A Phase 1b-2 Study of Niraparib Combination Therapies for the Treatment of Metastatic Castration-Resistant Prostate Cancer
Phase: PHASE2
Conditions: Prostatic Neoplasms, Castration-Resistant
Sponsor: Janssen Research & Development, LLC

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Status: Approved,  Date: 3 August 2021
Janssen Research & Development *
Clinical Protocol
A Phase 1b-2 Study of Niraparib Combination Therapies for the Treatment of Metastatic
Castration-Resistant Prostate Cancer
QUEST
Protocol 64091742PCR2002 Phase 1b-2
Amendment 7
JNJ-64091742 (niraparib)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics,
BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen Sciences Ireland
UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout the protocol to
represent these various legal entities; the sponsor is identified on the Contact Information page that
accompanies the protocol.
US sites of this study will be conducted under US Food & Drug Administration IND regulations
(21 CFR Part 312)
EudraCT NUMBER: 2017-003552-23
Status: 
Approved
Date: 
3 August 2021
Prepared by: Janssen Research & Development, LLC 
EDMS number: 
EDMS-ERI-147293608, 8.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT03431350

JNJ-64091742  (niraparib)
Clinical Protocol 64091742PCR2002 –Amendment 7
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Approved, Date: 3 August 2021
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol 
11 October 2017
Amendment 1 
07 December 2017
Amendment 2 
22 May 2018
Amendment 3 
28 November 2018
Amendment 4 
18 December 2019
Amendment 5 
04 March 2020
COVID-19 Appendix  
17 April 2020
Amendment 6 
29 October 2020
Amendment 7 
03 August 2021
Amendment 7 (03 August 2021)
Overall Rationale for the Amendment:  The overall reason for the amendment is to add a Long-term
Extension (LTE) Phase to allow subjects who benefit from the study treatment (Combination 1 or 2 or 3)
to continue to receive the same study treatment after the primary analysis is completed.
In conjunction with the start of the Long-term Extension Phase and given the well-characterized safety
profile of niraparib in the different combinations explored, data collection will be minimal, to lower the
burden to subjects.
Section Number 
and Name
Description of Change 
Brief Rationale
Synopsis (Overview
of Study Design);
3.1. Overview of
Study Design; 3.1.4.
Long-term
Extension Phase for
any Combination
Subgroup;
9.1.1. Overview;
9.1.4.1. Long-term
Extension Phase
With Minimal Data
Collection
Added text to include the Long-term Extension Phase in the
study design.
To provide detailed
information for the
Long-term Extension
Phase.
3.1. Overview of
Study Design
It was specified that each combination study will now have
5 phases.
3.1. Overview of
Study Design; 3.1.4.
Long-term
Extension Phase for
any Combination
Subgroup;
9.1.1. Overview;
9.1.4.1. Long-term
Extension Phase
With Minimal Data
Collection
Referred to the new Attachment 7 for details ofthe Long-term
Extension Phase.
3.1.1.
Combination 1:
Niraparib and
Cetrelimab
Added a note in the footnote of Figure 1 and Figure 2 to
specify that the Long-term Extension Phase is not included in
the schematic for Combination 1 and Combination 2.

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Approved, Date: 3 August 2021
Section Number 
and Name
Description of Change 
Brief Rationale
(Figure 1); 3.1.2.
Combination 2:
Niraparib and AAP
(Figure 2)
9.1.4.1. Long-term 
Extension With 
Minimal Data
Collection (new
subheading)
Provided information on the Long-term Extension Phase with
minimal data collection.
Attachment 7: 
Long-term 
Extension Phase 
(new attachment)
This attachment includes detailed information, including a
Time and Events Schedule, for the Long-term Extension Phase
with minimal data collection.
Attachment 8: 
Protocol 
Amendment History
The protocol amendment 6 summary table was moved to 
Attachment 8. 
To align with the
template requirement.
Throughout the 
protocol 
Minor formatting and spacing corrections were made. 
Minor errors were
noted.

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Approved, Date: 3 August 2021
TABLE OF CONTENTS
PROTOCOL AMENDMENTS....................................................................................................................... 2
TABLE OF CONTENTS............................................................................................................................... 4
LIST OF ATTACHMENTS............................................................................................................................ 8
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 8
SYNOPSIS.................................................................................................................................................... 9
ABBREVIATIONS...................................................................................................................................... 23
1. 
INTRODUCTION................................................................................................................................ 25
1.1. 
Background and Design Rationale ................................................................................................ 26
1.1.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 27
1.1.2. 
Combination 2: Niraparib and AAP............................................................................................. 29
1.1.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination Tablet........................ 30
1.2. 
Summary of Available Nonclinical and Clinical Data for Niraparib ................................................ 31
1.3. 
Summary of Available Nonclinical and Clinical Data for Combination Agents .............................. 32
1.3.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 32
1.3.2. 
Combination 2: Niraparib and AAP............................................................................................. 34
1.3.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination Tablet........................ 36
1.4. 
Benefit/Risk Assessment ............................................................................................................... 36
1.4.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 36
1.4.2. 
Combination 2: Niraparib and AAP............................................................................................. 37
1.4.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination Tablet........................ 38
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESES.......................................................................... 38
2.1. 
Objectives and Endpoints .............................................................................................................. 38
2.2. 
Hypotheses .................................................................................................................................... 41
2.2.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 41
2.2.2. 
Combination 2: Niraparib and AAP............................................................................................. 41
2.2.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination Tablet........................ 41
3. 
STUDY DESIGN AND RATIONALE................................................................................................. 42
3.1. 
Overview of Study Design.............................................................................................................. 42
3.1.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 42
3.1.2. 
Combination 2: Niraparib and AAP............................................................................................. 44
3.1.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination Tablet........................ 45
3.1.4. 
Long-term Extension Phase for any Combination Subgroup..................................................... 45
3.2. 
Dose Selection Rationale............................................................................................................... 45
3.2.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 46
3.2.2. 
Combination 2: Niraparib and AAP............................................................................................. 46
3.2.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination Tablet........................ 46
3.3. 
Biomarker Rationale....................................................................................................................... 47
3.3.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 47
3.3.2. 
Combination 2: Niraparib and AAP............................................................................................. 47
3.3.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination Tablet........................ 48
3.4. 
Safety Evaluation Criteria for Part 1............................................................................................... 48
3.5. 
Safety Evaluation Team (Combinations with Part 1)..................................................................... 49
4. 
SUBJECT POPULATION.................................................................................................................. 50
4.1. 
Prescreening Eligibility Criteria ...................................................................................................... 50
4.1.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 51
4.1.2. 
Combination 2: Niraparib and AAP............................................................................................. 51
4.2. 
Inclusion Criteria ............................................................................................................................ 51

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4.2.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 52
4.2.2. 
Combination 2: Niraparib and AAP............................................................................................. 53
4.3. 
Exclusion Criteria ........................................................................................................................... 53
4.3.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 55
4.3.2. 
Combination 2: Niraparib and AAP............................................................................................. 55
4.4. 
Lifestyle Considerations................................................................................................................. 56
5. 
TREATMENT ALLOCATION AND BLINDING................................................................................. 56
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 57
6.1. 
Study Drug Administration ............................................................................................................. 57
6.1.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 57
6.1.2. 
Combination 2: Niraparib and AAP............................................................................................. 58
6.1.3. 
Combination 3: Niraparib/AA Fixed-dose Combination Tablet................................................... 58
6.2. 
Dose Modification and Management of Toxicity............................................................................ 58
6.2.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 59
6.2.2. 
Combination 2: Niraparib and AAP............................................................................................. 64
6.2.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination Tablet........................ 66
6.3. 
Treatment of Overdose .................................................................................................................. 66
7. 
TREATMENT COMPLIANCE............................................................................................................ 67
7.1. 
Combination 1: Niraparib and Cetrelimab...................................................................................... 67
7.2. 
Combination 2: Niraparib and AAP................................................................................................ 67
8. 
PRIOR AND CONCOMITANT THERAPY ........................................................................................ 67
8.1. 
Prohibited Concomitant Therapies................................................................................................. 68
8.1.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 68
8.1.2. 
Combination 2: Niraparib and AAP............................................................................................. 68
8.2. 
Restricted Concomitant Medications ............................................................................................. 69
8.2.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 69
8.2.2. 
Combination 2: Niraparib and AAP............................................................................................. 69
9. 
STUDY EVALUATIONS.................................................................................................................... 69
9.1. 
Study Procedures........................................................................................................................... 69
9.1.1. 
Overview..................................................................................................................................... 69
9.1.2. 
Prescreening Phase for Biomarker Evaluation........................................................................... 70
9.1.3. 
Screening Phase ........................................................................................................................ 70
9.1.4. 
Treatment Phase ........................................................................................................................ 71
9.1.5. 
End-of-Treatment Visit................................................................................................................ 72
9.1.6. 
Follow-Up Phase ........................................................................................................................ 72
9.2. 
Antitumor Activity ........................................................................................................................... 72
9.2.1. 
Evaluations ................................................................................................................................. 72
9.2.2. 
Criteria ........................................................................................................................................ 73
9.3. 
Pharmacokinetics and Immunogenicity (Combination 1)............................................................... 74
9.3.1. 
Sample Collection and Handling (Combination 1)...................................................................... 74
9.3.2. 
Analytical Procedures (Combination 1)...................................................................................... 74
9.3.3. 
Pharmacokinetic Parameters (Combination 1)........................................................................... 75
9.4. 
Pharmacokinetic/Pharmacodynamic Evaluations (Combination 1 Only)....................................... 75
9.5. 
Biomarkers..................................................................................................................................... 75
9.5.1. 
Tumor Samples .......................................................................................................................... 76
9.5.2. 
Circulating Tumor Cells .............................................................................................................. 77
9.5.3. 
Circulating Tumor DNA- Combination 1 Only............................................................................. 77
9.5.4. 
Other Biomarker Assays............................................................................................................. 77
9.5.5. 
Non-steroidal Anti-inflammatory Drugs and Antibiotics (Combination 1)................................... 77
9.6. 
Medical Resource Utilization.......................................................................................................... 78
9.7. 
Safety Evaluations ......................................................................................................................... 78
9.8. 
Sample Collection and Handling.................................................................................................... 81

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10. SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL
FROM THE STUDY........................................................................................................................... 81
10.1. 
Completion ..................................................................................................................................... 81
10.2. 
Discontinuation of Study Treatment............................................................................................... 81
10.3. 
Withdrawal from the Study............................................................................................................. 82
10.4. 
Withdrawal from the Use of Research Samples............................................................................ 83
11. STATISTICAL METHODS................................................................................................................. 83
11.1. 
Analysis Populations...................................................................................................................... 83
11.2. 
Sample Size Determination ........................................................................................................... 83
11.2.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 83
11.2.2. 
Combination 2: Niraparib and AAP............................................................................................. 84
11.2.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination Tablet........................ 85
11.3. 
Antitumor Activity Analyses............................................................................................................ 85
11.3.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 85
11.3.2. 
Combination 2: Niraparib and AAP............................................................................................. 85
11.3.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination Tablet........................ 86
11.4. 
Pharmacokinetic and Immunogenicity Analyses (Combination 1 Only)........................................ 86
11.5. 
Biomarker Analyses ....................................................................................................................... 87
11.6. 
Pharmacokinetic/Pharmacodynamic Analyses (Combination 1)................................................... 87
11.7. 
Medical Resource Utilization.......................................................................................................... 87
11.8. 
Safety Analyses ............................................................................................................................. 87
11.9. 
Data Review Committee ................................................................................................................ 88
11.10. Futility Analysis .............................................................................................................................. 88
12. ADVERSE EVENT AND SERIOUS ADVERSE EVENT REPORTING ............................................ 89
12.1. 
Definitions ...................................................................................................................................... 89
12.1.1. 
Adverse Event and Serious Adverse Event Definitions and Classifications .............................. 89
12.1.2. 
Attribution Definitions.................................................................................................................. 90
12.1.3. 
Severity Criteria .......................................................................................................................... 91
12.2. 
Special Reporting Situations.......................................................................................................... 91
12.3. 
Procedures..................................................................................................................................... 91
12.3.1. 
All Adverse Events...................................................................................................................... 91
12.3.2. 
Serious Adverse Events ............................................................................................................. 93
12.3.3. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 94
12.3.4. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 94
12.3.5. 
Pregnancy................................................................................................................................... 94
12.3.6. 
Disease Progression and Death................................................................................................. 95
12.4. 
Contacting Sponsor Regarding Safety........................................................................................... 95
13. PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 95
13.1. 
Procedures..................................................................................................................................... 95
13.2. 
Contacting Sponsor Regarding Product Quality............................................................................ 96
14. STUDY DRUG INFORMATION......................................................................................................... 96
14.1. 
Physical Description of Study Drug(s)........................................................................................... 96
14.1.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 96
14.1.2. 
Combination 2: Niraparib and AAP............................................................................................. 97
14.2. 
Packaging ...................................................................................................................................... 97
14.2.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 97
14.2.2. 
Combination 2: Niraparib and AAP............................................................................................. 97
14.3. 
Labeling.......................................................................................................................................... 97
14.4. 
Preparation, Handling, and Storage............................................................................................... 97
14.4.1. 
Niraparib ..................................................................................................................................... 97
14.4.2. 
Cetrelimab .................................................................................................................................. 97
14.4.3. 
Abiraterone Acetate.................................................................................................................... 97
14.5. 
Drug Accountability........................................................................................................................ 98

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15. STUDY-SPECIFIC MATERIALS....................................................................................................... 98
16. ETHICAL ASPECTS......................................................................................................................... 99
16.1. 
Study-Specific Design Considerations........................................................................................... 99
16.1.1. 
Combination 1: Niraparib and Cetrelimab .................................................................................. 99
16.1.2. 
Combination 2: Niraparib and AAP............................................................................................. 99
16.1.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination Tablet........................ 99
16.2. 
Regulatory Ethics Compliance..................................................................................................... 100
16.2.1. 
Investigator Responsibilities..................................................................................................... 100
16.2.2. 
Independent Ethics Committee or Institutional Review Board ................................................. 100
16.2.3. 
Informed Consent ..................................................................................................................... 101
16.2.4. 
Privacy of Personal Data .......................................................................................................... 102
16.2.5. 
Long-term Retention of Samples for Additional Future Research............................................ 103
16.2.6. 
Country Selection ..................................................................................................................... 103
17. ADMINISTRATIVE REQUIREMENTS............................................................................................ 103
17.1. 
Protocol Amendments.................................................................................................................. 103
17.2. 
Regulatory Documentation .......................................................................................................... 104
17.2.1. 
Regulatory Approval/Notification .............................................................................................. 104
17.2.2. 
Required Prestudy Documentation........................................................................................... 104
17.3. 
Subject Identification, Enrollment, and Screening Logs .............................................................. 105
17.4. 
Source Documentation................................................................................................................. 105
17.5. 
Case Report Form Completion .................................................................................................... 106
17.6. 
Data Quality Assurance/Quality Control ...................................................................................... 106
17.7. 
Record Retention ......................................................................................................................... 107
17.8. 
Monitoring .................................................................................................................................... 107
17.9. 
Study Completion/Termination..................................................................................................... 108
17.9.1. 
Study Completion/End of Study................................................................................................ 108
17.9.2. 
Study Termination..................................................................................................................... 108
17.10. On-Site Audits.............................................................................................................................. 109
17.11. Use of Information and Publication .............................................................................................. 109
REFERENCES.......................................................................................................................................... 111
INVESTIGATOR AGREEMENT............................................................................................................... 181

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LIST OF ATTACHMENTS
Attachment 1: 
Combination 1: Guidelines for the Management of Immune-related Adverse
Events for Cetrelimab ............................................................................................................. 115
Attachment 2: 
ECOG Performance Status.......................................................................................... 119
Attachment 3: 
Anticipated Events ....................................................................................................... 120
Attachment 4: 
Additional Information on CYP450 Drug Interactions .................................................. 122
Attachment 5: 
Modified Schedule of Events for Combinations Closed to Enrollment........................ 123
Attachment 6: 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination.................... 128
Attachment 7: 
Long-term Extension Phase......................................................................................... 156
Attachment 8: 
Protocol Amendment History....................................................................................... 158
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Objectives and Endpoints for Part 1 ......................................................................................... 39
Table 2: 
Objectives and Endpoints for Part 2 ......................................................................................... 39
Table 3: 
Study Treatments for Combination 1 ........................................................................................ 57
Table 4: 
Niraparib Dose Modification/Reductions for Platelet Count and Neutrophil Count .................. 60
Table 5: 
Retreatment Criteria for Cetrelimab.......................................................................................... 61
Table 6: 
Management and Follow-up of Infusion-related Reactions ...................................................... 61
Table 7: 
Dose Modification Criteria for AST/ALT/Bilirubin Abnormalities for Niraparib and
Abiraterone Acetate Plus Prednisone....................................................................................... 65
Table 8: 
Biomarker Panel ....................................................................................................................... 75
Table 9: 
DRD and CDK12 Status and Cohort Eligibility in Combination 1 and Combination 2.............. 76
Table 10: Screening Laboratory Tests (Central Laboratory).................................................................... 79
Table 11: Clinical Safety Laboratory Tests (Central or Local Laboratory)................................................ 80
Table 12: Biomarker Panel ..................................................................................................................... 150
Table 13: Time and Events Schedule (Long-term Extension Phase)..................................................... 157
FIGURES
Figure 1: Schematic for Combination 1.................................................................................................... 44
Figure 2: Schematic for Combination 2.................................................................................................... 45

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SYNOPSIS
A Phase 1b-2 Study of Niraparib Combination Therapies for the Treatment of Metastatic Castration-
Resistant Prostate Cancer
Niraparib is an orally available, highly selective poly (adenosine diphosphate [ADP]-ribose) polymerase
(PARP) inhibitor, with potent activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair
polymerases. In this study, the sponsor intends to investigate niraparib in combination with other agents.
This protocol will describe the overall conduct of the study, which will begin with niraparib in combination
with anti-PD-1 monoclonal antibody, cetrelimab (JNJ-63723283) (Combination 1). The second
combination to be studied is niraparib in combination with ZYTIGA® (abiraterone acetate [AA]) plus
prednisone (referred to as AAP) (Combination 2). Under Amendment 4, enrollment into Combination 2
was closed. Under Amendment 6, enrollment into Combination 1 (Cohort 1A and Cohort 1B) is closed.
The third combination to be studied is niraparib plus abiraterone acetate in 2 fixed-dose combination (FDC)
tablets (CJNJ-67652000) (Combination 3). The sponsor may amend this protocol in future to investigate
additional niraparib combination therapies, if and when scientific data are available to support such studies.
OBJECTIVES, ENDPOINTS, AND HYPOTHESES- Combinations 1 and 2
Primary Objectives and Endpoints for Part 1*
Objectives 
Endpoints
Primary
 
To evaluate the tolerability of niraparib 
combination therapies for the treatment of
mCRPC
 
Determine 
the 
RP2D 
of 
niraparib
combination therapies
 
Incidence of specified toxicities
mCRPC=metastatic castration-resistant prostate cancer; RP2D=recommended Phase 2 dose
*The RP2D for niraparib and AAP was established in the sponsor Study 64091742PCR1001
(see Section 1.3.2). Therefore, Part 1 (dose-finding) was not conducted in this study for Combination 2.
Primary Objectives and Endpoints for Part 2
Objectives 
Endpoints
Primary
 
To evaluate the antitumor effect of the RP2D 
of niraparib combination therapies for the 
treatment of mCRPC  
 
Combination 1: Objective response rate (ORR)
of soft tissue (visceral or nodal disease) as
defined by RECIST 1.1 with no evidence of
bone progression according to PCWG3 criteria
 
Combination 2: Composite response rate (RR):
defined as 1 of the following by PCWG3:50
 
Objective 
response 
(confirmed 
per
RECIST 1.1), or
 
CTC response: defined as CTC=0 per
7.5 mL of blood at 8 weeks for subjects
who have CTC ≥1 at baseline or CTC<5
per 7.5 mL with CTC ≥5 at baseline,

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Objectives 
Endpoints
confirmed by a second consecutive value
obtained 4 or more weeks later, or
 
PSA decline of ≥50%, measured twice 3
to 4 weeks apart
 
To evaluate the safety of the RP2D of
niraparib combination therapies for the
treatment of mCRPC
 
Incidence and severity of AEs
AE=adverse event; CTC=circulating tumor cells; mCRPC=metastatic castration-resistant prostate cancer;
ORR=objective response rate; PCWG3=Prostate Cancer Working Group 3; PSA=prostate-specific antigen;
RECIST=Response Evaluation Criteria in Solid Tumors; RP2D=recommended Phase 2 dose
Hypotheses
Part 1 (Safety Run-in): An RP2D of niraparib when combined with  other anticancer agents can be
identified.
Part 2 (Dose Expansion): Niraparib administered in combination with other anticancer agents at the
selected RP2D is safe and has antitumor activity.
The hypotheses specific to Combination 1 are as follows:
 
That cetrelimab inhibition of PD-1 complements the antitumor activity of the PARP inhibitor,
niraparib, for effective and safe treatment of subjects with metastatic castration-resistant prostate
cancer (mCRPC) and DNA-repair gene defects (DRD) or CDK12 pathogenic alterations.
 
The combination of niraparib and cetrelimab is safe and has antitumor activity in subjects with mCRPC
who do not have DRD or CDK12 pathogenic alterations.
The hypothesis specific to Combination 2 is as follows:
 
Androgen receptor (AR) inhibition enhances the antitumor activity of PARP inhibition for the effective
and safe treatment of subjects with mCRPC and DRD. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESES- Combination 3
Objectives 
Endpoints
Primary
 To determine the relative bioavailability of 2 
regular-strength FDC tablet formulations of 
niraparib and AA with respect to niraparib and AA 
co-administered as SA under fasted conditions in
subjects with mCRPC
 PK parameters (Cmax, [Cmax/dose]niraparib, AUC0-168h,
[AUC0-168h/dose]niraparib) of niraparib and AA after a
single dose
Secondary
 To evaluate the PK of a low-strength FDC tablet 
formulations of niraparib and AA under fasted 
conditions in subjects with mCRPC  
 To assess the safety of niraparib in combination with 
AA in subjects with mCRPC
 PK parameters (Cmax, [Cmax/dose]niraparib, AUC0-168h,
[AUC0-168h/dose]niraparib) of niraparib and AA after a
single dose
 Adverse events and clinical laboratory safety
AA=abiraterone acetate; AUC0-168h=area under the plasma concentration versus time curve over 7 days; Cmax=
maximum observed plasma concentration after a single dose; FDC=fixed-dose combination;
mCRPC=metastatic castration-resistant prostate cancer; PK=pharmacokinetic; SA=single agent

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Hypothesis
Combination 3 is an estimation study to assess the relative bioavailability (BA) of niraparib and AA as FDC
tablet formulations compared to single agents (SA) under fasted conditions by providing the point estimate
and associated precisions of the geometric mean ratios (GMRs) between the FDC test formulations and the
SA reference formulation for the primary pharmacokinetic (PK) parameters. No formal hypothesis will be
tested. 
OVERVIEW OF STUDY DESIGN
This is a Phase 1b-2, multicenter, open-label study to select the RP2D of niraparib in combination with
other anticancer agents, followed by dose expansion that will enroll adult subjects with mCRPC.
Combination 3 includes a BA assessment as described below.
Combination 1
For Part 1, at least 6 evaluable subjects will be treated with niraparib 200 mg orally once daily in
combination with cetrelimab 480 mg IV once every 4 weeks. The sponsor may choose to enroll subjects to
additional dose regimens (ie, at least 6 additional evaluable subjects with cetrelimab and a modified dose
of niraparib [ie, 100 mg or 300 mg]), depending on the available data with the niraparib 200 mg cohort.
Once an RP2D has been established for the combination in Part 1, approximately 30 subjects will be
enrolled per cohort for Part 2. All subjects will be assigned to a cohort based on their biomarker status for
DRD (ie, Cohort 1A=BM+ or Cohort 1B=BM-) or BM+ for CDK12 pathogenic alterations, which will be
determined during the prescreening phase using a blood or tissue assay (as it becomes available). Note that
a futility analysis was performed for Cohort 1B after approximately 10 subjects were enrolled and evaluated
in Part 2. Based on the futility analysis conducted, a response rate (RR) of 13% was not achieved.
Accordingly, the biomarker negative cohort (Cohort 1B) was closed to new enrollment. Subjects that are
enrolled in this cohort and still on study may continue. Study-related assessments, study procedures, and
data collection will be modified under Amendment 6.
Subjects with CDK12 pathogenic alterations are eligible to enroll into cohort 1A (BM+) of Combination 1
(niraparib + cetrelimab). The basis for this inclusion was data from the olaparib PROfound study. Metastatic
castration-resistant prostate cancer patients who had CDK12 pathogenic alterations treated with olaparib
had a median rPFS of 5.09 months compared to an rPFS of 2.20 months on either abiraterone or
enzalutamide, demonstrating that patients with CDK12 pathogenic alterations achieved greater benefit from
a PARP inhibitor compared to antiandrogen agents. Furthermore, Antonarakis et al. concluded that a
proportion of these patients respond modestly to PD-1 inhibitors, potentially implicating CDK12 deficiency
in immunotherapy responsiveness. Because CDK12 appears to define a distinctly immunogenic class of
prostate cancer and also now that there is randomized clinical trial evidence that PARP inhibition confers
an rPFS advantage versus standard of care hormonal therapy, the combination of these two independent
mechanisms of action is expected to confer at least additive clinical benefit to the proposed eligible
population.
Under Amendment 6, enrollment into Combination 1 (Cohorts A and B) is closed. Only subjects who have
signed the prescreening or screening informed consent form prior to the approval date of Amendment 6
will be allowed to be enrolled if all inclusion/exclusion criteria for Combination 1A are met.
Combination 2
The RP2D for niraparib plus AAP was established as niraparib 200 mg and abiraterone acetate 1,000 mg
plus prednisone 10 mg (AAP) in the sponsor study 64091742PCR1001. Therefore, Part 1 (dose-finding)
was not conducted for Combination 2.
Combination 2 will explore the safety and efficacy of niraparib plus AAP in subjects with mCRPC and
DRD (biallelic and monoallelic) as determined during the Prescreening Phase using a blood or tissue assay.

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A total of approximately 80 subjects will be enrolled into 4 cohorts (BRCA biallelic loss [2A], other DRD
biallelic loss [2B], BRCA monoallelic loss [2C], and other DRD monoallelic loss [2D]), with approximately
20 subjects in each cohort.
Under Amendment 4, enrollment into Combination 2 is closed. Only subjects who have signed the informed
consent form prior to the approval date of Amendment 4 will be allowed to complete screening and be
enrolled if all prescreening inclusion/exclusion criteria for Combination 2 are met. Subjects already enrolled
in Combination 2 can continue to receive study medication until documented disease progression or the
subject discontinues the study treatment for any reason. Under Amendment 4, study-related assessments
will be per local practice, at the investigator’s discretion, and limited data will be collected.
Combination 3
Combination 3 is an open-label, multi-center, partly randomized (Cohort 1 only), parallel group study to
determine the PK and safety of 2 FDC tablet formulations of niraparib+AA in men with mCRPC. The study
will consist of a 21-day Screening Phase to determine eligibility, an open-label PK Assessment Phase of
8 days (Study Days 1-8, inclusive), followed by an Extension Phase during which treatment with SA
niraparib and AAP will be continued from Cycle 1 Day 1 (Study Day 8) until discontinuation.
During the PK Assessment Phase, 3 cohorts will be studied:
 
Cohort 1: subjects (N=34) will be randomized to receive a single dose of niraparib plus AA (200 mg
niraparib + 1,000 mg AA) given as FDC1 regular-strength tablet formulation (G010) (Treatment Arm
B [Cohort 1B], N=17) or as SAs (Treatment Arm A [Cohort 1A], N=17). Relative BA of the FDC1
regular-strength tablet will be assessed by comparing PK results from Cohort 1A to Cohort 1B.
 
Cohort 2: subjects (N=17) will be assigned to receive a single dose of niraparib plus AA (200 mg
niraparib + 1,000 mg AA) as FDC2 regular-strength tablet formulation (G012) (Treatment Arm C,
Cohort 2C). Relative BA of the FDC2 regular-strength tablet will be assessed by comparing the PK
results from Cohort 2C to Cohort 1A.
 
Cohort 3: subjects (N=17) will be assigned to receive a single dose of niraparib plus AA (100 mg
niraparib + 1,000 mg AA) as a low-strength FDC1 (G009) (Treatment Arm D [Cohort 3D]) or FDC2
(G014) (Treatment Arm E [Cohort 3E]) tablet formulation. The selection of Cohort 3D or 3E will be
based on the relative BA results from Cohorts 1 and 2. Relative BA of the FDC1 or FDC2 low-strength
tablet formulation will be assessed by comparing the PK results from Cohort 3D or 3E, respectively,
to Cohort 1A.
Long-term Extension Phase for any Combination Subgroup
The Long-term Extension Phase for the specified combination will start once the Amendment 7 has been
approved at the site and after the notification by the sponsor.
EVALUATIONS
Combination 1 and Combination 2
 
Antitumor evaluations include the following:
 
Tumor measurements: Chest, abdomen, and pelvis computed tomography (CT) or magnetic
resonance imaging (MRI) scans and whole-body bone scans (99mTc). Imaging will be assessed by
the investigator and derived by the sponsor, and these results will be used for the primary endpoint
analyses.
 
serum PSA (per PCWG3)
 
CTCs

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survival status
 
Biomarker evaluations: DRD and CDK12 will be evaluated as part of prescreening eligibility. Other
exploratory biomarker analyses will be performed as appropriate.
 
Safety evaluations: Safety assessments will be based on medical review of adverse event (AE) reports
and the results of vital sign measurements, physical examinations, clinical safety laboratory tests,
Eastern Cooperative Oncology Group Performance Score, and other safety evaluations at specified
timepoints described in Time and Events Schedules.
Combination 1
 
PK and immunogenicity evaluations: Blood samples will be collected to measure the plasma
concentration of niraparib, and if performed, its metabolite, M1, when dosed with the combination
agent. Systemic (serum or plasma) concentrations of each combination agent, and population PK
parameters and derived exposure will also be determined. Anti-drug antibodies will be determined, if
applicable.
Combination 3
PK evaluations: Blood samples will be collected to measure the plasma concentrations of niraparib and
abiraterone.
Safety evaluations: collection of AEs and SAEs during the PK Assessment Phase (Days 1-8, up to the 168-
hour PK sampling). Serious AEs only will be collected throughout the Extension Phase (from C1D1 up to
discontinuation of study drug).
STATISTICAL METHODS
Statistical methods are specific to each combination.
Combination 1
For Part 1 of the study, at least 6 evaluable subjects each will be initially enrolled. Non-evaluable subjects
will be replaced. For Part 2 of the study, approximately 30 subjects per cohort will be enrolled. It is
anticipated that the final analysis for ORR will occur approximately 6 months after the last subject in each
cohort is enrolled.
For Part 2 of the study, the primary endpoint for antitumor activity is ORR. Cohorts 1A and 1B will be
evaluated and analyzed independently.
For Cohort 1A, the null hypothesis that the ORR is ≤25% will be tested against the alternative hypothesis
that the ORR is ≥50%. Antitumor activity of niraparib and cetrelimab will be declared if the lower bound
of the 2-sided 90% exact confidence interval (CI) for ORR is >25%. With approximately 30 BM+ subjects,
Cohort 1A will have over 80% power such that the lower limit of the 90% CI for ORR exceeds 25%.
For Cohort 1B, the null hypothesis that the ORR is ≤10% will be tested against the alternative hypothesis
that the ORR is ≥30%. Antitumor activity of niraparib and cetrelimab will be declared if the lower bound
of the 2-sided 90% exact CI for ORR is >10%.
With Cohort 1A and Cohort 1B closed under Amendment 6 prior to reaching the originally proposed sample
size, only exploratory statistical analyses will be performed on efficacy data collected from subjects
enrolled in this combination. Details will be provided in the statistical analysis plan (SAP).

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Combination 2
For Combination 2, the primary endpoint for antitumor activity is composite response rate, defined as the
proportion of subjects who have objective response (confirmed per RECIST 1.1), or CTC response (CTC=0
per 7.5 mL of blood at 8 weeks for subjects who have CTC ≥1 at baseline or CTC<5 per 7.5 mL with CTC
≥5 at baseline, confirmed by a second consecutive value obtained 4 or more weeks later), or PSA decline
of ≥50%, measured twice 3 to 4 weeks apart.
For subjects with biallelic DRD (cohorts 2A or 2B), the null hypothesis of ≤33% will be tested against the
alternative hypothesis that the composite response rate is ≥62%. Antitumor activity of niraparib and AAP
will be declared if the lower bound of the 2 sided 90% exact CI for the composite response rate is >33%.
With approximately 20 subjects in Cohort 2A (or 2B), it will have over 80% power such that the lower limit
of the 90% CI for the composite response rate exceeds 33%. 
For subjects with monoallelic DRD (cohort 2C or 2D), the null hypothesis of ≤28% will be tested against
the alternative hypothesis that the composite response rate is ≥57%. Antitumor activity of niraparib and
AAP will be declared if the lower bound of the 2 sided 90% exact CI for the composite response rate is
>28%. With approximately 20 subjects in Cohorts 2C (or 2D), it will have over 80% power such that the
lower limit of the 90% CI for the composite response rate exceeds 28%.
With Combination 2 closed under Amendment 4 prior to reaching the originally proposed sample size, only
exploratory statistical analyses will be performed on data collected from subjects enrolled in this
combination. Details will be provided in the SAP.
Combination 3
In total, approximately 68 subjects will be enrolled into Combination 3. Approximately 34 subjects
(17 subjects per treatment arm) will be randomized into Cohort 1 (SA niraparib+AA), and 17 subjects will
be assigned to each of Cohorts 2 and 3 (non-randomized) to ensure that at least 15 PK evaluable subjects
from each arm complete the study.
The primary PK parameters for statistical analysis will be Cmax  and AUC0-168h  of niraparib and AA. An
analysis of variance model (ANOVA) with treatment as fixed effect will be applied to the log-transformed
PK parameters data. The differences in means between the test formulations and the reference as well as
the associated 90% CIs for the differences will be constructed from the model. The results will be back-
transformed to derive the GMRs and the 90% CIs of abiraterone and niraparib, respectively.
An interim PK analysis will be conducted after 8 PK evaluable subjects from each treatment group (N=16)
complete PK assessments over 168 hours. 

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b. 
EoT Visit: The EoT visit must be scheduled within 30 days after both study drugs are discontinued, or prior to administration of a new anti-prostate cancer
therapy, whichever occurs first.
c. 
Prescreening/ Screening Informed consent: Must be signed before first study-related activity.
d. 
Biomarker panel for eligibility: Part 1 subjects can be dosed prior to assay results; however, biomarker results are required prior to dosing for Part 2
(see Section 9.5). All subjects must have a blood sample collected to determine biomarker status using the sponsor’s assay, unless already eligible by a sponsor-
approved assay and reviewed by the sponsor (Tissue may also be used to determine eligibility as described in Section 9.5).
e. 
Prescreening SAEs: should only be collected if related to study procedures (e.g. blood collection)
f. 
Fresh biopsy: The screening visit biopsy is mandatory for all subjects and can be performed up to 56 days before Cycle 1 Day 1 provided no active treatment was
initiated during this time. Every effort should be made to obtain fresh biopsies at Cycle 1 Day 15 and EoT (if clinically feasible) (see Section 9.5.1).
g. 
Archival tumor sample: The archival tumor sample may be collected during Cycle 1 if not collected at screening.
h. 
Medical History: Medical history obtained during the Prescreeing Phase will be disease-specific only.
i. 
Screening laboratory tests: To be performed by the central laboratory (see Table 10). Central laboratory testing may also be performed more frequently
throughout the study as clinically indicated. Evaluations can be used for the Cycle 1 Day 1 assessments if performed within 14 days of Cycle 1 Day 1.
j. 
Physical examination: At screening, a full physical examination should be performed. During the Treatment Phase and at the EoT visit, limited symptom-directed
physical examination will be performed. Only clinically relevant abnormalities should be recorded as AEs in the eCRF.
k. 
Clinical safety laboratory tests: To be performed by the central or local laboratory (see Table 11). During Cycle 1, complete blood counts should be performed
weekly. Any subject with Grade ≥3 hematologic toxicity should also have their CBCs monitored weekly until resolution. All tests may also be performed more
frequently throughout the study as clinically indicated. Prior to infusion with cetrelimab, results for a subset of tests should be available to ensure retreatment
criteria are met, as per the guidelines in Section 6.2.1.2.1. Clinical safety laboratory tests should be done every 2 weeks for the first 2 cycles and then on Day 1 of
every cycle thereafter (or more frequently at the investigator’s discretion).
l. 
CT or MRI; Bone scan (99mTc): Chest, abdomen, and pelvis CT or MRI scans and whole-body bone scans (99mTc) must be evaluated at screening. Scans
performed ≤8 weeks of Cycle 1 Day 1 are allowed and may serve as screening scans. Subjects may have imaging performed within ±7 days of visits requiring
images. Scans performed ≤6 weeks prior to the EoT visit may serve as EoT scans. Details regarding collection of scans are provided in Section 9.2. If a subject has
documented radiographic progression during the Treatment Phase, additional radiographic assessments are not required during the Follow-up Phase.
m. Circulating tumor cells: Subsequent sample collection is required only if CTC is ≥1 at screening.
n. 
Whole blood for immunophenotyping: An additional blood collection will occur at Cycle 1 Day 8 for selected subjects in Part 1 of the study.
o. 
Serum for Cytokine Analysis: samples will be collected as indicated, but may also be collected at unscheduled visits, if deemed necessary by the investigator.

