Conditions: Prostatic Neoplasms
Keywords: Prostate cancer CRPC Metastatic castrate-resistant prostate cancer Prostate neoplasm Galahad Niraparib DNA anomalies DNA defect PARP inhibitor PARPi
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 289
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy, safety, and pharmacokinetics of niraparib in men with metastatic castration-resistant prostate cancer (mCRPC) and deoxyribonucleic acid (DNA) repair anomalies.

Detailed description:
This is a multicenter and open-label (participants and researchers are aware of the treatment that participants are receiving) study that consists of 4 phases: a Prescreening Phase for biomarker evaluation only, a Screening Phase, a Treatment Phase (Cycle 1 Day 1 and will continue until the study drug is discontinued), a Follow-up Phase (every 3 months after end of treatment visit), and a Long-term Extension Phase (until participants no longer derive benefit from treatment or until further notification on different means of study treatment). Participants will be monitored for safety during the study period, and up to 30 days after the last dose of study drug.

Arms:
arm 1: Participants will receive 300 milligram (mg) niraparib (3 capsules\*100 mg) orally once daily.

Interventions: intervention 1: Niraparib
Intervention descriptions: intervention 1: Participants will receive 300 mg niraparib (3 capsules\*100 mg) orally once daily.

Protocol document:
Prot_002.pdf: 
1
Status: Approved,  Date: 17 July 2020
Janssen Research & Development *
Clinical Protocol
A Phase 2 Efficacy and Safety Study of Niraparib in Men with Metastatic Castration-
Resistant Prostate Cancer and DNA-Repair Anomalies
Protocol 64091742PCR2001: The Galahad Study; Phase 2
AMENDMENT 8
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, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland 
UC; Janssen Biopharma Inc.; 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.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2016-002057-38
Status:
Approved
Date:
17 July 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-123250857, 11.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 4
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 28
TIME AND EVENTS SCHEDULE .............................................................................................................. 32
ABBREVIATIONS ...................................................................................................................................... 35
1.
INTRODUCTION................................................................................................................................ 37
1.1.
Background and Design Rationale ................................................................................................ 37
1.2.
Summary of Available Nonclinical and Clinical Data ..................................................................... 38
1.3.
Benefit/Risk Assessment ............................................................................................................... 39
2.
OBJECTIVES, ENDPOINTS/ASSESSMENTS, AND HYPOTHESIS............................................... 40
2.1.
Objectives and Endpoints/Assessments........................................................................................ 40
2.2.
Hypothesis ..................................................................................................................................... 41
3.
STUDY DESIGN ................................................................................................................................ 41
4.
SUBJECT POPULATION.................................................................................................................. 42
4.1.
Prescreening Eligibility Criteria ...................................................................................................... 42
4.2.
Inclusion Criteria ............................................................................................................................ 43
4.3.
Exclusion Criteria ........................................................................................................................... 45
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 46
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 47
6.1.
Study Drug Administration ............................................................................................................. 47
6.2.
Dose Modification and Management of Toxicity............................................................................ 47
6.2.1.
Non-hematologic Toxicities......................................................................................................... 47
6.2.1.1.
Hepatic Toxicities .................................................................................................................... 48
6.2.2.
Hematologic Toxicities................................................................................................................ 48
6.3.
Treatment Interruptions for Planned Procedures........................................................................... 49
7.
TREATMENT COMPLIANCE............................................................................................................ 50
8.
CONCOMITANT THERAPY.............................................................................................................. 50
8.1.
Prohibited Concomitant Medications ............................................................................................. 50
8.2.
Restricted Concomitant Medications ............................................................................................. 50
9.
STUDY EVALUATIONS .................................................................................................................... 51
9.1.
Study Procedures........................................................................................................................... 51
9.1.1.
Overview..................................................................................................................................... 51
9.1.2.
Prescreening Phase for Biomarker Evaluation........................................................................... 51
9.1.3.
Screening Phase ........................................................................................................................ 51
9.1.4.
Treatment Phase ........................................................................................................................ 52
9.1.5.
End-of-Treatment Visit................................................................................................................ 52
9.1.6.
Follow-up Phase......................................................................................................................... 53
9.1.7.
Long-term Extension Phase ....................................................................................................... 53
9.2.
Efficacy........................................................................................................................................... 53
9.2.1.
Evaluations ................................................................................................................................. 53
9.2.2.
Endpoint Criteria......................................................................................................................... 53
9.3.
Pharmacokinetics........................................................................................................................... 54


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9.3.1.
Sample Collection and Handling ................................................................................................ 54
9.3.2.
Analytical Procedures................................................................................................................. 55
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 55
9.4.
Patient-reported Outcomes............................................................................................................ 55
9.4.1.
BPI-SF ........................................................................................................................................ 55
9.4.2.
FACT-P....................................................................................................................................... 56
9.4.3.
EQ-5D-5L.................................................................................................................................... 56
9.5.
Pharmacodynamics........................................................................................................................ 56
9.6.
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 56
9.7.
Biomarkers ..................................................................................................................................... 56
9.7.1.
Evaluations ................................................................................................................................. 57
9.7.1.1.
Tissue Analysis........................................................................................................................ 57
9.7.1.2.
Circulating Tumor Cells ........................................................................................................... 57
9.7.1.3.
Whole Blood for RNA .............................................................................................................. 57
9.7.1.4.
Circulating Tumor DNA............................................................................................................ 57
9.7.1.5.
Saliva Testing .......................................................................................................................... 57
9.8.
Medical Resource Utilization.......................................................................................................... 57
9.9.
Safety ............................................................................................................................................. 58
9.10.
Sample Collection and Handling.................................................................................................... 60
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 60
10.1.
Discontinuation of Study Treatment............................................................................................... 60
10.2.
Withdrawal from the Study............................................................................................................. 61
10.3.
Withdrawal From the Use of Samples in Future Research............................................................ 61
11.
STATISTICAL METHODS................................................................................................................. 62
11.1.
Analysis Populations...................................................................................................................... 62
11.2.
Sample Size Determination ........................................................................................................... 62
11.3.
Efficacy Analyses ........................................................................................................................... 63
11.4.
Pharmacokinetic Analyses............................................................................................................. 63
11.5.
Pharmacodynamic Analyses.......................................................................................................... 63
11.6.
Biomarker Analyses ....................................................................................................................... 63
11.7.
Patient-reported Outcome Analyses .............................................................................................. 64
11.8.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 64
11.9.
Medical Resource Utilization Analyses.......................................................................................... 64
11.10.
Interim Analysis.............................................................................................................................. 64
11.11.
Safety Analyses ............................................................................................................................. 64
11.12.
Data Review Committee ................................................................................................................ 65
12.
ADVERSE EVENT REPORTING ...................................................................................................... 65
12.1.
Definitions ...................................................................................................................................... 66
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 66
12.1.2.
Attribution Definitions.................................................................................................................. 67
12.1.3.
Severity Criteria .......................................................................................................................... 67
12.2.
Special Reporting Situations.......................................................................................................... 68
12.3.
Procedures..................................................................................................................................... 68
12.3.1.
All Adverse Events...................................................................................................................... 68
12.3.2.
Serious Adverse Events ............................................................................................................. 69
12.3.3.
Pregnancy................................................................................................................................... 70
12.3.4.
Disease Progression and Death................................................................................................. 70
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 71
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 71
13.1.
Procedures..................................................................................................................................... 71
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 71
14.
STUDY DRUG INFORMATION......................................................................................................... 71
14.1.
Physical Description of Study Drug................................................................................................ 71


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14.2.
Packaging ...................................................................................................................................... 71
14.3.
Labeling.......................................................................................................................................... 72
14.4.
Preparation, Handling, and Storage............................................................................................... 72
14.5.
Drug Accountability ........................................................................................................................ 72
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 73
16.
ETHICAL ASPECTS ......................................................................................................................... 73
16.1.
Study-Specific Design Considerations........................................................................................... 73
16.2.
Regulatory Ethics Compliance....................................................................................................... 74
16.2.1.
Investigator Responsibilities ....................................................................................................... 74
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 74
16.2.3.
Informed Consent ....................................................................................................................... 75
16.2.4.
Privacy of Personal Data ............................................................................................................ 76
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 77
16.2.6.
Country Selection ....................................................................................................................... 77
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 77
17.1.
Protocol Amendments.................................................................................................................... 77
17.2.
Regulatory Documentation ............................................................................................................ 78
17.2.1.
Regulatory Approval/Notification ................................................................................................ 78
17.2.2.
Required Prestudy Documentation............................................................................................. 78
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 79
17.4.
Source Documentation................................................................................................................... 79
17.5.
Case Report Form Completion ...................................................................................................... 80
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 80
17.7.
Record Retention ........................................................................................................................... 81
17.8.
Monitoring ...................................................................................................................................... 81
17.9.
Study Completion/Termination....................................................................................................... 82
17.9.1.
Study Completion/End of Study.................................................................................................. 82
17.9.2.
Study Termination....................................................................................................................... 82
17.10.
On-Site Audits ................................................................................................................................ 82
17.11.
Use of Information and Publication................................................................................................ 82
REFERENCES............................................................................................................................................ 85
INVESTIGATOR AGREEMENT ............................................................................................................... 102
LIST OF ATTACHMENTS
Attachment 1:
Prostate Cancer Working Group 3 Criteria................................................................. 87
Attachment 2:
Summary of RECIST Criteria Version 1.1 with Integration of PCWG3 for 
Evaluation of Response.............................................................................................. 88
Attachment 3:
ECOG Performance Status ........................................................................................ 95
Attachment 4:
Medications That Could Potentially Cause QT Prolongation or Torsades De 
Pointes........................................................................................................................ 96
Attachment 5:
Substrates of CYP1A2................................................................................................ 97
Attachment 6:
Anticipated Events...................................................................................................... 98
Attachment 7:
Long-term Extension Phase ..................................................................................... 100
LIST OF IN-TEXT TABLES
TABLES
Table 1:
Study Objectives and Endpoints/Assessments ........................................................................ 40
Table 2:
Dose reduction for Drug-related Non-hematologic Toxicities................................................... 48
Table 3:
Dose Modification Criteria for AST/ALT/Bilirubin Abnormalities for Niraparib .......................... 48
Table 4:
Dose Modification/Reductions for Hematologic Toxicity (Platelet Count and Neutrophil 
Count) ....................................................................................................................................... 49


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Table 5: 
Biomarker Panel ....................................................................................................................... 56
Table 6:
Study Treatment Administration for the Long-term Extension Phase .................................... 100
Table 7: 
Time and Events Schedule (Long-term Extension Phase With Limited Data Collection) ...... 101


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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
10 June 2016
Amendment 1
07 July 2016
Amendment 2
25 January 2017
Amendment 3
04 October 2017
Amendment 4
20 March 2018
Amendment 5
30 November 2018
Amendment 6
20 June 2019
Amendment 7
30 October 2019
COVID-19 Appendix
17 April 2020
Amendment 8
17 July 2020
Amendments below are listed beginning with the most recent amendment.
Amendment 8 (17 July 2020)
The overall reasons for the amendment: (1) to add a Long-term Extension Phase, (2) to include subjects who 
have germline pathogenic BRCA (BRCA1 or BRCA2) mutations in the efficacy analyses, and (3) to provide 
updated patient enrollment recruitment requirements.
Applicable Section(s)
Description of Change(s)
Rationale: To allow subjects who are benefiting from therapy to continue to receive niraparib after the primary 
analysis is completed.
Synopsis (Overview of 
Study Design);
Time and Events
Schedule;
3. Study Design;
9.1.7. Long-term 
Extension Phase;
10.2. Withdrawal from 
the Study;
16.2.3. Informed 
Consent;
Attachment 7
Attachment 7 outlines the criteria for participation and procedures to be performed in 
the Long-term Extension Phase.
Added the option for remote/virtual consenting.
Rationale: To align the analysis population with the protocol entry criterion 7.2.b. that allows subjects with 
germline pathogenic BRCA1 or BRCA2 mutations to enroll.


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Applicable Section(s)
Description of Change(s)
Synopsis (Objectives, 
Endpoints/Assessments, 
and Hypothesis, 
Overview of Study 
Design, Statistical 
Methods);
2.1. Objectives and 
Endpoints/Assessments;
3. Study Design;
9.7. Biomarkers;
11.1. Analysis 
Populations;
11.3. Efficacy 
Analyses;
Added text indicating that subjects who have germline pathogenic BRCA (BRCA1 or 
BRCA2) mutations will be included in the efficacy analyses.
Rationale: The current number of planned subjects has been updated.
Synopsis (Overview of 
Study Design);
3. Study Design;
11.2. Sample Size 
Determination
Specified that the study will assess up to approximately 120 subjects with measurable 
disease, at least 75 subjects with BRCA (BRCA1 or BRCA2) mutations and 45 
subjects with non-BRCA DNA-repair anomalies, and that an additional cohort of at 
least 90 subjects with  non-measurable disease will be included.
The sample size estimates were adjusted accordingly.
Rationale: To align with niraparib core safety information.
6.2.1. Non-hematologic 
Toxicities
10.1. Discontinuation of 
Study Treatment
Added treatment-related hypertensive crisis or posterior reversible encephalopathy 
syndrome as conditions for which subject’s study treatment must be discontinued.
Rationale: To align with current internal protocol template.
12.3.4. Disease 
Progression and Death
Attachment 6: 
Anticipated Events
Instructions for reporting disease progression and death have been updated.
Instructions for reporting and assessing anticipated events have been updated.
COVID-19 Appendix (17 April 2020)
The overall reason for the appendix: to provide study-related guidance during the global coronavirus 
(COVID-19) pandemic.
Applicable Section(s)
Description of Change(s)
Rationale: For health and safety reasons, subjects may not be able to come to the study site for scheduled 
procedures.
COVID-19 Appendix
The standalone Appendix provides guidance to investigators for managing 
study-related procedures during the COVID-19 pandemic.
Amendment 7 (30 October 2019)


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The overall reason for the amendment: is to allow subjects with local germline pathogenic results for Breast 
Cancer gene 1 (BRCA1) or Breast Cancer gene 2 (BRCA2) DNA-repair defects (DRD) to enter the trial given the 
high likelihood of biallelic mutations.
Applicable Section(s)
Description of Change(s)
Rationale: As the enrollment was nearing completion to the anticipated number for subjects with non-
measurable disease (irrespective of mutational status), the number of subjects with non-measurable disease was 
increased to allow continued enrollment of such subjects up to an increased target number.
Synopsis (Overview 
of Study Design, 
Statistical Methods); 
3. Study Design; 
11.2. Sample Size 
Determination
Minor edits made to indicate the study will assess up to approximately 155 subjects with 
measurable disease who are biomarker-positive (blood- or tissue-based assay), and at 
least 60 subjects with non-measurable disease, regardless of DNA anomaly.
Rationale: Subject population clarified via notation of types of DNA-repair anomalies to allow inclusion of
subjects with local-test assessed germline pathogenic BRCA1 or BRCA2 mutations. Also include modifications 
to Prescreening Eligibility Criteria and Inclusion Criteria to align with previous Amendment that reflected the 
current clinical practice for the treatment of patients with metastatic prostate cancer based on protocol steering 
committee feedback and to reflect the characteristics of the third line mCRPC population.
4. Subject Population
Text was updated as follows (deletions appear in overstrike, new text in bold):
Male subjects over the age of 18 years with mCRPC and DNA-repair anomalies 
(biallelic mutations and germline pathogenic mutations only for BRCA1 or BRCA2 
mutations) who received a prior taxane-based chemotherapy and AR-targeted therapy
(second-generation or later) for the treatment of metastatic prostate cancer are eligible 
for the study.
4.1. Prescreening 
Eligibility Criteria
(Criterion 3.3)
Text was updated as follows (deletions appear in overstrike, new text in bold):
Must have received or be currently on at least 1 taxane-based chemotherapy or after 
second line of treatment for mCRPC metastatic prostate cancer and at least 1 AR-
targeted (second-generation or later) therapy.
4.2. Inclusion Criteria 
(Criterion 6.5 and 
7.2)
Text was updated as follows (deletions appear in overstrike, new text in bold):
Received a second-generation or later AR-targeted therapy (for example, abiraterone 
acetate plus prednisone, enzalutamide, apalutamide) for the treatment of metastatic 
prostate cancer with evidence of disease progression or non-metastatic castration-
resistant prostate cancer with evidence of subsequent metastasis.
Criterion 7.1 was modified (now noted as Criterion 7.2):
Biomarker-positive for DNA repair anomalies by at least one of the following criteria
(Ssee Section 9.7):
a.
Biallelic DNA-repair anomaly (refer to
Table 5) based on a 
sponsor-validated blood or tissue assay.
b. Germline pathogenic BRCA1 or BRCA2 by any test (somatic local results 
must be confirmed as positive by the sponsor-validated assay before 
dosing).
9.7. Biomarkers 
Text edited to characterize the primary efficacy population (ie, subjects confirmed to be 
biallelic BRCA1 or BRCA2 by a sponsor-validated blood-or tissue-based assay). 


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Applicable Section(s)
Description of Change(s)
11.1. Analysis 
Populations
Text was updated as follows (deletions appear in overstrike, new text in bold):
Enrolled Population: All subjects who are enrolled into the study. This population will be 
used for exploring efficacy/anti-tumor activity, subject disposition and biomarker 
analyses.
Primary EfficacyITT Population: All subjects who received at least 1 dose of study 
drug, hadhave biallelic BRCA1 or BRCA2 DNA repair anomalies as determined by a
per the sponsor-validated blood- or tissue-based assay. This population will be used for 
efficacy analyses.
Rationale: Revisions were made to rename the “intent-to-treat (ITT) Population” as the “Primary Efficacy 
Population”; to define study phases, biomarker panel collection periods, samples for collection, timing of when 
subjects can enter the treatment phase, and criteria for biomarker-positivity. 
Synopsis (Overview 
of Study Design); 
3. Study Design
Minor modifications made to describe the 4 study phases.
Synopsis (Overview 
of Study Design,
Subject Population);
4. Study Population
Minor edits to text, including clarification of when subjects received taxane-based 
chemotherapy and androgen receptor (AR)-targeted therapy.
Synopsis (Biomarker 
Evaluations)
Minor edits made regarding the use of whole blood for RNA and circulating tumor 
DNA.
Time and Events 
Schedule
The biomarker panel will be collected during either the Prescreening or Screening 
phases.
11.1. Analysis 
Populations; 
11.3. Efficacy 
Populations
Renamed the ITT Population as the Primary Efficacy Population.
Time and Events
Schedule (Tablenotes 
b, c, and d)
Text was updated as follows (deletions appear in overstrike, new text in bold):
b.
Biomarker panel: Blood and tissue samples will be collected for evaluation of 
biomarker-positivity during the Prescreening or Screening Phase (see 
Sections 9.1.2. and 9.7.). Note that the sponsor’s tissue based assay (archival or 
recently collected) may also be used to determine eligibility (see Section 9.7 for 
full details). Results obtained from the sponsor-validated assays from other 
Janssen-sponsored trials can be used to enter screening for this trial. 
Subjects who are positive for germline pathogenic BRCA1 or BRCA2 
mutations will be allowed to be screened and enter the treatment phase 
based on local test results (blood or saliva) and will be confirmed by the 
sponsor-validated assay retrospectively. Subjects who are positive for 
somatic pathogenic BRCA1 or BRCA2 mutations by local test results
(blood, saliva, or tissue) must be confirmed as positive by the sponsor-
validated assay during screening before being able to enter the treatment 
phase.
c.
Prescreening AEs: AEs and serious AEs related to blood or recent tumor tissue 
collection procedures, as well as death from any cause, will be collected for 
30 days after the procedures for subjects who sign the prescreening consent. 
d. Main study informed consent: Only biomarker positive subjects may sign the 
main study informed consent, whichMain study consent must be signed prior 
to the conduct of any study-related procedures in the Screening Phase.


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Applicable Section(s)
Description of Change(s)
9.1.2. Prescreening 
Phase for Biomarker 
Evaluation
Text revised to note that if the subject is biomarker-positive by the sponsor-validated 
blood- or tissue-based assay, then he is eligible to enter the Screening Phase. Subjects 
who are positive for pathogenic BRCA1 or BRCA2 mutations based on local test results 
(somatic or germline) can enter the Screening Phase.
9.1.3. Screening 
Phase
Criteria for screening and advancement to the treatment phase clarified as:

Subjects positive for germline pathogenic BRCA1 or BRAC2 mutations based 
on local test results (blood or saliva); 

Subjects positive for somatic pathogenic BRCA1 or BRAC2 mutations (blood, 
saliva, or tissue) based on local results confirmed as positive by the 
sponsor-validated assay during screening.
9.7. Biomarkers;
Table 5
Information on biomarker-positivity criteria (ie, genomic lesions required for positivity) 
was removed from text and Table 5, as the definitions for positivity may evolve.
Information on the method of histone deacetylase 2 gene (HDAC2) detection was also 
removed.
9.7.1. Evaluations
New subsections on tissue analysis and saliva testing were added as shown below:
9.7.1.1. Tumor tissue (either archival or recently collected) should be obtained to 
evaluate DRD status, and may also be used to identify markers associated with 
disease evolution, immune context, or response to study drugs. Tissue samples 
collected at screening may be used for concordance and bridging studies for the 
development of the assay. Furthermore, tumor tissue may be assessed for RNA 
signatures predictive of response to niraparib.
9.7.1.5. Testing via a saliva sample may be collected to evaluate for germline 
mutations. Subjects will be permitted to be screened and enter the treatment phase 
if positive for BRCA1 or BRCA2 germline pathogenic mutations.
11.3. Efficacy 
Analyses
The following text was added:
Anti-tumor activity, such as PSA response, CTC conversion, composite response 
rate, will be analyzed based on subgroups of the enrolled population of biallelic, 
monoallelic, and indeterminant (local test results only) biomarker status. Additional 
details will be provided in the SAP.
11.6. Biomarker 
Analyses
Text was updated as follows (deletions appear in overstrike, new text in bold):
The concordance of DNA-repair anomalies in genes between among tumor DNA and 
plasma ctDNA results will may be evaluated. Analysis of biallelic loss in comparison to 
monoallelic mutation calling will be performed to determine if monoallelic mutation 
calling can be a proxy for biallelic loss.
Rationale: To align guidance on the use of niraparib with selected concomitant medications.
1.2. Summary of 
Available Nonclinical 
and Clinical Data
Preclinical information on induction was updated.
8.2. Restricted 
Concomitant 
Medications
Text revised to qualify niraparib as a weak inducer of cytochrome P450 (CYP)1A2 in 
vitro, and to remove reference to P-glycoprotein (P-gp) inhibitors; further clarification 
was added regarding the concomitant use of niraparib with medications that are sensitive 
or moderately sensitive substrates of CYP1A2.
Attachment 5
Substrates of 
CYP1A2
The title of Attachment 5 was revised, and the list of CYP1A2 substrates and P-gP
inhibitors removed and replaced with links to relevant references.


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Applicable Section(s)
Description of Change(s)
Rationale: The noted conditions will be reported as part of the time to symptomatic skeletal events endpoint.
Attachment 6 
Anticipated Events
Deletion of the disease-specific events of pathological fracture, spinal cord compression, 
and cauda equine syndrome.
Rationale: Detail regarding specific blood collection tools was removed.
9.7.1.2. Circulating 
Tumor Cells; 
9.7.1.3. Whole Blood 
for RNA
Text describing the type of tube used for blood collection was deleted. 
9.7.1.4. Circulating 
Tumor DNA
Minor edits were made to address the use of plasma samples and assay development.
Rationale: Information added to note where follow-up measures will be documented, and to clarify the local 
regulations regarding contact if the subject withdraws consent.
10.2. Withdrawal 
from the Study
Text was updated as follows (bold text indicates new text):
The measures taken to follow up must be documented in the subjects’ source 
documents.
If the subject withdraws consent for all study-related procedures, then no further contact 
is permitted by the investigator or the sponsor, except as permitted by local 
regulations.
Rationale: Minor changes, corrections, and errors were addressed throughout the protocol.
17.11. Use of 
Information and 
Publication
Minor changes made as applicable in alignment with current protocol template.
Throughout the 
protocol
The term “patient” was revised to“subject” as appropriate. 
Minor grammatical, formatting, abbreviations, or spelling changes were made.
Amendment 6 (20 June 2019)
The overall reason for the amendment: is to modify and clarify the protocol’s inclusion and exclusion criteria 
to align with current clinical practice for the treatment of patients with metastatic prostate cancer based on 
protocol steering committee feedback and to reflect the characteristics of the third line mCRPC population.  
Applicable Section(s)
Description of Change(s)
Rationale: The protocol inclusion and exclusion criteria were revised to reflect the characteristics of the third line 
metastatic castration-resistant prostate cancer (mCRPC) population and to align with current clinical practice.  


