A Randomized Phase 3 Double-Blinded Study Comparing the Efficacy and Safety of Niraparib to Placebo in Participants With Either HER2-Negative BRCA-Mutated or Triple-Negative Breast Cancer With Molecular Disease Based on Presence of Circulating Tumor DNA After Definitive Therapy (ZEST)
Phase: PHASE3
Conditions: Neoplasms, Breast
Sponsor: GlaxoSmithKline

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Title Page 
A RANDOMIZED PHASE 3 DOUBLE-BLINDED STUDY 
COMPARING THE EFFICACY AND SAFETY OF 
NIRAPARIB TO PLACEBO IN PARTICIPANTS WITH 
EITHER HER2-NEGATIVE BRCA-MUTATED OR 
TRIPLE-NEGATIVE BREAST CANCER WITH 
MOLECULAR DISEASE BASED ON PRESENCE OF 
CIRCULATING TUMOR DNA AFTER DEFINITIVE 
THERAPY (ZEST) 
Brief Title: 
Efficacy and Safety Comparison of Niraparib to 
Placebo in Participants with HER2-Negative 
BRCAmut or Triple-Negative Breast Cancer with 
Molecular Disease Based on Presence of ctDNA 
Protocol Number: 
213831/Amendment 04 
Compound Number or Name: Niraparib (GSK3985771) 
Study Phase: 
Phase 3 
Sponsor Name and Legal 
Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency 
Identifying Number(s): 
IND Number 117580 
EudraCT Number 2020-003973-23 
Medical Monitor name and contact can be found in local study contact information 
document.  
 
Sponsor Signatory: 
Erin Hofstatter, MD 
Group Senior Medical Director, Oncology Clinical 
Development/Synthetic Lethality, GSK 
Approval Date: 
28 Nov 2023 
 
©2023 GSK group of companies or its licensor. All rights reserved. Unauthorized 
copying or use of this information is prohibited.  

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Document Identifier 
Amendment 04 
28 Nov 2023 
TMF-17007234 
Amendment 03 
02 June 2023 
TMF-16097940 
Amendment 02 FRA-1 
13 Feb 2023 
RPS-CLIN-050203 
Amendment 02 
05 Oct 2022 
TMF-14887215 
Amendment 1 FRA-1 
22 Feb 2022 
TMF-14472256 
Amendment 1 DEU-4 
07 Jan 2022 
TMF-14373986 
Amendment 01/ 
Amendment 01 DEU-3 
07-Oct-2021 
TMF-13772769/ 
TMF-14011986 
Amendment DEU-2 
10-Sep-2021 
TMF-13986489 
Amendment DEU-1 
26-Jul-2021 
TMF-13891990 
Amendment GBR-1 
30-Apr-2021 
TMF-12903338 
Original Protocol (00) 
25-Jan-2021 
TMF-11716064 
 
Amendment 04  
This amendment is considered substantial based on the criteria defined set forth in Article 
10(s) of Directive 2001/20/EC of the of the European Parliament and the Council of the 
European Union because it significantly impacts the scientific value of the study. 
Overall Rationale for the Current Amendment:  
The protocol has been amended to add Post-Analysis Continued Treatment (PACT) 
language to allow eligible participants to receive niraparib after the final analysis data 
cut-off. 
List of main changes in the protocol and their rationale: 
Section # and title 
Description of Change 
Brief Rationale 
Headers, title page, 
abbreviations, 
Protocol Amendment 
Summary of Changes, 
List of Abbreviation. 
Headers and title page were updated with 
new document number and amendment 
information; Protocol Amendment 
Summary of Changes section was updated 
to include rationale for this amendment; 
minor corrections and formatting 
adjustments, and to add clarification and/or 
remove discrepancies. 
Editorial changes as 
needed. 
Section 1.1 Synopsis 
Table 1 Objective and 
Endpoints 
Section 3 Objectives 
and Endpoints and 
Estimands 
Niraparib plasma concentration no longer 
applicable 
 
PK is no longer being 
analyzed due to the limited 
number of samples that 
were collected prior to 
stopping enrollment that 
are evaluable.  