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ABBREVIATIONS
99mTc 
technetium-99m
AA  
abiraterone acetate
ADT  
androgen deprivation therapy
AE 
adverse event
ALT  
alanine aminotransferase
AML 
acute myeloid leukemia
ANC  
absolute neutrophil count
AR  
androgen receptor
AST  
aspartate aminotransferase
AUC  
area under the curve
BA 
bioavailability
BM 
biomarker
BRCA  
breast cancer gene
CBC  
complete blood count
CI 
confidence interval
CLIA  
Clinical Laboratory Improvement Amendments
CMV  
cytomegalovirus
CR  
complete response
CRPC  
castration-resistant prostate cancer
CSR  
clinical study report
CT  
computed tomography
CTC  
circulating tumor cells
ctDNA  
circulating tumor DNA
DLT  
Dose-limiting toxicity
DNA  
deoxyribonucleic acid
DP  
drug product
DRC  
Data Review Committee
DRD  
DNA-repair gene defects
DSB  
double-stranded breaks
ECG  
electrocardiogram
ECOG PS  
Eastern Cooperative Oncology Group Performance Status
eCRF  
electronic case report form
EoT  
end-of-treatment
FIH  
first-in-human
FOIA  
Freedom of Information Act
GCP  
good clinical practice
GLP  
good laboratory practice
GnRHa 
gonadotropin releasing hormone analogue
HCV  
hepatitis C virus
HIV  
human immunodeficiency virus
HRR  
homologous recombination repair
ICF  
informed consent form
ICH  
International Council for Harmonisation
IEC  
Independent Ethics Committee
Ig 
immunoglobulin
irAE 
immune-related adverse event
IRB  
Institutional Review Board
IUD  
intrauterine device
IUS  
intrauterine hormone releasing system
IWRS  
interactive web response system
mCRPC  
metastatic castration-resistant prostate cancer
MDS  
myelodysplastic syndrome
MLR  
mixed lymphocyte reaction
MRI 
magnetic resonance imaging
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events

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NFAT  
nuclear factor of activated T-cells
ORR  
objective response rate
OS  
overall survival
PARP  
poly (adenosine diphosphate [ADP]-ribose) polymerase
PBMC  
peripheral blood mononuclear cell
PCWG3 
Prostate Cancer Working Group 3
PFS  
progression-free survival
PK 
pharmacokinetic(s)
PQC  
Product Quality Complaint
PR 
partial response
PRES  
Posterior Reversible Encephalopathy Syndrome
PSA  
prostate-specific antigen
RECIST  
Response Evaluation Criteria in Solid Tumors
RNA  
ribonucleic acid
RO  
receptor occupancy
RP2D  
recommended Phase 2 dose
rPFS  
radiographic progression-free survival
RR  
response rate
SAC  
safety assessment committee
SAE 
serious adverse event
SAP  
statistical analysis plan
SIPPM  
site investigational product preparation manual
SSE 
symptomatic skeletal event
TCR  
T-cell receptor
TEAE 
treatment-emergent adverse event
TSH  
thyroid-stimulating hormone
ULN  
upper limit of normal
US  
United States
WHO  
World Health Organization

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1. 
INTRODUCTION
Niraparib is an orally available, highly selective poly (adenosine diphosphate [ADP]-ribose)
polymerase (PARP) inhibitor, with potent activity against PARP-1 and PARP-2 deoxyribonucleic
acid (DNA)-repair polymerases.28 The sponsor licensed niraparib for the development of prostate
cancer from TESARO, who is currently conducting clinical studies of breast cancer (IND 117580),
ovarian cancer (IND 100996) and non-small cell lung cancer (134426). Niraparib was approved
in the United States (US) by the Food and Drug Administration (FDA) on 27 March 2017 for the
maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary
peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
Niraparib also received European Commission approval (16 November 2017) for use as a
monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high
grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response
(complete or partial) to platinum-based chemotherapy (EMA/CHMP/574018/2017).
In this study, the sponsor intends to investigate niraparib in combination with other agents
(hereafter, the combination of niraparib and other anticancer agent will be termed “niraparib
combination therapies” and the other anticancer agent will be termed “combination agent”) for the
treatment of metastatic castration-resistant prostate cancer (mCRPC). This protocol will describe
the overall conduct of the study, which will investigate Combination 1 (niraparib in combination
with cetrelimab [JNJ-63723283]), Combination 2 (niraparib in combination with ZYTIGA®
[abiraterone acetate] plus prednisone; hereafter referred to as AAP), and Combination 3 (a relative
bioavailability [BA] evaluation of fixed-dose combination [FDC] tablets of niraparib plus AA
versus niraparib plus AA administered as single agents) for the treatment of mCRPC. The sponsor
may amend this protocol in future to investigate additional niraparib combinations, if and when
scientific data are available to support such studies.
Cetrelimab is a fully human immunoglobulin (Ig) G4 kappa monoclonal antibody (mAb) that binds
to PD-1 with high affinity and specificity. It blocks binding to both PD-1 ligand 1 (PD-L1) and
PD-1 ligand 2 (PD-L2) to enhance pro-inflammatory cytokine production. Cetrelimab is currently
being investigated in a Phase 1-2, first-in-human (FIH) study in subjects with advanced cancers.
Abiraterone acetate [AA; JNJ-212082] is a pro-drug of abiraterone (JNJ-589485) 17-(3-pyridyl)
androsta-5,16-dien-3β-ol], an androgen biosynthesis inhibitor. Abiraterone selectively inhibits the
enzyme CYP17, which is found in the testes and adrenals, as well as in prostate tissues and
tumors.38 The clinical benefits of AAP for the treatment of prostate cancer were demonstrated in
3 large, randomized, double-blind, placebo-controlled Phase 3 studies. These studies included
patients with metastatic castration-resistant prostate cancer (mCRPC) post-chemotherapy
(COU-AA-301), chemotherapy-naïve patients (Study COU-AA-302), and patients with high-risk
metastatic hormone-naïve (mHNPC) disease (Study 212082PCR3011).9,13,42,46 AAP is currently
approved in more than 100 countries worldwide for the treatment of men with metastatic prostate
cancer (exact wording of indications vary by region).37
Two FDC drug products, FDC1 and FDC2, will be evaluated. The FDC drug product formulations
will be manufactured as immediate-release film-coated 50 mg niraparib/500 mg AA (FDC1 low
strength (G009) and FDC2 low strength (G014) or 100 mg niraparib/500 mg AA (FDC1 regular

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strength (G010 and FDC2 regular strength (G012) tablets for oral administration containing 79.70
mg or 159.40 mg of niraparib tosylate monohydrate drug substance, equivalent to 50 or 100 mg
niraparib free base, and 500 mg of AA drug substance.
The term "sponsor" used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
1.1. 
Background and Design Rationale
PARP inhibitors are currently being investigated alone and in various combination regimens for
the treatment of patients with prostate cancer. However, it is unclear if PARP inhibitors have an
effect on all prostate tumors, or just a subset with DNA-repair gene defects (DRD). Patients with
metastatic castration-resistant prostate cancer (mCRPC) and DRD (ie, biomarker positive [BM+]
patients) may have an improved response to single-agent PARP inhibitors compared with patients
without DNA-repair anomalies (ie, biomarker-negative [BM-] patients).35
The mechanism by which this is thought to occur has been well established. In response to
genotoxic insult, tumor cells recruit proteins, such as PARPs, to promote DNA-repair, which
allows tumor cells to survive. PARP inhibition leads to an accumulation of unrepaired single-
strand breaks, which result in stalling and collapse of replication forks and, consequently, to
double-strand breaks (DSBs). One way of repairing DSBs is through homologous recombination
repair (HRR), a type of DNA repair. If not repaired, DSBs result in cell death. When tumor cells
with DRD involving the HRR pathway (eg, breast cancer genes [BRCA]1/2) are treated with a
PARP inhibitor, they are unable to efficiently and accurately repair DSBs, which creates a
synthetic lethal condition.6,11,51 In patients with mCRPC, DNA-repair anomalies are identified in
approximately 20% to 30% of tumors.17,45
Clinical data from the TOPARP study with the PARP inhibitor, olaparib (Lynparza®), have
demonstrated potential efficacy in subjects with mCRPC whose tumors have DRD following
treatment with chemotherapy and androgen receptor (AR)-targeted agents.35 Initial data suggest
improvement in both radiographic progression-free survival (rPFS) and overall survival (OS) in
olaparib-treated subjects with either germline or somatic DRD (ie, subjects with BM+ tumors
containing defects in genes such as BRCA1, BRCA2, ATM, and FANCA, n 16) compared with
those subjects whose tumors did not have germline or somatic mutations or deletions (ie, BM-
subjects, n 34). In this study, rPFS was longer for those subjects whose tumors were BM+
compared with subjects whose tumors were BM- (median 9.8 months versus 2.7 months,
respectively). Though preliminary, OS data showed a similar trend (13.8 months versus
7.5 months); however, these findings are difficult to interpret given the small sample size (16 BM+
subjects) and retrospective biomarker analysis. Out of 32 subjects with measurable disease,
6 subjects had confirmed radiologic partial response (19%). Of the BM+ subjects in this subset, 5
out of 7 subjects had a confirmed radiologic partial response. In the TOPARP study, prostate
cancer subjects who were BM- appeared to have no significant response to treatment with olaparib.
The sponsor is currently investigating the efficacy and safety of single-agent 300 mg niraparib in
subjects with mCRPC and DRD in an ongoing Phase 2 study (64091742PCR2001). The sponsor
also explored the safety and antitumor activity of niraparib doses of 200 and 300 mg in

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combination with 1,000 mg abiraterone acetate plus 10 mg prednisone daily in subjects with or
without DNA-repair anomalies in the completed Phase 1b study (64091742PCR1001). This study
established the RP2D of niraparib in combination with AR-targeted therapy as niraparib 200 mg
plus AA 1,000 mg and prednisone 10 mg daily.47
Therapeutic strategies that combine other anticancer agents to create a synthetical lethal
environment are necessary to expand the cohort of patients who could benefit from treatment with
PARP inhibitors (ie, those without DRD), as well as improve the response of patients whose
tumors exhibit DRD. PARP inhibitors may be an important backbone therapy for the treatment of
prostate cancer with DRD. However, the exploration of different PARP inhibitor combination
strategies as separate clinical studies would be logistically difficult, time consuming, and delay
promising therapies from reaching patients in need. The rapid implementation of new research
findings within the protocol framework and study design is essential.4 Protocols that allow multiple
arms with different treatment combinations are increasingly being utilized to efficiently evaluate
multiple therapies for a particular disease type and have been shown to be substantially more
efficient than traditional study designs.58,61
Once efficacy analyses (if applicable) have been performed for each combination, those
combinations can be evaluated if further study is warranted. This strategy significantly reduces
time, number of subjects, and the cost needed to bring promising agents to the clinical setting.
Therefore, the sponsor has designed this protocol to efficiently evaluate niraparib in combination
with other anticancer agents as a treatment for prostate cancer, in an effort to help the greatest
number of patients in need.
1.1.1. 
Combination 1: Niraparib and Cetrelimab
The sponsor intends to investigate niraparib in combination with an anti-PD-1 mAb checkpoint
inhibitor, cetrelimab. The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors
to suppress immune control.59 The normal function of PD-1 is to suppress unwanted or excessive
immune responses, including autoimmune reactions. PD-1 is typically expressed on activated
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, regulatory T-cells, and natural
killer cells. PD-1 is an Ig superfamily member that negatively regulates antigen-receptor signaling
upon binding to its ligands, PD-L1 and PD-L2. PD-1 is a transmembrane glycoprotein with an Ig
variable-type ligand binding domain and a cytoplasmic tail responsible for binding to signaling
molecules.30 Following T-cell stimulation, PD-1 signaling is induced, causing dephosphorylation
of effector molecules involved in the CD3 T-cell signaling cascade.
The investigation of checkpoint inhibitors in prostate cancer is ongoing and some treatments have
shown some antitumor activity, albeit in very few subjects to date. In a Phase 1-2 study of the
CTLA-4 inhibitor, ipilimumab, in 28 tumor-evaluable subjects, 1 had a complete response (CR)
and 2 had unconfirmed partial response (PR).53 In a Phase 1 study of the anti-PD-1 mAb,
pembrolizumab, 2 out of 3 evaluable subjects had a PR to single-agent therapy.16 Though these
data are encouraging, the optimal setting and patient population for treatment with these agents
has not been established.

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Cetrelimab is a fully human IgG4 kappa anti-PD-1 mAb. Cetrelimab binds to PD-1 with high
affinity and specificity, blocks binding to both PD-L1 and PD-L2 ligands, enhances
pro-inflammatory cytokine production from ex vivo stimulated T-cells, and reduces tumor volume
in human PD-1 knock-in mice bearing MC38 murine colon carcinoma tumors. Cetrelimab is
currently being investigated in an FIH proof-of-concept study (Study 63723283LUC1001).
The rationale for combining a PARP inhibitor and a checkpoint inhibitor has a robust preclinical
foundation. In cell lines and animal models unselected for DRD, PARP inhibitors were associated
with upregulation of PD-L1 expression. Once treated with PD-L1 blockade, these cells became
sensitive to T-cell killing.26 In addition, tumor associated antigens are thought to be released by
PARP inhibitors and are hypothesized to potentiate the efficacy of checkpoint inhibitors. The
combination of the PARP inhibitor, niraparib, and the PD-1 inhibitor, cetrelimab, has the potential
to benefit patients with mCRPC who may or may not have DRD or CDK12 pathogenic alterations.
Niraparib is being investigated by TESARO in combination with the anti-PD-1 mAb,
pembrolizumab, for the treatment of recurrent, platinum-resistant ovarian cancer and triple-
negative breast cancer (Phase 1/2 TOPACIO study) in biomarker-unselected subjects. In the dose
escalation phase, a disease control rate of 69% was observed (9 of 13 evaluable subjects), including
3 PRs and 1 CR, in subjects with platinum-resistant ovarian cancer. With a dose of niraparib at
200 mg once daily, 1 of 7 subjects enrolled in Phase 1 of the study was reported with dose-limiting
toxicities (DLTs; Grade 3 anemia, Grade 4 neutropenia, and Grade 4 thrombocytopenia). At Dose
Level 2, 1 of 7 subjects was reported with 1 DLT of Grade 4 thrombocytopenia. No significant
overlapping toxicities were observed. The 200-mg dose was established as the RP2D for
combination studies with niraparib. However, patients who meet certain hematologic parameters
after at least 2 cycles of therapy are permitted to escalate to niraparib 300 mg once daily on or after
Cycle 3 Day 1, in an effort to potentially increase efficacy with the higher dose of niraparib. As of
August 2017, 2 subjects have been escalated from 200 mg to 300 mg niraparib after 2 cycles and
have had no Grade ≥3 events. Data from 83 subjects treated to date show no new safety signals
with the combination. Thirty subjects (36%) enrolled in Phase 2 of the study reported
treatment-related Grade ≥3 AEs that have been primarily hematologic (anemia, thrombocytopenia,
and fatigue). Preliminary data for antitumor activity are encouraging with 6 of 29 subjects with
ovarian cancer and 5 of 27 subjects with breast cancer showing at least a PR by Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1. Notably, responses have been observed in
subjects with BRCA-wild-type and PD-L1 negative tumors in both ovarian and triple-negative
breast cancers.32
In the mCRPC setting, Karzai et al have shown that olaparib plus the anti-PD-L1 checkpoint
inhibitor, durvalumab, showed signals of efficacy in subjects with mCRPC who were unselected
for DRD.29 Out of 16 subjects that were on the study for greater than 2 months, 7 had prostate-
specific antigen (PSA) declines of >50%, the 9-month progression-free survival (PFS) rate was
57.8%, and median PFS was not yet reached.1 AEs were generally manageable and Grade 3/4 AEs
included anemia (21%), thrombocytopenia (7%), neutropenia (7%), nausea (7%), and fatigue
(7%). Data on radiographic response rate are not yet available.

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The olaparib PROfound study showed that mCRPC patients who had CDK12 gene alterations
treated with olaparib had a median rPFS of 5.09 months compared to an rPFS of 2.20 months on
either abiraterone or enzalutamide, demonstrating that patients with CDK12 gene alterations
achieved greater benefit from a PARP inhibitor compared to antiandrogen agents.8 Furthermore,
Antonarakis et al. concluded that a proportion of these patients respond modestly to PD-1
inhibitors, potentially implicating CDK12 deficiency in immunotherapy responsiveness.3 Because
CDK12 appears to define a distinctly immunogenic class of prostate cancer and also now that there
is randomized clinical trial evidence that PARP inhibition confers a rPFS advantage versus
standard of care hormonal therapy, the combination of these two independent mechanisms of
action is expected to confer at least additive clinical benefit to the proposed eligible population. 
1.1.2. 
Combination 2: Niraparib and AAP
The sponsor will investigate niraparib in combination with AAP. In addition to facilitating
DNA-repair, dual roles for PARP in supporting AR activity have been observed in the preclinical
setting. PARP-1 is a potent modulator of both AR function and response to DNA damage.51
Primary human prostate tumor ex vivo cultures showed significant antitumor response to PARP
inhibition, which was correlated with diminished AR activity. Similarly, RNA-seq analysis
showed that AR regulated transcription of genes involved in DNA-repair in LNCaP cells after
androgen treatment.40 The impact of niraparib in combination with abiraterone was evaluated by
the sponsor in the human VCaP-prostate tumor model. Mice bearing VCaP tumors were treated
with niraparib either alone, or in combination with abiraterone. The combination of niraparib plus
abiraterone showed better inhibition of tumor growth and survival prolongation than the single
agents (sponsor data). This result further supports the hypothesis that combining a PARP inhibitor
with AA may benefit prostate cancer patients.
In the clinical setting, recent data have shown the efficacy of combining AR-targeted therapy and
a PARP inhibitor in patients with metastatic prostate cancer, but the patient population most
sensitive to this combination is not yet known. Patients treated with a combination of olaparib and
AAP had improved rPFS compared with those treated with AAP alone.7 This benefit was seen in
patients with and without DRD. A study of patients treated with the combination of veliparib and
AAP showed benefit only in tumors that were DRD positive.21 Patients whose tumors have DRD
may have different responses based on the type of mutation and gene type (e.g. monoallelic vs.
biallelic, BRCA vs. other). Therefore, further exploration of the efficacy of the AAP plus PARP
inhibitor combination based on the mutation and gene type is warranted.
In Study 64091742PCR1001 the sponsor evaluated niraparib in combination with AAP. Niraparib
200 mg was selected to be the optimal dose to be combined with AAP. The combination of 200 mg
niraparib+1,000 mg AA and 10 mg prednisone daily is also being evaluated in the ongoing
Phase 3, 
double-blind, 
randomized, 
placebo-controlled 
Study 64091742PCR3001
(MAGNITUDE). Study 64091742PCR3001 is intended to be the pivotal clinical study supporting
registration of niraparib in combination with AAP for the treatment of men with mCRPC (with
and without DRD). 

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1.1.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose
Combination Tablet
In parallel to Study 64091742PCR3001, as mentioned above, the Sponsor is pursuing development
of an FDC tablet formulation of niraparib and AA with the aim of simplifying the combination
regimen by reducing the pill burden. Based on the recommended dose of AA and the recommended
Phase 2 dose for niraparib under Study 64091742PCR1001, the combination of these 2 individual
products would require patients to be treated with up to 6 pills per day with the further addition of
1 to 2 tablets of prednisone or prednisolone. The FDC tablet presentation would reduce the number
of pills to 2 tablets per day. Reducing the pill burden for patients on oral medications for cancer
may improve compliance as cancer patients often take multiple oral medications for cancer and
for other comorbid conditions.15
The MAGNITUDE Study is a randomized, placebo-controlled, double-blind study investigating
niraparib and AAP versus AAP and placebo as first-line therapy for subjects with mCRPC. The
study stratifies subjects into 2 cohorts; those with HRR gene alterations (Cohort 1, n 400 planned
to be enrolled) and those with no HRR gene alterations (Cohort 2, n 600 planned to be enrolled).
Cohort 3 is an open-label cohort to evaluate the clinical efficacy and safety of the FDC tablet
formulation of niraparib and AA in subjects with HRR gene alterations. This cohort is expected to
enroll approximately 40 subjects (approximately 20 with BRCA alterations); enrollment will begin
after enrollment into Cohorts 1 and 2 have completed and when the sponsor opens Cohort 3 for
enrollment.
Data from a futility analysis of the cohort without HRR gene alterations (Cohort 2) was reviewed
by an Independent Data Monitoring Committee (IDMC) on 13 August 2020. A total of
233 subjects were included in the analysis, 117 in the niraparib and AAP arm and 116 in the AAP
arm. Baseline demographics, disease characteristics and prior treatments were generally balanced
across treatment groups. The IDMC determined that the futility rule was met, indicating the study
did not show additional benefit of adding niraparib to AAP in subjects with no HRR gene
alterations. No new safety signals were identified. Based on the IDMC recommendation, and after
review by the Sponsor Committee, further enrollment into Cohort 2 was not re-opened. Subjects
in Cohort 2 may remain on AAP, niraparib, or both. The MAGNITUDE study remains open to
complete enrollment into Cohort 1 and Cohort 3 in subjects with HRR gene alterations.
In Combination 3, the sponsor will evaluate the relative BA of 2 regular-strength and
1 low-strength FDC tablet formulations of niraparib plus AA compared to coadministration of
single agents (SA) of the available commercial formulations of niraparib capsules and AA tablets
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in subjects with mCRPC. The objective of evaluating Combination 3 in this platform protocol is
to determine the relative BA of the FDC formulations and select the 1 with favorable PK
parameters for further clinical development. Thus, FDC tablets will be given only as a single dose
for the purpose of assessing relative BA. Subjects will be dosed with single agents, as in
Combination 2, for the remainder of their treatment after the PK assessment is complete. The
design and procedures associated with Combination 3 are fully described in Attachment 6.
Cross-references and links back to the protocol have been made for general study-related
information (eg, background, administrative requirements).
It is expected that the 2 formulations of the regular-strength FDC tablets (2x100 mg
niraparib/500 mg AA), ie, FDC1 (G010) and FDC 2 (G012), would result in similar exposures of
niraparib and abiraterone when compared to the SAs.  See Section 14.1, for a physical description
of the FDC study drugs. The sponsor also developed 2 low-strength versions of the FDC tablet
formulations, FDC1 (G009) and FDC2 (G014). Each low-strength FDC tablet formulation has
50 mg niraparib and 500 mg AA. Based on the PK results from regular-strength FDC tablets, 1 of
the 2 low-strength FDC tablet formulations will be further tested to obtain additional PK
information.
The rationale to develop the low-strength FDC tablet is to address the need for patients who may
require a lower dosage of niraparib due to toxicity (eg, thrombocytopenia, neutropenia). Based on
data from Study 64091742PCR1001, in the niraparib plus AAP treatment group, 21% of subjects
with a starting niraparib dose of 200 mg had a reduction in niraparib to 100 mg, most frequently
due to cytopenias, and only 5% had a dose reduction in AA. Therefore, given the low rate of dose
reduction in AA, an FDC tablet formulation with a lower strength of AA is not being developed.
Due to the genotoxicity of niraparib, this relative BA of FDC will be evaluated in mCRPC patients,
regardless of DRD and prior line of therapy, but not in healthy volunteers.  Furthermore, mCRPC
is also the target population for the niraparib registration Study 64091742PCR3001.
1.2. 
Summary of Available Nonclinical and Clinical Data for Niraparib
A summary of the nonclinical and clinical information available for niraparib to date is provided
below. For the most comprehensive nonclinical and clinical information regarding niraparib, refer
to the latest version of the niraparib Investigator’s Brochure.24
Nonclinical Data
In cancer cell lines that have been silenced for BRCA1 or BRCA2 genes, or that have BRCA1 and
BRCA2 mutations, niraparib demonstrates anti-proliferative activity due to cell cycle arrest,
followed by apoptosis. Further, in vivo studies in mice showed that niraparib has antitumor activity
against BRCA1-deficient breast cancers and BRCA2-deficient pancreatic and ovarian cancers.
In toxicology studies, a dose-related (0 to 10 mg/kg) increase in mean arterial pressure and heart
rate was observed following 30-minute infusion to anesthetized dogs. There were no
treatment-related changes in blood flow, PR interval, or QTc interval in anesthetized dogs;
however, a small increase in QRS interval was observed at the 10 mg/kg dose. The peak niraparib
exposure following 10 mg/kg infusion was 4,896 ng/mL. In repeat-dose toxicity studies in rats and

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dogs, hematologic toxicities were observed but resolved by the end of the recovery period
(typically 15 to 28 days).
Clinical Data
Niraparib has been evaluated at various doses, alone and in combination with other anticancer
agents. With increasing doses, exposures increased linearly and dose-proportionally. Doses from
100 mg per day to 400 mg per day have shown antitumor activity. The DLT at 400 mg once daily
was thrombocytopenia. Niraparib is currently being investigated at 300 mg once daily as
monotherapy in ongoing registration clinical studies in ovarian and breast cancer and has been
approved in the US at that dose for the maintenance treatment of adult patients with recurrent
epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a CR or PR to
platinum-based chemotherapy.62 The dose of 300 mg is also being evaluated as monotherapy in
sponsor Study 64091742PCR2001 for the treatment of subjects with mCRPC and DRD. Doses of
200 mg and 300 mg niraparib are also being explored in various ongoing combination studies,
including sponsor study 64091742PCR1001 investigating niraparib and AAP and the TESARO
TOPACIO study in combination with pembrolizumab.55
In the Phase 3 registration NOVA study (NCT01847274) for subjects with ovarian cancer
previously treated with platinum-based chemotherapy, the most common Grade 3/4 AEs were
thrombocytopenia (29%), anemia (25%), and neutropenia (20%).62 Other important risks that have
been reported with the use of niraparib are hypertension, including hypertensive crisis and
myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).24 Preliminary safety data
obtained from the sponsor’s 64091742PCR2001 single-agent study suggest a similar safety profile
in subjects with mCRPC, with no new safety signals being observed to date (sponsor’s internal
data).
Following oral administration, niraparib is rapidly absorbed, with peak concentrations occurring
at about 3 hours postdose in subjects. The absolute bioavailability in humans is approximately
73%. Niraparib can be administered with or without food. Following multiple daily doses of
300 mg niraparib, the mean half-life is 36 hours. In a population pharmacokinetic (PK) analysis,
the apparent total clearance (CL/F) of niraparib was 16.2 L/h. Niraparib is cleared though renal
and hepatic metabolism, both as unchanged drug and as metabolites. In humans, M1 and M10
(glucuronides of M1) are the major circulating metabolites after single-dose administration, with
M1 being present at exposures comparable to or slightly higher than the parent drug. The
elimination of M1 appears to be parallel to that of the parent drug.
1.3. 
Summary of Available Nonclinical and Clinical Data for Combination
Agents
1.3.1. 
Combination 1: Niraparib and Cetrelimab
Cetrelimab is a fully human IgG4 kappa anti-PD-1 mAb containing the hinge-stabilizing S228P
mutation. This mutation prevents the fragment antigen binding arm exchange that normally occurs
with IgG4 antibodies.2 A summary of the nonclinical and clinical information available for
cetrelimab to date is provided below. For the most comprehensive nonclinical and clinical

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information regarding cetrelimab, refer to the latest version of the cetrelimab Investigator’s
Brochure.22
Nonclinical Data
Nonclinical Pharmacology
PD-1 blockade with cetrelimab enhanced T-cell function in vitro, as evidenced by dose dependent
increases in pro-inflammatory cytokine levels in mixed lymphocyte reaction (MLR) and
cytomegalovirus (CMV) recall assays. In addition, cetrelimab reversed PD-1 mediated suppression
of T-cell receptor signaling by promoting nuclear factor of activated T-cells (NFAT)-reporter
transcriptional activity in Jurkat T-cell lines. The in vitro activity of cetrelimab was comparable to
that observed for nivolumab and pembrolizumab analogues in the MLR, CMV, and
NFAT-reporter assays. In vivo, cetrelimab also inhibited tumor growth in human PD-1 knock-in
mice bearing MC38 murine colon carcinoma tumors and showed comparable antitumor efficacy
to a nivolumab analogue.
Toxicology
Data from the 4- and 5-week toxicology studies in cynomolgus monkeys indicate cetrelimab was
clinically well-tolerated and demonstrated evidence of pharmacology (T-cell dependent antibody
response enhancement). No cetrelimab-related effects were noted in cardiovascular, respiratory,
or central nervous system during the 5-week study. Primary cetrelimab-related findings noted in
4- and 5-week monkey studies at ≥10 mg/kg/wk included slight increases in monocyte counts and
prothrombin times in the 4-week study, and slight increases in prothrombin times. In the 5-week
study, the no-observed-adverse-effect level was 100 mg/kg/wk (mean Cmax  3,055.75 μg/mL and
AUCDay29 36 12,658.15 μg day/mL following the dose on Day 29). cetrelimab cytokine response in
vitro in human blood was similar to other immune-modulatory compounds with a low risk of
cytokine-release syndrome.
Clinical Data
Clinical experience with cetrelimab in humans is from an ongoing monotherapy
Study 63723283LUC1001. This is a multicenter, Phase 1-2, FIH study of cetrelimab in subjects
with advanced solid tumors. Part 1 of the study, initiated on 21 November 2016, consists of dose
escalation cohorts and PK/pharmacodynamic cohorts. cetrelimab is being evaluated in selected
solid tumor types including non-small-cell lung cancer, melanoma, bladder cancer, renal cancer,
small cell lung cancer, and gastric/esophageal cancer.
As of the data cutoff date of 4 September 2017, 76 subjects have received at least 1 dose of
cetrelimab. The duration of cetrelimab treatment ranged from 1 to 4 months; the number of doses
administered ranged from 1 to 14. Thirteen subjects had discontinued study treatment. Eleven
subjects discontinued due to progressive disease, 1 subject discontinued due to a
treatment-emergent AE (TEAE) of Grade 3 pneumonitis, and 1 subject died. AEs have been
consistent across tumor types following monotherapy and have not demonstrated a clear dose-
response relationship. Of the 76 treated subjects, 72 (94.7%) were reported with at least 1 TEAE.
The most frequently reported TEAEs (≥10% of subjects) were dyspnea (18.4%); diarrhea and

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anemia (17.1% each); asthenia, fatigue, and pyrexia (14.5% each); abdominal pain, nausea,
hypertension, and decreased appetite (11.8% each); and hyponatremia (10.5%).
Overall, the safety profile has been similar to that of other anti-PD1 agents (such as nivolumab and
pembrolizumab), although a higher percentage of treatment-emergent infusion-related reactions
have been observed to date. Eight of the 76 treated subjects were reported with treatment-emergent
infusion-related reactions (IRRs) as assessed by the investigator. The most frequently reported
treatment-emergent IRRs were nausea and generalized rash in 2 subjects each. Other events
reported as IRRs included malaise, dyspnea, non-cardiac chest pain, tachycardia, vomiting,
pyrexia, flushing, increased gamma-glutamyl transferase, an infusion reaction with no additional
symptoms reported, and body itching redness were reported by 1 subject each. All subjects who
were reported with IRRs received cetrelimab 240 mg once every 2 weeks, with the exception of
1 subject who received cetrelimab 460 mg once every 2 weeks and was reported with IRRs of
nausea, generalized rash, tachycardia, and vomiting. The IRRs reported in the study were mostly
Grade 1 or Grade 2. With the exception of increased gamma-glutamyl transferase and body itching
redness, the IRRs were transient and resolved with the interruption of study treatment. None of the
reported IRRs were considered serious AEs (SAEs). These data should be interpreted with caution
given the relatively small number of subjects dosed to date.
As of 4 September 2017, of the 76 subjects treated with cetrelimab, 64 were evaluable for response.
Five subjects, all of whom were receiving cetrelimab 240 mg once every 2 weeks and had either
NSCLC, melanoma, gastric cancer, or thymoma, had a PR (2 confirmed responses) and 30 subjects
(with NSCLC, melanoma, renal cell cancer, bladder cancer, gastric/esophageal cancer, or others)
had stable disease. As of 5 October 2017, 9 subjects have been treated with cetrelimab 480 mg
every 4 weeks. No subjects were reported with DLTs to date and the side effect profile is similar
to the 240 mg every 2 weeks dose. Efficacy analyses are not yet available for those subjects treated
with cetrelimab 480 mg every 4 weeks.
In 20 PK-evaluable subjects, serum concentration data following the first dose of cetrelimab
exhibited approximately linear PK. Maximum serum concentration (Cmax), minimum serum
concentration after the first dose (Cmin1), and area under the curve for 1 dosing interval (AUCtau)
increased in an approximately dose-proportional manner from 80 to 460 mg. Interpatient
variability was generally consistent with mAb therapeutics. PD-1 receptor occupancy on
circulating CD3+ T-cells was evaluated in 24 subjects and preliminary results indicated postdose
saturation following 80 to 460 mg once every 2 weeks and maintenance of relative saturation
throughout continued dosing in the majority of subjects.
1.3.2. 
Combination 2: Niraparib and AAP
AAP is approved for the treatment of patients with metastatic prostate cancer.64 A brief summary
of the clinical information available for AAP is provided below. For the most comprehensive
nonclinical and clinical information regarding AAP, refer to the latest version of the abiraterone
acetate Investigator’s Brochure.22
In clinical studies of subjects with metastatic prostate cancer, the most common AEs related to AA
include peripheral edema, hypokalemia, urinary tract infection, ALT increased, aspartate

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aminotransferase increased, dyspepsia, hematuria, hypertension, and fractures.13,64 AA should be
used with caution in subjects with a history of cardiovascular disease. Caution should be exercised
when treating subjects whose underlying medical conditions might be compromised by increases
in blood pressure, hypokalemia, or fluid retention.
Prednisone/prednisolone may be associated with fatigue, increased appetite, insomnia, weakness,
hyperglycemia, ecchymosis, and symptoms related to gastroesophageal reflux. With long-term
glucocorticoid therapy, subjects may develop Cushing’s syndrome, characterized by central
obesity, thin skin, easy bruising, bone loss, avascular necrosis of the hip, cataract and proximal
myopathy. Withdrawal of the corticosteroid may result in symptoms that include fever, myalgia,
fatigue, arthralgia, and malaise.
The combination of niraparib and AAP was evaluated in the Phase 1b study of subjects with
mCRPC (Study 64091742PCR1001). In this study, 27 subjects were included in the Safety
Population; 19 subjects in the niraparib 200 mg plus AAP cohort and 8 subjects in the niraparib
300 mg plus AAP cohort.
No dose-limiting toxicities (DLTs) were reported in the niraparib 200 mg plus AAP cohort during
Cycle 1 of the study (ie, the 28-day DLT evaluation period). In the niraparib 300 mg plus AAP
cohort, 1 DLT of Grade 3 fatigue, possibly related to niraparib and AAP, was reported in a patient
treated with niraparib 300 mg plus AAP; the niraparib dose was reduced, and the event did not
resolve. Two DLT-like events of Grade 4 neutropenia occurred at Day 29.
All patients (both niraparib 200 mg plus AAP and niraparib 300 mg plus AAP) reported at least 1
or more AEs of any grade. More Grade 3 or 4 events were observed in the niraparib 300 mg plus
AAP cohort (88%) than in the niraparib 200 mg plus AAP cohort (58%). The most frequently
reported TEAEs were nausea and vomiting in the 200 mg plus AAP cohort and fatigue in the
300 mg plus AAP cohort. The niraparib 300 mg plus AAP cohort also had more SAEs (38%) and
TEAEs leading to dose interruption/reduction (25%) than the niraparib 200 mg plus AAP cohort
(16% and 16%, respectively). AEs of special interest (AESIs) in this study are hematologic
toxicities and hypertension. Thrombocytopenia, anemia, and neutropenia were reported in
6 (31.6%), 3 (15.8%), and 3 (15.8%) patients, respectively, in the niraparib 200 mg plus AAP
cohort and 1 (12.5%), 2 (25.0%), and 2 (25.0%) patients, respectively, in the niraparib 300 mg
plus AAP cohort. Hypertension of any grade was reported in 5 (26.3%) patients in the niraparib
200 mg plus AAP cohort and 1 (12.5%) patient in the niraparib 300 mg plus AAP cohort. No
cardiac or cardiovascular-related deaths were observed in this study. 
The PK results showed the absence of a significant interaction between niraparib and AAP. The
PK parameters of niraparib when co-administered with AAP were within the target ranges of
niraparib monotherapy based on historical data.
The preliminary data observed to date show that the combination of niraparib plus AAP has a
safety profile that is similar to the safety profile of each drug alone. Given that subjects in the
niraparib 200 mg plus AAP cohort had fewer SAEs, AESIs, and TEAEs leading to dose

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interruption/reduction, as well as no DLT or DLT-equivalent Grade 4 toxicities, a dose of niraparib
200 mg was chosen as the RP2D for the combination.
1.3.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose
Combination Tablet
Refer to Section 1.2, for a summary of nonclinical and clinical data for niraparib and Section 1.3.2,
for a summary of data on the combination of niraparib and AA administered as single agents.
Information regarding the niraparib/AA FDC is in the niraparib/AA fixed-dose combination IB.25
1.4. 
Benefit/Risk Assessment
1.4.1. 
Combination 1: Niraparib and Cetrelimab
The combination of niraparib with cetrelimab is anticipated to have a positive benefit-risk profile
when used for the treatment of patients with metastatic prostate cancer, as proposed for this study.
This assessment is based on the following:
 
The nonclinical safety profiles for niraparib and cetrelimab appear to be non-overlapping and
distinct. Based on available nonclinical data, no additional relevant nonclinical findings are
anticipated for the niraparib and cetrelimab combination.
 
The PK profiles of niraparib and cetrelimab are distinct, and drug-drug interactions are not
expected. Based on their PK profiles and mechanisms of action, the risk of synergistic adverse
effects between niraparib and cetrelimab is considered low.
 
The safety profiles for niraparib and cetrelimab appear to be non-overlapping based on
currently  available data, and additional safety risks are not anticipated for niraparib and
cetrelimab combination. Adverse events associated with niraparib are primarily hematologic
and readily manageable, while those associated with cetrelimab are mainly immune-mediated
and are also manageable.
 
The proposed niraparib dose was selected based on available data from the ongoing niraparib
program. Niraparib has been combined with immune checkpoint inhibitors previously
(pembrolizumab, a PD-1 inhibitor/TOPACIO study). In the TOPACIO study, 1 of 6
DLT-eligible subjects was reported with multiple DLTs (Grade 3 anemia, Grade 4
neutropenia, and Grade 4 thrombocytopenia) at a dose of niraparib 200 mg once daily. At a
niraparib dose of 300 mg once daily, 1 of 6 subjects was reported with 1 DLT of Grade 4
thrombocytopenia; however, shortly after the evaluable period, a second subject experienced
AEs of epistaxis and Grade 4 thrombocytopenia that were considered DLT-equivalent. No
significant overlapping toxicities were observed. Niraparib 200 mg once daily in combination
with pembrolizumab 200 mg IV every 3 weeks was selected as the RP2D in the study.32
 
The TOPACIO study has since been amended such that subjects who tolerate niraparib
200 mg once daily for at least 2 cycles have the option to escalate to niraparib 300 mg
once daily, if they meet certain hematologic parameters, a strategy that will also be
included in the proposed study, 64091742PCR2002. This strategy is supported by a recent
safety update (as of August 2017) from the TOPACIO study in which less than 7% of
subjects in the dose expansion phase of the study have been reported with Grade ≥3
thrombocytopenia during the first treatment cycle, and in the 2 subjects who were

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escalated from niraparib 200 to 300 mg after 2 cycles, no Grade ≥3 events have been
reported.32
 
The proposed doses of cetrelimab were selected based on preliminary data from the ongoing
Study 63723283LUC1001, in which safety and antitumor activity was established at both
proposed doses. Though more subjects have been treated with the 240 mg once every 2 weeks
dosing schedule, the 480 mg once every 4 weeks dose is pharmacologically equivalent to
240 mg every 2 weeks based on preliminary PK data and is preferable for subject convenience.
Both dose regimens will be explored in this study.
Studies with the combination of similar PARP inhibitors and immune checkpoint inhibitors,
support the combination of niraparib and cetrelimab, which could potentially be a new treatment
option for men with mCRPC. The safety profiles for niraparib and cetrelimab appear to be
non-overlapping and manageable. The protocol design incorporates appropriate risk mitigation
measures, including a safety run-in period, SET monitoring, and targeted safety assessments.
Based on the information on the mechanism of action for both agents, completed nonclinical
studies, and the available clinical data, the sponsor considers that the assessment of benefit-risk
supports the administration of niraparib and cetrelimab combination in patients with mCRPC.
1.4.2. 
Combination 2: Niraparib and AAP
The combination of niraparib with AAP is anticipated to have a positive benefit-risk profile when
used for the treatment of patients with metastatic prostate cancer, as proposed for this study. This
assessment is based on the following:
 
AAP is an established standard-of-care (SOC) for the treatment of patients with metastatic
castration-resistant prostate cancer (mCRPC) and since 2015, AAP has been used more
commonly than other SOC therapies in patients with first-line mCRPC (ie, have not been
treated with any therapy in the metastatic castrate-resistant setting, except for androgen
deprivation therapy).
 
While niraparib is an investigational agent in the metastatic prostate cancer population, it has
been approved for the treatment of ovarian cancer and has a safety profile that has been
characterized through the conduct of clinical studies (see Section 1.2). Preliminary data from
sponsor studies to date suggest that the safety profile of niraparib in patients with metastatic
prostate cancer is similar to that described in the Zejula® label.62 Known toxicities for
niraparib include gastrointestinal events, hematological events (ie, thrombocytopenia,
neutropenia, anemia), and hypertension; however, these toxicities are manageable with
laboratory monitoring and appropriate intervention, such as dose interruptions. The sponsor
has also included a targeted monitoring plan and treatment guidelines to ensure appropriate
management of these known toxicities.
 
The toxicities for AAP are well established and include liver function abnormalities,
hypokalemia, and hypertension. These toxicities are manageable with interventions, including
proactive laboratory monitoring, dose interruptions, and dose reductions, if needed.
Preliminary data from sponsor Study 64091742PCR1001 (see Section 1.3.2) show that
niraparib and AAP can be combined safely. No overlap has been noted in the toxicity profiles
of niraparib and AAP, with the exception of hypertension, which can be managed medically.
 
PK data from Study 64091742PCR1001 also show that exposures for both drugs were
comparable to both compounds administered as a single agent.

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Given that the anticipated toxicities of both AAP and niraparib are recognizable through medical
oversight and laboratory monitoring and are able to be managed medically, and there is a potential
for increased efficacy of the combination for patients with incurable metastatic prostate cancer,
the sponsor considers that there is a positive benefit/risk profile and strong rationale for evaluating
niraparib with AAP for the treatment of patients with metastatic prostate cancer.
1.4.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose
Combination Tablet
The benefit-risk profile for the niraparib/AA FDC tablet is expected to be the same as for niraparib
and AA administered as SAs (Section 1.4.2).
The combination of niraparib plus AAP during the PK Assessment Phase in Combination 3 will
be administered to subjects with mCRPC, regardless of HRR gene alteration status. If not already
known, biomarker status assessment is recommended, and results can be used to guide further
treatment decisions during the Extension Phase. If the subject has had a previous result from the
sponsor’s required assays or a local result from a CLIA-certified or equivalent laboratory, then
after the subject grants a release, the data can be reviewed for biomarker status.
As discussed in Section 1.1.3, review of the safety data from Cohort 2 (subjects without HRR gene
alterations) randomized to the niraparib and AAP arm of the MAGNITUDE Study showed that
11 subjects (9%) had AEs leading to niraparib interruption or dose reduction within the first
30 days of treatment, and 2 subjects (2%) experienced AEs (glaucoma and increased ALT)
requiring niraparib interruption or dose reduction within the first 8 days of treatment. These data
from the MAGNITUDE study support the combined daily administration of niraparib and AAP.
In this study, after completion of the PK Assessment Phase and during the Extension Phase,
subjects will be allowed to continue niraparib and AAP or AAP alone at the investigator’s
discretion, informed by biomarker status as well as tolerability for individual subjects. Subjects
with HRR gene alterations will be recommended to continue combination treatment with niraparib
and AAP. Subjects without HRR gene alterations or those with unknown biomarker status may
continue therapy with niraparib and AAP or AAP alone at the investigator’s discretion.
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESES
See Attachment 6 for Objectives, Endpoints, and Hypotheses for Combination 3.
2.1. 
Objectives and Endpoints
Each combination study in this protocol comprises 2 parts; Part 1 will support the dose selection
for the niraparib combination therapies, as well as include PK sampling to evaluate for potential
drug-drug interactions, and Part 2 (dose expansion) will evaluate the RP2D of each niraparib
combination therapy in an expanded number of subjects. For combinations with a previously
established RP2D and drug-drug interaction data, Part 1 will not be conducted. The overall
objectives and endpoints for the study are provided in Table 1 and Table 2.
See Attachment 6, Section 2.1, for Objectives and Endpoints for Combination 3.

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Table 1: 
Objectives and Endpoints for Part 1
Objectives 
Endpoints
Primary
 
To evaluate the tolerability of niraparib 
combination therapies for the treatment of 
mCRPC
 
Determine the RP2D of niraparib combination
therapies
 
Incidence of specified toxicities (described in
Section 3.4)
Secondary
 
To characterize the PK and immunogenicity (if 
applicable) of niraparib combination therapies 
 
Plasma concentrations of niraparib and, if
performed, its major metabolite (M1), and plasma
or serum concentrations of the combination agent
 
Population PK parameters and derived exposure of
niraparib and combination agent
 
Anti-drug antibodies (if applicable)
mCRPC=metastatic castration-resistant prostate cancer; PK=pharmacokinetics; RP2D=recommended Phase 2 dose
Table 2: 
Objectives and Endpoints for Part 2
Objectives 
Endpoints
Primary
 
To evaluate the antitumor effect of the RP2D of 
niraparib combination therapies for treatment of
mCRPC
Combination 1
 
Objective response rate (ORR) of soft tissue
(visceral or nodal disease) as defined by RECIST 1.1
with no evidence of bone progression according to
PCWG3 criteria50
Combination 2
 
Composite response rate (RR): defined as 1 of the
following by PCWG3:50
 
Objective response (confirmed per RECIST
1.1), or
CTC response: defined as CTC=0 per 7.5 mL
of blood at 8 weeks for subjects who have
CTC ≥1 at baseline or CTC<5 per 7.5 mL with
CTC ≥5 at baseline, confirmed by a second
consecutive value obtained 4 or more weeks
later, or
 
PSA decline of ≥50%, measured twice 3 to
4 weeks apart
 
To evaluate the safety of the RP2D of niraparib 
combination therapies for the treatment of
mCRPC
Combinations 1 and 2
 
Incidence and severity of AEs
Secondary
 
To evaluate other response outcomes of niraparib 
combination therapies for the treatment of
mCRPC
Combinations 1 and 2
 
CTC response: defined as CTC=0 per 7.5 mL of
blood at 8 weeks for subjects who have CTC ≥1 at

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Table 2: 
Objectives and Endpoints for Part 2
Objectives 
Endpoints
baseline or CTC<5 per 7.5 mL with CTC ≥5 at
baseline, confirmed by a second consecutive value
obtained 4 or more weeks later
Combination 1 only
 
Composite response rate (RR): defined as 1 of the
following by PCWG3:50
 
Objective response (confirmed per RECIST
1.1), or
 
CTC response: defined as CTC=0 per 7.5 mL
of blood at 8 weeks for subjects who have
CTC ≥1 at baseline or CTC<5 per 7.5 mL with
CTC ≥5 at baseline, confirmed by a second
consecutive value obtained 4 or more weeks
later, or
 
PSA decline of ≥50%, measured twice 3 to
4 weeks apart.
Combination 2 only
 
Objective response rate (ORR) of soft tissue
(visceral or nodal disease) as defined by RECIST
1.1 with no evidence of bone progression according
to PCWG3 criteria50
 
To evaluate duration of response 
Combinations 1 and 2
 
Duration of objective response: time from complete
response (CR) or partial response (PR) to
radiographic progression of disease, unequivocal
clinical progression, or death, whichever occurs
first
 
OS: time from enrollment to death from any cause
 
To characterize the PK and immunogenicity (if 
applicable) of niraparib combination therapies
through sparse sampling
Combination 1 only
 
Plasma concentrations of niraparib and, if
performed, its major metabolite (M1) when dosed
with combination agent
 
Population PK parameters and derived exposure of
niraparib and combination agent
 
Anti-drug antibodies (if applicable)

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Table 2: 
Objectives and Endpoints for Part 2
Objectives 
Endpoints
Exploratory
 
To evaluate MOAs for niraparib combination 
therapies, as well as potential biomarkers
predictive of response and resistance
Combination 1 only
 
Assessment of biomarkers related to MOAs or
response/resistance for niraparib, other anticancer
agent, or the combination at baseline, on-treatment,
and at progression
 
To explore potential relationships between the PK 
of niraparib combination therapies, and any
associated clinical activity, pharmacodynamic
markers, or safety signals
Combination 1 only
 
Changes in levels of pharmacodynamic markers
(eg, PSA, CTCs)
AE=adverse event; CR=complete response; CTC=circulating tumor cell; mCRPC=metastatic castration-resistant
prostate cancer; MOA=mechanism of action; ORR=objective response rate; OS=overall survival; PCWG3=Prostate
Cancer Working Group 3; PR=partial response; PK=pharmacokinetics; PSA=prostate-specific antigen; RECIST=
Response Evaluation Criteria in Solid Tumors; RP2D=recommended Phase 2 dose; RR=response rate
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2. 
Hypotheses
Part 1 (Safety Run-in): An RP2D of niraparib when combined with other anticancer agents can
be identified.
Part 2 (Dose Expansion): Niraparib administered in combination with other anticancer agents at
the selected RP2D is safe and has antitumor activity.
2.2.1. 
Combination 1: Niraparib and Cetrelimab
The hypotheses for this combination are:
 
That cetrelimab inhibition of PD-1 complements the antitumor activity of the PARP inhibitor,
niraparib, for effective and safe treatment of subjects with mCRPC with DRD or CDK12
pathogenic alterations.
 