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Applicable Section(s)
Description of Change(s)
Synopsis (Overview of 
Study Design and 
Subject Population); 3. 
Study Design; 4. 
Subject Population; 4.2. 
Inclusion Criteria; 
9.1.2. Prescreening 
Phase for Biomarker 
Evaluation 
Prior to this amendment, potential subjects were required to progress on a taxane-
based chemotherapy, and AR-targeted therapy, both in mCRPC. In current clinical 
practice, based upon the CHAARTED and STAMPEDE data, taxane-based therapy is 
now given in the metastatic castration-sensitive prostate cancer (mCSPC) setting, such 
that resistance or intolerance to chemotherapy could have occurred in the mCSPC 
setting and rechallenge in the mCRPC setting would be of no benefit. Lavaud et al. 
observed those patients who received docetaxel rechallenge when they developed 
mCRPC have limited benefit from this treatment, as assessed by a PSA decline ≥50% 
obtained only in 14% of the patients in first- or second-line treatment.14
Therefore, this criterion has been amended, and potential subjects now need to have 
received AR-targeted therapy and taxane-based chemotherapy with evidence of 
disease progression, or discontinued taxane-based chemotherapy due to an adverse 
event, in either mCSPC or mCRPC. 
As the current inclusion requirements continue to require at least one prior taxane and 
progression on a prior AR-targeted agent and have mCRPC disease, the study 
population remains unchanged by recruiting subjects who have received 2 lines 
of therapy, with the protocol therapy comprising the third line and the overall benefit-
risk remains unchanged. This change was noted in Inclusion Criterion 5, Synopsis, 
and Sections 3, 4, and 9.1.2.
4.1. Prescreening 
Eligibility Criteria; 
9.1.2. Prescreening 
Phase for Biomarker 
Evaluation
Prescreening Criterion 2 was edited to remove ‘if feasible’ as a qualifier for a potential 
subject’s willingness to provide a tumor tissue sample, in order to highlight the 
importance of this sample. This change was also made in Section 9.1.2.
4.2. Inclusion Criteria
Inclusion Criterion 6 was edited to improve readability and implementation.  
Inclusion Criterion 14e was edited to correct the units used to report creatinine 
clearance.  
4.3. Exclusion Criteria
Exclusion Criterion 15 was amended to decrease the minimum number of days 
required between a transfusion or receipt of hematopoietic growth factors and Cycle 1 
Day 1 from 30 days to 14 days. No minimum number of days are now required prior 
to Cycle 1 Day 1 for receipt of an investigational agent for prostate cancer or major 
surgery. 
Rationale: Text in the protocol was updated to reflect that a sponsor-validated blood- and tissue-based biomarker 
assay to detect biallelic DNA-repair anomalies is now available.  
Synopsis (Objectives, 
Endpoints/Assessments, 
and Hypothesis); 
Synopsis (Overview of 
Study Design); Time 
and Events Schedule; 
2.1. Objectives and 
Endpoints/Assessments; 
3. Study Design; 9.1.2. 
Prescreening Phase for 
Biomarker Evaluation; 
9.7. Biomarkers; 11.1. 
Analysis Populations
Text in the protocol has been updated to reflect that a sponsor-validated blood- and 
tissue-based biomarker assay to detect biallelic DNA-repair anomalies is now 
available. As a result, the ITT Population is now defined as all subjects with biallelic 
DNA-repair anomalies as determined by a sponsor-validated blood- or tissue-based 
assay.
4.1. Prescreening 
Eligibility Criteria
For Criterion 2, ‘using a sponsor-validated assay’ was added to describe the method 
needed for determination of DNA-repair anomalies. 


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Applicable Section(s)
Description of Change(s)
Rationale: Serial PK sampling assessment on a subset of subjects has been removed from the protocol. The PK 
of niraparib monotherapy has been adequately characterized; therefore, only sparse PK sampling is required for 
this study. 
Synopsis 
(Pharmacokinetic 
Evaluations and 
Pharmacokinetics and 
Exposure-Response); 
Time and Events 
Schedule; 9.1.1. 
Overview; 9.3.1 Sample 
Collection and 
Handling; 9.3.3. 
Pharmacokinetic 
Parameters; 11.4. 
Pharmacokinetic 
Analyses
Text describing serial PK sampling was removed from the protocol.
Rationale: Clarification was added that the confirmation scan should occur 4 weeks after the first documentation 
of objective response for soft tissue disease (with the allowance of a 2-week window). This schedule is consistent 
with the current protocol attachments that describe RECIST 1.1. 
Time and Events 
Schedule; 9.2.2. 
Endpoints Criteria
The time of the confirmation scan was clarified to be 4 weeks after the first 
documentation of objective response for soft tissue disease (with the allowance of a 
2-week window). The schedule for subsequent scans will be based upon Cycle 1 Day 
1, and the confirmation scan will satisfy the scan requirements for the next occurring 
timepoint per the Time and Events Schedule.  
Rationale: Minor changes, corrections, and errors were addressed throughout the protocol.
Synopsis (Overview of 
Study Design); 3. Study 
Design
For consistency, ‘approximately’ was added before the number of subjects planned to 
be enrolled with BRCA1 or BRCA2 DNA-repair anomalies and the number of 
subjects planned to be enrolled with ATM, FANCA, PALB2, CHEK2, BRIP1, or 
HDAC2 DNA-repair anomalies.
2.1. Objectives and 
Endpoints/Assessment
Text for the exploratory endpoint ‘time to unequivocal clinical progression’ was 
edited for accuracy to include the word ‘clinical’.   
6.2.1. Non-hematologic 
toxicities
The title of Table 2 was edited by adding ‘drug-related’ in order to align with the text 
in Section 6.2.1.
9.1.3. Screening Phase
Removed that a subject requires sponsor approval and agreement to be rescreened. 
Rescreening is solely at the discretion of the investigator.
9.1.6. Follow-up Phase
Clarified that regular imaging should be collected from the EoT visit until 
radiographic progression only for subjects who have not started a subsequent 
treatment for prostate cancer or withdrawn consent. 
9.7. Biomarkers
Table 5 has been modified to provide further details on the different criteria used in 
the blood- versus tissue-based assays. 
Attachment 5
In the list of examples of CYP1A2 substrates, (R)warfarin was changed to warfarin.
Investigator Agreement 
Page
The name of the responsible medical officer has been updated from NamPhuong Tran, 
MD to Shinta Cheng, MD.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


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Amendment 5 (30 November 2018)
The overall reason for the amendment: Based on the updated safety information of niraparib with more 
subjects exposed to drug and to be consistent with clinical practice of physicians, changes were made to 
inclusion/exclusion criteria and other study-related procedures throughout the protocol.
Applicable Section(s)
Description of Change(s)
Rationale:  Changes were made due to anticipated availability of a tissue-based assay.
Synopsis, Objectives, 
Endpoints/Assessments, 
And Hypothesis, 
Overview of Study 
Design; Time and 
Events Schedule, 
footnote ‘b’; 9.1.2. 
Prescreening Phase for 
Biomarker Evaluation; 
9.7. Biomarkers
Throughout the protocol, the subject enrollment criteria to allow for enrollment based 
on tissue determination of DNA-repair anomalies once an algorithm that can 
distinguish biallelic from monoallelic DNA-repair anomalies is available was 
included.
Rationale: The anticoagulation criterion was removed as additional experience with niraparib has not suggested 
increased risk of bleeding if subjects are on anticoagulation agents.
4.3. Exclusion Criteria 
(Criterion 16)
Following text was deleted:
Subjects who are currently taking anticoagulation therapy (eg, warfarin, enoxaparin, 
dabigatran, rivaroxaban).
Rationale: Based on the updated safety information of niraparib, QT interval prolongation was not identified as 
a risk.
4.3. Exclusion Criteria 
(Criterion 11)
Following text was deleted:
Corrected QT interval by the Fridericia correction formula (QTcF) on the screening 
ECG >450 msec.
Rationale: Revision and modifications were made for clarity and consistency with the updated safety 
information of niraparib.
Time and Events 
Schedule
Timepoints of assessment of vital signs, blood pressure and physical examination 
were updated and frequency was reduced.
4.1. Prescreening 
Eligibility Criteria, 
Criterion 3
Text was updated as follows (bold text indicates new text):
Must have documented evidence of disease progression while be on or after second-
line of treatment for mCRPC.
4.2. Inclusion Criteria
(Criterion 5)
Text was updated as follows (bold text indicates new text):
Received at least 1 line of taxane-based chemotherapy for the treatment of mCRPC 
with documented evidence of disease progression prior to enrollment while on 
therapy or within 3 months after discontinuation of therapy in the castrate resistant 
setting.


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Applicable Section(s)
Description of Change(s)
4.2. Inclusion Criteria
(Criterion 6)
Text was updated as follows (bold text indicates new text):
Received at least 1 line of AR-targeted therapy (eg, abiraterone acetate plus 
prednisone, enzalutamide, apalutamide) for mCRPC with documented evidence of 
disease progression prior to enrollmentwhile on therapy or within 3 months after 
discontinuation of therapy in the castrate resistant setting.
4.2. Inclusion Criteria
(Criterion 14)
Criteria for certain screening laboratory parameters were updated as follows (bold 
text indicates new text):
e. Serum creatinine ≤1.5 x upper limit of normal (ULN), or a calculated cCreatinine 
clearance ≥630 mL/min/1.73 m2 using the Cockcroft Gault equation.
f
Serum potassium ≥3.5 mmol/L
g
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 x ULN, measure direct and 
indirect bilirubin, and if direct bilirubin is ≤1.5 x ULN, subject may be eligible)
h
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤3.0 x ULN or AST and ALT ≤5 x ULN in the presence of liver metastases
4.3. Exclusion Criteria 
(Criterion 4)
Text was updated as follows:
Known Symptomatic or impending cord compression, except if subject has received 
definitive treatment for this and demonstrates evidence of clinically stable disease.
4.3. Exclusion Criteria 
(Criterion 5)
Text was updated as follows:
Known Symptomatic uncontrolled brain or leptomeningeal metastases (controlled is
defined as CNS disease which has undergone treatment [eg, radiation or surgery] at 
least 15 days prior to Cycle 1 Day 1)
4.3. Exclusion Criteria 
(Criterion 10)
Text was updated as follows (bold text indicates new text):
Prior palliative radiotherapy ≤715 days prior to Cycle 1 Day 1. Radiotherapy given 
>7 days prior to Cycle 1 Day 1 is permitted as long as any AEs associated with 
radiotherapy have resolved to Grade 1 or baseline., with the exception of a single 
fraction of radiotherapy for the purposes of palliation, which is permitted.
4.3. Exclusion Criteria 
(Criterion 17)
Text was updated as follows (bold text indicates new text):
Subjects with uncontrolled (persistent) hypertension Grade ≥3 (ie, Stage 2 
hypertension [systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 
mm Hg]) confirmed by multiple readings defined as systolic blood pressure [BP] 
≥160 mm Hg or diastolic BP ≥100 mm Hg) despite medical management.
Table 5. Biomarker 
Panel and Criteria for 
Positivity
Control genes (AR, TP53, and CDK2NA) and the footnotes with related cross 
references in table were deleted from the table.
9.2.2. Endpoints Criteria
Text for bone scan progression was updated and clarified.
The text on duration of tumor response was updated to make it consistent with the 
secondary objective of study. Text was updated as follows (bold text indicates new 
text):
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), unequivocal clinical 
progression, or death, whichever occurs first.


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Applicable Section(s)
Description of Change(s)
9.9. Safety (Adverse 
Events)
Text was updated as follows:
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.
10.1. Discontinuation of 
Study Treatment

The criterion of need for chronic opioid analgesics under unequivocal clinical 
progression was removed.

The criterion of use of external beam radiation therapy to relieve skeletal 
symptoms under tumor progression was updated to “Radiation therapy”

The criterion of the need for tumor-related orthopedic surgical intervention under 
tumor progression was updated to “Surgical interventions for complications due to 
tumor progression”

“Diagnosis of MDS/AML” was newly added under criteria for discontinuation of 
study treatment.

Text was added indicating that “Palliative radiation therapy for bone pain may 
not require a subject to be discontinued from treatment, after discussion with 
the medical monitor.”
14.4. Preparation, 
Handling, and Storage
Following sentence was added: 
“Caregivers should handle niraparib with protection (eg, gloves)”
Rationale: Based on the updated safety information of niraparib, the requirements for ECGs have been modified.
Time and Events 
Schedule, including 
Footnote ‘g’; 9.9. Safety 
(Electrocardiogram 
[ECG])
Specified that triplicate ECGs are not required. A standard 12-lead ECG recording 
will be used in this study.
Footnote ‘g’ was updated as follows (bold text indicates new text):
Standard 12-lead ECGs will be performed at screening, at every cycle through 
Cycle 7, at every 3 cycles thereafter, at the EoT visit, and as clinically indicated.
The following text was deleted:
Triplicate ECGs must be performed at approximately the same time of day (±3 hours) 
at each cycle
Rationale: Benefit-risk assessment for niraparib monotherapy was added to supplement the protocol.
1.3. Benefit/Risk 
Assessment
Benefit-Risk Assessment section added.
Rationale: Dose modifications and management of drug toxicities (hematologic and non-hematologic) were 
updated to reflect the clinical practice of physicians.
6.2. Dose Modification 
and Management of 
Toxicity
It was clarified that any re-escalation of the reduced dose to a full starting dose should 
be discussed in advance with Sponsor’s medical monitor.
6.2.1. Non-hematologic 
Toxicities
Text was updated to clarify the dose modifications in drug-related Grade 3 or higher 
toxicities.
6.2.1.1. Hepatic 
Toxicities
Since hepatic toxicities are known potential side effect of niraparib, new section was 
added to clarify the dose modification criteria for hepatic toxicities. 
New Table 3. Dose Modification Criteria for AST/ALT/Bilirubin Abnormalities for 
Niraparib added.


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Applicable Section(s)
Description of Change(s)
6.2.2. Hematologic 
Toxicities
New text was added to clarify that the site should contact the Sponsor for discussion 
and consider discontinuation of niraparib if hematologic toxicity has not recovered to 
Grade 1 or baseline after 28 days of dose interruption or a diagnosis of MDS/AML is 
confirmed by a hematologist.
6.3. Treatment 
Interruptions for 
Planned Procedures
New section added to clarify the duration of interruption of nirparib dose for planned 
procedures that require hospitalization.
Table 4, Dose 
Modification/Reductions 
for Hematologic 
Toxicity (Platelet Count 
and White Blood Cell 
Count)
“White Blood Cell” was replaced with “Neutrophil” in the table header.
Rationale: To be consistent with Patient-reported Outcome (PRO) completion guidelines.
Time and Events 
Schedule; 9.1.1. 
Overview
Patient-reported Outcomes should be performed first prior to any study-related 
procedures if multiple assessments are planned at the same timepoint.
New footnote “i” was added in Time and Events Schedule.
Rationale:  Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 4 (20 March 2018)
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 primary reason for the amendment: is to improve the subject selection criteria based on using an 
enhanced biomarker assay and the corresponding statistical analysis plan, to remove Holter monitoring, and other 
minor changes throughout the protocol.
The rationale for and description of the changes are listed below, and representative revisions are sometimes 
provided; when revisions are provided verbatim, bold font denotes new text and strikethrough denotes deleted 
text.
Applicable Section(s)
Description of Change(s)
Rationale: Internal sponsor analyses on subjects enrolled in this study prior to 07 December 2017 showed that 
subjects with measurable mCRPC who have biallelic DNA-repair anomalies in BRCA1 or BRCA2 genes 
potentially have greater clinical benefit from treatment with niraparib. Therefore, the primary endpoint analysis 
of the study was amended to evaluate the response of these subjects. A secondary endpoint analysis to evaluate 
the response of subjects with other DNA-repair anomalies (in ATM, FANCA, PALB2, CHEK2, BRIP1, or 
HDAC2) was added. In addition, a futility analysis for subjects with measurable mCRPC who have biallelic 
DNA-repair anomalies in ATM, FANCA, PALB2, CHEK2, BRIP1, or HDAC2 was implemented to ensure that 
recruitment of these subjects is not continued if an adequate response is not initially observed.


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Applicable Section(s)
Description of Change(s)
Synopsis (Objectives, 
Endpoints/Assessments, 
and Hypothesis);
Synopsis (Overview of 
Study Design);
2.1. Objectives and 
Endpoints/Assessments;
3. Study Design
Updates were made to the patient population, the number of subjects enrolled in 
each population, and to the primary and secondary objectives and endpoints of the 
study.
Table 4
Revisions and clarifications were made to the table and footnotes, and a new 
footnote was added.
Synopsis (Statistical 
Methods);
11.2. Sample Size 
Determination
Descriptions of primary and secondary objectives with objective response rate 
(ORR) endpoint were revised based on updates to the patient population. In addition 
to the interim efficacy analysis for the primary endpoint (as in the original protocol),
a futility analysis for ORR based on Simon’s two-stage design was added for the 
secondary objective in subjects with measurable mCRPC who have biallelic DNA-
repair anomalies in ATM, FANCA, PALB2, CHEK2, BRIP1, or HDAC2.
11.1. Analysis Population
ITT Population: All subjects who have biallelic DNA-repair gene anomalies (as 
determined by the sponsor’s required blood-based assay) and were enrolled after 
07 December 2017. This population will be used for efficacy analyses.
11.3. Efficacy Analyses
The primary endpoint, ORR in subjects with measurable mCRPC and 
DNA-repair anomalies in BRCA1 or BRCA2 and ORR in subjects with 
measurable mCRPC and DNA-repair anomalies in ATM, FANCA, PALB2, 
CHEK2, BRIP1, or HDAC2, as defined in Section 2.1, will be calculated, and its 
2-sided 95% exact CI will also be presented.
The final analysis for ORR in subjects with measurable mCRPC and 
DNA-repair anomalies in BRCA1 or BRCA2 will be performed approximately 
6 months after the last subject with measurable disease and DNA-repair anomalies 
in BRCA1 or BRCA2 receives his first dose of study medication.
Rationale: Two more study visits were added to Cycle 1, to enhance safety monitoring.
Time and Events 
Schedule
Two columns were added to Cycle 1 (for Day 8 and Day 22 timepoints), to provide 
weekly monitoring during the first cycle.
Rationale: The requirement for Holter monitoring was removed, since triplicate ECGs are required on Day 1 of 
every cycle, and no concern for QT prolongation has been observed in other studies.
Synopsis 
(Pharmacokinetic 
Evaluations);
Time and Events 
Schedule, including 
Footnotes g and k;
9.3.1. Sample Collection 
and Handling;
9.9. Safety 
(Electrocardiogram 
[ECG])
The requirement for Holter monitoring was removed.
Specified that triplicate ECGs are required.
Rationale: Revisions and modifications were made throughout the protocol to increase clarity and consistency, to 
update the protocol based on revisions made during this amendment, or to correct omissions and errors.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made. 


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Applicable Section(s)
Description of Change(s)
Throughout the protocol
“3 months” was revised to “12 weeks” (or “12 weeks” was added in parenthesis 
after “3 months”), “6 months” was revised to “24 weeks”, “sponsor’s blood-based 
assay” was revised to “sponsor’s required blood-based assay”.
Time and Events 
Schedule;
9.1.3. Screening Phase
The Screening Phase was reduced from 35 days to 28 days in order to allow subjects 
to receive the Cycle 1 Day 1 dose sooner.
Abbreviations
Abbreviations and definitions were added.
4.1. Prescreening 
Eligibility Criteria
Criterion 4 was deleted. Details will be provided in the laboratory manual.
4.2. Inclusion Criteria 
(Criterion 8)
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).19 The PSA level at the screening visit should be ≥2 1 μg/L 
(2 1 ng/mL).
4.2. Inclusion Criteria 
(Criterion 14)
h.
Aspartate aminotransferase (AST) or and alanine aminotransferase (ALT) 
≤3.0 x ULN or AST and ALT ≤5 x ULN in the presence of liver metastases
i.
CTC count of ≥1 cells/7.5 mL blood (required only for patients with 
non-measurable soft tissue disease by RECIST 1.1)
6.2. Dose Modification 
and Management of 
Toxicity
For procedures while on treatment, dose interruption of up to 28 days is allowed. 
Dose interruptions of more than 28 days must be discussed in advance with the 
sponsor’s medical monitor.
6.2.1. Non-hematologic 
Toxicities
This section was revised for accuracy, and repetitions were removed.
6.2.2. Hematologic 
Toxicities
Repetitions were removed based on text added to Section 6.2. Management of 
anemia was amended to align with institutional standards of care.
The order of dose reductions for Grade ≥3 hematologic toxicity in Table 3 was 
revised to start with the highest dose, and a note was modified as shown below.

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 values return to baseline levels.
6.3. Treatment 
Continuation Criteria for 
the First Day of a New 
Cycle
Revisions were made to treatment continuation criteria for the first day of a new 
cycle.
8. Concomitant Therapy
Concurrent enrollment in another interventional investigational drug or device 
study is prohibited during the Treatment Phase.
9.1.2. Prescreening Phase 
for Biomarker Evaluation
The Prescreening Phase may occur at any time prior to the Screening Phase, 
including during while the subject’s subject is on a second-line of therapy 
provided the subject is demonstrating signs of progression (eg, rising PSA or 
radiographic progression).
If no tumor tissue is available, then the subject may agree be asked to have a new 
tumor tissue sample collected, if reasonable.
For consistency for changes in Section 4.1, the following sentence was deleted: 
“Subjects may be rescreened once for biomarker-positivity during the Prescreening 
Phase for the reasons described in Section 4.1, Criterion 4.”


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Applicable Section(s)
Description of Change(s)
9.7. Biomarkers
To be eligible for the study, subjects must be confirmed biomarker-positive by the 
sponsor’s required blood-based assay. To ensure that all subjects have the same 
biomarker data available for analysis (ie eg, for concordance and bridging studies), 
blood samples will be collected and analyzed from all subjects who sign the 
prescreening ICF. Tissue samples will also be collected for additional biomarker 
research.
Clarifications and revisions were made to Table 4 and its footnotes, and a new 
footnote was added.
10.2. Withdrawal from 
the Study
This can be done by telephone or by chart review or by public record search if 
permissible by local regulations.
10.3. Withdrawal From 
the Use of Samples in 
Future Research
The subject may withdraw consent for use of samples for future research (refer to 
Section 16.2.5, Long-Term Retention of Samples for Additional Future Research).
11.11. Safety Analyses 
(Clinical Laboratory 
Tests)
Clinical laboratory test results will be collected from screening through 30 days after 
last dose of study drug the EoT visit.
12.3.4. Disease 
Progression and Death
Fatal events (regardless of relationship to study drug) should be reported as SAEs 
for subjects until 30 days after EoT the last dose of study drug. Fatal events 
occurring after that 30-day period after the last dose of study drug will not be 
reported as SAEs and will be captured on the designated case report form for 
survival. Death is an outcome of an AE and not an AE itself. All reports of death 
within 30 days of EoT after the last dose of study drug should include an AE term 
for the cause of death (if known). Fatal events occurring after that 30 day EoT visit 
will not be reported as SAEs and will be captured on the designated case report form 
for survival.
15. Study-Specific 
Materials
Revisions were made to the supplies provided to the investigator.
16.2.3. Informed Consent
The physician may also recontact the subject for the purpose of obtaining consent to 
collect information about his survival status.
References
A new reference was added. The edition number and year were deleted from the 
citation for the Investigator’s Brochure.
Amendment 3 (4 October 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 primary reason for the amendment: is to include additional cardiac monitoring to better understand the 
cardiovascular effect of niraparib monotherapy in the prostate cancer population. This additional safety 
monitoring is precautionary only and is not indicative of a known cardiac signal for niraparib. An ITT Population 
was also added to allow for all subjects with biallelic DNA-repair anomalies to be analyzed separately for 
efficacy. Other minor changes (ie, removal of pharmacodynamics sampling and updates to the 
inclusion/exclusion criteria) are also included in this amendment.
Applicable Section(s)
Description of Change(s)
Rationale: Additional 12-lead electrocardiogram (ECG) Holter monitoring (24 hours) was added for subjects 
who are undergoing serial PK sampling for analysis of QT/QTc in relation to plasma concentrations of niraparib 
and M1.


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Applicable Section(s)
Description of Change(s)
Synopsis; Time and 
Events Schedule; 9.9.
Safety 
12-lead ECG Holter monitoring was added for subjects who are selected for serial 
PK sampling.
9.3.1. Sample Collection 
and Handling
A reference to Holter monitoring for subjects who undergo serial PK sampling was 
added.
Rationale: Subjects with biallelic DNA-repair anomalies are expected to have better clinical response outcomes 
than those subjects with monoallelic DNA-repair anomalies. Therefore, the sponsor intends to analyze these 
subjects separately for efficacy. To that end, an ITT Population comprising subjects who have biallelic 
DNA-repair gene anomalies (as determined by the sponsor’s blood-based assay) was added.
11.1. Analysis 
Populations
The Treated Population was amended to Enrolled Population to allow for all 
subjects enrolled in the study to be analyzed. An ITT Population was added to allow 
for all subjects with biallelic DNA-repair anomalies to be analyzed separately for 
efficacy.
Rationale: Pharmacodynamics sampling (ie, whole blood for isolation of PBMCs) was removed from the 
protocol. All blood samples collected to date are unusable due to contamination with high levels of poly-
adenosine diphosphate [ADP]-ribose (PAR), likely from red blood cell lysis. Furthermore, preliminary data 
suggest that >50% of this subject population would yield PBMC counts below the threshold needed to exceed the 
PAR lower limit of detection.
Synopsis: 
Pharmacodynamic 
Evaluations; Time and 
Events Schedule; 9.1.1. 
Overview; 9.1.4. 
Treatment Phase; 9.5. 
Pharmacodynamics; 9.6. 
Pharmacokinetic/ 
Pharmacodynamic 
Evaluations; 11.5 
Pharmacodynamic 
Analyses; 11.8. 
Pharmacokinetic/ 
Pharmacodynamic 
Analyses
Pharmacodynamics sampling and analyses were removed.
2.1. Objectives and 
Endpoints/Assessments
The exploratory endpoint to quantify PAR levels in PBMCs was removed.
Rationale: Minor amendments
Time and Events 
Schedule; 9.1.4. 
Treatment Phase; 9.1.5. 
End-of-Treatment Visit; 
12.3.4; Disease 
Progression and Death
The definition of End-of-Treatment visit was amended to clarify that the visit 
should occur 30 (±5) days after the last dose of study drug or 30 (±5) days after the 
end of study drug interruption period.
Time and Events 
Schedule
The footnote for blood pressure monitoring was removed. Blood pressure will be 
measured at every cycle until the End-of-Treatment visit; no cap on the number of 
cycles will be implemented.
Synopsis; Time and 
Events Schedule; 9.2.1. 
Evaluations; 9.2.2. 
Endpoints Criteria
The instructions regarding tumor measurements and collection of imaging scans 
was updated to clarify different procedures for soft tissue response versus bone scan 
progression. Reference to the protocol body for additional details was added in the 
Time and Events Schedule footnote.