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Section # and title 
Description of Change 
Brief Rationale 
Synopsis Section 1.1 
Section 1.3 Schedule 
of Activities 
Section 4.1 Overall 
Design 
Added guidelines for participants who 
continue treatment after the data cut-off 
(DCO) date of planned final 
analysis/database closure 
To provide continued 
treatment options to 
participants still deriving 
clinical benefit from 
treatment when the DCO 
is reached. 
Section 2.2.5 
Niraparib 
Information added for niraparib 
To provide information on 
the use of niraparib 
Section 4.1 Overall 
Design 
Table 12: Summary of 
Patient Management 
Under Protocol 
Amendment 04 
Visit schedule clarified for PACT Phase 
Clarification for study 
conduct under PACT. 
Section 4.4 End of 
Study Definition 
Section 6.7 Treatment 
After the End of the 
Study 
Added definition for end of study (EOS) 
Clarification for study 
conduct under PACT 
Phase for definition of the 
EOS. 
Section 6.1.1 
Niraparib 
Information added on dispense of Niraparib 
under current amendment. 
Clarification for study 
conduct under PACT 
Section 6.7.1 
Continued Access to 
Study Intervention  
Clarification for access to treatment during 
PACT Phase 
Clarification included 
regarding treatment 
following transitions to 
PACT Phase. 
Section 8.5.1 Time 
Period and Frequency 
for Collecting AE and 
SAE Information 
Included additional content to include 
information on collection of safety 
information via paper forms 
Language added for safety 
reporting requirements 
under PACT Phase of 
study. 
Clarification regarding 
study conduct outlining 
study 
requirements/assessments 
under PACT Phase for 
participants receiving 
access to study treatment 
(including procedures) 
following EOS. 
Section 10.5 
Appendix 5: 
Regulatory, Ethical, 
and Study Oversight 
Included additional content to describe 
management of data captured in CRF. 
Language added to outline 
changes to CRF reporting 
under PACT Phase of 
study. 

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Section # and title 
Description of Change 
Brief Rationale 
Considerations 
Management of data breaches and its 
communication to respective parities 
Text added as per EU 
CTR requirement. 
Section 10.8 
Appendix 8: AEs and 
SAEs 
Included additional content to describe 
management of 
SAEs/AESIs/AEs/Overdose/Pregnancy 
under PACT Phase 
Language added for 
management of 
SAEs/AESIs/AEs/ 
Overdose/Pregnancy 
PACT Phase of study. 
Section 10.9 
Appendix 9: 
Pregnancy Initial 
Notification Form 
Section 10.10. 
Appendix 10: Study 
pregnancy follow up 
form. 
Section 10.11 
Appendix 11: Serious 
Adverse Event (SAE) 
Reporting Form 
Addition of Pregnancy initial notification 
(Section 10.9) form, Study pregnancy 
follow up form (Section 10.10), and serious 
adverse reporting form (Section 10.11) 
Study Reference Manual 
(SRM) document is no 
longer being used; thus, 
forms previously contained 
in the SRM added to the 
protocol. 
 
 

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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ........................................................................................ 13 
1.1. 
Synopsis ..................................................................................................... 13 
1.2. 
Schema ...................................................................................................... 32 
1.3. 
Schedule of Activities .................................................................................. 38 
2. 
INTRODUCTION .................................................................................................... 73 
2.1. 
Study Rationale .......................................................................................... 73 
2.2. 
Background ................................................................................................ 75 
2.2.1. 
Overview of Breast Cancer .......................................................... 75 
2.2.2. 
Treatment Options for Patients with Operable HER2− 
Breast Cancer .............................................................................. 76 
2.2.3. 
HRD Status in TNBC ................................................................... 77 
2.2.4. 
PARP Inhibitors ........................................................................... 78 
2.2.5. 
Niraparib ...................................................................................... 79 
2.2.6. 
Circulating Tumor DNA ................................................................ 84 
2.3. 
Benefit/Risk Assessment ............................................................................ 86 
2.3.1. 
Risk Assessment ......................................................................... 86 
2.3.2. 
Benefit Assessment ..................................................................... 87 
2.3.3. 
Overall Benefit/Risk Conclusion ................................................... 89 
3. 
OBJECTIVES AND ENDPOINTS AND ESTIMANDS ............................................. 91 
4. 
STUDY DESIGN .................................................................................................... 93 
4.1. 
Overall Design ............................................................................................ 93 
4.2. 
Scientific Rationale for Study Design ........................................................ 104 
4.3. 
Justification for Dose ................................................................................ 108 
4.4. 
End of Study Definition ............................................................................. 109 
5. 
STUDY POPULATION ......................................................................................... 111 
5.1. 
Inclusion Criteria ....................................................................................... 115 
5.2. 
Exclusion Criteria ...................................................................................... 118 
5.3. 
Lifestyle Considerations ............................................................................ 120 
5.4. 
Prescreen Failures and Screen Failures ................................................... 120 
6. 
STUDY TREATMENTS AND CONCOMITANT THERAPY ................................... 122 
6.1. 
Study Treatments Administered ................................................................ 122 
6.1.1. 
Niraparib .................................................................................... 122 

