigation of 
immunotherapy agents to improve outcomes in mCRPC by employing different agents that work 
via varied mechanisms of action and are potentially synergistic.
5.4.2
Rationale for Co-administration of Nivolumab with Selected Therapeutic 
Agents in mCRPC
5.4.2.1
Nivolumab plus Rucaparib
PARP inhibitors, a cancer therapy targeting poly (ADP-ribose) polymerase, are the first clinically 
approved drugs designed to exploit synthetic lethality. DNA replication and error-repair are a 
critical component of cancer cell survival. Suppression of PARP leads to stalling of replication 
forks due to the accumulation of unrepaired single-strand breaks (SSBs). Stalled replication forks 
degrade into highly cytotoxic double-strand breaks (DSBs) if not corrected by appropriate repair 
mechanisms, which are essentially absent in HR-mutated cells.64 Since HR-mutated cells are 
incapable of homologous repair (considered the most precise DSB repair mechanism), PARP 
inhibition results in genomic instability and cell death.65 Thus, tumors that harbor a defect in HR 
(and likewise a defect in DSB repair) seem to be highly vulnerable to the effects of PARP 
inhibition. Notably, these tumors include somatic and germline BRCA-1 and BRCA-2 mutations.
In prostate cancer, there is a large subset of tumors with somatic mutations in genes involved in 
HR that have been reported to confer sensitivity to PARP inhibitors, including ATM, FANCA, 
CDK12, RAD51B, RAD51C, PALB2, CHEK2, and ETS gene fusions (TMPRSS2:ERG).66,67,68,69
It would be premature to draw conclusions about which PARP inhibitors are most effective in 
particular patient populations; at present, the different clinical trial designs and distinct patient 
populations used to assess different PARP inhibitors preclude such direct comparisons.
Olaparib was approved in the US and EU in 2014 for the treatment of BRCA-mutation-related 
ovarian cancer in the treatment (US) or maintenance (EU) setting. Rucaparib was approved in the 
US in December 2016 for the treatment of patients with deleterious BRCA-mutation (germline 
and/or somatic)-associated, advanced ovarian cancer who have been treated with 2 or more 
chemotherapies. In March 2017, niraparib was approved in the US for the maintenance treatment 
of adult patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer who have a 
complete or partial response to platinum-based chemotherapy.
Olaparib received a Food and Drug Administration (FDA) breakthrough therapy designation in 
2016 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 
acetate. The designation is based on data from the Phase 2 TOPARP-A trial which enrolled 
50 participants. Ninety-six percent (96%) of the participants included in the study had received 
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prior enzalutamide, while 28% had received prior abiraterone. In addition, 100% of the participants 
had received prior docetaxel, and 58% had received prior cabazitaxel. In this study, the response 
rate to olaparib monotherapy (a composite endpoint defined as any of the following: response per 
RECIST v1.1; PSA response; or conversion of circulating tumor cell count) was 33% in the 
49 evaluable participants. In the 16 participants with DNA-repair defects (DRD), 88% of 
participants had a response to olaparib vs 6% without DRD.69 rPFS and OS for participants who 
had DRD or “biomarker positivity” were 9.8 months and 13.8 months, respectively, versus 
2.7 months and 7.5 months, respectively, in those participants who were biomarker negative 
(p < 0.001 and p = 0.05 for respective analyses). Anemia (in 20% of participants) and fatigue (in 
12% of participants) were the most common Grades 3 and 4 AEs, in keeping with other studies of 
olaparib. Ongoing clinical trials are testing the use of olaparib alone or in combination in 
participants with prostate cancer who have never received chemotherapy (NCT03047135, 
NCT03012321, and NCT02324998).
Currently, rucaparib is being evaluated in men with mCRPC in a Phase 2 study (NCT02952534) 
and a Phase 3 study (NCT02975934). Overall, the safety profile of rucaparib is manageable and 
generally consistent across completed and ongoing clinical trials. The recently published results 
from the ARIEL2 (Part 1) study show that treatment-related AEs in ≥15% of participants were 
generally low grade and included (in decreasing order of frequency) nausea, fatigue, dysgeusia, 
transient transaminitis, decreased appetite, vomiting, constipation, anemia, and diarrhea.43
Additional details on the safety profile of rucaparib, including results from other clinical studies, 
are also available in the rucaparib IB.
The rationale for combining rucaparib with nivolumab in mCRPC derives from emerging data 
which demonstrate an important association between genomic loss of heterozygosity (LOH), high 
neoantigen load, and high expression of PD-1/PD-L1 in HRD tumors when compared with HR 
proficient ovarian cancers.70,71,72 BRCA1 and BRCA2 mutations have been reported to increase 
the number of tumor-infiltrating lymphocytes (TILs) and are associated with improved overall 
survival.73 A high mutational burden increases the likelihood of the development of tumor-specific 
neoepitopes that would confer clinical benefit from CTLA-4 and PD-1 blockade. Thus, it is 
hypothesized that increased DNA damage by PARP inhibition will increase the number of tumor 
neoantigens, creating a more antigenic environment in which to stimulate the immune 
microenvironment. 
The combination of immune checkpoint inhibitors and PARP inhibitors has been recently 
evaluated in 3 early phase studies.38,39,40 In a Phase 1 dose-escalation study of PD-L1 inhibitor 
durvalumab in combination with PARP inhibitor olaparib in 12 heavily pretreated participants
(10 with ovarian cancer and 2 with triple-negative breast cancer), there were 4 participants with 
partial response (duration of response ≥15 months and ≥11 months) and 8 participants with stable 
disease ≥4 months (median, 8 months [4 to 14.5 months]), yielding an 83% disease control rate.39
The most common treatment-emergent AE (TEAE) with durvalumab plus olaparib was 
hematologic toxicity, with no dose-limiting toxicity reported at the highest dose combination tested 
(olaparib 300 mg twice daily and durvalumab 1500 mg Q4W). The same combination is being 
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evaluated in an ongoing Phase 2 study in participants with mCRPC and appears to have clinical 
activity and to be well tolerated in an unselected patient population. Based on preliminary results 
in 19 participants (10 of whom are chemotherapy-naive), Grade 3/4 AEs included anemia 
(3/14, 21%), thrombocytopenia, lymphopenia, leukopenia, neutropenia, nausea, vomiting, 
hypertension, syncope, fatigue, UTI, and lung infection (1/14 each). Seven (7) out of 
16 participants (44%) on-study for more than 2 months had PSA declines > 50%. Four (4) out of 
17 response evaluable participants (23.5%) achieved a partial response per RECIST v1.1, with 
3 responders demonstrating BRCA2 mutations. Six (6)-month and 9-month PFS were 86.7% and 
57.8%, respectively. Median PFS had not yet been reached.38 In a Phase 1/1b study, the 
combination of anti-PD-1 BGB-A317 and PARP inhibitor BGB-290 was generally well tolerated 
in 43 participants with advanced solid tumors.40 Liver-related AEs were observed in 
12 participants; all events were reversible with or without corticosteroid treatment. Complete or 
partial response was observed in 11 participants, 4 of whom had confirmed PR or CR; responses 
were durable and observed in participants with wild̻type and mutant germline BRCA (gBRCA)
status. Taken together, these studies have not identified any new safety signals with the 
combination of a PARP inhibitor and a PD-L1 inhibitor.
PARP inhibitors have demonstrated activity in patients with HRD, which often occurs through 
genomic alterations (eg, BRCA1 and BRCA2 mutations) or epigenetic (eg, methylation) 
modifications.43,69,74,75 They have also demonstrated activity in platinum-sensitive, recurrent 
ovarian cancer patients, regardless of the presence or absence of a gBRCA or a sBRCA mutation
or other evidence of HRD.43 In patients treated with rucaparib who had platinum-sensitive ovarian 
carcinomas associated with a BRCA mutation or whose tumors were BRCA wild-type and LOH 
high, PFS was longer than in patients with tumors which were BRCA wild-type and LOH low. 
This has also been confirmed by topline data from the Phase 3 ARIEL3 trial, where the rucaparib 
arm improved PFS over placebo in both BRCA wild type/HRD+ and BRCA wild type/HRD-
subgroups, extending the potential usefulness of PARP inhibitors in the treatment setting beyond 
BRCA mutant tumors.
In addition, the combination of rucaparib and nivolumab has the potential for immuno-modulatory 
effects that may expand the activity of these agents beyond tumors with HRD. In the combination 
study of olaparib and durvalumab39, none of the women receiving durvalumab plus olaparib for 
more than 9 months had a germline or somatic mutation in BRCA or other HR genes. In order to 
explore both of these populations, Arm A will evaluate the combination of rucaparib and 
nivolumab in both HRD+ and HRD-/not evaluable participants.
Both post-chemotherapy (Arm A1) and chemotherapy-naïve participants (Arm A2) will be 
included in Arm A. Although the TOPARP-A clinical trial included only post-chemotherapy 
patients, a reduction in the intratumoral PARP1 protein expression has been observed after 
administration of chemotherapy, suggesting that treating chemotherapy-naïve patients with PARP 
inhibitors might increase the responsiveness to PARP1 inhibition.76 In the ongoing Phase 2 study 
evaluating the combination of olaparib and durvalumab in mCRPC, approximately 47% of 
participants enrolled thus far have not received prior chemotherapy. Furthermore, as previously 
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mentioned, several clinical trials are currently evaluating rucaparib (NCT02975934) and olaparib 
(NCT03012321; NCT03012321) in chemotherapy-naive, mCRPC participants. Therefore, based 
on the available evidence and on the potential benefit of adding nivolumab, this combination of
nivolumab and rucaparib is also anticipated to be effective in the pre-chemotherapy setting. 
5.4.2.2
Nivolumab plus Docetaxel
Docetaxel became the first chemotherapeutic agent to show an OS benefit in mCRPC, and was 
approved in combination with prednisone for this indication in the US in 2004. In the landmark 
TAX 327 Phase 3 trial18, 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. 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], 0.62-0.94; p = 0.009). 
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. 
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. 77 , 78 Docetaxel has been reported to increase the production of 
proinflammatory cytokines which may enhance the immune response.79 These findings have led 
to the development of clinical trials evaluating the combination of docetaxel and various immune 
therapy approaches. 80,81
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 non-
small cell lung cancer (NSCLC).47 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 
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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. 
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 who are considered candidates to receive 
standard chemotherapy. Prednisone 5 mg PO BID will be administered to participants assigned to 
the docetaxel arm, per prescribing information.
In light of these data, Arm B will evaluate the combination of nivolumab and docetaxel in mCRPC 
participants eligible for chemotherapy.
5.4.2.3
Nivolumab plus Enzalutamide
Enzalutamide was approved in the US for post-chemotherapy and chemotherapy-naïve mCRPC 
patients in 2012 and 2014, respectively. A double-blind, placebo-controlled Phase 3 study, 
AFFIRM, showed that enzalutamide improved median OS compared to the placebo group in men 
with mCRPC who had previously received docetaxel (18.4 vs. 13.6 months, respectively; 
p < 0.001)82. A similar trend was seen in the double-blind, randomized, placebo-controlled, 
Phase 3 PREVAIL study, where enzalutamide was evaluated in men with chemotherapy-naïve 
mCRPC that had progressed despite the use of ADT83. The study met its coprimary endpoints, 
with significant improvements for enzalutamide versus placebo in both rPFS and OS. At 12 months 
of follow-up, the rate of rPFS was 65% for enzalutamide-treated participants versus 14% for 
participants receiving placebo (81% risk reduction; hazard ratio, 0.19; 95% CI 0.15, 0.23; 
p  <  0.001). In an updated analysis of efficacy endpoints, median investigator-assessed rPFS was 
20.0 months (95% CI 18.9–22.1) in the enzalutamide arm and 5.4 months (95% CI 4.1–5.6) in the 
placebo arm. Median OS was 35.3 months (95% CI 32.2–not yet reached) in the enzalutamide arm 
and 31.3 months (95% CI 28.8– 34.2) in the placebo arm84.
While second-generation hormonal therapies such as enzalutamide and abiraterone represent 
significant advances in the treatment of mCRPC, approximately 20% to 40% of patients have 
primary resistance to these agents and exhibit no response with respect to PSA levels or other 
measures of clinical benefit 85 , 86 , 87 , 88 . Furthermore, among patients who initially have a 
serological or clinical response to enzalutamide or abiraterone, virtually all eventually acquire 
secondary resistance over time.
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The immunogenic modulation potential of ADT was first described using the murine TRAMP 
(transgenic adenocarcinoma of the mouse prostate) model of prostate carcinoma89. Exposure of 
TRAMP-C2 prostate tumor cells to enzalutamide significantly enhanced cell-surface expression 
of the death receptor Fas and MHC Class I resulting in improved sensitivity to immune-mediated 
lysis in vitro. Mice receiving the combination of enzalutamide and a therapeutic vaccine targeting 
Twist had significantly increased overall survival as compared to either no treatment or 
monotherapy alone. Notably, the effectiveness of the combination therapy increased with disease 
stage, with the greatest survival benefit seen in mice with advanced-stage prostate tumors. 
A follow-up study has demonstrated that prostate tumor cells harboring AR amplification, a major 
mechanism of ADT resistance, were rendered more sensitive to immune-mediated lysis in 
response to enzalutamide treatment, highlighting the potential efficacy of ADT-induced 
immunogenic modulation even in ADT-resistant patients.90 Various AR-dependent as well as AR-
independent mechanisms likely play a role in the development of resistance to these novel 
antiandrogens, including upregulation of AR and CYP17, induction of AR splice variants, AR 
point mutations, activation of alternative oncogenic signaling pathways, and immune evasion via 
PD-L1 upregulation. While both enzalutamide and abiraterone significantly prolonged OS for 
chemotherapy-naïve men with mCRPC, the efficacy of enzalutamide after abiraterone has only 
been evaluated in small retrospective studies which have indicated potential cross-resistance 
between treatment with abiraterone and enzalutamide.91,92 No robust criteria exist clinically to 
select one drug rather than the other.91,93 The presence of AR splice variants without the ligand-
binding domain has been associated with resistance to abiraterone and enzalutamide and could be 
one explanation for this significant cross-resistance.94
Furthermore, recent studies have shown that treatment of certain prostate cancer cell lines with 
anti-androgens (including enzalutamide) can induce tumoral PD-L1 expression and that 
enzalutamide-resistant prostate cancer cell lines demonstrate striking expression of PD-L1.95These 
results are aligned with preclinical findings indicating increased amounts of circulating 
PD-L1/2-positive dendritic cells and increased levels of tumor-intrinsic PD-L1 in mice with 
enzalutamide-resistant tumors.95,96 As such, immune evasion of prostate cancer via upregulation 
of PD-L1 may possibly play a role in the development of resistance to novel antiandrogen therapy 
such as enzalutamide or abiraterone. Based on these observations, the addition of pembrolizumab 
upon enzalutamide failure was evaluated in a single-arm, Phase 2 study. The study demonstrated
meaningful clinical activity to PD-1 blockade in men with mCRPC and no unexpected AEs.48
Findings from these studies provide a rationale for combination strategies that include ADT, 
particularly with enzalutamide, and immunotherapy as a promising treatment option for prostate 
cancer. In light of enzalutamide’s immunomodulatory capacity and the existing clinical data on 
the combination of pembrolizumab and enzalutamide, Arm C will explore the combination of 
enzalutamide and nivolumab in men with mCRPC who have demonstrated either primary or 
secondary resistance to abiraterone.
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5.4.3
Rationale for Sample Size Determination
Estimates of reference ORR-PCWG3 and RR-PSA in analysis cohorts from the 3 arms are 
provided in Table 5.4.3-1 for power assessments. See Section 10.1 for a description of the sample 
size calculation for each analysis cohort.
Table 5.4.3-1:
Estimates of Reference ORR and PSA Response (≥50%) 
Rate in Target Populations
Monotherapy in Target Population
ORR
PSA Response Rate
Rucaparib for target population in Arm A1
10%
20%
Rucaparib for target population in Arm A2
21%
47%
Docetaxel for target population in Arm B
21%
47%
Enzalutamide for target population in Arm C
10%
25%
For the power assessment with expected benefit in each analysis cohort in Arm A, the estimates 
of ORR and RR-PSA are based on the current SOC:
•
Arm A1 will include participants in the post-chemotherapy setting who would be treated with 
either second-line cabazitaxel or with supportive care only if they had already received 2 prior 
taxane-based regimens. The estimates of ORR and RR-PSA for second-line cabazitaxel are 
14% and 30%, respectively. According to studies conducted in the post-chemotherapy setting 
that compared second-generation hormone therapies with placebo, participants who received 
placebo had a 3% to 4% ORR and a 2% to 6% RR-PSA.82,88 Therefore, the estimates of 
10% ORR and 20% RR-PSA for SOC in the chosen population are considered appropriate.
•
Arm A2 will include participants who are chemotherapy-naive for mCRPC who have received 
prior treatment with abiraterone acetate and/or enzalutamide. The current SOC after 
progression with second-generation hormone therapies is docetaxel chemotherapy. Estimates
of ORR and RR-PSA for docetaxel monotherapy were extrapolated from the FIRSTANA 
Phase 3 study which evaluated docetaxel vs cabazitaxel as the first-line treatment of mCRPC.97
In the docetaxel arm (n = 391), ORR was 30.9% (RECIST v1.1) and 68% of participants had 
a PSA decline > 50%. Considering that a) the administration of docetaxel after one or both of 
newer AR pathway inhibitors may have less activity than in the pivotal trials 98, b) in the 
FIRSTANA study, only approximately 3% of participants had received prior abiraterone or 
enzalutamide, and c) the target population in Arm B will include a much higher percentage of 
participants who have received prior abiraterone or enzalutamide, the estimates based on the 
FIRSTANA study would be considered too optimistic. The estimate of RR-PSA was therefore 
modified taking into account the data from the COU-AA-302 post-hoc analysis where 
docetaxel post-abiraterone treatment led to a PSA response rate of 27%. 99 A null RR-PSA of 
47%, which is between those obtained in the FIRSTANA study and COU-AA-302 post hoc 
analysis, has been chosen. A similar RR-PSA was achieved in the docetaxel arm of TAX327 
study where 45% of participants had at least a 50% decrease in the serum PSA level.18 As the 
COU-AA-302 post-hoc analysis did not report the rate of radiological responses, the estimate 
of 21% ORR for docetaxel monotherapy was obtained by taking into account the ORR from 
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the FIRSTANA study and the ORR from a retrospective evaluation of the activity of docetaxel 
in patients previously treated with abiraterone (ORR of 11%).100
For the power assessment with expected benefit in Arm B, the estimates of 21% for ORR and 47% 
for RR-PSA are based on docetaxel monotherapy and follow the same rationale described in 
Arm A2.
For the power assessment with expected benefit in Arm C, the estimates of ORR and RR-PSA
were extrapolated from a Phase 4, multicenter, open-label, single-arm study of enzalutamide in 
participants with mCRPC who had progressive disease (PD) following prior treatment with 
abiraterone plus prednisone.101 The overall ORR in participants with measurable disease at study 
entry was 12% and PSA response rate was 26.5%. Although this prospective series included only 
participants likely to respond to enzalutamide (ie, those who previously responded for at least 6 
months to abiraterone) as opposed to the target population in Arm C which will include participants 
regardless of prior response to abiraterone, a similar RR-PSA (23.5%) was also reported in a small 
retrospective study in mCRPC participants treated with enzalutamide after abiraterone. 102
Therefore, the estimates of 10% ORR and 25% RR-PSA for enzalutamide monotherapy post-
abiraterone are considered appropriate in the chosen population.
Rationale for increasing the number of HRD negative/not evaluable participants in ARM A 
(amendment 02) 103,104
Results of recent studies suggest a benefit of PARPi combinations regardless of homologous 
recombination repair (HRR) mutation status. In a recently published phase II trial 103, 142 patients 
with mCPRC were randomly assigned to receive olaparib and abiraterone (n=71) or placebo and 
abiraterone (n=71). Olaparib in combination with abiraterone provided clinical efficacy benefit for 
patients with mCRPC compared with abiraterone alone regardless of HRR mutation status (rPFS 
in HRR mutation-positive subgroup: 17·8 months in the olaparib group vs 6·5 months in the 
placebo group; rPFS in wild-type HRR subgroup: 15·0 months in the olaparib group vs 9·7 months 
in the placebo group). Furthermore, the combination with nivolumab has the potential for immuno-
modulatory effects that may expand the activity of the combination beyond tumors with HRD. An
update on the results of the combination of immune checkpoint inhibitor durvalumab and PARP 
inhibitor olaparib104 showed that rPFS of the biomarker-negative group was greater than the rPFS 
reported with monotherapy olaparib (4.8 months vs 2.7 months, respectively). In this study, 2 out 
of the 9 patients with PSA responses were HRD-/not evaluable. 
Thus, the sample size of HRD negative/not evaluable patients in ARM A will be increased by a 
total of 30 subjects: 15 additional subjects in ARM A1 and 15 additional subjects in ARM A2.
This will extend the potential clinical benefit of the combination to additional HRD negative/not 
evaluable mCRPC patients and will increase the precision approach for the co-primary endpoints 
in treated subjects with measurable disease at baseline and HRD- status (please refer to Table 10.1-
1 for further statistical details).
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5.4.4
Rationale for Evaluating Asymptomatic or Minimally Symptomatic 
Metastatic CPRC Participants (ARM A2 and ARM C subjects)
Treatment for metastatic prostate cancer is not curative and treatment-related side effects can 
adversely affect QoL. Therefore, a question remains for asymptomatic patients as to whether to 
start therapy as soon as metastatic disease is diagnosed or whether to delay treatment until 
significant symptoms are present. In 2004, in the IMPACT trial, docetaxel became the first 
approved therapy to prolong survival for men with mCRPC. 18,19 Subsequently, since 2010, 
6 novel therapies have been shown to prolong survival in men with mCRPC.105 The trials have 
demonstrated prolongation of OS as well as trends toward preserved QoL, albeit less rigorously 
assessed and documented. 106 Of note, all of these new therapies in mCRPC have distinct 
mechanisms of action and include unique classes of agents: novel AR pathway inhibitors 
(abiraterone acetate [abiraterone] and enzalutamide) as well as a bone-targeting, alpha-emitting 
radionuclide, radium-223 chloride (radium-223) taxanes (docetaxel and cabazitaxel), and an 
immunotherapeutic agent (sipuleucel-T). 
Of the 6 new therapies that have been approved since 2010 for mCRPC, sipuleucel-T prolonged
OS among asymptomatic men with mCRPC, with a relative reduction of 22% in the risk of death
as compared to the placebo group, and an improvement of 4.1 months in median survival. It is 
believed that improved survival in the absence of significant PSA or tumor growth effects perhaps 
is a result of the effects on tumor progression kinetics, with slowed growth over time rather than 
immediate tumoral kill as evidenced with the use of cytotoxic chemotherapy. 107 Therefore, 
patients who exhibit aggressive disease would not be appropriate candidates for initial vaccine 
therapy, as the potential benefits from vaccine treatment tend to be delayed. Although the IMPACT 
trial shows that the separation of the curves was first apparent after about 6 months post-therapy 
across all participants, about half of the men subsequently commenced chemotherapy at a median 
of 12–13 months, suggesting that anticipation of a need for chemotherapy perhaps in the next 
6 months to 1 year should prompt the question regarding the appropriateness of institution of 
sipuleucel-T. Similar observations were also reported in other vaccine trials. For instance, in the 
National Cancer Institute PSA-TRICOM studies, participants were divided into those who have 
aggressive and indolent disease. Not surprisingly, those with a predicted Halabi nomogram 
survival of less than 18 months showed no marked improvement in survival while those who had 
a predicted Halabi nomogram survival of more than 18 months had a median survival that was not 
reached at the time of reporting. 108 More recently, 2 second-generation hormone therapies, 
abiraterone acetate85 and enzalutamide84 targeting inhibition of the AR signaling pathway have 
been investigated and shown to prolong OS in large Phase 3 trials in minimally symptomatic 
participants in the pre-docetaxel setting. Enzalutamide extended time to radiographic progression 
and death as well as improved OS in men with asymptomatic or minimally symptomatic mCRPC 
prior to receiving chemotherapy.84 Enzalutamide also delayed PSA progression, decline in 
performance status and time until the first skeletal-related event, and delayed median time to 
chemotherapy by 17 months, with a favorable tolerability profile. Similar to enzalutamide, 
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abiraterone was shown to delay radiographic progression and time to chemotherapy in men with 
mCRPC.85
While the successful registration of several drugs for mCRPC provided new options for treatment, 
they have also led to considerable uncertainty as to the best treatment choices, sequence of 
treatment options, and appropriate patient selection, with the achievement of durable, long-term 
responses remaining an elusive goal. 
For example, the timing of chemotherapy had always been a matter of debate, and with the advent 
of novel androgen therapies, the initiation of chemotherapy has become more protracted.109 One 
of the greatest concerns with the use of chemotherapy is myelosuppression, especially in light of 
potential comorbidities. Therefore, chemotherapy is often reserved for the more symptomatic 
patients (eg, those with pain or with rapid progression) such as those with fast PSA doubling times. 
However, patients who have symptomatic disease tend to have less benefit from docetaxel 
treatment and the presence of pain confers a worse OS .110,111
The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel 
reviewed the available evidence for the 10 most important areas of controversy in advanced 
prostate cancer (APC) management to provide management recommendations based on expert 
opinion in these situations.106 Of note, for participants with mCRPC in the absence of symptoms 
and imminent complications, two-thirds of the APCCC panel recommended that agents with 
potential for survival prolongation should be initiated within 4 to 8 weeks. 
Taken together, these data suggest that asymptomatic or minimally symptomatic mCRPC 
participants may in fact be optimal candidates for the evaluation of immunotherapy in combination 
with other therapeutic agents in ARM A2 and ARM C, with the possibility of achieving long term 
remission from disease.
5.4.5
Rationale for Treatment Beyond PSA Elevation
For consistency of trial reporting, the PCWG3 defines PSA progression as the date that an increase 
of 25% or more and an absolute increase of 2 ng/mL or more from the nadir are documented. For 
participants who had an initial PSA decline during treatment, this must be confirmed by a second 
consecutive value 3 or more weeks later. However, PSA progression alone is not necessarily an 
indication to stop treatment, because in some cases, PSA levels may rise slowly after an initial rise 
or stabilize after an initial rise with no other sign of clinical progression. Because there are cases 
in which additional years of disease control would not have been realized had therapy been stopped 
on the basis of PSA change alone, therapy will not be stopped for participants with apparent PSA 
progression alone. However, participants meeting criteria for discontinuation of therapy 
(Section 8) and PSA elevation will discontinue study treatment.
5.4.6
Rationale for Duration of Treatment
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 
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program indicate that most of the responses occur early, with a median time to response of 2-4 
months, and emerging data suggests 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 for toxicity maintain disease control in the absence of further treatment. 112
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.
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 non-small cell lung cancer (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 overall survival (OS) curve 
begins to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years.113 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%-18% for squamous and non-squamous NSCLC respectively).114
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.115
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.116
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
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1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
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, 1.20]). 
Of note,  the PFS curves in both groups plateau approximately 1 year after randomization (i.e., 
2 years after treatment initiation), suggesting that there may be minimal benefit in extending 
treatment beyond a total of 2 years. 117
Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O 
treatment beyond two years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer term treatment. For these 
reasons, in study CA2099KD, treatment with nivolumab will be given for a maximum of 2 years 
from the start of study treatment, in the absence of disease progression, unacceptable toxicity, 
withdrawal of participant consent, or the end of the study, whichever occurs sooner. 
Co-administered Medications
The duration of treatment for rucaparib, docetaxel, and enzalutamide 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.18 Administering more 
than 10 cycles of docetaxel has not demonstrated any further improvement in survival and is 
associated with more adverse effects.118,119 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. Rucaparib 
and ezalutamide will also be administered until disease progression, unacceptable toxicity, 
withdrawal of participant consent, or the end of the study, whichever occurs sooner. 
Please consult the rucaparib IB and current prescribing information for docetaxel and enzalutamide 
for further details concerning administration. 
5.4.7
Rationale for Nivolumab 30-Minute Infusion
Long infusion times place a burden on participants and treatment centers. Establishing that 
nivolumab can be safely administered using shorter infusion times of 30-minute duration in 
participants will diminish the burden, provided there is no change in the safety profile. 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 
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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 discontinuation, and immune-mediated AEs 
(IMAEs) including hypersensitivity/infusion reaction IMAEs. There were no new safety concerns
identified. For study CA2099KD, 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.
5.4.9
Rationale for Interim Analysis
An interim analysis will be performed in each arm when at least 50% of planned subjects have 
been treated, with at least 16 weeks of follow-up after first dose. The purpose of the interim 
analysis is to generate preliminary data that will inform decisions related to external studies, as 
well as determine if any of the study arms should be expanded to generate additional data that may 
support a regulatory filing. If the data from the initial interim analysis appear to be immature to 
support decision-making on the expansion of a specific study arm, a second interim analysis of 
that arm may be performed after enrollment has been completed and all treated patients have been 
followed for at least 16 weeks after first dose.
Expansion guidance for each arm, based on a comparison between interim ORR in that arm and 
the standard of care for the patient population in that arm, are described in Section 10.3.4. Given 
that arm expansion is intended to support a potential regulatory filing, the assumptions for standard 
of care references noted below may be different than those noted above in Table 5.4.3-1 in order 
to meet regulatory standards. 
In Arms A1 and A2, given the differential activity of PARP inhibitors in patients with HRD 
mutations, HRD+ and HRD-/NE subgroups may be analysed separately with independent 
expansion rules for each subgroup. The estimate of reference ORR for HRD+ subgroups in these 
arms is based on preliminary data from TRITON-2, where rucaparib monotherapy showed an ORR 
of 28% (13/46) in men with HRD+ mCRPC.120
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For the HRD-/NE subgroup in Arm A1, the estimate of reference ORR is based on the standard of 
care cabazitaxel in the docetaxel-pretreated mCRPC population (ORR 14%). For the HRD-/NE 
subgroup in Arm A2, the reference ORR is based on the standard of care docetaxel (ORR 21%) in 
chemo-naive mCRPC patients. Please refer to Section 10.1 for details on how the estimate of 21% 
ORR for docetaxel monotherapy was obtained. 
In Arms B and C, the expansion rules will apply to the all-comer population, as the impact of HRD 
status on sensitivity or resistance to docetaxel or novel hormonal therapies remains unclear at this 
time. A reference ORR of 21% for docetaxel monotherapy in mCRPC will be used in both arms.
Estimates for the reference ORR in each arm or subgroup may be adjusted as new data for 
treatments in these settings become available.
In any arm or subgroup that is expanded, interim analyses in the additional participants treated in 
the expansion with at least 16 weeks of follow-up after first dose may be performed if needed to 
determine if the data may be sufficient to support a regulatory filing.
5.5
Justification for Dose
5.5.1
Dose Justification for Nivolumab 
Nivolumab monotherapy has been extensively studied in multiple tumor types, including 
melanoma, NSCLC, RCC, cHL, small cell carcinoma of the head and neck (SCCHN) and 
urothelial carcinoma (UC), using body weight normalized dosing (mg/kg), and has been safely 
administered at doses up to 10 mg/kg Q2W. Nivolumab is currently approved for the treatment of 
the above-mentioned tumors using a regimen of either nivolumab 240 mg Q2W or nivolumab 
3 mg/kg Q2W. Additionally, nivolumab is currently approved for advanced melanoma in 
combination with ipilimumab using a regimen of nivolumab 1 mg/kg with ipilimumab 3 mg/kg 
administered every 3 weeks for 4 doses, and then nivolumab 3 mg/kg or 240 mg every 2 weeks in 
the maintenance phase.
5.5.1.1
Dose Justification for Nivolumab 480 mg IV Q4W
A nivolumab dose of 480 mg given every 4 weeks (Q4W) was selected for this study based on 
available PK, safety, and efficacy data. 
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 
indications1,2. 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 
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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 
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 
(34-180 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.
5.5.1.2
Dose Justification for Nivolumab 360 mg IV Q3W
Additionally, nivolumab will be administered as a flat dose of 360 mg once every 3 weeks (Q3W) 
in combination with docetaxel, in order to maintain synchronized dosing of both agents. The safety 
and efficacy of 360 mg Q3W flat dose of nivolumab is expected to be similar to the approved dose 
of 3 mg/kg Q2W. The nivolumab dose of 360 mg Q3W was selected based on clinical data and 
modeling and simulation approaches using PPK and exposure-response analyses of data from 
studies in multiple tumor types (melanoma, NSCLC, and RCC) where body-weight normalized 
dosing (mg/kg) has been used. Using the PPK model, the overall distributions of nivolumab 
average steady-state exposures (Cavgss) are comparable after treatment with either nivolumab 
3 mg/kg Q2W or 360 mg Q3W. The flat dose regimen of 360 mg Q3W is predicted to result in 
approximately 23% higher maximum steady state concentrations (Cmaxss) and approximately 6% 
lower steady state trough concentrations (Cminss) compared to the reference regimen of 3 mg/kg 
Q2W. Across the various tumor types in the clinical program, nivolumab has been shown to be 
safe and well tolerated up to a dose level of 10 mg/kg, and the relationship between nivolumab 
exposure and efficacy and safety has been found to be relatively flat. Although nivolumab Cmaxss 
is predicted to be higher following 360 mg Q3W, these exposures are predicted to be below the 
exposure ranges observed at doses up to 10 mg/kg Q2W used in the nivolumab clinical program, 
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and are not considered to put participants at increased risk. Similar to nivolumab 480 mg Q4W
regimen as described above, the exposures predicted following administration of nivolumab 360 
mg Q3W are on the flat part of the exposure-response curves for previously investigated tumors, 
melanoma, NSCLC, and RCC, and are not predicted to affect efficacy. Based on these data, 
nivolumab 360 mg Q3W is expected to have similar efficacy and safety profiles to nivolumab 
3 mg/kg Q2W. The nivolumab Q3W regimen with docetaxel is being investigated to allow the 
participant to receive both study medications on the visits to the clinic. 
5.5.2
Dose Justification for Nivolumab 480 mg IV Q4W and Rucaparib 600 mg
PO BID
As discussed in Section 5.4.2.1, a Phase 1 dose-escalation study of durvalumab in combination 
with olaparib in pretreated ovarian and triple-negative breast cancer patients is being conducted.39
The dose levels for this combination are also being evaluated in an ongoing Phase 2 study in 
participants with mCRPC and appears to be well tolerated, with the most common Grade 3/4 AEs 
also being hematologic toxicity.38 These studies have not identified any new safety signals when 
giving PARP inhibitor and an anti-PD-L1 antibody in combination. The starting dose for the 
combination of nivolumab plus rucaparib in this study will be the standard monotherapy doses for 
each agent, the mechanisms of action of the 2 agents are different and their toxicities are not 
predicted to be cumulative. Dosing of rucaparib in combination with nivolumab is based upon 
doses recommended in the current prescribing information for these agents. Please see this 
prescribing information and the respective IBs for nivolumab and rucaparib for further information 
on dosing. Dose Justification for Docetaxel 75 mg/m2 Q3W and Enzalutamide 160 mg PO QD.
Dosing of docetaxel and enzalutamide in combination with nivolumab is based upon doses 
recommended in the current prescribing information for these agents. Please see this prescribing 
information for more information.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Willing and able to provide informed consent
2) Type of Participant and Target Disease Characteristics
a) Histologic confirmation of adenocarcinoma of the prostate. Diagnosis must be stated in a 
pathology report and confirmed by the investigator.
b) Evidence of stage IV disease (as defined by AJCC criteria1) on previous bone, CT, and/or
MRI scan
c) 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 subjects who have not 
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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.
d) Documented prostate cancer progression as per PCWG3 criteria121 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 μg/L (2 ng/mL). 
* Participants who received an anti-androgen must have 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. 
Participants whose disease spread is limited to regional pelvic lymph nodes (N1) 
measuring at least 2 cm in short axis will be considered eligible.
iii) Radiographic disease progression in bone defined as appearance of 2 or more new bone 
lesions on bone scan.
NOTE: Radiographs must be collected and transmitted to the central imaging vendor at 
study entry
e) ECOG performance status 0-1 (Appendix 7)
f)
mCRPC participants will be assigned to a study arm as follows:
i)
Arm A: Participants must meet either of the following criteria: 
(1) Arm A1: Participants who have received at least 1 but no more than 2 prior taxane-
based regimens for castration-resistant disease. If docetaxel chemotherapy is used 
more than once, this will be considered as one regimen. Up to 2 second generation 
hormonal manipulations for castration-resistant disease are allowed.