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Applicable Section(s)
Description of Change(s)
Synopsis; 2.1. Objectives 
and 
Endpoints/Assessments
Clarified that the endpoint for CTC response should be performed for subjects who 
have baseline CTC >0.
Synopsis; 3. Study 
Design; 4. Subject 
Population
Clarified that subjects should have progressed on or after at least 1 line of taxane-
based chemotherapy and at least 1 line of AR-targeted therapy (eg, abiraterone 
acetate plus prednisone, enzalutamide, apalutamide).
4.1. Prescreening 
Eligibility Criteria
Criterion 2 was updated to state that tumor tissue samples should be collected “if 
feasible”. This is to allow subjects who may not be able to provide a tumor tissue 
sample to enter the study if a blood sample is available.
Criterion 3 was amended to ensure subjects have documented evidence of disease 
progression while on second-line of therapy.
Criterion 4 was updated to clarify when subjects could be rescreened for biomarker-
positivity.
4.2. Inclusion Criteria
Minor amendments were made to inclusion criteria 5 and 6 to clarify the timing of 
discontinuation for prior taxane-based chemotherapies or AR-targeted therapies. 
Criterion 7 was updated to remove the requirement for tumor tissue to be 
biomarker-positive, given that subjects may be biomarker-positive based on the 
blood-based assay.
4.3 Exclusion Criteria
Criterion 12 was deleted. Medications thought to cause QT prolongation were 
instead added to Section 8.2 Restricted Concomitant Medications.
Criterion 16 was added to exclude subjects who are taking anticoagulation therapy.
Criterion 17 was added to exclude subjects with uncontrolled Grade ≥3 
hypertension.
6.2.1. Non-hematologic 
Toxicities
Updated to include instructions for when subjects should be referred to a 
cardiologist and to allow for treatment interruption of Grade 1 and 2 non-
hematologic toxicities at the discretion of the investigator. Clarified that treatment-
related toxicities of Grade 3 or 4 require a dose reduction.
6.2.2. Hematologic 
Toxicities
Instructions for dose modifications/reductions for hematologic toxicities were 
updated to reflect toxicity grades, rather than specific laboratory values. 
6.3. Cycle 1 Day 1 and 
Treatment Continuation 
Criteria
New section added to provide criteria for allowing subjects to be retreated with 
study drug.
8.1. Prohibited 
Concomitant 
Medications; 8.2. 
Restricted Concomitant 
Medications
Medications thought to cause QT prolongation or torsades de pointes were changed 
from prohibited to restricted medications. 
9.1.2. Prescreening Phase 
for Biomarker Evaluation
Modified to allow for subjects who may not be able to provide a tumor tissue 
sample.
9.2.1. Evaluations; 
Information regarding collection of scans to determine objective response and 
radiographic progression was moved to Section 9.2.2. 
9.2.2. Endpoints Criteria
Information regarding collection of scans to determine objective response and 
radiographic progression was added to this section. 
9.7. Biomarkers
The requirement to have biomarker-positivity determined by tumor tissue was 
removed.


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Applicable Section(s)
Description of Change(s)
The positivity criteria for the biomarker assay was updated to reflect the current 
blood-based assay.
10.1. Discontinuation of 
Study Treatment
Updated to remove discontinuation due to drug-induced liver injury, as the 
information conflicted with toxicity management guidance provided in Section 6.
Updated QTc discontinuation criteria to state “clinically significant QTcF >500 
msec or QTc prolongation >60 ms above baseline”
11.2 Sample Size 
Determination
The anticipated enrollment duration was removed.
11.3. Efficacy Analyses
Updated to reflect that the primary efficacy analysis would be performed using the 
ITT Population.
11.10. Interim Analysis
Removed statement that no formal interim analysis would be performed. Interim 
analyses will be described in the statistical analysis plan.
12.3.1. All Adverse 
Events
Added the collection of related serious adverse events and deaths from any cause 
during the Prescreening Phase.
Attachment 1
Removed from protocol for copyright reasons.
Attachment 4
Removed from protocol, as a more comprehensive list of medications thought to 
cause QT prolongation was included in reference 17.
Attachment 6
Updated list of anticipated events to be disease-specific.
Rationale: Minor errors were noted and corrected
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made. 
Amendment 2 (25 January 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 a 
Type C Meeting with FDA held on 19 October 2016, as well as feedback from other health authorities.
Applicable Section(s)
Description of Change(s)
Rationale: The primary endpoint of the study was amended to comply with feedback from health authorities. The 
primary endpoint was changed from a composite endpoint to objective response rate (ORR). With this change, 
the subject population for the primary analysis will include only subjects with measurable disease. Subjects with 
non-measurable disease will still be included in the study to increase the size of the safety database and assess the 
activity of niraparib in this population.
Synopsis; 2.1. 
Objectives and 
Endpoints/Assessments
The primary endpoint is changed from a composite endpoint to an endpoint of 
objective response rate (ORR) in subjects with measurable disease.
Given that circulating tumor cell (CTC) response was no longer included in the 
primary endpoint, an additional secondary endpoint to measure CTC response was 
added. The exploratory endpoint to evaluate CTC counts was also updated based on the 
new secondary endpoint.
The original composite primary endpoint was changed to be an exploratory endpoint.


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Applicable Section(s)
Description of Change(s)
An additional exploratory endpoint of time to unequivocal progression was included.
Synopsis; 2.2. 
Hypothesis
The hypothesis was amended to reflect the new primary endpoint and corresponding 
statistical assumptions.
Synopsis; 3. Study 
Design
The study design was updated to amend the number of subjects to be included in the 
study, and to be aligned with Section 11.2 Sample Size Determination. Other 
administrative changes were made.
Synopsis; Time and 
Events Schedule; 9.1.4. 
Treatment Phase; 
9.2.1. Evaluations
The new primary endpoint of ORR requires confirmation of response; therefore, details 
of collection and review of imaging scans were updated and the time window for 
collection was changed from ±7 days to ±3 days.
Synopsis; 11.2. Sample 
Size Determination
The sample size calculations were amended to reflect the new primary endpoint of 
ORR. Sample size justification for subjects with non-measurable disease based on CTC 
RR was also added.
Synopsis; 11.3 
Efficacy Analyses
The efficacy analyses were amended to reflect the new primary endpoint of ORR. In 
addition, analysis of CTC RR was added to address the additional secondary endpoint 
of CTC response.
Rationale: To comply with US FDA recommendations
Time and Events 
Schedule
Safety testing at Cycle 2 Day 15 was added to ensure the safety of subjects early in the 
study, as recommended by US FDA.
Rationale: To collect additional PK samples to characterize exposure of niraparib and its metabolite M1.
Synopsis; Time and 
Events Schedule; 9.3. 
Pharmacokinetics; 
11.4. Pharmacokinetic 
Analyses
Additional serial PK samples were added in a subset of subjects at selected sites. 
Clarification was added that sparse PK sampling will be collected in all subjects.
9.1.1. Overview
The maximum volume of blood drawn at any visit was amended from 70 mL to 80 mL 
based on the additional PK collections required in a subset of subjects.
2.1. Objectives and 
Endpoints/Assessments
Additional exploratory endpoints were included to evaluate the steady-state PK of 
niraparib and its metabolite M1 in a subset of subjects.
Rationale: To clarify the subject population to be included in the study based on health authority and investigator 
feedback
4.1. Prescreening 
Eligibility Criteria
Criterion 3 was added to allow subjects who are on second-line therapy to enter the 
Prescreening Phase, although they will not be eligible to enter the Screening Phase 
until they have progressed on their second-line of therapy.
Criterion 4 was added to allow subjects who are biomarker-negative to be rescreened 
once, to determine if their tumor tissue was insufficient for analysis or to determine of 
their biomarker status changed over the course of their disease.
4.2. Inclusion Criteria
Criterion 4 was updated to clarify that prostate cancer of mixed histology is acceptable; 
however, subjects with the small cell pure phenotype of prostate cancer must be 
excluded from the study.
Criterion 5 was updated to specify that subjects must have documented evidence of 
disease progression on previous taxane-based chemotherapy.
Criterion 6 was updated to specify that subjects must have documented evidence of 
disease progression on previous AR-targeted therapy.


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Applicable Section(s)
Description of Change(s)
Criterion 8 was updated to specify that PSA progression must be determined per 
PCWG3 guidelines and radiographic progression must be determined as per RECIST 
1.1 (for soft tissue) or PCWG3 (for bone disease) criteria. Clear definitions of 
measurable and non-measurable disease were added. 
Criterion 14 was updated to amend platelet counts and serum albumin levels at 
screening. In addition, a criterion for CTC count was added (criterion 14.1.i) to define 
the permitted levels at screening.
4.3. Exclusion Criteria
Criterion 2 was updated to clarify that previous chemotherapy should only be an 
exclusion criterion if it was used for the treatment of prostate cancer.
Criterion 11 was corrected to exclude subjects with QTcF on the screening ECG 
>450 msec, as per ICH E14: The Clinical Evaluation of QT/QTc Interval prolongation 
and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.
Criterion 15 was amended to remove zoledronic acid and denosumab as prohibited 
prior therapies.
Rationale: To ensure consistency with Investigator’s Brochure
Time and Events 
Schedule
Additional blood pressure measurements were added; blood pressure should now be 
measured at all study visits.
6.2.1. Non-
hematologic toxicities
The time permitted for dose interruption was amended from 21 days to 28-days to 
reflect the Investigator’s Brochure and to align with treatment cycles.
6.2.2. Hematologic 
Toxicities
Recommendations for dose modification/reductions for hematologic toxicity were 
updated to reflect the current Investigator’s Brochure (version 6.0). Updates are 
captured in Table 4.
The time permitted for dose interruption was amended from 21 days to 28-days to 
reflect the Investigator’s Brochure and to align with treatment cycles.
9.9. Safety
Additional serum chemistry tests have been added and albumin will now be measured 
at all visits requiring laboratory testing (not just at screening). These new clinical 
laboratory tests were not added due to any new safety signals and are compliant with 
recommendations in Investigator Brochure version 5.
Attachment 6: 
Anticipated Events
Additional anticipated events were included to align with the Investigator’s Brochure.
Rationale: To comply with feedback from US FDA regarding the evaluable biomarker population for efficacy 
and to simplify instructions for investigators.
9.1.2. Prescreening 
Phase for Biomarker 
Evaluation
All subjects in the study are required to have tumor tissue and a blood sample collected 
for analysis of biomarkers. Details of how those samples will be analyzed and which 
assays will be used were condensed and were moved to Section 9.7 Biomarkers. 
New text was added to clarify that potential subjects can enter the Prescreening Phase 
if they are on second-line therapy.
Rationale: To clarify that imaging scans may be collected during follow-up from subjects who discontinue 
treatment for reasons other than radiographic progression.
Time and Events 
Schedule; 9.1.6. 
Follow-up Phase
The sponsor intends to collect imaging scans from subjects who discontinue treatment 
for reasons other than radiographic progression, in order to determine radiographic 
progression-free survival, provided the subject does not withdraw consent for 
collection of images. Therefore, collection of imaging scans during the Follow-up 
Phase was clarified, including the collection window to be applied (ie, every 3 months 
±2 weeks).


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Applicable Section(s)
Description of Change(s)
Rationale: To clarify withdrawal from study categories and the testing procedures permitted based on the type of 
withdrawal.
10.1. Discontinuation 
of Study Treatment
Additional categories for withdrawal from the study treatment were included and the 
procedures permitted for each category of withdrawal were clarified.
10.2. Withdrawal from 
the Study
Clarification was added for follow-up visits to allow for telephone or chart review. 
Clarification was also added regarding subjects who withdraw consent for all study-
related procedures; these subjects must not be contacted by the investigator or the 
sponsor.
Rationale: Minor amendments
Title Page
The study name “Galahad” was added.
Time and Events 
Schedule
Clarifications were added regarding the collection window for follow-up visits, the 
collection of related serious adverse events, the collection of symptomatic skeletal 
events, and the collection of patient-reported outcomes. Collection and review of 
imaging scans was also updated.
In order to clarify when assessments occur after Cycle 7 (ie, from Cycle 8 onwards), an 
additional column was added for assessments that occur on every cycle. As a result, 
footnotes stipulating that study drug dispensation and treatment compliance are to be 
completed every cycle were deleted.
Time and Events 
Schedule; 9.5 
Pharmacodynamics
Added text to allow the collection of PBMCs at select sites only, and for collection 
PBMCs to be discontinued at the sponsor’s discretion, based on the data collected.
6.1. Study Drug 
Administration
Clarified that missed doses do not cause cycles to be delayed or restarted.
11.10. Interim 
Analysis; 16.1. Study-
specific Design 
Considerations
Text describing a preliminary assessment of safety and efficacy in the first 30 subjects 
was removed. Information regarding this assessment will be included in the statistical 
analysis plan.
16.1. Study-specific 
Design Considerations
Amended to reflect the new primary endpoint and clarified that frequency of scanning 
is consistent with requirements to assess rPFS by PCWG3 criteria.
16.2.3. Informed 
Consent
Removed language regarding the process for informed consent when prior consent of a 
subject is not possible because this study will not enroll subjects who cannot give prior 
informed consent.
Attachment 2: 
Summary of RECIST 
Criteria Version 1.1 
with Integration of 
PCWG3 for Evaluation 
of Response
Updated the definitions of best overall response based on PCWG3 criteria.
Attachment 4: 
Prohibited Medications 
That Could Potentially 
Cause QT Prolongation 
or Torsades de Pointes
Clarified that the table provided is not a complete list and that new medications may be 
considered as appropriate.
Investigator 
Agreement
Updated the sponsor’s responsible Medical Officer.


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Applicable Section(s)
Description of Change(s)
Rationale: Minor errors were noted and corrected
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made. 
Amendment 1 (7 July 2016)
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 5 July 2016.
Applicable Section(s)
Description of Change(s)
Rationale: ECG monitoring at every cycle was added due to FDA concern regarding higher ECG abnormalities 
in the elderly population.
Time and Events 
Schedule
ECG monitoring was added at every cycle.
9.9. Safety 
Evaluations
ECG monitoring procedures were clarified.
Rationale: FDA recommendation that toxicities which have not resolved within 21 days should undergo dose 
reduction or discontinuation.
6.2.1. Non-
hematologic 
Toxicities
Toxicities leading to dose modification should be resolved within 21 days, instead of 28 
days.
Rationale: FDA recommendation that a hematologist must be consulted in the event of >1 transfusion or that did 
not recover to Grade 1 or less after 28 days.
6.2.2. Hematologic 
Toxicities
The recommendation for subjects to see a hematologist was changed to a requirement in 
cases of hematologic toxicity that required >1 transfusion or that did not recover to 
Grade 1 or less after 28 days. 
Rationale: FoundationOne® is the trademarked name for the commercial assay and cannot be used for the 
sponsor-approved test.
9.1.2. Prescreening 
Phase
The FoundationOne® gene panel name was removed.


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SYNOPSIS 
A Phase 2 Efficacy and Safety Study of Niraparib in Men with Metastatic Castration-Resistant 
Prostate Cancer and DNA-Repair Anomalies
Niraparib is an orally available, highly selective poly (adenosine diphosphate [ADP]-ribose) polymerase 
(PARP) inhibitor, with activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair 
polymerases. Niraparib is being investigated for the treatment of ovarian, breast, and prostate tumors in 
subjects with DNA-repair anomalies.
OBJECTIVES, ENDPOINTS/ASSESSMENTS, AND HYPOTHESIS
Efficacy objectives will be evaluated for subjects who have either biallelic DNA-repair anomalies (BRCA 
or non-BRCA) as determined by a sponsor-validated blood- or tissue-based assay or germline pathogenic 
BRCA (BRCA1 or BRCA2) mutation.
Objectives
Endpoints/Assessments
Primary

To assess the efficacy of niraparib in subjects 
with measurable mCRPC and who have either 
biallelic DNA-repair anomalies in BRCA 
(BRCA1 or BRCA2) or germline BRCA

Objective response rate (ORR) of soft tissue (visceral or nodal 
disease) as defined by Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 with no evidence of bone progression 
according to the PCWG3 criteria
Secondary

To assess the efficacy of niraparib in subjects 
with measurable mCRPC and DNA-repair 
anomalies in biallelic non-BRCA (ATM, 
FANCA, 
PALB2, 
CHEK2, 
BRIP1, 
or 
HDAC2)

Objective response rate of soft tissue (visceral or nodal disease) 
as defined by RECIST 1.1 with no evidence of bone progression 
according to the PCWG3 criteria

To assess the efficacy of niraparib in subjects 
with mCRPC and DNA-repair anomalies

Circulating tumor cell (CTC) response defined as CTC=0 per 
7.5 mL blood at 8 weeks post-baseline in subjects with baseline 
CTC >0

To evaluate response outcomes of niraparib in 
subjects with mCRPC and DNA-repair 
anomalies

OS: time from enrollment to death from any cause

As defined by PCWG3:

rPFS: time from enrollment to radiographic progression or 
death from any cause, whichever occurs first

Time to radiographic progression

Time to PSA progression 

Time to symptomatic skeletal event (SSE)

To evaluate the safety and tolerability of 
niraparib

Incidence of adverse events

Clinical laboratory test results

To evaluate duration of tumor response

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
Abbreviations: ATM=Ataxia Telangiectasia Mutated gene; BRCA1=Breast Cancer gene 1; BRCA2=Breast Cancer gene 2; 
BRIP1=BRCA1 Interacting Protein C-terminal Helicase 1 gene; CHEK2=Checkpoint Kinase 2 gene; CR=complete 
response; CTC=circulating tumor cell; DNA=deoxyribonucleic acid; FANCA=Fanconi Anemia Complementation 
Group A gene; HDAC2=Histone Deacetylase 2 gene; mCRPC=metastatic castration-resistant prostate cancer; 
ORR=objective response rate; OS=overall survival; PALB2=Partner and Localizer of BRCA2 gene; PCWG3=Prostate 
Cancer Working Group 3; PR=partial response; PSA=prostate specific antigen; RECIST=Response Evaluation Criteria 
in Solid Tumors; rPFS=radiographic progression-free survival; SSE=symptomatic skeletal event


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Hypothesis
Niraparib will demonstrate a >15% ORR in subjects with mCRPC and DNA-repair anomalies who have 
measurable disease.
OVERVIEW OF STUDY DESIGN
This is a Phase 2, multicenter, open-label study to assess the efficacy and safety of once daily dosing of 
300 mg niraparib in male subjects over the age of 18 years with mCRPC and DNA-repair anomalies who 
have received prior taxane-based chemotherapy and AR-targeted therapy.
The study will assess up to approximately 120 subjects with measurable disease who are either biallelic 
BRCA/non-BRCA according to a sponsor-validated blood- or tissue-based assay or who have a germline 
pathogenic BRCA mutation (approximately 75 subjects with DNA-repair anomalies in BRCA [BRCA1 or 
BRCA2] and approximately 45 subjects with DNA-repair anomalies in non-BRCA [ATM, FANCA, 
PALB2, CHEK2, BRIP1, or HDAC2]). In addition, at least 90 subjects with non-measurable disease (ie, 
bone disease only) regardless of their DNA anomaly (ie, BRCA or non-BRCA) will be included to evaluate 
the activity of niraparib in this population. Efficacy objectives will be evaluated on subjects who have either 
biallelic DNA-repair anomalies as determined by a sponsor-validated blood- or tissue-based assay or 
germline pathogenic BRCA (BRCA1 or BRCA2) mutation. All subjects will be monitored for safety during 
the study period, and up to 30 days after the last dose of study drug. Treatment will continue until disease 
progression, unacceptable toxicity, death, or the sponsor terminates the study.
The study will consist of 5 phases; a Prescreening Phase, a Screening Phase, a Treatment Phase, a Follow-
up Phase, and a Long-term Extension Phase.
SUBJECT POPULATION
Male subjects over the age of 18 years with mCRPC and DNA-repair anomalies who have received prior 
taxane-based chemotherapy and AR-targeted therapy are eligible for the study.
DOSAGE AND ADMINISTRATION
The study drug, niraparib 300 mg, will be provided as capsules (3 x 100 mg) for once daily oral 
administration. The capsules must be swallowed whole. Subjects should take their dose in the morning 
(with or without food).
EFFICACY EVALUATIONS
The efficacy 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 these 
results will be used for the primary endpoint analyses. Scans will also be collected and stored by 
a central vendor for central review if indicated. 

serum PSA

survival status 

CTC

SSEs
PHARMACOKINETIC EVALUATIONS
Sparse PK sampling will be collected from all subjects in this study. Blood samples to measure plasma 
levels of niraparib and its metabolite, M1, will be obtained on Cycle 1 Day 1 and Cycle 2 Day 1 at predose, 
and between 1 to 3 hours and between 4 to 6 hours postdose. 


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PATIENT-REPORTED OUTCOMES EVALUATIONS
PROs will be measured as per the Time and Events Schedule utilizing paper versions of the Brief Pain 
Inventory - Short Form questionnaire (BPI-SF), the Functional Assessment of Cancer Therapy-Prostate 
questionnaire (FACT-P), and the Euro-QoL questionnaire (EQ-5D-5L).
BIOMARKER EVALUATIONS
Biomarker evaluations will be conducted as specified in the Time and Events Schedule. CTCs will be 
evaluated for response to study drug. Whole blood for RNA may be used to evaluate potential mechanisms 
of resistance that may be observed following treatment with niraparib. Circulating tumor DNA (ctDNA) 
may be used to screen for changes in the levels or types of DNA-repair anomalies observed over time, to 
monitor for potential markers of resistance to niraparib, and for concordance and bridging studies with 
tumor tissue.
SAFETY EVALUATIONS
Safety assessments will be based on medical review of AE reports and the results of vital sign 
measurements, ECGs, physical examinations, clinical laboratory tests, ECOG PS, and other safety 
evaluations at specified timepoints as described in the Time and Events Schedule.
STATISTICAL METHODS
For the primary objective with ORR endpoint in subjects with measurable mCRPC and DNA-repair 
anomalies in BRCA1 or BRCA2, the null hypothesis that the ORR is ≤15% will be tested against the 
alternate hypothesis that the ORR is ≥32%. Efficacy of niraparib will be declared if the lower bound of the 
2-sided 95% Confidence Interval (CI) for ORR is >15%. With approximately 75 subjects with measurable 
disease and DNA-repair anomalies in BRCA (BRCA1 or BRCA2), the study will have over 90% power 
such that the lower limit of the 95% CI for ORR exceeds 16%. Assuming an enrollment duration of 
approximately 24 months, it is anticipated that the final analysis for ORR will occur at approximately 
30 months (approximately 6 months from last subject enrolled).
For the secondary objective with ORR endpoint in subjects with measurable mCRPC and DNA-repair 
anomalies in biallelic non-BRCA (ATM, FANCA, PALB2, CHEK2, BRIP1, or HDAC2), the null 
hypothesis that the ORR is ≤15% will be tested against the alternate hypothesis that the ORR is ≥32%. With 
a 1-sided of 0.05 and power of 80%, up to 45 subjects with measurable mCRPC and DNA-repair 
anomalies in biallelic non-BRCA (ATM, FANCA, PALB2, CHEK2, BRIP1, or HDAC2) are to be enrolled 
based on Simon’s two-stage design. At end of Stage 1, approximately 14 subjects will be evaluated for
ORR after at least 1 post-treatment scan and a confirmatory scan for Stage 1. Future enrollment in this 
group may be terminated if 2 or fewer responses are observed in the first stage. Otherwise, enrollment may 
proceed to the second stage with a total of 45 subjects combined for the 2 stages, and the null hypothesis 
will be rejected if 10 or more responses are observed.
Assuming the historical CTC response rate (CTC RR) of 20% (based on unpublished data from Study COU-
AA-301) and the target CTC RR of 40%, at least 60 subjects with non-measurable disease will be required 
to provide a lower bound of the 2-sided 95% CI greater than 20%, with a probability of 0.9.


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Efficacy Analyses
The primary endpoint, ORR, will be calculated, and its 2-sided 95% exact CI will also be presented. The 
final analysis for ORR will be performed approximately 6 months after the last subject with measurable 
disease receives his first dose of study medication.
Pharmacokinetics and Exposure-Response
A population PK analysis of plasma concentration-time data of niraparib will be performed using nonlinear 
mixed-effects modeling to estimate oral clearance (CL/F) and oral volume of distribution (V/F). Other PK 
parameters may be evaluated as appropriate.  
Safety Analyses
Subjects who receive at least 1 dose of study drug will be analyzed for safety. The safety parameters to be 
evaluated are the incidence, intensity, and type of AEs, vital signs measurements, ECGs, physical 
examination (abnormalities will be recorded as AEs), and clinical laboratory results.






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c
Prescreening AEs: AEs and serious AEs related to blood or recent tumor tissue collection procedures, as well as death from any cause, will be collected for 
30 days after the procedures for subjects who sign the prescreening consent.
d
Main study informed consent: Main study consent must be signed prior to the conduct of any study-related procedures in the Screening Phase.
e
Medical History: Medical history obtained during the Prescreening Phase will be disease-specific only.
f
Whole blood for cytogenetics: A blood sample collected at screening will be stored for evaluation if the sponsor's medical monitor finds evaluation necessary for 
assessing niraparib-related risk for MDS/AML (eg, the subject develops MDS/AML). The screening mutation profile will be analyzed to determine whether any 
mutations were present prior to study treatment. Details on sample collection and analysis are in the laboratory manual.
g
ECGs: Standard 12-lead ECGs will be performed at screening, at every cycle through Cycle 7, at every 3 cycles thereafter, at the EoT visit, and as clinically 
indicated (see Section 9.9 for details of ECG collection). Any known electrolyte imbalance should be treated prior to performing the ECG.
h
CT or MRI; Bone scan: Chest, abdomen, and pelvis CT or MRI scans and whole body bone scans (99mTc) must be evaluated at screening. Scans performed 
≤8 weeks prior to Cycle 1 Day 1 may serve as screening scans. Subjects may have imaging performed within ±3 days of visits requiring images. After first 
documentation of objective response for soft tissue disease, repeat imaging is required 4 weeks later (+ 2 weeks) for confirmation per RECIST 1.1. Details for the 
timing of subsequent scans are provided in Section 9.2.1. Progression of bone disease requires, repeat imaging. Details for confirmation and repeat imaging are 
provided in Section 9.2.1. Any subjects who discontinue treatment due to unequivocal clinical progression must have scans performed at the EoT visit prior to 
subsequent therapy. CT or MRI and bone scans performed ≤6 weeks prior to the EoT visit may serve as EoT scans.
i
PRO Questionnaires: If multiple assessments are scheduled for the same timepoint, it is recommended that procedures be performed in the following sequence: 
PROs, ECGs, vital signs, and blood draw.
j
Clinical safety laboratory tests: tests include hematology, chemistry, liver function, and other panels (ie, testosterone, PSA, albumin, alkaline phosphatase, and 
CD4 count; see Section 9.9). Tests will be done at every cycle, except for testosterone, and CD4 count (for HIV-positive subjects only), which are to be done at 
screening only. Required laboratory tests must be performed within ±2 days of the scheduled visit.
k
Sparse PK sampling: blood samples for sparse PK sampling will be collected on Cycle 1 Day 1 and Cycle 2 Day 1 and will be obtained predose, and between 1 to 
3 hours and between 4 to 6 hours postdose in all subjects. On Cycle 1 Day 15, and on Day 1 of Cycles 3, 4, 5, and 7, blood samples for PK analysis will be 
obtained predose only in all subjects.
l
Biomarker collection on Cycle 1 Day 1: Circulating tumor cells, whole blood for RNA, and plasma for ctDNA samples are to be collected predose on Cycle 1 
Day 1.
m
EoT visit: Circulating tumor cells, whole blood for RNA, and plasma for ctDNA sampling will occur at the time of radiographic progression or EoT visit 
(whichever is first).