The combination of niraparib and cetrelimab is safe and has antitumor activity in subjects with
mCRPC with DRD or CDK12 pathogenic alterations.
2.2.2. 
Combination 2: Niraparib and AAP
The hypothesis for this combination is:
 Androgen receptor (AR) inhibition enhances the antitumor activity of PARP inhibition for the
effective and safe treatment of subjects with mCRPC and DRD. A response rate of 62% is
expected for subjects with biallelic DRD, and 57% for subjects with monoallelic DRD. 
2.2.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose
Combination Tablet
See Attachment 6, Section 2.2, for Hypothesis for Combination 3. 

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3. 
STUDY DESIGN AND RATIONALE
3.1. 
Overview of Study Design
This is a Phase 1b-2, multicenter, open-label study to select the RP2D of niraparib in combination
with other anticancer agents, followed by dose expansion that will enroll adult subjects with
mCRPC who are either BM+ or BM- for DRD or BM+ for CDK12 pathogenic alterations (see
Section 
9.5, 
for 
description 
of 
biomarker-positivity 
criteria). 
Details 
regarding
combination-specific study design considerations are provided in the corresponding subsections
below.
The primary objectives of the study are to establish the RP2D of niraparib with various
combination agents (Part 1) and to evaluate the antitumor activity and safety of niraparib with
various combination agents (Part 2). Other objectives may include evaluating the PK of niraparib
and combination agents and investigating potential biomarkers that establish the
pharmacodynamic effect of each combination.
Each combination study will have 5 phases: a Prescreening Phase, a Screening Phase, a Treatment
Phase, a Follow-up Phase (see Section 9.1, and the Time and Events Schedules for details), and a
Long-term Extension Phase (see Attachment for details). Treatment cycles will be 28 days.
Subjects will begin receiving treatment on Cycle 1 Day 1, as described in Section 6. All subjects
will continue to receive the study drugs until disease progression, unacceptable toxicity, death, or
the sponsor terminates the study (see Section 10). Subjects will be monitored for safety during the
Prescreening, Screening, and Treatment Phases, and for up to 100 days after the last dose of study
drugs for Combination 1 and 30 days after the last dose of study drugs for Combination 2.
The end of the overall study (study completion) is defined as the last study assessment for the last
subject on study. However, each combination will also have a study completion date, defined as
the last study assessment for the last subject on each combination. Data for each combination will
be reported in a separate clinical study report (CSR). The sponsor may also establish an interim
data cutoff date for each CSR analysis at an earlier timepoint than the study completion date. The
data cutoff will be communicated to the sites. Subjects who continue to receive study drugs after
the data cutoff will continue to be monitored and data will be collected on study drug
administration, AEs, SAEs, laboratory abnormalities indicative of an AE, and concomitant
medications used to treat these events.
In the event of early study completion or study termination by the sponsor, (whether or not the
study endpoints are met), the sponsor will continue to provide study treatments until unequivocal
disease progression, unacceptable toxicity, or an alternate method is in place to avoid treatment
interruption.
3.1.1. 
Combination 1: Niraparib and Cetrelimab
This combination study will enroll adult subjects with mCRPC who are either BM+ (Cohort 1A)
or BM- (Cohort 1B) for DRD or BM+ for CDK12 pathogenic alterations based on the sponsor’s
blood or tissue assay. A schematic for this combination is provided in Figure 1.

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For Part 1 at least 6 evaluable subjects will be treated with niraparib 200 mg orally once daily in
combination with cetrelimab 480 mg IV once every 4 weeks.
Evaluable subjects for Part 1 are defined as those who have an event as defined by the safety
evaluation criteria (see Section 3.4) in Cycle 1, or complete at least 1 cycle of treatment and receive
at least 75% of the planned study drugs (ie, 75% niraparib capsules and 75% of cetrelimab
infusion/s). Non-evaluable subjects will be replaced. After at least 6 evaluable subjects have
completed the safety assessment period, a safety evaluation team (SET; see Section 3.5) will assess
the available data to determine the safety of the combination and make a decision to proceed with
Part 2 of the study (see Section 3.4). The sponsor may choose to enroll subjects to additional dose
regimens (ie, at least 6 additional evaluable subjects) with cetrelimab and a modified dose of
niraparib (ie, 100 mg or 300 mg), depending on the available data obtained from the niraparib
200 mg cohorts. The sponsor, in discussion with the SET, will decide which dose regimen will be
used for Part 2 of the study. After the safety evaluation period, the evaluable subjects will continue
in the study (Part 2) and will be evaluated in the final analysis based on their biomarker status (ie,
BM+ or BM-). If a subject was enrolled into the cetrelimab 240 mg every 2-week regimen under
a prior version of the protocol, the subject should be transitioned to cetrelimab 480 mg every
4 weeks once the protocol amendment and revised informed consent form (ICF) are approved at
the site, as required by local regulations.
Once an RP2D has been established for the combination in Part 1, approximately 30 subjects will
be enrolled per cohort for Part 2. Note that a futility analysis was performed for Cohort 1B after
approximately 10 subjects have been enrolled and evaluated in Part 2 (see Section 11.10). All
subjects will be assigned to a cohort based on their biomarker status for DRD or CDK12 (ie,
Cohort 1A BM+ or Cohort 1B BM-), which will be determined during the Prescreening Phase
using the sponsor blood or tissue assay. The total number of subjects to be enrolled in the study is
described in Section 11.2.
If a dose of niraparib 200 mg once daily is selected for the RP2D, then all subjects may receive an
escalated dose of niraparib 300 mg once daily on or after Cycle 3 Day 1, if they meet the following
criteria: platelets ≥100 x 109/L, hemoglobin ≥9.0 g/dL, and neutrophils ≥1.5 x 109/L for all
laboratory tests performed during the first 2 cycles after discussion with the medical monitor.

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FDA-approved single-agent dose for treatment of ovarian cancer is 300 mg once daily, based on
the NOVA study that evaluated single agent niraparib as maintenance therapy in subjects with
platinum-sensitive recurrent ovarian cancer.36 However, dose reductions and interruptions due to
hematologic toxicities have been common at that dose.
3.2.1. 
Combination 1: Niraparib and Cetrelimab
The proposed starting dose of niraparib for this combination (ie, 200 mg) is based on the RP2D
from the Phase 1 portion of the TOPACIO study, which is a combination study of niraparib plus
pembrolizumab for treatment of triple-negative breast cancer or platinum-resistant ovarian cancer.
Subjects were enrolled at 2 dose levels: Dose Level 1 (niraparib 200 mg once daily and
pembrolizumab 200 mg IV every 3 weeks) or Dose Level 2 (niraparib 300 mg once daily and
pembrolizumab 200 mg IV every 3 weeks). Out of 14 subjects, 12 were eligible for DLT
evaluation. At Dose Level 1, 1 of 6 DLT-eligible subjects was reported with multiple DLTs,
including Grade 3 anemia, Grade 4 neutropenia, and Grade 4 thrombocytopenia. At Dose Level 2,
1 of 6 DLT-eligible subjects was reported with 1 DLT of Grade 4 thrombocytopenia. An additional
subject was reported with an AE that was deemed to be DLT-equivalent; the subject had epistaxis
and Grade 4 thrombocytopenia soon after the DLT period. No significant overlapping toxicities
were noted and the RP2D for the TOPACIO study was established as niraparib 200 mg once daily
plus pembrolizumab 200 mg IV every 3 weeks.
However, niraparib 300 mg once daily is the FDA-approved dose for monotherapy treatment (for
ovarian cancer) and novel strategies are being designed to improve subject selection for this dose
while minimizing toxicity. The TOPACIO study has been amended such that subjects who tolerate
niraparib 200 mg once daily for at least 2 cycles have the option to escalate to niraparib 300 mg
once daily, if they meet certain hematologic parameters (see Section 3.1.1). This staggered
escalation strategy prevents needless toxicity in those subjects who are unable to tolerate the higher
dose of niraparib, while allowing those who can tolerate the higher dose to potentially maximize
antitumor activity. This strategy is supported by a recent safety update from the TOPACIO study,
which reported that less than 7% of Phase 2 subjects have been reported with Grade ≥3
thrombocytopenia during the first treatment cycle and that the 2 subjects who have been escalated
from niraparib 200 mg to 300 mg after 2 cycles have had no Grade ≥3 events to date.
For cetrelimab, the 480 mg once every 4 weeks dosing schedule was selected as it is an RP2D in
the cetrelimab single agent study (Study 63723283LUC1001) and is preferable to the 240 mg once
every 2 weeks dosing for subject convenience.22
3.2.2. 
Combination 2: Niraparib and AAP
The RP2D of niraparib in combination with AAP is 200 mg based on Study 64091742PCR1001
(See Section 1.3.2). The data from that study showed that the combination of niraparib plus AAP
has a safety profile that is similar to the safety profile of each drug alone.
3.2.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose
Combination Tablet
See Section 3.2.2.

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3.3. 
Biomarker Rationale
Subjects who are BM+ or BM- for DRD or BM+ for CDK12 may demonstrate different responses
to treatment with niraparib combination therapy. Note that cohort eligibility is different for each
combination, see Section 9.5, and Table 9 for details. In addition, analyzing the changes in
biomarkers that correspond with each subjects’ response may help to understand the MOA of that
response. For this reason, there are 2 parts to the biomarker plan for this protocol, as follows:
 
DRD and CDK12: Subjects in Combinations 1 and 2 will be prospectively assessed in the
prescreening phase to determine their biomarker status: DRD and CDK12 for Combination 1
and DRD for Combination 2 based on the criteria described in Section 9.5.
 
Exploratory biomarker collection for MOA determination for Combination 1: Biomarker
samples will be collected at the timepoints outlined in Time and Events Schedule 1 to analyze
the biological activity, MOA, and resistance mechanisms of the niraparib combination therapy
before, during, and after treatment.
3.3.1. 
Combination 1: Niraparib and Cetrelimab
Published results suggest that the expression of PD-L1 in some tumors correlates with response to
anti-PD-L1 therapy.20,54 In addition, mCRPC tumors with BRCA1 and/or BRCA2 mutations had
higher mutational burden compared to those without DRD.41 This increased mutational burden
may create neoantigens and correlate with response to anti-PD-L1 therapy. Therefore, PD-L1
expression, DRD and CDK12 will be retrospectively evaluated in tumor biopsies. To understand
the MOA of niraparib and cetrelimab in combination, tumor biopsies will also be retrospectively
evaluated for other immune- or prostate cancer-related biomarkers, such as tumor mutational
burden, and T-cell clonal change. Circulating immune- and tumor-related biomarkers will also be
evaluated as potential pharmacodynamic and response biomarkers.
Additional details of the biomarker evaluation plan are provided in Section 9.5. Full details of the
exploratory biomarker analyses will be included in a biomarker Statistical Analysis Plan for this
combination.
3.3.2. 
Combination 2: Niraparib and AAP
As noted in Section 1.1.2, the combination of the PARP inhibitor, niraparib, and the AR-targeted
therapy, AAP may be a safe and effective treatment for patients with metastatic prostate cancer
who have DRD. However, it is not known whether the type of mutation and gene may determine
response to the combination. mCRPC tumors with BRCA1 and/or BRCA2 mutations have been
found to have higher mutational burden compared to those without DRD, suggesting that these
tumors have different biologic behavior.41 Preclinical work has found dual roles for PARP in
supporting AR activity in which PARP-1 is a potent modulator of both AR function and response
to DNA damage.51 Therefore, this combination may be complementary because AR-controlled
DRD genes may affect efficient assembly of the DRD complex. To further evaluate this question,
this study will enroll DRD patients prospectively into 4 cohorts (BRCA biallelic loss [2A], other
DRD biallelic loss [2B], BRCA monoallelic loss [2C], and other DRD monoallelic loss [2D]) in
order to investigate differences in efficacy to the combination of niraparib and AAP. 

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3.3.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose
Combination Tablet
For Combination 3, biomarker status is not required to determine study eligibility. If not already
known, biomarker status assessment is recommended, and results can be used to guide further
treatment decisions during the Extension Phase (see Attachment 6).
3.4. 
Safety Evaluation Criteria for Part 1
For each combination, the safety evaluation period is defined as the first 28 days of treatment (ie,
Cycle 1) for the subjects in Part 1. If a subject receives less than 75% of each assigned dose during
Cycle 1 due to reasons other than for a specified toxicity criterion as described in this section (eg,
disease progression, missed appointments, non-compliance, subject withdrawal), then the
individual is not evaluable and may be replaced with a new subject.
A SET will meet after at least 6 evaluable subjects have completed the safety assessment period.
The SET will determine if a lower or higher dose cohort should be evaluated prior to proceeding
with the dose expansion part ofthe study (ie, 100 mg or 300 mg of niraparib). If more than 33%
of subjects (eg, more than 2 out of 6 subjects) in Part 1 have a specified toxicity (see criteria below),
then a new dose cohort will be opened with niraparib 100 mg once daily (ie, at least 6 new
evaluable subjects will be enrolled). If the SET determines that a higher dose of niraparib should
be explored (ie, niraparib 300 mg once daily), then a new dose cohort will be added with an
additional 6 evaluable subjects. All available safety data from non-evaluable subjects will also be
taken into consideration by the SET. The number of evaluable subjects per cohort enrolled in Part 1
may be expanded up to 9 at the discretion of the sponsor.
Note that after Cycle 1, subjects may continue to receive additional cycles of their originally
assigned dose of niraparib and cetrelimab while the study continues to enroll and other subjects
complete their evaluation period. Enrollment into Part 1 dose regimens will continue unless
>2 subjects are reported with a specified toxicity, at which time new subject enrollment will stop
in that dose regimen until after the SET convenes and makes recommendations regarding conduct
of the study. 
Toxicities will be graded for severity according to the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03 or later. Only toxicities that
occur during the safety evaluation period will be used for the purpose of defining specified
toxicities and for dose reduction decisions, but toxicities that occur during the entire treatment
period will be recorded and considered in decisions regarding dose expansion and escalation.
Cases may be discussed with the SET, if needed, to determine if toxicity meets the criteria.
The safety evaluation criteria are as follows:
 
Any Grade ≥3 non-hematological toxicity, with the following exceptions:
 
Anorexia, fever, or constipation
 
Fatigue that improves to Grade ≤2 in ≤7 days
 
Nausea lasting for ≤7 days responding to best supportive care

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Vomiting and diarrhea that resolves in ≤3 days with best supportive care
 
Laboratory abnormalities that do not require hospitalization and are not deemed to be
clinically significant by the investigator
 
Tumor flare (defined as local pain, irritation, or rash localized at sites of known or
suspected tumor) that improves to Grade ≤2 in ≤7 days
 
Elevation in AST or ALT for ≤7 days
 
Grade 3 hypertension that is controllable by medical therapy
 
Any treatment-related Grade 4 thrombocytopenia or Grade ≥3 thrombocytopenia requiring
platelet transfusion.
 
Any treatment-related Grade 4 neutropenia ≥7 days, or Grade 3 or 4 neutropenia associated
with infection or fever >38.5 degrees Celsius.
 
Any treatment-related SAE or subjectively intolerable toxicity judged by the SET as related
to study drugs.
Additional safety evaluation criteria for combination agents with a unique safety profile will be
added in subsections below, as appropriate.
3.5. 
Safety Evaluation Team (Combinations with Part 1)
A SET will be established by the sponsor for each combination. The SET consists of study
investigators, the sponsor compound clinical leaders, the sponsor medical monitor, the sponsor
medical safety officer, and the sponsor clinical pharmacologist; the sponsor statistician will be
consulted, as needed. The SET convenes as necessary for review of safety-related issues and must
meet after at least 6 evaluable subjects complete the safety assessment period for a given
combination. Any SET member may request a SET meeting, which should be convened within 3
working days. The SET reviews PK information and all safety data, including SAE, and all
Grade ≥3 AEs, including toxicity appearing after the safety evaluation period.
Decisions on dose reduction/modification, change in PK sampling times, and change in study drug
dosing and schedule in Part 1 will be performed in collaboration with the SET, and will be based
on available data and the following factors:
 
AE profile (type, severity, onset, and duration)
 
PK (Cmax/AUC)
 
Antitumor activity (clinical, biochemical, and radiographic data)
While the SET is reviewing the safety data, remaining subjects in Part 1 who have not been
reported with a specified toxicity (as described in Section 3.4) may continue to receive additional
cycles of their assigned dose of niraparib and combination agent, after consultation with the
sponsor. The established SET will monitor all available treatment-emergent data on an ongoing
basis throughout study conduct for the purpose of ensuring the continued safety of subjects
enrolled in this study. The SET will also be responsible for making a formal determination of
whether the study will proceed to Part 2.

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Decisions made by the SET will be documented and communicated to study investigators before
administration of study drugs to any subsequent subject. The Institutional Review Board
(IRB)/independent ethics committee (IEC) for each combination will be notified before
implementation of any SET decision, if required. Documented decisions should be retained in the
study master file and in study-site files. Decisions with the potential to affect subject safety (eg,
unfavorable change in benefit/risk assessment) will be promptly communicated to investigators
and regulatory authorities as appropriate. 
Note: a DRC will be established to monitor safety, study-related data, and study conduct for Part 2
of each combination (see Section 11.9).
The SET does not apply for Combination 3.
4. 
SUBJECT POPULATION
See Attachment 6 for a description of the Subject Population, Inclusion and Exclusion Criteria for
Combination 3.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the
following subsections. If there is a question about the inclusion or exclusion criteria below, the
investigator must consult with the appropriate sponsor representative and resolve any issues before
enrolling a subject in the study. Waivers for study eligibility criteria are not allowed. Screening
for eligible subjects will be performed within 28 days before administration of the study drugs,
unless otherwise specified. Combination-specific eligibility criteria are provided in separate
subsections, as appropriate.
4.1. 
Prescreening Eligibility Criteria
The following criteria must be met:
1. 
Criterion modified per Amendment 4.
1.1 Signed prescreening informed consent form.
2. 
Criterion modified per Amendment 4.
2.1 Criterion modified per Amendment 5.
2.2 Willing to provide a blood and tissue sample for analysis of DRD and CDK12
pathogenic alterations. Note: If the subject has a previous local test result (from a Clinical
Laboratory Improvement Amendments [CLIA]-certified or equivalent laboratory), the
data can be reviewed by the sponsor for determination of DRD and CDK12 pathogenic
alteration.
3. 
Criterion moved to Section 4.1.1, per Amendment 3.
4. 
Criterion deleted per Amendment 3.

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4.1.1. 
Combination 1: Niraparib and Cetrelimab
In addition to the criteria in 4.1, each potential subject for Combination 1 must satisfy the following
criteria:
1. 
At least 1, but no more than 2, lines of novel AR-targeted therapy (ie, abiraterone acetate
with prednisone, enzalutamide) for mCRPC. Subjects must have had at least 4 weeks of
AR-targeted therapy.
4.1.2. 
Combination 2: Niraparib and AAP
In addition to the criteria in 4.1, each potential subject for Combination 2 must satisfy the following
criteria:
1. 
Must have progressed on 1 prior line of novel AR-targeted therapy (ie, abiraterone
acetate with prednisone, enzalutamide) for mCRPC. Prior treatment with taxane-based
therapy and AR-targeted therapy outside of the mCRPC setting are allowed.
4.2. 
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1. 
Criterion modified per Amendment 2.
1.1 
18 years of age or older.
2. 
Willing to undergo all protocol-specified biopsies.
3. 
Diagnosis of prostate adenocarcinoma as confirmed by the investigator.
4. 
Criterion moved to Section 4.2.1, per Amendment 3.
5. 
Criterion moved to Section 4.2.1, per Amendment 3.
6. 
Criterion moved to Section 4.2.1, per Amendment 3.
7. 
Must have castrate levels of testosterone ≤50 ng/dL on a gonadotropin releasing hormone
analogue (GnRHa), or history of bilateral orchiectomy at study entry.
8. 
Progression of metastatic prostate cancer at study entry defined as having one or more of the
following:
a. PSA progression defined by a minimum of 2 rising PSA levels with an interval of ≥1
week between each determination (per Prostate Cancer Working Group 3 [PCWG3]
criteria).50 The PSA level at the screening visit should be ≥2 μg/L (2 ng/mL).
b. Radiographic progression by bone scan per PCWG3 or by soft tissue per
RECIST 1.1.9,50
9. 
Must be willing to continue GnRHa during the study if not surgically castrate.
10. Eastern Cooperative Oncology Group Performance Score (ECOG PS) Grade of 0 or 1
(see Attachment 2).

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11. Criterion modified per Amendment 3.
11.1 
Subjects who received prior therapy with an anti-androgen (eg, bicalutamide,
flutamide, nilutamide, enzalutamide, apalutamide) must have at least a 4-week wash-out prior
to enrollment.
12. Criterion modified per Amendment 6.
12.1 
While on study medication and for 3 months (Combination 2) or 5 months
(Combination 1) following the last dose of study medication, a male subject must agree to use
an adequate contraception method as deemed appropriate by the investigator and as specified
in Section 4.4, Lifestyle Considerations.
13. Criterion modified per Amendment 2.
13.1 
Clinical laboratory values at Screening:
a. Absolute neutrophil count (ANC) ≥1.5 x 109/L, independent of growth factors for 30
days
b. Hemoglobin ≥9.0 g/dL, independent of growth factors or transfusions for 30 days
c. Platelet count ≥100 x 109/L, independent of growth factors or transfusions for 30 days
d. Serum albumin ≥3.0 g/dL
e. Creatinine clearance ≥30 mL/min/1.73 m2 either calculated or directly measured via
24-hour urine collection.
f. Serum total bilirubin ≤1.5 x upper limit of normal (ULN) or direct bilirubin ≤1 x
ULN (Note: in subjects with Gilbert’s syndrome, if total bilirubin is >1.5 x ULN,
measure direct and indirect bilirubin, and if direct bilirubin is ≤1.5 x ULN, subject
may be eligible as determined by the medical monitor)
g. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN
h. Fasting glucose ≤250 mg/dL
14. A male subject must agree not to donate sperm while on study treatment and for 3 months
(Combination 2) or 5 months (Combination 1) following the last dose of study medication.
4.2.1. 
Combination 1: Niraparib and Cetrelimab
In addition to the criteria in Section 4.2, each potential subject for Combination 1 must satisfy the
following criteria:
1. 
Criterion modified per Amendment 4.
1.1 Criterion modified per Amendment 5.
1.2 Must have determination of biomarker positive for DRD (biallelic) or CDK12
pathogenic alterations by the sponsor’s blood or tissue assay, or a previous local test
result (from a CLIA-certified or equivalent laboratory) and reviewed by the sponsor to
confirm eligibility. For Part 1 of the study, subjects can be dosed prior to assay results
becoming available. Results are required prior to dosing for Part 2.

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2. 
Subjects must have measurable disease as defined by RECIST 1.19 (soft tissue lesion
of ≥10mm in the long axis or extrapelvic lymph node of ≥15mm in the short axis).
3. 
Must have previously received at least 1, but no more than 2, lines of novel AR-targeted
therapy (ie, abiraterone acetate with prednisone, enzalutamide) for mCRPC. Subjects
must have had at least 4 weeks of AR-targeted therapy.
4.2.2. 
Combination 2: Niraparib and AAP
In addition to the criteria in Section 4.2, each potential subject for Combination 2 must satisfy the
following criteria:
1. 
Must be biomarker positive for DRD by either the sponsor’s blood or tissue assay.
2. 
Must have progressed on 1 prior line of novel AR-targeted therapy (ie, abiraterone
acetate with prednisone, enzalutamide) for mCRPC. Prior treatment with taxane-based
therapy and AR-targeted therapy outside of the mCRPC setting are allowed.
4.3. 
Exclusion Criteria
Combination-specific exclusion criteria are provided in the appropriate subsections below. Any
potential subject who meets any of the following criteria will be excluded from participating in the
study:
1. 
Prior treatment with a PARP inhibitor.
2. 
History or current diagnosis of MDS/AML.
3. 
Criterion modified per Amendment 5.
Active malignancies (ie, progressing or requiring treatment change in the last
24 months) other than the disease being treated under study. The only allowed
exceptions are:
a. non-muscle invasive bladder cancer.
b. skin cancer (non-melanoma or melanoma) treated within the last 24 months that
is considered completely cured.
c. Breast cancer:
- 
adequately treated lobular carcinoma in situ or ductal carcinoma in situ,
- 
or history of localized breast cancer and receiving antihormonal agents and
considered to have a very low risk of recurrence.
d. Malignancy that is considered cured with minimal risk of recurrence.
4. 
Active infection requiring systemic therapy.
5. 
Allergies, hypersensitivity, or intolerance to niraparib or the corresponding excipients
(refer to the Investigator’s Brochures).24

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6. 
Human immunodeficiency virus (HIV)-positive subjects with 1 or more of the
following:
a. Not receiving highly active antiretroviral therapy.
b. A change in antiretroviral therapy within 6 months of the start of screening
(except if, after consultation with the sponsor on exclusion criterion 11.c, a
change is made to avoid a potential drug-drug interaction with the study drug).
c. Receiving antiretroviral therapy that may interfere with the study drug (consult
the sponsor for review of medication prior to enrollment).
d. CD4 count <350 cells/mm3 at screening.
e. An  acquired immunodeficiency syndrome-defining opportunistic infection
within 6 months of the start of screening.
7. 
Active hepatitis B virus (eg, hepatitis B surface antigen reactive) or active hepatitis C
virus (HCV) (eg, HCV ribonucleic acid [RNA] [qualitative] is detected).
8. 
If a subject has undergone major surgery, they must have recovered adequately from
the toxicities or complications from the intervention prior to starting therapy.
9. 
Criterion deleted per Amendment 2.
10. 
Any of the following ≤30 days prior to planned Cycle 1 Day 1:
a. A transfusion (platelets or red blood cells).
b. Hematopoietic growth factors.
c. An investigational agent for prostate cancer.
d. Major surgery (sponsor’s medical monitor should be consulted regarding what
constitutes major surgery).
e. Radiation therapy.
11. 
Symptomatic brain metastasis from prostate cancer.
12. 
Criterion modified per Amendment 3.
12.1 
Symptomatic congestive heart failure (New York Heart Association Class III or
IV heart disease), unstable angina pectoris, cardiac arrhythmia, or uncontrolled
hypertension defined as systolic blood pressure [BP] >160 mmHg or diastolic BP >100
mmHg). Note that subjects with a history of hypertension are allowed, if BP is
controlled to within these limits by anti-hypertensive treatment.
13. 
Any condition for which, in the opinion of the investigator or medical monitor,
participation would not be in the best interest of the subject (eg, compromise the well-
being) or that could prevent, limit, or confound the protocol-specified assessments.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a subject's clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the first dose of study drug is given such
that the individual no longer meets all eligibility criteria, then the subject should be excluded from

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participation in the study. Section 9.1.3, Screening Phase, describes options for rescreening.
Section 17.4, Source Documentation, describes the required documentation to support meeting the
enrollment criteria.
4.3.1. 
Combination 1: Niraparib and Cetrelimab
In addition to the exclusion criteria in Section 4.3, any potential subject that meets the following
criteria will be excluded from participation in Combination 1:
1. 
Criterion deleted per Amendment 2.
2. 
Criterion modified per Amendment 2.
2.1 
Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody (including
any antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
3. 
Subjects with a history of allergy to protein-based therapies or any significant drug allergy
(ie, anaphylaxis, heptatotoxicity, or immune-mediated thrombocytopenia or anemia).
4. 
History of (non-infectious) pneumonitis that required corticosteroids or current
pneumonitis.
5. 
Allergies, hypersensitivity, or intolerance to cetrelimab or the corresponding excipients
(refer to the Investigator’s Brochure).22,
6. 
Immunodeficiency or receiving systemic corticosteroid therapy or immunosuppressive
therapy (eg, cyclosporine) within 7 days prior to treatment allocation. The use of
physiologic doses of corticosteroids may be approved after consultation with the sponsor.
7. 
Active autoimmune disease that has required systemic treatment in the past 2 years (ie,
with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic
treatment.
8. 
Received a live vaccine within 30 days of the first dose of study drugs.
9. 
History of organ transplant, including allogeneic stem cell transplantation.
4.3.2. 
Combination 2: Niraparib and AAP
In addition to the exclusion criteria in Section 4.3, any potential subject that meets the following
criteria will be excluded from participation in Combination 2:
1. 
Allergies, hypersensitivity, or intolerance to abiraterone acetate or prednisone or the
corresponding excipients (refer to the Investigator’s Brochure).
2. 
Current evidence of any of the following:
a. Any medical condition that would make prednisone use contraindicated.

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b. Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg
prednisone (or equivalent) once daily
4.4. 
Lifestyle Considerations
Potential subjects must be willing and able to adhere to the following lifestyle restrictions during
the course of the study to be eligible for participation:
Must agree to always use a condom during sexual intercourse (even in case of prior vasectomy or
in case of intercourse with an already pregnant woman) or to remain abstinent during the study
and for 3 months (Combination 2) or 5 months (Combination 1) after the last study treatment
administration (Section 10.2, Discontinuation of Study Treatment).
If the subject is engaged in sexual activity with a woman of childbearing potential, then a condom
should be used along with another highly effective contraceptive method. Highly effective
methods of contraception (methods that can achieve a failure rate of less than 1% per year when
used consistently and correctly) include:
 
combined hormonal (estrogen + progesterone or progesterone only) contraception
associated with inhibition of ovulation: oral, injectable or implantable;
 
placement of an intrauterine device (IUD) or intrauterine hormone releasing system
(IUS);
 
bilateral tubal occlusion;
 
vasectomy;
 
sexual abstinence; please note that 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 treatments. The reliability of sexual abstinence
needs to be evaluated in relation to the duration of the clinical trial and the preferred and
usual lifestyle of the subject.
A highly effective contraceptive method should be used for the duration of the study and for
3 months (Combination 2) or 5 months (Combination 1) after the last study medication
administration.
5. 
TREATMENT ALLOCATION AND BLINDING
See Attachment 6 for Treatment Allocation information for Combination 3.
This is an open-label study; therefore, no blinding or randomization procedures will be performed.
Subject information will be entered by the site into the Interactive Web Response System (IWRS)
during prescreening and each subject will be assigned a subject identification number. A blood
sample will be collected and sent for testing for biomarker status using the sponsor’s assay. (Tissue
may also be used to determine eligibility as described in Section 9.5). The medical monitor or
designee will review selected clinical information and for Part 2 patients, results of biomarker
testing in order to assign the subject to the appropriate cohort.

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6. 
DOSAGE AND ADMINISTRATION
See Attachment 6 and Section 6.1.3, below for Dosage and Administration information for
Combination 3.
6.1. 
Study Drug Administration
All dosing information must be recorded in the electronic case report form (eCRF). Supply of
study drugs will be managed with a centralized IWRS.
Niraparib will be provided as 100 mg capsules for once daily oral administration. Subjects should
take their daily dose of niraparib around the same time every day with or without food. The
capsules must be swallowed whole. If a subject forgets to take their dose of niraparib at the regular
time, the dose may be taken within 12 hours, otherwise the dose should be omitted. Study-site
personnel will use the information in the pharmacy manual to instruct subjects on how to store
niraparib for at-home use as indicated for this protocol. For all site visits days and PK or
immunogenicity sampling days (as applicable to each combination), the subject must not take
niraparib at home in the morning; both study drugs should be administered at the investigational
site.
Although not considered study medication, subjects who have not undergone surgical castration
must continue to receive regularly prescribed GnRHa. Sites should contact the sponsor’s medical
monitor if interruption of GnRHa is required. All GnRHa therapies should be recorded in the
concomitant medication section of the eCRF.
6.1.1. 
Combination 1: Niraparib and Cetrelimab
The treatments to be used for this combination are detailed in Table 3.
Table 3: 
Study Treatments for Combination 1
Drug 
Dose 
Dose Frequency  
Route of 
Administration
Regimen
Niraparib 
200 mga 
Once daily  
Oral 
2 x 100 mg capsules
Cetrelimabb 
480 mg 
Every 4 weeks 
IV infusion 
Day 1 of each cycle
IV=intravenous
a This is the starting dose of niraparib. Based on data obtained in Part 1, the dose of niraparib may be reduced to
100 mg once daily, or increased to 300 mg once daily.
b On days that both study drugs are administered, niraparib will be taken at the study site within 0.5 hours
before the start ofinfusion of cetrelimab.
The infusion rate of cetrelimab should allow for the diluted drug product and flush to be infused
into the subject over 60 (±10) minutes for the initial dose. In the absence of IRRs or other safety
concerns, the infusion rate for subsequent infusions administering ≤100 mL IV bags of diluted
drug product may be increased to allow for diluted drug product to be infused into the subject over
30 (±10) minutes. Subjects should be carefully observed during cetrelimab infusions. Trained
study staff at the clinic should be prepared to intervene in case of an IRR. Resources necessary for
resuscitation (eg, agents such as epinephrine and aerosolized bronchodilator, medical equipment
such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available at the
bedside. Attention to staffing should be considered if multiple subjects will be dosed at the same

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time. If an IRR develops, then the infusion should be temporarily interrupted or slowed down and
the guidelines in Section 6.2.1.2.2, should be followed to manage the IRR.
For the first infusion, vital signs should be monitored before the start of the infusion, every 15 to
20 minutes during the infusion, at the end of infusion, and 2 hours (±15 min) after the end of
infusion. After the completion of the first infusion the subject may be discharged if considered
clinically stable and all other study procedures have been completed. During subsequent infusions
of cetrelimab, vital signs should be monitored predose, once during infusion, and at the end of
infusion. cetrelimab infusions will be prepared as described in the Investigational Product
Preparation Instructions.
6.1.2. 
Combination 2: Niraparib and AAP
All subjects will receive AAP from a central supply while on the Treatment Phase of the study.
Investigators should refer to the package insert for instructions regarding storage, handling, and
administration of AAP.64 AA will be provided as 4 x 250 mg tablets for a total dose of 1,000 mg
for once daily oral administration, and prednisone will be provided as 5 mg tablets for twice daily
oral administration (total daily dose of 10 mg). Niraparib will be provided as 2 x 100 mg capsules
for once daily oral administration.
Subjects should take their daily dose of study drugs in the morning on an empty stomach. No food
or liquids should be consumed for at least 2 hours before and for at least 1 hour after dosing. The
study drugs should be swallowed whole with water. Study drugs should be administered together,
except for prednisone, which may be taken at any time. If a subject forgets to take the study drugs
at the regular time (eg, niraparib alone, AAP alone, or both), then the dose should be omitted. For
treatment modifications due to toxicities see Section 6.2.
6.1.3. 
Combination 3: Niraparib/AA Fixed-dose Combination Tablet
See Attachment 6 for dosing instructions during the PK Assessment Phase.
See Section 6.1.2, above for dosing instructions during the Extension Phase.
6.2. 
Dose Modification and Management of Toxicity
All dose interruptions, discontinuations, and their reasons must be recorded in the eCRF.
Management of toxicities for niraparib should be performed as detailed in Section 6.2.1.
Management of toxicities for combination agents will be provided in the respective subsections
from Section 6.2.1.2, onwards. Cycle days are fixed based on the Cycle 1 Day 1 date and will not
change due to dose interruptions or delays.
The investigator should attempt to attribute the toxicity to niraparib or combination agent and
adjust accordingly. If the toxicity cannot be attributed solely to niraparib or combination agent or
both, then both study drugs should be interrupted. If either niraparib or combination agent is
permanently discontinued for toxicity, the other drug may be continued after discussion with the
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Niraparib combination therapy should be held for at least 24 hours (or longer if specified for the
combination agent) prior to significant procedures and should be resumed only when AEs related
to the procedure are resolved. Any potential procedures should be discussed with the sponsor’s
medical monitor prior to the procedure occurring.
6.2.1. 
Combination 1: Niraparib and Cetrelimab
6.2.1.1. 
Combination 1: Dose Modifications for Niraparib
6.2.1.1.1. 
Non-hematological Toxicities
For subjects who develop drug-related Grade 3 or higher toxicities, treatment must be withheld
and appropriate medical management per institutional standard should be instituted. Treatment
with study drug must not be reinitiated until symptoms of the toxicity have resolved to Grade 1 or
baseline. If dose reduction is used for AE management, then please note that only 1 dose-level
reduction will be permitted for niraparib (from 200 mg to 100 mg) (from 2 capsules to 1 capsule).
Niraparib must be discontinued for non-hematologic treatment-related Grade ≥3 toxicities lasting
more than 28 days while the subject is administered niraparib 100 mg once daily. Subjects
experiencing treatment-related hypertensive crisis will have study drug permanently discontinued.
For Combination 1 only: If a subject has been escalated to niraparib 300 mg once daily, treatment
must be interrupted for any non-hematological toxicity of Grade 3 or higher as above. However,
if the toxicity resolves to Grade 1 or baseline, the subject should restart treatment with niraparib
at 200 mg once daily and should not be re-escalated to the 300 mg dose. If the event recurs, the
rules should be followed as for those subjects who start and are maintained on niraparib dose of
200 mg once daily, as described in the prior paragraph.
Posterior Reversible Encephalopathy Syndrome (PRES)
Posterior Reversible Encephalopathy Syndrome (PRES) is a clinicoradiological syndrome
characterized by headache, seizures, altered mental status, visual loss and characterized by white
matter vasogenic edema affecting the posterior and parietal lobes of the brain predominantly.
Subjects who develop neurological symptoms suggestive for PRES should be immediately referred
for neurological assessment and intake of niraparib interrupted. If diagnosis of PRES is confirmed,
treatment with niraparib must be permanently discontinued. Blood pressure monitoring and
correction if necessary is one of the cornerstones of PRES management.
6.2.1.1.2. 
Hematologic Toxicity
Dose interruption/modification criteria for platelet and neutrophil counts will be based on the
criteria outlined in Table 4. For the management of anemia, supportive measures such as blood
transfusions may be performed as deemed necessary by the investigator per institutional standard-
of-care. If more than 1 blood transfusion is given within 4 weeks, the sponsor should be notified.
For Grade ≥3 anemia, niraparib should be interrupted until resolution to Grade <3 and discussed
with sponsor prior to resuming treatment. Once the dose of study drugs has been reduced, any re-
escalation must be discussed with the medical monitor.
The site should contact the sponsor for discussion and consider discontinuation of niraparib if:

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 
Hematologic toxicity has not recovered to Grade 1 or baseline after prolonged period of dose
interruption. Niraparib must be discontinued in case of inadequate recovery of platelet counts,
neutrophil counts and/or hemoglobin to acceptable levels (Grade 1 or baseline) within 28 days
of the dose interruption period, or if the subject has already undergone dose reduction to
100 mg once daily.
 
A diagnosis of MDS/AML is confirmed by a hematologist. During the course of the study,
subjects who receive a confirmed diagnosis of AML should discontinue niraparib. During the
course of the study, subjects who receive a diagnosis of MDS confirmed by bone marrow
biopsy and who require treatment for MDS beyond growth factor support and transfusions
should discontinue niraparib. For subjects requiring no therapy or supportive care for MDS,
continuation of niraparib treatment may be considered weighing the risk/benefit to the subject
and must be discussed with the sponsor.
Table 4: 
Niraparib Dose Modification/Reductions for Platelet Count and Neutrophil Count
Toxicity Grade 
Dose of Niraparib
Grade 1 
No Change, consider weekly monitoring
Grade 2 
At least weekly monitoring and consider interrupting until
≤Grade 1 or baseline and then resume at same dose with
recommendation of weekly monitoring for 28 days after restart.
If a subject had been escalated to niraparib 300 mg, resume
niraparib at 300 mg or 200 mg.b
Grade ≥3 
Interrupt until ≤Grade 1 or baseline, then:
 If subject was on 200 mg dose, resume at 200 mg or 100 mg
if there was rapid decline in the hematologic parameter soon
after initiation of niraparib, as judged by the investigator.
 If subject was on 300 mg, restart at 200 mg.a,b
 If subject was on 100 mg (because of non-hematologic
toxicity), discuss with sponsor prior to resuming treatment.
Weekly monitoring until resolution is required and
recommended for 28 days after restarting dose.
Second occurrence Grade ≥3 
Interrupt until ≤Grade 1 or baseline and restart at 1 dose-level
reduction.a Weekly monitoring until resolution is required and
recommended for 28 days after restarting dose.
If subject was on 100 mg, (because of non-hematologic
toxicity), discuss with sponsor prior to resuming treatment.
Third occurrence Grade ≥3 
Permanently discontinue
a. 
For each dose level reduction, decrease dose by 100 mg or 1 capsule of niraparib.
b. 
Applies only to Combination 1. Only subjects in this combination may escalate to niraparib 300 mg (in specific
instances).
Notes:
 
For subjects with a platelet count ≤10,000 cells/µL, prophylactic platelet transfusion per guidelines may be considered.
For subjects taking anticoagulant or antiplatelet therapy, consider the risk/benefit of interrupting these drugs or
prophylactic transfusion at an alternative threshold such as ≤20,000 cells/µL.
 
Weekly monitoring and/or interruption are not required if at baseline grade, eg, subject with baseline Hgb 9.1 (grade 2
anemia) does not need to be monitored weekly for grade 1 or 2 anemia.
 