(2) Arm A2: Participants who are chemotherapy-naive for mCRPC who have received 
prior treatment with at least 1 but no more than 2 second-generation hormonal 
manipulations (eg, abiraterone acetate,enzalutamide, apalutamide) for castration-
resistant disease up to 28 days prior to study arm assignment and are not candidates 
for or refuse immediate chemotherapy 
ii) Arm B: Participants who are chemotherapy-naive for mCRPC who are candidates to 
receive docetaxel chemotherapy. Up to 2 second-generation hormonal manipulations 
(eg, abiraterone acetate, enzalutamide, apalutamide) for castration-resistant disease are 
allowed up to 28 days prior to study arm assignment.
iii) Arm C: Participants who are chemotherapy-naive for mCRPC who have received prior 
treatment with abiraterone acetate for castration-resistant disease up to 28 days prior to 
study arm assignment without prior enzalutamide or apalutamide, and are not 
candidates for or refuse immediate chemotherapy.
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 treatment arm assignment.
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h) Prior prostate cancer vaccine therapy, radiation therapy, radium-223, antiandrogens (eg, 
flutamide), ketoconazole, and diethylstilbestrol (DES) or other estrogens, are allowed up 
to 28 days prior to study arm assignment. Note: bicalutamide or nilutamide must be 
discontinued within 6 weeks of study arm assignment.
i)
Participants with a history of response to an anti-androgen or adrenal androgen-
production inhibitor and with subsequent progression while receiving that anti-
androgen should be assessed for anti-androgen withdrawal response for 4 weeks, and 
must demonstrate progression as described in Inclusion Criterion 2d, and have stopped 
receiving the anti-androgen prior to treatment arm assignment.
ii) For participants who have never responded to anti-androgens, observation for anti-
androgen withdrawal response is not necessary.
i)
For Arm A2 and Arm C, asymptomatic or minimally symptomatic mCRPC according to 
Brief Pain Inventory - Short Form (BPI-SF) performed during screening:
i)
Asymptomatic is defined as BPI-SF item #3 score of 0 to 1
ii) Minimally symptomatic is defined as BPI-SF item #3 score of 2 to 4
Note: Any cancer-related pain must not require any opiate analgesics (including codeine 
and dextropropoxyphene) within 5 days prior to treatment initiation.
j)
Sufficient plasma and, fresh or archival tumor tissue obtained within 5 years prior to
enrollment from a metastatic tumor lesion or from a primary tumor lesion that has not been 
previously irradiated (formalin-fixed paraffin-embedded [FFPE] block or unstained tumor 
tissue sections). Tumor sample may be from core biopsy, punch biopsy, excisional biopsy, 
or surgical specimen). Fine needle aspiration is unacceptable for submission. See 
Section 9.8.2 for additional details. Central laboratory must confirm receipt of plasma and
tumor samples prior to IRT treatment arm assignment.
k) Results of central HRD testing of the submitted plasma or tumor samples must be available 
in IRT prior to treatment arm assignment. If local HRD test results obtained prior to 
enrollment are provided to Sponsor, they should be confirmed to be acceptable for 
treatment assignment, and results will be transmitted to IRT prior treatment arm assignment
3) Age and Reproductive Status
a) Males, ages 18 or local age of majority and older, inclusive.
b) Males who are sexually active with women of child-bearing potential (WOCBP) must 
agree to follow instructions for method(s) of contraception for the duration of study 
treatment and 7 months after the last dose of study treatment (ie, 90 days [duration of sperm 
turnover] plus the time required for the investigational drug to undergo approximately five 
half-lives).
c) Azoospermic males are exempt from contraceptive requirements. 
d) Male participants must be willing to refrain from sperm donation during the entire study 
and for 7 months after the last dose of study treatment plus 90 days (5 half-lives plus the 
duration of sperm turnover) after dosing has been completed.
Investigators shall counsel male participants who are sexually active with WOCBP on the 
importance of pregnancy prevention and the implications of an unexpected pregnancy. 
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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) Prior malignancy active within the previous 3 years 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 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 must be discussed with the BMS Medical 
Monitor or designee. Previously irradiated brain lesions are not considered measurable 
disease. 
c) Participants must have recovered from the effects of major surgery requiring general 
anesthesia or significant traumatic injury at least 14 days before treatment arm assignment.
d) Less than 1 year since resolution of ≥Grade 2 toxicity related to pelvic-targeted therapy
(eg, radiation enteritis).
e) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (NCI CTCAE version 4.03) 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.
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) Dementia, altered mental status, or any psychiatric condition that would prohibit the 
understanding or rendering of informed consent or completing QoL questionnaire.
h) 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.
i)
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.
j)
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.
k) The following exclusion criteria apply to Arm A only: 
i)
Participants with myelodysplastic syndrome/acute myeloid leukemia.
ii) Gastrointestinal disorders likely to interfere with absorption of the study medication
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l)
The following exclusion criterion applies to Arm B only: 
i)
Participants who have ≥Grade 2 peripheral neuropathy (NCI CTCAE version 4.03)
m) The following exclusion criteria apply to Arm C only: 
i)
History of seizure or any condition that may have a predisposition to seizure. Also, 
history of loss of consciousness or transient ischemic attack within 12 months of 
enrollment (Day 1 visit)  
ii) History of prostate cancer progression on ketoconazole
iii) Gastrointestinal disorders likely to interfere with absorption of the study medication
iv) History of Mobitz II second-degree or third-degree heart block without a permanent 
pacemaker in place
v) Hypotension as indicated by systolic blood pressure < 86 mm Hg at the screening visit
vi) Bradycardia as indicated by a heart rate of < 50 beats per minute on the screening ECG
vii)Uncontrolled hypertension as indicated by systolic blood pressure > 170 mm Hg or 
diastolic blood pressure > 105 mm Hg at the screening visit
n) 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 of faint renal 
activity (absent kidney sign).
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) Radiotherapy to the pelvic region within 3 months prior to treatment arm assignment 
d) Radiotherapy to symptomatic bone lesions within 14 days prior to treatment arm 
assignment.
e) The following exclusion criteria apply to Arm A only: 
i)
Prior PARP inhibitor treatment122, mitoxantrone, cyclophosphamide, or platinum-
based chemotherapy
ii) Arm A2 only: Prior chemotherapy for mCRPC. Prior docetaxel for metastatic 
hormone-sensitive prostate cancer is allowed if ≥12 months elapsed from last dose of 
docetaxel
f)
The following exclusion criterion applies to Arm B only: 
i)
Prior treatment with docetaxel or another chemotherapy agent for metastatic castration-
resistant prostate cancer. Prior docetaxel for metastatic hormone-sensitive prostate 
cancer is allowed if ≥ 12 months elapsed from last dose of docetaxel.
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g) The following exclusion criteria apply to Arm C only: 
i)
Prior chemotherapy for mCRPC. Prior docetaxel for metastatic hormone-sensitive 
prostate cancer is allowed if ≥12 months elapsed from last dose of docetaxel.
ii) Prior treatment with enzalutamide, apalutamide, or other novel androgen receptor 
inhibitor.
iii) Treatment with 5-α reductase inhibitors (eg, finasteride, dutasteride), estrogens, and/or 
cyproterone within 4 weeks prior to treatment arm assignment
h) Treatment with botanical preparations (eg herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 
2 weeks prior to treatment arm assignment. Refer to Section 7.7.1 for prohibited therapies.
i)
Participants who have received a live / attenuated vaccine within 30 days of first treatment
3) Physical and Laboratory Test Findings
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets <100×103/μL
d) Hemoglobin < 9.0 g/dL or ≤ 5.6 mmol/L
Note: Hemoglobin and platelet requirements cannot be met by use of recent transfusion or 
growth factor support (GSCF or erythropoietin) within 2 weeks prior to treatment 
allocation.
e) Serum creatinine > 1.5× ULN unless creatinine clearance ≥40 mL/min (measured or 
calculated using the Cockroft-Gault formula)
f)
AST/ALT: > 3.0× ULN
g) Total bilirubin >1.5× ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0× 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).
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components.
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under specific 
circumstances, and only in countries where local regulations permit, a person who has been 
imprisoned may be included 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.
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6.3
Lifestyle Restrictions
Participants assigned to Arm A should be advised to use appropriate sun protection due to the 
increased susceptibility to sunburn while taking rucaparib.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant re-enrollment: 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 treatment arm assignment 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 (IP), also known as investigational medicinal product (IMP) 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 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 SOC for a given diagnosis, may be considered as non-investigational 
products (non-IMP).
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Table 7-1:
Study treatments for CA2099KD
Product Description / 
Class and Dosage Form
Potency
IMP/
Non-IMP
Blinded or Open 
Label
Packaging / 
Appearance
Storage Conditions
(per label)
BMS-936558-01
(Nivolumab) Solution 
for Injectiona
100 mg (10 mg/mL)
IMP
Open Label
Vial (multiple vials per 
carton)
Store at 2° - 8 °C.
Protect from light and freezing.
Rucaparib
Immediate Release 
Tablets
200 mg/250mg/300 mg
IMP
Open Label
Tablets are provided in 
HDPE bottles
Store in the provided containers 
between 15° and 30°C.
Docetaxelb
80 mg
IMP
Open Label
Vials in various 
packaging 
configurations.
Refer to storage conditions on 
container label.
Prednisoneb
5 mg
Non-IMP
Open Label
Tablets in various 
packaging 
configurations.
Refer to storage conditions on 
container label.
Dexamethasoneb
4 mg
Non-IMP
Open Label
Tablets in various 
packaging configurations
Refer to storage conditions on 
container label.
Xtandi®
(enzalutamide)
40 mg
IMP
Open Label
Capsules in various 
packaging 
configurations.
Refer to storage conditions on 
container label.
a May be labeled as “BMS-936558-01” or “Nivolumab”
b Dexamethasone which is required for premedication, docetaxel and andprednisone are provided by BMS. Other corticosteroids as an alternative to dexamethasone 
can be used according to local standards. In countries where local sourcing is allowed, sites may use their local institutional equivalent of dexamethasone and 
prednisone.
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7.1
Treatments Administered
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.
Table 7.1-1:
Selection and Timing of Dose
Study Treatment
Unit dose 
strength(s)/
Dosage level(s)
Dosage formulation
Frequency of Administration
Route of Administration
Arm A
Nivolumab
480 mg
Every 4 weeks
Intravenous
Rucaparib
600 mg
Twice daily (BID)
By mouth
Arm B
Nivolumaba
360 mg
Every 3 weeks through Cycle 10
Intravenous
Docetaxel
75 mg/m2
Every 3 weeks through Cycle 10
Intravenous
Prednisone
5 mg
Twice daily (BID) co-administered 
with docetaxel
By mouth
Dexamethasone
8 mg
At 12 hours, 3 hours and 1 hour 
before the docetaxel infusion
By mouth
Arm C
Nivolumab
480 mg
Every 4 weeks
Intravenous
Enzalutamide
160 mg
Once daily (QD)
By mouth
a Nivolumab will be administered as monotherapy (480 mg Q4W) after 10 cycles of combination therapy with 
docetaxel, prednisone, and dexamethasone as of Cycle 11 until progression, unacceptable toxicity, withdrawal of 
consent, or completion of 24 months of nivolumab treatment, whichever occurs first.
There will be no dose escalations or reductions of nivolumab allowed. For Q3W and Q4W dosing 
cycles, 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. For Q4W dosing cycles, participants may 
be dosed within a ± 3 day window. Premedications are not recommended for the first dose of 
nivolumab.
Participants should be carefully monitored for infusion reactions during nivolumab or docetaxel 
administration. If an acute infusion reaction is noted, participants should be managed according to 
Section 7.1.4.
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.
For nivolumab, refer to the current version of the Investigator Brochure and/or Pharmacy Manual 
for complete storage, handling, dispensing, and infusion information.
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Nivolumab Injection, 100 mg/10 mL (10 mg/mL) and 40 mg/4 mL (10 mg/mL) Nivolumab 
injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron pore size, 
low-protein binding in-line filter at the protocol-specified doses. It is not to be administered as an 
IV push or bolus injection. When the dose is based on patient weight (ie, mg/kg), nivolumab 
injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, 
USP or 5% Dextrose Injection, USP to protein concentrations as low as 0.35 mg/mL. When the 
dose is fixed (eg, 240 mg flat dose), nivolumab injection can be infused undiluted or diluted so as 
not to exceed a total infusion volume of 120 mL. Nivolumab infusion must be promptly followed 
by a flush of diluent to clear the line. Instructions for dilution and infusion of nivolumab injection 
may be provided in the clinical protocol, pharmacy binder, or pharmacy reference sheet. Care must 
be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles.
Nivolumab plus Rucaparib (Arm A)
Participants will receive nivolumab IV at a dose of 480 mg as a 30-minute infusion on Day 1 of 
each treatment cycle (Q4W) until progression, unacceptable toxicity, completion of 24 months of 
treatment, withdrawal of consent, or the study ends, whichever occurs first. 
Participants will receive rucaparib at a dose of 600 mg orally with or without food twice daily 
every day of each treatment cycle until progression, unacceptable toxicity, withdrawal of consent, 
or the study ends, whichever occurs first. Rucaparib will be administered on an out-patient basis, 
except on study days when PK samples are obtained (see Table 9.5.2-1). Participants should begin 
study treatment within 3 calendar days of treatment arm assignment.
Participants should take rucaparib doses as close to 12 hours apart as possible, preferably at the same 
times every day. If a patient misses a dose (ie, does not take it within 4 hours of the scheduled time), 
the patient should skip the missed dose and resume taking rucaparib with the next scheduled dose. 
Missed or vomited doses should not be made up.
Nivolumab plus Docetaxel (Arm B)
Participants will receive nivolumab 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 (or equivalent dose of 
another corticosteroid) s 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 infusion, there is a 30-minute delay before the start of the docetaxel infusion 
to monitor the participant for signs of possible infusion reactions. 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. After the completion of Cycle 10, nivolumab dosing will change to 480 mg, with the 
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Cycle 11 dose given 3 weeks (± 3 days) after the Cycle 10 dose. Nivolumab 480 mg will then 
continue to be given alone as maintenance therapy Q4W (± 3 days). The treatment with nivolumab 
will be given until progression, unacceptable toxicity, completion of 24 months of treatment, 
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 treatment arm assignment.
Premedication:
There are no premedications recommended for nivolumab treatment.
For docetaxel, given the concurrent use of prednisone, the recommended premedication regimen 
is oral dexamethasone (or equivalent dose of another corticosteroid) 8 mg, 12 hours, 3 hours, and 
1 hour before the docetaxel infusion, however other 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 7.1.4.
Nivolumab plus Enzalutamide (Arm C)
Participants will receive nivolumab at a dose of 480 mg as a 30-minute infusion on Day 1 of each 
treatment cycle (Q4W) until progression, unacceptable toxicity, completion of 24 months of 
treatment, withdrawal of consent, or the study ends, whichever occurs first. 
Participants will receive enzalutamide at a dose of 160 mg orally once daily every day of each 
treatment cycle until progression, unacceptable toxicity, withdrawal of consent, or the study ends, 
whichever occurs first. Enzalutamide will be administered on an out-patient basis, except on study 
days when PK samples are obtained (see Table 9.5.2-1).Participants should begin study treatment 
within 3 calendar days of treatment arm assignment.
If a participant misses taking Enzalutamide at the usual time, the prescribed dose should be taken 
as close as possible to the usual time. If a patient misses a dose for a whole day, treatment should 
be resumed the following day with the usual daily dose.
Please refer to Section 7.4.4 for enzalutamide dose reductions and increases for participants who 
are receiving concomitant strong CYP2C8 inhibitors or strong CYP3A4 inducers.
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7.1.1
Dose Delay Criteria
Dose delay criteria for management of AEs during nivolumab, rucaparib, docetaxel, or 
enzalutamide treatment are outlined in this section. 
For Arm A and Arm C, dosing of nivolumab may be delayed without delay of rucaparib or 
enzalutamide dosing if toxicity is felt to be related to only nivolumab and not related to rucaparib 
or enzalutamide. Conversely, treatment with rucaparib or enzalutamide may be delayed or the dose 
reduced without delay of nivolumab dosing if toxicity is felt to be related to only rucaparib or 
enzalutamide and not related to nivolumab. However, if toxicity is considered related to all study 
drugs or if the investigator is unable to determine which study drug is the cause of the AE, then all 
study drugs in the combination should be delayed and, if appropriate, the dose of rucaparib or 
enzalutamide should be reduced.
For Arm B, dosing for all drugs should be delayed if any criteria in Section 7.1.1.1 (for nivolumab) 
or Section 7.1.1.3 (for docetaxel) are met. That is, nivolumab should be delayed if criteria for delay 
of docetaxel are met, and docetaxel should be delayed if criteria for delay of nivolumab are met.
Participants who require dose delay should be re-evaluated weekly or more frequently if clinically 
indicated and resume dosing when re-treatment criteria are met (Section 7.1.2).
7.1.1.1
Nivolumab
Nivolumab administration should be delayed for the following:
•
Grade 2 non-skin, drug-related AE, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT, and/or total bilirubin abnormalities*
* Note for Arm A: Elevated creatinine is among the most frequently reported treatment-related 
AEs for rucaparib monotherapy. Rucaparib is a potent inhibitor of MATE1 and MATE2-K 
transporters, which are involved in active secretion of creatinine. Rucaparib-mediated 
creatinine elevation occurs early in treatment (Day 15 of Cycle 1), and is not typically 
accompanied by elevations in urea (blood urea nitrogen [BUN]). Creatinine elevation resolves 
with dose holds of rucaparib and recurs with re-challenge. Rucaparib associated creatinine 
elevation has not been associated with evidence or reports of permanent renal impairment.
•
Grade 3 drug-related skin AE
•
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥3 AST, ALT, and/or total bilirubin will require dose discontinuation (see 
Section 8.1.1)*
* Note for Arm A: Elevated ALT/AST is among the most frequently reported treatment-
related AEs for rucaparib monotherapy. Rucaparib-related ALT/AST elevations occur 
early in treatment (ie, during Cycle 1 or by Day 1 of Cycle 2) and then resolve or stabilize 
over time. Rucaparib-associated elevations in ALT/AST are generally not accompanied by 
a concomitant elevation in bilirubin. For participants with ≥Grade 3 AST or ALT 
elevations with onset after Cycle 1 dosing, nivolumab dose discontinuation is not required 
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if AST and ALT elevations decline by Day 29 and toxicity, after the investigator discusses 
the case with the BMS Medical Monitor/designee, is considered to be mainly related to 
rucaparib.
•
Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Participants who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
7.1.1.2
Rucaparib
Treatment with rucaparib should be delayed and dose reduction considered for the following drug-
related AEs:
•
Grade 3 or 4 hematologic toxicity
−
In addition, if Grade ≥3 hematologic toxicity persists for > 14 consecutive days, or a 
dependence upon blood transfusion occurs, then weekly complete blood counts (CBC)
should be performed until resolution of the event. 
−
If, after 42 days of interruption of rucaparib, the hematologic toxicity has not recovered to 
CTCAE Grade ≤1 then the participant should be referred to a hematologist and analysis 
of the bone marrow with cytogenetic studies are recommended according to standard 
hematologic practice.
♦The bone marrow analysis should include a bone marrow aspirate (for cellular 
morphology, cytogenetic analysis, and flow cytometry) and a core biopsy (for bone 
marrow cellularity).
•
Grade 3 or 4 non-hematologic toxicity (except for alopecia, nausea, vomiting, or diarrhea 
adequately controlled with systemic antiemetic/antidiarrheal medication administered in 
standard doses according to the study center routine practice)
•
Grade 2 ALT/AST elevations* that do not decline within 2 weeks or continue to rise
•
Grade 3 ALT/AST elevations * that do not decline within 2 weeks or continue to rise
•
Grade 4 ALT/AST elevations*
* Note: Elevated ALT/AST is among the most frequently reported treatment-related AEs for 
rucaparib monotherapy. Rucaparib-related ALT/AST elevations occur early in treatment (ie, 
during Cycle 1 or by Day 1 of Cycle 2) and then resolve or stabilize over time. Elevations in 
ALT/AST are generally not accompanied by a concomitant elevation in bilirubin. Continuation 
of rucaparib with elevations of ALT/AST ≤Grade 3 is permitted provided bilirubin is < ULN 
and there are no other signs of liver dysfunction.
•
In addition, and at the discretion of the investigator, the dose of rucaparib could be held and/or 
reduced for Grade 2 toxicity not adequately controlled by concomitant medications and/or 
supportive care.
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Treatment with rucaparib must be delayed until the toxicity resolved to ≤CTCAE Grade 2. Twice 
daily (BID) dosing can then be resumed at either the same dose or a lower dose, per investigator
discretion. If treatment is resumed at the same dose, and the participant experiences the same 
toxicity, the dose is to be reduced following resolution of the event to ≤CTCAE Grade 2. If the 
participant continues to experience toxicity, additional dose reduction steps are permitted.
Rucaparib is a potent inhibitor of MATE1 and MATE2-K transporters, which are involved in 
active secretion of creatinine. Rucaparib-mediated creatinine elevation occurs early in treatment 
(Day 15 of Cycle 1) and then stabilizes with continued rucaparib treatment. Creatinine elevation 
is not typically accompanied by elevations in urea (BUN). Creatinine elevation resolves with dose 
holds of rucaparib and recurs with re-challenge. Creatinine elevation has not been associated with 
evidence or reports of permanent renal impairment. 
Dose reduction guidelines for rucaparib are presented in Section 7.4.2.
7.1.1.3
Docetaxel
Docetaxel administration should be delayed for the following on the day of planned dosing:
•
Any Grade ≥2 non-skin, drug-related AEs, with the following exceptions:
−
Grade 2 drug-related fatigue or laboratory abnormalities do not require dose delay
−
Grade 3 docetaxel-related enterocolitis of any duration requires discontinuation*
•
Any Grade 3 skin, drug-related AEAny Grade ≥3 drug-related laboratory abnormality, with 
the following exceptions for lymphopenia, neutrophil count, AST, ALT, or total bilirubin:
−
Grade 3 lymphopenia does not require dose delay
−
Should not be given if neutrophil counts are < 1500 cells/mm3
−
Should not be given if total bilirubin > upper limit of normal (ULN), or if AST and/or ALT 
> 1.5xULN concomitant with alkaline phosphatase > 2.5x ULN
•
Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Subsequent dose reductions may be required as per Section 7.4.3.
*Note: 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 (i.e. gastroenterologist) for assessment and full details of the 
participant’s exposure to docetaxel should be provided. 
Participants receiving docetaxel may receive growth factors (including G-CSF and erythropoietin) 
at the discretion of the investigator and following local guidelines.
7.1.1.4
Enzalutamide
If a participant experiences a Grade 2 drug-related AE or laboratory abnormality, dosing may 
continue but supportive care and more frequent monitoring should be implemented. For a 
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≥Grade 3 drug-related AE, laboratory abnormalities, or any intolerable adverse reactions, dosing 
should be withheld for at least 1 week and until symptoms improve to ≤Grade 2, then resumed at 
the same or a reduced dose (120 mg or 80 mg) if warranted. Dose reductions for enzalutamide are 
discussed in Section 7.4.4.
7.1.2
Criteria to Resume Study Treatment
For Arm A and Arm C, if dosing of both nivolumab and the combination agent (rucaparib or 
enzalutamide) have been delayed per the criteria specified in Section 7.1.1 above, and toxicity is 
felt to be related to both study drugs or it is not clear which study drug is the cause of toxicity, then 
participants may resume dosing when resuming criteria for BOTH nivolumab and the combination 
agent are met. The only exception is toxicities that are treated with a prolonged corticosteroid 
taper. In such cases, dosing with the combination agent may resume prior to nivolumab, when the 
criteria to resume dosing for the combination agent have been met. Nivolumab dosing may be 
resumed later, after completion of the corticosteroid taper and when criteria to resume nivolumab 
dosing have been met.
If dosing of both nivolumab and the combination agent (rucaparib or enzalutamide) have been 
delayed, and toxicity is later assessed by the investigator to be related to only one study drug, then 
dosing with the study drug which is not related to toxicity may resume prior to resuming the dosing 
of the study drug which is related to toxicity, at the investigator’s discretion.
For Arm B, participants may resume dosing when resuming criteria for BOTH nivolumab and 
docetaxel are met. That is, nivolumab and docetaxel must be administered together until 
completion of Cycle 10 or until treatment discontinuation. The only exception is toxicities that are 
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 
dosing may be resumed later, after completion of the corticosteroid taper and when criteria to 
resume nivolumab dosing have been met. It is allowed to administer either nivolumab or docetaxel 
if the other is discontinued due to toxicity, judging by the treating investigator if it is the best 
interest of the participants (see Section 8.1).
7.1.2.1
Nivolumab
Participants may resume treatment with nivolumab when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue.
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity.
•
For participants with Grade 2 AST, ALT, or total bilirubin elevations, dosing may resume 
when laboratory values return to baseline and management with corticosteroids, if needed, is 
complete.
•
Participants with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 8.1.1) should have treatment permanently discontinued.
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•
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the BMS Medical Monitor/designee.
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical 
Monitor/designee. Adrenal insufficiency requires discontinuation regardless of control with 
hormone replacement.
7.1.2.2
Rucaparib
Treatment with rucaparib may be resumed, when the toxicity resolves to ≤CTCAE Grade 2, at the 
same dose or a reduced dose at the investigator’s discretion. If the same dose is resumed and the 
toxicity recurs, then the dose should be reduced. See Section 7.4.2 for dose reduction instructions.
Rucaparib administration is permitted with elevations of ALT/AST ≤Grade 3, provided bilirubin 
is < ULN and there are no other signs of liver dysfunction.
For prolonged hematological toxicities, rucaparib administration should be interrupted and blood 
counts monitored weekly until recovery. If the levels have not recovered to Grade 1 or less after 
4 weeks, the participant should be referred to a hematologist for further investigations, including 
bone marrow analysis and blood sample for cytogenetics. If Myelodysplastic Syndrome/Acute 
Myeloid Leukemia is confirmed, treatment with rucaparib must be discontinued.
7.1.2.3
Docetaxel
Participants may resume treatment with docetaxel when the drug-related AE(s) resolve(s) to 
Grade ≤1 or baseline, with the following exceptions:
•
Participants may resume treatment in the presence of ANC ≥1500 / mm3
•
Participants may resume treatment in the presence of Grade 2 fatigue 
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity 
•
Participants with decreased neutrophil counts, or with elevations in total bilirubin, AST or ALT 
must meet criteria for resuming treatment according to the boxed warning contained within the 
docetaxel prescribing information
•
Participants with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 8.1.3) should have treatment permanently discontinued
When resuming docetaxel treatment, please follow the dose reduction recommendations noted in 
Section 7.4.3.
If treatment is delayed > 8 weeks, docetaxel treatment must be permanently discontinued, except 
as specified in Section 8.1.3.
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7.1.2.4
Enzalutamide
Participants may resume treatment with enzalutamide when the drug-related AE(s) resolve(s) to 
Grade 2 or lower severity. 
7.1.3
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is considered an I-O agent in this 
protocol. Early recognition and management of AEs associated with immuno-oncology agents 
may mitigate severe toxicity. Management algorithms have been developed to assist investigators 
in assessing and managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
•
Myocarditis
The above algorithms are found in the Appendix 6 of this protocol.
7.1.4
Treatment of Infusion-related Reactions (Nivolumab or Docetaxel)
Nivolumab
Since nivolumab contains only human immunoglobulin protein sequences, these sequences are 
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. All Grade 
3 or 4 infusion reactions should be reported within 24 hours to the BMS Medical Monitor/designee
and reported as SAEs if they meet the criteria. Infusion reactions should be graded according to 
NCI CTCAE (Version 4.03) guidelines.
Treatment recommendations are provided below 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.
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For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic medications indicated for ≥24 
hours):
•
Stop the study treatment 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 treatment 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 
should be administered at least 30 minutes before nivolumab infusion. 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 [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae (eg, renal impairment, 
pulmonary infiltrates). Grade 4: Life-threatening; pressor or ventilatory support indicated):
•
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. Participant should be monitored 
until the investigator is comfortable that the symptoms will not recur. Study drug will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
Docetaxel
Participants 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, such as severe hypotension, bronchospasm or generalized rash/erythema require 
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immediate discontinuation of docetaxel and appropriate therapy. Participants who have developed 
severe hypersensitivity reactions should not be re-challenged with docetaxel.
7.1.5
Treatment of Hypersensitivity or Allergic Reactions (Rucaparib or 
Enzalutamide)
Hypersensitivity or allergic reactions associated with treatment with rucaparib or enzalutamide 
should be managed per local SOC.
7.2
Method of Treatment Assignment
All participants will be centrally assigned to a treatment arm using an Interactive Response 
Technology (IRT) system. Before the study is initiated, each site will receive log-in information 
and directions on how to access the IRT.
After obtaining informed consent from the participant, the investigator or designee will register 
the participant for enrollment in IRT by following the enrollment procedures established by BMS.
Once enrolled in IRT, enrolled participants who have met all eligibility criteria, including 
completion of HRD testing of the submitted plasma and/or tumor sample by the central laboratory, 
will be ready for treatment arm assignment through the IRT. As approximately 20-25% of BRCA 
homozygous deletions are not detected by plasma analysis, the study will allow for the testing of 
both plasma and tissue samples to capture all possible HRD mutations.
For participants with local HRD test results obtained prior to enrollment, an unblinded Sponsor 
reviewer will confirm that they are acceptable for treatment arm assignment (refer to Section 5.1for 
definition of acceptable local results). Although completion of central HRD testing is not required 
for subjects with acceptable local HRD results, central laboratory must confirm receipt of plasma 
and tumor samples prior to IRT treatment arm assignment. Based on prior treatment history, 
presence or absence of measurable disease, eligibility for chemotherapy and HRD status, IRT will 
assign the participant to a treatment arm that has available spots. If more than 1 treatment arm has 
available spots, the investigator or designee will be able to choose the treatment arm for the 
participant (for guidance, refer to Figure 5.1-2). If there are no available spots in any of the 
treatment arms, the participant will be a screen failure. The BMS study team will update sites when 
enrollment in a treatment arm is nearing completion.
Retrospective plasma HRD testing will be performed in all subjects who were enrolled prior to 
global revised protocol 02. Participants initially assigned to an HRD-negative or not evaluable spot 
based on tumor testing who are found to be HRD positive on retrospective plasma testing will be 
re-assigned to the HRD positive group. As a result of re-assignment of HRD not-evaluable patients, 
additional slots may become available in the HRD negative/not-evaluable group and will be 
released to the sites. Study treatment will be dispensed at the study visits as listed in Schedule of 
Activities (Section 2).
7.3
Blinding
Blinding is not applicable, as this is an open-label study; however, the specific treatment to be 
taken by a participant will be assigned using an IRT, as specified in Section 7.2. Treatment arm 
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assignments will be released to the bioanalytical laboratory in order to minimize unnecessary 
analysis of samples.
The HRD status as determined by the central laboratory will be masked to investigator sites and 
participants and can be unmasked if requested by investigator sites at the time of radiographic 
progression or discontinuation of study treatment of a participant, whichever occurs later, and at 
final analyses. HRD status based on central laboratory testing may also be unmasked if requested 
by the investigator for participants who screen fail due to lack of available HRD negative of slots
at the time of treatment arm assignment. The HRD status determined by a local laboratory will be 
masked to BMS study team. Only those Sponsor personnel not directly involved in the assessment 
of safety and efficacy in the study will review local and central HRD status up to discontinuation 
of study therapy or final analyses. During the DMC review, the HRD status will be transferred to 
an independent data center to perform analyses as needed.
In the event that a germline mutation is suspected based on the results from central analyses of 
tumor tissue (or ctDNA), these results will be provided to the treating physician and the participant
may be referred by the investigator for confirmation and genetic counseling per institutional 
guidelines.
As specified in Section 10.3.4, interim analyses by HRD status may be unblinded to a small BMS 
team outside the immediate CA2099KD study team to inform internal decision making on further 
clinical development in prostate cancer and determine if any arm in the study should be expanded 
to generate additional data that may support a regulatory filing.
Members of the immediate study team (site-facing BMS team members) will remain blinded to 
the HRD status of individual study participants in order to maintain study integrity until the final 
analysis.
7.4
Dosage Modification
For all participants, the following medications are prohibited during the study (unless utilized to 
treat a drug-related AE):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.2)
•
Any concurrent non-protocol-specified anti-neoplastic therapy (ie, chemotherapy, hormonal 
therapy other than ADT, immunotherapy, extensive or non-palliative radiotherapy, standard or 
investigational agents for CRPC)
7.4.1
Nivolumab
There will be no dose modifications permitted for nivolumab.
7.4.2
Rucaparib
Rucaparib dose reduction steps are provided in Table 7.4.2-1.
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Table 7.4.2-1:
Dose Reduction for Rucaparib
Dose Reduction
Dose
Starting Dose
600 mg twice daily
First Dose Reduction
500 mg twice daily
Second Dose Reduction
400 mg twice daily
Third Dose Reduction
300 mg twice daily
*Consultation with the BMS Medical Monitor/designee is required before reducing to the Third 
Dose Reduction Level.
After 3 dose reductions, if a participant continues to experience toxicity, or if dosing is interrupted 
for more than 14 consecutive days due to toxicity, treatment should be discontinued unless 
otherwise agreed between the investigator and the Sponsor (see Section 8.1.2). Dose re-escalation 
upon resolution of toxicity to ≤ CTCAE Grade 1 is permitted at the discretion of the investigator.
7.4.3
Docetaxel
Dose reductions of docetaxel may be required114 and will be performed according to Table 7.4.3-
1.
Table 7.4.3-1:
Dose Reductions for Docetaxel
Dose Level
Docetaxel
Starting dose
75 mg/m²
First dose reduction
60 mg/m²
Second dose reduction
45 mg/m²
Third dose reduction
Discontinue docetaxel
Doses of docetaxel will be modified for participants who experience any of the following 
conditions during docetaxel treatment:
•
Febrile neutropenia (body temperature ≥38.5°C and neutrophils < 1,000 cell/mm3)
•
Neutrophils < 500 cell/mm³ for more than one week despite growth factor support
•
Severe or cumulative cutaneous reactions
•
Other Grade 3/4 non-hematological toxicities.
Participants should have treatment delayed according to Section 7.1.1.3, and then resumed at 
1 dose level reduction (60 mg/m2). Should these AEs occur after the first dose reduction, then a 
second dose reduction to 45 mg/m2 is permitted. If a third dose reduction is required, then the 
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participant should discontinue docetaxel treatment and enter the follow-up phase. The dose which 
has been reduced for toxicity must not be re-escalated. 
Participants who develop Grade ≥3 peripheral neuropathy, or who otherwise meet criteria 
specified in Section 8.1.3, should discontinue docetaxel treatment and enter the follow-up phase.
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 patient will continue docetaxel treatment in the 
absence of major toxicity, disease progression or any other discontinuation criteria as defined in 
Section 8.1.3.
7.4.4
Enzalutamide
Participants who experience a Grade 3 or greater toxicity that cannot be ameliorated by the use of 
adequate medical intervention should have their treatment interrupted until the toxicity improves 
to a Grade 2 or lower severity. Participants may subsequently be re-started on study drug, at the 
same dose or at a reduced dose (120 mg or 80 mg) if warranted, at the investigator’s discretion. 
Enzalutamide doses will not be re-escalated once reduced, unless a concomitant strong CYP3A4 
inducer is started or a strong CYP2C8 inhibitor is discontinued (see below).
As stated in the prescribing information for enzalutamide, strong inhibitors (eg, gemfibrozil) of 
CYP2C8 are to be avoided or used with caution during enzalutamide treatment. If participants 
must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced 
to 80 mg once daily. If co-administration of the strong CYP2C8 inhibitor is discontinued, the 
enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP2C8 
inhibitor.
The concomitant use of strong CYP3A4 inducers (eg, phenytoin) should be avoided if possible. If 
a strong CYP3A4 inducer must be co-administered, the enzalutamide dose should be increased 
from 160 mg to 240 mg once daily. If co-administration of the strong CYP3A4 inducer is 