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ABBREVIATIONS
99mTc
technetium-99m
AE
adverse event
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
AR
androgen receptor
AST
aspartate aminotransferase
ATM
Ataxia Telangiectasia Mutated gene
AUC
area under the curve
BPI-SF
Brief Pain Inventory - Short Form questionnaire
BRCA1
Breast Cancer gene 1
BRCA2
Breast Cancer gene 2
BRIP1
BRCA1 Interacting Protein C-terminal Helicase 1 gene
CBC
complete blood count
CHEK2
Checkpoint Kinase 2 gene
CI
confidence interval
CNS
central nervous system
CR
complete response
CT
computed tomography
CTC
circulating tumor cells
ctDNA
circulating tumor DNA
CYP
cytochrome P450
DNA
deoxyribonucleic acid
DRD
DNA-repair defects
DRC
Data Review Committee
DSB
double-stranded breaks
ECG
electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
electronic case report form
EoT
End-of-Treatment
EQ-5D-5L
Euro-QoL questionnaire
FACT-P
Functional Assessment of Cancer Therapy-Prostate questionnaire
FANCA
Fanconi Anemia Complementation Group A gene
GCP
good clinical practice
GnRHa
gonadotropin releasing hormone analog
HDAC2
Histone Deacetylase 2 gene
HIV
human immunodeficiency virus
HR
homologous recombination
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
intent-to-treat
LFT
liver function test
LTE
Long-term Extension
mCRPC
metastatic castration-resistant prostate cancer
mCSPC
metastatic castration-sensitive prostate cancer
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse Events
ORR
objective response rate 
OS
overall survival
PALB2
Partner and Localizer of BRCA2 gene
PARP
poly (adenosine diphosphate [ADP]-ribose) polymerase
PCWG3
Prostate Cancer Working Group 3


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PK
pharmacokinetic(s)
P-gp
P-glycoprotein
PQC
Product Quality Complaint
PR
partial response
PRO
patient-reported outcome(s) 
PSA
prostate specific antigen
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
rPFS
radiographic progression-free survival
SAE
serious adverse event
SAP
statistical analysis plan
SSB
single stranded break
SSE
symptomatic skeletal event
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
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 activity against PARP-1 and PARP-2 deoxyribonucleic acid 
(DNA)-repair polymerases.13 Niraparib is being investigated for the treatment of ovarian, breast, 
and prostate tumors in patients with DNA-repair anomalies.
1.1.
Background and Design Rationale
PARPs are enzymes responsible for repair of DNA single-strand breaks (SSBs) through a process 
called base excision repair.1 PARP inhibition leads to an accumulation of unrepaired SSBs, which 
result in stalling and collapse of replication forks and, consequently, to double-stranded breaks 
(DSBs). Normally, DSBs are repaired through homologous recombination (HR). If not repaired, 
DSBs result in cell death. When tumor cells with DNA-repair defects involving the HR pathway 
(eg, Breast Cancer gene [BRCA]1, BRCA2) are treated with a PARP inhibitor, they are unable to 
efficiently and accurately repair DSBs, which creates a synthetic lethal condition.2,7 In men with 
metastatic castration-resistant prostate cancers (mCRPC), tumors with DNA-repair anomalies 
account for approximately 20% to 30% of the sporadic cancers.9,18
For many years, the established standard of care for men with mCRPC was docetaxel 
chemotherapy.4 More recently, androgen receptor (AR)-targeted agents such as abiraterone acetate 
(ZYTIGA®) in combination with prednisone and enzalutamide (XTANDI®) have improved time 
to progression and survival rates, when indirectly compared to docetaxel.10 However, there 
remains a subset of patients who either do not respond, or become refractory to these treatments. 
No approved therapeutic options are currently available for such patients. Platinum-based 
chemotherapy has been tested in a number of clinical studies in molecularly unselected prostate 
cancer patients with limited results and significant toxicities.3,5 PARP inhibition may be a 
treatment option for mCRPC patients with DNA-repair anomalies following chemotherapy and 
AR-targeted agents.
Recently, the PARP inhibitor, olaparib, was investigated in a Phase 2 study to assess efficacy and 
safety in patients with mCRPC post-chemotherapy and AR-targeted agents.16 Genetic sequencing 
identified homozygous deletions, deleterious mutations, or both in DNA-repair genes, including, 
but not limited to BRCA1, BRCA2, Ataxia Telangiectasia Mutated gene (ATM), Fanconi anemia 
genes, and Checkpoint Kinase 2 gene (CHEK2) in tumor samples.16 Sixteen of 49 patients had a 
response (33%; 95% confidence interval [CI]: 20%, 48%). Response was defined as one or more 
of the following: objective response, circulating tumor cell (CTC) conversion, or prostate specific 
antigen (PSA) decline ≤50%. Of these 16 patients, 14 (88%) had a response to olaparib and were 
biomarker-positive for anomalies in DNA-repair genes, including all 7 patients with BRCA2 loss 
(4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 patients with ATM 
aberrations. Conversely, only 2 of 33 biomarker-negative patient tumors (6%) had a response. 
Radiographic progression-free survival (rPFS) was significantly longer in the biomarker-positive 
group than in the biomarker-negative group (median: 9.8 versus 2.7 months, respectively). Overall 
survival (OS) was also prolonged in the biomarker-positive group versus the biomarker-negative 
group (median: 13.8 months versus 7.5 months, respectively).


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Taken together, the nonclinical and clinical data, and lack of available treatment options, provide 
a strong rationale to investigate the role of PARP inhibition with niraparib in mCRPC patients and 
DNA-repair anomalies following chemotherapy and approved AR-targeted agents.
1.2.
Summary of Available Nonclinical and Clinical Data
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 Investigator's Brochure.12
Nonclinical Studies
In cancer cell lines that have been silenced for BRCA1 or BRCA2 genes, or that have BRCA1 or 
BRCA2 mutations, niraparib demonstrates anti-proliferative activity due to cell cycle arrest, 
followed by apoptosis. In vivo studies in mice showed that niraparib has antitumor activity against 
BRCA1-deficient breast cancer, BRCA2-deficient pancreatic cancer, and serous ovarian cancer.
Niraparib is not a potent inhibitor or inducer of cytochrome P450 (CYP) enzymes; therefore, it is 
considered to have low potential to cause drug-drug interactions. However, preclinical data show 
that niraparib is a weak inducer of CYP1A2 but not M1. Niraparib is a low clearance drug, and 
limited metabolism with involvement of multiple metabolic enzymes (both CYPs and non-CYPs) 
was observed in vitro. Therefore, no major changes in niraparib pharmacokinetics (PK) are 
expected when co-administered with modulators of CYP enzymes. Niraparib is a P-gp substrate. 
In animal studies, distribution of niraparib to the central nervous system (CNS) was observed; 
however, niraparib had no effect on neurological function in a CNS safety study using conscious 
mice. QTc interval was unaffected in anesthetized dogs; however, mean arterial pressure, heart 
rate, and QRS cardiac interval were increased. In repeat-dose toxicity studies in rats and dogs, 
hematologic toxicities were observed but resolved by the end of the recovery period (typically 
15 to 28 days).
Clinical Studies
Niraparib is currently being investigated in ongoing Phase 2 and 3 registration clinical studies in 
ovarian and breast cancer. Niraparib has been evaluated in 144 subjects in Phase 1 studies (as a 
monotherapy and in combination). In Study PN001, 104 subjects with solid tumors, including 
subjects with prostate cancer (n=23) were evaluated at doses up to 400 mg once daily. 
Dose-proportional PK with an elimination half-life of 30 to 40 hours were observed. Antitumor 
activity with niraparib was observed in subjects at dose levels ranging from 60 to 400 mg. The 
dose limiting toxicity at 400 mg once daily was thrombocytopenia; the maximum tolerated dose 
and recommended Phase 2 dose for further development of niraparib was 300 mg.
In Study PN001, all subjects (104) were reported with adverse events (AEs) and 90% of subjects 
were reported with drug-related AEs. Serious AEs (SAEs) were reported in 34% of subjects and 
10% of subjects were reported with drug-related SAEs. Only 3% of subjects discontinued 
treatment due to drug-related SAEs. The most common AEs (>30%) were nausea (57%), fatigue 
(56%), anemia (49%), constipation and vomiting (39% each), thrombocytopenia (35%), and 
decreased appetite (34%). The AEs responsible for discontinuation were electrocardiogram (ECG) 


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QT prolonged, fatigue, thrombocytopenia, intestinal obstruction, neoplasm malignant (disease 
progression), papilledema, pneumonitis, and vomiting. Six subjects died during the study: 4 due 
to disease progression, 1 due to sepsis, and 1 due to cerebral infarction. The safety profile of 
niraparib demonstrates AEs primarily within the blood and lymphatic and gastrointestinal System 
Organ Classes that are generally mild to moderate in severity and resolve with dose 
reduction/discontinuation.
1.3.
Benefit/Risk Assessment
Niraparib, administered as monotherapy, is anticipated to have a positive benefit-risk profile when 
used for the treatment of patients with mCRPC and DNA-repair anomalies, as proposed for this 
study. This assessment is based on the following:

During clinical development in subjects with advanced solid tumors, the most common AEs 
(>25% of subjects) were nausea, fatigue, anemia, vomiting, thrombocytopenia, constipation, 
and decreased appetite. A small number of cases of myelodysplastic syndrome (MDS)/ acute 
myeloid leukemia (AML), including fatal cases, have been reported in clinical studies of 
niraparib. The safety profile of niraparib demonstrates AEs that are generally mild to moderate 
in severity and are manageable with dose interruption or dose reduction. Preliminary data 
obtained from the current study suggest a similar profile in prostate cancer to the established 
safety profile of niraparib in other indications, with no new safety signals being observed to 
date.

Dose-proportional PK with an elimination half-life of 30 to 40 hours were observed at doses 
up to 400 mg once daily in patients with solid tumors and with prostate cancer. Antitumor 
activity with niraparib was observed in subjects at dose levels ranging from 60 to 400 mg. The 
dose limiting toxicity at 400 mg once daily was thrombocytopenia; the maximum tolerated 
dose and recommended Phase 2 dose for further development of niraparib was 300 mg.

While niraparib is an investigational agent in the metastatic prostate cancer population, it has 
been approved for the treatment of ovarian cancer. The safety profile of niraparib has been 
characterized in clinical studies discussed in Section 1.2. Preliminary data from sponsor 
studies suggest that the safety profile of niraparib in patients with metastatic prostate cancer 
is similar to that described in the Zejula® label.24,25 Known toxicities for niraparib include 
gastrointestinal events, hematological events (ie, thrombocytopenia, neutropenia, anemia), 
and hypertension. These toxicities are managed by monitoring the appropriate laboratory 
values and making the appropriate medical interventions, such as dose interruptions. The 
protocol also includes a targeted monitoring plan and treatment guidelines to ensure 
appropriate management of toxicities.
Given that the anticipated toxicities of niraparib are recognizable through medical oversight and 
laboratory monitoring and are able to be managed medically, and there is a potential for increased 
efficacy in patients with incurable mCRPC, the sponsor considers that there is a positive 
benefit/risk profile and strong rationale for evaluating niraparib, a PARP inhibitor, in  treatment of 
mCRPC patients with DNA-repair anomalies. 


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2.
OBJECTIVES, ENDPOINTS/ASSESSMENTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints/Assessments
Efficacy objectives will be evaluated for subjects meeting the selection criteria that are described 
in Table 5.
Table 1:
Study Objectives and Endpoints/Assessments
Objectives
Endpoints/Assessments
Primary

To assess the efficacy of niraparib in 
subjects with measurable mCRPC and 
who have either biallelic DNA-repair 
anomalies in BRCA (BRCA1 or BRCA2) 
or germline BRCA

Objective response rate (ORR) of soft tissue (visceral or 
nodal disease) as defined by Response Evaluation Criteria 
in Solid Tumors (RECIST) 1.1 with no evidence of bone 
progression according to the PCWG3 criteria20
Secondary

To assess the efficacy of niraparib in 
subjects with measurable mCRPC and 
DNA-repair anomalies in biallelic non-
BRCA (ATM FANCA, PALB2, CHEK2, 
BRIP1, or HDAC2)

Objective response rate of soft tissue (visceral or nodal 
disease) as defined by RECIST 1.1 with no evidence of 
bone progression according to the PCWG3 criteria20

To assess the efficacy of niraparib in 
subjects with mCRPC and DNA-repair 
anomalies

CTC response defined as CTC=0 per 7.5 mL blood at 8 
weeks post-baseline in subjects with baseline CTC >0

To 
evaluate 
response 
outcomes 
of 
niraparib in subjects with mCRPC and 
DNA-repair anomalies

OS: time from enrollment to death from any cause

As defined by PCWG3:20

rPFS: time from enrollment to radiographic 
progression or death from any cause, whichever 
occurs first

Time to radiographic progression

Time to PSA progression 

Time to symptomatic skeletal event (SSE)

To evaluate the safety and tolerability of 
niraparib

Incidence of adverse events

Clinical laboratory test results

To evaluate duration of tumor response

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
Exploratory

To assess the efficacy of niraparib in 
subjects with mCRPC and DNA-repair 
anomalies

Response rate (RR): defined as 1 of the following by 
PCWG3:20

Objective response (confirmed per RECIST 1.1), or

Conversion of CTC from ≥5 cells per 7.5 mL blood 
at baseline to <5 cells per 7.5 mL blood nadir, 
confirmed by a second consecutive value obtained 4 
or more weeks later, or


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Objectives
Endpoints/Assessments

PSA decline of ≥50%, measured twice 3 to 4 weeks 
apart

Time to unequivocal clinical progression

To evaluate the population PK of niraparib 
and exposure-response relationships

Analysis of niraparib oral clearance (CL/F), oral volume 
of distribution (V/F), and derived measures of exposure 
(eg, area under the curve [AUC])

Effect of demographic and physio-pathological covariates 
on niraparib PK parameters

Analysis of relationships between exposure and safety or 
efficacy endpoints.

To evaluate the steady-state PK of 
niraparib and its metabolite M1

Cmax, Tmax, Ctrough, AUC0-24 of niraparib and its metabolite 
M1 in a subset of subjects

To evaluate the concordance between 
tissue-based 
and 
blood-based 
methodologies for detection of genomic 
alterations

Comparison of gene alterations in DNA from tissue and 
in circulating tumor DNA (ctDNA) from plasma

To evaluate potential DNA and RNA 
biomarkers predictive of response and 
resistance

Changes in the levels or types of DNA and RNA 
biomarkers observed over time

To evaluate the effect of niraparib on 
circulating tumor cells (CTCs)

Changes in CTC counts observed over time

To evaluate subject-relevant experiences 
(disease-related 
symptoms, 
treatment-
related symptoms, and health-related 
quality of life)

Time to deterioration in subject-relevant experiences
Abbreviations: ATM=Ataxia Telangiectasia Mutated gene; AUC=area under the curve; BRCA1=Breast Cancer gene 1; 
BRCA2= Breast Cancer gene 2; BRIP1=BRCA1 Interacting Protein C-terminal Helicase 1 gene; CHEK2=Checkpoint 
Kinase 2 gene; CR=complete response; CTC=circulating tumor cell; ctDNA=circulating tumor DNA; 
DNA=deoxyribonucleic acid; FANCA=Fanconi Anemia Complementation Group A gene; HDAC2=Histone 
Deacetylase 2 gene; mCRPC=metastatic castration-resistant prostate cancer; ORR=objective response rate; OS=overall 
survival; PALB2=Partner and Localizer of BRCA2 gene; PCWG3=Prostate Cancer Working Group 3; PD=progressive 
disease; PK=pharmacokinetics; PR=partial response; PSA=prostate specific antigen; RECIST= Response Evaluation 
Criteria in Solid Tumors; rPFS=radiographic progression-free survival; RNA=ribonucleic acid; RR=response rate; 
SSE=symptomatic skeletal event.
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2.
Hypothesis
Niraparib will demonstrate a >15% ORR in subjects with mCRPC and DNA-repair anomalies who 
have measurable disease.
3.
STUDY DESIGN
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.
This is a Phase 2, multicenter, open-label study to assess the efficacy and safety of once daily 
dosing of 300 mg niraparib in male subjects over the age of 18 years with mCRPC and DNA-repair 


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anomalies who have received prior taxane-based chemotherapy and AR-targeted therapy. The 
study will assess up to approximately 120 subjects with measurable disease who are biomarker-
positive, as define in Section 9.7 (approximately 75 subjects with DNA-repair anomalies in BRCA 
[BRCA1 or BRCA2] and approximately 45 subjects with biallelic DNA-repair anomalies in non-
BRCA [ATM, FANCA, PALB2, CHEK2, BRIP1, or HDAC2]). In addition, at least 90 subjects 
with non-measurable disease (ie, bone disease only) regardless of their DNA anomaly (ie, BRCA 
or non-BRCA) will be included to evaluate the activity of niraparib in this population. Efficacy 
objectives will be evaluated for subjects meeting the selection criteria that are described in Table 5. 
All subjects will be monitored for safety during the study period, and up to 30 days after the last 
dose of study drug. Treatment will continue until disease progression, unacceptable toxicity, death,
or the sponsor terminates the study (see Section 10).
The study will consist of 5 phases; a Prescreening Phase, a Screening Phase, a Treatment Phase, a 
Follow-up Phase, and a Long-term Extension Phase (see Section 9.1 for details). 
4.
SUBJECT POPULATION
Male subjects over the age of 18 years with mCRPC and DNA-repair anomalies (biallelic 
mutations and germline pathogenic mutations only for BRCA1 or BRCA2 mutations) who 
received prior taxane-based chemotherapy and AR-targeted therapy (second-generation or later)
are eligible for the study.
4.1.
Prescreening Eligibility Criteria
1.
Signed prescreening informed consent form (ICF).
2.
Criterion modified per Amendment 3.  
2.1. Criterion modified per Amendment 6.
2.2. Willing to provide a tumor tissue sample (archival or recently collected), and a blood 
sample for analysis of DNA-repair anomalies using a sponsor-validated assay.
3.
Criterion modified per Amendment 3.
3.1. Criterion modified per Amendment 5.
3.2. Criterion modified per Amendment 7.
3.3 Must have received or be currently on at least 1 taxane-based chemotherapy for 
metastatic prostate cancer and at least 1 AR-targeted (second-generation or later) therapy.
4.
Criterion modified per Amendment 3.
4.1. Criterion deleted per Amendment 4.


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4.2.
Inclusion Criteria
1.
Male
2.
>18 years of age (or the legal age of consent in the jurisdiction in which the study is taking 
place).
3.
Signed main study ICF indicating that the subject understands the purpose of, and 
procedures required for, the study and is willing to participate in the study.
4.
Criterion modified per Amendment 2.
4.1. Histologically confirmed prostate cancer (mixed histology is acceptable, with the 
exception of the small cell pure phenotype, which is excluded).
5.
Criterion modified per Amendment 2.
5.1. Criterion modified per Amendment 3.
5.2. Criterion modified per Amendment 5.
5.3. Criterion modified per Amendment 6.
5.4. Received a taxane-based chemotherapy for the treatment of metastatic prostate cancer 
with evidence of disease progression on or after treatment, or discontinued from a taxane-
based chemotherapy due to an adverse event.
6.
Criterion modified per Amendment 2.
6.1. Criterion modified per Amendment 3. 
6.2. Criterion modified per Amendment 5.
6.3. Criterion modified per Amendment 6.
6.4. Criterion modified per Amendment 7.
6.5. Received a second-generation or later AR-targeted therapy (for example, abiraterone 
acetate plus prednisone, enzalutamide, apalutamide) for the treatment of metastatic 
prostate cancer with evidence of disease progression or non-metastatic castration-resistant 
prostate cancer with evidence of subsequent metastasis.
7.
Criterion modified per Amendment 3. 
7.1. Criterion modified per Amendment 7.
7.2. Biomarker-positive by at least one of the following criteria (see Section 9.7):
a.
Biallelic DNA-repair anomaly (refer to Table 5) based on a sponsor-validated 
blood or tissue assay.
b. Germline pathogenic BRCA1 or BRCA2 by any test (somatic local results must 
be confirmed as positive by the sponsor-validated assay before dosing).
8.
Criterion modified per Amendment 2.
8.1. Criterion modified per Amendment 4.


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8.2. Progression of metastatic prostate cancer in the setting of castrate levels of 
testosterone ≤50 ng/dL on a gonadotropin releasing hormone analog (GnRHa), or history 
of bilateral orchiectomy 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).20 The PSA level at the screening visit should be ≥1 μg/L 
(1 ng/mL).
b.
Radiographic progression of soft tissue by RECIST 1.1 or bone disease by 
PCWG3 criteria20 as defined below:
I.
Soft tissue disease (measurable) by RECIST 1.1 defined as having one 
or more of the following:
i. Nodal disease (pelvic or extrapelvic [retroperitoneal, 
mediastinal, thoracic, other]) with lesions ≥1.5 cm in the short 
axis.
ii. Visceral disease (lung, liver, adrenal) with lesions ≥1 cm in the 
long axis.
II.
Bone disease (non-measurable) defined as having bone lesions in the
absence of measurable soft tissue disease.
9.
Must be able to continue GnRHa during the course of the study if not surgically castrate.
10.
Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤2 (see 
Attachment 3).
11.
Must be able to swallow whole capsules.
12.
Subject must agree to use medically accepted and highly effective methods of 
contraception during the course of the study and for 3 months after the last dose of study 
drug.
13.
To avoid risk of drug exposure through the ejaculate (even men with vasectomies), 
subjects must agree while on study drug and for 3 months following the last dose of study 
drug to:
a.
Use a condom during sexual activity.
b.
Not donate sperm.
14.
Criterion modified per Amendment 2.
14.1. Criterion modified per Amendment 4.
14.2. Criterion modified per Amendment 5.
14.3. Criterion modified per Amendment 6.
14.4. At screening, the following laboratory parameters must be met:
a.
Absolute neutrophil count (ANC) ≥1.5 x 109/L
b.
Hemoglobin ≥9.0 g/dL


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c.
Platelet count ≥100 x 109/L
d.
Serum albumin ≥3 g/dL
e.
Creatinine clearance ≥30 mL/min 
f.
Criterion deleted per Amendment 5.
g.
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 direct bilirubin is 
≤1.5 x ULN, subject may be eligible)
h.
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤3.0 x ULN
i.
CTC count of ≥1 cells/7.5 mL blood (required only for patients with 
non-measurable soft tissue disease by RECIST 1.1)
4.3.
Exclusion Criteria
1.
Prior treatment with a PARP inhibitor.
2.
Criterion modified per Amendment 2. 
2.1. Prior platinum-based chemotherapy for the treatment of prostate cancer.
3.
Known history or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid 
leukemia (AML).
4.
Criterion modified per Amendment 5.
4.1. Symptomatic or impending cord compression, except if subject has received 
definitive treatment for this and demonstrates evidence of clinically stable disease.
5.
Criterion modified per Amendment 5.
5.1. Symptomatic brain metastases.
6.
Known allergies, hypersensitivity, or intolerance to niraparib or its excipients (refer to 
Investigator's Brochure).12
7.
Any condition for which, in the opinion of the investigator or sponsor, 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.
8.
Known disorder affecting gastrointestinal absorption.
9.
Active cancer (other than prostate cancer; or basal cell or squamous cell skin cancer, 
non-muscle invasive bladder cancer [stages pTaG1 and pTaG2], or any other cancer in 
situ currently in complete remission) within 2 years prior to Cycle 1 Day 1.
10.
Criterion modified per Amendment 5.


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10.1
Prior palliative radiotherapy ≤7 days prior to Cycle 1 Day 1. Radiotherapy given 
>7 days prior to Cycle 1 Day 1 is permitted as long as any AEs associated with 
radiotherapy have resolved to Grade 1 or baseline.
11.
Criterion modified per Amendment 2.
11.1. Criterion deleted per Amendment 5
12.
Criterion deleted per Amendment 3.
13.
History of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, 
ventricular fibrillation, torsades de pointes).
14.
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 14.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 at screening
e.
An acquired immunodeficiency syndrome-defining opportunistic infection 
within 6 months of the start of screening
15.
Criterion modified per Amendment 2.
15.1. Criterion modified per Amendment 6.
15.2. ≤14 days prior to Cycle 1 Day 1 had:
a.
a transfusion (platelets or red blood cells)
b.
chemotherapy
c.
hematopoietic growth factors
16.
Criterion deleted per Amendment 5.
17.
Criterion modified per Amendment 5.
17.1. Subjects with uncontrolled (persistent) hypertension defined as systolic blood 
pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg despite medical 
management.
5.
TREATMENT ALLOCATION AND BLINDING
This is an open-label, single-treatment study; therefore, blinding and randomization procedures 
are not applicable.


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6.
DOSAGE AND ADMINISTRATION
For the purpose of this study, ‘study drug’ refers to niraparib. All dosing information must be 
recorded in the electronic case report form (eCRF). The 300 mg once daily dose was chosen based 
on the PK, pharmacodynamics, clinical activity, safety, and tolerability profiles of niraparib,12 and 
is the same as the dose under investigation in two Phase 3 studies in subjects with ovarian and 
breast cancer.
6.1.
Study Drug Administration
The study drug, niraparib 300 mg, will be provided as capsules (3 x 100 mg) for once daily oral 
administration. The capsules must be swallowed whole. Subjects should take their dose in the 
morning (with or without food). Although not considered study medication, subjects who have not 
undergone surgical castration must continue to receive regularly prescribed GnRHa. 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.
A treatment cycle is defined as 28 days, irrespective of missed doses. Subjects will begin taking 
study drug on Day 1 of Cycle 1. Sufficient study drug for each treatment cycle will be distributed 
on the first day of each cycle. If subjects miss a dose, then that dose should be replaced if the 
subject remembers within an approximate 12-hour window. Otherwise, subjects should take the 
next dose the following day, without compensating for the missed dose. Missed doses should be 
recorded in the eCRF.
6.2.
Dose Modification and Management of Toxicity
All dose interruptions and dose reductions (including missed doses) and the reason for the 
interruption/reduction are to be recorded in the eCRF. Management of toxicities should be 
performed as detailed in Sections 6.2.1 and 6.2.2. Once the dose of study drug is reduced, any 
re-escalation to a full starting dose must be discussed in advance with the sponsor’s medical 
monitor. 
6.2.1.
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. Patients experiencing treatment-related hypertensive crisis or who have a confirmed 
diagnosis of posterior reversible encephalopathy syndrome will have study drug permanently 
discontinued. Dose reduction for AE management should be performed as described in Table 2.
It is recommended that subjects be referred to a cardiologist for further evaluation if they meet any 
of the following criteria:

QTcF on ECG >480 msec at any visit. 