If subject requires platelet transfusion or has neutropenic fever or neutropenia requiring granulocyte colony stimulating
factor deemed to be related to niraparib toxicity, restart at 1 dose level reduction.

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 
The investigator believes that because of treatment-emergent toxicity, it is in the best interest
of the subject to discontinue study treatment.
 
Grade 4 toxicities except for endocrinopathies that are controlled with replacement hormones.
 
Grade 2 or 3 immune-related AEs (irAEs) that persist despite treatment modifications or
corticosteroid dosing cannot be reduced to 10 mg prednisone or equivalent per day within
12 weeks.
 
A treatment-related AE that does not resolve to Grade ≤1 within 12 weeks of the last dose of
study drug unless otherwise agreed to by the sponsor medical monitor.
 
Any non-hematological treatment-related event that occurs a second time at Grade 3
severity.
 
Grade 3 (or recurrent Grade 2) pneumonitis.
 
Grade 3 nephritis with creatinine ≥3 x ULN.
 
Grade 3 elevation of AST or ALT or total bilirubin that does not resolve with supportive
measures, as described in Attachment 1.
 
Grade 3 IRRs.
 
Immune-mediated encephalitis.
If a subject's treatment with cetrelimab is discontinued, this will not result in automatic withdrawal
of the subject from the study. As above, the subject can continue niraparib if there is no evidence
of disease progression and is otherwise tolerating treatment. Once a subject meets the cetrelimab
discontinuation criteria, the subject may not be retreated with cetrelimab.
6.2.1.2.5. 
Guidelines for Management of Immune-related Adverse Events and
Adverse Events of Clinical Interest for Cetrelimab
Therapy with immuno-oncology agents such as cetrelimab may lead to specific irAEs. Early
recognition and management of these irAEs may mitigate more severe/subsequent toxicity.
However, differential diagnoses, including non-inflammatory etiologies as well as the impact of
the underlying malignant disease or concomitant medication, should be considered according to
standard medical practice.
Algorithms have been developed to assist investigators in assessing and managing specific irAEs
following administration of nivolumab38 and pembrolizumab.31 The guidelines specific to the
management of cetrelimab are summarized as follows:
1. Subjects should be evaluated to identify any alternative etiology.
2. In the absence of a clear alternative etiology, all events of an inflammatory nature should be
considered immune-related.
3. Symptomatic and topical therapy should be considered for low-grade events.
4. Systemic corticosteroids should be considered for a persistent low-grade event or for a severe
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5. More potent immunosuppressives should be considered for events not responding to systemic
corticosteroids (eg, anti-TNF agents or mycophenolate).
For management of individual toxicities, follow the guidance in Attachment 1.
6.2.2. 
Combination 2: Niraparib and AAP
Refer to Section 6.2.1.1, for niraparib dose modifications.
6.2.2.1. 
Combination 2: Dose Modifications for AAP
For Combination 2, once the dose of any study drug is reduced, any re-escalation to a full starting
dose must be discussed in advance with the sponsor’s medical monitor (with the exception of dose
reduction for LFT-related toxicity, for which no dose re-escalation will be permitted, as discussed
in Section 6.2.2.1.2).
In general, dose interruptions/modifications should be managed as follows:
 
Grade 1 or Grade 2 toxicities should be managed symptomatically without requiring dose
adjustments or dose interruptions; however, closer monitoring (laboratory or clinic visits)
should be considered.
 
The dose ofprednisone can remain unchanged with dose modifications of niraparib or AA.
If either study drug is permanently discontinued due to toxicity, the other study drug (niraparib or
AA) may be continued. Prednisone should be discontinued (with a taper if clinically indicated) if
AA is permanently discontinued.
6.2.2.1.1. 
Non-hematologic Toxicities
For subjects who develop drug-related Grade 3 or higher toxicities, treatment must be withheld
and appropriate medical management per institutional standard should be instituted. Treatment
with study drug must not be reinitiated until symptoms of the toxicity have resolved to Grade 1 or
baseline. If the toxicity cannot be definitively attributed to either niraparib only, then both niraparib
and AA should be interrupted. If study drugs are to be restarted, then AA should be restarted first.
If there is continued resolution of the AE to baseline/Grade 1, then niraparib may be restarted at
least 7 days after restarting AA. If dose reduction is used for AE management, then please note
the following:
 
Only 1 dose-level reduction will be permitted for niraparib (from 200 mg to 100 mg) (from
2 capsules to 1 capsule).
 
For AA, up to 2 dose-level reductions are permitted. At each dose-level reduction, the dose
will be reduced by 1 tablet (250 mg) of AA, for example 4 to 3 tablets or 3 to 2 tablets.
6.2.2.1.2. 
Hepatic Toxicities
Hepatic toxicities are a known potential side effect of AAP and niraparib, but are more common
with AAP treatment.22,24 Table 7 provides dose recommendations for subjects who develop liver
function test abnormalities during treatment with niraparib and AAP. During dose interruptions,
LFTs should be monitored at least weekly. For Grade ≥2 liver function test (LFT) abnormalities,

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LFTs should be monitored at least weekly until Grade 1 or baseline. For subjects being retreated,
serum transaminases should be monitored at a minimum of every 2 weeks for 3 months and
monthly for the next 3 months and then follow the Time and Events Schedule.
Table 7: 
Dose Modification Criteria for AST/ALT/Bilirubin Abnormalities for Niraparib and
Abiraterone Acetate Plus Prednisone
Toxicity 
Grade 
Dose of Niraparib 
Dose of Abiraterone Acetate 
Dose of
Prednisone
Grade 1 
No change. 
No change. 
No change.
Grade 2 
No change. 
No change. 
No change.
Grade 3 
Interrupt until return to baseline. 
Then, resume at previous dose at 
least 7 days after AA has been 
started without AST/ALT/bilirubin 
abnormalities and only after 
discussion and agreement with  
medical monitor.
AST/ALT/bilirubin must be
confirmed Grade 1 or baseline
before restarting.
Interrupt until return to baseline or 
to AST or ALT ≤3 x ULN and total
bilirubin ≤1.5 x ULN, resume at
750 mg (3 tablets) only after
discussion and agreement with
medical monitor.
No change.
Recurrence 
Grade 3 
Interrupt until return to baseline. 
Then, resume at 1 dose-level 
reduction at least 7 days after AA 
has been started without 
AST/ALT/bilirubin abnormalities 
and only after discussion and 
agreement with medical monitor.
Interrupt until return to baseline or 
to AST or ALT ≤3 x ULN and total
bilirubin ≤1.5 x ULN, resume at
500 mg (2 tablets) only after
discussion and agreement with
medical monitor.
No change.
Grade 4 
Must be interrupted and discussed 
with medical monitor.a 
Must be interrupted and discussed 
with medical monitor. a 
No change or
consider tapering if
AA discontinued.
AA=abiraterone acetate; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of
normal
a 
Must be discussed with medical monitor prior to any restart.
If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases should
be measured immediately. If a subject develops severe hepatotoxicity (ALT 20 x ULN) anytime
while receiving AA, subjects should be discontinued from treatment and retreatment with AA
should not be attempted. Re-escalation of AA or niraparib is not permitted if the dose reduction
was due to elevated LFTs.
Subjects who develop a concurrent elevation of ALT >3 x ULN and a total bilirubin >2 x ULN in
the absence of biliary obstruction or other causes responsible for the concurrent elevation should
be permanently discontinued from treatment with study drugs.
6.2.2.1.3. 
Hypokalemia
Hypokalemia is a known side effect of AAP.22 Niraparib does not need to be interrupted/modified
for hypokalemia.

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For subjects who develop hypokalemia on study treatment, maintenance of the subject’s potassium
level at 4.0 mM or higher should be considered. If hypokalemia persists despite optimal potassium
supplementation and adequate oral intake, the dose of prednisone may be increased by 5 mg/day
and documented in the study medication eCRF. The increased dose of prednisone (or
prednisolone) must be obtained locally from an open-label source (eg, a prescription provided by
investigator) and documented as a concomitant medication. For Grade ≥3 hypokalemia, AA must
be interrupted, and appropriate medical management instituted (eg, obtain ECG and provide
potassium supplement). Treatment with AA should not be reinitiated until hypokalemia has
resolved to Grade 1 or baseline.
6.2.2.1.4. 
Treatment Interruptions for Procedures
Both niraparib and AA should be held for at least 24 hours prior to procedures that require
hospitalization. Study drugs should be resumed only when AEs related to the procedure are
resolved. Prednisone can be continued during AA interruption.
6.2.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose
Combination Tablet
Refer to Section 6.2.1.1, for niraparib dose modifications and Section 6.2.2.1, for AAP dose
modifications.
6.3. 
Treatment of Overdose
For this study, any dose of niraparib, AA, niraparib/AA FDC, cetrelimab, or prednisone greater
than the protocol-specified daily dose of study medication will be considered an overdose. This
may also apply to increased exposure to AA arising due to the study medication being taken with
food (ie, without fasting). Overdose is addressed in the niraparib (Zejula®), AA, and RAYOS
product information62,64,43 and in the cetrelimab IB23 as: 
 
Niraparib: There is no specific treatment in the event of niraparib overdose. Physicians should
follow general supportive measures, hold niraparib, and treat symptomatically. Serial
complete blood counts should also be obtained.
 
AA: There is no specific antidote. In the event of an overdose, stop AA, undertake general
supportive measures, including monitoring for arrhythmias and cardiac failure, and assess
liver function.
 
Cetrelimab: There is no known specific antidote for overdose with cetrelimab.
Treatment of overdose of cetrelimab should consist of general supportive care.
 
Prednisone/prednisolone: Treatment of acute overdose is by immediate gastric lavage or
emesis followed by supportive and symptomatic therapy.
In the event of an overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.
 
Closely monitor the subject for AE/SAE and laboratory abnormalities until niraparib, AA, 
cetrelimab, or prednisone/prednisolone can no longer be detected systemically (at least
30 days).

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 
Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the Medical Monitor based on the clinical evaluation of the subject.
7. 
TREATMENT COMPLIANCE
For niraparib, a count of all capsules provided by the sponsor will be conducted during the
Treatment Phase (Extension Phase for Combination 3) of this study. Niraparib will be dispensed
and dosing compliance will be assessed at study visits as described in the relevant Time and Events
Schedule: Attachment 5 (Combinations 1 and 2) and Attachment 6, Time and Events Schedule 1A
(Combination 3). In the absence of toxicity, if the dosing compliance is not 100%, then
investigators or designated study-site personnel should re-instruct subjects regarding proper dosing
procedures and the subject may continue study treatment.
The study site must maintain accurate records demonstrating dates and amount of study drugs
received, to whom dispensed (subject-by-subject accounting), and accounts of any study drugs
accidentally or deliberately destroyed. For any study drugs taken orally, the amount of study drugs
dispensed will be recorded and compared with the amount returned. At the end of the study,
reconciliation must be made between the amount of study drugs supplied, dispensed, and
subsequently destroyed or returned to the sponsor or its representative (see also Section 14.5).
7.1. 
Combination 1: Niraparib and Cetrelimab
For cetrelimab, administration should be under the supervision of the investigator or qualified
investigational site staff at study visits. The total volume of cetrelimab infused will be compared
to the total volume prepared to determine compliance with each dose administered. The
instructions for preparing and administering cetrelimab will be provided in the Site Investigational
Product Preparation Manual (SIPPM).
7.2. 
Combination 2: Niraparib and AAP
For AAP, a count of all tablets provided by the sponsor will be conducted during the Treatment
Phase of this study. AAP will be dispensed, and dosing compliance will be assessed at study visits
as described in Attachment 5. In the absence of toxicity, if the dosing compliance is not 100%,
then investigators or designated study-site personnel should re-instruct subjects regarding proper
dosing procedures.
8. 
PRIOR AND CONCOMITANT THERAPY
See Attachment 6 for Prior and Concomitant Therapy for Combination 3.
All previous therapies for prostate cancer must be collected. Concomitant therapies must be
recorded throughout each combination study beginning with the signing of the ICF to the end-of-
treatment (EoT) visit. In addition, concomitant medications for AEs and SAEs related to the study
drugs must be recorded up to 100 days after the last dose of study drugs for Combination 1 and
30 days after the last dose of study drugs for Combination 2. For Combination 1 only, all non-
steroidal anti-inflammatory drugs (NSAIDs; eg, celecoxib) and antibiotics used 30 days prior to
signing the ICF at prescreening until the EoT visit should be collected and entered into the eCRF

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(see Section 9.5.5). Note that bone-strengthening regimens are permitted if clinically indicated. If
bone-strengthening agents are prescribed, the choice of agent is at the discretion of the investigator.
All therapies different from the study drugs must also be recorded in the eCRF. For subjects who
have not undergone orchiectomy, concurrent treatment with a GnRHa to maintain testosterone
<50 ng/dL should be documented as a concomitant medication in the eCRF. Recorded information
will include a description of the type of the drug, treatment period, dosing regimen, route of
administration, and indication. Concurrent enrollment in another investigational drug or device
study during the Treatment Phase is prohibited.
8.1. 
Prohibited Concomitant Therapies
The sponsor must be notified of any instances in which prohibited therapies are administered. If
the permissibility of a specific drug/treatment is in question, the sponsor should be contacted.
Combination-specific prohibited therapies are provided in the respective subsections.
 
Investigational agents other than study drugs
 
Other PARP inhibitors
 
Other anticancer therapies, excluding GnRHa
 
Testosterone
 
Radiotherapy (except as described in Section 10.2)
 
Chemotherapy
 
Radiopharmaceuticals such as radium-223 (223Ra), strontium (89Sr), samarium (153Sm), or
similar analogues
 
Live virus vaccines
8.1.1. 
Combination 1: Niraparib and Cetrelimab
 
Agents that target the androgen axis, other than GnRHa (eg, anti-androgens such as
enzalutamide and apalutamide; CYP17 inhibitors such as abiraterone acetate with prednisone)
 
Immunosuppressants (eg, cyclosporine, infliximab). However, the use of immunosuppressive
medications for the management of irAEs, IRRs, or in subjects with contrast allergies is
acceptable. In addition, use of inhaled, topical, and intranasal corticosteroids is permitted.
8.1.2. 
Combination 2: Niraparib and AAP
 
Agents that target the androgen axis, other than GnRHa (eg, anti-androgens such as
enzalutamide and apalutamide; CYP17 inhibitors such as ketoconazole)
 
Diethylstilbestrol (DES) or similar estrogen receptor agonists
 
Pomegranates and pomegranate juice
 
Spironolactone
Strong inducers of CYP3A4 (eg, rifampin)

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8.2. 
Restricted Concomitant Medications
For the most current information regarding potential drug-drug interactions with niraparib or
combination agents and concomitant study medication, refer to the latest version of the appropriate
Investigator’s Brochures.22,24 Agents that can increase the risk of bleeding (anticoagulants and
antiplatelet therapies) should be used with caution especially in subjects experiencing
thrombocytopenia.
8.2.1. 
Combination 1: Niraparib and Cetrelimab
Not applicable for Combination 1.
8.2.2. 
Combination 2: Niraparib and AAP
Restrictions based on the drug interaction potential of niraparib with AAP are as follows:
 
Substrates of CYP2D6: caution is advised when AA is administered with medicinal products
activated by or metabolized by CYP2D6, particularly with medicinal products that have a
narrow therapeutic index. Dose reduction of medicinal products with a narrow therapeutic
index that are metabolized by CYP2D6 should be considered. Examples of medicinal products
metabolized by CYP2D6 include metoprolol, propranolol, desipramine, venlafaxine,
haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol (the latter
3 products requiring CYP2D6 to form their active analgesic metabolites).
 
Substrates of CYP2C8: In a CYP2C8 drug-drug interaction study in healthy subjects, the AUC
of pioglitazone was increased by 46% when pioglitazone was administered with a single-dose
of 1000 mg AA. Although these results indicate that no clinically meaningful increases in
exposure are expected when AA is combined with drugs that are predominantly eliminated by
CYP2C8, subjects should be monitored for signs of toxicity related to a CYP2C8 substrate
with a narrow therapeutic index (eg, paclitaxel) if used concomitantly with AA.
For the most current information regarding potential drug-drug interactions with niraparib and
AAP, refer to the latest versions of the Investigator’s Brochure for niraparib and AA.22,23
Additional information is provided in Attachment 4.
9. 
STUDY EVALUATIONS
See Attachment 6 and Section 9.1.2.3, below for Study Evaluations for Combination 3.
9.1. 
Study Procedures
9.1.1. 
Overview
Under Amendment 6, Time and Events Schedules 1 (Combination 1) and 3 (Combination 2) are
superseded by Attachment 5; Time and Events Schedule 2 is obsolete.
The Time and Events Schedules summarize the frequency and timing of assessments applicable to
this protocol and associated combination studies. If multiple assessments are scheduled for the
same timepoint, it is recommended that procedures be performed in the following sequence: ECGs,
vital signs, and any type of blood draw last. Blood collections for pharmacokinetic and
immunogenicity assessments should be kept as close to the specified time as possible
(Combination 1 only). Actual dates and times of assessments will be recorded in the source

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documentation. Other measurements may be done earlier than specified timepoints if needed.
Medical resource utilization data will also be collected. Refer to Section 9.6, Medical Resource
Utilization for details.
For each subject, the planned maximum amount of blood drawn will not exceed 70 mL at any visit.
Refer to the study Laboratory Manual for details regarding blood volumes to be collected for each
visit. Repeat or unscheduled samples may be taken for safety reasons or for technical issues with
the samples.
The Long-term Extension Phase for the specified combination will start once the Amendment 7
has been approved at the site and after the notification by the sponsor (Attachment ).
9.1.2. 
Prescreening Phase for Biomarker Evaluation
Subjects will be required to sign a prescreening specific ICF and provide baseline demographic
information and disease-specific medical history. After signing the prescreening ICF, all subjects
in Combinations 1 and 2 must have a blood sample collected to determine biomarker status, unless
already eligible by a sponsor assay (Tissue may also be used to determine eligibility as described
in Section 9.5). If a subject has been determined to be biomarker positive by sponsor approved
assay with confirmation by sponsor review, a blood sample is still required. SAEs related to the
blood collection procedure, as well as deaths from any cause, will be collected from the time the
prescreening ICF is signed until 30 days after the procedure occurs (see Section 12.3.1). For Part 1
of the study, subjects may begin dosing prior to the results of biomarker assay becoming available.
For Part 2 of the study, Subjects must have a result available prior to dosing. If the sample used to
determine eligibility fails to produce a conclusive result, subjects may have testing performed
again once.
9.1.2.1. 
Combination 1: Niraparib and Cetrelimab
For Combination 1, subjects will be assigned to a cohort based on their biomarker status (DRD
[biallelic] or CDK12 pathogenic alteration).
9.1.2.2. 
Combination 2: Niraparib and AAP
For Combination 2, subjects will be eligible to proceed to the Screening Phase if determined to
have DRD (see Section 9.5). 
9.1.2.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose
Combination Tablet
For Combination 3, biomarker status is not required to determine study eligibility. If not already
known, biomarker status assessment is recommended, and results can be used to guide further
treatment decisions during the Extension Phase (see Attachment 6).
9.1.3. 
Screening Phase
During this phase, eligibility criteria will be reviewed and evaluations performed as specified in
Time and Events Schedules. Screening procedures may be performed within 28 days before
Cycle 1 Day 1, unless otherwise specified. Imaging will be accepted up to 8 weeks prior to Cycle 1
Day 1. The screening physical exam, PSA and clinical safety laboratory evaluations can be used

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for Cycle 1 Day 1 assessments if performed within 14 days of Cycle 1 Day 1. Details of screening
laboratory tests are provided in Section 9.7, and Table 10. Assessments performed as part of the
subject’s routine clinical evaluation and not specifically for this study need not be repeated after
signed informed consent has been obtained, provided the assessments fulfill the study requirements
and are performed within the specified timeframe prior to enrollment.
A blood sample for cytogenetics will be collected at screening and will be stored for evaluation if
the sponsor's medical monitor finds evaluation necessary for assessing niraparib-related risk for
MDS/AML (eg, the patient develops MDS/AML). The screening mutation profile will be analyzed
to determine whether any mutations were present prior to study treatment. Details on cytogenetics
sample collection and analysis are in the Laboratory Manual.
Subjects who do not meet all inclusion criteria, or who meet an exclusion criterion, may be
rescreened once. Rescreening is at the discretion of the investigator and requires sponsor approval
and agreement. Subjects who are to be rescreened must sign a new ICF before rescreening.
Subjects rescreened within 28 days of planned enrollment may use the initial screening laboratory
results, CT/MRI and bone scans (if still within 8 weeks of Cycle 1 Day 1) to determine eligibility
if not the reason for the rescreening. All other rescreening and subsequent enrollment activities
must be conducted in accordance with all protocol defined windows and timelines.
9.1.4. 
Treatment Phase
The Treatment Phase will begin at Cycle 1 Day 1 and will continue until the EoT visit. All site
visits during the Treatment Phase will have a ±3-day window. Study visits will be calculated from
the Cycle 1 Day 1 date. Refer to the Time and Events Schedules for treatment visits and
assessments during the Treatment Phase.
For all site visits days and PK or immunogenicity sampling days (as applicable to each
combination), the subject must not take niraparib at home in the morning; both study drugs should
be administered at the investigational site. Details of PK or immunogenicity sampling days and
times are provided in the Time and Events Schedule corresponding to the applicable combination.
Additional details regarding PK or immunogenicity sampling (as applicable to each combination)
are provided in Section 9.3. Details of blood sample handling and storage procedures for PK or
immunogenicity are provided in each study Laboratory Manual.
Clinical evaluations and laboratory studies may be repeated more frequently, if clinically
indicated. Treatment will continue until disease progression, unacceptable toxicity, death, or the
sponsor terminates the study (see Section 10).
9.1.4.1. 
Long-term Extension Phase With Minimal Data Collection
After primary analysis of a combination, and the sponsor’s subsequent decision and notification
to limit further data collection, all subjects still in the Treatment Phase of that combination will be
offered the option to enter the Long-term Extension Phase of the study. All subjects must sign the
ICF for the Long-term Extension Phase before entering it. Details for the Long-term Extension
Phase are provided in Attachment .

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If niraparib or the combination-specific drug(s) are commercially available, subjects might be
offered to change to the commercially available drug. If a dedicated Extension study or Post-Trial
Access program becomes available, then all subjects who comply with the entry criteria for that
study and consent to that study should be transferred to that study. In both scenarios, the subject
will discontinue from the current study.
The Long-term Extension Phase for the specified combination will start once the Amendment 7
has been approved at the site and after the notification by the sponsor, sites will collect only the
data specified in Attachment .
9.1.5. 
End-of-Treatment Visit
An EoT visit must be scheduled within 30 days after study drugs are discontinued, or prior to
administration of a new anti-prostate cancer therapy, whichever occurs first. Refer to the Time and
Events Schedules for required assessments at the EoT visit. If a subject is unable to return to the
site for the EoT visit, then the subject should be contacted to collect AEs or SAEs that occurred,
and concomitant medications taken, within 100 days after the last dose of study drugs for
Combination 1 and 30 days for Combinations 2 and 3, unless the subject received subsequent
therapy, has died, is lost to follow-up, or has withdrawn consent. If the information on concomitant
therapies and AEs is obtained via telephone contact, then written documentation of the
communication must be available for review in the source documents. If the subject dies, then the
date and cause of death will be collected and documented in the eCRF.
Note that bone, CT, or MRI scans performed ≤6 weeks prior to the EoT visit may serve as EoT
scans.
9.1.6. 
Follow-Up Phase
Once a subject has completed the Treatment Phase, deaths regardless of causality and SAEs
thought to be related to study drugs, including associated concomitant medications, will be
collected and reported within 24 hours of discovery or notification of the event. Related AEs
should be reported as per the procedures in Section 12.3.1. If the follow-up information is obtained
via telephone contact, then written documentation of the communication must be available for
review in the source documents.
Once a subject has completed the Treatment Phase for a reason other than radiographic
progression, CT, MRI, or bone scans (99mTc) will be collected every 3 months (±2 weeks) until
confirmed radiographic progression or initiation of subsequent therapy, provided the subject does
not withdraw consent. If a subject has documented radiographic progression during the Treatment
Phase, additional radiographic assessments are not required during the Follow-up Phase.
9.2. 
Antitumor Activity
9.2.1. 
Evaluations
Antitumor activity evaluations will be conducted as specified in the Time and Events Schedule for
each combination.  Unscheduled assessments should be considered if clinically indicated and
results collected in the eCRF. The antitumor activity evaluations include the following:

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 
Tumor measurements: Chest, abdomen, and pelvis CT or MRI scans and whole-body bone
scans (99mTc). The same imaging modality should be used throughout the evaluation of an
individual subject. Imaging will be assessed by the investigator and the sponsor and these
results will be used for the primary endpoint analyses.
 
serum PSA
 
CTCs
 
survival status
For Combination 1 only: Evaluation of treatment response will also be assessed by the immune-
related RECIST Criteria.9
9.2.2. 
Criteria
Objective response of soft tissue (visceral or nodal disease) is defined by Response Evaluation
Criteria in Solid Tumors (RECIST) 1.1 with no evidence of bone progression on bone scan
according to the PCWG3 criteria:
 
Tumor response of soft tissue lesions will only be evaluated for subjects with baseline
measurable disease assessed by CT or MRI as defined in RECIST 1.1.
 
After first documentation of soft tissue response (CR or PR), repeat imaging is required
≥4 weeks later for confirmation.
Radiographic progression by tumor assessment should be evaluated according to RECIST 1.1 for
soft tissue disease and PCWG3 for bone disease (ie, to evaluate duration of response) as follows:
 
Progression of soft tissue lesions measured by CT or MRI as defined in RECIST 1.1.
 
Progression by bone lesions observed by bone scan and based on PCWG3. Under these
criteria, any bone progression must be confirmed by a subsequent scan ≥6 weeks later. The
Week 8 scan (first post-treatment scan) should be used as the reference scan to which all
subsequent scans are compared to determine progression. Bone progression is defined as one
of the following:
1. Subject whose Week 8 scan is observed to have ≥2 new bone lesions compared to baseline
scan will need to have a confirmatory scan performed ≥6 weeks later and would fall into one
of the 2 categories below:
a. Subject whose confirmatory scan (which is performed ≥6 weeks later) shows ≥2 new
lesions compared to the Week 8 scan (ie, a total of ≥4 new lesions compared to baseline
scan) will be considered to have bone scan progression at Week 8.
b. Subject whose confirmatory scan did not show ≥2 new lesions compared to the Week
8 scan will not be considered to have bone scan progression at that time. The Week 8 scan
will be considered as the reference scan to which subsequent scans are compared.
2. For a subject whose Week 8 scan does not have ≥2 new bone lesions compared to baseline
scan, the FIRST scan timepoint that shows ≥2 new lesions compared with the Week 8 scan
will be considered as the bone scan progression timepoint if these new lesions are confirmed
by a subsequent scan ≥6 weeks later.

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Evaluation of treatment response by PSA, imaging, and CTCs will be performed according to
PCWG3 criteria.50 Duration of tumor response will be assessed only for those subjects who have
an objective tumor response by RECIST 1.1. The duration of tumor response will be assessed from
the first time of observed CR/PR to the date of radiographic progression (as per PCWG3).
See Section 10.2, for details regarding discontinuation of study medication for disease progression.
9.3. 
Pharmacokinetics and Immunogenicity (Combination 1)
As of Amendment 6, pharmacokinetic and immunogenicity assessments for Combination 1 are no
longer being performed.
See Attachment 6 for pharmacokinetic assessments for Combination 3.
Blood samples will be collected to measure the plasma concentration of niraparib, and if
performed, its metabolite, M1. Plasma or serum concentration of the combination agent, and
immunogenicity (if applicable) will also be assessed. In addition, serum or plasma collected for
PK or immunogenicity analyses may be used to evaluate safety or antitumor activity concerns
arising during or after the study period. Genetic analyses will not be performed on these samples.
Subject confidentiality will be maintained.
9.3.1. 
Sample Collection and Handling (Combination 1)
See the appropriate combination Time and Events Schedule for details of PK or immunogenicity
sample collection (as applicable to each combination). Samples will be tested by the sponsor or
sponsor's designee. The exact dates and times of blood sampling must be recorded. Refer to the
study Laboratory Manual for sample collection requirements. Additional information about the
collection, handling, and shipment of biological samples can be found in the study Laboratory
Manual.
9.3.2. 
Analytical Procedures (Combination 1)
Plasma samples will be analyzed to determine concentrations of niraparib using a validated liquid
chromatography/mass spectrometry (LC/MS) method by, or under the supervision of, the sponsor.
If performed, the concentration of niraparib’s M1 metabolite may be determined with a qualified
or validated LC-MS method. Concentration of the combination agent (and immunogenicity, if
applicable) will also be determined by a validated assay, as appropriate.
After completion of quantitative analysis, the remaining plasma samples will be stored at -70°C
for investigative metabolite identification/profiling as deemed necessary by the sponsor (to be
reported separately from this study).
9.3.2.1. 
Combination 1: Niraparib and Cetrelimab
Serum samples will be analyzed to determine the concentrations of cetrelimab and the generation
of antibodies to cetrelimab using validated immunoassay methods. Other analyses may be
performed to further verify the stability of antibodies to cetrelimab and/or characterize the
immunogenicity of cetrelimab. Immunogenicity analysis may be conducted on PK samples
collected at other time points, if deemed necessary.

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9.3.3. 
Pharmacokinetic Parameters (Combination 1)
Plasma concentrations of niraparib and M1 (if performed) will be summarized by timepoint. Note:
time zero is in reference to administration of niraparib or combination agent, as appropriate.
Population PK parameters may be derived as appropriate. Concentration-time data may be
combined with other studies and analyzed using a nonlinear mixed-effects modeling approach.
9.3.3.1. 
Combination 1: Niraparib and Cetrelimab
The following PK parameters will be calculated for cetrelimab as data permit:
 
Cmax  
maximum observed concentration
 
tmax  
time to reach the maximum plasma concentration
 
Ctrough  
minimum observed (ie, predose) concentration following multiple dosing
9.4. 
Pharmacokinetic/Pharmacodynamic Evaluations (Combination 1 Only)
Exposure-response relationship will be explored for key antitumor activity (eg, PSA) and safety
parameters as data allow.
9.5. 
Biomarkers
All subjects in Combinations 1 and 2 must be evaluated for DRD and CDK12 before being enrolled
into the study. Subjects must have DRD status assessed by the sponsor’s required blood or tissue
assays. CDK12 status will be assessed by tissue assay until blood assay becomes available. If
previous local testing (by CLIA-certified or equivalent laboratory) shows DRD or CDK12
pathogenic alteration and result is reviewed by sponsor to confirm eligibility, subject may enter
screening. However, blood and tissue should be collected and assessed for DRD and CDK12 by
sponsor’s required assays.
The biomarkers of interest for Combinations 1 and 2 are listed in Table 8. The criteria for cohort
eligibility in Combination 1 and Combination 2 are listed in Table 9.
Table 8: 
Biomarker Panel
Genes 
Definition
BRCA1 
Breast Cancer gene 1
BRCA2 
Breast Cancer gene 2
FANCA  
Fanconi Anemia Complementation Group A gene
PALB2 
Partner and Localizer of BRCA2 gene
CHEK2 
Checkpoint Kinase 2 gene
BRIP1 
BRCA1 Interacting Protein C-terminal Helicase 1 gene
HDAC2a 
Histone Deacetylase 2 gene
ATM  
Ataxia Telangiectasia Mutated gene
CDK12b 
Cyclin Dependent Kinase 12
a HDAC2 is only detected by the blood-based assay
b 
CDK12 is detected by the tumor assay and blood assay (once it becomes available)

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Table 9: 
DRD and CDK12 Status and Cohort Eligibility in Combination 1 and Combination 2
DRD status (blood or tissue*) 
Combination 1 Eligibility  
Combination 2 Eligibility
BRCA biallelic loss 
Cohort 1A  
Cohort 2A
Other gene biallelic loss 
Cohort 1A  
Cohort 2B
CDK12 pathogenic alteration 
Cohort 1A  
Not applicable
BRCA monoallelic pathogenic loss 
Not eligible 
Cohort 2C
Other monoallelic pathogenic loss 
Not eligible 
Cohort 2D
Negative for DRD  
Not eligible 
Not eligible
Note: biomarkers are not collected for Combination 3.
* Once tissue algorithm is available for study use.
Biomarker status will not be required to determine study eligibility in Combination 3. If not already
known, biomarker status assessment is recommended, and results can be used to guide further
treatment decisions during the Extension Phase (see Attachment 6 for further information.)
On-study Biomarker Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and
clinical RRs. Biomarker analyses may be deferred or not performed, if during or at the end of the
study, it becomes clear that the analyses will not have sufficient scientific value for biomarker
evaluation, or if there are not enough samples or responders to allow for adequate biomarker
evaluation. In the event a combination is terminated early or shows poor antitumor activity,
completion of biomarker assessments is based on justification and intended utility of the data.
Additional Collections
If it is determined at any time before combination completion that additional material is needed
from a tumor sample for the successful completion of the protocol-specified analyses, the sponsor
may request that additional material be retrieved from existing samples. Also, based on emerging
scientific evidence, the sponsor may request additional material from previously collected tumor
samples during or after study completion for a retrospective analysis. In this case, such analyses
would be specific to research related to the study drug(s) or diseases being investigated.
9.5.1. 
Tumor Samples
Tumor samples will not be collected in Combination 3.
Archival formalin-fixed paraffin-embedded tumor samples will be collected during Screening, if
feasible. If unable to collect at Screening, archival tumor sample may be collected during Cycle 1.
Combination 1: Niraparib and Cetrelimab
Tumor samples may be used to examine proteins, RNA, and DNA biomarkers related to treatment
response or resistance to treatment with the combination therapy and other immune-related or
prostate cancer-related biomarkers.
These tumor biomarkers may include, but are not limited to, biomarkers that have been associated
with response to PARP inhibitors, AR targeting agents, or anti-PD(L)-1 treatment, such as DRD,35

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AR anomalies, mismatch repair,34 PD-L1,20,54 and tumor mutational burden.42 PD-L1 expression
will be retrospectively evaluated in tumor samples collected before, during and after treatment.
In this combination, fresh biopsies are mandatory at screening. Every effort should also be made
to collect fresh biopsies at Cycle 1 Day 15 and EoT (if clinically feasible). Soft tissue biopsies are
preferred; however, bone biopsies are allowed. The same organ system should be biopsied
throughout the study, if clinically feasible.
9.5.2. 
Circulating Tumor Cells
Circulating tumor cells will not be evaluated in Combination 3.
Circulating tumor cells (CTCs) may be enumerated to determine CTC response to treatment and
may be evaluated for gene and protein expression. 
9.5.3. 
Circulating Tumor DNA- Combination 1 Only
Plasma-based circulating tumor DNA (ctDNA) will be evaluated for mutations in genes associated
with DNA-damage response or CDK12 pathogenic alterations at the timepoints described in Time
and Events Schedule 1. ctDNA may also be used to assess the presence of AR mutations, copy
number changes, and other genes associated with resistance to niraparib combination therapy or
prostate cancer disease biology.
9.5.4. 
Other Biomarker Assays
Other biomarker assays are not applicable for Combinations 2 and 3.
9.5.4.1. 
Combination 1: Niraparib and Cetrelimab
Whole blood samples may be examined by flow cytometry for markers of activated/effector T-
cells, T-cell counts and other immune cell markers at the timepoints described in Time and Events
Schedule 1 as part of immunophenotyping analysis. Peripheral blood mononuclear cells (PBMCs)
may also be isolated from whole blood samples to obtain their derivatives (eg, RNA and DNA)
and evaluated for immune-related, tumor type related, and other exploratory biomarkers (eg,
alterations in gene expression, clonal T-cell expansion, or as germline reference for tumor-based
genomic biomarkers). These biomarker analyses may include, but are not limited to, T-cell
receptor sequencing, evaluation of mRNA expression of interferon-γ pathway genes, and gene
signatures of T-cells and other immune cells. PBMC samples may also be used as reference
samples for next generation sequencing analysis of tumor samples to determine if genetic
alterations identified in tumor samples are somatic (ie, tumor specific). Blood samples will be
processed to obtain plasma and serum for the determination of changes in blood-based biomarkers,
such as cytokines, soluble PD-L1, mRNA expression of PD-L1 and other immune- or
tumor-related biomarkers.
9.5.5. 
Non-steroidal Anti-inflammatory Drugs and Antibiotics
(Combination 1)
Use of NSAIDs and antibiotics will be collected to explore whether subjects who have recently
taken these agents may have changes to the tumor microenvironment, which may result in a

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different response to the study drugs.27,63 Collection of NSAID and antibiotic use will be from
30 days prior to screening until the EoT visit.
9.6. 
Medical Resource Utilization
Medical resource utilization information will not be collected in Combination 3.
Medical resource utilization data, associated with medical encounters, will be collected in the
eCRF by the investigator and study-site personnel for all subjects throughout the study.
Protocol-mandated procedures, tests, and encounters are excluded. The data collected may be used
to conduct exploratory economic analyses and will include:
 
Number and duration of medical care encounters, including surgeries, and other selected
procedures (inpatient and outpatient)
 
Duration of hospitalization (total days length of stay, including duration by wards;
eg, intensive care unit)
 
Number and character of diagnostic and therapeutic tests and procedures
 
Outpatient medical encounters and treatments (including physician or emergency room visits,
tests and procedures, and medications)
9.7. 
Safety Evaluations
Safety assessments will be based on medical review of AE reports and the results of vital sign
measurements, physical examinations, clinical safety laboratory tests, ECOG PS, and other safety
evaluations at specified timepoints as described in the Time and Events Schedule for each
combination: Attachment 5 (Combinations 1 and 2), and Time and Events Schedule 1A in
Attachment 6 (Combination 3). Any clinically significant abnormalities persisting at the end of the
study/early withdrawal will be followed by the investigator until resolution or until a clinically
stable condition is reached.
Adverse Events
Potential AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or
the subject's legally acceptable representative) for the duration of the study and investigators will
determine if the events are recorded as AEs. AEs will be followed by the investigator as specified
in Section 12, Adverse Event Reporting.
Clinical Safety Laboratory Tests
Clinical Safety Laboratory Tests for Combination 3 are in Attachment 6.
Blood samples to assess the safety and antitumor activity of study drugs will be collected. The
investigator must review laboratory results, document this review, and record any clinically
relevant changes occurring during the study in the AE section of the eCRF. For each laboratory
abnormality reported as an AE, the following laboratory values should be reported in the laboratory
section of the eCRF: the value indicative of the onset of each toxicity grade; the most abnormal
value observed during the AE, and the value supporting recovery to Grade 1 or to baseline values.

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Tests will be performed at the timepoints outlined in Time and Events Schedule. Required
laboratory tests must be performed within ±3 days of the scheduled visit during the Treatment
Phase (windows of ±5 days and ±2 weeks are applicable at the EoT visit and during the Follow-up
Phase, respectively). During Cycle 1, complete blood counts (CBCs) must be performed weekly
and then as per the timepoints described in the Time and Events Schedule. In the event of additional
safety monitoring, unscheduled laboratory assessments may be performed as required. Screening
laboratory tests will be performed by the central laboratory and are detailed in Table 10. Clinical
safety laboratory tests during the Treatment Phase and at EoT will be performed using local
laboratories and are detailed in Table 11.
For suspected MDS/AML while a subject is receiving treatment or being followed for post-
treatment assessments, bone marrow aspirate and biopsy testing must be completed by a
hematologist. A whole blood sample will also be collected for cytogenetic analysis (mutations of
select myeloid-associated genes) at screening. If needed, cytogenetic analysis will be done
centrally for standardized evaluation. Testing completed as part of standard-of-care is sufficient if
the methods are acceptable to the sponsor's medical monitor. The study site must receive a copy
of the hematologist’s report of aspirate/biopsy findings, which must include a classification
according to World Health Organization (WHO) criteria,57 and other sample testing reports related
to MDS/AML. Data from the report will be entered on the appropriate eCRF pages and the site
must keep a copy of the report with the subject’s study file.
Table 10: 
Screening Laboratory Tests (Central Laboratory)
Hematology Panel
-CBC (hemoglobin, white blood cell count, platelets, absolute lymphocyte count, and ANC)
Serum Chemistry Panel
-creatinine 
-lactate dehydrogenase 
-glucosea
-potassiumb
Liver Function Tests
-AST  
-alkaline phosphatase 
-ALT
-serum total bilirubin (if abnormal,
measure direct bilirubin)
Other Laboratory Tests
-testosterone 
-TSHc 
-HgbA1cc
-PSAd 
-urinalysisc 
-serum albumin
-serology (HIV and CD4 count if
indicatede, HBsAg, HepB core
antibody, HCV antibody)
ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate aminotransferase;
CBC=complete blood count; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HgbA1c=hemoglobin
A1c; HIV=human immunodeficiency virus; TSH=thyroid-stimulating hormone
Note: all screening laboratory tests may also be performed during the study as clinically indicated. Tests will be
performed at the central laboratory.
a 
Fasting glucose in Combination 2.
b 
Potassium for Combination 2 only.
c 
TSH, HgbA1c, and urinalysis for Combination 1 only.
d 
PSA is tested at screening and as per the timepoints detailed in Time and Events Schedule.
e 
HIV and CD4 count should be only performed if indicated by prior medical history.

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Table 11: 
Clinical Safety Laboratory Tests (Central or Local Laboratory)
Hematology Panel
-CBC (hemoglobin, white blood cell count, platelets, absolute lymphocyte count, and ANC)
Serum Chemistry Panel
-creatinine 
-lactate dehydrogenase 
- glucosea
-potassiumb
Liver Function Tests
-AST  
-alkaline phosphatase 
-ALT
-total bilirubin (if abnormal,
measure direct bilirubin)
ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate aminotransferase;
CBC=complete blood count
Note: all clinical safety laboratory tests may be performed more frequently during the study as clinically
indicated. Tests will be performed at the central or local laboratory.
a 
Fasting glucose in Combination 1 and fasting glucose in Combination 2.
b 
Potassium for Combination 2 only
Electrocardiogram (ECG)
ECGs (12-lead) will be recorded at screening. Any known electrolyte imbalance should be treated
prior to performing the ECG. Subjects are to reside in a quiet setting without distractions (eg,
television, cell phones, and staff talking) for ECG measurements. Subjects should rest in a supine
position for at least 10 minutes before ECG collection and should refrain from talking or moving
arms or legs. Clinically significant abnormalities noted at the time of screening will be documented
in the subject’s medical history and recorded on the eCRF.
Vital Signs
Body temperature, heart rate, and blood pressure will be recorded at the timepoints outlined in
Time and Events Schedules. As hypertension has been reported with niraparib, blood pressure
should be monitored weekly during the first 2 months of treatment (Cycles 1-2), and then monthly
thereafter. Blood pressure monitoring can occur at clinic visit or may also be reported to the site
by the subject, by home nurse, or by other method deemed reliable by the investigator. Follow the
instructions in Section 6.1.1, for vital sign assessments during cetrelimab infusion.
Physical Examination
The screening physical examination will include, at a minimum, the general appearance of the
subject, height and weight, examination of the skin, ears, nose, throat, lungs, heart, abdomen,
extremities, musculoskeletal system, lymphatic system, and nervous system. During the Treatment
Phase and at the EoT visit, limited symptom-directed physical examination and weight assessment
is required. Only clinically relevant abnormalities found on physical examination should be
recorded and reported as AEs in the eCRF.