discontinued, the enzalutamide dose should be returned to the dose used prior to initiation of the 
strong CYP3A4 inducer.
7.5
Preparation/Handling/Storage/Accountability
For nivolumab, refer to the current version of the Investigator Brochure and/or Pharmacy Manual 
for complete storage, handling, dispensing, and infusion information.
For rucaparib, refer to the current version of the Investigator Brochure and/or Pharmacy Manual 
for complete storage, handling, and dispensing.
For docetaxel, prednisone, dexamethasone, and enzalutamide, refer to the current prescribing 
information for complete storage, handling, dispensing, and administration information.
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 
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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 the BMS study team contacted 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).
•
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
Not applicable.
7.6
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the participant’s 
medical record and eCRF. Participants will be provided with a medication diary in which to record 
study drug doses taken by mouth and will be instructed to bring this diary and study drug containers 
(rucaparib, prednisone, dexamethasone and enzalutamide) to clinic visits.
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
All Arms
For all participants, 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 botanical preparation (eg, herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
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medical prescription or if its use (even without a medical prescription) has been legalized 
locally
•
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
Arm A
For participants in Arm A (nivolumab plus rucaparib), rucaparib is a moderate inhibitor of 
CYP1A2 and a weak inhibitor of CYP2C9, CYP2C19, and CYP3A4 in vivo. Caution should be 
used for concomitant substrate medications with narrow therapeutic windows. Examples of such 
medications are listed below:
•
CYP1A2 substrates: tizanidine, theophylline
•
CYP2C9 substrates: warfarin, phenytoin
•
CYP2C19 substrates: S-mephenytoin
•
CYP3A: alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine
Dose adjustment maybe considered for these medications, if clinically indicated. Participants 
taking warfarin should have their international normalized ratios (INRs) monitored regularly per 
standard clinical practice.
In vitro, rucaparib is a potent inhibitor of MATE 1 and MATE2-K, a moderate inhibitor of OCT1, 
and a weak inhibitor of OCT2. As inhibition of these transporters could increase renal elimination 
of metformin and decrease liver uptake of metformin, caution is advised when metformin is co-
administered with rucaparib. In addition, rucaparib is an inhibitor of BCRP with an IC50 value 
suggesting potential BCRP inhibition and increased exposures of medicinal products that are 
BCRP substrates (eg, rosuvastatin).
Therapies considered necessary for the participant’s well-being may be given at the discretion of 
the investigator and should be documented on the eCRF. Other concomitant medications, except 
for analgesics, chronic treatments for concomitant medical conditions, or agents required for life-
threatening medical problems, should be avoided. Herbal and complementary therapies should not 
be encouraged because of unknown side effects and potential drug interactions, but any taken by 
the participant should be documented appropriately on the eCRF. 
Because rucaparib is a moderate inhibitor of P-gp in vitro, caution should be exercised for 
participants receiving study drug and requiring concomitant medication with digoxin. Participants 
taking digoxin should have their digoxin levels monitored after starting study treatment and then 
regularly per standard clinical practice. Caution should also be exercised for concomitant use of 
certain statin drugs (eg, rosuvastatin and fluvastatin) due to potential increase in exposure from 
inhibition of BCRP and CYP2C9.
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Arm B
For participants in Arm B (nivolumab plus docetaxel), strong CYP3A4 inhibitors should be 
avoided during the treatment with docetaxel. This includes, but is not limited to:
•
Ketoconazole
•
Itraconazole
•
Clarithromycin
•
Atazanavir
•
Indinavir
•
Nefazodone
•
Nelfinavir
•
Ritonavir
•
Saquinavir
•
Teithromycin
•
Voriconazole
Arm C
For participants in Arm C (nivolumab plus enzalutamide), enzalutamide is an inducer and inhibitor 
of several CYP isoenzymes and susceptible to many drug interactions. Since the half-life of 
enzalutamide is 5.8 days, the effects on enzymes may persist for ≥1 month after stopping the drug.
Co-administration with warfarin and coumarin-like anticoagulants should be avoided. If
enzalutamide (Xtandi) is co-administered with an anticoagulant metabolised by CYP2C9 (such as 
warfarin or acenocoumarol), additional International Normalised Ratio (INR) monitoring should 
be conducted.
CYP3A4 inhibitors may increase enzalutamide exposure, but the clinical significance is unclear 
and no dosage adjustment is recommended. Enzalutamide is a substrate of CYP2C8 and an 
inducer/inhibitor of CYP2B6. Per the enzalutamide current prescribing information, strong 
inhibitors of CYP2C8 should be avoided. See Section 7.4.4 for more information on dose 
reductions for enzalutamide.
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of treatment 
arm assignment are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
>10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
7.7.2.1
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 
contrast regimen for each participant. Imaging contraindications and contrast risks should be 
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considered in this assessment. Participants with renal insufficiency should be assessed as to 
whether or not they should receive contrast and, if so, what type and dose of contrast 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. MRI 
contrast should not be given to this participant population. In addition, participants are excluded 
from MRI if they have tattoos, metallic implants, pacemakers, etc.
The ultimate decision to perform MRI in an individual participant in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee.
7.7.3
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.
7.7.3.1
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 8.1.5) 
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.
Treatment with rucaparib should be held prior to initiation of radiation therapy and until the patient 
has recovered from any radiation-related toxicity.
For docetaxel and enzalutamide local standard of care guidelines should be followed. 
7.8
Treatment After the End of the Study
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 7.1. 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 
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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
General Information on Study Treatment Discontinuation
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 AE, laboratory abnormality, or intercurrent illness that, 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 BMS
•
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.)
•
Participant meets criteria for radiographic progression per PCWG3 criteria or clinical 
progression (as defined in Section 9.1.2) unless criteria for treatment beyond progression have 
been met (see Section 8.1.5).
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Table 2-2 and Table 2-3. 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 drug 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.
Discontinuation of Specific Study Treatments (Nivolumab, Rucaparib, Docetaxel, or 
Enzalutamide)
The assessment for discontinuation of nivolumab and the combination agent (rucaparib, docetaxel, 
or enzalutamide) 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 
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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.
8.1.1
Nivolumab Dose Discontinuation
Nivolumab treatment should be permanently discontinued for any of the following:
•
Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment 
•
Any Grade 3 non-skin, drug-related AE lasting >7 days or that recurs, with the following 
exceptions: laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm,
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies
−
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, 
neurologic toxicity, 
myocarditis, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation
−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement.
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia >7 days or associated with bleeding requires 
discontinuation
♦Grade ≥3 drug-related AST, ALT, or total bilirubin requires discontinuation*
* In most cases of Grade 3 AST or ALT elevation, study treatment(s) will be 
permanently discontinued. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study treatment(s), a discussion between 
the investigator and the BMS Medical Monitor/designee must occur.
* Note for Arm A: Elevated ALT/AST is among the most frequently reported 
treatment-related AEs for rucaparib monotherapy. Rucaparib-related ALT/AST 
elevations occur early in treatment (ie, in Cycle 1 or by Day 1 of Cycle 2) and then 
resolve or stabilize over time. Rucaparib associated elevations in ALT/AST are 
generally not accompanied by a concomitant elevation in bilirubin.
♦Concurrent AST or ALT >3× ULN and total bilirubin >2× ULN
•
Any Grade 4 drug-related AE or laboratory abnormality (including but not limited to 
creatinine, AST, ALT, or total bilirubin), except for the following events that do not require 
discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
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−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy AEs, such as, hyper- or hypothyroidism, or glucose 
intolerance, that resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor/designee.
Grade 4 drug-related adrenal insufficiency or 
hypophysitis requires discontinuation regardless of control with hormone replacement.
•
Any event that leads to delay in dosing lasting > 8 weeks (Q3W cycle) or > 10 weeks (Q4W 
cycle) from the previous dose requires discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs 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 
BMS Medical Monitor/designee.
Prior to re-initiating treatment in a participant with a dosing delay lasting > 8 weeks (Q3W cycle) 
or > 10 weeks (Q4W cycle), the BMS Medical Monitor/designee must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed. Periodic study visits to 
assess safety and laboratory studies should also continue every 6 weeks or more frequently if 
clinically indicated during such dosing delays.
•
Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
investigator, presents a substantial clinical risk to the participant with continued nivolumab 
dosing
Note for Arm A: Elevated creatinine is among the most frequently reported treatment-related AEs 
for rucaparib monotherapy. Rucaparib is a potent inhibitor of MATE1 and MATE2-K transporters, 
which are involved in active secretion of creatinine. Rucaparib-mediated creatinine elevation 
occurs early in treatment (Day 15 of Cycle 1), and is not typically accompanied by elevations in 
urea (BUN). Creatinine elevation resolves with dose holds of rucaparib and recurs with re-
challenge. Rucaparib associated creatinine elevation has not been associated with evidence or 
reports of permanent renal impairment.
8.1.2
Rucaparib Discontinuation
•
If a participant continues to experience toxicity despite multiple dose reduction steps as per 
Section 7.4.2, or if dosing with rucaparib is interrupted for > 14 consecutive days due to 
toxicity, treatment should be discontinued, unless otherwise agreed between the investigator 
and the Sponsor on a case-by-case basis. Prior to re-initiating treatment in a participant with a 
dosing delay lasting > 14 days, the BMS Medical Monitor/designee must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed. 
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•
Rucaparib treatment must be discontinued if Myelodysplastic Syndrome (MDS)/Acute 
Myeloid Leukemia (AML) is confirmed.
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the participant with continued rucaparib
dosing.
8.1.3
Docetaxel Discontinuation
Docetaxel treatment should be permanently discontinued for the following:
•
Any Grade ≥3 peripheral neuropathy
•
Any Grade 3 non-skin drug-related AE lasting > 7 days, with the following exceptions:
−
Grade 3 docetaxel-related enterocolitis of any duration requires discontinuation*
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
♦Grade 3 drug-related thrombocytopenia associated with bleeding requires 
discontinuation
♦Any drug-related liver function test (LFT) abnormality that meets the following criteria 
requires discontinuation: 
o
AST or ALT > 5~10x ULN for > 2 weeks
o
AST or ALT > 10x ULN
o
Total bilirubin > 5x ULN
o
Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN
•
Any Grade 4 drug-related AE or laboratory abnormality, except for the following events which 
do not require discontinuation:
−
Grade 4 neutropenia
−
Grade 4 lymphopenia or leukopenia
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
•
Any dosing delay lasting > 8 weeks with the following exceptions:
−
Dosing delays > 8 weeks that occur for non-drug-related reasons may be allowed if 
approved by the BMS Medical Monitor/designee. Prior to re-initiating treatment in a 
participant with a dosing delay lasting > 8 weeks, the BMS Medical Monitor/designee must 
be consulted. Tumor assessments should continue as per protocol even if dosing is delayed.
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the participant with continued docetaxel 
dosing.
*Note: 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 
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to the appropriate specialist (i.e. gastroenterologist) for assessment and full details of the 
participant’s exposure to docetaxel should be provided. 
8.1.4
Enzalutamide Discontinuation
Treatment with enzalutamide should be discontinued for any of the following:
•
Seizure or posterior reversible encephalopathy syndrome (PRES)
•
Creatinine > 305 μmol/L (4.0 mg/dL)
•
Liver function tests (AST, ALT, or total bilirubin) > 5x ULN
•
An absolute neutrophil count of ≤750/μL
•
A platelet count of < 50,000/μL
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the participant with continued enzalutamide
dosing.
•
Any dose delays lasting > 10 weeks with the following exceptions:
−
Dosing delays > 10 weeks that occur for non-drug-related reasons may be allowed if 
approved by the BMS Medical Monitor/designee. Prior to re-initiating treatment in a 
participant with a dosing delay lasting > 10 weeks, the BMS Medical Monitor/designee 
must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed.
8.1.5
Nivolumab Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.29
Participants treated with nivolumab will be permitted to continue nivolumab treatment beyond 
initial PCWG3-defined PD, assessed by the investigator (see Table 9.1.2-1 and Appendix 5) up to 
a maximum of 24 months from date of first dose, as long as they meet the following criteria:
•
Investigator-assessed clinical benefit
•
Tolerance of study drug
•
Stable performance status
•
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 nivolumab 
treatment. All other elements of the main consent including description of reasonably 
foreseeable risks or discomforts, or other alternative treatment options will still apply.
•
At the discretion of the investigator, rucaparib (Arm A1 or A2) and enzalutamide (Arm C) may 
also be continued beyond progression with nivolumab. Docetaxel (Arm B) may be continued 
beyond progression with nivolumab but docetaxel may not continue beyond Cycle 10.
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Re-assessment Following Initial Assessment of Progression
A radiographic assessment/ scan should be performed within 6 weeks (if progression is based on 
soft-tissue lesions [identified on CT or MRI]) or within 8 weeks (if progression is based only on 
bone lesions identified on bone scan) of initial investigator-assessed progression. 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.
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the trial and continue to receive monitoring according 
to the Schedule of Activities (Section 2).
For the participants who continue study therapy beyond progression, further progression is defined 
as per RECIST v1.1 (for soft tissue progression) or PCWG3 criteria (for bone progression, see 
Appendix 5), whichever occurs first as follows:
Further disease progression by RECIST v1.1 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 measureable 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-measureable at the time of initial progression may 
become measureable 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 further progression.
Confirmed PSA progression alone is not necessarily an indication to stop treatment.
8.1.6
Post Study Treatment Follow-up
In this study, radiographic PFS and OS are important secondary endpoints which require longer 
follow-up. 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 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 on all treated participants outside of the protocol-
defined window (see Section 2). At the time of this request, each participant will be contacted to 
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determine their survival status unless the participant has withdrawn consent for all contact or is 
lost to follow-up, including information of subsequent therapy.
8.2
Discontinuation 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 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.
Participants who discontinue treatment for reasons other than radiographic disease progression 
will stay on study and continue study-related disease assessments until radiographic disease 
progression (see Section 9.1.2 below), subject withdrawal from the trial, or becoming lost to 
follow-up. All participants will be followed for survival.
8.3
Lost to Follow-Up
•
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.
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•
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
•
Study procedures and timing are summarized in the Schedule of Activities (Section 2).
•
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 the 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 treatment arm assignment. The investigator will 
maintain a screening log to record details of all participants screened and to confirm eligibility 
or record reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of 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.
Additional measures, including non-study-required laboratory tests, should be performed 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.
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg. dyspnea, cough,
and fever) consistent with possible pulmonary AEs, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in Appendix 6.
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
Study evaluations will take place in accordance with the Schedule of Activities in Section 2.
Radiographic tumor response will be assessed at 8 weeks after first dose ( ± 7 days), then every 8
weeks (± 7 days) for the first 24 weeks (until Week 25 ± 7 days) and every 12 weeks (± 7 days) 
thereafter, until disease progression is documented (and confirmed if confirmation is required) or 
treatment is discontinued (whichever occurs later). This tumor assessment schedule should be 
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followed regardless of treatment schedule or dose delays. Additional scans at other time points 
may be performed if clinically indicated.
9.1.1
Imaging Assessment for the Study
Images will be submitted to an imaging core laboratory for storage and potential future blinded 
independent central review (BICR) per Sponsor request. Sites should be trained prior to scanning 
the first study participant. Image acquisition guidelines and submission process will be outlined in 
the CA2099KD Imaging Manual to be provided by the core lab. 
Bone lesions will be assessed using Technetium-99m (Tc-99m) based radionuclide bone scans. 
Anterior and posterior whole body planar images should be acquired. Additional (including spot 
views and SPECT) images should also be submitted if acquired.
Soft tissue lesions will be preferably assessed with contrast-enhanced computed tomography (CT) 
scans acquired on dedicated CT equipment (preferred for this study). Contrast-enhanced CT of the 
chest, abdomen, pelvis, and other known/suspected sites of soft tissue disease should be performed 
for tumor assessments.
Should a participant have contraindication for CT intravenous contrast, a non-contrast CT of the 
chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of 
soft tissue disease should be obtained. 
Should a participant have contraindication for both MRI and CT intravenous contrasts, a non-
contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of soft tissue disease should be obtained. 
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, a non-contrast CT of the chest, abdomen, pelvis, and 
other known/suspected sites of soft tissue disease is acceptable.
CT and MRI scans 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 time points.
Use of CT component of a PET/CT scanner: Combined modality scanning such as with 
FDG-PET/CT is increasingly used in clinical care, and is a modality/technology that is in rapid 
evolution; therefore, the recommendations outlined here may change quickly with time. At present, 
low dose or attenuation correction CT portions of a combined FDG-PET/CT are of limited use in 
anatomically-based efficacy assessments and it is therefore suggested that they should not be 
substituted for dedicated diagnostic contrast enhanced CT scans for anatomically-based RECIST 
measurements. However, if a site can document that the CT performed as part of a FDG-PET/CT 
is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion 
of the FDG-PET/CT can be used for tumor measurements. Note, however, that the FDG-PET 
portion of the CT introduces additional data which may bias an investigator if it is not routinely or 
serially performed.
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Assessments will be performed at baseline and at the time points described per PCWG3 criteria 
until disease progression per PCWG3 criteria (Appendix 5), or discontinuation of study treatment, 
whichever occurs later. Tumor assessments at other time points may be performed if clinically 
indicated and should be submitted to the central imaging vendor. Assessments of PR and CR must 
be confirmed at least 4 weeks after initial response. A BOR of stable disease can only be made 
after the participant is on-study for a minimum of 49 days from the date of treatment initiation (ie,
first dose). Changes in tumor measurements and tumor responses will be assessed by the 
investigator per study design using PCWG3 criteria. Investigators will also report the number and 
size of new lesions that appear while on study. The time point of tumor assessments will be 
reported on the eCRF based on the investigator’s assessment 
For participants who are treated beyond PCWG3-defined progression, tumor assessments will 
continue to be performed until discontinuation of study treatment (typically upon evidence of 
further progression, as defined in Section 8.1.5).
Any additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled time points and/or at an outside institution) should be collected for 
PCWG3 tumor assessment and submitted to the BICR.
9.1.2
Disease Response Evaluation
The consensus guidelines of the PCWG3 have been taken into consideration for the determination 
of radiographic disease progression assessment. 
All target and non-target sites of disease identified on the baseline assessment should be reassessed 
with the same imaging modality at subsequent assessments. Bone lesions should be assessed with 
Tc-99m based bone scans.
Disease Progression Criteria
At each disease assessment, PD will be determined using the criteria based on PCWG3. 
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 5 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, confirmed on the next scan (performed 
at least 6 weeks later) AND with at least 2 
additional lesions 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. In addition, participants must also 
meet progression criteria per PCWG3 for measurable disease and/or bone disease (Table 9.1.2-1
above).
Participant who discontinue treatment without documented radiographic progression will continue 
to have PSA performed every 8weeks (± 7 days) until radiographic progression or the start of 
subsequent systemic cancer therapy, whichever occurs first. PSA evaluation beyond radiographic 
progression or the start of subsequent systemic cancer therapy to confirm PSA response or PSA 
progression should be performed as needed.
9.2
Adverse Events
The definitions of an AE or serious SAE 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. 
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Contacts for SAE reporting are specified in Appendix 3.
Immune-mediated AEs 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 that were exacerbated 
by the induction of autoimmunity. Information supporting the assessment will be collected on the 
participant’s eCRF.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of non-serious AE information should begin at initiation of study treatment until 
the time points specified in the Schedule of Activities (Section 2). 
Section 5.6 in the nivolumab IB and Section 6.6 in the rucaparib IB present the Reference Safety 
Information to determine expectedness of SAEs for expedited reporting. Following the 
participant’s written consent to participate in the study, all SAEs, whether related or not related to 
study treatment, must be collected, including those thought to be associated with protocol-
specified procedures.
All SAEs must be collected that occur during the screening period and within 100 days of the last 
dose of study treatment. For participants assigned to treatment and never treated with study drug, 
SAEs should be collected for 30 days from the date of treatment arm assignment.
If applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg, a 
follow-up biopsy).
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or a protocol-specified procedure.
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF.
•
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 within 24 hours of these 
data being available.
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
AEs 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 
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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.
All nonserious 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.
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
•
Non-serious 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 non-serious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
All identified non-serious AEs must be recorded and described on the non-serious 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.
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification of SAEs by the investigator to the Sponsor 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 IBs and will notify the IRB/IEC, if appropriate according to local requirements.
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Title 21 
Code of Federal Regulations (CFR) Parts 312 and 320. A suspected unexpected serious adverse 
reaction (SUSAR) 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
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for BMS 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.
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9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious 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)
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 9.2.4 for reporting details).
Potential drug induced liver injury is defined as:
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND 
2) Total bilirubin > 2 times 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
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 non-serious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 9.2.4).
There is no specific treatment in the event of rucaparib overdose, and symptoms of overdose are 
not established. In the event of suspected overdose, physicians should follow general supportive 
measures and should treat symptomatically. 
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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. 
There is no antidote for enzalutamide overdose. In the event of an overdose, treatment with 
enzalutamide should be stopped and general supportive measures initiated taking into 
consideration the half-life of 5.8 days. Participants may be at increased risk of seizures following 
an overdose.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 2).
Some of the assessments referred to in this protocol 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.
9.4.1
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report. Please refer to the 
Schedule of Activities in Section 2 and Table 9.4.1-1 for details regarding required laboratory tests.
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Table 9.4.1-1:
Laboratory Assessments for Study CA2099KD
Hematology 
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Serum Chemistry
Aspartate aminotransferase (AST)
Albumin at screening and as clinically indicated
Alanine aminotransferase (ALT)
ACTH at screening and as clinically indicated
Total bilirubin
Cortisol at screening and as clinically indicated
Alkaline phosphatase
Sodium
Lactate dehydrogenase (LDH)
Potassium
Creatinine
Chloride
Blood Urea Nitrogen (BUN)
Calcium
Glucose (fasting) (at screening only)
Phosphate
TSH, Free T3, Free T4
Magnesium
TSH, with reflexive fT3 and fT4 if TSH is abnormal -
on treatment
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
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)
HRD Status
9.4.2
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. 
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9.5
Pharmacokinetics
9.5.1
Background
Nivolumab
The pharmacokinetics (PK) of nivolumab were studied in participants over a dose range of 0.1 to 
10 mg/kg administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. 
Nivolumab clearance (CL) decreases over time, with a mean maximal reduction (% coefficient of 
variation [CV%]) from baseline values of approximately 24.5% (47.6%), resulting in a geometric 
mean steady state clearance (CLss) (CV%) of 8.2 mL/h (53.9%). The decrease in CLss is not 
considered clinically relevant. The geometric mean volume of distribution at steady state (Vss) 
was 6.8 L (27.3%), and geometric mean elimination half-life (t1/2) was 25 days (77.5%). Steady 
state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg Q2W, 
and systemic accumulation was approximately 3.7-fold. The exposure to nivolumab increased 
dose-proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The 
clearance of nivolumab increased with increasing body weight. The PPK analysis suggested that 
the following factors had no clinically important effect on the CL of nivolumab: age (29 to 
87 years), gender, race, baseline LDH, PD-L1. A PPK analysis suggested no difference in CL of 
nivolumab based on age, gender, race, tumor type, baseline tumor size, and hepatic impairment.
Although ECOG status, baseline GFR, albumin and body weight had an effect on nivolumab CL, 
the effect was not clinically meaningful. PPK and exposure response analyses have been 
performed to support use of nivolumab 240 mg Q2W, 360 mg Q3W, and 480 mg Q4W dosing 
regimens in addition to the 3 mg/kg Q2W regimen. A flat dose of nivolumab 240 mg Q2W was 
selected since it is identical to a dose of 3 mg/kg for subjects weighing 80 kg, the observed median 
body weight in nivolumab-treated cancer patients, while the nivolumab 360 mg Q3W and 480 mg 
Q4W regimens allow flexibility of dosing with less frequent visits and in combination with other 
agents using alternative dosing schedules to Q2W. Using a PPK model, the overall distributions 
of nivolumab exposures (Cavgss, Cminss, Cmaxss, and Cmin1) are comparable after treatment 
with either nivolumab 3 mg/kg or 240 mg Q2W. Following nivolumab 360 mg Q3W and 480 mg 
Q4W, Cavgss are expected to be similar to those following nivolumab 3 mg/kg or 240 mg Q2W, 
while Cminss are predicted to be, respectively, 6% and ~16% lower and are not considered to be 
clinically relevant. Following nivolumab 360 mg Q3W and 480 mg Q4W, Cmaxss are predicted 
to be approximately ~23% and ~43% greater, respectively, relative to that following nivolumab 
3 mg/kg Q2W dosing. However, the range of nivolumab exposures (median and 90% prediction 
intervals) following administration of 240 mg flat Q2W, 360 mg Q3W, and 480 mg Q4W regimens 
across a wide 35 to 160 kg weight range are predicted to be maintained well below the 
corresponding exposures observed with the well-tolerated 10 mg/kg nivolumab Q2W dosing 
regimen.
Additional information on the clinical pharmacology of nivolumab can be found in the nivolumab 
IB. 
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Rucaparib
The mean oral bioavailability following a single oral dose of 12 to 120 mg rucaparib was 36%. 
Following oral administration of rucaparib of 40 to 500 mg and 240 mg to 840 mg BID, rucaparib 
exposures, as measure by Cmax and AUC, increased approximately dose proportionally. The 
steady-state accumulation following QD dosing was 1.06 to 1.8 for Cmax, and 1.6 to 2.33 for 
AUC0-24. And the steady-state accumulation following BID dosing was in the range of 2.6 to 4.9 
for Cmax, and 1.47 to 5.44 for AUC0-12. The mean Tmax and t1/2 were approximately 4 hours 
and 17 hours, respectively. A potential food effect was evaluated at 600 mg. A high-fat meal 
increased Cmax and AUC0-24 by 20% and 38%, respectively, and delayed Tmax by 2.5 hours as 
compared to that under fasted conditions. A high-fat meal did not change PK variability, and the 
food effect is not considered clinically meaningful based on collective clinical efficacy and safety 
data. Thus, rucaparib can be taken with or without food. 
In this study, trough plasma concentrations of rucaparib will be determined for all participants 
receiving rucaparib as described in Table 9.5.2-1. Details of plasma rucaparib PK sample 
collection and processing procedures will be provided to the study sites in the laboratorymanual. 
Plasma concentrations for rucaparib will be determined using a validated HPLC-MS/MS method.
Additional information on the clinical pharmacology of rucaparib can be found in the rucaparib 
IB.
Enzalutamide
The pharmacokinetics of enzalutamide have been evaluated in prostate cancer patients and in 
healthy male subjects. The mean terminal half-life (t1/2) for enzalutamide in patients after a single 
oral dose is 5.8 days (range 2.8 to 10.2 days), and steady state is achieved in approximately one 
month. Maximum plasma concentrations (Cmax) of enzalutamide in patients are observed 1 to 2 
hours after administration. Daily fluctuations in plasma concentrations are low (peak-to-trough 
ratio of 1.25). Based on a mass balance study in humans, oral absorption of enzalutamide is 
estimated to be at least 84.2%. With daily oral administration, enzalutamide accumulates
approximately 8.3-fold relative to a single dose. Daily fluctuations in plasma concentrations are 
low (peak-to-trough ratio of 1.25). 
Clearance of enzalutamide is primarily via hepatic metabolism, producing an active metabolite 
that is equally as active as enzalutamide and circulates at approximately the same plasma 
concentration as enzalutamide. Enzalutamide is not a substrate of the efflux transporters P-gp or 
BCRP. At steady state, the mean Cmax values for enzalutamide and its active metabolite are 16.6 
μg/mL (23% coefficient of variation [CV]) and 12.7 μg/mL (30 %CV), respectively. 
Food has no clinically significant effect on the extent of absorption. In clinical trials, enzalutamide 
(Xtandi) was administered without regard to food. 
The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose 
is 110 L (29% CV). The volume of distribution of enzalutamide is greater than the volume of total 
body water, indicative of extensive extravascular distribution. 
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Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. The active metabolite 
is 95% bound to plasma proteins. There was no protein binding displacement between 
enzalutamide and other highly bound drugs (warfarin, ibuprofen and salicylic acid) in vitro.
Enzalutamide is metabolised by CYP2C8 and to a lesser extent by CYP3A4/5, both of which play 
a role in the formation of the active metabolite. In vitro, N-desmethyl enzalutamide (active) is 
metabolised to the carboxylic acid metabolite (inactive) by carboxylesterase 1, which also plays a 
minor role in the metabolism of enzalutamide to the carboxylic acid metabolite. N-desmethyl 
enzalutamide was not metabolised by CYPs in vitro. 
In this study, predose plasma concentrations of enzalutamide will be determined for all participants 
receiving enzalutamide as described in Table 9.5.2-1. Details of plasma enzalutamide PK sample 
collection and processing procedures will be provided to the study sites in the laboratory manual. 
Plasma concentrations for enzalutamide will be determined using a validated HPLC-MS/MS 
method. Additional information on the clinical pharmacology of enzalutamide can be found in the 
enzalutamide prescribing information.
9.5.2
Pharmacokinetics Assessments
This study evaluates the effect of nivolumab combined with rucaparib, docetaxel, or enzalutamide 
in participants with mCRPC and affords the opportunity to assess the pharmacokinetics of 
nivolumab. Given that the hypothesis is that nivolumab plus each of these combination therapies 
will improve efficacy compared to any agent alone, nivolumab PK 
 will be 
collected in the study. In addition, rucaparib and enzalutamide PK will be assessed in the study.
Samples for PK (nivolumab, rucaparib and enzalutamide) assessment will be collected for all 
participants receiving nivolumab or nivolumab/rucaprib or nivolumab/enzalutamide as described 
in Table 9.5.2-1. All time points are relative to the start of study treatment administration. All 
on-treatment 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.
Blood samples should be drawn from a site other than the nivolumab infusion site (ie, contralateral 
arm) on days of infusion. All samples collected pre-dose should be taken just prior to the 
administration from the contralateral arm (ie, the arm not used for the infusion). A pretreatment 
PK sample before C1D1 can be collected from the same site as where the infusion will be 
administered. All nivolumab PK samples after C1D1 should be collected from contralateral arm 
to prevent sample contamination at the collection site. If the nivolumab infusion was interrupted, 
the interruption details will also be documented on the CRF. Blood samples will be processed to 
collect serum and stored preferably at -70°C (samples may be stored at -20°C up to 2 months). 
Further details of pharmacokinetic 
 sample collection and processing will be 
provided to the site in the laboratory manual. Serum concentration analyses for nivolumab and 
plasma concentration analyses for rucaparib and enzalutamide will be performed by validated 
bioanalytical methods(s).
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Table 9.5.2-1:
Pharmacokinetic 
 Sample Collections (CA2099KD)
Study Day (Cycle, Day)a
(1 Cycle = 4 Weeks for 
Arms A and C
1 Cycle = 3 Weeks for Arm 
B up to Cycle 10 then 4 
weeks at Cycle 11 and 
thereafter)
Time 
(Event)
Time (Relative to 
Start of Infusion)
Pharmacokinetic 
Blood Sample for 
Nivolumab
Pharmacokinetic 
Blood Sample for 
Rucaparib
Pharmacokinetic 
Blood Sample for 
Enzalutamide
C1D1
(Predose)b
00:00
X
(EOI 
nivo)c
00:30
X
C2D1
(Predose)b
00:00
X
X
X
(EOI 
nivo)c
00:30
X
C3D1
(Predose)b
00:00
X
X
X
C4D1
(Predose)b
00:00
X
X
C5D1
(Predose)b
00:00
C10D1
(Predose)b
00:00
CXD1: Every 4 cycles after 
C10 D1 (ie, C14D1, C18D1, 
etc.)
(Predose)b
00:00
X
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Table 9.5.2-1:
Pharmacokinetic 
 Sample Collections (CA2099KD)
Study Day (Cycle, Day)a
(1 Cycle = 4 Weeks for 
Arms A and C
1 Cycle = 3 Weeks for Arm 
B up to Cycle 10 then 4 
weeks at Cycle 11 and 
thereafter)
Time 
(Event)
Time (Relative to 
Start of Infusion)
Pharmacokinetic 
Blood Sample for 
Nivolumab
Pharmacokinetic 
Blood Sample for 
Rucaparib
Pharmacokinetic 
Blood Sample for 
Enzalutamide
Safety Follow-up Visits 1 
(Approximately 30 days) & 
2 (Approximately  
100 Days) from the 
Discontinuation of
Nivolumab during sampling 
period or at 2 yrs.
NA
X
a If a participant discontinues nivolumab treatment during the sampling period (ie, prior to 2 yrs.), they will move to sampling at the follow-up visits
b All predose samples for nivolumab should be taken (preferably within 30 minutes) prior to the start of nivolumab infusion. All nivolumab PK samples after 
C1D1 should be collected from contralateral arm to prevent sample contamination at the collection site. All predose samples for rucaparib and enzalutamide 
should be taken prior to the morning dose. 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 EOI-nivo: End of Infusion samples for nivolumab. EOI samples should be collected immediately (preferably within 2 - 5 minutes) prior to the end of the 
30 minute nivolumab infusion. If the end of infusion is delayed, the collection of the EOI samples should be delayed accordingly. Please ensure accurate 
collection of time/date of sample collection. EOI samples may not be collected from the same IV access as drug was administered
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9.8.2
Tumor Tissue Specimens
Pre-treatment tumor tissue is mandatory, and defined as a biopsy or surgical specimen obtained 
within 5 years prior to enrollment from a metastatic soft tissue tumor lesion or from a primary 
tumor lesion that has not been previously irradiated. 
 