Persistent hypertension ≥Grade 3 despite medical intervention.


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Table 2:
Dose reduction for Drug-related Non-hematologic Toxicities
Event
Restarting Dose
After first Grade 3 or 4 treatment-related SAE/AE
200 mg QD
After second Grade 3 or 4 treatment-related SAE/AE
100 mg QD
After third Grade 3 or 4 treatment-related SAE/AE for ≥28 days
Discontinue or contact sponsor
QD=once daily; SAE/AE=serious adverse event/adverse event
6.2.1.1.
Hepatic Toxicities
Hepatic toxicities are known potential side effect of niraparib.12 Table 3 provides dose 
recommendations for subjects who develop liver function test (LFT) abnormalities during 
treatment with niraparib. During dose interruptions, LFTs should be monitored at least weekly. 
For Grade ≥2 LFT abnormalities, 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.
Table 3:
Dose Modification Criteria for AST/ALT/Bilirubin Abnormalities for Niraparib
Toxicity Grade
Dose of Niraparib
Grade 1 
No change.
Grade 2
No change.
Grade 3
Interrupt until return to baseline. When AST/ALT/bilirubin are confirmed 
Grade 1 or baseline, niraparib can be resumed at previous dose.
Recurrence Grade 3
Interrupt until return to baseline. Then, resume at one dose level reduction. 
Grade 4
Must be interrupted and discussed with medical monitor.a
ALT=alanine aminotransferase; AST=aspartate aminotransferase
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 or AST >20 x ULN) 
anytime while receiving niraparib, subjects should be discontinued from treatment and retreatment 
should not be attempted. Re-escalation of 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 the study drug treatment.
6.2.2.
Hematologic Toxicities
Dose interruption/modification criteria for hematologic toxicities will be based on the blood counts 
outlined in Table 4. If dose interruption or modification is required at any point on study due to 
hematologic toxicity, weekly blood draws for complete blood count (CBC) will be monitored until 
AE resolution (to the specified levels in Table 4). To ensure safety of the new dose, weekly blood 
draws for CBC will also be required for an additional 28 days after AE resolution, after which, 
monitoring per the Time and Events Schedule may resume.
Study drug dose modification/reduction criteria for thrombocytopenia and neutropenia will be 
based on the criteria outlined in Table 4. For the management of anemia, supportive measures such 


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as blood transfusion 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, study drug should be interrupted until resolution to <Grade 3, and 
restarted after discussion with the sponsor to determine if a dose level reduction is required.
The site should contact the sponsor for discussion and consider discontinuation of niraparib if 
hematologic toxicity has not recovered to Grade 1 or baseline after 28 days of dose interruption, 
or a diagnosis of MDS/AML is confirmed by a hematologist. 
Table 4:
Dose Modification/Reductions for Hematologic Toxicity (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. 
Grade ≥3 
Interrupt until ≤Grade 1 or baseline, then:
If subject was on 300 mg, restart at 200 mg (ie, 1 dose 
level reduction)a
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 100 mg, permanently discontinue 
study drug
Weekly monitoring for 28 days is recommended after 
restarting dose.
Second occurrence Grade ≥3
Interrupt until ≤Grade 1 or baseline and restart at 1 
dose-level reduction.a Weekly monitoring for 28 days 
after restarting dose is recommended.
If subject was on 100 mg, permanently discontinue study 
drug.
Third occurrence Grade ≥3
Permanently discontinue. 
a
For each dose-level reduction, decrease dose by 100 mg or 1 capsule of niraparib.
Notes:

For subjects with a platelet count ≤10,000 cells/µL, prophylactic platelet transfusion per guidelines may be 
considered. For subjects taking anti-coagulant or anti-platelet therapy, consider the risk/benefit of 
interrupting these drugs or prophylactic transfusion at an alternative threshold such as ≤20,000 cells/µL.

Supportive measures like blood transfusions may be performed as deemed necessary by the investigator.

Weekly monitoring and/or interruption are not required if values return to baseline levels.

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.
6.3.
Treatment Interruptions for Planned Procedures
Niraparib should be held for at least 24 hours prior to planned procedures that require 
hospitalization and should be resumed only when AEs related to the procedure are improved to 
Grade 1 or resolved.


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7.
TREATMENT COMPLIANCE
A count of all study drug provided by the sponsor will be conducted during the Treatment Phase 
of this study. Study drug will be dispensed and dosing compliance will be assessed at study visits 
as described in the Time and Events Schedule. 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 drug 
received, to whom dispensed (subject-by-subject accounting), and accounts of any study drug 
accidentally or deliberately destroyed. The amount of study drug 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 drug supplied, dispensed, and subsequently destroyed or returned to the 
sponsor or its representative (see also Section 14.5).
8.
CONCOMITANT THERAPY
Concomitant therapies must be recorded throughout the study beginning with the signing of the 
main study informed consent to 30 days after the last dose of study drug. All therapies different 
from the study drug must be recorded 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 interventional investigational drug or device study is prohibited 
during the Treatment Phase.
8.1.
Prohibited Concomitant Medications
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered:
1.
Chemotherapeutic, biologic, hormonal (exception: subjects must continue GnRHa 
during the course of the study if not surgically castrate), or other agents with 
antitumor effect against prostate cancer.
2.
Live virus vaccines. An increased risk of infection by the administration of live virus 
vaccines has been observed with conventional chemotherapy. Effects with niraparib 
are unknown and therefore live virus vaccines should not be administered. Note that 
inactivated bacterial and virus vaccines are permitted.
8.2.
Restricted Concomitant Medications
1.
Niraparib is a weak inducer of CYP1A2 in vitro; therefore, caution should be used 
with drugs that are sensitive substrates of CYP1A2 or moderately sensitive substrates 
of CYP1A2 with a narrow therapeutic range (refer to the Investigator’s Brochure12; 
for additional information, see Attachment 5).
2.
Although no large changes in the mean QTc interval (>20 msec) were detected in a 
study following the treatment of niraparib 300 mg once daily, caution should be used 
for medications that could potentially cause QT prolongation or torsades de pointes.17


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9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, PK, biomarker, 
Patient-reported Outcomes (PRO), and safety measurements applicable to this study. Medical 
resource utilization data will also be collected; refer to Section 9.8 for details.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures 
be performed in the following sequence: PROs, ECGs, vital signs, and blood draw. Blood 
collections for PK assessments should be kept as close to the specified time as possible. Other 
measurements may be done earlier than specified timepoints if needed. Actual dates and times of 
assessments will be recorded in the source documentation and eCRF.
For each subject, the maximum amount of blood drawn will not exceed 70 mL at any visit. Refer 
to the 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.
Prescreening Phase for Biomarker Evaluation
The Prescreening Phase will evaluate if a potential study subject is biomarker-positive for 
DNA-repair anomalies (see Section 9.7). All subjects will be required to sign a specific ICF for 
the Prescreening Phase and provide baseline demographic characteristics and disease-specific 
medical history. The Prescreening Phase may occur at any time for subjects with mCRPC prior to 
the Screening Phase.
During the Prescreening or Screening Phase, a blood sample will be collected. In addition, a tumor 
tissue sample (either archival or recently collected) should also be collected. If no tumor tissue is 
available, then the subject will be asked to have a new tumor tissue sample collected. Tissue 
(archival or recently collected) may also be used to determine eligibility.
If the subject is biomarker-positive by the sponsor-validated blood- or tissue-based assay, then he 
is eligible to enter the Screening Phase. Subjects who are positive for pathogenic BRCA1 or 
BRCA2 mutations based on local test results (somatic or germline) can enter the Screening Phase.
AEs and SAEs related to the blood or recent tissue collection procedures will be collected for 
30 days after the procedures. Tissue samples collected during the Prescreening Phase will be 
analyzed for concordance with the blood-based sample results.
9.1.3.
Screening Phase
All biomarker-positive subjects must sign the main study ICF prior to the conduct of any 
study-related procedures in the Screening Phase. Subjects who are positive for germline 
pathogenic BRCA1 or BRCA2 mutations based on local test results (blood or saliva) can be 
screened and enter the treatment phase and subjects who are positive for somatic pathogenic 
BRCA1 or BRCA2 mutations (blood, saliva, or tissue) based on local results must be confirmed 


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as positive by the sponsor-validated assay during screening before being able to enter the treatment 
phase.
Eligibility criteria will be reviewed and a complete clinical evaluation will be performed as 
specified in the Time and Events Schedule. Screening procedures will be performed up to 28 days 
before Cycle 1 Day 1, unless otherwise specified. Imaging will be accepted up to 8 weeks prior to 
Cycle 1 Day 1. Screening clinical safety laboratory evaluations can be used for Cycle 1 Day 1 
assessments if performed within 14 days of Cycle 1.
Subjects who do not meet all inclusion criteria, or who meet an exclusion criterion, may be 
rescreened. Rescreening is at the discretion of the investigator. 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, computed tomography (CT)/magnetic resonance 
imaging (MRI) and bone scans (if still within 8 weeks of Cycle 1 Day 1) to determine eligibility 
if not the reason for the rescreening.
9.1.4.
Treatment Phase
The Treatment Phase will begin at Cycle 1 Day 1 and will continue until the study drug is 
discontinued. The last measurements taken on Day 1 of Cycle 1 before administration of the study 
drug or at screening (whichever value was last) will be defined as the baseline values. Visits for 
each cycle will have a ±3-day window, unless otherwise specified. Study visits will be calculated 
from the Cycle 1 Day 1 date, irrespective of any treatment interruptions. Subjects may have 
imaging performed within ±3 days of visits requiring images. Refer to the Time and Events 
Schedule for treatment visits and assessments during the Treatment Phase.
For PK sampling days, the subject must not take the study drug at home on the morning of study 
visits. Study drug should be taken at the site. Details of PK sampling days and times are provided 
in the Time and Events Schedule. Additional details regarding PK sampling are provided in 
Section 9.3. Details of blood sample handling and storage procedures for PK are provided in the 
laboratory manual.
Clinical evaluations and laboratory studies may be repeated more frequently, if clinically 
indicated. Study drug treatment will continue until disease progression, unacceptable toxicity, 
death, or the sponsor terminates the study (see Section 10). Once the subject discontinues study 
drug, the subject must complete the End-of-Treatment (EoT) visit within 30 (±5) days after the 
last dose of study drug, and enter the Follow-up Phase. (Note: for subjects with a dose interruption 
who discontinue study drug, the EoT visit must occur within 30 [±14] days after the last dose of 
study drug).
9.1.5.
End-of-Treatment Visit
An EoT visit must occur 30 (±5) days after the last dose of study drug or prior to administration 
of a new anti-prostate cancer therapy, whichever occurs first. (Note: for subjects with a dose 
interruption who discontinue study drug, the EoT visit must occur within 30 [±14] days after the 


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last dose of study drug). If a subject is unable to return to the site for the EoT visit, the subject 
should be contacted to collect AEs that occurred though 30 days after the last dose of study drug.
9.1.6.
Follow-up Phase
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 (12 weeks 
±2 weeks) from the EoT visit until confirmed radiographic progression, provided the subject has 
not started a subsequent treatment for prostate cancer and 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. In addition, survival follow-up and SSEs 
will be performed every 3 months (12 weeks ±2 weeks) either via clinic visits, telephone 
interview, chart review, or other convenient methods. Deaths regardless of causality and SAEs 
thought to be related to study drugs (including diagnosis of MDS/AML) will be collected and 
reported within 24 hours of discovery or notification of the event. 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.
9.1.7.
Long-term Extension Phase
See Attachment 7 for the criteria for participation and procedures to be performed during the 
Long-term Extension Phase.
9.2.
Efficacy
9.2.1.
Evaluations
Efficacy evaluations will be conducted as specified in the Time and Events Schedule. Unscheduled 
assessments should be considered if clinically indicated, and results collected in the eCRF. The 
efficacy evaluations include the following:

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 these results will be used for the primary 
endpoint analyses. Scans will also be collected and stored by a central vendor for central 
review if indicated.

serum PSA

CTC

survival status

SSEs
9.2.2.
Endpoint Criteria
Objective response of soft tissue (visceral or nodal disease) is defined by Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 (see Attachment 2) with no evidence of bone progression 
on bone scan according to the PCWG3 criteria:


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
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 (+ 2-week window) for confirmation per RECIST 1.1. The schedule for 
subsequent scans will be based upon Cycle 1 Day 1, and the confirmation scan will satisfy the 
scan requirements for the next occurring timepoint per the Time and Events Schedule. 
Radiographic progression by tumor assessment should be evaluated according to RECIST 1.1 for 
soft tissue disease and PCWG3 for bone disease 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 PCWG3.20 Bone progression 
is defined as one of the following, depending on what is observed at the Week 8 scan and what 
is observed on the confirmatory scan (which is performed ≥6 weeks later) :
1. Subject whose Week 8 scan is observed to have ≥2 new bone lesions compared with the 
baseline scan would fall into one of the 2 categories below:
a.
Subject whose confirmatory scan shows ≥2 new lesions compared with the Week 8 
scan (ie. a total of ≥4 new lesions compared with the 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 with the 
Week 8 scan will not be considered to have bone scan progression. The Week 8 scan 
will be considered as the bone scan to which subsequent scans are compared. 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.
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.
Evaluation of treatment response by PSA, imaging, and CTCs performed according to PCWG3 
criteria. Duration of tumor response will be assessed only for those subjects who have an objective 
tumor response by RECIST 1.1 (see Attachment 2). The duration of tumor response will be 
assessed from the first time of observed CR/PR to the date of radiographic progression, 
unequivocal clinical progression, or death, whichever occurs first.
See Section 10.1 for details regarding discontinuation of study medication for disease progression.
9.3.
Pharmacokinetics
9.3.1.
Sample Collection and Handling
Sparse PK sampling will be collected from all subjects in this study. Blood samples to measure 
plasma levels of niraparib and its metabolite, M1, will be obtained on Cycle 1 Day 1 and Cycle 2 
Day 1 at predose, and between 1 to 3 hours and between 4 to 6 hours postdose. On Cycle 1 Day 15, 


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and on Day 1 of Cycles 3, 4, 5, and 7, blood samples for PK analysis will be obtained predose only 
in all subjects as per the Time and Events Schedule.
Other metabolite(s) of niraparib may also be measured in collected PK samples. Other 
measurements may be done earlier than the specified timepoints if needed. Actual dates and times 
of dose administration and assessments, as well as date and time of previous dose will be recorded 
in the laboratory requisition form. Note that if a visit has pre- or postdose samples, the date and 
time of the 2 samples and of the dose administered in the clinic and prior dose taken at home must 
be recorded. Refer to the laboratory manual for sample collection requirements, shipping 
instructions, and specified controlled temperatures for storage.
9.3.2.
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of niraparib and its metabolite, M1, 
using a validated, specific, and sensitive assay method by, or under the supervision of, the sponsor. 
If other metabolite(s) are analyzed quantitatively in the plasma samples, plasma concentration of 
the metabolites will be reported.
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).
9.3.3.
Pharmacokinetic Parameters
Based on the individual plasma concentration-time data, using the actual dose taken and the actual 
sampling times, PK parameters and exposure of niraparib will be derived using population PK 
modeling. Baseline covariates (eg, body weight, age, creatinine clearance, race) may be included 
in the model, if relevant. Data from this study may be pooled with data from other clinical studies.
9.4.
Patient-reported Outcomes
The goal of collecting PRO data is to explore if subjects experience treatment benefits in pain, 
fatigue, and or functional status. PROs will be measured utilizing the Brief Pain Inventory - Short 
Form questionnaire (BPI-SF), the Functional Assessment of Cancer Therapy-Prostate 
questionnaire (FACT-P), and the Euro-QoL questionnaire (EQ-5D-5L). All visit-specific PRO 
assessments are strongly encouraged to be conducted and completed before any tests, procedures, 
or other consultations for that visit. The PRO assessments will be captured on paper and results 
entered into the eCRF. Detailed instructions for administering the PRO questionnaires will be 
provided in a PRO manual.
9.4.1.
BPI-SF
The BPI-SF (24-hour recall) includes a front and back body diagram for the subject to identify the 
location of his pain. The interference items measure how much pain has interfered with recent 
daily activities, including general activity, walking, work, mood, enjoyment of life, relations with 
others, and sleep. BPI pain interference is scored as the mean of the 7 interference items.


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9.4.2.
FACT-P
The FACT-P will provide an assessment of the subject’s self-reported functional status, 
well-being, and prostate cancer-related symptoms. The FACT-P questionnaire includes a general 
functional status scale (consisting of 4 subscales: physical well-being, social and family 
well-being, emotional well-being, and functional well-being) and a prostate cancer-specific 
subscale with items including urination, bowel movement, and erectile function. Total score is 
calculated with general function and prostate-cancer-specific scores and ranges from 0 to 156 
(higher scores indicate better functional status).
9.4.3.
EQ-5D-5L
The EQ-5D-5L is a standardized measure of health status developed by the EuroQoL Group to 
provide a simple, generic measure of health for clinical and economic appraisal (EuroQoL Group, 
1990). The EQ-5D-5L is composed of the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, 
slight problems, moderate problems, severe problems, and unable to/extreme problems. The EQ 
visual analog scale records the respondents’ self-rated health as ‘Best imaginable health state’ and 
‘Worst imaginable health state’.
9.5.
Pharmacodynamics
Pharmacodynamics assessment was removed per Amendment 3.
9.6.
Pharmacokinetic/Pharmacodynamic Evaluations
Exposure-response relationship will be explored for key efficacy (eg, RR, PSA) and safety 
parameters as data allow.
9.7.
Biomarkers
To be included in the primary efficacy population, subjects must be confirmed to be either biallelic 
BRCA (BRCA1 or BRCA2) by a sponsor-validated blood- or tissue-based assay or have a 
germline pathogenic BRCA (BRCA1 or BRCA2) mutation (archival or recently collected), see 
Section 9.1.2.
The biomarkers of interest for this study are listed in Table 5. 
Table 5: 
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
HDAC2
Histone Deacetylase 2 gene
ATM
Ataxia Telangiectasia Mutated gene


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9.7.1.
Evaluations
Biomarker evaluations will be conducted as specified in the Time and Events Schedule and are 
described in Sections 9.7.1.1 to 9.7.1.5.
9.7.1.1.
Tissue Analysis
Tumor tissue (either archival or recently collected) should be obtained to evaluate DRD status, and 
may also be used to identify markers associated with disease evolution, immune context, or 
response to study drugs. Tissue samples collected at screening may be used for concordance and 
bridging studies for the development of the assay. Furthermore, tumor tissue may be assessed for 
RNA signatures predictive of response to niraparib.
9.7.1.2.
Circulating Tumor Cells
Blood samples for CTC enumeration will be collected at timepoints specified in the Time and 
Events Schedule. CTC enumeration will be evaluated at the central laboratory, to assess response 
to study drug.
9.7.1.3.
Whole Blood for RNA
Whole blood samples will be collected as specified in the Time and Events Schedule. Multiple 
ribonucleic acid (RNA) transcripts found in prostate tumors are detectable in the RNA and analysis 
of these samples will allow evaluation of potential mechanisms of resistance that may emerge with 
niraparib.
9.7.1.4.
Circulating Tumor DNA
Plasma samples collected during the course of treatment may be used to screen for changes in the 
levels or types of DNA-repair anomalies observed over time by circulating tumor DNA (ctDNA), 
and to monitor for potential markers of resistance to niraparib. Samples collected at screening and 
Cycle 1 Day 1 may be used for concordance and bridging studies with tumor tissue as well as 
development of the assay.
9.7.1.5.
Saliva Testing
Testing via a saliva sample may be collected to evaluate for germline mutations. Subjects will be 
permitted to be screened and enter the treatment phase if positive for BRCA1 or BRCA2 germline 
pathogenic mutations.
9.8.
Medical Resource Utilization
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).


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
Duration and cause 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).
9.9.
Safety
Safety assessments will be based on medical review of AE reports and the results of vital sign 
measurements, ECGs (12-lead), physical examinations, clinical laboratory tests, ECOG PS, and 
other safety evaluations at specified timepoints as described in the Time and Events Schedule. Any 
clinically significant abnormalities persisting at the EoT visit will be followed by the investigator 
until resolution or death, whichever comes first.
Adverse Events
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. AEs will be followed by the 
investigator as specified in Section 12, Adverse Event Reporting.
Clinical Laboratory Tests
Blood samples to assess the safety of study drug 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.
Required laboratory tests must be performed within ±2 days of the scheduled visit. In the event of 
additional safety monitoring, unscheduled laboratory assessments may be performed as required.
For any suspected MDS/AML case reported while a subject is receiving treatment or being 
followed for post-treatment assessments, bone marrow aspirate and biopsy testing must be 
completed by a local hematologist. A whole blood sample will also be collected for cytogenetic 
analysis (mutations of select myeloid-associated genes). Testing completed as part of standard of 
care is sufficient as long as 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,22 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.


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The following tests will be performed by the central laboratory as outlined in the Time and Events 
Schedule:

Hematology Panel
-CBC (hemoglobin, white blood cell count, platelets, absolute lymphocyte count, and ANC)

Serum Chemistry Panel
-sodium
-lactate dehydrogenase 
-potassium
-calcium
-creatinine
-glucose
-magnesium
-uric acid
-inorganic phosphorus
-gamma glutamyltransferase
-total protein
-chloride
-blood urea nitrogen

Liver Functions Tests
-AST
-ALT
-total bilirubin (if above normal, measure 
direct bilirubin)

Other Laboratory Tests
-testosterone (screening only)
-PSA
-albumin 
-alkaline phosphatase
-CD4 count for HIV-positive subjects only 
(screening only)
Electrocardiogram (ECG)
Standard 12-lead ECGs will be recorded at the timepoints outlined in the Time and Events 
Schedule. Any known electrolyte imbalance should be treated prior to performing the ECG. ECGs 
should be recorded on the same device, if at all possible, to avoid ECG device variability. 
Computer-generated interpretations of ECGs should be reviewed for data integrity and 
reasonableness by the investigator. Subjects are to reside in a quiet setting without distractions (eg, 
television, cell phones, and staff talking) at each scheduled timepoint 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. 
Clinically significant abnormalities noted during the Treatment Phase and at the EoT visit will be 
recorded on the Adverse Event section of the eCRF.


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Vital Signs
Body temperature, heart rate, and blood pressure will be recorded at the timepoints outlined in the 
Time and Events Schedule.
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.
ECOG Performance Status
The ECOG PS scale (provided in Attachment 3) 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.
9.10.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the laboratory requisition 
form. Refer to the Time and Events Schedule for the timing and frequency of all sample collections. 
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Discontinuation of Study Treatment
A subject will not be automatically withdrawn from the study if he discontinues study drug.
Subjects who discontinue study drug should complete the EoT visit within 30 (±5) days of the last 
dose of study drug or the end of the dose interruption period since the last dose of study drug. 
Subjects should ordinarily be maintained on study treatment 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 on study treatment, at the 
investigator’s discretion. Study treatment will be continued for subjects who have increasing PSA 
values in the absence of radiographic or unequivocal clinical progression. Although serial PSA’s 
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 study 
therapy.20 However, a subject's study treatment must be discontinued for:

Study drug-related toxicity as defined in Section 6.2.

Unequivocal clinical progression defined as:

Deterioration in ECOG PS to Grade 3 or higher.


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
Need to initiate any of the following because of tumor progression (even in the absence 
of radiographic evidence of disease):
o
Alternative anticancer therapy for prostate cancer.
o
Radiation therapy.
o
Surgical interventions for complications due to tumor progression.

Clinically significant QTcF ≥500 ms or QTc prolongation >60 ms above baseline.

Diagnosis of MDS/AML.