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ECOG Performance Status
The ECOG PS scale (provided in Attachment 2) will be used to grade changes in the subject’s
daily living activities. The frequency of ECOG PS assessment is provided in the Time and Events
Schedule for each combination.
9.8. 
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory
requisition form. Refer to Time and Events Schedules for the timing and frequency of all sample
collections. Instructions for the collection, handling, storage, and shipment of samples are found
in the study Laboratory Manual that will be provided. Collection, handling, storage, and shipment
of samples must be under the specified, and where applicable, controlled temperature conditions
as indicated in the study Laboratory Manual.
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/
WITHDRAWAL FROM THE STUDY
See Attachment 6 for instructions on Completion, Discontinuation of Study Treatment, and
Withdrawal from Study for Combination 3.
10.1. Completion
A subject will be considered to have completed the combination study if assessments have been
completed through the end of the Follow-up Phase. A subject will be considered to have completed
the Treatment Phase when study drug is discontinued for any reason. A safety follow-up visit
should be planned.
10.2. Discontinuation of Study Treatment
A subject will not be automatically withdrawn from the combination study if they discontinue the
study drugs. Subjects who discontinue the study drugs should complete the EoT visit within
30 days of the last dose of study drug or prior to administration of a new anti-prostate cancer
therapy, whichever occurs first. Subjects should ordinarily be maintained on niraparib combination
therapy until confirmed radiographic progression. If the subject has radiographic progression but
no unequivocal clinical progression and alternate treatment is not initiated, the subject may
continue niraparib combination therapy at the investigator’s discretion. Niraparib combination
therapy will be continued for subjects who have increasing PSA values in the absence of
radiographic or unequivocal clinical progression. Although serial PSA values will be measured on
this study, progression or change in PSA values is not considered a reliable measure of disease
progression and should not be used as an indication to discontinue combination therapy.50
However, a subject's niraparib combination therapy must be discontinued for:
 
Combination drug-related toxicity as defined in Section 6.2.
 
Unequivocal clinical progression defined as one or more of the following:
 
Deterioration in ECOG PS to Grade 3 or higher.
 
Need to initiate any of the following because of tumor progression (even in the absence
of radiographic evidence of disease):

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o 
Alternative anticancer therapy for prostate cancer.
o 
Radiation therapy.
o 
Surgical interventions for complications due to tumor progression.
 
Treatment-related hypertensive crisis or posterior reversible encephalopathy syndrome.
 
The investigator believes it is in the best interest of the subject to discontinue study drug.
 
Withdrawal of consent for continued treatment (subject’s decision to discontinue for any
reason).
Palliative radiation therapy for bone pain may not require a subject to be discontinued from
treatment, after discussion with the medical monitor. Note: subjects who discontinue the study
drugs for any reason remain on study and must follow all study evaluations described in Section 9,
and outlined in the applicable Time and Events Schedules. Study data for survival and subsequent
therapies will continue to be collected after discontinuation of treatment, unless the subject
withdraws consent for further study participation.
In the event of early study completion or study termination by the sponsor, (whether or not the
study endpoints are met), the sponsor will continue to provide study treatments until unequivocal
disease progression, unacceptable toxicity, or an alternate method is in place to avoid treatment
interruption.
10.3. Withdrawal from the Study
A subject will be considered withdrawn from the combination study (ie, Treatment Phase and
Follow-up Phase) for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent for subsequent data collection
 
Combination study is terminated by the sponsor
If a subject is lost to follow-up, effort must be made by the study-site personnel to contact the
subject and determine endpoint status and the reason for discontinuation/withdrawal. The
measures taken to follow-up must be documented. The informed consent will stipulate that even
if a subject decides to discontinue the study drugs, the subject will agree to be contacted
periodically by the investigator to assess endpoint status and for collection of safety data as per the
Time and Events Schedule for each combination. This can be done by telephone or by chart review.
If the subject withdraws consent for all study-related procedures, then no further contact is
permitted by the investigator or the sponsor.
When a subject withdraws before completing the combination study, the reason for withdrawal is
to be documented in the eCRF and in the source document. Study drugs assigned to the withdrawn
subject may not be assigned to another subject. Subjects who withdraw will not be replaced.

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10.4. Withdrawal from the Use of Research Samples
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5,
Long-term Retention of Samples for Additional Future Research). In such a case, samples will be
destroyed after they are no longer needed for the clinical study. Details of the sample retention for
research are presented in the ICF.
11. 
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the antitumor activity and safety data
is outlined below. Specific details will be provided in the Statistical Analysis Plan.
A general description of the statistical methods for Combination 3 is in Attachment 6 (except for
safety analysis).
11.1. Analysis Populations
All analysis populations are applicable to each combination.
Intent-to-Treat (ITT) Population: All subjects who are enrolled into a combination study and have
at least 1 dose of both study drugs at the selected RP2D.
Safety Population: All subjects who receive at least 1 dose of study drug. This population will be
used for evaluating safety and treatment compliance.
Pharmacokinetics Populations (PK): Subjects who have received at least1 dose of both study drugs
and have at least 1 concentration value. PK population is for Combination 1 only.
Continuous variables will be summarized using descriptive statistics such as mean, median,
standard deviation (SD), and range. Categorical variables will be summarized using frequency
tables.
11.2. Sample Size Determination
11.2.1. 
Combination 1: Niraparib and Cetrelimab
For Part 1 of the study, at least 6 evaluable subjects (defined in Section 3.1) will initially be
enrolled. Additional dose regimens may be enrolled as discussed in Section 3.1.1. Non-evaluable
subjects will be replaced.
For Part 2 of the study, approximately 30 subjects per cohort (ie, Cohort 1A BM+ or Cohort
1B BM-) were to be enrolled. However, a futility analysis was performed for Cohort 1B after
approximately 10 subjects have been enrolled and evaluated (see Section 11.10). It is anticipated
that the final analysis for the primary endpoint of ORR (defined in Section 11.3) will occur
approximately 6 months after the last subject in each cohort is enrolled. Note that Cohorts 1A and
1B will be evaluated and analyzed independently.

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As described in Section 1.1, there is limited data with single-agent PARP inhibitors for the
treatment of mCRPC. The statistical assumptions are derived from the TOPARP study in which 6
out of 32 subjects with measurable disease had a confirmed radiologic response.35 However, these
results included data from subjects who were BM-, so the actual response rate for BM+ subjects
is potentially higher. The response rate for anti-PD-1 agents in mCRPC is unknown; however, a
minimal single agent response rate (5% to 10%) is estimated. Therefore, for this combination to
be considered clinically meaningful, the observed response rate should be higher than the additive
response of each treatment alone, thus a response rate of greater than 50% was established.
For Cohort 1A, the null hypothesis that the ORR is ≤25% will be tested against the alternative
hypothesis that the ORR is ≥50%. Antitumor activity of niraparib and cetrelimab will be declared
if the lower bound of the 2-sided 90% exact confidence interval (CI) for ORR is >25%. With
approximately 30 BM+ subjects, Cohort 1A will have over 80% power such that the lower limit
of the 90% CI for ORR exceeds 25%.
The response rate from the TOPARP study for single agent olaparib in prostate cancer is based on
1 subject with measurable disease who had a response, despite being BM-. The single-agent
activity of niraparib is likely around 5% and the single-agent activity of anti-PD-1 in this
population is similar to the BM+ population at 5% to 10%. Therefore, for this combination to be
considered clinically meaningful, the response rate should be at least as efficacious as a
chemotherapy-type regimen in this setting, hence a response rate of 30% was selected.
For Cohort 1B, the null hypothesis that the ORR is ≤10% will be tested against the alternative
hypothesis that the ORR is ≥30%. Antitumor activity of niraparib and cetrelimab will be declared
if the lower bound of the 2-sided 90% exact CI for ORR is >10%.49 With approximately
30 BM- subjects, Cohort 1B will have over 80% power such that the lower limit of the 90% CI for
ORR exceeds 10%.
11.2.2. 
Combination 2: Niraparib and AAP
For Combination 2, approximately 20 subjects per cohort will be enrolled; It is anticipated that the
final analysis for the primary endpoint of response rate (defined in Section 11.3) will occur
approximately 6 months after the last subject is enrolled.
As described in Section 1, there is limited data with single-agent PARP inhibitors for the treatment
of mCRPC.
In a study of mCRPC subjects treated with olaparib, a composite response rate of 33% was
observed regardless of biomarker status.35 Subjects with mCRPC who have DRD may have greater
benefit from the combination of Niraparib and AAP. For Cohort 2A and 2B the null hypothesis of
composite response rate ≤33% will be tested against the alternative hypothesis of composite
response rate ≥62%. Antitumor activity of niraparib and AAP for Cohort 2A (or 2B) will be
declared if the lower bound of the 2 sided 90% exact confidence interval (CI) for the composite
response rate is >33%. With approximately 20 subjects in Cohort 2A (or 2B), it will have over
80% power such that the lower limit of the 90% CI for the composite response rate exceeds 33%.

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Based on the proposed mechanism of action of PARP inhibitors, subjects whose tumors have only
monoallelic loss of a DRD gene may not have as robust a response to treatment as those with
biallelic loss.9 Therefore, for Cohort 2C and 2D the null hypothesis that the composite response
rate ≤28% will be tested against the alternative hypothesis of composite response rate ≥57%.
Antitumor activity of niraparib and AAP for Cohort 2C (or 2D) will be declared if the lower bound
of the 2 sided 90% exact confidence interval (CI) for the composite response rate is >28%. With
approximately 20 subjects in Cohorts 2C (or 2D), it will have over 80% power such that the lower
limit of the 90% CI for the composite response rate exceeds 28%.
11.2.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose
Combination Tablet
See Attachment 6 for sample size determination for Combination 3.
11.3. Antitumor Activity Analyses
11.3.1. 
Combination 1: Niraparib and Cetrelimab
Primary Endpoint
Subjects dosed during Part 1 at the selected RP2D combination will be included as part of the ITT
Population.
The primary endpoint for Part 2 is ORR, defined as the proportion of subjects who achieve CR or
PR determined by RECIST 1.1 criteria with no evidence of bone progression according to PCWG3
criteria. The analysis of primary endpoint will be performed based on the ITT Population, and
ORR will be presented along with a 90% 2-sided exact CI.
Secondary Endpoints
The analyses for secondary endpoints will be performed based on the ITT Population.
 
RR will be reported along with a 90% 2-sided exact CI.
 
The distribution of OS will be summarized using the Kaplan-Meier method.
 
CTC response rate will be presented with a 90% 2-sided exact CI.
Exploratory analyses only will be performed on efficacy data collected from subjects enrolled in
this combination, pending data availability. Details will be provided in the SAP.
11.3.2. 
Combination 2: Niraparib and AAP
The primary endpoint for Combination 2 is composite response rate, defined as the proportion of
subjects who have a composite response. The composite response is defined as 1 of the following
by PCWG3:
 
Objective response (confirmed per RECIST 1.1), or
 
CTC response: defined as CTC 0 per 7.5 mL of blood at 8 weeks for subjects who have CTC
≥1 at baseline or CTC<5 per 7.5 mL with CTC ≥5 at baseline, confirmed by a second
consecutive value obtained 4 or more weeks later, or

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 
PSA decline of ≥50%, measured twice 3 to 4 weeks apart.
The analysis of primary endpoint will be performed based on the subjects who receive
Combination 2 in the ITT Population, and composite response rate will be presented along with a
90% 2-sided exact CI.
The analyses of secondary endpoints for Combination 2 will be performed based on the subjects
who receive Combination 2 in the ITT Population.
 
ORR will be reported along with a 90% 2-sided exact CI.
 
CTC response rate will be presented with a 90% 2-sided exact CI.
Exploratory analyses only will be performed on efficacy data collected from subjects enrolled in
this combination, pending data availability. Details will be provided in the statistical analysis plan
(SAP).
11.3.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose
Combination Tablet
Antitumor activity will not be assessed in Combination 3.
11.4. Pharmacokinetic and Immunogenicity Analyses (Combination 1 Only)
Plasma concentration-time data of niraparib, and its metabolite, as appropriate, will be summarized
using descriptive statistics. Population PK analysis may be performed using nonlinear
mixed-effects modeling for niraparib combination therapy. Data may be combined with those of
other selected studies to support a relevant structural model. Available baseline subject
characteristics (demographics, laboratory variables, genotypes, race, etc.) will be tested as
potential covariates affecting PK parameters. Details will be given in a population PK analysis
plan and the results of the population PK analysis will be presented in a separate report.
Plasma or serum concentration-time data of the combination agent will be summarized using
descriptive statistics. The incidence of anti-combination agent antibodies (if applicable) will be
summarized for all subjects who receive at least 1 dose of combination agent and have appropriate
samples for detection of antibodies to the combination agent (ie, subjects with at least 1 sample
obtained after their first dose of combination agent). In addition, subjects who are positive for
anti-drug antibodies (if applicable) will be listed. Other immunogenicity analyses may be
performed to further characterize the immune responses that are generated (if applicable).
A snapshot date for PK samples to be analyzed will be defined, if required. Samples collected
before this date will be analyzed for niraparib combination and included in the population PK
analysis. Samples collected after the snapshot date will be analyzed at a later date and may be
included in a population PK re-analysis when they become available after database lock.
Data will be listed for all subjects with available plasma/serum concentrations per treatment group.
Subjects will be excluded from the PK analysis if their data do not allow for accurate assessment
of the PK (eg, incomplete administration of the study drug; missing information of dosing and
sampling times; concentration data not sufficient for PK parameter calculation).

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All concentrations below the lowest quantifiable concentration or missing data will be labeled as
such in the concentration database. All subjects and samples excluded from the analysis will be
clearly documented in the study report.
For each treatment group, descriptive statistics, including arithmetic mean, SD, coefficient of
variation, median, minimum, and maximum will be calculated for all individual derived PK
parameters including exposure information of niraparib, its M1 metabolite (if performed), and
combination agents, as applicable.
11.5. Biomarker Analyses
Planned biomarker analyses may be deferred if emerging study data show no likelihood of
providing useful scientific information. Appropriate details of these exploratory analyses will be
included in the biomarker Statistical Analysis Plan for each combination and results will be
presented in a separate report.
11.6. Pharmacokinetic/Pharmacodynamic Analyses (Combination 1)
If sufficient data are available, then other PK/pharmacodynamic modeling may be performed,
including exploring the relationship between systemic (plasma or serum) concentrations of
niraparib and combination agent, and endpoints of antitumor activity and safety. If performed,
details and results of the analysis will be presented in a separate report.
11.7. Medical Resource Utilization
This does not apply to Combination 3.
The analysis will be prepared separately and will not be a part of the CSR.
11.8. Safety Analyses
Treatment-emergent AEs will be coded using the most current Medical Dictionary for Regulatory
Activities and will be graded according to the NCI-CTCAE, Version 4.03 or later.
Treatment-emergent AEs are those events that occur or worsen on or after first dose of study drug
through 100 days after the last dose of study drugs for Combination 1 and 30 days after the last
dose of study drugs for Combinations 2 and 3, or prior to administration of a subsequent therapy,
whichever occurs first, and will be included in the analysis. AEs will be summarized by System
Organ Class and Preferred Term and will be presented overall and by treatment group. SAEs and
deaths will be provided in a listing. All AEs resulting in discontinuation, dose modification, dosing
interruption, or treatment delay of study drug will also be listed and tabulated by preferred term.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be
calculated for each laboratory analyte at baseline and for observed values and changes from
baseline at each scheduled timepoint as appropriate. Parameters with predefined toxicity grades
will be summarized. Change from baseline to the worst grade experienced by the subject during
the study will be provided as shift tables.

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Vital Signs
Descriptive statistics of heart rate and blood pressure (systolic and diastolic) (supine) values and
changes from baseline will be summarized. The percentage of subjects with clinically important
changes from baseline will be summarized.
Physical Examination
Clinically relevant abnormalities observed during the physical examination will be recorded and
summarized as AEs.
11.9. Data Review Committee
This does not apply to Combination 3.
For each combination, a DRC will be established to monitor data from Part 2 on an ongoing basis
to ensure the continuing safety of the subjects enrolled in the study. The committee will meet at
least every 6 months to review interim data. After the review, the DRC will make
recommendations regarding the continuation of the combination. The details will be provided in a
separate DRC charter, which will be provided to the DRC members.
The DRC will consist of at least 1 medical expert in the relevant therapeutic area and at least 1
statistician. The DRC responsibilities, authorities, and procedures will be documented in its
charter.
11.10. Futility Analysis
The interim analysis of BA in Combination 3 is described in Attachment 6.
For Combination 1, a futility analysis (based on a Simon 2-stage design) was to be performed for
Cohort 1B when approximately 10 BM- subjects are enrolled in Part 2 of the study. Further
enrollment into the BM- cohort was to be held while the futility analysis was performed. If the
response rate is 13% or less (ie, 0 or 1 responders) for the subjects included in the futility analysis,
then the cohort was to close, otherwise the cohort was to be fully enrolled with approximately
30 subjects (see Section 11.2.1).
The pre-planned futility analysis was recently performed on the biomarker negative subjects
(Cohort 1B) enrolled in phase 2 of niraparib + cetrelimab of the QUEST study. Based on the
analysis conducted, a response rate of 13% was not achieved. Accordingly, the biomarker negative
cohort (Cohort 1B) was closed to new enrollment. Subjects that are enrolled in this cohort and still
on study may continue without any change to their status.
No futility analysis was planned for Combination 1 Cohort 1A. However, a DRC meeting was held
after 18 subjects enrolled in Combination 1A. The ORR for the 18 subjects enrolled was 22%
(95% confidence interval: 8%, 44%). Based on the current response rate, the chance of obtaining
a 50% response rate in Combination 1A as hypothesized in the protocol by completing the cohort
(n 30) is <1%. The DRC recommended closing enrollment of Combination 1A based on the low
probability of success.

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12. 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and Product Quality Complaints (PQC), from clinical studies are crucial for the protection of
subjects, investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The
sponsor has established Standard Operating Procedures in conformity with regulatory
requirements worldwide to ensure appropriate reporting of safety information; all clinical studies
conducted by the sponsor or its affiliates will be conducted in accordance with those procedures.
Safety reporting requirements for subjects in Combination 1 or 2 are outlined in Attachment 5, and
for Combination 3 are outlined in Attachment 6.
12.1. Definitions
12.1.1. 
Adverse Event and Serious Adverse Event Definitions and
Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have
a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended
sign (including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product. (Definition per International Council for
Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 12.3.1, All
Adverse Events, for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for
Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect

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 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be immediately
life-threatening or result in death or hospitalization but may jeopardize the subject or may require
intervention to prevent one of the other outcomes listed in the definition above. These should
usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study drug and the event (eg, death from anaphylaxis), the event must be reported as
a serious and unexpected suspected adverse reaction even if it is a component of the study endpoint
(eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For niraparib and other combination agents, the expectedness of an
AE will be determined by whether or not it is listed in the respective Investigator's Brochure. For
other combination agents that may have a marketing authorization, the expectedness of an AE will
be determined by whether or not it is listed in the package insert/summary  of product
characteristics.
Adverse Event Associated With the Use of the Drug
An AE is considered associated with the use of the drug if the attribution is possible, probable, or
very likely by the definitions listed in Section 12.1.2, Attribution Definitions.
12.1.2. 
Attribution Definitions
Not Related
An AE that is not related to the use of the drug.
Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant
disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the drug. An alternative explanation, eg, concomitant
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore,
the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the drug. The relationship in time is suggestive
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant drug(s),
concomitant disease(s).

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Very Likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an
alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in time
is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3. 
Severity Criteria
An assessment of severity grade will be made using the NCI-CTCAE (version 4.03 or later). Any
AE not listed in the NCI-CTCAE will be graded according to the investigator’s clinical judgment
using the standard grades as follows:
Grade 1 (Mild): Awareness of symptoms that are easily tolerated, causing minimal discomfort
and not interfering with everyday activities.
Grade 2 (Moderate): Sufficient discomfort is present to cause interference with normal activity.
Grade 3 (Severe): Extreme distress, causing significant impairment of functioning or
incapacitation. Prevents normal everyday activities.
Grade 4, Life-threatening: Urgent intervention indicated.
Grade 5, Death: Death.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the subject (eg, laboratory abnormalities).
12.2. Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety
evaluation include, but are not limited to:
 
Overdose of a sponsor study drug
 
Suspected abuse/misuse of a sponsor study drug
 
Inadvertent, accidental, or occupational exposure to a sponsor study drug
 
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without subject/patient exposure to the
Johnson & Johnson medicinal product, eg, product name confusion, product label confusion,
intercepted prescribing or dispensing errors)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of an SAE should be recorded on the serious adverse event page of the eCRF.
12.3. Procedures
12.3.1. 
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated ICF is obtained until completion of the subject's last study-related

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procedure, which may include contact for follow-up of safety. For Combination 3, all AEs and
SAEs will be reported from the time a signed and dated ICF is obtained through the PK Assessment
Phase. Only SAEs will be reported under Amendment 4 for Combination 2 and during the
Extension Phase of Combination 3 (after the 168-hour PK sampling on Day 8).
SAEs, including those spontaneously reported to the investigator within 100 days after the last
dose of study drugs for Combination 1 and 30 days after the last dose of study drugs for
Combinations 2 and 3, must be reported using the Serious Adverse Event Form. In addition, SAEs
related to the blood collection procedure, as well as death from any cause, during the Prescreening
Phase will also be reported from the time the ICF is signed until 30 days after the procedure occurs.
These Prescreening Phase SAEs should only be reported to the sponsor’s pharmacovigilance team
using paper SAE forms and should not be entered into the eCRF. For any of these subjects who
subsequently enter the Screening Phase, the events need to be entered into the eCRF. The sponsor
will evaluate any safety information that is spontaneously reported by an investigator beyond the
time frame specified in the protocol.
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether they
are protocol-specific assessments. Anticipated events will be recorded and reported as described
in Attachment 3.
All AEs, regardless of seriousness, severity, or presumed relationship to study drugs, must be
recorded using medical terminology in the source document and the eCRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory
infection"). Investigators must record in the eCRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). For anticipated events
reported as individual SAEs the sponsor will make a determination of relatedness in addition to
and independent of the investigator’s assessment. The sponsor will periodically evaluate the
accumulating data and, when there is sufficient evidence and the sponsor has determined there is
a reasonable possibility that the drug caused a serious anticipated event, they will submit a safety
report in narrative format to the investigators (and the head of the investigational institute where
required). The investigator (or sponsor where required) must report SUSARs to the appropriate
Independent Ethics Committee (IEC)/IRB that approved the protocol unless otherwise required
and documented by the IEC/IRB.
For all studies with an outpatient phase, the subject must be provided with a "wallet (study) card"
and instructed to carry this card with them for the duration of the study indicating the following:
 
Study number
 
Statement, in the local language(s), that the subject is participating in a clinical study

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 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical staff only)
 
Site number
 
Subject number
12.3.2. 
Serious Adverse Events
All SAEs, as well as PQC, occurring during the study must be reported to the appropriate sponsor
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form, which must be completed and signed by a physician from the study site and transmitted to
the sponsor within 24 hours. The initial and follow-up reports of an SAE should be made by
facsimile (fax) or email. Telephone reporting should be the exception and the reporter should be
asked to complete the appropriate form(s) first.
All SAEs that have not resolved by the end of the study, or that have not resolved upon
discontinuation of the subject's participation in the study, must be followed until any of the
following occurs:
 
The event resolves
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents’ other than the study drugs or to factors unrelated to
study conduct
 
It becomes unlikely that any additional information can be obtained (subject or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the
course of a subject's participation in a study must be reported as an SAE, except hospitalizations
for the following:
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF).
 
A standard procedure for protocol therapy administration. Hospitalization or prolonged
hospitalization for a complication of therapy administration will be reported as an SAE.
 
The administration of blood or platelet transfusion. Hospitalization or prolonged
hospitalization for a complication of such transfusion remains a reportable SAE.
 
A procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy,
sampling for laboratory tests, bone marrow sampling, pharmacokinetic, or biomarker blood
sampling). Hospitalization or prolonged hospitalization for a complication of such procedures
remains a reportable SAE.

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 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility).
Disease progression should not be recorded as an AE or SAE term; instead, signs and symptoms
of clinical sequelae resulting from disease progression/lack of antitumor activity will be reported
if they fulfill the SAE definition (refer to Section 12.1.1, Adverse Event Definitions and
Classifications).
During the Follow-up Phase of the study, deaths regardless of causality will be reported in the
eCRF. SAEs, including those spontaneously reported to the investigator within 100 days after the
last dose of study drugs for Combination 1 and 30 days after the last dose of study drugs for
Combinations 2 and 3, must be reported using the Serious Adverse Event Form. SAEs that occur
after 100 days following the last administration of study drugs for Combination 1 and 30 days after
the last dose of study drugs for Combinations 2 and 3, which are thought to be related to the study
drugs, will be collected and reported via the Serious Adverse Event Form within 24 hours of
discovery or notification of the event and documented per standard procedures.
12.3.3. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the subject is the preferred method to inquire about AE occurrence.
Solicited AEs
Solicited AEs are predefined local and systemic events for which the subject is specifically
questioned.
Unsolicited AEs
Unsolicited AEs are all adverse events for which the subject is not specifically questioned.
12.3.4. 
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or
PQC as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals. Adverse
events, including pregnancy, will be followed by the investigator as specified in Sections 12.3, and
13.
12.3.5. 
Pregnancy
While the effect of niraparib on sperm is unknown, PARP inhibitors disrupt DNA-repair of dividing
cells and niraparib was observed to be genotoxic in in vitro studies.24 Therefore, pregnancy is
contraindicated and pregnancies in partners of male subjects included in the study should be reported
by the study-site personnel within 24 hours of their knowledge of the event using the appropriate
pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death,
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and must be reported using

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the Serious Adverse Event Form. Follow-up information regarding the outcome of the pregnancy
and any postnatal sequelae in the infant will be required.
12.3.6. 
Disease Progression and Death
It is anticipated that a proportion of subjects will experience disease progression, which will not
by itself be considered as an AE, even if it results in death during the AE reporting period. If other
AEs/SAEs occur in relation to disease progression, then those AEs/SAEs must be reported per
AE/SAE reporting requirements described in Section 12.3.1, All Adverse Events and
Section 12.3.2, Serious Adverse Events, respectively.
All subjects must be followed for survival until death and information relating to a subject’s death
(eg, date of death and primary cause of death) should be recorded. Fatal events (regardless of
relationship to study drug) should be reported as SAEs for subjects until 100 days after the last
dose of both study drugs for Combination 1 and 30 days after the last dose of study drugs for
Combinations 2 and 3. Death is an outcome of an AE and not an AE itself. All reports of death
within the reporting period should include an AE term for the cause of death (if known). Fatal
events occurring after the reporting period will not be reported as SAEs and will be captured on
the designated case report form.
12.4. Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
13. 
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality,
durability, reliability, or performance of a distributed product, including its labeling, drug delivery
system, or package integrity. A PQC may have an impact on the safety and antitumor activity of
the product. In addition, it includes any technical complaints, defined as any complaint that
indicates a potential quality issue during manufacturing, packaging, release testing, stability
monitoring, dose preparation, storage or distribution of the product or the drug delivery system.
Timely, accurate, and complete reporting and analysis of PQC information from studies are crucial
for the protection of subjects, investigators, and the sponsor, and are mandated by regulatory
agencies worldwide. The sponsor has established procedures in conformity with regulatory
requirements worldwide to ensure appropriate reporting of PQC information; all studies conducted
by the sponsor or its affiliates will be conducted in accordance with those procedures.
13.1. Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
If the defect is combined with an SAE, the study-site personnel must report the PQC to the sponsor
according to the SAE reporting timelines (refer to Section 12.3.2, Serious Adverse Events). A

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sample of the suspected product should be maintained under the correct storage conditions until a
shipment request is received from the sponsor.
13.2. Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.
14. 
STUDY DRUG INFORMATION
See Attachment 6 for Study Drug Information for Combination 3.
14.1. Physical Description of Study Drug(s)
The niraparib capsule supplied for this study contains 100 mg of niraparib. It will be manufactured
and provided under the responsibility of the sponsor. Refer to the Investigator's Brochure for a list
of excipients.24
14.1.1. 
Combination 1: Niraparib and Cetrelimab
Manufacturing changes to the cetrelimab drug substance and drug product may occur during this
study. The drug product may be changed from a frozen liquid in vial to a lyophilized drug product.
The host-cell line and the core amino acid sequence of the cetrelimab mAb remains unchanged for
the frozen and lyophilized product. Comprehensive nonclinical comparability studies will be
performed to assess the biochemical, biophysical, and biological characteristics of the lyophilized
drug product to ensure that there is no impact on subject safety and product quality. The drug
substance and drug product manufacturing changes, along with the results of the comparability
studies will be submitted to the health authorities prior to introduction of the lyophilized product
into the clinical program. The transition will happen as logistically allowed by the study.
Frozen Liquid in Vial
The cetrelimab frozen formulation is a sterile, frozen liquid in an 8R glass vial with serum stopper
and aluminum seal with flip-off cap. Each vial of cetrelimab clinical study material is filled with
3.3 mL of a 10 mg/mL solution of cetrelimab (including 10% overfill).
Lyophilized
cetrelimab is supplied as a single-use, lyophilized product. cetrelimab final labeled product
contains 3.3 mL at 30 mg/mL. The dosage form includes a 10% overfill and has been designed to
deliver 90 mg of cetrelimab per vial. Cetrelimab is presented in an 8R glass vial with a 20 mm
Coated Lyo stopper and 20 mm flip-off seal.
Both drug products will be manufactured and provided under the responsibility of the sponsor.
Refer to the cetrelimab IB for a list of excipients for both the frozen liquid and lyophilized drug
products.22

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14.1.2. 
Combination 2: Niraparib and AAP
The AA tablet supplied for this study contains 250 mg of AA. Refer to the Investigator's Brochure
for a list of excipients.22 Prednisone tablets containing 5 mg prednisone will be provided directly
by the sponsor.
14.2. Packaging
Niraparib 100 mg capsules will be packaged in high-density polyethylene bottles with
child-resistant closures.
14.2.1. 
Combination 1: Niraparib and Cetrelimab
Cetrelimab vials will be packaged in kits (cartons). The investigational supplies will be uniquely
packaged to assure that they are appropriately managed throughout the supply chain process.
cetrelimab vials will not be dispensed in child-resistant packaging.
14.2.2. 
Combination 2: Niraparib and AAP
AA 250 mg tablets will be packaged in high-density polyethylene bottles with child-resistant
closures. Prednisone tablets will be packaged in blister packs or bottles.
14.3. Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4. Preparation, Handling, and Storage
Refer to the pharmacy manual/study-site investigational product and procedures manual for
additional guidance on study drug preparation, handling, and storage.
The study drugs must be stored in a secure area and administered only to subjects entered into the
clinical study in accordance with the conditions specified in this protocol. Subjects should be
advised to keep all medications out of reach and sight of children.
14.4.1. 
Niraparib
Niraparib may have adverse effects on a fetus in utero. Caregivers should handle niraparib with
protection (eg, gloves). Study-site personnel will instruct subjects on how to store niraparib for at-
home use as indicated for this protocol.
14.4.2. 
Cetrelimab
Cetrelimab 10 mg/mL must be stored frozen at controlled temperatures and protected from light.
Specific storage temperature conditions will be provided separately. Protection from light is not
required during infusion. Cetrelimab will be administered at the study site by study-site personnel
using the guidelines provided in the pharmacy manual. Refer to the SIPPM for additional guidance
on cetrelimab 10 mg/mL preparation, handling, and storage.
14.4.3. 
Abiraterone Acetate
AA is contraindicated in women who are or may potentially be pregnant. There are no human data

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on the use of AA in pregnancy. Maternal use of CYP17 inhibitor is expected to produce changes
in hormonal levels that may affect the development of the fetus. Women who are pregnant or may
be pregnant should not handle AA without protection (eg, gloves). In an oral developmental
toxicity study in the rat, abiraterone acetate affected pregnancy.
14.5. Drug Accountability
The investigator is responsible for ensuring that all study drugs received at the site are inventoried
and accounted for throughout the study. The dispensing of study drugs to the subject, and the return
of study drugs from the subject, must be documented on the drug accountability form. Subjects,
or their legally acceptable representatives where applicable, must be instructed to return all original
containers, whether empty or containing study drugs. All study drugs will be stored and disposed
of according to the sponsor's instructions. Study-site personnel must not combine contents of the
study drugs containers. Any study drug administered to the subject must be documented on the
drug accountability form.
Study drugs must be handled in strict accordance with the protocol and the container label and
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study drugs, and study drugs returned by the subject, must be
available for verification by the sponsor's study-site monitor during on-site monitoring visits. The
return to the sponsor of unused study drugs, or used returned study drugs for destruction, will be
documented on the drug return form. When the study site is an authorized destruction unit and
study drug supplies are destroyed on-site, this must also be documented on the drug return form.
Study drugs should be dispensed under the supervision of the investigator or a qualified member
of the study-site personnel, or by a hospital/clinic pharmacist. Study drugs will be supplied only
to subjects participating in the study. Returned study drugs must not be dispensed again, even to
the same subject. Whenever a subject brings his study drugs to the study site for pill count, this is
not seen as a return of supplies. Study drugs may not be relabeled or reassigned for use by other
subjects. The investigator agrees neither to dispense the study drugs from, nor store them at, any
site other than the study sites agreed upon with the sponsor.
15. 
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:
 
Study protocol 
 
Investigator's Brochure 
 
Sample ICFs
 
Laboratory manual
 
Electronic data capture (eDC) manual 
 
NCI-CTCAE Version 4.03 (or later)
 
SIPPM/study-site investigational product 
and procedures manual
 
PCWG3 guidelines
 
IWRS manual 
 
RECIST guidelines, version 1.1
 
Pharmacy manual

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16. 
ETHICAL ASPECTS
16.1. Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the
study, subjects will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be
withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and
potential AEs of the study, and provide their consent voluntarily will be enrolled.
As with all clinical and PK studies, there are risks associated with venipuncture and multiple blood
sample collection. To avoid multiple venipunctures, the use of intravenous indwelling catheters is
permitted in this study. The blood sample collection scheme will be designed to collect the
minimum number of blood samples that can determine the safety, antitumor activity, PK,
pharmacodynamics, and biomarker requirements of the study. Note that the total volume of blood
to be collected is an estimate (see Section 9.1.1); the actual amount may vary depending on
laboratory standard procedures. The volume of blood to be drawn is considered customary and
acceptable for subjects participating in an oncology study and is deemed reasonable over the time
frame of the study, based upon the standards of the WHO.60
16.1.1. 
Combination 1: Niraparib and Cetrelimab
This is an open-label study to assess the safety, antitumor activity, PK, and determine the RP2D of
niraparib when dosed in combination with cetrelimab, in subjects with prostate cancer over the age
of 18 years, with and without DRD or CDK12 pathogenic alteration. Given that there remains a
high unmet need for treatment of prostate cancer in patients who are refractory to available
therapies and that the adverse effect profile of these therapies together is likely to be manageable,
the sponsor considers that the benefit of treatment with niraparib in combination with cetrelimab
outweighs the potential risks involved (as described in Section 1.4.1).
16.1.2. 
Combination 2: Niraparib and AAP
This is an open-label study to assess the safety and antitumor activity of 200 mg niraparib when
dosed in combination with 1,000 mg AA and 10 mg (2 x 5 mg) prednisone, in subjects over the
age of 18 years with metastatic prostate cancer. The potential benefits of treatment with niraparib
and AAP in men with metastatic prostate cancer, both with and without prospectively selected
DRD, outweighs the potential risks involved as described in Section 1.4.2.
16.1.3. 
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose
Combination Tablet
This is an open-label study to assess the relative BA of FDC tablet formulations of niraparib and
AA, in subjects over the age of 18 years with metastatic prostate cancer. During the PK Assessment
Phase, all subjects will receive 200 mg niraparib in combination with 1,000 mg AA and 10 mg
prednisone (as SAs). Analysis of safety data from Cohort 2 (no HRR gene alterations) of the
MAGNITUDE Study (see Section 1.4.3) supports treatment of subjects with metastatic prostate
cancer and no HRR gene alterations with niraparib plus AAP for approximately 22 days.

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The results of the futility analysis of the MAGNITUDE Study (see Section 1.1.2) did not show
additional benefit of adding niraparib to AAP in subjects with no HRR gene alterations. Therefore,
during the Extension Phase of this study, subjects with HRR gene alterations will be recommended
to continue combination treatment with AAP and niraparib, and subjects without HRR gene
alterations may continue therapy with AAP plus niraparib or AAP at the investigator’s discretion
guided by biomarker status. The potential benefits of treatment with niraparib and AAP in men
with metastatic prostate cancer with prospectively selected HRR gene alterations outweigh the
potential risks involved as described in Section 1.4.2
16.2. Regulatory Ethics Compliance
16.2.1. 
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and
country-specific requirements.
GCP is an international ethical and scientific quality standard for designing, conducting, recording,
and reporting studies that involve the participation of human subjects. Compliance with this
standard provides public assurance that the rights, safety, and well-being of study subjects are
protected, consistent with the principles that originated in the Declaration of Helsinki, and that the
study data are credible.
16.2.2. 
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the subjects)
 
Investigator's Brochure (or equivalent information) and amendments/addenda
 
Sponsor-approved subject recruiting materials
 
Information on compensation for study-related injuries or payment to subjects for
participation in the study, if applicable
 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for subjects
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
subjects, data or study conduct, unless required locally), the ICF, applicable recruiting materials,
and subject compensation programs, and the sponsor has received a copy of this approval. This

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approval letter must be dated and must clearly identify the IEC/IRB and the documents being
approved.
During the study, the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for subjects, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to subjects
 
If applicable, new or revised subject recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to subjects for participation
in the study, if applicable
 
New edition(s) of the Investigator's Brochure and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug
 
New information that may adversely affect the safety of the subjects or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects
 
Report of deaths of subjects under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB.
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s). At least once a year, the IEC/IRB will be asked to review and reapprove this study,
where required. At the end of the study, the investigator (or sponsor where required) will notify
the IEC/IRB about the study completion (if applicable, the notification will be submitted through
the head of investigational institution).
16.2.3. 
Informed Consent
Each subject must give written consent according to local requirements after the nature of the study
has been fully explained. The ICF(s) must be signed before performance of any study-related
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing
IEC/IRB and be in a language that the subject can read and understand. Informed consent may be
obtained remotely. Refer to local applicable guidelines to ensure compliance. The informed
consent should be in accordance with principles that originated in the Declaration of Helsinki,
current ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy.

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There are two informed consent forms (ICFs) for this study, one for prescreening (biomarker
testing) and one for entry into the study. Before enrollment in the study, the investigator or an
authorized member of the study-site personnel must explain to potential subjects the aims,
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort
participation in the study may entail. Subjects will be informed that their participation is voluntary
and that they may withdraw consent to participate at any time. They will be informed that choosing
not to participate will not affect the care the subject will receive for the treatment of their disease.
Subjects will be told that alternative treatments are available if they refuse to take part and that
such refusal will not prejudice future treatment. Finally, they will be told that the investigator will
maintain a subject identification register for the purposes of long-term follow-up if needed and
that their records may be accessed by health authorities and authorized sponsor personnel without
violating the confidentiality of the subject, to the extent permitted by the applicable law(s) or
regulations. By signing the ICF the subject is authorizing such access, which includes permission
to obtain information about his survival status and agrees to allow his study physician to recontact
the subject for the purpose of obtaining consent for additional safety evaluations, and subsequent
disease-related treatments, if needed. The physician may also recontact the subject for the purpose
of obtaining consent to collect information about his survival status.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. After
this explanation and before entry into the study, consent should be appropriately recorded by means
of the subject's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject. Where local regulations require, a separate ICF may be used for the
required DNA component of the study.
In accordance with local regulations, all subjects enrolled in the study will be required to sign an
updated informed consent form to continue in the study under Amendment 6.
16.2.4. 
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be limited
to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of
personal data and for the investigator/institution to allow direct access to his or her original medical
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and
regulatory inspection. This consent also addresses the transfer of the data to other entities and to
other countries.

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The subject has the right to request through the investigator access to his or her personal data and
the right to request rectification of any data that are not correct or complete. Reasonable steps will
be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
Exploratory DNA, pharmacogenomics, biomarker, and PK research is not conducted under
standards appropriate for the return of data to subjects. In addition, the sponsor cannot make
decisions as to the significance of any findings resulting from exploratory research. Therefore,
exploratory research data will not be returned to subjects or investigators, unless required by law
or local regulations. Privacy and confidentiality of data generated in the future on stored samples
will be protected by the same standards applicable to all other clinical data.
16.2.5. 
Long-term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand niraparib and other therapies, to
understand prostate cancer, to understand differential drug responders, and to develop tests/assays
related to niraparib and other therapies and prostate cancer. The research may begin at any time
during the study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be
stored for research (refer to Section 10.4, Withdrawal From the Use of Samples in Future
Research).
16.2.6. 
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help
ensure access to the developed product if the need for the product persists, unless explicitly
addressed as a specific ethical consideration in Section 16.1, Study-Specific Design
Considerations.
17. 
ADMINISTRATIVE REQUIREMENTS
17.1. Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involves only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative

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listed in the Contact Information page(s), which will be provided as a separate document. Except
in emergency situations, this contact should be made before implementing any departure from the
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the
situation and agree on an appropriate course of action. The data recorded in the eCRF and source
documents will reflect any departure from the protocol, and the source documents will describe
this departure and the circumstances requiring it.
17.2. Regulatory Documentation
17.2.1. 
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
17.2.2. 
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the
study site:
 
Protocol and amendment(s), if any, signed and dated by the principal investigator.
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, subject compensation programs. This approval must clearly identify the specific
protocol by title and number and must be signed (or sealed, where appropriate per local
regulations) by the chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study-site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable.
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable.
 
Documentation of investigator qualifications (eg, curriculum vitae).
 
Completed investigator financial disclosure form from the principal investigator, where
required.
 
Signed and dated Clinical Trial Agreement, which includes the financial agreement.
 