 Submission of fewer than 15 unstained slides 
may be acceptable in some circumstances following discussion with the BMS Medical 
Monitor/designee. An associated pathology report should accompany each submitted tumor 
sample specimen.
Tumor tissue samples obtained within 5 years prior to enrollment must be submitted during 
screening. The submitted tumor sample must undergo central HRD testing in order to 
prospectively assess each participant’s HRD tumor status, which is required for treatment arm 
assignment in IRT, unless local HRD test results obtained prior to enrollment are provided to the 
Sponsor and confirmed to be acceptable for treatment assignment. Plasma HRD test results will 
be also used to characterize patients, and transmitted to IRT system prior to treatment assignment.
The results of central HRD testing will be submitted by the core laboratory to the IRT. Sites and 
the BMS study team will remain blinded to each participant’s HRD status if determined by the 
central core laboratory. Sites may be provided with the results of a participant’s HRD screening 
test at the time of radiographic progression or study treatment discontinuation, whichever occurs 
later. In the event that a germline mutation is identified from central analyses of tumor tissue (or 
ctDNA), these results will be provided to the treating physician and the participant may be referred 
by the investigator for genetic counseling per institutional guidelines.
For participants with bone-only disease or inaccessible soft tissue lesions; a minimum of 3 fresh 
core bone biopsies must be obtained during screening if archival SOFT tissue (less than 5 years 
old) is unavailable. The first 2 samples should be used to (1) confirm disease and presence of tumor 
cells by local pathology review and 
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10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
Approximately 330 participants with mCRPC will be enrolled and treated in 3 arms. 
Planned sample size is summarized in Table 10.1-1 by arm and analysis cohort, which is further 
divided into smaller subgroups by prior treatment, measurable disease at baseline and the HRD 
test results.
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Table 10.1-1:
Sample Size by Arm/Analysis Cohort
Arm/Cohort
Prior Therapy
Measurable
Disease
HRD
Size
Arm A (Nivolumab + Rucaparib)
    A1: HRD+ 
Taxane
Anyb
Positive
40
    A1: HRD-
Taxane
Anyb
Negative
40
    A2: HRD+
Abi and/or Enzaa
Anyb
Positive
60
    A2: HRD-
Abi and/or Enzaa
Anyb
Negative
40
    A1 for ORR
Taxane
Yes
Any
48
    A2 for ORR
Abi and/or Enzaa
Yes
Any
60
    A1 for RR-PSA/PFS
Taxane
Anyb
Any
80
    A2 for RR-PSA/PFS
Abi and/or Enzaa
Anyb
Any
100
    A-HRD+ for ORR
Any
Yes
Positive
60
    A-HRD- for ORR 
Any
Yes
Negative
48
    A-HRD+ for RR-PSA/PFS
Any
Anyb
Positive
100
    A-HRD- for RR-PSA/PFS
Any
Anyb
Negative
80
Arm B (Nivolumab + Docetaxel) 
    B: HRD+ b
Abi and/or Enzac
Anyb
Positive
25
    B: HRD- b
Abi and/or Enzac
Anyb
Negative
60
    B for ORR
Abi and/or Enzac
Yesb
Any
51
    B for RR-PSA/PFS
Abi and/or Enzac
Anyb
Any
85
Arm C (Nivolumab + Enzalutamide)
    C: HRD+ b
Abi onlya
Anyb
Positive
25
    C: HRD- b
Abi onlya
Anyb
Negative
40
    C for ORR
Abi onlya
Yes
Any
39
    C for RR-PSA/PFS
Abi onlya
Anyb
Any
65
a No immediate chemotherapy
b 60% of participants in each treatment arm are required to have measurable disease
c Need immediate chemotherapy
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The sample size is calculated using the precision approach for the co-primary endpoints, ie, ORR,
as assessed by investigator per PCWG3, among treated participants with measurable disease at 
baseline in an analysis cohort, and RR-PSA among treated participants in an analysis cohort. 
Table 10.1-2 provides the precision for potential response rates. For example, if 6 or more 
responders are observed among 30 participants in an analysis cohort, then the lower limit of the 
95% CI for the response rate is above 7.7%.
Table 10.1-2:
Exact 95% CI for ORR and RR-PSA
Participants
Responders
Observed Rate
Lower Limit
Upper Limit
30
6
20.0%
7.7%
38.6%
30
11
36.7%
19.9%
56.1%
39
10
25.6%
13.0%
42.1%
39
15
38.5%
23.4%
55.4%
50
10
20.0%
10.0%
33.7%
50
15
30.0%
17.9%
44.6%
51
18
35.3%
22.4%
44.9%
51
23
45.1%
31.1%
59.7%
60
43
71.7%
58.6%
81.5%
60
48
80.0%
67.7%
89.2%
65
26
40.0%
28.0%
52.9%
65
31
47.7%
35.1%
60.5%
85
53
62.4%
51.2%
72.6%
85
58
68.2%
57.2%
77.9%
100
78
78.0%
68.6%
85.7%
100
83
83.0%
74.2%
89.8%
Powers are assessed for ORR and RR-PSA, using the one-arm binomial test. Estimates of reference 
ORR and RR-PSA are based on the current SOC for the target populations for each analysis cohort 
in this study; see Table 5.4.3-1. A target ORR for a promising combination treatment is assumed 
as an increase of 15% or more compared to the current SOC in an analysis cohort. As shown in 
Table 10.1-3, powers are assessed at a 1-sided alpha of 10% using the method from Fleiss 
(1981).128 In addition, the planned number of treated participants will also provide an adequate 
power for detecting a 10% absolute increase in RR-PSA for the combination compared to SOC
and provide a stable estimate of median rPFS for each analysis cohort.
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Table 10.1-3:
Power for ORR in Participants with Measurable Disease at Baseline
Analysis Cohort/Arm
Participants
Null ORR
Target ORR
Power
A1
48
10%
25%
94%
A2
60
21%
36%
91%
B
51
21%
36%
87%
C
39
10%
25%
89%
The accrual duration is approximately 15 months, based on a monthly enrollment rate of 
22 participants, and the follow-up period will be 12 months. The final analysis of the co-primary 
endpoints of ORR and RR-PSA will occur approximately 2.5 years after the first participant is 
treated in an analysis cohort/arm and may be performed independently from other cohorts/arms if 
enrollment is completed at different times across the cohorts/arms. This will allow sufficient 
follow-up for a stable estimate of BOR and DOR, and an adequate safety assessment. Additional 
survival analyses may be conducted for up to 5 years after treatment initiation following the 
updated analysis of the co-primary endpoints.
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign an informed consent form and are 
registered into the IRT
Treated
All enrolled participants who receive any dose of study therapy 
(ie, any component therapy in the combination for each analysis 
cohort). This is the primary dataset for the analyses of study 
conduct, study population, efficacy, exposure, safety, and outcome 
research.
Response evaluable
All treated participants who have measurable disease at baseline 
as assessed by investigator per PCWG3
HRD+ 
and 
Response 
evaluable
All response-evaluable participants who had HRD+ status at 
baseline
HRD-/Not evaluable and 
Response evaluable
All response evaluable participants who had HRD- status or not 
evaluable status at baseline
Pharmacokinetic
All treated participants with available serum concentration vs time
data for nivolumab
All treated participants with available plasma concentration vs 
time data for rucaparib 
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Population
Description
All treated participants with available plasma concentration vs 
time data for enzalutamide
10.3
Statistical Analyses
The statistical analysis plan 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.
A description of the participant population will be included in the statistical output reported, 
including subgroups of age, gender, and race.
10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Co-Primary
•
ORR-PCWG3
•
Estimate of ORR-PCWG3 and corresponding 2-
sided exact 95% CI using the Clopper-Pearson 
method by the HRD status and analysis cohort for all 
response evaluable participants.
•
RR-PSA
•
RR-PSA will be analyzed by the HRD status and 
analysis cohort for all treated participants in the 
same way as for ORR-PCWG3.
Secondary
•
rPFS
•
TTR and DOR per PCWG3
•
TTP-PSA
•
OS
Time to event distribution (rPFS, DOR-PCWG3 for 
responders, TTR-PCWG3 for responders, TTP-PSA, 
OS) will be estimated by the HRD status and analysis 
cohort for treated participants using Kaplan Meier 
techniques. This will be performed for PFS(s), OS and 
DOR. Median survival time along with 95% CI will be 
constructed by analysis cohort based on a log-log 
transformed CI for the survivor function. Rates at fixed 
time points will be derived from the Kaplan Meier 
estimate and corresponding CI will be derived by 
analysis cohort based on Greenwood formula for 
variance derivation and on log-log transformation 
applied on the survivor function.
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Endpoint
Statistical Analysis Methods
10.3.2
Safety Analyses
Endpoint
Statistical Analysis Methods
Incidence of AEs, SAEs, 
AEs leading to 
discontinuation, deaths AEs 
will be graded according to
CTCAE Version 4.03
Frequency distribution of treated participants with AE using the 
worst
common terminology criteria grade on treatment. 
Participants will be counted once at the preferred term (PT) level, 
once at the system organ class (SOC) level, and once in the 
“Total participant” row at their worst common terminology 
criteria grade, regardless of SOC or PT.
Laboratory abnormalities
Laboratory values will be 
graded according to 
CTCAE Version 4.03
Laboratory shift table using worst common terminology criteria 
grade on treatment per participant.
10.3.3
Other Analyses 
Pharmacokinetic Analyses
The nivolumab concentration versus time data obtained in this study will be combined with data 
from other studies in the clinical development program to develop a PPK model. This model will 
be used to evaluate the effects of intrinsic and extrinsic covariates on the PK of nivolumab to 
determine measures of individual exposure (such as steady state peak, trough and time-averaged 
concentration). Pharmacokinetic drug-drug interaction between nivolumab and other component 
drugs will be studied by a PPK approach. Model-determined exposures will be used for exposure-
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response analyses of selected efficacy and safety endpoints if the data permit. The PPK analysis 
will be presented separately from the main clinical study report. 
The trough plasma concentrations of rucaparib and enzalutamide versus time data will be analyzed, 
including summary statistics and plotting. Post hoc estimates of PK parameters and exposures will 
be estimated for each participant using the existing or updated PPK model. The estimated 
exposures will be used for exposure-response analyses of selected efficacy and safety endpoints if 
the data permit. The PPK analysis may be presented separately from the main clinical study report.
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10.3.4
Interim Analyses
An interim analysis will be performed in each arm when at least 50% of planned participants have 
been treated, with at least 16 weeks of follow-up after first dose. The purpose of the interim 
analysis is to generate preliminary data that will inform decisions related to external studies, as 
well as determine if any of the study arms should be expanded to generate additional data that may 
support a regulatory filing. If the data from the initial interim analysis appear to be immature to 
support decision-making on the expansion of a specific study arm, a second interim analysis of 
that arm may be performed after enrollment has been completed and all treated patients have been 
followed for at least 16 weeks after first dose.
After the interim analysis, an expansion for each arm may be triggered based on review of the 
totality of available data by a small unblinded BMS team outside of the CA2099KD team (see 
Section 7.3) if a clinically meaningful response compared to the historical standard of care [SOC] 
for the population in that arm or subgroup is observed.. Table 10.3.4-1 provides some examples of 
potential response rates observed at the interim analysis and the precision for potential sample 
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sizes to be expanded to for each arm or HRD subgroup, if applicable, based on the historical ORR 
for SOC in that arm or HRD subgroup. (See Rationale for Interim Analysis in Section 5.4.9 for 
more details regarding the historical ORR assumptions for each arm/subgroup.) For example, if an 
interim ORR of 43% is observed for HRD+ participants in Arm A1 (15% improvement over the 
historical ORR for SOC in this subgroup), the sample size of HRD+ in Arm A1 could be expanded 
up to ~ 46 participants measurable disease. Summaries and listings of efficacy and safety for 
treated participants with at least 16 weeks of follow-up and by HRD status will be shared with the 
DMC after the interim analysis in each arm. In any arm or subgroup that is expanded, interim 
analyses in the additional participants treated in the expansion with at least 16 weeks of follow-up 
after first dose may be performed if needed to determine if the data may be sufficient to support a 
regulatory filing.
Table 10.3.4-1:
Exact 95% CI for Potential Observed ORR and Potential Sample 
Size
Arm/subgroup
SOC 
Historical 
ORR 
Observed ORR
N (meas 
disease)
Lower Limit 
(%)
Upper Limit 
(%)
A1 or A2 HRD+
28%
43%
46
28.9
58.9
48%
29
29.4
67.5
A1 HRD-
14%
29%
34
15.1
47.5
34%
20
15.4
59.2
A2 HRD-
21%
36%
41
22.1
53.1
41%
24
22.1
63.3
B or C All-Comers
21%
36%
41
22.1
53.1
41%
24
22.1
63.3
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11
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19 Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with 
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30 Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus 
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55 Arlen PM, Mohebtash M, Madan RA, et al. Promising novel immunotherapies and 
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69 Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate 
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84 Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in Men with Chemotherapy-naïve 
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98 Aggarwal R, Halabi S, Kelly WK et al. The effect of prior androgen synthesis inhibition on 
outcomes of subsequent therapy with docetaxel in subjects with metastatic castrate-resistant 
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99 de Bono JS, Smith MR, Saad F, et al. Subsequent Chemotherapy and Treatment Patterns After 
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101 De Bono JS, Chowdhury S, Feyerabend S, et al. Efficacy and safety of enzalutamide (ENZA) 
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110 Armstrong AJ, Garrett-Mayer ES, Yang YC, et al. A contemporary prognostic nomogram for 
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122 Anwar M, Aslam HM, Anwar S. PARP inhibitors. Hered Cancer Clin Pract. 2015; 13:4.
 