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 study 
treatment for any reason remain on study and must follow all study evaluations described in 
Section 9 and outlined in the Time and Events Schedule.
10.2.
Withdrawal from the Study
A subject will be considered withdrawn from the study (ie, Treatment Phase, Follow-up Phase, 
Long-term Extension Phase) for any of the following reasons:

Lost to follow-up 

Withdrawal of consent for subsequent data collection

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 in the subjects’ source documents. The informed 
consent will stipulate that even if a subject decides to discontinue the study drug, he will agree to 
be contacted periodically by the investigator to assess endpoint status. This can be done by 
telephone, by chart review, or by public record search if permissible by local regulations. If the 
subject withdraws consent for all study-related procedures, then no further contact is permitted by 
the investigator or the sponsor, except as permitted by local regulations.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn subject 
may not be assigned to another subject. Subjects who withdraw will not be replaced.
10.3.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for future research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will be 


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destroyed after they are no longer needed for the clinical study. Details of the sample retention for 
research are presented in the main 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 efficacy and safety data is outlined 
below. Specific details will be provided in the statistical analysis plan (SAP).
11.1.
Analysis Populations
Enrolled Population: All subjects who are enrolled into the study. This population will be used for 
exploring efficacy/anti-tumor activity, subject disposition and biomarker analyses.
Primary Efficacy Population: All subjects who received at least 1 dose of study drug, had either 
biallelic BRCA (BRCA1 or BRCA2) per the sponsor-validated blood- or tissue-based assay, or 
germline pathogenic BRCA (BRCA1 or BRCA2) mutation. 
Safety Population: All subjects who received at least 1 dose of study drug. This population will be 
used for evaluating safety and treatment compliance.
Patient-report Outcomes Population (PRO): All subjects who completed the baseline assessment 
and at least 1 post-baseline assessment of BPI-SF, FACT-P, or EQ-5D-5L questionnaires.
Population Pharmacokinetics Populations (PK): All subjects who received 1 dose of study drug 
and have at least 1 blood sample obtained post-treatment.
11.2.
Sample Size Determination
For the primary objective with ORR endpoint in subjects with measurable mCRPC and 
DNA-repair anomalies in BRCA1 or BRCA2, defined in Section 2.1, the null hypothesis that the 
ORR is ≤15% will be tested against the alternate hypothesis that the ORR is ≥32%. Efficacy of 
niraparib will be declared if the lower bound of the 2-sided 95% exact CI for ORR is >15%.19 With 
approximately 75 subjects with measurable disease and DNA-repair anomalies in BRCA1 or 
BRCA2, the study will have over 90% power such that the lower limit of the 95% CI for ORR
exceeds 16%. It is anticipated that the final analysis for ORR will occur at approximately 
30 months (approximately 6 months from last subject enrolled).
For the secondary objective with ORR endpoint in subjects with measurable mCRPC and 
DNA-repair anomalies in biallelic non-BRCA (ATM, FANCA, PALB2, CHEK2, BRIP1, or 
HDAC2), the null hypothesis that the ORR is ≤15% will be tested against the alternate hypothesis 
that the ORR is ≥32%. With a 1-sided of 0.05 and power of 80%, up to 45 subjects with
measurable mCRPC and DNA-repair anomalies in non-BRCA (ATM, FANCA, PALB2, CHEK2, 
BRIP1, or HDAC2) are to be enrolled based on Simon’s two-stage design.14 At end of Stage 1, 
approximately 14 subjects will be evaluated for ORR after at least 1 post-treatment scan and a 
confirmatory scan for Stage 1. Future enrollment in this group may be terminated if 2 or fewer 
responses are observed in the first stage. Otherwise, enrollment may proceed to the second stage 


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with a total of 45 subjects combined for the 2 stages, and the null hypothesis will be rejected if 
10 or more responses are observed.
Assuming the historical CTC response rate (CTC RR) of 
 
and the target CTC RR of 40%, at least 60 subjects with non-measurable 
disease will be required to provide a lower bound of the 2-sided 95% CI greater than 20%, with a 
probability of 0.9.
11.3.
Efficacy Analyses
ORR in subjects with measurable mCRPC and DNA-repair anomalies in either biallelic BRCA 
(BRCA1 or BRCA2)
or germline BRCA (BRCA1 or BRCA2), and ORR in subjects with 
measurable mCRPC and DNA-repair anomalies in biallelic non-BRCA (ATM, FANCA, PALB2, 
CHEK2, BRIP1, or HDAC2), as defined in Section 2.1, will be calculated, and its 2-sided 95% 
exact CI will also be presented. For the calculation of ORR, subjects in the Primary Efficacy
Population who discontinue treatment prior to any efficacy assessments will be considered as non-
responders. The final analysis for ORR in subjects with measurable mCRPC and DNA-repair 
anomalies in BRCA1 or BRCA2 will be performed approximately 6 months after the last subject 
with measurable disease and DNA-repair anomalies in BRCA1 or BRCA2 receives his first dose 
of study medication.
The analysis for CTC RR will be tabulated and its 2-sided 95% exact CI will also be presented. 
The distribution of the time-to-event endpoints will be described using the Kaplan-Meier method. 
Additional details will be provided in the SAP.
Anti-tumor activity, such as PSA response, CTC conversion, composite response rate, will be 
analyzed based on subgroups of the enrolled population of biallelic, monoallelic, and 
indeterminant (local test results only) biomarker status. Additional details will be provided in the 
SAP.
11.4.
Pharmacokinetic Analyses
Individual niraparib (and its metabolite, M1) concentration-time data will be listed and 
summarized by time and visit. In addition, a population PK analysis of plasma concentration-time 
data of niraparib will be performed using nonlinear mixed-effects modeling to estimate oral 
clearance (CL/F) and oral volume of distribution (V/F). Other PK parameters may be evaluated as 
appropriate. Subject characteristics of interest (eg, body weight, age, renal function) may be 
evaluated as potential covariates affecting PK parameters. Details of the population PK analysis 
results will be presented in a separate report.
11.5.
Pharmacodynamic Analyses
Pharmacodynamics analyses were removed per Amendment 3.
11.6.
Biomarker Analyses
The concordance of DNA-repair anomalies in genes among tumor DNA and plasma ctDNA results 
may be evaluated. 
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The association of biomarker-positivity with clinical response or time-to-event endpoints may be 
assessed using appropriate statistical methods, (such as analysis of variance, categorical, or 
survival models), depending on the endpoints. Correlation of baseline biomarker expression levels 
with clinical response or relevant time to-event endpoints may be performed to identify responsive 
(or resistant) subgroups. Appropriate details of these exploratory analyses will be included in the 
biomarker SAP.
11.7.
Patient-reported Outcome Analyses
BPI-SF, FACT-P, and EQ-5D-5L will be summarized over time using descriptive statistics. Time 
to degradation (threshold to be defined in the SAP) may be analyzed using the Kaplan-Meier 
method.
11.8.
Pharmacokinetic/Pharmacodynamic Analyses
The relationship between measure of exposure (eg, derived AUC or predose concentrations) and 
key efficacy (eg, RR, PSA) and safety parameters, will be explored graphically, as data allow. In 
addition, the relationship may be characterized using an appropriate PK/pharmacodynamics or 
logistic regression model. Details will be provided in a separate report.
11.9.
Medical Resource Utilization Analyses
The analysis will be prepared separately and will not be a part of the Clinical Study Report.
11.10. Interim Analysis
Refer to the SAP for any interim analyses to be conducted.
11.11. Safety Analyses
Subjects who receive at least 1 dose of study drug will be analyzed for safety. The safety 
parameters to be evaluated are the incidence, intensity, and type of AEs, vital signs measurements, 
ECGs, physical examination (abnormalities will be recorded as AEs), and clinical laboratory 
results.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) and will be graded according to the 
National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
version 4.03 or later. Treatment-emergent AEs (TEAEs) are those events that occur on or worsen 
after first dose of study drug through 30 days after the last dose of study drug and will be included 
in the analysis. AEs will be summarized by System Organ Class and Preferred Term. 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. 
TEAEs will be summarized by System Organ Class, Preferred Term, toxicity grade, and 
relationship to study drug. SAEs and deaths will also be summarized. Summaries, listings, or 
subject narratives may be provided, as appropriate, for those subjects who die, who discontinue 
treatment due to an AE, or who experience a severe AE or an SAE.


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Clinical Laboratory Tests
Clinical laboratory test results will be collected from screening through the EoT visit. Laboratory 
data will be summarized by type of laboratory test. Reference ranges and markedly abnormal 
results will be used in the summary of laboratory data. Worst toxicity grade during treatment will 
be presented, according to NCI-CTCAE (version 4.03 or later). A listing of subjects with any 
markedly abnormal laboratory results will also be provided.
Electrocardiogram (ECG)
ECG data will be summarized by ECG parameter, as appropriate. Descriptive statistics will be 
calculated at baseline and for observed values and changes from baseline at each scheduled 
timepoint. The last available predose ECG will be used as baseline. Frequency tabulations of the 
abnormalities will be made.
Vital Signs
Descriptive statistics of pulse/heart rate, blood pressure, and temperature values and changes from 
baseline will be summarized at each scheduled timepoint. The percentage of subjects with values 
beyond clinically important limits will be summarized.
11.12. Data Review Committee
A DRC will be established for this study to review the planned analysis (see Section 11.10) and 
ongoing safety data. The DRC may include individuals both internal and external to the sponsor 
who are knowledgeable in the disease area. The DRC responsibilities, authorities, and procedures 
will be documented in a separate document.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information 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.


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12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(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 Conference on 
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 1) starting with the signing of the prescreening ICF for AEs related 
to blood and recent tumor tissue collection during the Prescreening Phase, and 2) starting with the 
signing of the main study ICF for all other AEs (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

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.


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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, the expectedness of an AE will be determined by 
whether or not it is listed in the Investigator's Brochure.
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).
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 


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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 or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to the 
sponsor study drug, eg, name confusion)
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 AE 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 main study ICF is obtained until completion of the subject's last study-
related procedure, which may include contact for follow-up of safety. SAEs, including those 
spontaneously reported to the investigator through 30 days after the last dose of study drug, must 
be reported using the Serious Adverse Event Form. In addition, SAEs related to blood or recent 
tumor tissue collection procedures, as well as death from any cause, during the Prescreening Phase 
will also be reported from the time the prescreening ICF is signed until 30 days after the 
procedure/s occur. 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 sign the main ICF, 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 a 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 6.
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, 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, 


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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) associated with the use of 
the study drug. 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, will submit a safety report in narrative format to the investigators (and the head 
of the institute). The investigator (or sponsor where required) must report these events to the 
appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved 
the protocol unless otherwise required and documented by the IEC/IRB.
For all studies with an outpatient phase, including open-label studies, 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

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 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).
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


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
The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug 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).
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 efficacy 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 30 days after the 
last dose of study drug, must be reported using the Serious Adverse Event Form. SAEs that occur 
after 30 days following the last drug administration thought to be related to study drug will be 
collected and reported via the Serious Adverse Event Form within 24 hours of discovery or 
notification of the event and documented.
12.3.3.
Pregnancy
While the effect of the study drug on sperm is unknown, PARP inhibitors disrupt DNA-repair of 
dividing cells and niraparib was observed to be genotoxic in in vitro studies.12 Therefore, 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. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.3.4.
Disease Progression and Death
Progression of disease should not be considered nor should be reported as an adverse event (or 
serious adverse event). However, signs and symptoms of disease progression or of clinical 
sequelae resulting from disease progression/lack of efficacy that are determined by the investigator 
to be of clinical significance should be reported per the usual reporting requirements (refer to 
Section 12 Adverse Event Reporting and Section 13 Product Quality Complaint Handling).
As OS is an endpoint of the study, 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 30 days after the last dose of study drug. Fatal events occurring after that 30-day 
period after the last dose of study drug will not be reported as SAEs and will be captured on the 


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designated case report form for survival. Death is an outcome of an AE and not an AE itself. All 
reports of death within 30 days after the last dose of study drug should include an AE term for the 
cause of death (if known).
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, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. 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 sample of the suspected product should be maintained 
for further investigation if requested by 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
14.1.
Physical Description of Study Drug
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.12
14.2.
Packaging
Niraparib 100 mg capsules will be packaged in high-density polyethylene bottles with 
child-resistant closures.


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14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
The study drug 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 the study drug out of reach and sight of children.
Niraparib may have adverse effects on a fetus in utero. Caregivers should handle niraparib with 
protection (eg, gloves). It is not known whether niraparib is present in, or has transient effects on 
the composition of semen. To avoid risk of drug exposure through the ejaculate (even men with 
vasectomies), subjects must use a condom during sexual activity while on study drug and for 3 
months following the last dose of study drug. Donation of sperm is not allowed while on study 
drug and for 3 months following the last dose of study drug. Refer to the pharmacy manual/study 
site investigational product and procedures manual for additional guidance on study drug 
preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the return 
of study drug 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 drug. All study drug will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study drug containers.
Study drug 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 drug, and study drug 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 drug, or used returned study drug 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 drug 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 drug will be supplied only to 
subjects participating in the study. Returned study drug must not be dispensed again, even to the 
same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.


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15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator's Brochure

PRO questionnaires

Pharmacy manual/study-site investigational 
product and procedures manual

RECIST 1.1

Electronic data capture (eDC) Manual

Sample prescreening ICF

Laboratory manual

Sample main study ICF

Recruitment materials
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
This is an open-label study to evaluate the efficacy and safety of niraparib in men with mCRPC 
and DNA-repair anomalies. While niraparib is an investigational PARP inhibitor, responses to a 
drug with a similar mechanism of action (olaparib; see Section 1.1) have been observed in men 
with mCRPC. Subjects with DNA-repair anomalies exhibited better response rates compared to 
subjects without DNA-repair anomalies. Given these promising clinical data, the benefit of 
treatment with niraparib in men with mCRPC and prospectively selected DNA-repair anomalies 
outweighs the potential risks involved.
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.
All participating subjects will receive full supportive care and will be followed closely for efficacy 
and safety throughout the study. As objective response is the primary endpoint, scheduled imaging 
is incorporated into the protocol. The timing of imaging is designed to evaluate response and 
capture progression events and allow the clinical investigator to make timely treatment decisions, 
yet balancing this with preventing subject overexposure to radiation. The frequency of scanning is 
consistent with requirements to assess rPFS by PCWG3 criteria.20 A DRC will be commissioned 
to review the efficacy and safety of the treatment on an ongoing basis and make recommendations 
as to the future conduct of the study. 
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 was designed to collect the minimum 
number of blood samples that can determine the efficacy, safety, PK, 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 


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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.23
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 
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:


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
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 provide consent according to local requirements after the nature of the study 
has been fully explained; consenting will include remote/virtual consent or written consent. 
Consent must be given 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. 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.
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 


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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 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.
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 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.
The subject has the right to request through the investigator access to his 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, biomarker, and pharmacokinetics 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.


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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, to understand prostate 
cancer in patients with DNA-repair anomalies, to understand differential drug responders, and to 
develop tests/assays related to niraparib and prostate cancer in patients with DNA-repair 
anomalies. 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.
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 
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.


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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.

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.


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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 date of birth. In cases where the subject is not enrolled into the study, the date seen and date 
of birth 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 documentation 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 efficacy 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; paper PROs; 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.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
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 4.2, Inclusion Criteria and 
Section 4.3, 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
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 


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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 the 
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 case report form 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-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.


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17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
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 
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.


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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.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. 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
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 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 


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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 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 Clinical Study Report 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 Clinical Study Report has been issued will be reported in 
a separate report and will not require a revision of the Clinical Study Report. 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 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 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 after the study end date, 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 important intellectual content; and given final approval of the 


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version to be 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. The disclosure of the final study results will be performed after the end of study in order 
to ensure the statistical analyses are relevant.


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of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008;26(22):3785-3790.
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Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of 
poly(ADPribose) polymerase. Nature. 2005 Apr 14;434(7035):913-917.
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Buonerba C, Federico P, D'Aniello C, et al. Phase II trial of cisplatin plus prednisone in docetaxel-refractory 
castration-resistant prostate cancer patients. Cancer Chemother Pharmacol. 2011 Jun;67(6):1455-1461.
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Drake CG, Sharma P, Gerritsen W. Metastatic castration-resistant prostate cancer: new therapies, novel 
combination strategies and implications for immunotherapy. Oncogene. 2014 Oct 23;33(43):5053-5064.
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Droz JP, Muracciole X, Mottet N, et al. Phase II study of oxaliplatin versus oxaliplatin combined with 
infusional 5-fluorouracil in hormone refractory metastatic prostate cancer patients. Ann Oncol. 2003 
Aug;14(8):1291-1298.
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Eisenhauer EA, Therasse P, Bogaerts, et al. New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
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Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic 
strategy. Nature. 2005;434(7035):917-921.
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FDA: Drug Development and Drug Interactions: Table of Substrates, Inhibitors, and Inducers. Available at: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/u
cm093664 htm. Accessed 26 May 2016.
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Grasso CS, Wu YM, Robinson DR, et al. The mutational landscape of lethal castration-resistant prostate 
cancer. Nature. 2012;487: 239–243.
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Gupta E, Guthrie T, Tan W. Changing paradigms in management of metastatic Castration Resistant Prostate 
Cancer (mCRPC). BMC Urol. 2014 Jul 25;14:55.
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Indiana University Department of Medicine: P450 Drug Interaction Table. 
http://medicine.iupui.edu/CLINPHARM/ddis/main-table.
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Investigator’s Brochure: Niraparib. Tesaro, Inc.
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Jones P, Wilcoxen K, Rowley M, Toniatti C. Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for 
the Treatment of Tumors with Defective Homologous Recombination. J Med Chem. 2015 Apr 23;58(8):3302-
3314.
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Lavaud P, Gravis G, Foulon S, et al. Anticancer Activity and Tolerance of Treatments Received Beyond 
Progression in Men Treated Upfront with Androgen Deprivation Therapy With or Without Docetaxel for 
Metastatic Castrate-naïve Prostate Cancer in the GETUG-AFU 15 Phase 3 Trial. Eur Erol. 2018; 73 (5): 696-
703. 
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Lin Y, Shih WJ. Adaptive two-stage designs for single-arm phase IIA cancer clinical trials. Biometrics. 
2004;60(2):482-490.
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Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl 
J Med. 2015 Oct 29;373(18):1697-1708.
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QTDrugs List. http://www.crediblemeds.org.
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Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 
2015;161(5):1215-1228.
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Sartor O and Gillessen S. Treatment sequencing in metastatic castrate-resistant prostate cancer. Asian J Androl. 
2014 May-Jun;16(3):426-431.
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Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: 
Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016 
Apr 20;34(12):1402-1418.


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21.
Smith MR, De Bono JS, Sternberg CN, et al. Final analysis of COMET-1: Cabozantinib (Cabo) versus 
prednisone (Pred) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) previously treated 
with docetaxel (D) and abiraterone (A) and/or enzalutamide (E). J Clin Oncol 33. 2015 ASCO Genitourinary 
Cancer Symposium Abstracts (suppl 7, abstr 139). Available at: 
http://meeting.ascopubs.org/cgi/content/abstract/33/7_suppl/139?sid=33f6458c-01a9-4463-b904-1b61ffb5fa06
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Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) 
classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 
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WHO technical report series 840 (1994): Requirements for the blood collection, processing, and quality control 
of blood, blood components, and plasma derivatives. Available at: 
http://www.who.int/bloodproducts/publications/WHO_TRS_840_A2.pdf . Accessed 27 May 2016.
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Zejula Summary of Product Characteristics 2017. Available at: 
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Zejula® United States Prescribing Information 2018. Available at: https://www.zejula.com/prescribing-
information. Accessed on: 15 November 2018.


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Attachment 1: Prostate Cancer Working Group 3 Criteria
Attachment removed per Amendment 3.


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Attachment 2: Summary of RECIST Criteria Version 1.1 with Integration of PCWG3 for Evaluation 
of Response
The following information was extracted from Section 3, Section 4, and Appendix I of the New Response 
Evaluation Criteria in Solid Tumors: revised RECIST guideline (version 1.1) authored by Eisenhauer et al 
(2009).6
3.
Measurability of tumor at baseline
3.1
Definitions
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as follows:
3.1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
The following two methods of measure are not allowed in this protocol:

10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable)

20 mm by chest X-ray

Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must 
be 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
See also ‘Baseline documentation of target and non-target lesions’ in section 4.2 of the RECIST 
guideline for information on lymph node measurement.
3.1.2
Non-measurable
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with 10 
to <15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly non-measurable 
include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, and abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques.
3.2
Specifications by methods of measurements
3.2.1
Measurement of lesions
All measurements should be recorded in metric notation, using calipers if clinically assessed. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 4 weeks 
before the beginning of the treatment.
3.2.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up. Imaging based evaluation should always be done rather 
than clinical examination.


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4.
Tumor response evaluation
4.1
Assessment of overall tumor burden and measurable disease
To assess objective response or future progression, it is necessary to estimate the overall tumor burden at 
baseline and use this as a comparator for subsequent measurements.
4.2
Baseline documentation of ‘target’ and ‘non-target’ lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions 
total (and a maximum of two lesions per organ) representative of all involved organs should be identified 
as target lesions and will be recorded and measured at baseline (this means in instances where patients have 
only one or two organ sites involved a maximum of two and four lesions respectively will be recorded). For 
evidence to support the selection of only five target lesions, see analyses on a large prospective database in 
the article by Bogaerts et al. (Reference #10 in Eisenhauer publication).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion, which can be measured 
reproducibly, should be selected.
Lymph nodes merit special mention since they are normal anatomical structures, which may be visible by 
imaging even if not involved by tumor. As noted in Section 3, pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 15 mm by CT 
scan. Only the short axis of these nodes will contribute to the baseline sum. The short axis of the node is 
the diameter normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of 
these measures is the short axis. For example, an abdominal node which is reported as being 20 mm•30 mm 
has a short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should 
be recorded as the node measurement (See also the example in Fig. 4 in Appendix II of the Eisenhauer 
reference). All other pathological nodes (those with short axis 10 mm but <15 mm) should be considered 
non-target lesions. Nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will 
be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, 
then as noted above, only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-target 
lesions and should also be recorded at baseline. Measurements are not required and these lesions should be 
followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ (more details to follow). In 
addition, it is possible to record multiple non-target lesions involving the same organ as a single item on 
the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).
4.3
Response criteria
This section provides the definitions of the criteria used to determine objective tumor response for target 
lesions.
4.3.1
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm.


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Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters.
Progressive Disease: At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
progressive disease, taking as reference the smallest sum diameters while on study.
4.3.2
Special notes on the assessment of target lesions
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even if the 
nodes regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal lymph node 
is defined as having a short axis of <10 mm. Case report forms or other data collection methods may 
therefore be designed to have target nodal lesions recorded in a separate section where, in order to qualify 
for CR, each node must achieve a short axis <10 mm. For PR, SD and progressive disease, the actual short 
axis measurement of the nodes is to be included in the sum of target lesions.
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, even 
when very small (eg 2 mm). However, sometimes lesions or lymph nodes which are recorded as target 
lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being ‘too small to measure’. When this occurs it is important that a 
value be recorded on the CRF. If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but 
too small to measure, a default value of 5 mm should be assigned (Note: It is less likely that this rule will 
be used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this circumstance as 
well). This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible; therefore 
providing this default value will prevent false responses or progressions based upon measurement error. To 
reiterate, however, if the radiologist is able to provide an actual measure, that should be recorded, even if it 
is below 5 mm.
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest diameters of 
the fragmented portions should be added together to calculate the target lesion sum. Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
4.3.3
Evaluation of non-target lesions
This section provides the definitions of the criteria used to determine the tumor response for the group of 
non-target lesions. While some non-target lesions may actually be measurable, they need not be measured 
and instead should be assessed only qualitatively at the timepoints specified in the protocol.
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (<10 mm short axis).


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Non-CR/Non-progressive disease: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.
Progressive Disease: Unequivocal progression (see comments below) of existing non-target lesions. (Note: 
the appearance of one or more new lesions is also considered progression).
4.3.4
Special notes on assessment of progression of non-target disease
The concept of progression of non-target disease requires additional explanation as follows:
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal progression’ on the 
basis of the non-target disease, there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of SD or PR in target disease, the overall tumor burden has increased sufficiently 
to merit discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to quality for unequivocal progression status. The designation of overall progression 
solely on the basis of change in non-target disease in the face of SD or PR of target disease will therefore 
be extremely rare.
When the patient has only non-measurable disease. This circumstance arises in some Phase studies when 
it is not a criterion of study entry to have measurable disease. The same general concepts apply here as 
noted above, however, in this instance there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden. Because worsening in non-target disease 
cannot be easily quantified (by definition: if all lesions are truly non-measurable) a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase in overall disease 
burden based on the change in non-measurable disease is comparable in magnitude to the increase that 
would be required to declare progressive disease for measurable disease: i.e. an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase 
in lymphangitic disease from localized to widespread, or may be described in protocols as ‘sufficient to
require a change in therapy.’ If ‘unequivocal progression’ is seen, the patient should be considered to have 
had overall progressive disease at that point. While it would be ideal to have objective criteria to apply to 
non-measurable disease, the very nature of that disease makes it impossible to do so, therefore the increase 
must be substantial.
4.3.5
New lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments on 
detection of new lesions are important. There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e. not attributable to 
differences in scanning technique, change in imaging modality or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or flare of pre-existing 
lesions). This is particularly important when the patient’s baseline lesions show partial or complete 
response. For example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic 
lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. An example of this is the patient who has 
visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals metastases. 
The patient’s brain metastases are considered to be evidence of progressive disease even if he/she did not 
have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan.


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4.4.1
Timepoint response
It is assumed that at each protocol-specified timepoint, a response assessment occurs. Table 1 in this 
attachment provides a summary of the overall response status calculation at each timepoint for patients who 
have measurable disease at baseline.
For all timepoints when patients have non-measurable (therefore non-target) disease only, the RECIST 1.1 
and PCWG3 timepoint response will be integrated to determine the overall timepoint response.
4.4.2
Missing assessments and inevaluable designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not evaluable (NE) at 
that timepoint. If only a subset of lesion measurements are made at an assessment, usually the case is also 
considered NE at that timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesion(s) would not change the assigned timepoint response. This would be most likely 
to happen in the case of progressive disease. For example, if a patient had a baseline sum of 50 mm with 
three measured lesions and at follow-up only two lesions were assessed, but those gave a sum of 80 mm, 
the patient will have achieved progressive disease status, regardless of the contribution of the missing 
lesion.
4.4.3
Best overall response: all timepoints
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). The patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria.