Any other documentation required by local regulations.
The following documents must be provided to the sponsor before enrollment of the first subject:
 
Completed investigator financial disclosure forms from all subinvestigators

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 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
17.3. Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy
identification of each subject during and after the study. This document will be reviewed by the
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All
reports and communications relating to the study will identify subjects by subject identification
and age at initial informed consent. In cases where the subject is not enrolled into the study, the
date seen and age at initial informed consent will be used. The investigator must also complete a
subject screening log, which reports on all subjects who were seen to determine eligibility for
inclusion in the study.
17.4. Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following
to confirm data collected in the eCRF: subject identification, eligibility, and study identification;
study discussion and date of signed informed consent; dates of visits; results of safety and
antitumor activity parameters as required by the protocol; record of all AEs and follow-up of AEs;
concomitant medication; drug receipt/dispensing/return records; study drug administration
information; and date of study completion and reason for early discontinuation of study drug or
withdrawal from the study, if applicable. In addition, the author of an entry in the source documents
should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The minimum source documentation requirements for Section 4.1, Prescreening Eligibility
Criteria, Section 4.1.1, Inclusion Criteria, and Section 4.2.1, Exclusion Criteria that specify a need
for documented medical history are as follows:
 
Referral letter from treating physician or
 
Complete history of medical notes at the site
 
Discharge summaries

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Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by subject interview or other protocol required assessment (eg, physical examination,
laboratory assessment) and documented in the source documents.
An electronic source system may be utilized, which contains data traditionally maintained in a
hospital or clinic record to document medical care (eg, electronic source documents) as well as the
clinical study-specific data fields as determined by the protocol. This data is electronically
extracted for use by the sponsor. If the electronic source system is utilized, references made to the
eCRF in the protocol include the electronic source system, but information collected through the
electronic source system may not be limited to that found in the eCRF. Data in this system may be
considered source documentation.
17.5. Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
All eCRF entries, corrections, and alterations must be made by the investigator or authorized
study-site personnel. The investigator must verify that all data entries in the eCRF are accurate and
correct.
The study data will be transcribed by study-site personnel from the source documents onto an
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the subject's source documents. Data must be entered into
eCRF in English. The eCRF must be completed as soon as possible after a subject visit and the
forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be completed
by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed after
the initial entry into the eCRF, this can be done in either of the following ways:
 
Investigator and study-site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
17.6. Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory into the sponsor's data base.
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before
the start of the study. The sponsor will review the eCRF for accuracy and completeness during on-

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site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with
the investigator or designee, as appropriate. After upload of the data into the study database they
will be verified for accuracy and consistency with the data sources.
17.7. Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each subject, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
17.8. Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study-site visit log that will be kept at the study site. The first
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits,
the monitor will compare the data entered into the eCRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source
documents will be identified to ensure that all sources of original data required to complete the
eCRF are known to the sponsor and study-site personnel and are accessible for verification by the
sponsor study-site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the
relevant study-site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will

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meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study-site personnel will be available to provide an update on the progress of the
study at the site.
17.9. Study Completion/Termination
17.9.1. 
Study Completion/End of Study
The study is considered completed with the last study assessment for the last subject participating
in the study. The final data from the study site will be sent to the sponsor (or designee) after
completion of the final subject assessment at that study site, in the time frame specified in the
Clinical Trial Agreement. Further information on the reporting of data from each combination can
be found in Section 3.1.
17.9.2. 
Study Termination
The sponsor reserves the right to close the study site, close an individual cohort or combination
arm, or terminate the study at any time for any reason at the sole discretion of the sponsor. If the
sponsor decides to close a cohort, this will be communicated through a letter to the investigator.
Study sites will be closed upon study completion. A study site is considered closed when all
required documents and study supplies have been collected and a study-site closure visit has been
performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 
Inadequate recruitment of subjects by the investigator
 
Discontinuation of further study drug development

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17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Subject privacy must, however, be respected.
The investigator and study-site personnel are responsible for being present and available for
consultation during routinely scheduled study-site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding niraparib or other combination
agents or the sponsor's operations (eg, patent application, formulas, manufacturing processes,
basic scientific data, prior clinical data, formulation information) supplied by the sponsor to the
investigator and not previously published, and any data, including exploratory biomarker research
data, generated as a result of this study, are considered confidential and remain the sole property
of the sponsor. The investigator agrees to maintain this information in confidence and use this
information only to accomplish this study, and will not use it for other purposes without the
sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development of niraparib and other combination agents,
and thus may be disclosed as required to other clinical investigators or regulatory agencies. To
permit the information derived from the clinical studies to be used, the investigator is obligated to
provide the sponsor with all data obtained in the study.
The results of the study will be reported in a CSR generated by the sponsor and will contain data
from all study sites that participated in the study as per protocol. Recruitment performance or
specific expertise related to the nature and the key assessment parameters of the study will be used
to determine a coordinating investigator for the study. Results of exploratory biomarker analyses
performed after the CSR has been issued will be reported in a separate report and will not require
a revision of the CSR. Study subject identifiers will not be used in publication of results. Any work
created in connection with performance of the study and contained in the data that can benefit from
copyright protection (except any publication by the investigator as provided for below) shall be
the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to

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publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and substudy approaches, secondary results generally should not be
published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months of the availability of the final data (tables, listings,
graphs), or the sponsor confirms there will be no multicenter study publication. Authorship of
publications resulting from this study will be based on the guidelines on authorship, such as those
described in the ICMJE Recommendations for the Conduct, Reporting, Editing and Publication of
Scholarly Work in Medical Journals, which state that the named authors must have made a
significant contribution to the conception or design of the work; or the acquisition, analysis, or
interpretation of the data for the work; and drafted the work or revised it critically for the important
intellectual content; and given final approval of the version to the published; and agreed 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.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law.

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Attachment 2: ECOG Performance Status
ECOG Grade Scale (with Karnofsky conversion)
0 
Fully active, able to carry on all predisease performance without restriction.
(Karnofsky 90-100)
1 
Restricted in physically strenuous activity but ambulatory and able to carry out
work on a light or sedentary nature, eg, light housework, office work. (Karnofsky
70-80)
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.
Up and about more than 50% of waking hours. (Karnofsky 50-60)
3 
Capable of only limited self-care; confined to bed or chair more than 50% of
waking hours. (Karnofsky 30-40)
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or
chair. (Karnofsky 10-20)
5 
Dead. (Karnofsky 0)

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Attachment 3: Anticipated Events
Anticipated Event
An anticipated event is an AE (serious or non-serious) that commonly occurs as a consequence of
the underlying disease or condition under investigation (disease-specific events), or background
regimen (androgen deprivation therapy [ADT] events).
For the purposes of this study, the following events will be considered anticipated events:
Disease-specific Events 
ADT Events
erectile dysfunction  
depression
hematuria 
gynecomastia
incontinence 
libido decreased
lymphoedema 
osteoporosis
nocturia 
sexual dysfunction
painful ejaculation  
testicular atrophy
prostatic specific antigen
increased
ureteric obstruction
urethral obstruction
urinary flow decreased
urinary hesitation
urinary tract obstruction
Reporting of Anticipated Events
All AEs will be recorded in the eCRF regardless of whether considered to be anticipated events
and will be reported to the sponsor as described in Section 12.3.1, Any anticipated event that meets
serious criteria will be reported to the sponsor as described in Section 12.3.2. Each anticipated
event will be assessed by the investigator at the individual case level and if considered to be drug-
related will undergo expedited reporting (if appropriate) as per applicable clinical trial legislation
to Health Authorities and IRB/IECs. If an anticipated event is considered disease-related or not
related to study drug the event will be exempt from expedited reporting.
To meet US regulatory clinical trial legislation, the sponsor will perform aggregate review of
anticipated events as outlined below, and if determined to be drug-related will implement
expedited reporting of these events to Health Authorities and IRBs/IECs. If an interim analysis of
trial results leads to an unblinded, aggregate review of safety data by the study team, the sponsor
may terminate the review of pre-specified anticipated events outlined above.

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Safety Assessment Committee (SAC)
A Safety Assessment Committee (SAC) will be established to perform reviews of pre-specified
anticipated events at an aggregate level. The SAC is a safety committee within the sponsor’s
organization that is independent of the sponsor’s study team. The SAC will meet to aid in the
recommendation to the sponsor’s study team as to whether there is a reasonable possibility that an
anticipated event is related to the study intervention based on a review of the aggregate data by
arm.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold
to trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated
Events Safety Monitoring Plan.

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Attachment 4: Additional Information on CYP450 Drug Interactions
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla
beling/ucm093664.htm12
http://medicine.iupui.edu/clinpharm/ddis/table.aspx

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Attachment 5: Modified Schedule of Events for Combinations Closed to Enrollment
This attachment outlines instructions for continuation of treatment and required follow-up for the
remaining subjects in combinations closed to enrollment.
When a combination is closed under an amendment, subjects who had signed the informed consent
form prior to the approval date of the amendment will be allowed to complete screening and be
enrolled if all inclusion/exclusion criteria for the combination (Sections 4.1, 4.2, and 4.3) are met.
Subjects already enrolled in a closed combination can continue to receive study medication until
documented disease progression or the subject discontinues the study treatment for any reason as
described in this attachment.
Under Attachment 5, limited data, including safety assessments will be collected. Other prostate
cancer-related assessments will be per local practice, at the investigator’s discretion.
Treatment Phase
Enrolled subjects must sign an updated informed consent form to continue in the study under an
amendment. Subjects may continue to receive study medication as long as (in the opinion of the
investigator) the subject is receiving benefit and not experiencing unacceptable toxicity; or until
such time that the subject needs to start other anti-cancer treatment, withdraws consent, or is
discontinued due to decision by the investigator or subject.
During the Treatment Phase, the subject will continue to receive treatment according to the dosing
regimen outlined in Section 6, Dosage and Administration. An interactive web response system
will be used to manage drug supply; study medication will be shipped directly to the site. The
subject will be provided with a sufficient supply of oral study drug until the next planned visit, and
drug accountability will occur at each site visit. Cycle numbering will continue from the last cycle
the subject completed prior to switching to the modified schedule (ie, Cycle “X”). The first cycle
under the amendment will be Cycle “X+1”.
Subjects enrolled in Combination 1 will receive cetrelimab in the clinic. Before each IV
administration of cetrelimab and oral dose of niraparib, mandatory laboratory tests (hematology
and blood chemistry) and general physical status must be reviewed. Please follow instructions in
Section 6.2.1.2.1, of the protocol for cetrelimab retreatment criteria.
Attachment 5: Modified Schedule of Events for Combinations Closed to Enrollment
Study Drug Preparation and Dispensing Instructions
Study drug administration and dosing compliance should be assessed at each site visit. A count of
all oral study drug provided by the sponsor will be conducted in the Treatment Phase.
The study site must maintain accurate drug accountability records including dates and amount of
study drug received, to whom dispensed, and accounts of any study drug accidentally or
deliberately destroyed. Reconciliation must be made between the amount ofstudy drug supplied,

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dispensed, and subsequently destroyed or returned to sponsor or its representative.
See Section 14.5, for instructions on drug accountability.
Dose modifications and Management of Toxicity
Please follow instructions in Sections 6.2.1, and 6.2.2, of the protocol.
For prohibited and restricted concomitant therapies, follow Sections 8.1, and 8.2, respectively of
the protocol.
Study Evaluations to be Performed
Study evaluations will be performed according to the combination-specific Modified Schedule of
Events below. Any additional assessments not specified in the Modified Schedule of Events can
be performed at the discretion of the investigator according to routine practice.
Information regarding serious adverse events (as defined in Section 12.3.2) will be transmitted to
the sponsor using the Serious Adverse Event Form, which must be completed and signed by a
member of the investigational staff, and transmitted to the sponsor within 24 hours. The initial and
follow-up reports of a serious adverse event should be made by facsimile (fax). An End-of-
Treatment Visit or phone call for a safety assessment should take place within 30 days after the
last dose of study medication is administered.
Efficacy Evaluations to be Performed
Investigators should monitor and assess the subject for response to treatment or disease
progression according to routine practice. (Refer to the Modified Schedule of Events below for
efficacy evaluations.)
Safety Evaluations to be Performed
Safety assessments as outlined in the Modified Schedule of Events provided in this attachment
will be performed while continuing treatment and for up to 100 days for subjects in
Combination 1 and up to 30 days for subjects in Combination 2 after the last dose of study
medication or until the start of subsequent systemic anticancer therapy. Any serious adverse
event occurring during the study must be reported to the sponsor by investigational staff within
24 hours of their knowledge of the event.
Biomarker samples
No further samples, including archival formalin-fixed paraffin-embedded tumor samples, will
be collected.
Attachment 5: Modified Schedule of Events for Combinations Closed to Enrollment
End-of-Treatment Visit
The End-of-treatment visit should occur within 30 days after administration of the last dose of
study medication. 

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Subject Completion
The subject is considered to have completed the Treatment phase of the study after discontinuing
treatment for any reason and having had a safety assessment at the End-of-treatment Visit or the
subject is lost to follow-up.
The subject's study treatment will be discontinued if:
 
The investigator or sponsor believes (eg, for safety or tolerability reasons such as an adverse
event) that it is in the best interest of the subject to stop treatment
 
The investigator believes the subject is no longer receiving clinical benefit from continued
treatment
 
The sponsor terminates the study
Subjects who discontinue the study drugs should complete the EoT visit within 30 days of the last
dose of study drug or prior to administration of a new anti-prostate cancer therapy, whichever
occurs first. For subjects enrolled in Combination 1, another safety assessment via scheduled visit
or phone call should take place within 100 to 114 days after the last dose of study medication is
administered.
Subject Withdrawal From the Study
The subject will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent
 
Investigator’s decision
Source Documentation
At a minimum, the type and level of detail of source data available for the study subject should
be consistent with that commonly recorded at the site as a basis for standard medical care. This
should also include: subject identification and study  identification; study  discussion  and date
of updated informed consent; dates of visits; serious adverse event information; drug dispensing/
return records (ie, bottle numbers) and study drug administration  information. (See Section 17.4)

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Attachment 5: Modified Schedule of Events for Combinations Closed to Enrollment
Modified Schedule of Events for Combination 1
Treatment Phase 
End of
Treatment
Phase
Visit or
Phone Call
Follow-up
Phase
CYCLE
(treatment   cycle is
defined as 28 days)
Amendment 6 
Cycle X+11 
Every Cycle 
Until Treatment 
Discontinuation
End-of-
Treatment Visit2
Day 100-114
after the last
dose of
study
medication2
Every 3
Months
Informed consent3 
X
Physical examination, 
including body weight
X 
X 
X
Vital signs (blood 
pressure, temperature,
heart rate)4
X 
X 
X
Dispense oral study drug 
X 
X5
Cetrelimab- IV Q4W  
(CxD1+7)6
X 
X
Drug accountability  
X 
X5 
X
Adverse events and 
serious adverse events7
X 
X 
X 
X
Hematology (central or 
local)8
X 
X
Blood chemistry (central 
or local)8
X 
X
CT or MRI; Bone scan 
(99mTc) 
At the discretion of the investigator according to routine
practice.
Survival status and 
subsequent therapies9 
Collected continuously from signing the ICF until the end of study (including during the
Follow up Phase)
CT=computed tomography; ICF=informed consent form; MRI=magnetic resonance imaging;
99mTc=technetium-99m.
1 
Cycle “X+1” will be the first cycle under Amendment 6. Cycle “X” is the last cycle the subject completed prior to switching
to the modified schedule.
2 
EoT Visit: The EoT visit for a safety assessment must be scheduled within 30 days after both study drugs are discontinued, or
prior to administration of a new anti prostate cancer therapy, whichever occurs first. Another safety assessment via scheduled
visit or phone call should take place within 100 to 114 days after the last dose of study medication is administered.
3 
Subjects who have signed the informed consent form prior to implementation of Amendment 6 will be allowed to complete
screening and be enrolled if all inclusion/exclusion criteria are met. For those subjects who are currently enrolled in
Combination 1, the investigator is to confirm that the subject is receiving benefit from the study drug in order to continue on
study.
4
Blood pressure should be assessed weekly during the first 2 months of treatment (Cycles 1 and 2), then monthly from Cycle 3
onward. Follow instructions in Section 6.1.1, for vital sign assessments during cetrelimab infusion.
5
The subject will be provided with a sufficient supply of oral study drug until the next planned visit. Drug accountability will
occur at each site visit.
6
For cetrelimab retreatment criteria and instructions for dose delay refer to Section 6.2.1.2.
7
See Section 12.3.1, and 12.3.2, for instructions on reporting adverse events and serious adverse events.
8
Hematology: Complete blood count should be performed weekly during the first month of treatment (Cycle 1). Blood
chemistry tests to be performed are fasting glucose, AST, ALT and bilirubin. Liver function tests should be performed every
other week during the first 3 months of treatment (Cycles 1 through 3). See Section 6, of the protocol for retreatment criteria
for cetrelimab, dose modification, and management of toxicity for study medications.
9 
Study data for survival and subsequent therapies will continue to be collected after discontinuation of treatment, unless the
subject withdraws consent for further study participation.

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Attachment 5: Modified Schedule of Events for Combinations Closed to Enrollment
Modified Schedule of Events for Combination 2
Treatment Phase 
End of Treatment 
Phase 
Follow-up
Phase
CYCLE  
(treatment   cycle is 
defined as 28 days) 
Amendment 4 
Cycle X+11 
Every Cycle 
Through Cycle 12; 
Cycle 13 and 
Beyond, Every 2
Cycles Until
Treatment
Discontinuation2
End-of-Treatment 
Visit (within 30 
days of last dose)3
Every 3
months
Visit Window  
(±3 days) 
(±5 days) 
(±2 weeks)
Study Procedures4
Informed consent5 
X
Dispense study drug 
X 
X6
Drug accountability  
X 
X6 
X
Serious Adverse Events7 
X 
X 
X
CT or MRI; Bone scan 
(99mTc)
At the discretion of the investigator according to routine practice.
Clinical safety 
laboratory tests (central 
or local)
At the discretion of the investigator according to routine practice
and per local label for abiraterone acetate.
Blood pressure 
Every 2 cycles.
Serum PSA  
At the discretion of the investigator according to routine practice.
Survival Status and 
subsequent therapies8 
Collected continuously from signing the ICF until the end of study (including during
the Follow up Phase)
CT=computed tomography; EoT=End of Treatment; ICF=informed consent form; MRI=magnetic resonance
imaging; PSA=prostate-specific antigen; 99mTc=technetium-99m.
1 
Cycle “X+1” will be the first cycle under Amendment 4. Cycle “X” is the last cycle the subject completed prior
to switching to the modified schedule.
2 
Study visits may have a ±4-day window.
3 
EoT Visit: The EoT visit for a safety assessment must be scheduled within 30 days after both study drugs are
discontinued, or prior to administration of a new anti-prostate cancer therapy, whichever occurs first.
4 
Response and safety evaluations (other than serious adverse event reporting) are to be performed at the
discretion of the investigator according to routine practice.
5 
Only subjects who have signed the informed consent form prior to the Internal Review Board/Internal Ethical
Committee approval date of Amendment 4 will be allowed to complete screening and be enrolled if all
inclusion/exclusion criteria for Combination 2 are met. For those subjects who are currently enrolled in
Combination 2, the investigator is to confirm that the subject is receiving benefit from the study drug in order to
continue on study.
6 
The subject will be provided with a sufficient supply of study drug until the next scheduled visit. Drug
accountability will occur at each site visit.
7 
See Section 12.3.1, and 12.3.2, of the protocol for instructions on reporting adverse events and serious adverse
events.
8 
Study data for survival and subsequent therapies will continue to be collected after discontinuation of treatment,
unless the subject withdraws consent for further study participation.

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Attachment 6: Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination
This Attachment outlines the design and procedures associated with Combination 3. Cross
references back to the protocol are included as appropriate.

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TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................................ 129
1. 
INTRODUCTION .................................................................................................................... 134
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESES............................................................... 134
2.1. 
Objectives and Endpoints ....................................................................................................... 134
2.2. 
Hypothesis .............................................................................................................................. 134
3. 
STUDY DESIGN..................................................................................................................... 134
3.1. 
Overview of Study Design ...................................................................................................... 134
3.2. 
Dose Selection Rationale ....................................................................................................... 137
3.3. 
Safety Evaluation Criteria ....................................................................................................... 138
4. 
SUBJECT POPULATION ....................................................................................................... 138
4.1. 
Inclusion Criteria ..................................................................................................................... 138
4.2. 
Exclusion Criteria.................................................................................................................... 139
4.3. 
Prohibitions and Restrictions .................................................................................................. 141
5. 
TREATMENT ALLOCATION AND BLINDING ....................................................................... 142
5.1. 
Randomization........................................................................................................................ 142
5.2. 
Blinding ................................................................................................................................... 142
6. 
DOSAGE AND ADMINISTRATION........................................................................................ 142
6.1. 
Study Drug Administration ...................................................................................................... 142
6.1.1. 
Pharmacokinetic Assessment Phase ..................................................................................... 142
6.1.2. 
Extension Phase..................................................................................................................... 144
6.2. 
Dose Modification and Management of Toxicity During Extension Phase............................. 144
7. 
TREATMENT COMPLIANCE................................................................................................. 144
8. 
PRIOR AND CONCOMITANT THERAPY.............................................................................. 144
8.1. 
Prohibited Concomitant Therapies ......................................................................................... 145
8.2. 
Restricted Concomitant Medications ...................................................................................... 145
9. 
STUDY EVALUATIONS.......................................................................................................... 145
9.1. 
Study Procedures ................................................................................................................... 145
9.1.1. 
Overview................................................................................................................................. 145
9.1.2. 
Screening Phase..................................................................................................................... 146
9.1.3. 
PK Assessment Phase ........................................................................................................... 146
9.1.4. 
Extension Phase..................................................................................................................... 146
9.1.5. 
End-of-Treatment Visit............................................................................................................ 147
9.2. 
Antitumor Activity.................................................................................................................... 147
9.3. 
Pharmacokinetic Evaluations.................................................................................................. 147
9.3.1. 
PK Sample Collection and Handling....................................................................................... 147
9.3.2. 
Analytical Procedures ............................................................................................................. 147
9.3.3. 
Pharmacokinetic Parameters.................................................................................................. 147
9.4. 
Safety Evaluations .................................................................................................................. 148
9.5. 
Sample Collection and Handling............................................................................................. 149
9.6 
Biomarkers.............................................................................................................................. 149
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY
TREATMENT/WITHDRAWAL FROM THE STUDY............................................................... 150
10.1. 
Completion.............................................................................................................................. 150
10.2. 
Discontinuation of Study Treatment........................................................................................ 150
10.3. 
Subject Withdrawal From the Study ....................................................................................... 151
10.4. 
Withdrawal from the Use of Research Samples..................................................................... 151
11. 
STATISTICAL CONSIDERATIONS........................................................................................ 151
11.1. 
Sample Size Determination .................................................................................................... 151
11.2. 
Pharmacokinetic Analysis....................................................................................................... 152
11.2.1. 
Descriptive Statistical Analysis of Pharmacokinetic Data....................................................... 152
11.2.2. 
Statistical Analysis of Relative Bioavailability......................................................................... 153
12. 
ADVERSE EVENT REPORTING ........................................................................................... 153
13. 
PRODUCT QUALITY COMPLAINT HANDLING.................................................................... 153
14. 
STUDY DRUG INFORMATION.............................................................................................. 153
14.1. 
Physical Description of Study Drugs....................................................................................... 153
14.1.1. 
Niraparib/Abiraterone Acetate Fixed-Dose Combination Tablet ............................................ 153

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14.2. 
Packaging ............................................................................................................................... 154
14.3. 
Labeling .................................................................................................................................. 154
14.4. 
Preparation, Handling, and Storage ....................................................................................... 154
14.5. 
Drug Accountability................................................................................................................. 154
15. 
STUDY-SPECIFIC MATERIALS ............................................................................................ 154
16. 
ETHICAL ASPECTS............................................................................................................... 154
17. 
ADMINISTRATIVE REQUIREMENTS.................................................................................... 155
REFERENCES.......................................................................................................................................... 155

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1. 
INTRODUCTION
See the Protocol Introduction for an overall summary of Background Design Rationale
(Section 1.1), Available Nonclinical and Clinical Data for Niraparib (Section 1.2), Summary of
Available Nonclinical and Clinical Data for Combination Agents (Section 1.3), and Benefit/Risk
Assessment (Section 1.4).
For this ongoing Combination, the terminology for biomarkers has been revised; “DRD and
CDK12 pathogenic alterations” have been replaced with “homologous recombination repair
(HRR) gene alterations” to indicate the inclusion of alterations outside of the DNA-repair pathway
(eg, CDK12).
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESES
2.1. 
Objectives and Endpoints
Objectives 
Endpoints
Primary
 To determine the relative bioavailability of 2 
regular-strength FDC tablet formulations of 
niraparib and AA with respect to niraparib and AA 
co-administered as SA under fasted conditions in
subjects with mCRPC
 PK parameters (Cmax, [Cmax/dose]niraparib, AUC0-168h,
[AUC0-168h/dose]niraparib) of niraparib and AA after a
single dose
Secondary
 To evaluate the PK of a low-strength FDC tablet 
formulations of niraparib and AA under fasted 
conditions in subjects with mCRPC  
 To assess the safety of niraparib in combination with
AA in subjects with mCRPC
 PK parameters (Cmax, [Cmax/dose]niraparib, AUC0-168h,
[AUC0-168h/dose]niraparib) of niraparib and AA after a
single dose
 Adverse events and clinical laboratory safety
AA=abiraterone acetate; AUC0-168h=area under the plasma concentration versus time curve over 7 days; Cmax=
maximum observed plasma concentration after a single dose; FDC=fixed-dose combination;
mCRPC=metastatic castration-resistant prostate cancer; PK=pharmacokinetic; SA=single agent
2.2. 
Hypothesis
Combination 3 is an estimation study to assess the relative BA of niraparib and AA as FDC tablet
formulations compared to SA under fasted conditions by providing the point estimate and
associated precisions of the geometric mean ratios (GMRs) between the FDC test formulations
and the SA reference formulation for the primary PK parameters. No formal hypothesis will be
tested. 
3. 
STUDY DESIGN
3.1. 
Overview of Study Design
See Protocol Section 3.1, for general information regarding the end-of-study and
end-of-combination definitions, as well as information related to clinical study reports, data cutoff
dates, and monitoring of subjects who continue to receive study drug(s) after the data cutoff.
Combination 3 is an open-label, multi-center, partly randomized (Cohort 1 only), parallel group
study to determine the PK and safety of 2 FDC tablet formulations of niraparib+AA in men with

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mCRPC. The study will consist of a 21-day Screening Phase to determine eligibility, an open-label
PK Assessment Phase of 8 days (Study Days 1-8, inclusive), followed by an Extension Phase
during which treatment will be continued from Cycle 1 Day 1 (Study Day 8) until discontinuation.
Subjects are recommended to submit tissue for identification of HRR gene alterations. Subjects
testing positive for an HRR gene alteration will be advised to continue treatment with niraparib
and AAP. Subjects testing negative for HRR gene alterations or for whom HRR gene alteration
status is unknown will be allowed to continue treatment with niraparib and AAP or AAP alone at
the investigator’s discretion. Treatment will be continued from Cycle 1 Day 1 (Study Day 8) until
discontinuation.
During the PK Assessment Phase, 3 cohorts will be studied. The Study Design is presented in
Table 1 below.
 
Cohort 1: subjects (N 34) will be randomized to receive a single dose of niraparib plus AA
(200 mg niraparib + 1,000 mg AA) given as FDC1 regular-strength tablet formulation (G010)
(Treatment Arm B [Cohort 1B], N 17) or as SAs (Treatment Arm A [Cohort 1A], N 17).
Relative BA of the FDC1 regular-strength tablet will be assessed by comparing PK results
from Cohort 1A to Cohort 1B.
 
Cohort 2: subjects (N 17) will be assigned to receive a single dose of niraparib plus AA
(200 mg niraparib + 1,000 mg AA) as FDC2 regular-strength tablet formulation (G012)
(Treatment Arm C, Cohort 2C). Relative BA of the FDC2 regular-strength tablet will be
assessed by comparing the PK results from Cohort 2C to Cohort 1A.
 
Cohort 3: subjects (N 17) will be assigned to receive a single dose of niraparib plus AA
(100 mg niraparib + 1,000 mg AA) as a low-strength FDC1 (G009) (Treatment Arm D
[Cohort 3D]) or FDC2 (G014) (Treatment Arm E [Cohort 3E]) tablet formulation. The
selection of Cohort 3D or 3E will be based on the relative BA results from Cohorts 1 and 2.
Relative BA of the FDC1 or FDC2 low-strength tablet formulation will be assessed by
comparing the PK results from Cohort 3D or 3E, respectively, to Cohort 1A.
In total, approximately 68 subjects will be enrolled. Approximately 34 subjects with mCRPC are
planned to be enrolled in Cohort 1 and approximately 17 subjects with mCRPC are planned to be
enrolled in each of Cohorts 2 and 3.
Subjects will be randomly assigned to 1 of 2 treatment arms in Cohort 1 which include Treatments
A and B as shown in Table 1. Subjects will be assigned to Treatment C in Cohort 2 and Treatment
D or E in Cohort 3 (based on the interim analysis results for Cohort 1).

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Table 1: 
Study Cohorts and Treatments
PK Assessment Phase
(fasting)a
Extension Phaseb
(modified fasting)c
Cohort
Treatment
Arm
No. of
Subjects
Study Days 1-8
(C1D1  until EOT)
C1D1= Study Day 8 after
168-hr PK sample
1 
A 
17
Single Dose
200 mg niraparib/1,000 mg AA as SA
niraparib 200 mg QD
AA 1,000 mg QD
prednisone 5 mg BID
as SA
or
AA 1,000 mg QD
prednisone 5 mg BID
as SAd 
B 
17 
Single Dose
200 mg niraparib/1,000 mg AA as FDC1
regular-strength tablets (G010)
2
C 
17 
Single Dose 
200 mg niraparib/1,000 mg AA as FDC2 
regular-strength tablets (G012) 
3
D or E 
17
Single Dose 
100 mg niraparib/1,000 mg AA as FDC1
(G009) or FDC2 (G014) low-strength
tablets
Treatments A and B will be randomized; whereas subjects will be assigned to Treatment C and D or E
AA=abiraterone acetate; BID=twice daily; EOT=end of treatment; FDC=fixed-dose combination; QD=once daily;
SA=single agent
Treatment A: 2 x 100 mg capsules niraparib plus 4 X 250 mg tablets AA current commercial formulation
Treatment B: 2 x FDC1 regular-strength tablets (100 mg niraparib/500 mg AA)
Treatment C: 2 x FDC2 regular-strength tablets (100 mg niraparib/500 mg AA)
Treatments D or E: 2 x FDC1 or FDC2 low-strength tablets (50 mg niraparib/500 mg AA)
a Subjects must fast from food and fluids (excluding noncarbonated water) for at least 10 hours before dosing. Intake
of water is allowed until 2 hours before study drug intake.
b Subjects continue treatment until disease progression, withdrawal of consent, loss to follow-up, lack of clinical
benefit in the opinion of the investigator, or sponsor ends the study.
c Modified fasting defined as study drug intake on empty stomach only: intake at least 1 hour before or at least 2
hours after a meal.
d Subjects will receive niraparib + AA or AA alone QD, each in combination with 5 mg prednisone (or
prednisolone) BID, during the Extension Phase at the investigator’s discretion guided by HRR gene alteration status.
Enrollment will start in Cohort 1 first. Subjects will be randomized1:1 to Cohort 1B and Cohort 1A
in a parallel group design. Pharmacokinetic sampling will be performed up to 168 hours post-dose
on Study Day 8 (Cycle 1 Day 1). An interim PK analysis will be conducted after 8 PK evaluable
subjects from each treatment group (N 16) complete PK assessments over 168 hours. Results from
the interim analysis will determine the initiation of Cohort 2 and Cohort 3.  Enrollment will
continue during the interim PK analysis.
All subjects in Cohort 2 and Cohort 3 will follow the same PK assessments as described for Cohort
1 in the above paragraph.
Cohort 2 will test FDC 2 regular strength (G012).
Cohort 3 will test the low strength of 1 of the FDC tablet formulations (FDC 1 [G009] or FDC2
[G014]).

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Combination 3 procedures and timepoints are summarized in Time and Events Schedule 1A; PK
assessments are summarized in Time and Events Schedule 1B.
Biomarker status is not required to determine study eligibility. If not already known, biomarker
status assessment is recommended, and results can be used to guide further treatment decisions
during the Extension Phase.
Based on the results of the interim analysis from the MAGNITUDE Study (see Section 1.1.3), the
IDMC determined that the futility rule was met, indicating the study did not show additional
benefit of adding niraparib to AAP in subjects with no HRR gene alterations. No new safety signals
were identified.
After completion of the PK Assessment Phase, subjects will enter the Extension Phase to receive
treatment with either niraparib 200 mg once daily plus AA 1,000 mg once daily (both as SAs) and
prednisone/prednisolone 5 mg twice daily or AA 1,000 mg once daily and prednisone/prednisolone
5 mg twice daily; treatment cycles are 28 days. Subjects testing positive for HRR gene alterations
will be advised to continue treatment with niraparib and AAP. Subjects testing negative for HRR
gene alterations or for whom HRR gene alteration status is unknown will be allowed to continue
treatment with niraparib and AAP or AAP alone at the investigator’s discretion.
Study 
evaluations 
during 
Extension 
Phase 
will 
be 
performed 
according 
to
Time and Events Schedule 1A. Any additional assessment not specified in this table can be
performed at the discretion of the investigator according to routine practice. Treatment will
continue until discontinuation for disease progression, unacceptable toxicity, withdrawal of
consent, loss to follow up, lack of clinical benefit in the opinion of the investigator, start of
subsequent anticancer therapy, or the Sponsor ends the study (see Protocol Section 10).
In the event of early study completion or study termination by the sponsor, (whether or not the
study endpoints are met), the sponsor will continue to provide study treatments until unequivocal
disease progression, unacceptable toxicity, or an alternate method is in place to avoid treatment
interruption.
3.2. 
Dose Selection Rationale
The RP2D of niraparib in combination with AAP is 200 mg based on Study 64091742PCR1001
(See Protocol Section 3.2.2).
CCI

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3.3. 
Safety Evaluation Criteria
Safety evaluations will be performed as outlined in Time and Events Schedule 1A.
4. 
SUBJECT POPULATION
Investigators should ensure that all enrollment criteria have been met at screening. If a subject's
status changes (including laboratory results or receipt of additional medical records) after
screening but before the first dose of study treatment is given such that he no longer meets all
eligibility criteria, then the subject should be excluded from participation. Retesting of values
(eg, safety laboratory assessments) that lead to exclusion will be allowed once using an
unscheduled visit during the Screening Phase to reassess eligibility.
4.1. 
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in Combination 3.
1. 
Male
2. 
>18 years of age (or higher legal age of consent in the jurisdiction in which the study is
taking place).
3. 
Signed informed consent form (ICF) indicating that he understands the purpose of, and
procedures required for, the study and is willing to participate in the study.
4. 
Histologically or cytologically confirmed prostate cancer.
5. 
Diagnosedwith mCRPC, who in the opinion of the investigator may benefit from treatment
in Combination 3 of this study.
6. 
Able to continue GnRHa therapy during the study if not surgically castrate (ie, subjects
who has not undergone bilateral orchiectomy).
7. 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤1.
8. 
Toxicity associated with prior chemotherapy or radiotherapy has resolved to Grade ≤1
(except alopecia or Grade ≤2 neuropathy) at screening.
9. 
Criterion modified per Amendment 6
9.1 
While on study medication and for 3 months following the last dose of study
medication, a male subject must agree to use an adequate contraception method as deemed
appropriate by the investigator and as specified in Section 4.3. Prohibitions and
Restrictions
10. 
Subject must agree not to donate sperm while on study treatment, and for 3 months
following the last dose of study treatment.
11. 
At screening, the following laboratory parameters must be met:

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a. Absolute neutrophil count (ANC) ≥1.5 x 109/L independent of growth factors for
30 days
b. Hemoglobin ≥9.0 g/dL independent of transfusion for 30 days
c. Platelet count ≥100 x 109/L independent of growth factors or transfusion for 30 days
d. Serum albumin ≥3.0 g/dL
e. Serum creatinine ≤1.5 × the upper limit of normal (ULN), or a calculated creatinine
clearance ≥30 mL/min/1.73 m2 using the MDRD or CKD-EPI equation
f. Serum total bilirubin ≤1.5× ULN or direct bilirubin ≤1 x ULN (Note: In subjects with
Gilbert’s syndrome, if total bilirubin is >1.5 × ULN, measure direct and indirect
bilirubin, and if direct bilirubin is ≤1.5 × ULN, subject may be eligible)
g. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤3 x ULN
h. Fasting glucose ≤ 250 mg/dL
12. 
Subject must be willing and able to adhere to the prohibitions and restrictions specified in
Section 4.3.
13. 
Subject must be able to swallow the study drug tablet or capsule whole.
4.2. 
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating
in Combination 3.
1. 
Symptomatic brain metastases.
2. 
Prior disease progression during combination treatment with AA and PARPi. Prior
discontinuation of treatment with AA or PARPi due to AA- or PARPi-related toxicity.
3. 
History or current diagnosis of myelodysplastic syndrome/acute myeloid leukemia
(MDS/AML).
4. 
Active malignancies (ie, progressing or requiring treatment change in the last
24 months) other than the disease being treated under study. The only allowed
exceptions are:
a. non-muscle invasive bladder cancer.
b. skin cancer (non-melanoma or melanoma) treated within the last 24 months that is
considered completely cured.
c. Breast cancer:
 
adequately treated lobular carcinoma in situ or ductal carcinoma in situ,
 
or history of localized breast cancer and receiving antihormonal agents and
considered to have a very low risk of recurrence.
d. Malignancy that is considered cured with minimal risk of recurrence

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5. 
Known allergies, hypersensitivity, or intolerance to niraparib or AA or the
corresponding excipients of niraparib/AA.
6. 
Any condition for which, in the opinion of the investigator, participation would not be
in the best interest of the patient (eg, compromise the well-being) or that could prevent,
limit, or confound the protocol-specified assessments.
7. 
Known disorder affecting gastrointestinal absorption. The eligibility of subjects with
prior gastrointestinal surgery, which may affect gastrointestinal absorption (eg, partial
gastrectomy and small/large bowel resection) should be discussed with the sponsor’s
medical monitor.
8. 
Severe or unstable angina, myocardial infarction or ischemia requiring coronary artery
bypass graft or stent within the previous 6 months, symptomatic congestive heart
failure, arterial or venous thromboembolic events (eg, pulmonary embolism,
cerebrovascular accident including transient ischemic attacks), or clinically significant
ventricular arrhythmias within 6 months prior to randomization or New York Heart
Association (NYHA) Class II to IV heart disease.
9. 
Presence of uncontrolled hypertension (systolic blood pressure [BP] ≥ 160 mmHg or
diastolic BP ≥ 100 mmHg). Subjects with a history of hypertension are allowed
provided that BP is controlled to within these limits (systolic BP < 160 mmHg and
diastolic BP < 100 mm Hg) by anti-hypertensive treatment.
10. 
Subjects with lack of safe and reliable peripheral intravenous access.
11. 
History of adrenal dysfunction.
12. 
Human immunodeficiency virus (HIV)-positive patients with 1 or more of the
following:
a. Not receiving highly active antiretroviral therapy
b. A change in antiretroviral therapy within 6 months of the start of screening (except
if, after consultation with the sponsor on exclusion criterion 13.c, a change is made
to avoid a potential drug-drug interaction with the study drug)
c. Receiving antiretroviral therapy that may interfere with study treatment (consult the
sponsor for review of medication prior to enrollment)
d. CD4 count <350 at screening
e. An acquired immunodeficiency syndrome-defining opportunistic infection within 6
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13. 
Prior antitumor therapy as follows, before the first dose of study drug (Study Day 1):
a. anti-androgen therapy: abiraterone acetate within 2 weeks, enzalutamide within
8 weeks, apalutamide within 6 weeks, other anti-androgens (eg, bicalutamide,
flutamide, nilutamide) within 2 weeks, and PARPi (eg. olaparib, niraparib,
rucaparib) within 2 weeks
b. chemotherapy or immunotherapy for treatment of prostate cancer within 28 days
c. investigational agent for treatment of prostate cancer within 28 days.
14. 
If a subject has undergone major surgery, they must have recovered adequately from
the toxicities or complications from the intervention prior to starting therapy.
15. 
Active hepatitis B virus (eg. Hepatitis b surface antigen reactive) or hepatitis C virus
(HCV) (eg. HCV RNA quantitative is detected) or chronic liver disease (as evidenced
by ascites or bleeding disorders secondary to hepatic dysfunction).
4.3. 
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and restrictions
during the study to be eligible for participation:
1. Must agree to always use a condom during sexual intercourse (even in case of prior vasectomy
or in case of intercourse with an already pregnant woman) or remain abstinent during the study
and for 3 months after the last study treatment administration (Section 10.2, Discontinuation
of Study Treatment).
If the patient is engaged in sexual activity with a woman of childbearing potential, then a
condom should be used along with another highly effective contraceptive method.  Highly
effective methods of contraception (methods that can achieve a failure rate of less than 1%
per year when used consistently and correctly) include:
 
combined hormonal (estrogen + progesterone or progesterone only) contraception
associated with inhibition of ovulation: oral, injectable or implantable;
 
placement of an intrauterine device (IUD) or intrauterine hormone releasing system
(IUS);
 
bilateral tubal occlusion;
 
vasectomy;
 
sexual abstinence; please note that 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 treatments. The reliability of sexual abstinence
needs to be evaluated in relation to the duration of the clinical trial and the preferred and
usual lifestyle of the subject.
A highly effective contraceptive method should be used for the duration of the study and for
3 months after the last study medication administration.
2. May not consume food or beverages containing grapefruit, Seville oranges, or quinine from
24 hours (72 hours in the case of grapefruit and Seville oranges) before each intensive PK
sample collection day until after the last PK sample is collected in relation to the specific PK
sampling period.

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3. May not consume alcohol from 24 hours before each intensive PK sample collection day until
after the last PK sample is collected in relation to the specific PK sampling period. Moderate
(limited) alcohol consumption is allowed on other study days.
5. 
TREATMENT ALLOCATION AND BLINDING
5.1. 
Randomization
Randomization will be used in Cohort 1 between Treatment Arms A and B only to avoid bias in
the assignment of subjects to treatment sequence groups, to increase the likelihood that known and
unknown patient attributes (eg, demographic and baseline characteristics) are evenly balanced
across treatment sequence groups, and to enhance the validity of statistical comparisons across the
groups.
Approximately 34 subjects (17 subjects per arm) will be enrolled into Cohort 1 of the study
(2 parallel treatment arms). As subjects qualify for the study, they will be assigned a subject
randomization number in strict sequential order. Based on a computer-generated randomization
schedule prepared under the sponsor’s supervision before the start of the study, subjects will be
randomly assigned to receive the treatments in 1 of 2 possible treatment groups (A, B). Assignment
to treatment group will occur before a subject receives the study drug.
Subjects who drop out during the PK assessment phase may be replaced to assure at least
30 subjects complete Cohort 1. Subjects who are replaced during the PK Assessment Phase may
continue to the Extension Phase.
Cohorts 2 and 3 are nonrandomized. Subjects will be assigned to Treatment C in Cohort 2 and
Treatment D or E in Cohort 3.
5.2. 
Blinding
Blinding will not be used because the primary endpoint, the assessment of specified PK
parameters, is not subject to bias from the subjects or observers.
6. 
DOSAGE AND ADMINISTRATION
An interactive web response system (IWRS) will be used to manage drug supply during both the
PK Assessment and Extension Phases; study medication will be shipped directly to the site.
There are separate dosing and administration schedules for the PK and Extension Phases of
Combination 3 (see Time and Events Schedule 1A and 1B).
6.1. 
Study Drug Administration
6.1.1. 
Pharmacokinetic Assessment Phase
During the PK Assessment phase (Day 1 through 8), all subjects will be assigned to one of the
treatment arms below.