 
 
 
 
 
 
128 Fleiss JL, Levin B, Paik MC. Statistical Methods for Rates and Proportions, Second Edition.
John Wiley & Sons (1981).
 
 
 
 
 
 
 
 
 
 
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
ACTH
adrenocorticotropic hormone
ADT
androgen deprivation therapy
AE
adverse event
AIDS
Acquired Immunodeficiency Syndrome
AJCC
American Joint Committee on Cancer
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
Acute myeloid leukemia
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BICR
Blinded Independent Central Review
BID, bid
bis in die, twice daily
BMS
Bristol-Myers Squibb
BOR
best overall response
BPI-SF
Brief Pain Inventory - Short Form
BP
blood pressure
BRCA
breast cancer susceptibility gene
BUN
blood urea nitrogen
Ca++
calcium
Cavgss
average concentration at steady state
CBC
complete blood count
cHL
Classical Hodgkin Lymphoma
CI
confidence interval
C1-
chloride
Cmaxss
maximum observed concentration at steady state
Cminss
minimum observed concentration at steady state
CNS
Central Nervous System
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Term
Definition
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form, paper or electronic
CRPC
castration-resistant prostate cancer
crPFS
clinical/radiographic progression-free survival
CT
Computed tomography
CTAg
clinical trial agreement
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome p-450
DDI
drug-drug interaction
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose
FU
Follow-up
GnHR
gonadotropin releasing hormone
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HBVsAG
Hepatitis b virus surface antigen
HCV
hepatitis C virus
Hep B/C
Hepatitis B or Hepatitis C
HIV
Human Immunodeficiency Virus
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Term
Definition
HR
homologous recombination
HRD
Homologous Recombination Deficiency
HSPC
hormone-sensitive prostate cancer
IB
Investigator Brochure
ICF
Informed Consent Form
IEC
Independent Ethics Committee
IMAE
immune-mediated adverse event
IMP
investigational medicinal products
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
K+
potassium
LDH
lactate dehydrogenase
LFT
liver function test
LHRH
luteinizing hormone releasing hormone
mCRPC
metastatic castration-resistant prostate cancer
MDS
myelodysplastic syndrome
MHC
major histocompatibility complex
MRI
Magnetic Resonance Imaging
MTD
maximum tolerated dose
Na+
sodium
N/A
not applicable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
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Term
Definition
ORR
objective response rate
OS
overall survival
PAP
Prostatic acid phosphatase
PARP
Poly (ADP-ribose) polymerase 
PAPRi
PARP inhibitor
PCWG3
Prostate Cancer Clinical Trials Working Group 3
PD
progressive disease
PD-L1
programmed death ligand no. 1
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PO
By mouth
PPK
population pharmacokinetics
PSA
prostate-specific antigen
PSMA
prostate-specific membrane antigen
PT
Preferred Term
QXW
every x weeks
QD, qd
quaque die, once daily
QoL
quality of life
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
rPFS
radiographic progression-free survival
RR
respiration rate
RR-PSA
PSA response rate
SAE
serious adverse event
SmPC
Summary of Product Characteristics
SNP
single nucleotide polymorphism
SOC
Standard of Care
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Term
Definition
SSBD/DSB
Single/double strand breaks
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAA
tumor-associated antigen
T. Bili
total bilirubin
TCR
T cell receptor
TIL
tumor infiltrating lymphocytes
Treg
regulatory T-cells
TSH
thyroid stimulating hormone
TTR
time to response
ULN
upper limit of normal
USP
United States Pharmacopoeia
USPI
United States Prescribing Information
WOCBP
women of childbearing potential
WNOCBP
women not of childbearing potential
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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 (e.g., 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. 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. 
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.
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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 to 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. 
Sponsor or designee will provide the investigator with an appropriate (i.e., 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.
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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 
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), 
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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 nivolumab, rucaparib, docetaxel, and enzalutamide (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 (e.g., lost, wasted) 
•
amount destroyed at study site, if 
applicable
•
amount returned to BMS
•
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 drug 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. 
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. 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. On site 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 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents.
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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 (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., 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 (e.g., 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, i.e., 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
•
National Coordinating Investigator 
•
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)
•
Other criteria (as determined by the study team)
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 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
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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).
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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.
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 (e.g., 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
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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
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 9.2.7 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 9.2.5 for reporting pregnancies).
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.
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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.
REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study drug, 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 FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment.*
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation/or implantation (These methods of contraception cannot be used by 
WOCBP participants in studies where hormonal contraception is prohibited b 
−
oral (birth control pills)
−
intravaginal (vaginal birth control suppositories, rings, creams, gels)
−
transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
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Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited) b
•
Intrauterine hormone-releasing system (IUS )(This method of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is prohibited)c
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception*
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
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Unacceptable Methods of Contraception*
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
* Local laws and regulations may require use of alternative and/or additional contraception 
methods.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment 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 7 months after the end of study treatment.
•
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 7 months after the end of 
treatment 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 7 months after the end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 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
PCWG3 GUIDELINES (WITH MODIFIED RECIST V1.1 CRITERIA 
FOR SOFT TISSUE LESION ASSESSMENT)
Participants with metastatic castration-resistant prostate cancer may have only soft tissue lesions, 
only bone lesions, or both soft tissue lesions and bone lesions. PCWG3 guidelines use modified 
RECIST 1.1 criteria for evaluation of soft tissue lesions, including lymph nodes, but have special 
rules for evaluation of metastatic bone lesions.1 Each section below will specify the guidelines for 
assessment of soft tissue lesions and bone lesions separately.
1
EVALUATION OF BASELINE LESIONS
1.1
Soft Tissue Lesions
At baseline, soft tissue lesions, including lymph nodes, should be evaluated by CT or MRI and
will be categorized as measurable or non-measurable as follows. 
1.1.1
Measurable
Measurable disease is defined by presence of at least one measurable tumor lesion. Measurable 
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 5mm.
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.
1.1.2
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 
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non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
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.
Tumor lesions situated in a previously irradiated area are usually not considered measurable unless 
there has been demonstrated progression in the lesion.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.1.3
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Soft Tissue 
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 target lesions can be selected per organ system. For example, a maximum 
of 5 lung lesions can be selected. A maximum of 5 lymph node lesions 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 of 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 of diameters will be used as reference to further characterize any objective tumor regression 
in the measurable dimension of the disease.
All other soft tissue 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. 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’).
1.2
Bone Lesions
Bone lesions should only be evaluated with Technecium-99m based radionuclide bone scan as per 
PCWG3. The number of bone lesions identified on the baseline radionuclide bone scan, as well as 
the anatomic location of each bone lesion, should be noted. In this study, bone lesions should be 
reported and followed separately from soft tissue non-target lesions.
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2
POST-BASELINE DISEASE ASSESSMENT
Participants with any soft tissue lesions at baseline that can be followed as target and/or non-target 
lesions on CT or MRI scans should be evaluated per the rules described Section 2.1. Participants 
with only bone lesions at baseline should be evaluated per the rules described in Section 2.1.2.
2.1
Post-Baseline Evaluation in Participants with Baseline Soft Tissue 
Lesions
2.1.1
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.
•
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 PD as defined above. 
2.1.1.1
Special Notes on the Assessment of Target Lesions
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.
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 
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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.
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’.
2.1.2
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.
2.1.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
When the participant 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.
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When the participant 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 participants 
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% 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 participant 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.
2.1.3
New Lesions
2.1.3.1
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 posttreatment 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 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.
2.1.3.2
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 participant’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 PD. A lesion identified on a 
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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 participant who has visceral 
disease at baseline and while on study has a CT or MRI brain ordered which reveals metastases. 
The participant’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 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. Response Assessment.
2.1.3.3
Participants with New Bone Lesions and New Soft Tissue Lesions
Participants may develop new bone lesions (identified on radionuclide bone scans) at a different 
time point than new soft tissue lesions (identified on CT or MRI). If progression is based solely 
on the identification of new lesions and new bone lesions and new soft tissue lesions are identified 
at different time points, then the time point at which any new lesion (bone or soft tissue) was first 
identified should be the date of progression (taking into account the need for subsequent 
confirmatory bone scan for new bone lesions, as mentioned above).
2.1.4
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.1.4-1 provides a 
summary of the overall response status calculation at each time point for participants who have 
measurable disease at baseline. When participants have non-measurable (therefore non-target) soft 
tissue disease only, Table 2.1.4-2 is to be used. 
Table 2.1.4-1:
Time Point Response: Participants With Target (± 
Non-Target) Disease
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
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Table 2.1.4-2:
Time Point Response: Participants with 
Non-target Soft Tissue Disease Only
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
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.
2.1.5
Best Overall Response 
The best overall response (BOR) 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 
participant’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.
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 2.1.5-1. In this study, a BOR of SD can only be made if a tumor assessment meeting SD 
criteria was performed at least 49 days after the date of first treatment.
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 participants with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.1.5-1:
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
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Table 2.1.5-1:
Best Overall Response (Confirmation of CR&PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BEST Overall Response
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
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 participant 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.
2.1.6
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: New bone lesions identified on radionuclide bone scan must be 
confirmed, as specified in Section 2.1.5. Progression of disease should also be verified in cases 
where progression is suspected based solely on an equivocal new lesion. If repeat scans confirm 
that the new lesion is an unequivocal tumor lesion, 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 PD.
2.2
Post-Baseline Evaluation in Participants with Baseline Bone-Only 
Disease 
Complete or partial response in bone lesions cannot be accurately assessed on radionuclide bone 
scan. Progression in participants who only have bone lesions at baseline is based only on the 
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identification of new lesions (either bone or soft tissue) that meet the criteria specified in 
Section 2.1.3. Therefore, participants who have bone-only disease at baseline should have an 
overall response of stable disease for any time point that does not document new lesions according 
to the criteria specified in Section 2.1.3. If new lesions meeting the criteria specified in 
Section 2.1.3 are identified at any time point (with a subsequent confirmatory bone scan for new 
bone lesions), then the overall response for that time point is progression. The first time point 
documenting new lesions should be the date of progression in participants with bone-only disease 
at baseline.
1
Scher HL, 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;34:1402-18.
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APPENDIX 6
MANAGEMENT ALGORITHMS 
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 
therapeutic 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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165
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Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Revised Protocol No.: 04
Date: 08-Aug-2019
166
Approved
5.0
v
Approved
2.0
v


Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Revised Protocol No.: 04
Date: 08-Aug-2019
167
Approved
5.0
v
Approved
2.0
v


Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Revised Protocol No.: 04
Date: 08-Aug-2019
168
Approved
5.0
v
Approved
2.0
v


Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Revised Protocol No.: 04
Date: 08-Aug-2019
169
Approved
5.0
v
Approved
2.0
v


Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Revised Protocol No.: 04
Date: 08-Aug-2019
170
Approved
5.0
v
Approved
2.0
v


Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Revised Protocol No.: 04
Date: 08-Aug-2019
171
Approved
5.0
v
Approved
2.0
v


Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Revised Protocol No.: 04
Date: 08-Aug-2019
172
Approved
5.0
v
Approved
2.0
v


Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Revised Protocol No.: 04
Date: 08-Aug-2019
173
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Clinical Protocol
CA2099KD
BMS-936558
nivolumab
APPENDIX 7
PERFORMANCE STATUS SCALES - ECOG
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., 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
Source: Oken MM, Creech RH, Tomey 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.
Revised Protocol No.: 04
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CA2099KD
BMS-936558
nivolumab
APPENDIX 8
COUNTRY SPECIFIC REQUIREMENTS
Argentina, Czech Republic, France, Germany, Italy, Peru, Spain, and Any Other Countries 
Where Exclusion of HIV Positive Participants Is Locally Mandated
Country-specific language
Section 2 Schedule of Activities, 
Table 2-1: 
Screening Procedural Outline -
Laboratory Tests
Add “HIV” to the list of laboratory tests
Section 6.2 Exclusion
Criteria, Exclusion criterion 2h
“Known history of testing positive for human immunodeficiency
virus (HIV) or known acquired immunodeficiency syndrome
(AIDS)”to be replaced with “Positive test for HIV”.
Section 9.4 SafetyAssessments
(baseline laboratory
assessments)
Add “HIV” test to Baseline local laboratory assessments to be
done within 14 days prior to first dose.
Revised Protocol No.: 04
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CA2099KD
BMS-936558
nivolumab
APPENDIX 9
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 03, 31-Jan-2019
This Global Revised Protocol 03 introduces an interim analysis in each arm when at least 50% of 
planned participants have been treated with at least 16 weeks of follow-up from first dose. The 
purpose of the interim analysis is to generate preliminary data that will inform internal decision-
making related to external studies being planned or conducted by the Sponsor, as well as to 
determine if any of the arms should be expanded to generate additional data that may support 
regulatory filing. In addition, this revised protocol clarifies the timing of the final analysis for each 
arm, incorporates changes from administrative letters, incorporates updated nivolumab clinical 
program protocol standards, and makes minor clarifications for consistency throughout the 
protocol document.
This Revised Protocol 03 applies in all countries, at all sites, to all future participants enrolled in 
the study and, where applicable, to all participants currently enrolled in the study.
Summary of key changes of Revised Protocol 03
Section Number 
& Title
Description of Change
Brief Rationale
Synopsis, Section 5.2 
Number of 
Participants
Arm A divided into Arms A1 and A2
To clarify each sub arm 
enrollment/assignment goal within 
Arm A
Section 5.1 
Overall Design
Updated percentage of available spots 
designated for participants who are HRD 
positive, HRD negative, or HRD not evaluable
To clarify the overall percentage of 
treated participants by HRD status
Section 5.4.6 
Rationale for 
Duration of 
Treatment
Updated language describing optimal duration 
of immunotherapy with nivolumab
To meet current standards
Section 5.4.9 
Rationale for Interim 
Analysis
Added rationale for interim analysis
To clarify the inclusion of interim 
analysis to generate preliminary 
data that will inform internal 
decision-making related to external 
studies and for potential cohort 
expansion to generate additional 
data that may support a regulatory 
filing
Section 5.5.1.1 
Dose Justification for 
Nivolumab 480 mg 
IV Q4W
Updated language justifying nivolumab dosage 
of 480 mg IV Q4W
To meet current standards
Revised Protocol No.: 04
Date: 08-Aug-2019
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CA2099KD
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 03
Section Number 
& Title
Description of Change
Brief Rationale
Section 6.2 
Exclusion Criteria
Added language defining superscan
To clarify exclusion criterion for 
participants who have undergone a 
superscan on Technecium-99m
radionuclide bone scans
Section 7.1 
Treatments 
Administered
Updated language specifying ± 3 day dosing 
window and a recommendation against 
premedications for the first dose of nivolumab
To meet current standards
Section 7.3
Blinding
Included text describing unblinding of a small 
BMS team outside the CA2099KD study team 
to interim analyses by HRD status
To clarify that the CA2099KD 
study team will remain blinded to 
central HRD status of participants 
in order to maintain study integrity
Section 7.4.3 
Docetaxel
Added text providing instructions regarding 
changes in or stoppage of prednisone or 
prednisolone
To clarify the use of prednisone 
and prednisolone in Arm B
Section 7.7.1 
Prohibited and/or 
Restricted 
Treatments
Revised text regarding prohibition of 
immunosuppressive agents and 
immunosuppressive doses of systemic 
corticosteroids during treatment with nivolumab
Updated text regarding use of live / attenuated 
vaccines
To clarify the use of systemic 
corticosteroids is prohibited during 
treatment with nivolumab
To meet current standards
Section 8.1.1 
Nivolumab Dose 
Discontinuation
Added Grade 3 myocarditis to list of events 
necessitating discontinuation from nivolumab
To meet current standards
Section 8.1.6
Post Study Treatment 
Follow-up
Updated post-study follow-up text
To meet current standards
Section 9.2.2
Method of Detecting 
AEs and SAEs
Updated collection period for nonserious AEs to 
specify a minimum of 100 days following 
discontinuation of study treatment
To meet current standards
Section 10.1
Sample Size 
Determination
Modified text regarding the final analysis of the 
co-primary endpoints of ORR and RR-PSA
To clarify that the final analysis 
may be performed independently 
from other cohorts/arms if 
enrollment is completed at different 
times across the cohorts/arms
Revised Protocol No.: 04
Date: 08-Aug-2019
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CA2099KD
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 03
Section Number 
& Title
Description of Change
Brief Rationale
Section 10.3.4
Interim Analyses
Added section detailing performance of an 
interim statistical analysis when at least 50% of 
planned participants have been treated with at 
least 16 weeks of follow-up after first dose
To generate preliminary data that 
will inform decisions related to 
external studies, as well as 
determine if any of the study arms 
should be expanded to generate 
additional data that may support a 
regulatory filing
Appendix 6, IO 
Management
Updated treatment algorithms 
Hepatic AE, Grade 3-4, an asterisk was removed 
from “Discontinue I-0 therapy” 
To meet current standards
Corrected typographical error
Various
Updated NCI CTCAE v 4.03 to .5.0
To meet current standards
ALL
Minor edits made throughout document to align 
sections for consistency
Minor, therefore have not been 
summarized
Overall Rationale for the Revised Protocol 02, 10-Sep-2018
This Global Revised Protocol 02 clarifies content in the Schedule of Activities, including updates 
for PSA 
 testing and plasma testing, clarifies requirements for inclusion and exclusion 
criteria, increases patient number in Arm A,  provides further guidance for tumor sample collection 
in case of bone only disease,clarifies method of treatment assignment,incorporates language to 
define disease progression by PSA, incorporates updated nivolumab clinical program protocol 
standards, and makes minor clarifications for consistency throughout document.
This Revised Protocol 02 applies in all countries, at all sites, to all future participants enrolled in 
the study, and where applicable, to all participants currently enrolled in the study.
Revised Protocol No.: 04
Date: 08-Aug-2019
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CA2099KD
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number 
& Title
Description of Change
Brief Rationale
Synopsis, Key 
Inclusion Criteria
Section 6.1, Inclusion 
Criteria
Central blood plasma added.
Local HRD test results wording added
Clarification about radiographic progression 
added
Wording for previous treatment has been added 
to Arm A1 : Up to 2 second generation 
hormonal manipulations for castration resistant 
disease are allowed.
Arm A2: at least 1 , not more than 2. 
Apalutamide added
Arm B : added Apalutamide 
Added wording about superscans not allowed
Please see sections below 
Section 2 Schedule of 
Activities
1) Central blood plasma testing added
2) Local HRD results wording added
3) Clarification of PSA testing after 
discontinuation added
1) Central blood plasma testing 
added to facilitate patient inclusion 
The addition of prospective plasma 
HRD testing will increase the 
chances of identifying the HRD 
status in a higher number of 
patients than using tumor samples 
only.
2) Inclusion of patients based on 
local HRD status will shorten their 
screening time as they will not be 
required to wait for central HRD 
results.
3) Clarification PSA testing added 
to align with co- primary end point 
analysis and PCWG3 definition. 
Section 4 -
Objectives and end 
points. 
Table 4-1  Co-
primary, Secondary 
PSA response wording clarified
TTP- PSA wording added
Clarification PSA testing added 
to align with co- primary end 
point analysis and PCWG3 
definition.
Study design 5.1
Figure 5.1-1 
Section 5.2 Number 
of participants  
Updates patient number 
Apalutamide in Arm A2 . Arm B and Arm C 
added.
Clarification about HRD  + ve definition added
Clarification about screening added
To clarify previous treatment 
allowed as Apalutamide is being 
used more widely in prostate cancer 
patients following positive results 
of SPARTAN study
Section 5.4.3 
Rationale for sample 
size
Rationale for Increasing the number of HRD 
negative/not evaluable participants in Arm A
As described in section 5.4.3, the 
sample size was revised to extend 
the potential clinical benefit of 
PARPi combinations to additional 
HRD negative/not evaluable 
mCRPC patients, following 
Revised Protocol No.: 04
Date: 08-Aug-2019
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CA2099KD
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number 
& Title
Description of Change
Brief Rationale
recently reported benefit of PARPi 
combinations regardless of HRD 
status. 
Section 6.1 Inclusion 
criteria
1) Inclusion criteria 2b updated , M1 metastatic 
wording updated
2) Inclusion criteria 2d) ii) updated to include 
clarification about ( N1) measuring at least 2 cm 
in short axis
3) Inclusion criteria 2f)i)(2) wording to include 
at least 1 but not more than 2 second-generation 
hormonal manipulations and apalutamide
Inclusion criteria 2f)ii) Arm B to include 
apalutamide
Inclusion criteria 2f)iii) Arm C to include 
apalutamide
4) Inclusion criteria 2j) to include plasma 
and/fresh or archival tumor tissue. To clarify 
that central laboratory must confirm receipt of 
plasma and tumor samples prior to IRT 
treatment arm assignment 
1) “M1 metastatic” wording 
contradicted with inclusion 
criterion 2d) ii) and was therefore 
replaced by “Stage IV”, so both 
criteria are now aligned to allow 
patients with pelvic lymph nodes
metastases in the study. 
2) To ensure adequate disease 
volume to evaluate co-primary 
ORR endpoint.
3) To clarify previous treatment 
allowed as Apalutamide is being 
used more widely in prostate cancer 
patients following positive results 
of SPARTAN study
4) To mandate plasma HRD testing 
and clarify process for accepting 
local HRD results.
Section 6.2 Exclusion 
criteria
Exclusion criteria 1k) has been added  to 
prohibited patients with superscan or 
technecium-99mm radionuclide bone scans 
participation
Exclusion criteria 2g) ii)  has been added to 
exclude patients with  Prior treatment with 
enzalutamide,  apalutamide, or other novel 
androgen receptor inhibitor to be eligible for 
Arm C
To exclude patients with 
superscans since they are not 
evaluable for response and 
progression endpoints. 
To clarify criteria of entry for Arm 
C
Section 7.1 
Treatment 
Administered.
Table 7-1 Study 
treatments for 
CA2099KD
1)
Footnote table 7.1,. b) wording has been 
updated to include clarification about 
Prednisone and Dexamethasone required as 
premedication to Docetaxel infusion. 
Wording allowing other corticosteroids has 
been added. 
2)
Added languages regarding Rucaparib 
doses window for Arm A
3)
Added language to allow IV dexamethasone 
and other corticosteroids for Arm B
Added language regarding Enzalutamide 
window for Arm C
1)
To clarify use of prednisone 
and dexamethasone and 
allowing other corticosteroids 
as per local standards. 
2)
To Clarify Rucaparib doses 
window.
3)
Ref To clarify use of 
corticosteroids in Arm B
To clarify Enzalutamide window
Section 7.1.1 Dose 
delay criteria
7.1.1.2 and 7.1.2.2 
Rucaparib
Delete wording about alkaline phosphatase 
< 3 xULN
To avoid unnecessary dose delays, 
as alkaline phosphatase is often 
elevated in prostate cancer and 
cannot be used reliably as a 
measure of hepatic function.
Revised Protocol No.: 04
Date: 08-Aug-2019
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Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number 
& Title
Description of Change
Brief Rationale
Section 7.2 Method 
of treatment 
assignment
Added wording to allow HRD plasma testing, 
previous local HRD test results, and 
retrospective plasma HRD testing. 
Refer to previous rationale 
regarding HRD
Section 7.3 Blinding
Added language regarding HRD results release 
and masking local HRD test results to BMS 
study team
To clarify HRD test results blinding 
and masking.
Section 7.1.2.2 
palliative Local 
Therapy
Added clarification regarding holding Rucaparib 
treatment prior to initiation of radiation therapy 
and until patient has recovered from radioation-
related toxicities
To ensure radiotherapy and 
rucaparib are administered safely in 
ARM A patients. 
Section 9.1.1 
Imaging assessment 
for the study 
Section 9.1.2 Disease 
response evaluation
Added wording regarding disease progression 
by PSA (PSA progression0
Please refer to rationale above
Section 10 Statistical 
Consideration
Table 10.1-1 and 
Table 10.1-3
Update participant number and power 
The sample size was revised to 
extend the potential clinical benefit 
of PARPi combinations to 
additional HRD negative/not 
evaluable mCRPC patients, 
following recently reported benefit 
of PARPi combinations regardless 
of HRD status.
Reference 
Updated to include new references 
To include new references 
Overall Rationale for the Revised Protocol 01, 22-Mar-2018
This Global Revised Protocol 01 clarifies content in the Schedule of Activities, including updates 
for PSA 
 testing 
, clarifies requirements for inclusion 
and exclusion criteria, provides further guidance for Docetaxel discontinuation criteria, adds 
language to Prohibited and/or Restricted Treatments section for Arm C, adds enzalutamide 
background information, provides additional guidance for PK sampling including addition of an 
enzalutamide PK sample collection, incorporates updated nivolumab clinical program protocol 
standards, updates Study Director information and makes minor clarifications for consistency 
throughout document.
This Revised Protocol 01 applies in all countries, at all sites, to all future participants enrolled in 
the study, and where applicable, to all participants currently enrolled in the study.
Revised Protocol No.: 04
Date: 08-Aug-2019
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Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Title Page
Added new Study Director contact 
information
Study Director has been added to 
study.
Synopsis, Key Inclusion 
Criteria
Section 6.1, Inclusion 
Criteria
Further guidance provided for histologic 
confirmation of adenocarcinoma of the 
prostate
Details added for participants who have not 
had an orchiectomy
Clarifications and further guidance added 
regarding documented prostate cancer 
progression
Language (“for mCRPC”) added for 
chemotherapy-naive participants 
Language “for Arm A2 and Arm C” added 
to clarify requirement for participants who 
are asymptomatic or minimally 
symptomatic according to Brief Pain 
Inventory - Short Form (BPI-SF)
Language added to provide further 
detail. 
Language revised to clarify that 
radiographic progression is required 
for inclusion, since PSA progression 
alone does not meet criteria 
requirement.
Language added to define participant 
population for Arm A, B and C as 
chemotherapy-naive in the context of 
castration resistant disease.
Language updated to clarify that 
asymptomatic or minimally 
symptomatic mCRPC participants 
will not be enrolled into Treatment 
Arm B
Section 2 Schedule of 
Activities 
The header language designating cycles was 
updated to remove reference to “C24” and 
instead refer to “subsequent cycles”.
PSA laboratory tests designated as “Local”
“C24” reference was misleading 
since Nivolumab program standards 
specify a maximum treatment period 
of 24 months from first dose.
PSA testing is to be performed 
locally, not centrally.
Revised Protocol No.: 04
Date: 08-Aug-2019
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Clinical Protocol
CA2099KD
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Section 5.4.4 Rationale 
for Evaluating 
Asymptomatic or 
Minimally Symptomatic 
Metastatic CPRC 
Participants
Language “for Arm A2 and Arm C” added 
to clarify requirement for participants who 
are asymptomatic or minimally 
symptomatic according to Brief Pain 
Inventory - Short Form (BPI-SF)
Language updated to clarify that 
asymptomatic or minimally 
symptomatic mCRPC participants 
will not be enrolled into Treatment 
Arm B
Section 6.2 Exclusion 
Criteria
Section 7.7.1 Prohibited 
and/or Restricted 
Treatments
Language added as Exclusion criteria 2)i) 
prohibiting live/attenuated vaccine within 
30 days of first treatment and prohibiting 
live/attenuated vaccines during the study
Criteria added to satisfy health 
authority request.
Section 7.1.1.3 Docetaxel
Added language that Grade 3 docetaxel-
related enterocolitis requires discontinuation 
and provided additional guidance for rare 
cases.
Language incorporates 
recommendations issued by the 
INCA (National Cancer Institute of 
France)
Section 7.7.1 Prohibited 
and/or Restricted 
Treatments
For All Arms section, language was added 
regarding use of marijuana.
For Arm C  section, language was added 
regarding co-administration with warfarin 
and coumarin-like anticoagulants and co-
administration of Xtandi with an 
anticoagulant metabolised by CYP2C9 
(such as warfarin or acenocoumarol)
Clarifies marijuana as treatment for 
cancer or its symptoms, as permitted 
if obtained by medical prescription or 
without a medical prescription where 
has been legalized locally
Language added to align with 
prescription information per 
enzalutamide SmPC
Section 8.1.3 Docetaxel 
Discontinuation
Added language that Grade 3 docetaxel-
related enterocolitis requires discontinuation 
and provided additional guidance for rare 
cases.
Language incorporates 
recommendations issued by the 
INCA (National Cancer Institute of 
France)
Section 9.1.2 Disease 
Response Evaluation
Guidance added that participants who have 
initial PSA decline during treatment, must 
have confirmation with a second 
consecutive value 3 or more weeks later
Language added to clarify 
requirements when determining PSA 
progression
Section 9.5 
Pharmacokinetics
Added background information for 
Enzalutamide 
Language incorporates enzalutamide 
SmPC
Section 9.5.2 
Pharmacokinetics 
Assessments
Guidance added that all nivolumab PK 
samples after C1D1 should be collected 
from contralateral arm
Table 9.5.2-1 was updated to add PK blood 
sample for Enzalutamide
Language revised to prevent sample 
contamination at the collection site
Enzalutamide PK will be assesses in 
the study
Revised Protocol No.: 04
Date: 08-Aug-2019
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CA2099KD
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
All
Minor clarifications across sections for 
consistency 
Updates per nivolumab program 
standardized language, including rationale 
for maximum duration of nivolumab 
treatment of 2 years
Language updated for consistency 
throughout document
Language updated to align with 
nivolumab program standards.
Accumulating data suggest that 
treatment beyond 2 years is unlikely 
to confer additional clinically 
meaningful benefit, risk of 
progression after discontinuing 
treatment at 2 years is low and 
although immunotherapy is well 
tolerated, participants will be at risk 
for additional toxicity with longer 
term treatment.
Revised Protocol No.: 04
Date: 08-Aug-2019
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SAP_001.pdf: 
Official Title of Study: 
Phase 2 Study of Nivolumab in Combination with Either Rucaparib, Docetaxel, or Enzalutamide in Men 
with Castration-resistant Metastatic Prostate Cancer (CheckMate 9KD: CHECKpoint pathway and 
nivoluMAb clinical Trial Evaluation 9KD) 
 