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Table 1: Overall Timepoint Response - Subjects with Target (+/- Non-target) Disease +/- Bone Disease
Target 
lesions
Non-target 
lesions
New 
lesions
Overall 
RECIST v1.1 
response 
(nodal/visceral)
Best overall response 
RECIST v1.1 when 
confirmation is 
requireda
Overall PCWG3 
response (bone, 
when applicable)
Overall 
radiographic 
response
CR
CR
No
CR
≥4 wks. Confirmationb
CR = Non-PD + no 
focal uptake 
(lesion count = 0)
CR
CR
CR
No
CR
≥4 wks. Confirmationb
SD = Non-PD
PR
CR
CR
No
CR
≥4 wks. Confirmationb
PD 
PD
CR
Non-CR/non-
PD
No
PR
≥4 wks. Confirmationb
CR = Non-PD + no 
focal uptake 
(lesion count = 0)
PR
CR
Non-CR/non-
PD
No
PR
≥4 wks. Confirmationb
SD = Non-PD
PR
CR
Non-CR/non-
PD
No
PR
≥4 wks. Confirmationb
PD 
PD
CR
Not evaluated
No
PR
≥4 wks. Confirmationb
CR = Non-PD + no 
focal uptake 
(lesion count = 0)
PR
CR
Not evaluated
No
PR
≥4 wks. Confirmationb
SD = Non-PD
PR
CR
Not evaluated
No
PR
≥4 wks. Confirmationb
PD 
PD
CR
CR
No
CR
≥4 wks. Confirmationb
NE (i.e. poor scan 
quality, superscan)
NE
PR
Non-CR/Non-
PD/ not 
evaluated
No
PR
≥4 wks. Confirmationb
CR = Non-PD + no 
focal uptake (lesion 
count = 0)
PR
PR
Non-CR/Non-
PD/ not 
evaluated
No
PR
≥4 wks. Confirmationb
SD = Non-PD
PR
PR
Non-CR/Non-
PD/ not 
evaluated
No
PR
≥4 wks. Confirmationb
PD 
PD
PR
Non-CR/Non-
PD/ not 
evaluated
No
PR
≥4 wks. Confirmationb
NE (i.e. poor scan 
quality, superscan)
NE
SD
Non-PD or 
not all 
evaluated
No
SD
SD
Any except PD
SD
SD
Non-PD or 
not all 
evaluated
No
SD
SD
NE (i.e. poor scan 
quality, superscan)
NE
Not all 
evaluated
Non-PD
No
NE
NE
Any except PD
NE
Not all 
evaluated
Non-PD
No
NE
NE
PD
PD
Not done
NA
NA
Non-PD
NE
PD
PD
NE
NE
CR
CR
No
CR
≥4 wks. Confirmationb
Not done
NE
CR
CR
No
CR
≥4 wks. Confirmationb
NE
CR
CR
No
CR
≥4 wks. Confirmationb
NE
CR
Non-
CR/non-PD
No
PR
≥4 wks. Confirmationb
NE
CR
Non-
CR/non-PD
No
PR
≥4 wks. Confirmationb
NE
CR
Non-
CR/non-PD
No
PR
≥4 wks. Confirmationb
NE
CR
Not 
evaluated
No
PR
≥4 wks. Confirmationb
NE


JNJ-64091742  (niraparib)
Clinical Protocol 64091742PCR2001 Amendment 8
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Approved, Date: 17 July 2020
Target 
lesions
Non-target 
lesions
New 
lesions
Overall 
RECIST v1.1 
response 
(nodal/visceral)
Best overall response 
RECIST v1.1 when 
confirmation is 
requireda
Overall PCWG3 
response (bone, 
when applicable)
Overall 
radiographic 
response
CR
Not 
evaluated
No
PR
≥4 wks. Confirmationb
NE
CR
Not 
evaluated
No
PR
≥4 wks. Confirmationb
NE
SD
Non-PD or 
not all 
evaluated
No
SD
SD
NE
SD
Non-PD or 
not all 
evaluated
No
SD
SD
NE
Not all 
evaluated
Non-PD
No
NE
NE
NE
Not all 
evaluated
Non-PD
No
NE
NE
NE
PD
Any
Yes or 
No
PD
PD
PD
Any
PDc
Yes or 
No
PD
PD
PD
Any
Any
Yes
PD
PD
PD
PD
Any
Yes or 
No
PD
PD
Any
PD
Any
PDc
Yes or 
No
PD
PD
Any
PD
Any
Any
Yes
PD
PD
Any
PD
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; NE=not evaluable; 
wks=weeks
a. See Eisenhauer et al for further details on what is evidence of a new lesion.6
b. Only for non-randomized studies with response as primary endpoint.
c. Unequivocal progression in non-target lesions may be accepted as disease progression.
Note: Subjects with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort should 
be made to document the objective progression even after discontinuation of treatment.


JNJ-64091742  (niraparib)
Clinical Protocol 64091742PCR2001 Amendment 8
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Approved, Date: 17 July 2020
Attachment 3: 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)


JNJ-64091742  (niraparib)
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96
Approved, Date: 17 July 2020
Attachment 4: Medications That Could Potentially Cause QT Prolongation or Torsades De Pointes
Attachment deleted per Protocol Amendment 3.


JNJ-64091742  (niraparib)
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Approved, Date: 17 July 2020
Attachment 5: Substrates of CYP1A2
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeli
ng/ucm093664.htm8
http://medicine.iupui.edu/CLINPHARM/ddis/main-table11


JNJ-64091742  (niraparib)
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98
Approved, Date: 17 July 2020
Attachment 6: Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease-specific events) or background regimen 
(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 adverse events will be recorded in the CRF regardless of whether considered to be anticipated events
and will be reported to the sponsor as described in Section 12.3.1, All Adverse Events. Any anticipated 
event that meets SAE criteria will be reported to the sponsor as described in Section 12.3.2, Serious Adverse 
Events. 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) per applicable clinical trial 
legislation to Health Authorities and IRB/ECs. 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/ECs. 
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


JNJ-64091742  (niraparib)
Clinical Protocol 64091742PCR2001 Amendment 8
99
Approved, Date: 17 July 2020
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.
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.


JNJ-64091742  (niraparib)
Clinical Protocol 64091742PCR2001 Amendment 8
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Approved, Date: 17 July 2020
Attachment 7: Long-term Extension Phase 
The LTE Phase will begin after completion of the primary analysis and subsequent notification to 
the sites. The sponsor will continue to provide study drug until subjects no longer derive benefit 
from treatment or until further notification by the sponsor on a different means for continued 
supply of study treatment.
At the time of initiation of the LTE Phase, subjects who elect not to continue in the LTE Phase 
will be discontinued from the study within approximately 3 months from the initiation of the LTE 
Phase at the site. Subjects who progress and are no longer deriving clinical benefit and require 
subsequent treatment will be discontinued from the study and will receive such treatment at the 
discretion of the investigator. 
The LTE Phase will begin when both Amendment 8 is approved at the site and the sponsor has 
notified the site of the start of the LTE.

Subjects who are still receiving niraparib will be offered the option to continue to receive 
niraparib.

Subjects who are in the Follow-up Phase of the main study will be discontinued from the study 
and all data collection will cease.

Subjects must provide updated informed consent (signed form or remote) to continue in the 
LTE Phase of the study. 
Study Treatment Administration
Study Treatment During the Long-term Extension
Study treatment will be administered orally on an outpatient basis. A treatment cycle is defined as 
28 days. Sufficient study drug for each treatment cycle will be distributed as specified in Table 7. 
Subjects will receive niraparib according to the schedule in Table 6. If a subject was receiving a 
lower dose of niraparib, he should continue on that lower dose in the LTE Phase.
Table 6:
Study Treatment Administration for the Long-term Extension Phase
Study Treatment
Daily Dose
Schedule
Niraparib
300 mg (3×100 mg tablets)
Once daily with or without food
If a dose of niraparib is missed, the dose should only be replaced if the subject remembers and 
takes the dose within a 12-hour window; otherwise, it should be omitted and should not be made 
up or taken with the next dose the following day. 
Dose modifications for toxicity are provided in Section 6.2 of the protocol.
Prohibitions and Restrictions
Refer to protocol Sections 8.1 and 8.2 for prohibited and restricted concomitant medications.





SAP_003.pdf: 
1 
Approved, Date: 22 February 2021  
 
Janssen Research & Development * 
 
 
Statistical Analysis Plan 
 
A Phase 2 Efficacy and Safety Study of Niraparib in Men with Metastatic Castration-
Resistant Prostate Cancer and DNA-Repair Anomalies 
 
Protocol 64091742PCR2001; Phase 2 
 
 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 Aragon Pharmaceuticals Inc, Janssen Biotech, Inc.; Janssen 
Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Infectious 
Diseases BVBA; Janssen R&D Ireland; 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. 
 
Status: 
Approved   
Date: 
22 February 2021 
Prepared by: 
Janssen Research & Development, LLC 
 
 
 
Compliance:  The study described in this report was performed according to the principles of Good Clinical Practice (GCP).  
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.


JNJ-64091742 (Niraparib)  
 
 
 
Statistical Analysis Plan 64091742PCR2001  
2 
Approved, Date: 22 February 2021  
TABLE OF CONTENTS 
TABLE OF CONTENTS .......................................................................................................................... 2 
ABBREVIATIONS ................................................................................................................................... 4 
1. 
INTRODUCTION ............................................................................................................................ 5 
1.1. 
Trial Objectives ........................................................................................................................... 5 
1.2. 
Trial Design................................................................................................................................. 6 
1.3. 
Statistical Hypothesis for Trial Primary Objective ......................................................................... 7 
1.4. 
Sample Size Justification ............................................................................................................ 7 
1.5. 
Randomization and Blinding ........................................................................................................ 7 
2. 
GENERAL ANALYSIS DEFINITIONS ............................................................................................ 8 
2.1. 
Pooling Algorithm for Analysis Centers ........................................................................................ 8 
2.2. 
Analysis Sets .............................................................................................................................. 8 
2.3. 
Definition of Subgroups ............................................................................................................... 9 
3. 
INTERIM DATA REVIEW AND DATA REVIEW COMMITTEE ........................................................ 9 
3.1. 
Data Review Committee (DRC) ................................................................................................... 9 
3.2. 
Preliminary Efficacy and Safety Review ....................................................................................... 9 
3.3. 
Futility Analysis ......................................................................................................................... 10 
4. 
SUBJECT INFORMATION ........................................................................................................... 11 
4.1. 
Demographics and Baseline Characteristics .............................................................................. 11 
4.2. 
Disposition Information .............................................................................................................. 11 
4.3. 
Treatment Compliance .............................................................................................................. 11 
4.4. 
Duration of Exposure ................................................................................................................ 12 
4.5. 
Protocol Deviations ................................................................................................................... 12 
4.6. 
Prior and Concomitant Medications and Subsequent Therapies ................................................ 12 
5. 
EFFICACY ................................................................................................................................... 12 
5.1. 
Analysis Specifications .............................................................................................................. 13 
5.1.1. 
Level of Significance .............................................................................................................. 13 
5.1.2. 
Data Handling Rules .............................................................................................................. 13 
5.2. 
Primary Endpoint ...................................................................................................................... 14 
5.2.1. 
Definition ............................................................................................................................... 14 
5.2.2. 
Estimand ............................................................................................................................... 14 
5.2.3. 
Analysis Methods ................................................................................................................... 15 
5.3. 
Secondary Endpoints ................................................................................................................ 15 
5.3.1. 
Definitions.............................................................................................................................. 15 
5.3.2. 
Analysis Methods ................................................................................................................... 18 
5.4. 
Other Endpoints ........................................................................................................................ 18 
5.4.1. 
Definition ............................................................................................................................... 18 
5.4.2. 
Analysis Methods ................................................................................................................... 19 
6. 
Safety .......................................................................................................................................... 19 
6.1. 
Adverse Events ......................................................................................................................... 20 
6.2. 
Clinical Laboratory Tests ........................................................................................................... 21 
6.3. 
Vital Signs ................................................................................................................................. 21 
6.4. 
Physical Examination ................................................................................................................ 22 
6.5. 
Electrocardiogram ..................................................................................................................... 22 
7. 
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................ 22 
8. 
BIOMARKERS ............................................................................................................................. 22 
9. 
PATIENT-REPORTED OUTCOMES ............................................................................................ 22 


JNJ-64091742 (Niraparib)  
 
 
 
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10. 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ............................................ 23 
REFERENCES ...................................................................................................................................... 24 
 
 
 
 


JNJ-64091742 (Niraparib)  
 
 
 
Statistical Analysis Plan 64091742PCR2001  
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ABBREVIATIONS 
 
AE 
adverse event 
AR 
androgen receptor 
ANCOVA 
analysis of covariance 
BCF 
biochemical failure 
BICR 
blinded independent central review 
CI 
confidence interval 
CRF 
case report form 
CRPC 
castration-resistant prostate cancer 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
IDMC 
Independent Data Monitoring Committee 
RT 
external-beam radiation therapy 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EPIC 
Prostate Index Composite 
FACT-P 
Functional Assessment of Cancer Therapy-Prostate 
FDA 
Food and Drug Administration 
GnRH 
gonadotropin releasing hormone 
HR 
hazard ratio 
ICH 
International Conference on Harmonization 
IHC 
immunohistochemistry 
ITT 
Intent-to-Treat 
IWRS 
interactive web response system 
K-M 
Kaplan-Meier  
MedDRA 
Medical Dictionary for Regulatory Activities 
MFS 
metastasis-free survival 
MRU 
medical resource utilization 
OS 
overall survival 
PD 
pharmacodynamic 
PK 
pharmacokinetic(s) 
PRO 
patient reported outcome 
PSA 
prostate specific antigen 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
 
 
 
 
 
 
 
 
 


JNJ-64091742 (Niraparib)  
 
 
 
Statistical Analysis Plan 64091742PCR2001  
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Approved, Date: 22 February 2021  
1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the definitions of analysis sets, derived variables, and 
statistical methods for all planned statistical analyses for protocol 64091742PCR2001. The SAP 
is intended to supplement the study protocol. Any deviations from this SAP will be described in 
the clinical study report (CSR). 
1.1. 
Trial Objectives 
The overall objectives and endpoints/assessments for the study are provided in Table 1 
Table 1: 
Study Objectives and Endpoints/Assessments 
Objectives 
Endpoints/Assessments 
Primary 
 
To assess the efficacy of niraparib in 
subjects with measurable mCRPC and 
BRCA mutation  
 
Objective response rate (ORR) of soft tissue (visceral or 
nodal disease) as defined by Response Evaluation Criteria 
in Solid Tumors (RECIST) 1.1 with no evidence of bone 
progression according to the PCWG3 criteria  
Secondary 
 
To assess the efficacy of niraparib in 
subjects with measurable mCRPC and 
non-BRCA mutation 
 
ORR of soft tissue (visceral or nodal disease) as defined 
by RECIST 1.1 with no evidence of bone progression 
according to the PCWG3 criteria 
 
To assess the efficacy of niraparib in 
subjects with mCRPC and DNA-repair 
anomalies 
 
CTC response defined as CTC=0 per 7.5 mL blood at 8 
weeks post-baseline in subjects with baseline CTC >0 
 
To 
evaluate 
response 
outcomes 
of 
niraparib in subjects with mCRPC and 
DNA-repair anomalies (BRCA, non-
BRCA) 
 
OS: time from enrollment to death from any cause 
 
As defined by PCWG3 
 
rPFS: time from enrollment to radiographic 
progression or death from any cause, whichever 
occurs first 
 
Time to radiographic progression 
 
Time to PSA progression  
 
Time to symptomatic skeletal event (SSE) 
 
To evaluate the safety and tolerability of 
niraparib 
 
Incidence of adverse events 
 
Clinical laboratory test results 
 
To evaluate duration of tumor response 
(BRCA, non-BRCA) 
 
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 
Exploratory 
 
To assess the efficacy of niraparib in 
subjects with mCRPC and DNA-repair 
anomalies 
 
Composite Response rate (CRR), where composite 
response is defined as 1 of the following by PCWG3:  
 
Objective response (as defined by RECIST 1.1), or  
 
Conversion of CTC from ≥5 cells per 7.5 mL blood 
at baseline to <5 cells per 7.5 mL blood nadir, 
confirmed by a second consecutive value obtained 4 
or more weeks later, or 


JNJ-64091742 (Niraparib)  
 
 
 
Statistical Analysis Plan 64091742PCR2001  
6 
Approved, Date: 22 February 2021  
Objectives 
Endpoints/Assessments 
 
PSA decline of ≥50% from baseline, measured twice 
3 to 4 weeks apart 
 
Time to unequivocal clinical progression (defined in 
section 5.4.1) 
 
To evaluate the population PK of niraparib 
and exposure-response relationships 
 
Analysis of niraparib oral clearance (CL/F), oral volume 
of distribution (V/F), and derived measures of exposure 
(e.g., area under the curve [AUC]) 
 
Effect of demographic and physio-pathological covariates 
on niraparib PK parameters 
 
Analysis of relationships between exposure and safety or 
efficacy endpoints. 
 
To evaluate the steady-state PK of 
niraparib and its metabolite M1 
 
Cmax, Tmax, Ctrough, AUC0-24 of niraparib and its metabolite 
M1 in a subset of subjects 
 
To evaluate the concordance between 
tissue-based 
and 
blood-based 
methodologies for detection of genomic 
alterations 
 
Comparison of gene alterations in DNA from tissue and 
in circulating tumor DNA (ctDNA) from plasma 
 
To evaluate potential DNA and RNA 
biomarkers predictive of response and 
resistance 
 
Changes in the levels or types of DNA and RNA 
biomarkers observed over time 
 
To evaluate the effect of niraparib on 
circulating tumor cells (CTCs) 
 
Changes in CTC counts observed over time 
 
To evaluate subject-relevant experiences 
(disease-related symptoms, treatment-
related symptoms, and health-related 
quality of life) 
 
Assessment of subject-relevant experience data including 
BPI-SF, FACT-P and EQ-5D-5L  
 
Time to deterioration in subject-relevant experiences 
Abbreviations: ATM=Ataxia Telangiectasia Mutated gene; AUC=area under the curve; BRCA1=Breast Cancer gene 1; 
BRCA2= Breast Cancer gene 2; BRIP1=BRCA1 Interacting Protein C-terminal Helicase 1 gene; CHEK2=Checkpoint 
Kinase 2 gene; CR=complete response; CTC=circulating tumor cell; ctDNA=circulating tumor DNA; 
DNA=deoxyribonucleic acid; FANCA=Fanconi Anemia Complementation Group A gene; HDAC2=Histone 
Deacetylase 2 gene; mCRPC=metastatic castration-resistant prostate cancer; ORR=objective response rate; OS=overall 
survival; PALB2=Partner and Localizer of BRCA2 gene; PCWG3=Prostate Cancer Working Group 3; PD=progressive 
disease; PK=pharmacokinetics; PR=partial response; PSA=prostate specific antigen; RECIST= Response Evaluation 
Criteria in Solid Tumors; rPFS=radiographic progression-free survival; RNA=ribonucleic acid; RR=response rate; 
SSE=symptomatic skeletal event. 
 
Summary tables of subject study disposition, treatment disposition, study compliance, TEAE, and 
death will include COVID-19 related information to assess impact on data. 
1.2. 
Trial Design 
This is a Phase 2, multicenter, open-label study to assess the efficacy and safety of once daily 
dosing of 300 mg niraparib in male subjects over the age of 18 years with mCRPC and DNA-repair 
anomalies who have received prior taxane-based chemotherapy and AR-targeted therapy. The 
study will assess up to approximately 120 subjects with measurable disease who are biomarker-
positive, as defined in Section 9.7 of the protocol (approximately 75 subjects with a BRCA 
anomaly (defined as either biallelic DNA-repair anomaly in BRCA [BRCA1 or BRCA2] or 
germline BRCA DNA-repair anomaly) and approximately 45 subjects with non-BRCA anomaly 


JNJ-64091742 (Niraparib)  
 
 
 
Statistical Analysis Plan 64091742PCR2001  
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Approved, Date: 22 February 2021  
(defined as biallelic DNA-repair anomalies in ATM, FANCA, PALB2, CHEK2, BRIP1, or 
HDAC2). In addition, at least 90 subjects with non-measurable mCRPC (i.e., bone disease only) 
and DNA-repair anomalies (both BRCA and non-BRCA) will be included to evaluate the activity 
of niraparib in this population. All subjects will be monitored for safety during the study period, 
and up to 30 days after the last dose of study drug. Treatment will continue until disease 
progression, unacceptable toxicity, death, or the sponsor terminates the study. 
The study will consist of 4 phases; a Prescreening Phase, a Screening Phase, a Treatment Phase, 
and a Follow-up Phase. After approximately 30 subjects have been enrolled and observed for 8 
weeks or more, a preliminary review of the efficacy and safety data will be performed by a Data 
Review Committee (DRC). Enrollment will not be suspended while the DRC reviews these data. 
To be eligible for the study, subjects must have a DNA-repair anomaly by either: a) a sponsor-
validated blood or tissue assay or b) a germline pathogenic BRCA1/BRCA2 DNA-repair anomaly 
by any test. A subject’s results indicating a somatic DNA-repair anomaly must be confirmed as 
positive by a sponsor-validated assay before enrollment (defined as Cycle 1 Day 1).  
1.3. 
Statistical Hypothesis for Trial Primary Objective 
Niraparib will demonstrate a >15% objective response rate (ORR, per RECIST 1.1) in subjects 
with mCRPC and DNA-repair anomalies who have measurable disease.  
1.4. 
Sample Size Justification 
For the primary objective using the ORR endpoint in subjects with measurable disease, mCRPC 
and BRCA anomaly, efficacy of niraparib will be declared if the lower bound of the 2-sided 95% 
exact CI for ORR is >15%.  With approximately 75 such subjects, the study will have over 90% 
power to determine if the lower limit of the 95% CI for ORR exceeds 16%.  
 
For the secondary objective evaluating the ORR endpoint in subjects with measurable disease, 
mCRPC and non-BRCA anomaly, the null hypothesis that the ORR is ≤15% will be tested against 
the alternate hypothesis that the ORR is ≥32%. With a 1-sided α of 0.05 and power of 80%, up to 
45 such subjects are to be enrolled based on Simon’s two-stage design.  At end of Stage 1, 
approximately 14 subjects will be evaluated for ORR after at least 1 post-treatment scan and a 
confirmatory scan.  Future enrollment in this group may be terminated if 2 or fewer responses are 
observed in the first stage. Otherwise, enrollment may proceed to the second stage with a total of 
approximately 45 subjects combined for the 2 stages, and the null hypothesis will be rejected if 10 
or more responses are observed. 
 
Assuming a historical CTC response rate (CTC RR) of 
 and 
a target CTC RR of 40%, approximately 60 subjects with non-measurable disease (BRCA and 
non-BRCA) will be required to provide a lower bound of the 2-sided 95% CI greater than 20%, 
with a probability of 0.9. 
1.5. 
Randomization and Blinding 
This is an open-label, single-treatment study; therefore, blinding and randomization procedures 
are not applicable. 
CCI


JNJ-64091742 (Niraparib)  
 
 
 
Statistical Analysis Plan 64091742PCR2001  
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2. 
GENERAL ANALYSIS DEFINITIONS 
The date of enrollment is the date of the first dose of study medication and is also Cycle 1 Day 1.  
Study Day is calculated based on this date. Positive study days will count forward from Study Day 
1.  Study Day -1 will be the day before Study Day 1, and all subsequent negative study days will 
be measured backward from Study Day -1. There will be no Study Day 0. The first dose starts on 
Day 1 of Cycle 1. Unless otherwise specified, baseline value is defined as the closest measurement 
prior to or on the date of the first dose of study drug. Change from baseline will be defined as 
(post-baseline value – baseline value). 
Treatment Duration is calculated as the duration of time from the date of the first dose of study 
drug to the date of last dose of the study drug, i.e., date of last dose – date of first dose + 1. 
Time to Event is calculated as the number of days from the date of enrollment to the date of the 
event of interest, i.e., date of event of interest – date of enrollment + 1.  Time to event or duration 
of event endpoints will be based on the actual date of the event, not visit number or visit date.  
Continuous/numerical variables will be summarized using mean, standard deviation (SD), median, 
minimum, and maximum. Categorical variables will be summarized using count and percentage. 
Missing data will be handled using a data as observed approach, no imputation will be 
implemented unless specified.  
2.1. 
Pooling Algorithm for Analysis Centers 
There is no plan to pool data across centers (study sites) for analyses.  
2.2. 
Analysis Sets 
Multiple analysis sets will be defined for analysis purposes.  
Enrolled Analysis Set: All subjects who are enrolled into the study.  
Efficacy Analysis Set: All subjects who received at least 1 dose of study drug and have BRCA 
(biallelic or germline DNA-repair anomalies) or non-BRCA (biallelic DNA-repair anomaly). 
 BRCA analysis set (Primary Efficacy Analysis): a subset of efficacy analysis set with 
BRCA subjects (biallelic or germline DNA-repair anomalies).   
 Non-BRCA analysis set: a subset of efficacy analysis set with non-BRCA subjects 
(biallelic DNA-repair anomaly).  
Safety Analysis Set: All subjects who received at least 1 dose of study drug (same population as 
the Enrolled Analysis Set).  
Patient-report Outcomes Analysis Set (PRO): All subjects who completed the baseline assessment 
and at least 1 post-baseline assessment of BPI-SF, FACT-P, or EQ-5D-5L questionnaires. 