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Study Treatment
Reference Treatment
 
Treatment A (SA): 200 mg niraparib commercial formulation given as 2 X 100 mg capsules
plus 1,000 mg AA current commercial formulation given as 4 X 250 mg tablets, administered
orally under fasted conditions.
Test Treatments
 
Treatment B (FDC1 regular-strength [G010]): 200 mg niraparib/1,000 mg AA given as 2 X
FDC1 regular-strength (G010) tablets (100 mg niraparib/500 mg AA), administered orally
under fasted conditions.
 
Treatment C (FDC2 regular-strength [G012]): 200 mg niraparib/1,000 mg AA given as 2 X
FDC2 regular-strength (G012) tablets (100 mg niraparib/500 mg AA), administered orally
under fasted conditions.
 
Treatment D (FDC1 low-strength [G009]): 100 mg niraparib/1,000 mg AA given as 2 X FDC1
low-strength (G009) tablets (50 mg niraparib/500 mg AA), administered orally under fasted
conditions.
 
Treatment E (FDC2 low-strength [G014]): 100 mg niraparib/1,000 mg AA given as 2 X FDC2
low-strength (G014) tablets (50 mg niraparib/500 mg AA), administered orally under fasted
conditions.
Dosing Instructions
 
Subjects must refrain from taking the study drugs on the mornings of study visits designated
for PK sampling until seen at the site.
 
On intensive PK sampling day (Study Day 1) in Cohorts 1-3:
 
Subjects must fast from food and fluids (excluding noncarbonated water) for at least
10 hours before dosing. Intake of water is allowed until 2 hours before study drug intake.
 
The study drugs will be administered orally shortly after the planned pre-dose PK
sampling is completed with a total amount of 240 mL noncarbonated water. An additional
50 mL of noncarbonated water is allowed if necessary. Study treatment must be
swallowed whole and not chewed, divided, dissolved, or crushed.
 
Subjects will receive a low-fat breakfast exactly 1 hour after study drug administration
and will continue fasting until 4 hours after study drug administration. The breakfast
should be eaten completely within 30 minutes or less.
 
The drinking of noncarbonated water is allowed from 1 hour after study drug
administration onwards.
 
Lunch will be served on intensive PK sampling day after collection of the 4-hour PK
blood sample.
 
Dinner/evening meal should be consumed between 4 and 8 hours after lunch. A light
snack may be consumed between lunch and dinner.
 
Subjects who vomit 2 times at or before 3 hours after dosing of study drugs will be
non-evaluable for PK assessment and will be replaced. Subjects who vomit beyond

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3 hours after dosing of study drugs can continue the PK assessments if the subject and
investigator agree.
 
On Study Day 8 (Cycle 1 Day 1) study drugs will be taken after the planned pre-dose PK
sampling is completed.
6.1.2. 
Extension Phase
During the Extension Phase, subjects will receive either niraparib 200 mg once daily plus AA
1,000 mg once daily or AA 1,000 mg once daily (as SAs) under modified fasted conditions each
with prednisone/prednisolone 5 mg twice daily; treatment cycles are 28 days. Treatment will be at
the discretion of the investigator guided by HRR gene alteration status. See Protocol Section 6.1,
and 6.1.2, for dosage and administration instructions.
6.2. 
Dose Modification and Management of Toxicity During Extension
Phase
Refer to Protocol Section 6.2, Dose Modification and Management of Toxicity, and Section 6.2.3,
Combination 3: Niraparib/Abiraterone Acetate Fixed-dose Combination Tablet, for dose
modification instructions.
7. 
TREATMENT COMPLIANCE
During the PK Assessment Phase, study treatment will be administered at the study site under the
supervision of study-site personnel.
During the Extension Phase, study drug administration and dosing compliance should be assessed
as described in Time and Events Schedule 1A. A count of all study drug provided by the sponsor
should be conducted. See Protocol Sections 7, and 7.2, for further instructions regarding
niraparib+AAP and AAP compliance during the Extension Phase of Combination 3.
8. 
PRIOR AND CONCOMITANT THERAPY
All prior therapy for prostate cancer must be collected. Concomitant therapies must be recorded
beginning with the signing of the ICF to the end of the PK assessment phase. In addition,
concomitant medications for drug-related SAEs that occur during the Extension Phase must be
recorded up to 30 days after the last dose of study drugs.
Modification of an effective preexisting therapy should not be made for the explicit purpose of
entering a patient into the study. All subjects should maintain the same medications throughout
the entire study period, as medically feasible, with minimum introduction of new chronic therapies
up to the start of the Extension Phase (Study Day 8 [Cycle 1 Day 1] ). All therapies different from
the study treatment must be recorded in the eCRF.
Continuous treatment with a GnRHa, or surgical castration, is mandatory for all subjects. The
choice of GnRHa is at the discretion of the investigator. Dose and dose schedule (without
interruption) will be consistent with the prescribing information and should be adjusted, if
clinically indicated, to maintain castrate concentrations of testosterone. Recorded information will

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include a description of the type of the drug, treatment period, dosing regimen, route of
administration, and indication.
See Exclusion Criteria 13 in Section 4.2, of this Attachment for prior anti-cancer therapy wash-out
period.
8.1. 
Prohibited Concomitant Therapies
The sponsor must be notified in advance (or as soon as possible thereafter) of instances in which
prohibited therapies are administered.
The following concomitant medications are prohibited during the duration of the study:
 
Anticancer therapies other than the study drugs, excluding GnRHa
 
Experimental agents other than the study drugs
 
Strong CYP3A4 inducers (See Protocol Attachment 4)
 
Prednisone >10 mg (or any other corticosteroid for systemic use) per day is prohibited during
the PK assessment phase. Patients receiving prednisone ≤10 mg (or any other corticosteroid
for systemic use) per day prior to enrollment can continue the same dose during the PK
assessment phase
The following concomitant medications are prohibited within 4 weeks prior to and during the PK
Assessment Phase up to the start of the Extension Phase.
 
Inhibitors/inducers of P-glycoprotein (P-gp), gene ABCB1:
 
inhibitors: amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan,
cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole,
ketoconazole, lopinavir and ritonavir, quercetin, quinidine, ranolazine, ticagrelor,
verapamil
 
inducers: avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort,
tipranavir/ritonavir
8.2. 
Restricted Concomitant Medications
Refer to Protocol Section 8.2, Restricted Concomitant Medications, and Section 8.2.2,
Combination 2: Niraparib and AAP for instructions.
9. 
STUDY EVALUATIONS
9.1. 
Study Procedures
9.1.1. 
Overview
The Time and Events Schedules 1A and 1B summarize the frequency and timing of PK and safety
assessments applicable to Combination 3.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures
be performed in the following sequence: ECGs, vital signs, and any type of blood draw last. Actual
dates and times of assessments will be recorded in the source documentation.

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For each subject, the planned maximum amount of blood drawn will not exceed 70 mL at any visit.
Refer to the study Laboratory Manual for details regarding blood volumes to be collected for each
visit. Repeat or unscheduled samples may be taken for safety reasons or for technical issues with
the samples.
9.1.2. 
Screening Phase
During the Screening Phase, eligibility criteria will be reviewed and evaluations performed as
specified in Time and Events Schedule 1A. Screening procedures may be performed within
21 days before Study Day 1, unless otherwise specified. The screening physical exam and clinical
safety laboratory evaluations can be used for Study Day 1 assessments if performed within
14 days. Assessments performed as part of the subject’s routine clinical evaluation and not
specifically for this study need not be repeated after signed informed consent form (ICF) has been
obtained, provided the assessments fulfill the study requirements and are performed within the
specified timeframe prior to enrollment.
Subjects who do not meet all inclusion criteria, or who meet an exclusion criterion, may be
rescreened once. Rescreening is at the discretion of the investigator and requires sponsor approval
and agreement. Subjects who are to be rescreened must sign a new ICF before rescreening.
Subjects rescreened within 28 days of planned enrollment may use the initial screening laboratory
results to determine eligibility if not the reason for the rescreening. All other rescreening and
subsequent enrollment activities must be conducted in accordance with all protocol defined
windows and timelines.
9.1.3. 
PK Assessment Phase
The PK assessment phase will begin on Study Day 1 and end on Study Day 8 after completion of
the 168-hour PK sampling. An overview of procedures and timepoints is provided in Time and
Events Schedules 1A and 1B. A description of PK evaluations is in Section 9.3, of this
Amendment.
9.1.4. 
Extension Phase
The Extension Phase will start on Study Day 8 (Cycle 1 Day 1) after completion of the 168-hour
PK sampling in the PK Assessment Phase. Subjects testing positive for HRR gene alterations will
be advised to continue treatment with niraparib and AAP. Subjects testing negative for HRR gene
alterations or for whom HRR gene alteration status is unknown will be allowed to continue
treatment with niraparib and AAP or AAP alone at the investigator’s discretion. Treatment during
the Extension Phase will be administered as single agents: niraparib 200 mg once daily, AA 1,000
mg once daily, and prednisone/prednisolone 5 mg twice daily in 28-day cycles.
Study evaluations during the Extension Phase will be performed according to Time and Events
Schedule 1A. Any additional assessments not specified in Time and Events Schedule 1A may be
performed at the discretion of the investigator according to routine practice. Treatment will
continue until discontinuation for disease progression, unacceptable toxicity, withdrawal of
consent, loss to follow-up, lack of clinical benefit in the opinion of the investigator, start of
subsequent anticancer therapy, or the sponsor ends the study.

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9.1.5. 
End-of-Treatment Visit
See Protocol Section 9.1.5, End-of-Treatment Visit. For Combination 3, this visit can take place
as a scheduled visit or phone call at the discretion of the investigator.
9.2. 
Antitumor Activity
No antitumor assessments will be done for Combination 3.
9.3. 
Pharmacokinetic Evaluations
9.3.1. 
PK Sample Collection and Handling
Venous blood samples will be collected for determination of plasma concentrations of study drugs
at time points specified in the PK Time and Events Schedule 1B and processed, handled and
identified according to the laboratory manual. The exact dates and times of blood sample collection
must be recorded in the laboratory requisition form.
9.3.2. 
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of niraparib and abiraterone using a
validated, specific and sensitive liquid chromatography/mass spectrometry/mass spectrometry
(LC-MS/MS) method under the supervision of the sponsor’s Department of Bioanalysis. If
required, some plasma samples may be analyzed to document the presence of circulating
metabolites using a qualified research method.
9.3.3. 
Pharmacokinetic Parameters
Pharmacokinetic analysis will be the responsibility of the sponsor in accordance with the current
Clinical PK Guideline. Additional PK parameters and details of the PK analysis, including data
handling rules and software used to perform PK analysis, will be provided in the Clinical
Pharmacology Analysis Plan. Based on the individual plasma concentration-time data, using the
actual sampling times, the following PK parameters will be derived for both niraparib and
abiraterone:
Cmax  
[Cmax/ dose]niraparib 
maximum observed analyte concentration niraparib Cmax
maximum 
observed 
analyte 
concentration 
niraparib Cmax
normalized by the doseniraparib
tmax  
the actual sampling time to reach the maximum observed analyte
concentration
AUC0 168h  
area under the plasma concentration-time curve from time 0 to
168 hours post dosing
[AUC0 168h/dose]niraparib 
area under the plasma concentration-time curve for niraparib from
time 0 to 168 hours post dosing

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9.4. 
Safety Evaluations
See Protocol Section 9.7, and specific instructions below for Combination 3.
Adverse Events
Adverse events must be reported according to the instructions in Protocol Section 12.
During the PK Assessment Phase, all AEs (serious and non-serious) must be reported. Beginning
with the Extension Phase (Day 8, after the 168-hour PK sampling), only SAEs must be reported.
Clinical Safety Laboratory Tests
Screening clinical laboratory tests should be performed centrally as outlined in Table 2. During
the Extension Phase, clinical safety laboratory assessments (see  Table 3) must be performed every
1-2 weeks for the first 3 cycles according to the timepoints in Time and Events Schedule 1A. From
Cycle 4 onward, safety laboratory assessments will be at the discretion of the investigator
according to routine practice. The safety laboratory tests may be performed centrally or locally.
The investigator must review laboratory results, document this review, and record any clinically
relevant changes occurring during the study (all AEs during the PK Assessment Phase and SAEs
only during the Extension Phase) in the AE section of the eCRF. For each laboratory abnormality
reported as an AE, the following laboratory values should be reported in the laboratory section of
the eCRF: the value indicative of the onset of each toxicity grade; the most abnormal value
observed during the AE, and the value supporting recovery to Grade 1 or to baseline values.
Table 2: Screening Laboratory Tests (Central Laboratory)
Hematology Panel
-CBC (hemoglobin, white blood cell count, platelets, absolute lymphocyte count, and ANC)
Serum Chemistry Panel
-creatinine
-glucosea
-potassium
Liver Function Tests
-ALT
-AST
-alkaline phosphatase
-serum total bilirubin (if abnormal,
measure direct bilirubin)
Other Laboratory Tests
-serum albumin
-serology (HIV and CD4 count if
indicatedb, HBsAg, HepB core
antibody, HCV antibody)
ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate aminotransferase;
CBC=complete blood cell count; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus;
HgbA1c=hemoglobin A1c; HIV=human immunodeficiency virus
a Fasting glucose.
bHIV and CD4 count should be only performed if indicated by prior medical history.

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Table 3: Clinical Safety Laboratory Tests (Local or Central Laboratory)
Hematology Panel
-CBC (hemoglobin, white blood cell count, platelets, absolute lymphocyte count, and ANC)a
Serum Chemistry Panel
-creatinine
-glucose
-potassium
Liver Function Testsb
-ALT
-AST
-alkaline phosphatase
-serum total bilirubin (if abnormal,
measure direct bilirubin)
ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate aminotransferase;
CBC=complete blood count cell count
a CBC should be performed according to local label for niraparib: weekly during Cycle 1, monthly during
Cycles 2-12, and then periodically after this time.
b Liver function tests should be performed according to local label for abiraterone acetate every 2 weeks (eg,
on Day 1 and 15) during Cycles 1-3, and then monthly thereafter.
For suspected MDS/AML while a subject is receiving treatment or being followed for
post-treatment assessments, bone marrow aspirate and biopsy testing must be completed by a
hematologist. A whole blood sample will also be collected for cytogenetic analysis (mutations of
select myeloid-associated genes) at screening. If needed, cytogenetic analysis will be done
centrally for standardized evaluation. Testing completed as part ofstandard-of-care is sufficient if
the methods are acceptable to the sponsor's medical monitor. The study site must receive a copy
of the hematologist’s report of aspirate/biopsy findings, which must include a classification
according to World Health Organization (WHO) criteria and other sample testing reports related
to MDS/AML. Data from the report will be entered on the appropriate eCRF pages and the site
must keep a copy of the report with the subject’s study file.
Other Safety Evaluations
Other safety evaluations are ECG, vital sign, physical examination, and ECOG PS evaluations.
See Protocol Section 9.7, for descriptions.
9.5. 
Sample Collection and Handling
See Protocol Section 9.8, for sample collection and handling instructions.
9.6 
Biomarkers
In Cohort 3, HRR gene alteration status is not required to determine study eligibility; however, it
can be used to guide treatment during the Extension Phase.
Subjects can have HRR gene alteration status (Table 12) assessed by the sponsor from tumor tissue
(archival) unless subjects have had a previous result from the sponsor’s assays or a local test
performed in a CLIA-certified or equivalent laboratory. If the subject has had a previous result
from the sponsor’s required assays or a local result from a CLIA-certified or equivalent laboratory,

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then after the subject grants a release, the data can be reviewed for biomarker status. Local tests
may be performed using tumor tissue, plasma, saliva, or blood.
Subjects testing positive for HRR gene alterations will be advised to continue treatment with
niraparib and AAP. Subjects testing negative for HRR gene alterations or for whom HRR gene
alteration status is unknown will be allowed to continue treatment with niraparib and AAP or AAP
alone at investigator’s discretion.
Table 12: 
Biomarker Panel
Genes 
Definition
Adjustments to the biomarker panel of specific HRR gene alterations may be made based on
evidence from emerging data. Any biomarker-related changes will be communicated to
investigators via letter.
Additional biomarker tests may be performed on remaining tumor tissue samples (where allowed
by local regulations). These additional tests may be used to help develop a diagnostic test to
identify patients suitable for treatment with therapeutic regimens that include niraparib. Data
generated may be used to understand response or resistance to niraparib and AAP combination
therapy and data may be combined in a meta-analysis with data from other similar studies.
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY
TREATMENT/WITHDRAWAL FROM THE STUDY
10.1. 
Completion
The subject is considered to have completed the study after discontinuing treatment in the
Extension Phase for any reason and having had a follow-up (End-of-treatment) safety assessment
or the subject is lost to follow-up.
10.2. 
Discontinuation of Study Treatment
Subjects who discontinue the study drugs should complete the EoT visit within 30 days (7 days)
of the last dose of study drug or prior to administration of a new anti-prostate cancer therapy,
whichever occurs first. The subject's study treatment will be discontinued if:
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 
The investigator or sponsor believes (eg, for safety or tolerability reasons such as an adverse
event) that it is in the best interest of the subject to stop treatment (refer to Protocol
Section  6.2)
 
The investigator believes the subject is no longer receiving clinical benefit from continued
treatment
 
Withdrawal of consent for continued treatment (subject’s decision to discontinue for any
reason).
 
The sponsor terminates the study
In the event of early study completion or study termination by the sponsor, (whether or not the
study endpoints are met), the sponsor will continue to provide study treatments until unequivocal
disease progression, unacceptable toxicity, or an alternate method is in place to avoid treatment
interruption.
10.3. 
Subject Withdrawal From the Study
The subject will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent
 
Investigator’s decision
10.4. 
Withdrawal from the Use of Research Samples
See Protocol Section 10.4.
11. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze PK for Combination 3 is outlined below.
Specific details will be provided in the Clinical Pharmacokinetic Analysis Plan.
11.1. 
Sample Size Determination 
The sample size calculation for Combination 3 is based on statistical estimation enabling the study
to provide an estimate on the magnitude of the relative BA between the test formulations and
reference formulation with a precision close to the equivalence limit of (80%, 125%).
Based on the study data under single dose condition (212082PCR1007/abiraterone and TESARO-
GSK 3000-01-004 Tablet Pilot BA/Niraparib Assumption at Table 4), a sample size of 30 PK
evaluable subjects (15 per arm) will provide the point estimates of the GMRs between test and
reference with following precisions (see Table 4). All subjects who have at least
1 noncompartmental PK parameter estimated will be considered PK evaluable
In total, approximately 68 subjects will be enrolled into Combination 3. Approximately 34 subjects
(17 subjects per treatment group) will be randomized into Cohort 1, and 17 subjects will be
assigned to each of Cohorts 2 and 3 (non-randomized) to ensure that at least 15 PK evaluable
subjects from each arm complete the study.

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Table 4: Precisions of the point estimates for GMR
Compound
Primary PK
Parameter
Assumption on
Inter-subject CV  
90% CI
Abiraterone
Cmax  
64%  
(70%, 143%)
AUC  
57% 
(73%, 137%)
Niraparib
Cmax  
49% 
(76%, 132%)
AUC  
59% 
(72%, 139%)
11.2. 
Pharmacokinetic Analysis
11.2.1. 
Descriptive Statistical Analysis of Pharmacokinetic Data
All concentration-time data from subjects who have sufficient and interpretable drug exposure data
will be included for the calculation of the noncompartmental PK parameters.
Data will be listed for all subjects with available study drug plasma concentrations per treatment.
All concentrations below LLOQ or missing data will be labeled as such in the concentration data
listings. Concentrations below LLOQ will be treated as 0 in the summary statistics and for the
calculation of PK parameters. All subjects and samples excluded from the analysis will be clearly
documented in the CSR.
Factors that may influence the study drug plasma concentrations (eg, vomiting, concomitant
medication, fever, high pre-dose concentration) will be checked. If an influencing factor is present,
a decision will be made by the PK/PD leader, whether to include or exclude the specific sample(s)
or subject.
Reasons for exclusion of a subject or a sample from the analysis include, but are not limited, to the
following:
 
Pre-dose plasma concentrations equal to or higher than 5% of Cmax
 
Vomiting occurred at or before 2 times median tmax after study drug administration
 
Noncompliance with study procedures affecting PK (eg, concomitant medication)
For each treatment, descriptive statistics, including arithmetic mean, SD, coefficient of variation,
geometric mean, median, minimum, and maximum will be calculated for the plasma
concentrations at each sampling time and for all PK parameters.
Graphical representations of the results will include, but are not limited to, the following graphs:
 
Log-linear and linear-linear plasma concentration-time profiles for each individual
 
Log-linear and linear-linear plasma concentration-time profiles for the mean values per
treatment

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11.2.2. 
Statistical Analysis of Relative Bioavailability
The primary PK parameters for statistical analysis will be Cmax and AUC0 168h of niraparib and AA.
All PK evaluable subjects will be included in the statistical analysis. PK parameters data for both
abiraterone and niraparib will be log-transformed prior to the analysis.
Cohort 1. An analysis of variance model (ANOVA) with treatment as fixed effect will be applied
to the log-transformed PK parameters data. The differences in means between the test formulations
and the reference as well as the associated 90% CIs for the differences will be constructed from
the model. The results will be back-transformed to derive the GMRs and the 90% CIs of
abiraterone and niraparib, respectively, for the following pair: FDC1 regular-strength (G010) vs
regular-strength SA.
Cohort 2. The same statistical analysis procedure as mentioned above will be applied to derive the
GMRs and associated 90% CIs of abiraterone and niraparib, respectively, for the pair: FDC2
regular-strength (G012) vs regular-strength SA (from Cohort 1).
Cohort 3. The primary PK parameters for statistical analysis will be dose normalized (to 200 mg)
Cmax  and AUC0 168h  for niraparib; Cmax  and AUC0 168h  of AA.  The same statistical model as
mentioned above will be applied to derive the GMRs and the 90% CIs of Abiraterone and Niraparib
respectively between treatment arm in Cohort 3 vs. reference arm in Cohort 1.
Upon completion of PK assessment phase (up to Study Day 8) for the first 8 subjects enrolled from
each arm in Cohort 1, statistical analysis for Cmax, AUC0 168 for both niraparib and abiraterone will
be performed on the 16 subjects in a similar way as described above. The interim PK data will be
summarized for informational purpose and will not require a database lock.
Cohort 2 and 3 will be started after the interim PK results readout in Cohort 1.
An interim analysis at N 8 for Cohort 2 following the same procedure as above may be performed
by comparing Treatment C (Cohort 2) vs. Treatment A (Cohort 1A).
12. 
ADVERSE EVENT REPORTING
Refer to Protocol Section 12, for adverse event reporting procedures
13. 
PRODUCT QUALITY COMPLAINT HANDLING
Refer to Protocol Section 13, Product Quality Complaint Handling for instructions.
14. 
STUDY DRUG INFORMATION
14.1. 
Physical Description of Study Drugs
See Protocol Section 14.1.2, for physical descriptions of SA niraparib, AA, and prednisone.
14.1.1. 
Niraparib/Abiraterone Acetate Fixed-Dose Combination Tablet
The FDC drug product formulations will be manufactured as immediate-release film-coated
50 mg niraparib/500 mg AA (low strength) or 100 mg niraparib/500 mg AA (regular strength)

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tablets for oral administration containing 79.70 mg or 159.40 mg of niraparib tosylate monohydrate
drug substance, equivalent to 50 or 100 mg niraparib free base, and 500 mg of AA drug substance.
The drug product will be manufactured and provided under the responsibility of the sponsor.
FDC1 regular strength (formulation number CJNJ67652000-G010) and FDC1 low-strength
(formulation number CJNJ67652000-G009) tablets include the following excipients:
hypromellose, sodium lauryl sulphate, lactose monohydrate, crospovidone, silicified
microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate and Opadry color
coating
FDC2 regular strength (formulation number CJNJ67652000-G012) and FDC2 low-strength
(formulation number CJNJ67652000-G014) tablets include the following excipients:
microcrystalline cellulose, sodium lauryl sulphate, lactose monohydrate, crospovidone, silicified
microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate and Opadry color
coating
FDC1 regular-strength and FDC1 low-strength tablets are manufactured using fluid bed
co-granulation of AA and niraparib tosylate monohydrate.
FDC2 regular-strength and FDC2 low-strength tablets are manufactured using dry granulation and
roller compaction of AA and niraparib tosylate monohydrate.
14.2. 
Packaging
See Protocol Section 14.2.2, for packaging information for SA niraparib and AA.
The FDC tablet formulations will be packaged in high-density polyethylene bottles with
child-resistant closures.
14.3. 
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4. 
Preparation, Handling, and Storage
See Protocol Section 14.4.1, and 14.4.3, respectively, for preparation, handling, and storage
information for SA niraparib and AA.
14.5. 
Drug Accountability
Refer to Protocol Section 14.5, for instructions on drug accountability.
15. 
STUDY-SPECIFIC MATERIALS
Refer to Protocol Section 15, Study-specific Materials.
16. 
ETHICAL ASPECTS
Refer to Protocol Section 16, Ethical Aspects.

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17. 
ADMINISTRATIVE REQUIREMENTS
Refer to Protocol Section 17, Administrative Requirements
REFERENCES
One new reference, Given 2017,15 was added for Combination 3. See Protocol Section References.

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Attachment 7: Long-term Extension Phase
After the primary analysis, the sponsor’s decision, and subsequent notification to limit further data
collection for a given combination, the Long-term Extension Phase for that combination will begin.
The sponsor will continue to provide study treatment until subjects meet criteria for
discontinuation of treatment (see protocol Section 10.2) or until further notification by the sponsor
on a different means for continued supply of study treatment, whichever occurs first. Study
treatment is defined as niraparib or the Janssen compound(s) or both in the given combination.
The Long-term Extension Phase for a given combination will begin when both the Amendment 7
is approved at the site and the sponsor has notified the site of the start of the Long-term Extension
for that combination:
 
Subjects who are still receiving niraparib in the Treatment Phase will be offered the option to
continue to receive niraparib, either alone or with the accompanying study drug(s) in the
respective combination.
 
Subjects who are still receiving the specific combination drug(s) without niraparib in the
Treatment Phase will be offered the option to continue to receive the specific combination
drug(s). If the combination-specific drug(s) are commercially available, subjects might be
offered to change to the commercially available drug.
 
Subjects who have ended treatment and who are in the Follow-up Phase will be discontinued
from the study and all data collection will cease. These subjects will be considered to have
completed the study.
Study Treatment Administration
ADT administration
Refer to Section 6.1, of the protocol.
Study treatment
A treatment cycle is defined as per the Time and Event schedule of each given combination.
Specifics of study treatment are provided in Protocol Section 6, pertaining to the Dosage and
Administration for each combination. Sufficient study drug for each treatment cycle will be
distributed as specified in Table 13. Dose modifications for toxicity are provided in Section 6.2,
of the protocol.
If a subject was on a lower dose of niraparib or of the combination-specific drug(s) in the
Treatment Phase of the combination cohort of the study, the subject should continue on the lower
dose(s) in the Long-term Extension Phase.
Prohibitions and Restrictions
Refer to protocol Sections 4.4, 8.1, and 8.2.
Study Procedures for the Long-term Extension
All subjects continuing in the Long-term Extension Phase will follow the schedule of procedures
provided in Table 13.

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Attachment 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located directly before the
Table of Contents (TOC).
Amendment 6 (29 October 2020)
The overall reasons for the amendment:
1. To close enrollment into Combination 1 (Cohorts 1A and 1B). Based on the results of the pre-planned futility
analysis of biomarker negative subjects (Cohort 1B), a response rate of 13% was not achieved. For Cohort 1A,
the Data Review Committee (DRC) reviewed data on the first 18 subjects enrolled. The overall response rate
was 22% (95% confidence interval: 8%, 44%). Based on the current response rate, the chance of obtaining a
50% response rate in Cohort 1A, as hypothesized in the protocol by completing the cohort (n=30), is <1%.
Therefore, the DRC recommended closing enrollment of Cohort 1A based on the low probability of success.
2. To give investigators the option of prescribing either niraparib and abiraterone acetate plus prednisone (AAP)
or AAP alone during the Extension Phase in Combination 3. This change in study design is based on the
outcome of the per protocol futility analysis conducted in the ongoing Phase 3 MAGNITUDE study
(64091742PCR3001) of niraparib and AAP versus AAP for the treatment of subjects with metastatic prostate
cancer, which showed there was no additional benefit of adding niraparib to AAP for the treatment of subjects
without homologous recombination repair (HRR) gene alterations. No unexpected or new safety signals were
identified by the Independent Data Monitoring Committee. 
 These data support
the combined daily administration of niraparib and AAP in subjects with metastatic castration-resistant prostate
cancer (mCRPC) as planned during the 8-day PK Assessment Phase of Combination 3. Therefore, the Sponsor
believes completion of the PK portion of Combination 3, and consideration of HRR status during extended
exposure to the niraparib/AAP combination, preserves the ability to complete the main objective of
Combination 3 while ensuring subjects and investigators have the information required to make long-term
treatment decisions. 
3. To revise safety monitoring and guidance based on updates to the niraparib core safety information.
Applicable Section(s) 
Description of Change(s)
Rationale: Review of early response data suggests the combination of niraparib and cetrelimab is not likely to
show benefit in men with mCRPC.
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Applicable Section(s) 
Description of Change(s)
Synopsis, Overview of 
Study Design, 
Statistical Methods;
Time and Events 
Schedule 1; 
Time and Events 
Schedule 2;
3.1.1. Combination 1: 
Niraparib and 
Cetrelimab;
9.3. Pharmacokinetics 
and Immunogenicity
(Combination 1); 
9.7. Safety 
Evaluations;
11.3.1. Combination 1;
11.10. Futility
Analysis;
Attachment 5:
Modified Schedule of
Events for
Combinations Closed
to Enrollment
Added text that under Amendment 6, Combination 1 (Cohorts 1A and 1B) is closed to
enrollment.
Added information in text and into Attachment 5 that indicates a modified schedule of
assessments will be followed for subjects in Combination 1; Time and Events
Schedules 1 and 2 no longer apply.
Added text indicating that only exploratory statistical analyses will be performed on
efficacy data collected from subjects in Combination 1.
Added text describing the analyses that resulted in the decision to close Combination 1.
Modified Attachment 5 to allow it to be used for any combination that is closed to
enrollment.
Rationale: Futility analysis results from the MAGNITUDE Study (64091742PCR3001) did not show additional
benefit of adding niraparib to AAP in subjects without HRR gene alterations.
1.1.3. Combination 3: 
Niraparib/AA FDC; 
1.4.3. Combination 3: 
Niraparib/AA FDC;
3.3.3. Combination 3: 
Niraparib/AA FDC; 
9.1.2.3. Combination 
3;
9.5. Biomarkers;
16.1.3. Combination 3; 
Attachment 6 (A6): 
(A6) Time and Events
Schedule 1A, (A6)
3.1. Overview of
Study Design, Table 1,
(A6) 6.1.2. Extension
Phase, (A6) 9.1.4.
Extension Phase, (A6)
9.6 Biomarkers
Added a summary of the MAGNITUDE Study futility analysis 
 supporting the combined administration of niraparib and AAP during the PK
Assessment Phase.
Added text indicating that during the Extension Phase, subjects will be allowed to
continue niraparib and AAP or AAP alone at the investigator’s discretion guided by
biomarker status and tolerability of the treatment.
Added text indicating that, if not already known, biomarker status assessment is
recommended, and results can be used to guide further treatment decisions during the
Extension Phase.
Rationale: Hypertension has been reported with both niraparib and abiraterone acetate and to align with niraparib
and AA product information.
9.7. Safety 
Evaluations; 
Attachment 6, (A6)
Time and Events
Schedule 1A
Added additional timepoints for vital signs assessments and laboratory safety
evaluations.
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Applicable Section(s) 
Description of Change(s)
Rationale: To align with the definitions and methods of contraception described in the Clinical Trials Facilitation
and Coordination Group guidelines.
4.2. Inclusion Criteria; 
4.4. Lifestyle 
Considerations; 
Attachment 6, (A6) 
Sec 4.1. Inclusion 
Criteria, (A6) 4.3. 
Prohibitions and
Restrictions 
Inclusion criterion #12: Amended text to indicate that study participants must agree to
use an adequate contraceptive method for the period indicated per Combination, as
deemed appropriate by the investigator and as specified under Section 4.4. Lifestyle
Considerations.
Inclusion criterion #9 (for Combination 3): Amended text to indicate that study
participants must agree to use an adequate contraception method for the period
indicated.
Added additional details on what are considered highly effective contraception methods
in Section 4.3.
Rationale: The lowest dose of niraparib is 100 mg; further dose reduction is not allowed per protocol.
6.2.1.1.1. Non- 
hematological 
Toxicities 
Added instruction that niraparib must be discontinued for non-hematologic
treatment-related Grade ≥3 toxicities lasting more than 28 days while the subject is
administered niraparib 100 mg once daily.
Rationale: To align with recent core labeling changes for niraparib.
6.2.1.1.1. Non- 
hematological 
Toxicities; 
6.6.1.1.2. Hematologic
Toxicity; 
10.2. Discontinuation 
of Study Treatment 
Added instructions that participants experiencing hypertensive crisis or who are
symptomatic for or diagnosed with posterior reversible encephalopathy syndrome
(PRES) should discontinue treatment with niraparib.
Added/clarified dosing modification instructions for participants who experience
inadequate recovery of platelet counts, neutrophil counts, and/or hemoglobin levels, or
who develop acute myeloid leukemia or myelodysplastic syndrome.
Rationale: To allow enrollment of subjects whose tumors have alterations in genes outside the DNA repair
pathway (eg, cyclin-dependent kinase 12 gene).
Throughout protocol 
Attachment 6, 9.6. 
Biomarkers, Table 12
For Combination 3, replaced DRD with HRR (homologous recombination repair).
Added Table 12 Biomarker Panel.
Added that additional biomarker tests may be performed on remaining tumor tissue.
Rationale: To align with product information.
6.3. Treatment of 
Overdose 
Added instructions for the treatment of subjects who experience an overdose of
niraparib, AA, or prednisone.
Rationale: To align with Janssen protocol template and current study procedures.

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Applicable Section(s) 
Description of Change(s)
9.3. Pharmacokinetics 
and Immunogenicity 
(Combination 1);
12. Adverse Event and 
Serious Adverse Event
Reporting; 
12.1.1. Adverse Event 
and Serious Adverse
Event Definitions and 
Classifications;
12.2. Special 
Reporting Situations; 
12.3.2. Serious
Adverse Events; 
12.3.3. Method of
Detecting Adverse 
Events and Serious 
Adverse Events;
12.3.4. Follow-up of 
Adverse Events and 
Serious Adverse 
Events;
13. Product Quality
Complaint Handling;
13.1. Procedures;
14.4. Preparation
Handling, and Storage;
14.4.2. Cetrelimab;
17.3. Subject
Identification,
Enrollment, and
Screening Logs;
17.8. Monitoring;
17.9.2. Study
Termination
Modified text related to adverse event, serious adverse event, product quality
complaint, and other safety handling, reporting and follow up.
Added text to allow remote consenting and monitoring.
Added text indicating genetic analyses will not be performed on blood samples
collected for PK or immunogenicity assessments.
New text added to describe methods of detecting adverse events.
Added information regarding the preparation, handling, and storage of investigational
product.
Clarified that cetrelimab administration guidelines are in the pharmacy manual.
Clarified that reports and communications related to the study will identify subjects by
subject identification and age at initial informed consent.
Added text clarifying that the sponsor reserves the right to close an individual cohort or
combination, and that this will be communicated to sites through a letter to the
investigator.
Rationale: To correct minor errors and inconsistencies.
Throughout the 
protocol 
10.1. Completion  
Attachment 6, Time 
and Events Schedule
1B, Sec 8.1. 
Prohibited
Concomitant
Therapies
Consistent notation has been applied when referring to abiraterone acetate (AA) plus
prednisone (AAP).
Updated abbreviations.
Added reference to the new niraparib/AA FDC Investigator’s Brochure and prednisone
product information (RAYOS) and updated the reference for ZYTIGA product
information.
Clarified the conditions under which subjects will be considered to have completed the
Treatment Phase and study.
PK sampling windows were added and clarifying footnotes added.
Clarified restrictions regarding concomitant prednisone use.

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COVID-19 Appendix (17 April 2020)
The overall reason for the appendix: to provide study-related guidance during the global coronavirus
(SARS-CoV-2) pandemic.
Applicable Section(s) 
Description of Change(s)
Rationale: For health and safety reasons during the SARS-CoV-2 pandemic, subjects may not be able to come
to the study site for scheduled procedures. An Urgent Safety Measure, dated 31 March 2020, was applied to
implement this COVID-19 Appendix.
COVID-19 Appendix  
The standalone Appendix provides guidance to investigators for managing
study-related procedures during the SARS-CoV-2 pandemic.

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Amendment 5(04 March 2020)
The overall reason for the amendment: to add Combination 3, which will investigate the relative
bioavailability and safety of niraparib plus abiraterone acetate administered in a fixed-dose combination tablet.
Applicable Section(s) 
Description of Change(s)
Rationale: In parallel to Study 64091742PCR3001, the pivotal clinical study supporting registration of niraparib
in combination with AA-P for the treatment of men with mCRPC (with and without DRD), the Sponsor is pursuing
development of a fixed-dose combination (FDC) tablet formulation of niraparib and AA with the aim of simplifying
the combination regimen by reducing the pill burden. Based on the recommended dose of AA and the recommended
Phase 2 dose for niraparib under Study 64091742PCR1001, the combination of these 2 individual products would
require patients to be treated with up to 6 pills per day with the further addition of 1 to 2 tablets of prednisone or
prednisolone. The FDC tablet presentation would reduce the number of pills to 2 tablets per day instead of 6.
Reducing the pill burden for patients on oral medications for cancer may improve compliance as cancer patients
often take multiple oral medications for cancer and for other comorbid conditions. Due to the genotoxicity of
niraparib, this relative BA of FDC will be evaluated in mCRPC patients, regardless of DRD status and prior line of
therapy, but not in healthy volunteers. The objective is to evaluate the relative bioavailability (BA) of the FDC
tablets (Combination 3) in comparison to the single agent combination after single-dose administration. The results
will facilitate the decision for which formulation is selected for other clinical trials as appropriate.
Synopsis; 
Throughout the 
protocol; References 
Attachment 6 
Language referring to Combination 3 has been added in the appropriate sections of the
protocol.
Givens 2017 added to References
Attachment 6 has been added, which outlines the rationale, design, and procedures
associated with Combination 3
Rationale: Study design: A single dose of FDC will be given to subjects to generate PK parameters, ie, Cmax  and
AUC0-168h over 7 days for the assessment of relative bioavailability compared to single agent combination. Subjects
will then enter an extension phase of combined single-agent niraparib+abiraterone acetate tablets (plus
prednisone/prednisolone) so they can continue to receive potential therapeutic benefit.
Synopsis; 
Throughout the 
protocol
Attachment 6 
Language referring to Combination 3 has been added in the appropriate sections of the
protocol.
Attachment 6 has been added, which outlines the rationale, design, and procedures
associated with Combination 3
Rationale: To allow positive DRD or CDK12 testing results from certified laboratories with sponsor review to
confirm eligibility as acceptable for screening. This review of local results from certified laboratories will allow
subjects with known DRD and CDK12 pathogenic alterations to begin screening procedures.
4.1. Prescreening 
Eligibility Criteria; 
4.2.1. Combination 1: 
Niraparib and
Cetrelimab;
9.1.2. Prescreening
Phase for Biomarker
Evaluation
9.5. Biomarkers
Language has been added to indicate that DRD or CDK12 results from CLIA-certified
or equivalent laboratories may be used to determine biomarker eligibility provided this
is confirmed by sponsor’s review.

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Applicable Section(s) 
Description of Change(s)
Rationale: To clarify that subjects with any CDK12 pathogenic alterations are eligible for Cohort 1. The
sponsor’s current blood and tissue assay is unable to distinguish between monoallelic and biallelic CDK12
alterations.
Synopsis Hypotheses 
Part 2 and Overview 
of Study Design;
Following Sections
for Combination 1:
Niraparib and
Cetrelimab: 1.1.1.,
2.2.1., 3.1., 3.1.1.,
4.1., 4.2.1., 9.1.2.1.,
9.5, Table 9, 9.5.3.,
16.1.1.
4.1. Prescreening 
Eligibility Criteria; 
9.5. Biomarkers;
Where CDK12 has been mentioned, it has been clarified that this refers to CDK12
pathogenic alterations.
Added that CDK12 status will be assessed by tissue assay until blood assay becomes
available.
Rationale: For subject convenience and flexibility.
Time and Events 
Schedule 1: Study
Procedures and
Assessments for
Combination 1
(Niraparib and
Cetrelimab);
Table 11
Attachment 5-
Modified Schedule of
Events Under
Amendment 4
Central or local laboratories may be used for safety laboratory assessments
Rationale: To continue to provide drug for study participants who are benefitting from treatment.
3.1. Overview of 
Study Design; 
10.2. Discontinuation 
of Study Treatment
Language has been added indicating the Sponsor will continue to provide study drug for
subjects who are benefitting from treatment at the time of early study completion or
study termination by the Sponsor.
Rationale: Standard Janssen language for exclusion criteria related to malignancy has changed.
4.3. Exclusion 
Criteria
Exclusion criterion 3. has been updated with current protocol template language.