 
NCT Number: NCT03338790 
Document Date (Date in which document was last revised): December 19, 2019 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A PHASE 2 STUDY OF NIVOLUMAB IN COMBINATION WITH EITHER RUCAPARIB,
DOCETAXEL, OR ENZALUTAMIDE IN MEN WITH CASTRATION-RESISTANT
METASTATIC PROSTATE CANCER
PROTOCOL CA2099KD
VERSION # 2.1
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Statistical Analysis Plan
CA2099KD
BMS-936558
nivolumab
2
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT....................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
LIST OF FIGURES ....................................................................................................................5
1
BACKGROUND AND RATIONALE......................................................................6
2
STUDY DESCRIPTION ..........................................................................................6
2.1
Study Design ............................................................................................................6
2.2
Treatment Assignment..............................................................................................8
2.3
Blinding and Unblinding...........................................................................................8
2.4
Protocol Amendments...............................................................................................9
2.5
Data Monitoring Committee ...................................................................................10
3
OBJECTIVES ........................................................................................................10
3.1
Primary...................................................................................................................10
3.2
Secondary...............................................................................................................10
4
ENDPOINTS..........................................................................................................11
4.1
Primary Efficacy Endpoints....................................................................................11
4.1.1
Objective Response Rate.........................................................................................11
4.1.2
PSA Response Rate.................................................................................................11
4.2
Secondary Efficacy Endpoints ................................................................................12
4.2.1
Radiographic Progression Free Survival ................................................................12
4.2.2
Time to Objective Response and Duration of Response...........................................12
4.2.3
Time to PSA Progression........................................................................................13
4.2.4
Overall Survival .....................................................................................................13
4.4
Safety Endpoints.....................................................................................................14
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Statistical Analysis Plan
CA2099KD
BMS-936558
nivolumab
3
4.5
Pharmacokinetics....................................................................................................14
5
SAMPLE SIZE AND POWER...............................................................................14
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................17
6.1
Study Periods..........................................................................................................17
6.1.1
Baseline (Pre-Treatment) Period ............................................................................17
6.1.2
On-Study (On-Treatment) Period............................................................................18
6.1.3
Follow-up (Post-Treatment) Period ........................................................................19
6.2
Treatment Regimens...............................................................................................19
6.3
Populations for Analyses ........................................................................................19
7
STATISTICAL ANALYSIS...................................................................................20
7.1
General Methods ....................................................................................................20
7.2
Study Conduct........................................................................................................20
7.2.1
Accrual...................................................................................................................20
7.2.2
Relevant Protocol Deviations..................................................................................21
7.3
Study Population ....................................................................................................22
7.3.1
Participant Disposition and Discontinuation of Study Therapy...............................22
7.3.2
Demography and Participant Characteristics.........................................................22
7.3.3
Medical History......................................................................................................24
7.3.4
Prior Therapy.........................................................................................................24
7.3.5
Baseline Examinations............................................................................................24
7.4
Extent of Exposure .................................................................................................24
7.4.1
Administration of Study Therapy.............................................................................24
7.4.2
Modifications of Study Therapy ..............................................................................26
7.4.2.1
Dose Delays ...........................................................................................................26
7.4.2.2
Infusion Interrupted and Rate Reduced...................................................................26
7.4.2.3
Dose Reduction.......................................................................................................26
7.4.3
Concomitant Medications.......................................................................................27
7.4.4
Treatment Beyond Disease Progression..................................................................27
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CA2099KD
BMS-936558
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4
7.4.5
Subsequent Cancer Therapy ...................................................................................27
7.5
Efficacy..................................................................................................................27
7.5.1
Objective Response Rate per PCWG3.....................................................................28
7.5.2
PSA Response Rate.................................................................................................28
7.5.3
Radiographic Progression-Free Survival................................................................28
7.5.4
Time to Objective Response and Duration of Response per PCWG3 .......................29
7.5.5
Time to PSA Progression........................................................................................29
7.5.6
Overall Survival .....................................................................................................29
7.6
Safety.....................................................................................................................30
7.6.1
Deaths ....................................................................................................................30
7.6.2
Serious Adverse Events...........................................................................................30
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................30
7.6.4
Adverse Events Leading to Dose Modification........................................................30
7.6.5
Adverse Events .......................................................................................................31
7.6.6
Select Adverse Events .............................................................................................31
7.6.7
Immune Modulating Medication .............................................................................31
7.6.8
Multiple Events.......................................................................................................31
7.6.10
Immune-Mediated Adverse Events ..........................................................................31
7.6.11
Laboratory Parameters...........................................................................................31
7.6.12
Vital Signs and Pulse Oximetry...............................................................................31
7.6.14
Adverse Events by Subgroup...................................................................................31
7.8
Pharmacokinetics....................................................................................................33
7.8.1
Pharmacokinetics of Nivolumab .............................................................................33
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7.8.2
Pharmacokinetics of Rucaparib/ Enzalutamide.......................................................33
7.10
Interim Analysis .....................................................................................................34
8
CONVENTIONS....................................................................................................36
8.1
Conventions for Partial or Missing Dates................................................................36
9
CONTENT OF REPORTS .....................................................................................37
10
REFERENCES.......................................................................................................38
LIST OF TABLES
Table 2.4-1:
Protocol Amendments ..............................................................................9
Table 5-1:
Sample Size by Arm/Analysis Cohort.....................................................15
Table 5-2:
Exact 95% CI for ORR and RR-PSA......................................................16
Table 5-3:
Power for ORR in Participants with Measurable Disease at 
Baseline..................................................................................................17
Table 7.4.1-1:
Study Therapy Parameters......................................................................25
Table 7.4.1-2:
Study Therapy Parameters (Rucaparib and Enzalutamide) ......................26
Table 7.10-1:
Exact 95% CI for Potential Observed ORR and Potential Sample 
Size ........................................................................................................35
LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic...........................................................................7
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1
BACKGROUND AND RATIONALE
CA2099KD is a Phase 2 study of nivolumab in combination with either rucaparib, docetaxel, or
enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC).
Prostate cancer is a leading cause of cancer mortality in men worldwide. Since 2010, six new
therapeutic agents with diverse mechanisms of action have been added to the therapeutic
armamentarium. 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
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; see details in Section 3.2 of protocol.
Research Hypothesis:
Nivolumab in combination with rucaparib, docetaxel, or enzalutamide can be given safely and will
demonstrate meaningful clinical activity in participants with mCRPC.
Schedule of Analyses:
The final analysis of the co-primary endpoints of objective response rate per the Prostate Cancer
Clinical Trials Working Group 3 (PCWG3) criteria and response rate of prostate-specific antigen
(PSA) will occur after all the participants have been followed up for approximately 12 months
since treatment initiation in a cohort.
In addition, the first safety interim will occur when approximately 15 participants in a cohort (A1,
A2, B or C) or approximately 50 participants combined from all four cohorts, whichever occurs
first, have been treated and evaluated for at least 8 weeks. Subsequent safety interim reviews will
be held approximately every 6 months after the first interim review until the final analysis.
An interim analysis with efficacy data will be performed in each arm when at least 50% of planned 
participants have been treated with first dose at least 16 weeks prior to the cutoff date for the interim 
analysis database lock. All treated subjects whose first dose date is at least 16 weeks before the cutoff 
date for the interim analysis database lock will be included in the interim analysis.
2
STUDY DESCRIPTION
2.1
Study Design
This is a Phase 2 study of nivolumab in  combination with either rucaparib, docetaxel, or
enzalutamide in men with mCRPC. The study design schematic is presented in Figure 2.1-1.
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Figure 2.1-1:
Study Design Schematic
Three arms, including 4 parallel cohorts, are as follows:
•
Arm A (nivolumab plus rucaparib):
o
Arm A1: Participants who have received at least one but no more than 2 prior taxane-based
regimens for castration-resistant disease. If docetaxel chemotherapy is used more than
once, this will be considered as one regimen.
o
Arm A2: Chemotherapy-naive participants who have received prior treatment with
abiraterone acetate and/or enzalutamide for castration-resistant disease up to 28 days prior
to study arm assignment and are not candidates for or refuse immediate chemotherapy
•
Arm B (nivolumab plus docetaxel): Chemotherapy-naive participants who are candidates to
receive docetaxel chemotherapy. Up to 2 second-generation hormonal manipulations (eg,
abiraterone acetate and/or enzalutamide) in the mCRPC setting are allowed up to 28 days prior
to study arm assignment.
•
Arm C (nivolumab plus enzalutamide): Chemotherapy-naive participants who have received
prior treatment with abiraterone acetate in the mCRPC setting up to 28 days prior to study arm
assignment without prior enzalutamide, and are not candidates for or refuse immediate
chemotherapy.
Enrollment in any of the study arms may be terminated early due to poor accrual.
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2.2
Treatment Assignment
All participants will be centrally assigned to a treatment arm using an Interactive Response
Technology (IRT) system. After obtaining informed consent from the participant, the investigator
or designee will register the participant for enrollment in IRT by following the enrollment
procedures established by BMS.
Once enrolled in IRT, enrolled participants who have met all eligibility
criteria, including
completion of homologous recombination deficiency(HRD) testing ofthe submitted tumor sample
by the central laboratory, will be ready for treatment arm assignment through the IRT. Based on
prior treatment history, presence or absence of measurable disease, eligibility for chemotherapy
and HRD status, IRT will assign the participant to a treatment arm that has available spots. If more
than one treatment arm has available spots, the investigator or designee will be able to choose the
treatment arm for the participant (for guidance, refer to Figure 5.1-2 of the protocol). If there are
no available spots in any of the treatment arms, the participant will be a screen failure. The BMS
study team will update sites when enrollment in a treatment arm is nearing completion.
The HRD status will be determined by central laboratory testing during screening. A participant is
considered HRD+ if they have a deleterious genomic alteration (protein truncating or splice site
mutation, homozygous deletion, large protein truncating rearrangement, or deleterious missense
mutation) in at least one of the following homologous recombination deficiency genes: BRCA1,
BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B,
RAD51C, RAD51D, or RAD54L.
2.3
Blinding and Unblinding
This is an open-label study. However, the specific treatment to be taken by a participant will be
assigned using an IRT, as specified in Section 7.2 of the protocol. Treatment arm assignments will
be released to the bioanalytical laboratory in order to minimize unnecessary analysis of samples.
The HRD status as determined by the central laboratory will be masked to investigator sites and
participants and can be unmasked at the time of radiographic progression or discontinuation of
study treatment of a participant, whichever occurs later, and at final analyses. In addition, only
those Sponsor personnel not directly involved in the assessment of safety in the study will review
HRD status up to discontinuation of study therapy or final analyses. During the Data Monitoring
Committee (DMC) review, the HRD status will be transferred to an independent data center to
perform analyses as needed.
In the event that a germline mutation is suspected based on the results from central analyses of
tumor tissue (or circulating tumor DNA [ctDNA]), these results will be provided to the treating
physician and the participant may be referred by the investigator for confirmation and genetic
counseling per institutional guidelines.
As specified in protocol Section 7.3, interim analyses by HRD status may be unblinded to a small 
BMS team outside the immediate CA2099KD study team to inform internal decision making on 
further clinical development in prostate cancer and determine if any arm in the study should be 
expanded to generate additional data that may support a regulatory filing.
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Members of the immediate study team (site-facing BMS team members) will remain blinded to 
the HRD status of individual study participants in order to maintain study integrity until the final 
analysis.
2.4
Protocol Amendments
This SAP incorporates the following amendment:
Table 2.4-1:
Protocol Amendments
Amendment
Date of Issue
Summary of Major Changes
Revised Protocol 01
(Incorporate Amendment 01)
22-Mar-2018
PSA testing is to be performed locally, not centrally;
Guidance added that participants who have initial
PSA decline during treatment, must have 
confirmation with a second consecutive value 3 or 
more weeks later;
Enzalutamide pharmacokinetics will be assessed in the 
study.
Revised Protocol 02
10-Sep-2018
Clarifies procedure requirement in the Schedule of 
Activities;
Clarifies requirements for inclusion and exclusion 
criteria;
Updates study design to increase the patient 
population;
Adds language to allow plasma HRD testing and 
previous local results;
Provides further guidance for Dexamethasone and 
corticosteroids use;
Clarifies language for Rucaparib dosing;
Clarifies language for Enzalutamide dosing;
Adds language to clarify disease progression by PSA;
Incorporates updated nivolumab clinical program 
protocol standards
Revised Protocol 03
31-Jan-2019
Introduces an interim analysis in each arm
when at least 50% of planned participants have been 
treated with first dose at least 16 weeks prior to the 
cutoff date for the interim analysis database lock;
Clarifies the timing of the final analysis for each arm, 
incorporates changes from administrative letters, 
Incorporates updated nivolumab clinical program 
protocol standards.
Revised Protocol 04
TBD
Changed NCI CTCAE v 5.0 back to v.4.03
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Table 2.4-1:
Protocol Amendments
Amendment
Date of Issue
Summary of Major Changes
Clarified that enrollment in any study arm may be 
terminated early due to poor accrual
Added a potential second IA after completion of 
enrollment and at least 16 weeks follow-up after first 
dose in each arm if first IA is immature, as well as IA 
in additional participants treated in any expanded arm 
or subgroup with at least 16 weeks of follow-up after 
first dose if needed to support regulatory interactions
Clarified that the immediate study team members will 
remain blinded to Homologous recombination 
deficiency (HRD) status of individual study 
participants
2.5
Data Monitoring Committee
An independent DMC will be instituted and meet regularly to ensure that participant safety is
carefully monitored. The DMC will convene additional ad hoc meetings if necessary. Following
each meeting, the DMC will recommend continuation, modification, or discontinuation of the
study based on observed toxicities and efficacy. A separate DMC charter will describe the
activities of this committee in more detail. 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.
3
OBJECTIVES
3.1
Primary
•
To evaluate the objective response rate per PCWG3 (ORR-PCWG3) in HRD+ participants and
in all treated participants.
•
To evaluate PSA response rate (RR-PSA) in HRD+ participants and in all treated participants.
3.2
Secondary
•
To evaluate radiographic progression-free survival (rPFS) in HRD+ participants and in all
treated participants.
•
To evaluate time to response (TTR) and duration of response (DOR) per PCWG3 (TTR-
PCWG3 and DOR-PCWG3) in HRD+ participants and in all treated participants
•
To estimate time to PSA progression (TTP-PSA) in HRD+ participants and in all treated
participants
•
To assess overall survival (OS) in HRD+ participants and in all treated participants
•
To evaluate overall safety and tolerability
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4
ENDPOINTS
4.1
Primary Efficacy Endpoints
4.1.1
Objective Response Rate
Objective response rate per PCWG3 (ORR-PCWG3) is the proportion of participants who have
confirmed complete or partial best overall response (BOR) per PCWG3 among treated participants
with measurable disease at baseline. The BOR is assessed per investigator per PCWG3 and is
recorded between treatment initiation and the date of objectively documented progression per
PCWG3 or the date of start of subsequent cancer therapies (as recorded in the Subsequent Cancer
Therapy Case Report Form [CRF] pages), whichever occurs first. For participants without
documented progression or subsequent cancer therapy, all available response assessments will
contribute to the BOR assessment. Tumor assessments are scheduled to be performed every 8 
weeks for 24 weeks following treatment initiation and thereafter every 12 weeks until documented
radiographic progression per PCWG3.
If BOR per the Blinded Independent Central Review (BICR) is available, ORR per BICR will be
defined in the same way as for ORR per the investigator.
4.1.2
PSA Response Rate
Response rate of PSA (RR-PSA) is defined as the proportion of subjects with 50% or greater 
decrease in PSA from baseline to the lowest post-baseline PSA result within each randomized arm, 
confirmed by a second value obtained 3 or more weeks later that occurs prior to PSA progression.
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4.2
Secondary Efficacy Endpoints
Secondary endpoints will be analyzed at the time of the co-primary endpoint analysis.
4.2.1
Radiographic Progression Free Survival
Radiographic progression-free survival (rPFS) is the time from treatment initiation to the first date
ofdocumented radiographic progressions per PCWG3 or death due to any cause, whichever occurs
first.
The following radiographic progressive diseases will be collected and documented as assessed by
the investigator. The date of progression for each type is defined in Table 9.1.2-1 of the protocol.
•
Soft tissue disease progression by RECIST v1.1 modified per PCWG3. Date of first
unequivocal progression of soft tissue lesion will be recorded in the Disease Progression CRF
page.
•
Bone disease progression per PCWG3. Date of bone progression will be recorded in the
Disease Progression CRF page.
The following censoring rules will be used to define rPFS endpoint for primary analysis.
•
Participants who did not progress or die will be censored on the date of their last evaluable
tumor and/or bone assessment.
•
Participants who did not have any post-treatment tumor and bone assessments and did not die
will be censored on the date of first treatment.
•
Participants who receive subsequent cancer therapy prior to progression or death will be
censored at date of last evaluable tumor or bone assessment up to start of any subsequent
systemic cancer therapy.
•
Participants without baseline tumor assessment for soft tissues or bone lesions and who are not
known to have died will be censored at the date of first treatment.
If rPFS per BICR is available, rPFS per BICR will be defined in the same way as for rPFS per the
investigator.
4.2.2
Time to Objective Response and Duration of Response
Time to objective response (TTR) per PCWG3 is the time from treatment initiation to the date of
the first documented CR or PR per PCWG3. 
Duration of response (DOR) per PCWG3 is the time from the date of first response (CR/PR per
PCWG3) to the date of first documented radiographic progression per PCWG3 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 cancer therapy.
If TTR/DOR per BICR are available, TTR/DOR per BICR will be defined in the same way as for
TTR/DOR per the investigator.
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4.2.3
Time to PSA Progression
Time to progression by PSA (TTP-PSA) is the time from treatment initiation to the date of first
confirmed progression in PSA per PCWG3 in treated participants. Date of disease progression by
PSA will be recorded in the Disease Progression CRF page.
PSA progression is defined as:
•
If there is a decline from baseline in PSA, a PSA progression is recorded at the time when the 
first PSA increase is ≥ 25% and ≥ 2 ng/mL above the nadir from start of therapy, which is 
confirmed by a second value 3 or more weeks later (i.e., a confirmed rising trend à PSA 
progression holds even if the confirmatory second value is lower than the first, providing both 
values show a 25% increase from the nadir – only values on or after week 12 are used when 
determining PSA progression);
•
If there is no decline from baseline in PSA, PSA progression is recorded at the time when a 
PSA increase is ≥ 25% and ≥ 2 ng/mL above the baseline after 12 weeks from start of therapy.
For participants who have no confirmed progression by PSA, the time will be censored at the date
of last PSA evaluation or at the date oftreatment initiation for participants with no PSA evaluation.
4.2.4
Overall Survival
Overall survival (OS) is the time from treatment initiation to the date of death from any cause. For
participants who are alive, their survival time will be censored at the last known alive date. OS
will be censored for participants at the date of first treatment if they had no follow up.
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4.4
Safety Endpoints
Safety and tolerability of nivolumab combined with rucaparib, docetaxel, or enzalutamide is one
of secondary study objectives. Overall safety and tolerability will be measured by the incidence of
adverse events, serious adverse events, adverse events leading to discontinuation, deaths, specific
laboratory abnormalities (worst grade) and changes from baseline. Toxicities will be graded using
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
version 4.03. See details in the Core Safety SAP1.
4.5
Pharmacokinetics
The nivolumab and rucaparib concentration versus time data obtained in this study will be
combined with data from other studies in the clinical development program to develop a population
pharmacokinetic model. This model will be used to evaluate the effects of intrinsic and extrinsic
covariates on the pharmacokinetics of nivolumab and rucaparib to determine measures of
individual exposure (such as steady state peak, trough and time-averaged concentration).
Pharmacokinetic drug-drug interaction between nivolumab and rucaparib will be studied by
population pharmacokinetic approach. Model determined exposures will be used for exposure
response analyses of selected efficacy and safety endpoints.
5
SAMPLE SIZE AND POWER
Approximately 330 participants with mCRPC will be enrolled and treated in 3 arms.
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Planned sample size is summarized in Table 5-1 by arm and cohort, which is further divided into
smaller subgroups by prior treatment, measurable disease at baseline and the HRD test results.
Table 5-1:
Sample Size by Arm/Analysis Cohort
Arm/Cohort
Prior Therapy
Measurable 
Disease
HRD
Size
Arm A (Nivolumab + Rucaparib)
    A1: HRD+ 
Taxane
Anyb
Positive
40
    A1: HRD-
Taxane
Anyb
Negative
40
    A2: HRD+
Abi and/or Enzaa
Anyb
Positive
60
    A2: HRD-
Abi and/or Enzaa
Anyb
Negative
40
    A1 for ORR
Taxane
Yes
Any
48
    A2 for ORR
Abi and/or Enzaa
Yes
Any
60
    A1 for RR-PSA/PFS
Taxane
Anyb
Any
80
    A2 for RR-PSA/PFS
Abi and/or Enzaa
Anyb
Any
100
    A-HRD+ for ORR
Any
Yes
Positive
60
    A-HRD- for ORR 
Any
Yes
Negative
48
    A-HRD+ for RR-PSA
Any
Anyb
Positive
100
    A-HRD- for RR-PSA
Any
Anyb
Negative
80
Arm B (Nivolumab + Docetaxel)
    B: HRD+ b
Abi and/or Enzac
Anyb
Positive
25
    B: HRD- b
Abi and/or Enzac
Anyb
Negative
60
    B for ORR
Abi and/or Enzac
Yesb
Any
51
    B for RR-PSA
Abi and/or Enzac
Anyb
Any
85
Arm C (Nivolumab + Enzalutamide)
    C: HRD+ b
Abi onlya
Anyb
Positive
25
    C: HRD- b
Abi onlya
Anyb
Negative
40
    C for ORR
Abi onlya
Yes
Any
39
    C for RR-PSA/PFS
Abi onlya
Anyb
Any
65
a No immediate chemotherapy
b 60% of participants in each treatment arm are required to have measurable disease
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c Need immediate chemotherapy
The sample size is calculated using the precision approach for the co-primary endpoints, ie, ORR,
as assessed by investigator per PCWG3, among treated participants with measurable disease at
baseline in a cohort, and RR-PSA among treated participants in a cohort. Table 5-2 provides
the precision for potential response rates. For example, if 6 or more responders are observed
among 30 participants in a cohort, then the lower limit of the 95% CI for the response rate is 
above 7.7%.
Table 5-2:
Exact 95% CI for ORR and RR-PSA
Participants
Responders
Observed Rate
Lower Limit
Upper Limit
30
6
20.0%
7.7%
38.6%
30
11
36.7%
19.9%
56.1%
39
10
25.6%
13.0%
42.1%
39
15
38.5%
23.4%
55.4%
50
10
20.0%
10.0%
33.7%
50
15
30.0%
17.9%
44.6%
51
18
35.3%
22.4%
44.9%
51
23
45.1%
31.1%
59.7%
60
43
71.7%
58.6%
81.5%
60
48
80.0%
67.7%
89.2%
65
26
40.0%
28.0%
52.9%
65
31
47.7%
35.1%
60.5%
85
53
62.4%
51.2%
72.6%
85
58
68.2%
57.2%
77.9%
100
78
78.0%
68.6%
85.7%
100
83
83.0%
74.2%
89.8%
Powers are assessed for ORR and RR-PSA, using the one-arm binomial test. Estimates of reference
ORR and RR-PSA are based on the current SOC for the target populations for each cohort in this
study; see Table 5.4.3-1 of the protocol. A target ORR for a promising combination treatment is
assumed as an increase of 15% or more compared to the current SOC in a cohort. As shown in
Table 5-3, powers are assessed at a 1-sided alpha of 10% using the method from Fleiss (1981).2 In
addition, the planned number of treated participants will also provide an adequate power for
detecting a 10% absolute increase in RR-PSA for the combination compared to SOC and provide
a stable estimate of median rPFS for each cohort.
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Table 5-3:
Power for ORR in Participants with Measurable Disease at Baseline
Analysis 
Cohort/Arm
Participants
Null ORR
Target ORR
Power
A1
48
10%
25%
94%
A2
60
21%
36%
91%
B
51
21%
36%
87%
C
39
10%
25%
89%
The accrual duration is approximately 15 months, based on a monthly enrollment rate of 22
participants, and the follow-up period will be 12 months. The final analysis of the co-primary
endpoints of ORR and RR-PSA will occur approximately 2.5 years after the first participant is
treated in a cohort and the final analysis of a cohort/arm may be performed independently from 
other cohorts/arms if enrollment is completed at different times across the cohorts/arms. This will
allow sufficient follow-up for a stable estimate of BOR and DOR, and an adequate safety
assessment. Additional survival analyses may be conducted for up to 5 years after treatment 
initiation following the updated analysis of the co-primary endpoints.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
This study consists of three periods used for analyses: pre-treatment, on-treatment (i.e.,
combination therapy and monotherapy), and post-treatment.
6.1.1
Baseline (Pre-Treatment) Period
Baseline evaluations or events will be defined as evaluations or events that occur before the date
and time of the first dose of study treatment. Evaluations on the same date and time of the first
dose of study treatment will be considered as baseline evaluations.
In cases where the time (onset time of event or evaluation time and dosing time) is missing or not
collected, the following definitions will apply:
•
Pre-treatment adverse events will be defined as adverse events with an onset date prior to but
not including the day of the first dose of study treatment
•
Baseline evaluations (laboratory tests, pulse oximetry and vital signs) will be defined as
evaluations with a date on or prior to the day of first dose of study treatment
If there are multiple valid assessments, the assessment that is closest to day (and time if collected)
of the first dose of study treatment will be used as the baseline in the analyses. If multiple
assessments are collected at the same date (and time if collected), the assessment with the latest
database entry date (and time if collected) will be considered as baseline.
If more than one tumor biopsy specimen is available, baseline
will be
determined from the most recently collected specimen (prior to first dose of study treatment) with
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a measurable result. If all specimens for a given participant are either indeterminate or unknown,
then the
will be considered indeterminate as long as at least one specimen is
indeterminate. Otherwise,
will be considered unknown. Other biomarker results
at baseline, including the HRD status
, will be determined in the same way as for
baseline 
.
•
Baseline for Nivolumab Monotherapy Period in Arm B
Baseline evaluations or events for the nivolumab monotherapy period will be defined as
evaluations or events that occur before the date and time of the first dose of nivolumab 480 mg flat
dose and after the last combination dose date. Evaluations on the same date and time of the first
dose of nivolumab 480 mg will be considered as baseline evaluations. Conventions for handling
missing or not collected time and multiple assessments will be as described above except that the
nivolumab 480 mg dosing date will replace the study dosing date.
6.1.2
On-Study (On-Treatment) Period
On-treatment adverse events will be defined as adverse events with an onset date-time on or after
the date-time of the first dose of study treatment (or with an onset date on or after the day of first
dose of study treatment if time is not collected or is missing). An adverse event will be counted as
on-treatment if the event occurred within 30 days (or 100 days depending on analysis) of the last
dose of study treatment.
On-treatment evaluations (laboratory tests, pulse oximetry and vital signs) will be defined as
evaluations taken after the day (and time, if collected and not missing) of first dose of study
treatment. An evaluation will be counted as on-treatment if it occurred within 30 days (or 100 days
depending on analysis) of the last dose of study treatment.
The on-treatment period may be further divided into the following sub-periods in Arm B.
•
Combination Treatment Period in Arm B
Combination dosing is defined as any medication recorded on ‘Record of Study Medication’ CRF
page with a visit label containing the text ‘nivolumab 360 mg’ and with total volume infused > 0
mL.
On-treatment adverse events during the combination period will be defined as adverse events with
an onset date-time on or after the date-time of the first dose of combination study treatment (or
with an onset date on or after the day of first dose of combination study treatment if time is not  