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Pharmacokinetics Analysis Set (PK): All subjects who received 1 dose of study drug and have at 
least 1 blood sample for PK obtained post-baseline. 
2.3. 
Definition of Subgroups 
In order to assess the consistency of treatment benefit across different subject subpopulations, the 
planned analyses may also be carried out using the following subgroups if appropriate: 
 Baseline measurable disease status as defined by RECIST 1.12 (non-measurable disease 
is bone disease only) 
 Baseline Eastern Cooperative Oncology Group (ECOG) performance status (0-1 versus 
2) 
 Baseline Age (<70, ≥70 years) 
 Baseline visceral disease (visceral disease versus non-visceral disease for all subjects) 
 Biomarker status (BRCA, non-BRCA) 
3. 
INTERIM DATA REVIEW AND DATA REVIEW COMMITTEE  
3.1. 
Data Review Committee (DRC) 
A DRC will be established for this study to review the planned analyses. The DRC may include 
individuals both internal and external to the sponsor who are knowledgeable in the disease area.  
The DRC responsibilities, authorities, and procedures will be documented in detail in a separate 
DRC charter. 
3.2. 
Futility Analysis and Safety Review 
3.2.1 BRCA Subjects 
A futility analysis with a preliminary review of the efficacy and safety data will be performed after 
approximately 30 subjects with measurable disease as defined by RECIST 1.12 who have biallelic 
DNA-repair BRCA gene anomalies (as defined by the sponsor’s blood-based assay) have been 
enrolled and observed for at least 4 cycles. The objective of this review is to have a preliminary 
benefit/risk evaluation to continue the trial. Data scope for the preliminary review may include the 
following information as appropriate: 
 Descriptive summary of subject disposition, exposure, and baseline disease characteristics 
 Descriptive summary of safety parameters such as treatment emergent adverse events 
(TEAEs), SAEs, death, and key lab parameters 
 Descriptive summary of the following efficacy endpoints will be provided: 
o Objective response rate (ORR) based on investigator assessment 
o Duration of objective response 


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o CTC response defined as CTC=0 per 7.5 mL blood at 8 weeks post-baseline in 
subjects with baseline CTC >0 
o Composite response rate (CRR), where composite response is defined as 1 or more 
of the following 
 Objective response (as defined by RECIST 1.1 with no evidence of bone 
progression according to the PCWG3 criteria) based on investigator 
assessment 
 Conversion of CTC from ≥5 cells per 7.5 mL blood at baseline to <5 cells 
per 7.5 mL blood nadir, confirmed by a second consecutive value obtained 
4 or more weeks later, or 
 PSA decline of ≥50% from baseline, measured twice 3 to 4 weeks apart 
 An early look at the primary endpoint of objective response rate (ORR) may be carried out.  
Lack of clinical activity may be considered if the observed number of responses is ≤3 out 
of 30 subjects.  Under the assumption that the null hypothesis of true ORR ≤15% vs. 
alternate hypothesis of true ORR ≥32%, this statistical guideline will control the false 
negative rate to be <1%, i.e., declaring lack of clinical activity when underlying response 
rate has treatment benefit.  There is no penalty for alpha spending for this analysis. 
3.2.2 Non-BRCA Subjects 
A futility analysis will be performed after approximately 14 non-BRCA subjects with measurable 
disease as defined by RECIST 1.12 who are enrolled under protocol amendment 4 or later and 
observed for at least 4 cycles. The objective of the futility analysis is to determine if non-BRCA 
enrollment continues. Data scope for this futility analysis may include the following information 
as appropriate: 
 Descriptive summary of subject disposition, exposure, and baseline disease characteristics 
 Descriptive summary of safety parameters such as treatment emergent adverse events 
(TEAEs), SAEs, death, and key lab parameters 
 Descriptive summary of the following efficacy endpoints will be provided: 
o Objective response rate (ORR) based on investigator assessment 
o Duration of objective response 
o CTC response defined as CTC=0 per 7.5 mL blood at 8 weeks post-baseline 
baseline in subjects with baseline CTC >0 
o Composite response rate (RR), where composite response is defined as 1 of the 
following 
 Objective response (confirmed per RECIST 1.1) based on investigator 
assessment, or 


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 Conversion of CTC from ≥5 cells per 7.5 mL blood at baseline to <5 cells 
per 7.5 mL blood nadir, confirmed by a second consecutive value obtained 
4 or more weeks later, or 
 PSA decline of ≥50% from baseline, measured twice 3 to 4 weeks apart 
Lack of clinical activity may be considered if the observed number of responses is ≤2 out of the 
14 subjects.   
4. 
SUBJECT INFORMATION 
The number of subjects in each analysis set will be summarized. In addition, the distribution of 
subjects by site ID will be presented unless otherwise noted. 
4.1. 
Demographics and Baseline Characteristics 
The following parameters in table 1 will be summarized using the enrolled analysis set and the 
primary efficacy analysis set: 
Table 1:  
Demographic and Baseline Characteristics Variables 
Continuous Variables: 
Summary Type 
 Age (years) 
Descriptive statistics (N, 
mean, standard deviation 
[SD], median and range 
[minimum and 
maximum]) 
 Weight (kg), Height (cm) 
 Baseline PSA, hemoglobin, CTC, platelet, neutrophil, lactate dehydrogenase,   
Alkaline phosphatase, testosterone value 
 Time from initial diagnosis to Day1 Cycle 1  
Categorical Variables 
 
 Age <65 years, ≥65 to 69 years, ≥70 to 74 years, ≥ 75 years  
Frequency distribution 
with the number and 
percentage of subjects in 
each category 
 Racea (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, Other, Multiple) 
 Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
 Baseline ECOG performance status (0, 1, 2) 
 Gleason score at diagnosis  
 Extent of disease progression (Bone, Visceral, Lymph Node, Soft Tissue) 
 Evidence of disease progression at study entry 
 
 Number of prior therapies (Number of AR-targeted therapies, taxane-based 
chemotherapy, cytotoxic chemotherapy, and other therapies) 
 
 
a If multiple race categories are indicated, the race is recorded as ‘Multiple'  Note that collection of race and 
ethnicity is limited to countries were permitted. 
 
4.2. 
Disposition Information 
The number and percentage of subjects who are enrolled, dosed, who discontinue study treatment 
and discontinue the study (including reasons) will be summarized using the enrolled analysis set  
and the primary efficacy analysis set specified in Section 2.2. 
4.3. 
Treatment Compliance  
Treatment compliance and dose modifications will be summarized using the safety analysis set. 
Subjects should take a total of 3 capsules of niraparib (3 x 100 mg) once daily during the treatment 
phase, unless subjects experience toxicity resulting in protocol-specified dosing modifications.  


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Treatment compliance will be summarized descriptively and will be calculated as ratio of 
actual dose intensity/planned dose intensity * 100%. 
 Dose intensity is defined as the total amount of drug given in a fixed unit of time. Subjects with 
at least one dose reduction or with dose interruption and the reason for the dose modification will 
be summarized. 
4.4. 
Duration of Exposure 
Duration of exposure will be summarized using the safety analysis set and the primary efficacy 
analysis set, in terms of treatment duration in cycles and in months, which are calculated as the 
number of days with dosing record divided by 30.4375 (i.e., number of days in a month calculated 
as 365.25/12). 
4.5. 
Protocol Deviations 
Major Protocol deviations will be summarized using the enrolled analysis set. Protocol deviations 
were reviewed per SOP by a cross functional team during the regularly scheduled protocol 
deviation meetings and assessed if they are considered major protocol deviations. The final list 
will be compiled prior to database lock.  Examples of major protocol deviations may include, but 
are not limited to, the following categories: 
 Deviation from inclusion/exclusion criteria  
 Major study drug dosing errors or dose modifications that are not within the protocol 
specifications that may compromise subject safety or efficacy assessments 
 Administration of prohibited concomitant medication during the study treatment period 
 Other deviation that impacts subject safety  
4.6. 
Prior and Concomitant Medications and Subsequent Therapies 
Prior and concomitant medications will be summarized by WHO Drug therapeutic class and 
generic medication name using the enrolled analysis set and the primary efficacy analysis set. Prior 
medications are those taken (with medication start date) prior to Cycle 1 Day 1. Concomitant 
medications are those, other than study drug, taken during the Treatment Phase.  
Subsequent prostate cancer therapies received after the Treatment Phase will be summarized using 
the efficacy and the primary efficacy analyses sets. If the therapy is medication, then it will also 
be summarized by World Health Organization (WHO) Drug therapeutic class and generic 
medication name. 
5. 
EFFICACY 
A summary of the planned analyses for efficacy endpoints are listed in Table 2, more details can 
be found in subsequent sections. All secondary efficacy endpoints will also be analyzed based on 
the two populations in terms of biomarker status (BRCA versus non-BRCA DNA-repair 
anomalies).  


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Table 2: 
Planned Analyses for Efficacy Endpoints 
Endpoint 
Analysis Method 
Primary 
endpoint 
Objective response rate 
(ORR) 
 
Descriptive summary 
 
Two-sided 95% exact confidence interval 
Secondary 
endpoints 
OS 
 
K-M plot  
 
Descriptive summaries  
CTC response rate 
 
Descriptive summaries  
 
Two-sided 95% exact confidence interval  
rPFS 
Time to radiographic 
progression 
 
K-M plot  
 
Descriptive summaries  
Time to PSA 
progression 
Time to symptomatic 
skeletal event (SSE) 
Duration of objective 
response 
 
K-M plot  
 
Descriptive summaries  
 
Waterfall plot for PSA  
Exploratory 
endpoints 
Response Rate (RR) as 
defined in Section 1.1 
 
Descriptive summary  
 
Two-sided 95% exact confidence interval  
Change from baseline 
in CTC over time 
 
Descriptive summary over time  
 
Time to degradation in 
BPI-SF worst pain 
intensity score 
 
K-M plot  
 
Descriptive summary 
Time to FACT-P total 
score degradation  
 
K-M plot  
 
Descriptive summary 
BPI-SF Worst Pain 
Intensity score, 
FACT-P total score, 
and EQ-5D-5L VAS 
score 
 
Descriptive summary  
 
 
5.1. 
Analysis Specifications 
5.1.1. 
Level of Significance 
In general, all confidence intervals will be calculated on the two-sided 95% confidence level (CI), 
unless otherwise specified. 
5.1.2. 
Data Handling Rules 
In general, no imputation method is planned for handling missing or incomplete data unless 
specified otherwise.  Sensitivity analyses with censoring rules may be conducted if warranted 
and will be documented in the clinical study report. 
The following imputation rule will be used for missing dates in the assessment of an event: 
Partial event onset dates will be imputed as follows: 
 If the onset date of an event is missing day only, it will be set to the earliest of: 


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 
First day of the month that the event occurred, if month/year of the onset of event is 
different than the month/year of the Day 1 
 
The day of Day 1, if the month/year of the onset of AE is the same as month/year of the 
Day 1 and month/year of the event resolution date is different 
 
The day of Day 1 or day of event resolution date, whichever is earliest, if month/year of 
the onset of event and month/year of the Day 1 and month/year of the event resolution 
date are same 
 If the onset date of an event is missing both day and month, it will be set to the earliest of: 
 
January 1 of the year of onset, if this date is on or after the Day 1 
 
Month and day of the Day 1, if this date is the same year that the event occurred 
 
Last day of the year if the year of the event onset is prior to the year of the Day 1, 
 
The event resolution date. 
 Completely missing onset dates will not be imputed. 
 
Partial event resolution dates not marked as ongoing will be imputed as follows: 
 
If the resolution date of an event is missing day only, it will be set to the earliest of the last 
day of the month of occurrence of resolution or the day of the date of death, if the death 
occurred in that month. 
 
If the resolution date of an event is missing both day and month, it will be set to the earliest 
of December 31 of the year or the day and month of the date of death, if the death occurred in 
that year. 
 
Completely missing resolution dates will not be imputed. 
5.2. 
Primary Endpoint 
5.2.1. 
Definition 
The primary endpoint is Objective response rate (ORR), defined as the proportion of subjects with 
BRCA DNA-repair anomalies and measurable disease whose best response is either complete 
response (CR) or partial response (PR) as defined by RECIST 1.12 and who have no evidence of 
bone progression according to the PCWG3 criteria3.   
5.2.2. 
Estimand 
The primary estimand, the main clinical quantity of interest to be estimated in this study, is defined 
by the following four components: 
 Population: all subjects with measurable disease in the BRCA analysis set. 
 Variable: ORR based on investigator assessment. 
 Intercurrent events and strategies:  
Missing baseline assessment  
Assume non-response 


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No post baseline response 
assessment  
Assume non-response 
 
 Population-level summary: ORR will be summarized for BRCA analysis set along with 
95% 2-sided exact CI. 
5.2.3. 
Analysis Methods 
ORR final analysis will be performed approximately 6 months from Cycle 1 Day 1 of the last 
subject with a BRCA DNA-repair anomaly and measurable disease and measurable disease. 
Objective response as determined by investigator assessment will be considered as the primary 
analysis. 
Additionally, all enrolled subjects with a non- BRCA DNA-repair anomaly and measurable disease 
as defined by RECIST 1.12 will be analyzed for objective response.   
Subjects who discontinue the study without a response assessment will be considered as non-
responders in the analysis. The objective response rate will be calculated and its 2-sided 95% exact 
CI will be presented.  In addition, the counts and percentage of subjects in each response category 
(CR, PR, etc.) will be tabulated.  
5.3. 
Secondary Endpoints 
5.3.1. 
Definitions 
CTC response rate is defined as the proportion of subjects with baseline CTC>0 whose CTC=0 
per 7.5 mL blood at 8 weeks post-baseline.  
OS is defined as time from enrollment to death from any cause.  Subjects alive at time of analysis 
will be censored on the last date the subject was known to be alive. 
Time to radiographic progression is defined as time from enrollment to radiographic progression 
(as determined by the investigator) or death due to disease progression, whichever occurs first.   
Radiographic progression is determined by first occurrence of progression, assessed by 
investigator. Radiographic progression should be evaluated as follows: 
• 
Progression of lesions measured by CT or MRI as defined by RECIST 1.1.  
• 
Bone progression observed on 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 baseline 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 would fall 
into one of the 2 categories below: 


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a. Subject whose confirmatory scan (which is performed ≥6 weeks later) shows ≥2 
new lesions compared to the Week 8 scan (i.e., 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 does not show ≥2 new lesions compared to the 
Week 8 scan will not be considered to have bone scan progression. The Week 8 
scan will be considered as the baseline scan to which subsequent scans are 
compared. The first scan timepoint that shows ≥2 new lesions compared with the 
Week 8 scan will be considered as the bone progression timepoint if these new 
lesions are confirmed by a subsequent scan ≥6 weeks later. 
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 progression timepoint if these new lesions are 
confirmed by a subsequent scan ≥6 weeks later. 
Subjects without radiographic progression or death will be censored at the last disease assessment 
date if they never start subsequent anti-cancer therapy. Subjects who begin a subsequent anti-
cancer therapy will be censored the date of the last assessment prior to starting a new anti-cancer 
therapy. Key censoring rules are summarized below. 
Scenario 
Censoring Rule 
No disease assessment at baseline 
or 
No disease assessment after baseline  
Censored on the date of enrollment  
 
Subjects who are lost to follow-up or withdraw 
from study prior to documented disease 
progression or death 
Censored on the date of the last disease assessment  
Subjects who receive new systemic anti-cancer 
therapy known or intended for the treatment of 
mCRPC during the study prior to documented 
disease progression or death 
Censored on the date of the last disease assessment prior 
to the start of the new systemic anti-cancer therapy 
Subjects with no evidence of radiographic 
progressive disease or death 
Censored on the date of the last disease assessment  
Subjects who miss ≥2 consecutive planned 
radiographic scans or have ≥2 consecutive 
unevaluable scans immediately followed by 
progression or death 
Censored on the date of the last disease assessment 
before the missed/unevaluable scans  
No postbaseline assessment and death occurred 
after missed 2 or more planned disease 
assessments 
Censored on the date of enrollment  
 
Time to PSA progression is defined as time from enrollment to the first date of documented PSA 
progression based on PCWG3 criteria.  Subjects with no PSA progression at the time of analysis 
will be censored on the last known date with no progression. Subjects without a baseline PSA or 
without any post baseline values will be censored on enrollment date. 
Time to symptomatic skeletal event (SSE) is defined as the time from enrollment to the first 
occurrence of one of the following symptomatic skeletal events: 


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 Tumor-related spinal cord compression 
 Radiation to bone to relieve skeletal symptoms  
 Surgery to bone or need for tumor-related orthopedic surgical intervention  
 Symptomatic or pathologic fracture 
 
Subjects with no symptomatic skeletal event at the time of analysis will be censored on the last 
SSE assessment.   Death is not an event for SSE. 
Duration of objective response is defined as time from complete response or partial response to 
radiographic progression of disease, unequivocal clinical progression or death, whichever occurs 
first.  
5.3.2. 
Analysis Methods 
ORR in BRCA and non-BRCA subjects will be analyzed in the same way. 
Following analyses on CTC response will be performed for BRCA and non-BRCA analysis sets, 
measurable and non-measurable subgroups:  
 Descriptive summaries  
 CTC response rate will be tabulated and its 2-sided 95% exact CI  
 Waterfall plots of percent change in CTC will also be presented that show the percentage 
change in CTC counts from baseline to 8 weeks as well as CTC count declines.  
All time-to-event endpoints will be evaluated using Kaplan-Meier method for BRCA and non-
BRCA analysis sets.  Median time to event and the corresponding 95% CI will be provided. 
Descriptive summaries will be provided for BRCA and non-BRCA analysis sets. In addition, 
waterfall plots for PSA will be presented for to demonstrate the percentage of change in PSA from 
baseline to 12 weeks (or earlier for those who discontinue therapy), as well as the maximal decline 
in PSA. 
5.4. 
Other Endpoints 
Exploratory endpoints include composite response rate (CRR) as defined in Section 1.1, Time to 
unequivocal clinical progression, change from baseline in CTC counts over time, Time to 
degradation in BPI-SF worst pain intensity score, Time to FACT-P total score degradation, and 
BPI-SF Worst Pain Intensity score, FACT-P total score, and EQ-5D-5L VAS score (see section 9 
for definition).   
5.4.1. 
Definition 
Composite response rate (CRR), where composite response defined as 1 of the following: 
 Objective response (as defined by RECIST 1.1 with no evidence of bone progression 
according to the PCWG3 criteria), or 


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 Conversion of CTC from ≥5 cells per 7.5 mL blood at baseline to <5 cells per 7.5 mL blood 
nadir, confirmed by a second consecutive value obtained 4 or more weeks later, or 
 PSA decline of ≥50% from baseline, measured twice 3 to 4 weeks apart. 
 
CTC0 with confirmation is defined as CTC drop to 0 post-baseline (confirmed by a second 
consecutive value obtained 4 or more weeks later) for subjects with baseline CTC>0. 
Time to unequivocal clinical progression is defined as time from enrollment to unequivocal clinical 
progression or death due to disease progression.  Subjects without unequivocal clinical progression 
or death will be censored at the last disease assessment date if never start of subsequent anti-cancer 
therapy or censored at the last disease assessment date prior to the start of the subsequent anti-
cancer therapy if started subsequent anti-cancer therapy.  
Unequivocal clinical progression per protocol is defined as one or more of 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): 
o Alternative anticancer therapy for prostate cancer. 
o Radiation therapy. 
o Surgical interventions for complications due to tumor progression. 
 
Change from baseline in CTC counts over time is defined as the change from baseline in CTC 
counts at each CTC assessment time point.  
5.4.2. 
Analysis Methods 
Response rate will be tabulated and its 2-sided 95% exact CI will be presented. To calculate CTC 
conversion, subjects who have CTC< 5 cells per 7.5 mL blood at baseline will be removed from 
the analysis. In addition, the number and percentage of subjects meeting each response criterion 
(RR, CTC conversion, and PSA decline of 50%) will be tabulated.  
The median time to degradation in BPI-SF worst pain intensity score and Time to FACT-P total 
score degradation will be estimated using a Kaplan-Meier technique.  Subjects who did not 
experience degradation were censored at last data point collected for the PRO assessment.  In cases 
where median values cannot be computed because less than 50% of subjects experienced 
degradation, 25th percentiles will be reported and compared instead. 


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Change from baseline in CTC counts over time, in BPI-SF Worst Pain Intensity score, FACT-P 
total score, and EQ-5D-5L VAS score will be summarized and longitudinal plots will be provided.  
Exploratory analyses of CTC0 and CTC conversion with confirmation will be performed to 
evaluate their impact on OS, rPFS.  
6. 
Safety 
The safety parameters to be evaluated are the incidence, intensity, and type of adverse events (AE), 
vital signs, ECG, and clinical laboratory results.  
Unless otherwise specified, no inferential statistical analyses will be performed in analyzing the 
safety data. 
6.1. 
Adverse Events 
Subjects will be assessed for adverse events at each monthly clinic visit while on the study.  
Adverse events (AEs) will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.031 or later and coded to preferred term and system organ 
class (SOC) using the MedDRA version 18.0 or later. 
All AEs reported on or after the date of first dose until 30 days (inclusive) after the last dose of 
study drug will be considered treatment-emergent and will be summarized. 
AE incidence rates will be summarized with frequency and percentage by SOC and preferred term, 
with all subjects treated as the denominator, unless otherwise specified. In addition, AE incidence 
rates will also be summarized by severity and relationship to study drug. Treatment-related AEs 
are those judged by the Investigator to be at least possibly related to the study drug. Subjects with 
multiple occurrences of events will only be counted once at the maximum severity to study drug 
for each preferred team, SOC, and overall. Deaths that occur within 30 days after the last dose of 
study drug are defined as on-study deaths. 
Summary tables of the following AEs will be provided: 
 Overall summary of AEs:  the number and percentage of subjects who experienced any AE, 
number of subjects with Grade 3/4 AEs, any serious adverse event (SAE), any treatment-
related AE, any treatment-related SAE, AE leading to treatment discontinuation, AE 
leading to death, and  all deaths within 30 days of last dose 
 All AEs by SOC and preferred term 
 Most frequent AEs by SOC and preferred term (reported in ≥ 5% of subjects) 
 All AEs by SOC, preferred term, and toxicity grade 
 Grades 3 or 4 AEs by SOC and preferred term 
 Treatment-related AEs by SOC and preferred term 
 Treatment-related AEs by SOC, preferred term, and toxicity grade 
 Most frequent treatment-related Grades 3 and 4 AEs (reported in ≥ 5% of subjects) 


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 All AEs that led to death by SOC and preferred term 
 All AEs that led to study drug discontinuation by SOC and preferred term. Study drug 
discontinuation will be determined from the End of Treatment CRF (where reason for 
termination is “Adverse Event”) and the specific AE will be determined from the AE eCRF 
page (where action taken is “Withdrawn from Study”) 
 All AEs that led to study drug discontinuation by SOC, preferred term, and toxicity grade 
 All AEs that lead to study drug dose modification by SOC and preferred term 
 All SAEs by SOC and preferred term 
 All SAEs by SOC, preferred term, and toxicity grade 
 Deaths by time period (Treatment Phase, Follow-up Phase) and cause of death 
Subject listings of all Grades 3 or 4 AEs, all SAEs, AEs that led to study drug discontinuation, 
dose modification, and all deaths will be provided as well. 
Narratives will be written for the following subjects in the final clinical study report: 
 Subjects who die within 30 days of the last dose of study drug 
 Subjects who discontinue study drug due to adverse events  
 Subjects who have a treatment-related serious adverse event  
 Subjects who experience a grade 3 or higher AE of special interest (thrombocytopenia, 
anemia, neutropenia, MDS and AML) 
6.2. 
Clinical Laboratory Tests 
For continuous/numerical measurements, descriptive statistics will be provided at baseline and for 
observed values and changes from baseline at each scheduled time point. The number and 
percentage of subjects with abnormal laboratory values will be summarized. The number and 
percentage of subjects whose NCI-CTCAE (version 4.03 or later) toxicity grades of ≥ 3 will also 
be summarized. For selected key laboratory measurements, changes in toxicity grade from baseline 
to the worst grade experienced by the subject during the Treatment Phase and the Study will be 
summarized using shift tables.   
A listing of subjects who develop toxicities of Grade ≥ 3 will be provided for each laboratory 
parameter. 
6.3. 
Vital Signs  
Descriptive statistics of blood pressure (systolic and diastolic) and body weight values and changes 
from baseline will be summarized at each scheduled time point. Descriptive statistics of other vital 
signs (body temperature, heart rate, respiratory rate) at baseline will also be summarized.  
Baseline vital signs, blood pressure (systolic and diastolic), and heart rate will be summarized.  Only blood 
pressure and heart rate are reported during the treatment phase. Subjects with markedly abnormalities in 


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blood pressure as compared to baseline will be summarized according to the following categories defined 
below.  
Parameter 
Criteria for Markedly Abnormality 
Systolic Blood 
Pressure 
Absolute result < 90 mmHg and decrease from baseline > 20 mmHg  
Absolute result > 160 mmHg and increase from baseline > 20 mmHg 
Diastolic Blood 
Pressure 
Absolute result < 50 mmHg and decrease from baseline > 10 mmHg  
Absolute result > 100 mmHg and increase from baseline > 10 mmHg 
Weight 
10 - < 20% weight loss from baseline 
 
 
6.4. 
Physical Examination 
Abnormal findings deemed clinically significant in physical examination will be recorded and 
summarized as AEs.  
6.5. 
Electrocardiogram 
Electrocardiogram parameters will be summarized using descriptive statistics. The number and 
percentage of subjects with values beyond clinically important limits will also be summarized. 
7. 
PHARMACOKINETICS/PHARMACODYNAMICS 
Pharmacokinetic analyses will be performed and summarized in a separate report. 
8. 
BIOMARKERS 
Biomarker analyses will be performed and summarized in a separate technical report. 
9. 
PATIENT-REPORTED OUTCOMES 
Patient-reported outcome (PRO) assessments include BPI-SF, FACT-P and EQ-5D-5L, which will 
be analyzed to assess the subjects’ perspective of response to treatment.  
 
Missing PRO assessments will be calculated as the expected number of assessments for a particular 
visit minus the actual number of assessments received for that visit. Compliance (% received and % 
missing forms) will be tabulated for each visit. Expected number of assessments per visit will be 
determined by subject-level study completion status. Separate tables will be produced for FACT-
P Total, BPI-SF, and EQ-5D-5L. 
 
Descriptive statistics (N, Mean, Standard Deviation, Median, Min, Max for observed and changes 
from baseline) will be provided for each component of the BPI-SF, FACT-P and EQ-5D-5L. 
Components are as follows:  
 FACT-P Total (PWB + SWB + EWB + FWB + PCS; Range: 0-156) 


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 FACT-P Physical Wellbeing (PWB) (Items GP1-GP7; Range: 0-28) 
 FACT-P Social/Family Wellbeing (SFWB) (Items GS1-GS7; Range: 0-28) 
 FACT-P Emotional Wellbeing (EWB) (Items GE1-GE6; Range: 0-24) 
 FACT-P Functional Wellbeing (FWB) (Items GF1-GF7; Range: 0-28) 
 FACT General (FACT-G) (PWB + SFWB + EWB + FWB; Range: 0-108) 
 FACT-P Prostate Cancer Subscale (PCS) (Sum of items C2, C6, P1-P7, BL2, P8, Bl5; 
Range: 0-48) 
 FACT-P Trial Outcome Index (TOI) (PWB + FWB + PCS; Range: 0-104) 
 FACT-P Pain-related Scale (PRS) (Sum of items P1-P3, GP4; Range: 0-16) 
 FACT Advanced Prostate Symptom Index (FAPSI-8) (Sum of items GP1, GP4, GE6, C2, 
P2, P3, P7, P8 Range: 0-32) 
 EQ-5D-5L VAS 
 EQ-5D-5L Health Utility Score 
 BPI-SF Pain Severity Index (PSI) (Items 3-6; Range: 0 – 40) 
 BPI-SF Pain Interference Index (PII) (Items 9A – 9G; Range: 0 – 70) 
 
 
Time to degradation in FACT-P Total and BPI-SF worst pain intensity item (#3) will be 
determined using the meaningful change threshold values: 
 FACT-P Total: 10-point reduction from baseline 
 BPI-SF worst pain intensity item: 30% reduction from baseline 
The median time to degradation in each total score will be estimated using a Kaplan-Meier 
technique. Subjects who do not experience degradation will be censored at last data point 
collected for the PRO assessment. In cases where median values cannot be computed because 
less than 50% of subjects experienced degradation, 25th percentiles will be reported and 
compared instead. 
10. 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS 
Data collected on medical resource utilization (MRU) will be used in the construction of economic 
model. The modeling and reporting will be provided in a separate report. 


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REFERENCES 
1. 
NCCN Clinical Practice Guidelines in Oncology (NCCN Guideline®) Prostate Cancer. Version 3.2012 
(www.NCCN.org). 
2. 
Eisenhauer EA, Therasse P, Bogaerts, et al. New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247. 
3. 
Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: 
Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016 
Apr 20;34(12):1402-1418.