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Amendment 4 (18 December 2019)
The overall reasons for the amendment: The overall reason for the amendment is to close enrollment in
Combination 2 because the objective of evaluating the antitumor effect of the RP2D of niraparib and AA-P for the
treatment of mCRPC (metastatic castration-resistant prostate cancer) has been achieved by the totality of internal
and external data available. After an evaluation conducted by the Data Review Committee of the ongoing safety and
efficacy from subjects enrolled to date, the safety profile for niraparib remains consistent with no new safety signals
identified. Efficacy data from QUEST Combination 2, coupled with external data published on other PARP
inhibitors, support that patients harboring BRCA1/2 alterations derive the most clinical benefit relative to other
DRD genes evaluated. Evaluating BRCA and other DRD anti-tumor activity further in Combination 2 of the
QUEST study is no longer warranted.
Combination 1 –The CDK12 gene was added to the accepted biomarker panel for eligibility to enroll into cohort
1A (BM+) of Combination 1 (niraparib + cetrelimab). The basis for this inclusion was data from the olaparib
PROfound study. Metastatic castration-resistant prostate cancer patients who had CDK12 gene alterations treated
with olaparib had a median rPFS of 5.09 months compared to an rPFS of 2.20 months on either abiraterone or
enzalutamide, demonstrating that patients with CDK12 gene alterations achieved greater benefit from a PARP
inhibitor compared to antiandrogen agents. Furthermore, Antonarakis et al. concluded that a proportion of these
patients respond modestly to PD-1 inhibitors, potentially implicating CDK12 deficiency in immunotherapy
responsiveness. Because CDK12 appears to define a distinctly immunogenic class of prostate cancer and also now
that there is randomized clinical trial evidence that PARP inhibition confers an rPFS advantage versus standard of
care hormonal therapy, the combination of these two independent mechanisms of action is expected to confer at
least additive clinical benefit to the proposed eligible patient population.
Applicable Section(s) 
Description of Change(s)
Rationale: All relevant sections of the protocol have been revised to indicate that Combination 2 is closed to
further enrollment. This amendment will allow subjects already enrolled into Combination 2 to continue study
medication while reducing study procedures and limiting data collection.
Synopsis 
A statement was added describing the closure of enrollment in Combination 2 under
Amendment 4. 
3.1.2. Combination 2: 
Niraparib and AA-P  
The following statement was added: “Study Continuation Under Amendment 4 for
Combination 2. Under Amendment 4, Combination 2 has been closed to
enrollment. Subjects already enrolled in Combination 2 can continue to receive
study medication by following the procedures outlined in Attachment 5. The
subject is considered to have completed the study after discontinuing treatment for
any reason and having had a follow-up (End-of-treatment) safety assessment or the
subject is lost to follow-up.”
9.1.1. Overview; 12. 
Adverse Event 
Reporting
A statement was added to provide guidance for Combination 2 subjects continuing in the
study under Amendment 4.
Rationale: To provide guidance for currently enrolled subjects in Combination 2 as to the updated Time and Events
schedule.
Synopsis 
The following statement was added: “Under Amendment 4, enrollment into
Combination 2 is closed. Only subjects who have signed the informed consent form
prior to the approval date of Amendment 4 will be allowed to complete screening
and be enrolled if all prescreening inclusion/exclusion criteria for Combination 2 are
met. Subjects already enrolled in Combination 2 can continue to receive study
medication until documented disease progression or the subject discontinues the
study treatment for any reason as described in Attachment 5. Under Attachment 5,
study-related assessments will be per local practice, at the investigator’s discretion,
and limited data will be collected. Study procedures for Combination 2 subjects to
be followed under Amendment 4 are outlined in Attachment 5. For all subjects in
Combination 2, once Amendment 4 is approved, Attachment 5, which overrules the
protocol body text, should be followed.”

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Time and Events 
Schedule 3 
The following statement was added to the Time and Events Schedule 3: “(To be
replaced by the Modified Schedule of Events provided in Attachment 5 once
Amendment 4 is approved)”.
Attachment 5 
The Modified Schedule of Events in Attachment 5 was added and supersedes Time and
Events Schedule 3 for subjects continuing the study in Combination 2.
Rationale: To amend the description of the statistical analysis for Combination 2 under Amendment 4.
Synopsis Statistical 
Methods 
The following statement describing the statistical analysis for Combination 2 was added:
“With Combination 2 closed under Amendment 4 prior to reaching the originally
proposed sample size, only exploratory statistical analyses will be performed on data
collected from subjects enrolled in this combination. Details will be provided in the
statistical analysis plan (SAP).”
11.3.2. Combination 2: 
Niraparib and AA-P  
The following statement describing the statistical analysis for Combination 2 was added:
“Exploratory analyses only will be performed on efficacy data collected from
subjects enrolled in this combination, pending data availability. Details will be
provided in the statistical analysis plan (SAP).”
Rationale: Per ICH and GCP guidelines, the subject is to sign an updated informed consent form when trial
procedures are modified.
Time and Event 
Schedule 1 
The informed consent row was updated to include the Prescreening informed
consent.
Footnote “c” was modified to include the term Prescreening.
4.1. Prescreening 
Eligibility Criteria 
Included a new requirement for subject to sign the prescreening informed consent
indicating the subject understands the purpose of the study and procedures required to
participate in the study.
9.1.2. Prescreening 
Phase for Biomarker
Evaluation
Clarified the consent requirements for biomarker analysis.
16.2.3. Informed 
Consent 
A statement was added to clarify the purpose of the prescreening informed consent
and the screening informed consent.
A statement was added regarding requirement for enrolled subjects to sign an updated
informed consent form in order to continue in the study under Amendment 4.
Rationale: Solid organ transplant rejection and acute graft-versus-host disease have been reported in subjects
treated with PD-1 inhibitors.
4.3.1. Combination 1: 
Niraparib and 
Cetrelimab
Criterion #9 was added to exclude subjects with a history of organ transplant, including
allogeneic stem cell transplantation.
Rationale: Based on recent data that show patients with mCRPC and CDK12 gene alterations benefit from
treatment with a PARP inhibitor and possibly with treatment with immunotherapy, patients will biallelic loss of
CDK12 will now be permitted to be enrolled into cohort 1A (BM+) of combination 1 (niraparib + cetrelimab). This
data strongly suggests that CDK12 appears to define a distinctly immunogenic class of prostate cancer and with the
addition of the randomized clinical trial evidence that PARP inhibition confers an rPFS advantage versus standard
of care hormonal therapy, the combination of these two independent mechanisms of action is expected to confer at
least additive clinical benefit to the proposed eligible population.
Synopsis 
Biomarker evaluations were updated to include CDK12.

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For Combination 1, the following statement was amended as follows: All subjects will
be assigned to a cohort based on their biomarker status for DRD (ie, Cohort 1A=BM+
or Cohort 1B=BM-) or BM+ for CDK12, which will be determined during the
prescreening phase using a blood or tissue assay.
Synopsis Hypothesis;
2.2.1. Combination 1:
Niraparib and Cetrelimab
For Combination 1, the following statement was amended as follows:
 “That cetrelimab JNJ 63723283 inhibition of PD-1 complements the antitumor
activity of the PARP inhibitor, niraparib, for effective and safe treatment of
subjects with metastatic castration-resistant prostate cancer (mCRPC) and
DNA-repair gene defects (DRD) or CDK12 gene loss.
 The combination of niraparib and cetrelimab JNJ 63723283 is safe and has
antitumor activity in subjects with mCRPC who do not have DRD or CDK12
gene loss.
Synopsis Overview of
Study Design; 1.1.1.
Combination 1: Niraparib
and Cetrelimab
Statement added to describe the rationale for including the CDK12 biomarker. 
Time and Events 
Schedule 1
Footnote “a” was amended to include the CDK12 biomarker.
1.1.1. Combination 1: 
Niraparib and Cetrelimab 
The following statement was amended: “The combination of the PARP inhibitor,
niraparib, and the PD-1 inhibitor, cetrelimab, has the potential to benefit patients with
mCRPC who may or may not have DRD or CDK12 gene loss.”
The following statement was deleted: “Taken together, these data suggest that the
combination of a PARP inhibitor and a checkpoint inhibitor may be a potential
treatment for patients with mCRPC, including those with DRD (ie BM+) to potentiate
the response to the PARP inhibitor, as well as those without DRD (ie, BM ), by
creating an environment that improves tumor responsiveness to treatment.”
3.1. Overview of Study 
Design  
The following statement was amended: “This is a Phase 1b-2, multicenter, open-label
study to select the RP2D of niraparib in combination with other anticancer agents,
followed by dose expansion that will enroll adult subjects with mCRPC who are either
BM+ or BM- for DRD or BM+ for CDK12 (see Section 9.5, for description of
biomarker-positivity criteria).”
3.1.1. Combination 1: 
Niraparib and Cetrelimab 
The following statement was amended: “This combination study will enroll adult
subjects with mCRPC who are either BM+ (Cohort 1A) or BM- (Cohort 1B) for DRD
or BM+ for CDK12 based on the sponsor’s blood or tissue assay.”
3.1.1. Combination 1: 
Niraparib and 
Cetrelimab; 3.3. 
Biomarker Rationale;
3.3.1. Combination 1:
Niraparib and
Cetrelimab; 16.1.1.
Combination 1: Niraparib
and Cetrelimab
Text updated with CDK12 biomarker were appropriate. DRD and CDK12 biomarker
status will be evaluated at the prescreening visit. Eligible subjects are to be BM+
(Cohort 1A) or BM- (Cohort 1B) for DRD or BM+ for CDK12.
3.3. Biomarker Rationale 
The following statement was amended: “Subjects who are BM+ or BM- for DRD or
BM+ for CDK12 may demonstrate different responses to treatment with niraparib
combination therapy.”
4.1. Prescreening 
Eligibility Criteria 
Prescreening eligibility criterion #2 was modified to include the analysis of CDK12 for
blood and tissue samples. The sponsor can review data to determine the CDK12 status
procured from a subject’s sample that was previously analyzed by the sponsor’s assays. 

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4.2.1. Combination 1: 
Niraparib and Cetrelimab 
Inclusion criterion #1 was modified as follows: “Must have determination of biomarker
status positive for DRD or CDK12 (biallelic) (either BM+ or BM ) by the sponsor’s
blood or tissue assay. For Part 1 of the study, subjects can be dosed prior to assay
results becoming available. Results are required prior to dosing for Part 2.”
9.1.2.1. Combination 1: 
Niraparib and Cetrelimab 
The following statement was amended as follows: “For Combination 1, subjects will be
assigned to a cohort based on their biomarker status (ie, BM+ or BM ) (DRD and
CDK12 [biallelic]). Once approximately 30 subjects have been enrolled in a cohort, that
cohort will close and no additional subjects will be added. 
9.5. Biomarkers 
Text has been updated to include the biomarker CDK12.
A row has been added to the bottom of Table 8 to include CDK12 (Cyclin Dependent
Kinase 12).
The title of Table 9 has been amended to include CDK12. The content of Table 9 has
been updated to show subjects who have other gene biallelic loss are eligible for
Cohort 1A of Combination 1. Table 9 also shows subjects who have BRCA
monoallelic pathogenic loss, other monoallelic pathogenic loss, or are negative for
DRD are not eligible for Combination 1.
Rationale: To provide updated futility analysis results to investigators participating in this study.
3.1.1. Combination 1: 
Niraparib and
Cetrelimab; 11.2.1.
Combination 1:
Niraparib and
Cetrelimab
Text amended to show futility analysis has been completed.
Synopsis; 11.10. 
Futility Analysis
The results of the futility analysis were added.
Rationale: To amend the guidance for the reporting of anticipated events.
Attachment 3 
Updated standard text for the reporting of anticipated events replaced the former
instructions for the reporting of anticipated events.
Rationale: Minor changes, corrections, and errors were addressed throughout the protocol.
All sections 
JNJ-63723283 was changed to cetrelimab.
Title page 
The study title was edited to include “QUEST”.
Synopsis 
The following statement amended: “The second combination to be studied will be is
niraparib in combination with ZYTIGA® (abiraterone acetate) and prednisone (referred to
as AA-P) (Combination 2).”
The following statement was amended in 2 locations in the Synopsis: “Part 1 will not was
not conducted for Combination 2, as the RP2D for niraparib plus AA-P was established in
the sponsor study 64091742PCR1001.”
The following statement was amended in the Synopsis for consistency: “Part 1 will not be
conducted for Combination 2, as the The RP2D for niraparib plus AA-P was established
in the sponsor Study 64091742PCR1001 (see Section 1.3.2). Therefore, Part 1 (dose-
finding) will not was not conducted in this study for Combination 2.”
Abbreviations 
Abbreviations list updated to reflect updated content of the protocol.
3.1.2. Combination 2: 
Niraparib and AA-P  
The following statement was amended in Section 3.1.2, for consistency: “The RP2D for
niraparib plus AA-P was established in the sponsor Study 64091742PCR1001 (see
Section 1.3.2). Therefore, Part 1 was not conducted in this study for Combination 2.”

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3.4. Safety Evaluation 
Criteria for Part 1; 3.5.
Safety Evaluation Team
(Combinations with Part
1)
“An” SET was replaced with “A” SET.
9.7. Safety Evaluations 
(Table 10 and Table 11) 
Footnote “a” was amended to show that fasting glucose in Combination 2 is required at
screening and during the treatment phase of the study.
References 
Two new references were cited within the body of the protocol and added to the list of
references (reference #3: Antonarakis E, Isaacsson-Velho P, Agarwal N, Et al and
reference #8 deBono J, Fizazi K, Saad F, et al).
Amendment 3 (28 November 2018)
The overall reason for the amendment: The overall reason for the amendment is to investigate the use of a
second niraparib combination therapy for the treatment of subjects with mCRPC and DNA-repair gene defects.
The second combination therapy (Combination 2) consists of niraparib in combination with abiraterone acetate
and prednisone (referred to as AA-P). 
Applicable Section(s) 
Description of Change(s)
Rationale: The protocol was modified in order to investigate the safe and effective use of Combination 2
(niraparib and AA-P) for the treatment of subjects with mCRPC and DNA-repair gene defects.
Synopsis 
Information on Combination 2 was added to the synopsis, including a
summary of the endpoints, hypothesis, study design, and statistical
methodology. Information specific for Combination 1 was identified.
Time and Events Table 1; Time and 
Events Table 3 
Time and Events Table 3 outlining study procedures for Combination 2
was added. Clarified that Time and Events Table 1 is specific for
Combination 1.
1. Introduction 
Updated to include information on anticancer combination agent AA-P.
1.1. Background and Design 
Rationale
The recommended Phase 2 dose for Combination 2 was added.
1.1.2. Combination 2: Niraparib and 
AA-P 
The rationale for combining niraparib and AA-P for the treatment of
patients with metastatic prostate cancer was added in a new section.
1.3.2. Combination 2: Niraparib and 
AA-P 
A summary of the available clinical information for AA-P was added in a
new section.
1.4. Benefit/Risk Assessment; 1.4.1 
Combination 1: Niraparib and 
JNJ-63723283; 1.4.2. Combination 
2: Niraparib and AA-P
New section for benefit/risk assessment for both Combination 1 and
Combination 2 was added. (Benefit/risk assessment for Combination 1
was previously in separate benefit/risk assessment document.)
2.1. Objectives and Endpoints; 
11.3.2. Combination 2: Niraparib 
and AA-P
Endpoints for Combination 2 were added. Text was clarified to indicate
information specific for Combination 1.
2.2.2. Combination 2: Niraparib and 
AA-P
Hypothesis for Combination 2 was added in a new section.
3.1. Overview of Study Design  
Section edited to be applicable for both Combination 1 and Combination
2. 

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Applicable Section(s) 
Description of Change(s)
3.1.2. Combination 2: Niraparib and 
AA-P; Figure 2 
Overview of study design and schematic for Combination 2 was added in
a new section.
3.2.2. Combination 2: Niraparib and 
AA-P
Dose selection rationale for Combination 2 was added in a new section.
3.3. Biomarker Rationale 
Indicated that exploratory biomarkers collection will occur only for
Combination 1. Added a cross reference to Section 9.5, to provide further
information on cohort eligibility based on DRD status.
3.3.2 Combination 2: Niraparib and 
AA-P
Biomarker rationale for Combination 2 was added in a new section.
3.5. Safety Evaluation Team 
(Combinations with Part 1) 
Clarified that the Safety Evaluation Team is only used for Part 1 of the
study.
4.1. Prescreening Eligibility Criteria 
Section edited so that criteria is applicable for both Combination 1 and
Combination 2. As a result, Criterion 3 (specific for Combination 1) was
relocated to Section 4.1.1.
4.1.1. Combination 1: Niraparib and 
JNJ-63723283 
Inclusion criterion specific for Combination 1 was relocated from 4.1 to
this new section.
4.1.2. Combination 2: Niraparib and 
AA-P 
A prescreening criterion specific for Combination 2 was added in a new
section.
4.2. Inclusion Criteria 
Section edited so that criteria is applicable for both Combination 1 and
Combination 2. As a result, criteria specific for Combination 1 (Criterion
4, 5, and 6) were relocated to Section 4.2.1.
4.2.1. Combination 1: Niraparib and 
JNJ-63723283 
Inclusion criteria specific for Combination 1 were relocated from 4.2 to
this new section.
4.2.2. Combination 2: Niraparib and 
AA-P 
Inclusion criteria specific for Combination 2 were added in a new
section.
4.3.2. Combination 2: Niraparib and 
AA-P 
Exclusion criteria specific for Combination 2 were added in a new
section.
6.1.2. Combination 2: Niraparib and 
AA-P 
Instructions for the administration of AA-P were added were added in a
new section.
6.2.1.1. Combination 1: Dose 
Modifications for Niraparib 
Dose modification instructions applicable only to Combination 1 were
identified.
6.2.2. Combination 2: Niraparib and 
AA-P  
Dose modification instructions for AA-P were added in a new section,
including information on management of non-hematologic toxicities,
hepatic toxicities, and hypokalemia as well as information on treatment
interruptions for procedures.
7.2. Combination 2: Niraparib and 
AA-P
Treatment compliance procedures for AA-P were added in a new section.
8. Prior and Concomitant Therapy; 
9.5.5. Non-steroidal Anti- 
inflammatory Drugs and Antibiotics 
Indicated that collection of NSAID and antibiotic use is for Combination
1 only. Also, the timing for the collection of this information was
clarified.
8.1 Prohibited Concomitant 
Therapies; 8.1.1. Combination 1: 
Niraparib and JNJ-63723283; 8.1.2. 
Combination 2: Niraparib and AA-P 
Section 8.1, was edited to include only medications prohibited for both
Combination 1 and Combination 2. Live virus vaccine was relocated
from 8.1.1 to 8.1 as it is prohibited in both combinations. Medications
prohibited in Combination 2 were added in new Section 8.1.2. 

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Applicable Section(s) 
Description of Change(s)
8.2.2. Combination 2: Niraparib and 
AA-P 
Restricted concomitant medications specific for Combination 2 were
added in a new section.
9.1.1. Overview; 9.3 
Pharmacokinetics and 
Immunogenicity; 9.4.
Pharmacokinetic /Pharmacodynamic
Evaluations; 11.1 Analysis
Populations; 11.4 Pharmacokinetic
and Immunogenicity Analyses; 11.6
Pharmacokinetic /Pharmacodynamic
Analyses
Indicated that pharmacokinetics and immunogenicity will be assessed for
Combination 1 only.
9.1.2. Prescreening Phase for 
Biomarker Evaluation; 9.1.2.1: 
Combination 1: Niraparib and 
JNJ-63723283; 9.1.2.2. Combination 
2: Niraparib and AA-P
Section 9.1.2. was edited to be applicable for both Combination 1 and
Combination 2, and repetitive text was removed. Text specific for
Combination 1 was relocated to new Section 9.1.2.1. Information for
Combination 2 was added to new Section 9.1.2.2. 
3.1. Overview of Study Design; 8. 
Prior and Concomitant Therapy; 
9.1.5. End-of-Treatment Visit; 11.8. 
Safety Analyses; 12.3.1. All Adverse 
Events; 12.3.2 Serious Adverse
Events; 12.3.4. Disease Progression
and Death
Text was edited to indicate that AEs, SAEs, and concomitant medications
should be collected until 30 days after the last dose of study drugs, unless
the subject received subsequent therapy for Combination 2. Indicated that
this information is collected for 100 days for Combination 1.
9.2.1. Evaluations 
Indicated that evaluation of treatment response will be assessed by
immune-related RECIST criteria for Combination 1 only.
9.5. Biomarkers; 9.5.1 Tumor 
Samples 
Text was edited to be applicable for both Combination 1 and
Combination 2. Also, indicated text only applicable to each combination.
9.5.3. Circulating Tumor DNA  
Indicated that section is only applicable for Combination 1.
9.7. Safety Evaluations 
Text was edited to be applicable for both Combination 1 and
Combination 2. For subsection Clinical Safety Laboratory Tests, the
laboratory tests that are specific for each combination were identified.
11.2.2. Combination 2: Niraparib 
and AA-P 
Sample size determination for Combination 2 was added in a new
section.
11.3 Antitumor Activity Analyses; 
11.3.1. Combination 1: Niraparib 
and JNJ-63723283; 11.3.2.
Combination 2: Niraparib and AA-P
Moved information specific for Combination 1 to new section 11.3.1.
Added information for Combination 2 in new section 11.3.2.
11.10. Futility Analysis 
Indicated that futility analysis will be performed only for Combination 1
only.
14.1.2. Combination 2: Niraparib 
and AA-P 
Physical description of AA tablets and prednisone tablets was added in a
new section.
14.2.2. Combination 2: Niraparib 
and AA-P 
Description of packaging for AA tablets and prednisone tablets was
added in a new section.
14.4. Preparation, Handling, and 
Storage; 14.4.1. Niraparib, 14.4.2. 
JNJ-63723283, and 14.4.3. AA 
Section reorganized to include 3 subsections, one for each medication
(Niraparib, JNJ-63723283, and Abiraterone Acetate). Information for AA
was added to new section 14.4.3, including information on drug exposure
in women who are pregnant or may potentially be pregnant.

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Applicable Section(s) 
Description of Change(s)
16.1.2. Combination 2: Niraparib 
and AA-P 
Study specific design considerations for Combination 2 were added in a
new section.
17.9.1. Study Completion/End of 
Study  
A cross references to Section 3.1, was added to provide further
information on the data reporting for each individual combination.
Attachment 4: Additional 
Information on CYP450 Drug 
Interactions 
Websites with information on CYP450 drug metabolism were added to
provide information on medications with the potential for drug-drug
interactions with Combination 2.
Rationale: For Combination 1, information on entry criteria and study procedures was reworded for clarity,
edited to align with current practices, or updated to add more flexibility.
Time and Events Schedule 1 
The header was edited and a footnote was added to indicate that subjects
should enter the Screening Phase within 6 weeks of receiving a final
DRD result. For the prescreening SAEs and deaths row, clarification was
added that this information should only be collected if related to study
procedures. For the inclusion/exclusion row, an ‘X’ was added in the
Prescreening row which was inadvertently omitted in previous versions.
The physical exam on Day 15 of Cycle 1 and Cycle 2 and vital signs on
Day 15 of Cycle 1 have been removed as these assessments are no longer
required after additional experience with the study drugs. For the clinical
safety laboratory tests row, testing by central laboratory was added as an
option for these tests. For the survival status row, the text describing the
collection period was edited for clarity. For the AE/SAEs and
concomitant medications row, a cross reference was added to the
protocol section with complete information on this topic.
Time and Events Schedule 1; 9.5.1. 
Tumor Samples 
Updated to allow collecting of archival tumor sample during Cycle 1, if
not collected at screening.
Time and Events Schedule 1; 9.1.5. 
End-of-Treatment Visit; Section 
11.8. Safety Analyses
The term ‘anti-prostate cancer therapy’ was replaced with ‘subsequent
therapy’.
Time and Events Schedule 2 
PK and immunogenicity assessments should be taken at the designated
timepoints on Day 1 of Cycle 3 to 4. ‘Day 1’ was added to the table, as
this information was inadvertently not included in the previous versions.
2.1. Objective and Endpoints 
The definition of CTC response was updated to align with the definition
used in Combination 2.
4.1 Prescreening Eligibility Criteria 
Criterion 4 was deleted, and this information was moved to Section 9.1.2.
4.1.1. Combination 1: Niraparib and 
JNJ-63723283 
For Criterion 1, reworded text (changed eg to ie) to exclude prior
treatment with experimental novel AR-targeted therapies that may not
have a proven benefit for the treatment of mCRPC.
4.2. Inclusion Criteria 
For Criterion 11, the 4-week wash-out requirement for AA-P was
removed; however, the wash-out is still needed for other anti-androgens. 
4.2.1. Combination 1: Niraparib and 
JNJ-63723283 
For Criterion 4, reworded text (changed eg to ie) to exclude prior
treatment with experimental novel AR-targeted therapies that may not
have a proven benefit for the treatment of mCRPC.
4.3. Exclusion Criteria 
A definition for uncontrolled hypertension was added to Criterion 12. 
6.1.1. Combination 1: Niraparib and 
JNJ-63723283 
The infusion instructions for JNJ-63723283 were updated to align with
the latest version of the investigational product preparation instructions.

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Applicable Section(s) 
Description of Change(s)
6.2. Dose Modification and 
Management of Toxicity  
Instruction that cycle days are fixed based upon Cycle 1 Day 1 regardless
of dose interruptions or delays was added.
6.2.1.1.1. Non-hematological 
Toxicities; 6.2.1.1.2. Hematologic 
Toxicity  
Section 6.2.1.1.1, was reworded for readability and also to clarify that
niraparib is only available in 100 mg capsules, so only one dose
reduction is possible. This information was also clarified in Table 4 in
Section 6.2.1.1.2.
9.1.3. Screening Phase 
Text was updated to allow the screening physical exam and screening
PSA laboratory evaluation to be used for the Cycle 1 Day 1 assessments,
if performed within 14 days of Cycle 1 Day 1.
9.5 Biomarkers 
Table 8 was modified so that only the genes that qualify a subject as
biomarker positive are displayed. The genes that do not result in the
qualification of a subject as biomarker positive were deleted from this
table. Added that HDAC2 is only detected by the blood-based assay.
9.5.1 Tumor Samples 
Text was reorganized and edited to align with current study procedures.
9.5.2. Circulating Tumor Cells 
Information on whole blood sample processing was removed as not
applicable to this section. 
9.7. Safety Evaluations 
Clarified that HIV and CD4 count only need to be performed if indicated
by a subject’s prior medical history. As blasts are no longer clinically
relevant, they were removed from the complete blood count differential. 
10.2. Discontinuation of Study 
Treatment 
Instruction was added that palliative radiation for bone pain may not be
considered unequivocal clinical progression and requires medical
monitor discussion. Clarification was added that data for survival and
subsequent therapies needs to be collected after discontinuation of
treatment.
11.3.1. Combination 1: Niraparib 
and JNJ-63723283 
Clarified that the secondary endpoint is CTC response rate rather than
CTC response.
11.8. Safety Analyses; 12.1.3. 
Severity Criteria; 15 Study Specific 
Materials
Text updated to reflect that toxicities can be graded by NCI-CTCAE
version 4.03 or also by a later NCI-CTCAE version.
12.3.4. Disease Progression and 
Death  
Instruction that disease progression, even if it results in death during the
AE reporting period, should not be reported as an adverse event was
expanded. 
14.4.1. Niraparib 
Added that niraparib capsules should be handled with gloves.
Rationale: A subject’s biomarker status may be determined by a blood or tissue assay (when the tissue assay is
available for study use) for both Combination 1 and Combination 2.
Synopsis; 3.1.1. Combination 1: 
Niraparib and JNJ-63723283; 5. 
Treatment Allocation and Blinding;
4.2.1. Combination 1: Niraparib and
JNJ-63723283; 9.1.2. Prescreening
Phase for Biomarker Evaluation
Updated text to state that biomarker status for DRD can be also be
determined by a tissue assay.
Time and Events Schedule 1 
Updated the Biomarker panel for eligibility footnote to add a cross
reference to Section 9.5, where more detail on biomarkers is provided.
Updated archival tumor sample footnote to clarify that the archival tumor
sample can be collected during Cycle 1 only if unable to collect during
screening.

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Applicable Section(s) 
Description of Change(s)
4.1 Prescreening Eligibility Criteria 
Criterion 2 was updated to reflect that biomarker status can be
determined by a blood or tissue assay. A previous sample analyzed by a
Sponsor assay can also be used to determine biomarker status.
4.2.1. Combination 1: Niraparib and 
JNJ-63723283 
Criterion 1 was updated to reflect that biomarker status can be
determined by a blood or tissue assay.
9.5. Biomarkers 
Section updated to indicate that biomarker status can also be determined
by tissue for Combination 1. Table 9 added to provide cohort eligibility
in Combination 1 and Combination 2 based upon DRD status.
Rationale: The term DNA-repair anomalies has been updated to DNA-repair gene defects (DRD) to align with
terminology currently used in the niraparib clinical development program.
Throughout the document 
The term DNA-repair anomalies was replaced with DRD.
Rationale: Minor changes, corrections, and errors were addressed throughout the protocol
1. Introduction 
Updated to include correct EMA approval date for niraparib.
1.1. Background and Design 
Rationale 
Sentence on the strategy for the analyses and future study of potential
combination therapies has been updated. Redundant sentence on the
addition of future combinations was deleted. Doses administered in
Phase 2 Study 64091742PCR2001 were corrected.
3.3.1. Combination 1: Niraparib and 
JNJ-63723283 
New published data on mutational burden and anti-PD-L1 response of
mCRPC tumors was added.
16.1.1. Combination 1: Niraparib 
and JNJ-63723283 
Removed information already presented in Section 1.4.1, and provided a
cross-link to this information instead. 
References 
Citations for new publications referenced in the protocol as a result of
Amendment 3 were added.
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made.

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Amendment 2 (22 May 2018)
The overall reason for the amendment: The overall reason for the amendment is to identify that the
JNJ-63723283 dose of 480 mg once every 4 weeks is the recommended Phase 2 dose (RP2D) and to remove the
JNJ-63723283 240 mg once every 2 week dose regimen from Part 1 of the study. In addition, the amendment
addresses feedback from investigators regarding inclusion and exclusion criteria that allows additional treatment
options prior to study entry. No impact on subject safety is anticipated.
Applicable Section(s) 
Description of Change(s)
Rationale: The JNJ-63723283 480 mg once every 4 weeks dose has been selected as a recommended Phase 2
dose for the single agent JNJ-63723283 study (Study 63723283LUC1001). Safety and pharmacokinetic (PK)
equivalency between the 240 mg once every 2 weeks and 480 mg once every 4 weeks doses has been established.
The extended dosing interval provides increased patient convenience with no anticipated effect on safety.
Synopsis: Overview of study 
design; 
Time and Events Schedule 1; 
Time and Events Schedule 2;
3.1.1. Combination-1:
Niraparib and
JNJ-63723283;
Figure 1: Schematic for
Combination 1;
3.2.1. Combination-1:
Niraparib and
JNJ-63723283;
6.1.1. Combination-1:
Niraparib and
JNJ-63723283: Table 4
Study Treatments
Text related to observations, assessments, and administration of the
JNJ-63723283 RP2D dose 240 mg once every 2 weeks removed throughout the
protocol.
3.2.1. Combination-1: 
Niraparib and JNJ-63723283 
Text clarified that the JNJ-63723283 480 mg once every 4 weeks dosing
schedule was selected as it is an RP2D in the JNJ-63723283 single agent study
(Study 63723283LUC1001) and is preferable to the 240 mg once every 2 weeks
dosing for subject convenience.
Rationale: To address feedback from principal investigators and to allow additional standard-of-care options
prior to study entry.
4.3. Exclusion Criteria 
Criterion 9 for prohibition against prior radium treatment or treatment with other
therapeutic radiopharmaceutical for prostate cancer was removed.
4.3.1. Combination-1: 
Niraparib and JNJ-63723283 
Criterion 1 for prohibition against prior treatment with sipuleucel-T was
removed.
Criterion 2 was updated to remove the prohibition against prior therapy with anti-
CTLA4.
Rationale: To address the transition of subjects enrolled into the JNJ-63723283 240 mg every 2 week regimen to
the JNJ-63723283 480mg every 4 weeks regimen.
3.1.1. Combination-1: 
Niraparib and JNJ-63723283 
Text added to indicate that subjects enrolled into the JNJ-63723283 240 mg
every 2 week regimen under a prior version of the protocol should be transitioned
to JNJ-63723283 480mg every 4 weeks once the protocol amendment and
revised informed consent form are approved at the site, as required by local
regulations.

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Applicable Section(s) 
Description of Change(s)
Rationale: To provide for subject convenience as biomarker status does not determine cohort in Part 1 of the
study.
4.2. Inclusion Criteria; 
9.1.2. Prescreen Phase for 
Biomarker Evaluation  
Criterion 4 and subsequent text revised to indicate that subjects can be dosed
prior to biomarker assay results becoming available in Part 1. Results are
required prior to dosing for Part 2.
5. Treatment Allocation and 
Blinding 
Direction provided to medical monitor or designee to review biomarker results in
Part 2 in assigning subjects to the appropriate cohort.
9.1.3. Screening Phase 
Text specifying subject assignment to cohort based on biomarker status at
screening removed.
Rationale: To clarify that blood should not be drawn if there are no circulating tumor cells (CTCs) at screening
in order to prevent unnecessary blood draws for this exploratory outcome.
Time and Events Schedule 1: 
Circulating Tumor Cells 
Footnote “j” added to clarify that collection of subsequent CTC samples are
required only if CTC ≥1 at screening.
Rationale: To provide flexibility for PK sample collection and for subject convenience.
Time and Events Schedule 2 
For Cycle 1 and Cycles 2-3, the time of sample collection was lengthened from
2.5 to 4 hours to 2.5 to 6 hours.
For Cycle 1 Day 2, the time of sample collection was extended to all day on Day
2 (within 8 hours of the Day 1 end of infusion).
For Cycle 1 Day 4 and Day 8, the time of sample collection was extended to
±1 day of the end of infusion on Day 1.
PK sample collections removed at Cycle 5 Days 2, 4, and 8, Cycle 7 Days 1 and
15, and at Cycles 9-10 Days 1 and 15 and replaced by Day 15 collections
(±2 days of the end of infusion on Day 1) at Cycles 1 and 2.
Rationale: To align with the other protocols in the niraparib program and ensure consistency of management of
niraparib adverse events.
6.2.1.2. Hematologic 
Toxicities 
Dose interruption/modification criteria were modified to align with other
niraparib protocols.
Text regarding supportive care for multiple blood transfusions was revised. Text
regarding weekly CBC counts in the event of an adverse event was removed.
Text regarding instructions for diagnosis of myelodysplastic syndrome/acute
myeloid leukemia was updated.
Table 5 was revised to update the management of Grade 3 or second occurrence
of Grade ≥3 toxicities.
Rationale: Development of JNJ-63723283 study drug in progress.
14.1.1. Combination-1: 
Niraparib and JNJ-63723283 
Text regarding development of lyophilized study drug added to allow for
flexibility to move to another equivalent study drug formulation. New drug
descriptions for JNJ-63723283 frozen liquid in vial and lyophilized product
provided.
14.2.1. Combination-1: 
Niraparib and JNJ-63723283
New packaging descriptions for JNJ-63723283 vials provided.

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Applicable Section(s) 
Description of Change(s)
Rationale: Alignment of text with recent protocol template changes.
Title page 
Text updated that US sites of this study will be conducted under US Food &
Drug Administration IND regulations (21 CFR Part 312)
Time and Event Schedule 1: 
Informed Consent 
New footnote “b” clarified that the informed consent must be signed before first
study-related activity.
9.7. Safety Evaluations 
Replaced “clinically stable endpoint” with “clinically stable condition”.
17.11. Use of Information 
and Publication  
Added the text in bold: ‘key assessment parameters of the study will be used to
determine a coordinating investigator for the study’.
Replaced “within 12 months of the availability of the final data..” with “within
18 months…”
Revised the text beginning ‘Authorship of publications...’
Rationale: Minor changes, corrections, and errors were addressed throughout the protocol.
Time and Events Schedule 1: 
Biomarker panel for 
eligibility
New footnote “c” clarified that Part 1 subjects can be dosed prior to assay results
but biomarker results are required prior to dosing in Part 2.
Time and Events Schedule 1: 
Fresh biopsy  
Footnote “d” clarified that the screening visit biopsy can be performed up to 56
days before Cycle 1 Day 1 provided no active treatment was initiated during the
time.
Time and Events Schedule 1: 
Treatment compliance 
Treatment compliance will no longer be assessed on Day 15 of each cycle;
therefore, the “X” on Day 15 (all cycles) has been removed.
Time and Events Schedule 1: 
Clinical safety laboratory 
tests 
Per footnote” h” clinical safety laboratory tests are to be obtained on Cycle 1 and
Cycle 2 Day 1 and Day 15 and on Day 1 for all subsequent cycles (or more
frequently at investigator discretion). Day 15 assessments at Cycle 3, Cycles
4-12, and Cycles 13 and Beyond removed. 
Time and Events Schedule 2 
PK timepoint scheduled for preinfusion JNJ-63723283 (480 mg every 4 weeks)
on Cycle 5 Day 15 removed. 
Synopsis; 
11.2.1. Combination-1: 
Niraparib and JNJ-63723283
Text revised to indicate at least 6 subjects to be initially enrolled in Part 1.
Reference to cohorts and dose regimen 1 and 2 removed.
1. Introduction 
Text updated to indicate European Commission approval of niraparib on 20
November 2017.
1.1.1. Combination-1: 
Niraparib and 
JNJ-63723283; 
1.3.1. Combination-1:
Niraparib and JNJ-63723283
Text revised to streamline history of Study 63723283LUC1001. Detailed text
regarding the 240 mg once every 2 weeks and 480 mg once every 4 weeks
removed.
2.1. Objectives and 
Endpoints: Table 2 
Objectives and Endpoints for
Part 2
“Baseline” changed to “screening” for consistency with assessment in Time and
Events Schedule 1.
3.1.1. Combination-1: 
Niraparib and 
JNJ-63723283;
3.4. Safety Evaluation
Criteria for Part 1
Text modified to clarify that a SET meeting will occur after at least 6 evaluable
subjects have completed the safety assessment period.

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Applicable Section(s) 
Description of Change(s)
Synopsis: Overview of study 
design; 
3.1.1. Combination-1: 
Niraparib and JNJ-63723283
Text corrected to read “The sponsor may choose to enroll subjects to additional
dose regimens (ie, at least 6 additional evaluable subjects) with
JNJ-63723283….”.
4.2. Inclusion Criteria  
Criterion 1 text clarified to 18 years of age or older.
Criterion 13g modified to include aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) ≤3 x ULN. Text indicting “or” removed.
8.1.1. Combination-1: 
Niraparib and JNJ-63723283 
Ipilimumab (CTLA-4) is considered an investigational agent and is covered in
Section 8.1, (Prohibited Concomitant Therapies). Text regarding specific
immunotherapy and ipilimumab in Section 8.1.1. removed.
9.2.2. Criteria 
Bone disease progression criteria was updated to better align with PCWG3
criteria.
11.1. Analysis Population  
Text clarified that the ITT and PK analysis populations included subjects who
had received at least 1 dose of both study drugs.
11.9. Data Review 
Committees 
Text added to specify that the Data Review Committee (DRC) charter will be
provided to the members of the DRC.
14.2.1. Combination-1: 
Niraparib and JNJ-63723283 
Text modified to indicate study drug to be packaged in kits with appropriate
management throughout the supply chain process. Study drug will not be
dispensed in child-resistant packaging.
Attachment 1 
Title changed to “Guidelines for the management of Immune-related Adverse
Events for JNJ-63723283” to highlight that management can evolve over time
and that sites should also refer to institutional standard-of-care.
References 
Investigator Brochure references streamlined. Subsequent references resequenced
throughout document.
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made.

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Amendment 1 (07 December 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is to address feedback from
FDA received 9 November 2017 and a comment from MHRA received 29 November 2017. Other minor changes
were also made.
Applicable Section(s) 
Description of Change(s)
Rationale: There are limited data regarding the potential for a PARP inhibitor and a checkpoint inhibitor to have
clinical benefit in subjects who are biomarker-negative (BM-). Therefore, a futility analysis for the BM- cohort
(Cohort 1B) in Part 2 was added to allow for the cohort to be stopped if less than 1 subject has a clinical response
after approximately 10 subjects are enrolled.
3.1.1. Combination 1: 
Niraparib and JNJ- 
63723283; 11.2.1.
Combination 1:
Niraparib and JNJ-
63723283
Reference was added to a new section (Section 11.10) for the futility analysis for Cohort
1B
11.10. Futility 
Analysis 
New section added to summarize the futility analysis to be performed for Cohort 1B (ie,
BM- subjects).
Rationale: Weekly monitoring for complete blood counts (CBCs) was added to the first cycle of treatment to
ensure the safety of subjects, given that niraparib has a known hematologic toxicity profile. In addition, subjects
who are reported with Grade ≥3 hematologic toxicities will be required to have their CBCs monitored weekly
until resolution.
Time and Events 
Schedule 1; 9.7
Safety Evaluations
Updated to include weekly CBC testing for the first cycle of treatment.
6.2.1.2. Hematologic 
Toxicity 
Weekly monitoring of CBCs was changed from “recommended” to “required and
recommended for 28 days after restarting dose” for subjects reported with Grade ≥3
hematologic toxicities.
Rationale: The safety evaluation criteria for non-hematologic toxicities in Part 1 was amended to categorize all
Grade ≥3 non-hematologic toxicities as dose-limiting, with a list of exceptions based on the known toxicities for
the disease.
3.4. Safety Evaluation 
Criteria for Part 1 
The safety evaluation criterion for Grade ≥3 non-hematologic toxicities was amended to
include all Grade ≥3 events as dose-limiting, except for the specified exceptions.
Rationale: The sponsor does not intend to explore doses of niraparib beyond 300 mg once daily, which is the
maximum tolerated dose observed with single-agent treatment. Therefore, the sponsor has removed the statement
that alternate doses and dose schedules may be explored.
3.5. Safety Evaluation 
Team  
The statement that the SET may consider exploration of alternate doses and dose
schedules was removed at the request of MHRA.
Rationale: The retreatment criterion for JNJ-63723283 regarding platelet counts was amended to ensure
subjects’ platelet counts returned to ≥50,000 cells/µL without receiving a platelet transfusion.
6.2.2.1. Retreatment 
Criteria for JNJ- 
63723283
Table 6 was amended to clarify that platelet transfusions are not allowed to return
subject’s platelet counts to ≥50,000 cells/µL.

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Applicable Section(s) 
Description of Change(s)
Rationale: The use of bone-strengthening agents is typical in this patient population (ie, mCRPC) and the
sponsor does not prohibit their use. However, the protocol did not previously specify that bone-strengthening
agents were permitted. The protocol has been updated to add language allowing for the use of bone-strengthening
agents at the discretion of the investigator.
8. Prior and 
Concomitant Therapy  
A statement was added that bone-strengthening agents are permitted and the choice of
agent is at the discretion of the investigator.
Rationale: Given that the sponsor’s blood-based assay is developmental and still undergoing validation, the
specific mutations that will be used to determine biomarker-positivity were removed.
9.5. Biomarkers 
Table 8 (and associated text) describing the criteria for biomarker-positivity was updated
to include the genes of interest, but remove the specific mutations that may be used to
assign a subject as biomarker positive.
Rationale: Minor error in Time and Events Schedule 2 was corrected.
Time and Events 
Schedule 2 
The table previously indicated that samples would be collected on Cycle 1 Day 15 for
niraparib testing; however, this will not be done. The collections were removed from the
table.
Other minor amendments were made to the table.
Rationale: Minor errors were noted and corrected
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.

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Approved, Date: 3 August 2021
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
, MD
Institution: 
Janssen Research & Development
Signature: 
[electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD

Signature
User 
Date 
Reason
 
03-Aug-2021 
19:44:01
(GMT)
Document Approval
PPD