collected or is missing). An adverse event will be counted as on-treatment during combination
therapy if the event occurred within 30 days (or 100 days depending on analysis) of the last dose
of combination study treatment for treated participants who do not continue nivolumab 480
monotherapy and if the event occurred within 30 days of the last dose of combination study
treatment and prior to start of nivolumab 480 mg monotherapy.
On-treatment evaluations (laboratory tests) during combination will be defined as evaluations
taken after the day (and time, if collected and not missing) of first dose of combination study
treatment. An evaluation will be counted as on-treatment during combination if it occurred within
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30 days (or 100 days depending on analysis) of the last dose of combination study treatment for
treated participants who do not continue nivolumab 480 mg monotherapy or if it occurred within
30 days of the last dose of combination study treatment and prior to start of nivolumab 480 mg
monotherapy.
•
Nivolumab Monotherapy Treatment Period in Arm B
Nivolumab 480 mg dosing is defined as any medication recorded on ‘Record of Study Medication’
CRF page with a visit label containing the text ‘Nivolumab 480’ and with total dose delivered > 0
mg.
On-treatment adverse events during the nivolumab 480 mg monotherapy period will be defined as
AEs with an onset date-time on or after the date-time of the first dose of nivolumab 480 mg study
treatment (or with an onset date on or after the day of first dose of nivolumab 480 mg study
treatment if time is not collected or is missing). An AE will be counted as on-treatment if the event
occurred within 30 days (or 100 days depending on analysis) of the last dose of nivolumab 480 mg
study treatment.
On-treatment evaluations (laboratorytests) during nivolumab 480 mg monotherapywill be defined
as evaluations taken after the day(and time, if collected and not missing) of first dose of nivolumab
480 mg study treatment. An evaluation will be counted as on-treatment if it occurred within 30
days (or 100 days depending on analysis) of the last dose of nivolumab 480 mg study treatment.
6.1.3
Follow-up (Post-Treatment) Period
The post-treatment period is defined as 30 days after last dose of study therapy.
6.2
Treatment Regimens
Participants eligible will be given up to 24 months of nivolumab in combination with either
rucaparib, docetaxel, or enzalutamide until recurrence of disease, unacceptable toxicity, or
participant withdrawal of consent. Treatment administration in each arm is as follows:
•
Arm A dosing: nivolumab 480 mg IV Q4W plus rucaparib 600 mg PO BID
•
Arm B dosing: nivolumab 360 mg Q3W plus docetaxel 75 mg/m2 IV Q3W plus prednisone
5 mg PO BID co-administered with docetaxel plus dexamethasone 8 mg PO administered in 3
doses prior to docetaxel infusion. Docetaxel is given up to a maximum of 10 cycles. Nivolumab
480 mg Q4W will be administered as monotherapy after Cycle 10.
•
Arm C dosing: nivolumab 480 mg Q4W plus enzalutamide 160 mg PO QD
An analysis by the HRD status and cohort will performed for 4 cohorts: A1, A2, B, and C, and
within each cohort for HRD+ and HRD-/Not evaluable, respectively. The HRD status will be
determined by the central laboratory as recorded in IRT. Additional sensitivity analyses by the
HRD status per CRF will be performed if the concordance rate of the HRD status between IRT
and CRF is less than 90%.
6.3
Populations for Analyses
•
Enrolled: All participants who sign an informed consent form and are registered into the IRT.
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•
Treated: All enrolled participants who receive any dose of study therapy (ie, any component
therapy in the combination for each cohort). This is the primary dataset for the analyses of
study conduct, study population, efficacy, exposure, safety, and outcome research.
•
Response Evaluable: All treated participants who have measurable disease at baseline as
assessed by investigator per PCWG3.
•
HRD+ and Response Evaluable: All response-evaluable participants who had HRD+ status
at baseline.
•
HRD-/Not Evaluable and Response Evaluable: All response evaluable participants who had
HRD- status or not evaluable status at baseline
•
Pharmacokinetic: All treated participants with available serum concentration vs time data for
nivolumab; All treated participants with available plasma concentration vs time data for
rucaparib.
7
STATISTICAL ANALYSIS
7.1
General Methods
Unless otherwise noted, the following subsections describe tabulations of discrete variables, by
the frequency and proportion of participants falling into each category, grouped by cohort (with
total). Percentages given in these tables will be rounded and, therefore, may not always sum to
100%. Continuous variables will be summarized by the HRD status and cohort using the mean,
standard deviation, median, minimum and maximum values. If a missing category is not being
presented in the data display, only those participants with non-missing values for the parameter
being assessed are included in the percentage calculation.
Time to event distribution will be estimated using Kaplan Meier techniques. This will be done for
endpoints progression free survival(s), overall survival and duration of response. Median survival
time along with 95% CI will be constructed based on a log-log transformed CI for the survivor
function.3,4 Rates at fixed time points will be derived from the Kaplan Meier estimate and
corresponding CI will be derived based on Greenwood formula5 for variance derivation and on
log-log transformation applied on the survivor function.6
CIs for binomial proportions will be derived using the Clopper-Pearson method. 7
There are no statistical hypotheses in this study.
7.2
Study Conduct
7.2.1
Accrual
The accrual pattern will be summarized per country, investigational site, and per month for all
enrolled participants and for all treated participants. The informed consent date, the first dosing
date, country, investigational site will be presented in a by-participant listing of accrual.
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7.2.2
Relevant Protocol Deviations
The following programmable deviations are considered as relevant deviations that may affect the
interpretability of the study results. Non-programmable related eligibility and on-treatment
protocol deviations as well as significant (both programmable and non-programmable) eligibility
and on-treatment protocol deviations will be reported through ClinSIGHT listings.
The following relevant deviations will be summarized by the HRD status and cohort and combined
and listed for all treated participants:
•
Relevant eligibility deviations:
o
Did not sign informed consent (Inclusion Criteria 1a)
o
Had ECOG performance status of 2 or higher (Inclusion Criteria 2e)
o
Did not have metastatic M1 disease (Inclusion Criteria 2b)
o
Baseline testosterone level > 50 ng/dL (Inclusion Criteria 2c)
o
Received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or
checkpoint pathways (Exclusion Criteria 2b)
o
Received pelvic-targeted radiotherapy within 3 months prior to the start of study therapy
(Exclusion Criteria 2c)
o
Received
prior
PARP
inhibitor
treatment,
mitoxantrone,
cyclophosphamide,
or
platinumbased chemotherapy (Exclusion Criteria 2ei), applied to Arm A only
o
Subjects who did not receive prior taxanes chemotherapy for mCRPC, Inclusion Criteria
1fi1), applied to Arm A1 only
o
Received prior chemotherapy for mCRPC. Prior docetaxel for metastatic hormone-
sensitive prostate cancer is allowed if ≥4 weeks elapsed from last dose of docetaxel
(Exclusion Criteria 2eii), applied to Arm A2 only
o
Received prior treatment with docetaxel or another chemotherapy agent for metastatic
prostate cancer (Exclusion Criteria 2fi),, applied to Arm B only
o
Subjects who did not receive prior abiraterone acetate and/or enzalutamide (Inclusion
Criteria 2fii),, applied to Arm B only
o
Received i) prior chemotherapy for mCRPC. Prior docetaxel for metastatic hormone-
sensitive prostate cancer is allowed if ≥4 weeks elapsed from last dose of docetaxel, ii)
prior treatment with enzalutamide, and/or iii) Treatment with 5-α reductase inhibitors (eg,
finasteride, dutasteride), estrogens, and/or cyproterone within 4 weeks of the screening
visit (Exclusion Criteria 2g), applied to Arm C only
o
Subjects who did not receive prior abiraterone acetate and/or enzalutamide (Inclusion
Criteria 2fiii), applied to Arm C only
o
Had BPI-SF item # 3 score of 5 or higher (Inclusion Criteria 2i)
•
Relevant on-study deviations:
o
Received prohibited and/or restricted treatments (see Section of 7.7.1 of the protocol),
while receiving study treatment.
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7.3
Study Population
7.3.1
Participant Disposition and Discontinuation of Study Therapy
•
Number  of  participants  treated,  not  treated  and  reasons  for  not  being  treated  will  be 
summarized for enrolled participants.
•
Number of participants who discontinued study therapy and reason for discontinuation will be 
summarized by the HRD status and cohort and combined for all treated participants.
By-participant listing of first dosing date in respective treatment phase or reasons for being not 
treated will be provided.
7.3.2
Demography and Participant Characteristics
The following demographics and baseline characteristics will be summarized by the HRD status
and cohort and combined for all treated participants. The corresponding by-participant listing will
be provided.
•
Age in years
•
Age category I (< 70, ≥ 70)
•
Age category II (< 65, ≥ 65-<75, ≥ 75)
•
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native
Hawaiian or Other Pacific Islander, Other)
•
Region (US, EU, Rest of World [ROW])
The following baseline disease characteristics will be summarized by the HRD status and cohort
and combined for all treated participants. The corresponding by-participant listing will be
provided.
•
Time from initial disease diagnosis to initiation of study therapy, including summary statistics
and frequencies (<1, 1-<2, 2-<3, 3-<4, 4-<5, ≥5 years)
•
Disease stage at initial diagnosis (Stage I, IIA, IIB, III, IV)
•
M status at initial disease diagnosis (M0, M1, unknown, not reported)
•
Cell type at initial disease diagnosis (adenocarcinoma, other, unknown, not reported)
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•
Gleason score (≤ 7, > 7, not reported)
•
Disease stage at study entry (Stage IV, not reported)
•
M status at study entry (M1, not reported)
•
Cell type at study entry (adenocarcinoma, other, not reported)
•
History of brain metastasis (yes, no)
•
Height (cm)
•
Baseline Weight (kg)
•
Baseline ECOG performance status (0, 1)
•
Number of bone lesions at baseline (0, <4, ≥4)
•
PSA (summary statistics and ≥median of PSA from all treated participants in 4 cohorts, <
median)
•
The HRD Status per IRT (Positive, Negative, Not evaluable)
•
The HRD Status per CRF (Positive, Negative, Not evaluable)
•
LDH (≤ULN, >ULN)
•
LDH (≤2*ULN, > 2*ULN)
•
Hemoglobin (< 11 g/dl, > 11 g/dl, not reported)
•
Alkaline phosphatase (< 1.5 x ULN, > 1.5 x ULN, not reported)
•
Lactate dehydrogenase (< 200 IU/L, ≥ 200 IU/L, not reported)
•
Visceral metastases in soft tissue (yes, no) from lung, adrenal and other sites
•
Presence of measurable disease per IRT (yes, no)
•
Baseline bisphosphonate use (yes vs no)
•
Smoking status (current/former, never smoked, not reported, unknown)
The following tumor lesions from both CT and bone scans and as assessed per investigator at
baseline will be also summarized by the HRD status and cohort and combined for all treated
participants: The corresponding by-participant listing will be provided.
•
All lesions per investigator tumor assessment at baseline: sites of disease, number of disease
sites per participant
•
Target lesions per investigator tumor assessment at baseline: presence of target lesions, site of
target lesion, sum of longest diameter of target lesion
•
Investigator’s tumor assessment and disease sites (all lesions, index lesions)
The concordance rate, defined as the percentage of the HRD status that agree (positive, negative,
not evaluable [including not reported]) between the IRT and CRF of the total number of results
(positive, negative, not evaluable [including not reported]) will be summarized by the HRD status
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and cohort and combined for all treated participants: The corresponding by-participant listing will
be provided.
7.3.3
Medical History
By-participant listing of general medical history will be produced.
7.3.4
Prior Therapy
The following prior therapy will be summarized by the HRD status and cohort and combined for
all treated participants.
•
Prior systemic therapy
•
Prior cancer hormonal therapy (yes, no) by the following category
o
Anti-androgens (e.g., enzalutamide, bicalutamide, flutamide, nilutamide) or
o
Androgen synthesis inhibitors (e.g., abiraterone, aminoglutethamide, ketoconazole),
o
LHRH]/GnRH analogues
•
Prior surgery related to cancer (yes, no)
•
Prior radiotherapy (yes, no)
By-participant listings of prior systemic therapy and prior anti-cancer hormonal therapies will be
produced.
7.3.5
Baseline Examinations
Participants with abnormal baseline physical exam results will be tabulated by examination criteria
(e.g., neck, cardiovascular, lungs, etc.) and by the HRD status and cohort and combined for all
treated participants.
7.4
Extent of Exposure
The exposure data will be summarized by the HRD status and cohort for all treated participants
across the entire treatment period. In addition,
the exposure data will also be summarized
respectively for the combination and nivolumab 480 mg monotherapy period in Arm B. By-
participant listing of dosing information as well as batch/label information will be provided.
Listing of participants who received prednisone and dexamethasone in Arm B will be produced.
7.4.1
Administration of Study Therapy
Duration of study therapy (nivolumab, rucaparib, docetaxel, and enzalutamide) will be presented
by the HRD status and cohort for the combination and component therapy, respectively. Duration
of combination therapy is defined as the time from the first dosing date of any component therapies
of the combination to the last dosing date of any component therapies of the combination. In
addition, duration of the combination and nivolumab monotherapy will be presented for
participants treated in nivolumab monotherapy in Arm B.
Duration of study therapy will be presented using a Kaplan-Meier curve whereby the last dose date
will be the event date for those participants who are off study therapy. Median duration of study
therapy and associated 95% CI will be provided. Participants who are still on study therapy will
be censored on their last dose date. In addition, duration of study therapy will be summarized in
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a table with descriptive statistics (mean, minimum, and maximum). The percentage of participants
with studytherapy duration > 3 months, > 6 months, > 9 months, and > 12 months will be tabulated.
The following parameters will be summarized by the HRD status and cohort for each component
therapy in the combination (and by treatment period in Arm B, i.e., the combination phase and
nivolumab monotherapy phase) for all treated participants; see Table 7.4.1-1 and Table 7.4.1-2.
•
Number of doses received
•
Cumulative dose in mg/kg
•
Relative dose intensity (%) (< 50%; 50 - < 70%; 70 - < 90%; 90 - < 110%; ≥ 110%)
•
Infusion duration in minutes, applicable to nivolumab and docetaxel
•
Duration of study therapy
Table 7.4.1-1:
Study Therapy Parameters 
Nivolumab (Arm A, C)
Docetaxel
Dosing Schedule per Protocol
Arm A and C: 480 mg IV Q4W
Arm B: 360 mg IV Q3W
75 mg/m2 IV Q3W
Dose
Dose (mg) = total dose delivered as
recorded on Record of Study
Medication CRF
Dose (mg/m2) = total dose 
administered in mg at each dosing 
date is collected on the CRF and 
BSA is derived from baseline 
weight and height also collected on 
the CRF
Cumulative Dose
Cum Dose (mg) is the sum of the
doses administered to a participant
Cum Dose (mg/m2) is the sum of
the doses (mg/m2) administered to a
participant
Relative Dose Intensity (%)
Arm A and C: [Cumulative dose 
(mg)/( (Last dose date – first dose 
date + 28) × 480/28)] × 100
[Cumulative dose (mg/m2) /( (Last 
dose date – first dose date + 21) × 
75/21)] × 100
Infusion Duration (mins)
Each infusion duration is calculated 
as infusion stop date/time - infusion 
start date/time.
Each infusion duration is calculated 
as infusion stop date/time - infusion 
start date/time.
Duration of Treatment
last dose date - first dose date + 1
last dose date - first dose date + 1
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Table 7.4.1-2:
Study Therapy Parameters (Rucaparib and Enzalutamide)
Rucaparib
Enzalutamide
Dosing Schedule per
Protocol
600 mg PO BID
160 mg PO QD
Dose
Dose (mg) = total dose delivered as
recorded on Record of Study Medication 
CRF
Dose (mg) = total dose delivered as
recorded on Record of Study 
Medication CRF
Cumulative Dose
Cum Dose (mg) is the sum of the doses 
administered to a participant
Dose (mg) = total dose delivered as
recorded on Record of Study 
Medication CRF
Relative Dose Intensity (%)
[Cumulative dose (mg) /((Last dose date –
first dose date + 1) × 600*2)] × 100
[Cumulative dose (mg) /( (Last dose 
date – first dose date + 1) × 160)] × 
100
Duration of Treatment
Last dose date - Start dose date +1
Last dose date - Start dose date +1
7.4.2
Modifications of Study Therapy
Dose escalations, reductions and omissions are not permitted for nivolumab in this study. Dose
delays will be summarized.
7.4.2.1
Dose Delays
Each nivolumab and docetaxel infusion may be delayed per the Dose Changes CRF pages. All
study drugs must be delayed until treatment can resume. Reason for dose delay will be retrieved
from the Dose Changes CRF pages.
•
Number of participants with at least one dose delayed, reason for first delay, number of dose 
delays, and length of delay will be summarized by cohort.
By-participant listing of all dose delays and reasons will be provided.
7.4.2.2
Infusion Interrupted and Rate Reduced
The infusion interruptions and the IV infusion reduction rates will be summarized by study drug
(nivolumab and docetaxel) and by the HRD status will be summarized for all treated participants.
•
Number of participants with at least one dose infusion interruption, the reason for the first
interruption, and the number of infusion interruptions.
•
Number of participants with at least one rate of infusion reduced, the reason for first reduction,
and number of rate reductions
By-participant listing of all infusion interruptions and rate reductions and all the corresponding
reasons and will be provided.
7.4.2.3
Dose Reduction
Dose reduction of docetaxel from last cycle will be recorded in the Dose Changes CRF pages, and
will be summarized by the HRD status for all treated participants in Arm B.
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•
Number of participants with at least one dose reduction, reason for first reduction, and number
of dose reductions will be summarized by cohort.
In addition, dose reduction of rucaparib will be recorded in the Study Medication CRF pages, and
will be summarized by the HRD status and cohort in Arm A.
By-participant listing of all dose reduction and reasons will be provided.
7.4.3
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken at
any time on-treatment (i.e., on or after the first day of study therapy and within 100 days following
the last dose of study therapy), will be coded using the WHO Drug Dictionary.
•
Concomitant medications (participants with any  concomitant medication, participants by
medication class and generic term)
By-participant listing of
concomitant medications will be produced. In addition, listings of
participants who received immunosuppressive agents and steroids will be produced.
7.4.4
Treatment Beyond Disease Progression
A participant listing of participants who received study treatment beyond progression will be
provided.
7.4.5
Subsequent Cancer Therapy
Therapies received subsequent to discontinuation of studytherapy will be summarized by the HRD
status and cohort and combined for all treated participants.
•
Frequency of participants with subsequent systemic cancer therapy as recorded in subsequent
therapy CRF pages by type (any, immunotherapy only, chemotherapy only, hormonal only,
immunotherapy
and
chemotherapy,
immunotherapy
and
hormonal,
hormonal
and
chemotherapy, immunotherapy, hormonal and chemotherapy, other)
•
Time from initiation of study therapy to first systemic cancer subsequent therapy (median,
range)
By-participant listing of subsequent systemic cancer therapies (including dates of therapy) will be
produced.
7.5
Efficacy
All efficacy analyses will be performed by the HRD status and cohort as applicable to either (i)
treated participants with measurable disease by RECIST v1.1 and/or (ii) all treated participants in
a cohort.
To assess consistency of treatment effects in an efficacy endpoint across subgroups, the following
pre-defined subsets will be used in the corresponding subgroup analyses, if there are more than 10
participants in the subset.
•
Age category I (< 70, ≥ 70)
•
Age category II (< 65, ≥ 65-<75, ≥ 75)
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•
Race (White, Black or African American, Others)
•
Region (US, EU, ROW)
•
Gleason score (≤7, > 7, not reported)
•
Cell type at study entry (adenocarcinoma, other, not reported)
•
History of brain metastasis (yes, no)
•
Baseline ECOG performance status (0, 1)
•
Number of bone lesions at baseline (0, <4, ≥4)
•
PSA (summary statistics and ≥median of PSA from all treated participants in 4 cohorts, <
median)
•
HRD Status per IRT
•
HRD Status per CRF
•
LDH (≤ULN, >ULN)
•
LDH (≤2*ULN, > 2*ULN)f
•
Visceral metastases in soft tissue (yes, no) from lung, adrenal and other sites
•
Presence of measurable disease per IRT (yes, no)
•
Baseline bisphosphonate use (yes, no)
7.5.1
Objective Response Rate per PCWG3
For co-primary endpoint of ORR per PCWG3, estimated rates and corresponding 2-sided exact
95% CIs will be calculated using the Clopper-Pearson method by the HRD status and cohort for
all response evaluable participants.
To assess consistency of treatment effects in ORR in different subsets, a forest plot of the ORRs
and corresponding 2-sided exact 95% CIs will be produced for the following subgroups in a
stratum, if a stratum has more than 10 participants.
ORR per PCWG3 per BICR, if available, will be analyzed in the same way as for ORR per PCWG3
per investigator.
7.5.2
PSA Response Rate
RR-PSA will be analyzed by the HRD status and cohort for all treated participants in the same
way as for ORR per PCWG3.
7.5.3
Radiographic Progression-Free Survival
For secondary endpoint of radiographic progression free survival (rPFS) per investigator, Kaplan-
Meier plots will be presented. The estimates of the median and corresponding log-log transformed
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two-sided 95% confidence intervals will be calculated.8 The rates at months 6 and 12 and
corresponding 95% CIs will be estimated via the Kaplan-Meier methodology.
The 1-year rPFS rate, median and corresponding two-sided log-log transformed 95% CIs will be
calculated for the pre-defined subsets in a stratum, if a stratum has more than 10 participants.
rPFS per BICR, if available, will be analyzed in the same way as for rPFS per investigator.
7.5.4
Time to Objective Response and Duration of Response per PCWG3
Summary statistics of time to objective response (TTR) will be provided by the HRD status and
cohort for treated participants with a BOR of CR or PR. TTR curves will be estimated using the
Kaplan-Meier methodology by the HRD status and cohort for all treated participants. Due to small
sizes for each stratum, spider plots will be provided by the HRD status and cohort for all treated
participants.
Duration of response (DOR) will be summarized for participants with a BOR of PR or CR per
investigator using the Kaplan-Meier methodology. Median values, along with two-sided 95% CIs
will also be calculated.
TTR/DOR per BIRC, if available, will be analyzed in the same way as for TTR/DOR per
investigator.
7.5.5
Time to PSA Progression
For time to PSA progression, Kaplan-Meier plots will be presented by the HRD status and cohort
for all treated participants. The estimates of the median and corresponding log-log transformed
two-sided 95% CIs will be calculated. The rates at months 3, 6, 9 and 12 and corresponding 95%
CIs will be estimated via the Kaplan-Meier methodology.
7.5.6
Overall Survival
For overall survival, Kaplan-Meier plots will be presented by the HRD status and cohort for all
treated participants. The estimates of the median and corresponding log-log transformed two-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. The extent of follow-up, defined as the time from
treatment initiation to last OS contact (whether status is alive or dead), will be summarized by the
HRD status and cohort for all treated participants.
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7.6
Safety
All the safety analyses will be performed by the HRD status and cohort and total for all treated
participants. Descriptive statistics of safety will be presented using the NCI CTCAE v4.03 by the
HRD status and cohort and combined. All AEs, drug-related adverse events, serious adverse events
(SAEs) and drug-related SAEs will be tabulated using the worst grade per NCI CTCAE v4.03 by
system organ class and preferred term. On-study lab parameters including hematology,
coagulation, chemistry, liver function, thyroid, adrenal and renal function will be summarized
using worse grade by NCI CTCAE v4.03. In addition, immune mediated adverse events incident
rate is defined as the proportion participants with any grade adverse events among participants
treated by each cohort and total. Events reported from the first dose and up to and including 100
days following the last dose of study treatment could be included in estimating this incidence rate.
Details are in the Core Safety SAP. 1
7.6.1
Deaths
Refer to Core Safety SAP.
7.6.2
Serious Adverse Events
Refer to Core Safety SAP.
Summaries of SAEs and drug-related SAEs with onset during the nivolumab monotherapy period
in Arm B (using the 30-day safety window only) will also be provided for all participants treated
in the nivolumab monotherapy period.
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
See Core Safety SAP.
Summaries of adverse events leading to discontinuation and drug-related adverse events leading
to discontinuation with onset during the nivolumab monotherapy period in Arm B (using the 30-
day safety window) will also be provided for all participants treated in the nivolumab
monotherapy.
7.6.4
Adverse Events Leading to Dose Modification
See Core Safety SAP.
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7.6.5
Adverse Events
Refer to Core Safety SAP.
Summaries of adverse events and drug-related adverse events will also be provided separately for
events with onset during the combination therapy for all treated participants in Arm B and for
events with onset during the monotherapy period for all participants treated in nivolumab 480 mg
monotherapy in Arm B. These additional summaries by treatment period will be performed using
the 30-day safety window only.
7.6.6
Select Adverse Events
Refer to Core Safety SAP.
7.6.7
Immune Modulating Medication
Refer to Core Safety SAP.
7.6.8
Multiple Events
Refer to Core Safety SAP.
7.6.10
Immune-Mediated Adverse Events
Refer to Core Safety SAP.
7.6.11
Laboratory Parameters
Refer to Core Safety SAP.
Lipase and Amylase will be added to the list of lab parameters to be summarized.
7.6.12
Vital Signs and Pulse Oximetry
Refer to Core Safety SAP.
7.6.14
Adverse Events by Subgroup
Refer to Core Safety SAP.
Categories for region will be US, EU and ROW.
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7.8
Pharmacokinetics
7.8.1
Pharmacokinetics of Nivolumab
The nivolumab concentration versus time data obtained in this study will be combined with data
from other studies in the clinical development program to develop a PPK model. This model will
be used to evaluate the effects of intrinsic and extrinsic covariates on the PK of nivolumab to
determine measures of individual exposure (such as steady state peak, trough and time-averaged
concentration). Pharmacokinetic drug-drug interaction between nivolumab and other component
drugs will be studied by a PPK approach. Model-determined exposures will be used for exposure-
response analyses of selected efficacy and safety endpoints if the data permit. The PPK analysis
will be presented separately from the Clinical Study Report (CSR).
7.8.2
Pharmacokinetics of Rucaparib/ Enzalutamide
The trough plasma concentrations of rucaparib and enzalutamide data will be analyzed,
respectively, including summary statistics and plotting. Post hoc estimates of PK parameters and
exposures will be estimated for each participant using the existing or updated PPK model. The
estimated exposures will be used for exposure-response analyses of selected efficacy and safety
endpoints if the data permit. The PPK analysis may be presented separately from the CSR.
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7.10
Interim Analysis
An interim analysis may be performed in each arm when at least 50% of planned participants have
been treated with first dose at least 16 weeks prior to the cutoff date for the interim analysis 
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database lock. The purpose of the interim analysis is to generate preliminary data that will inform 
decisions related to external studies, as well as determine if any of the study arms should be 
expanded to generate additional data that may support a regulatory filing. If the data from the 
initial interim analysis appear to be immature to support decision-making on the expansion of a 
specific study arm, a second interim analysis of that arm may be performed after enrollment has 
been completed and all treated patients have been followed for at least 16 weeks after first dose.
After the interim analysis, an expansion for each arm may be triggered based on review of the
totality of available data by a small unblinded BMS team outside of the CA2099KD team (see
Section 7.3) if a clinically meaningful response compared to the historical standard of care [SOC]
for the population in that arm or subgroup is observed. Table 7.12-1 provides some examples of
potential response rates observed at the interim analysis and the precision for potential sample
sizes to be expanded to for each arm or HRD subgroup, if applicable, based on the historical ORR
for SOC in that arm or HRD subgroup. (See Rationale for Interim Analysis in Section 5.4.9 in 
protocol for more details regarding the historical ORR assumptions for each arm/subgroup.) For 
example, if an interim ORR of 43% is observed for HRD+ participants in Arm A1 (15% 
improvement over the historical ORR for SOC in this subgroup), the sample size of HRD+ in Arm 
A1 could be expanded up to ~ 46 participants with measurable disease. For the interim analysis, 
the analysis population is defined as all treated subjects whose first dose date is at least 16 weeks 
before the cutoff date for the interim analysis database lock, and analysis will also be performed 
by HRD status.  Summaries and listings of efficacy and safety will be produced at the interim, and 
the interim results will be shared with the DMC after the interim analysis in each arm. In any arm 
or subgroup that is expanded, interim analyses in the additional participants treated in the 
expansion with at least 16 weeks of follow-up after first dose may be performed if needed to 
determine if the data may be sufficient to support a regulatory filing.
Table 7.10-1:
Exact 95% CI for Potential Observed ORR and Potential Sample 
Size
Arm/subgroup
SOC Historical 
ORR 
Observed ORR
N (meas 
disease)
Lower Limit 
(%)
Upper Limit 
(%)
A1 or A2 HRD+
28%
43%
46
28.9
58.9
48%
29
29.4
67.5
A1 HRD-
14%
29%
34
15.1
47.5
34%
20
15.4
59.2
A2 HRD-
21%
36%
41
22.1
53.1
41%
24
22.1
63.3
B or C All-
Comers
21%
36%
41
22.1
53.1
41%
24
22.1
63.3
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8
CONVENTIONS
Unless otherwise noted, the following conventions should be understood to apply. Further
conventions may be detailed in the Data Presentation Plan (DPP).
The duration between two dates will be calculated as difference between the two dates. Study Day
1 or first dose date is the date of first dose of study therapy.
•
if the assessment is before the first dose then the study day associated with an assessment will
be calculated as [assessment date] - [first dose date]
•
if the assessment is on or after first dose then the study day will be calculated as [assessment
date] - [first dose date]+1.
In the absence of evidence of discontinuation of therapy, participants will be assumed still to be
on-study.
Events with an onset prior to Day 1 (or to the first dosing date, for non-treated participants) will
constitute pretreatment events.
Events will be considered as occurring within X days (e.g. deaths within 30 days, deaths and
adverse events within 100 days) of last dose of study medication if [event date] minus [last dosing
date] ≤X. The following factors will convert days to months or years: 1 month = 30.4375 days, 1
year = 365.25 days.
8.1
Conventions for Partial or Missing Dates
See Core Safety SAP.
For death dates, the following conventions will be used for imputing partial dates:
•
Ifonly the day of the month is missing, the first ofthe month will be used to replace the missing
day. The imputed date will be compared to the last known date alive and the maximum will be
considered as the death date.
•
If the month or the year is missing, the death date will be imputed as the last known date alive.
•
If the date is completely missing but the reason for death is present the death date will be
imputed as the last known date alive.
For date of progression, the following conventions will be used for imputing partial dates:
•
Ifonly the day of the month is missing, the first ofthe month will be used to replace the missing
day*.
•
If the day and month are missing or a date is completely missing, it will be considered as
missing.
* In cases where the date of death is present and complete, the imputed progression date will be
compared to the date of death. The minimum of the imputed progression date and date of death
will be considered as the date of progression.
For other partial/missing dates not covered by Core Safety SAP, the following conventions may
be used:
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•
If only the day of the month is missing, the 15th of the month will be used to replace the
missing day.
•
If both the day and the month are missing, “July 1” will be used to replace the missing
information.
•
If a date is completely missing, it will be considered as missing.
9
CONTENT OF REPORTS
The table, figure and listing outputs that will be produced will be described in DPP for this study.
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10
REFERENCES
1
Core Safety Statistical Analysis Plan for Nivolumab Program v5.0.
2
Fleiss JL, Levin B, Paik MC. Statistical Methods for Rates and Proportions, Second Edition.   
John Wiley & Sons (1981).
3
Brookmeyer R. and Crowley J. A confidence interval for the median survival time. Biometrics
38:29-41, 1982
4
Klein, J. P. and Moeschberger, M. L. (1997), Survival Analysis: Techniques for Censored and
Truncated Data, New York: Springer-Verlag.
5
Greenwood, M. The errors of sampling of the survivorship tables, Reports on Public Health
and Statistical Subjects, 33, Appendix 1, HMSO, London, 1926
6
Kalbfleisch, J. D. and Prentice, R. L. (1980), The Statistical Analysis of Failure Time Data,
New York: John Wiley & Sons.
7
Clopper, CJ and Pearson, ES. The use of confidence or fiducial limits illustrated in the case of
the binomial. Biometrika 26: 404-413, 1934
8
Kalbfleisch RL. The Statistical Analysis of Failure Time Data. Wiley-Interscience 2002.
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