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6.2. 
Preparation, Handling, Storage, and Accountability .................................. 124 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ......................... 125 
6.3.1. 
Randomization ........................................................................... 125 
6.3.2. 
Stratification ............................................................................... 125 
6.3.3. 
Blinding and Breaking the Blind ................................................. 125 
6.4. 
Planned Dose Adjustments ....................................................................... 126 
6.4.1. 
Dose Levels and Dose Adjustment ............................................ 126 
6.5. 
Study Treatment Compliance .................................................................... 128 
6.6. 
Treatment of Overdose ............................................................................. 128 
6.7. 
Treatment After the End of the Study ........................................................ 129 
6.7.1. 
Continued Access to Study Intervention .................................... 129 
6.8. 
Concomitant Medications and Nondrug Therapies .................................... 130 
6.8.1. 
Prohibited Medications and Nondrug Therapies......................... 130 
6.8.2. 
Other Study Restrictions ............................................................ 132 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................... 133 
7.1. 
Withdrawal/Stopping Criteria..................................................................... 133 
7.1.1. 
Liver Chemistry Stopping Criteria .............................................. 134 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................. 137 
7.3. 
Lost to Follow-up ...................................................................................... 137 
7.3.1. 
Further Biomedical Research Maintaining Confidential 
Participant Information ............................................................... 138 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................... 139 
8.1. 
General Guidelines ................................................................................... 139 
8.1.1. 
General Guidance for Treatment Continuity When 
Participants Are Unable to Come into the Clinic ......................... 139 
8.2. 
Screening and Baseline Assessments ...................................................... 143 
8.2.1. 
Baseline Assessments at Screening .......................................... 143 
8.2.2. 
Baseline CT/MRI and Bone Scan .............................................. 143 
8.3. 
Efficacy Assessments ............................................................................... 144 
8.3.1. 
Postbaseline Imaging and Tumor Assessment .......................... 144 
8.3.2. 
Exploratory Efficacy Endpoint: Disease-Free Survival ............... 145 
8.3.3. 
Exploratory Efficacy Endpoint: Distant Recurrence-Free 
Survival ...................................................................................... 148 
8.3.4. 
Exploratory Efficacy Endpoint: Time to First Subsequent 
Therapy ..................................................................................... 148 

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8.3.5. 
Exploratory Efficacy Endpoint: Time to First Subsequent 
Chemotherapy ........................................................................... 148 
8.3.6. 
Exploratory Efficacy Endpoint: Time to Symptomatic 
Progression ............................................................................... 148 
8.3.7. 
Exploratory Efficacy Endpoint: Invasive Disease-Free 
Survival ...................................................................................... 148 
8.3.8. 
Exploratory Efficacy Endpoint: Invasive Breast Cancer-
Free Survival ............................................................................. 149 
8.4. 
Safety Assessments ................................................................................. 150 
8.4.1. 
Physical Examinations ............................................................... 150 
8.4.2. 
ECOG Performance Status ........................................................ 150 
8.4.3. 
Vital Signs .................................................................................. 150 
8.4.4. 
Electrocardiograms .................................................................... 151 
8.4.5. 
Clinical Safety Laboratory Tests ................................................ 151 
8.4.6. 
Pregnancy Testing ..................................................................... 152 
8.5. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting .................................................................................................. 152 
8.5.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................. 153 
8.5.2. 
Method of Detecting AEs and SAEs ........................................... 154 
8.5.3. 
Follow-up of AEs and SAEs ....................................................... 154 
8.5.4. 
Regulatory Reporting Requirements for SAEs ........................... 154 
8.5.5. 
Pregnancy ................................................................................. 154 
8.5.6. 
Cardiovascular and Death Events .............................................. 155 
8.5.7. 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs............................................. 155 
8.5.8. 
Adverse Events of Special Interest ............................................ 156 
8.6. 
Pharmacokinetics ..................................................................................... 156 
8.7. 
Genetics ................................................................................................... 157 
8.8. 
Translational Research ............................................................................. 157 
8.8.1. 
Tumor Tissue Collection at Time of Disease Recurrence ........... 158 
8.9. 
Patient-Reported Outcome Measures ....................................................... 159 
8.9.1. 
EORTC-QLQ-C30 ...................................................................... 159 
8.9.2. 
PRO-CTCAE ............................................................................. 160 
8.9.3. 
FACT-GP5 ................................................................................. 160 
8.9.4. 
EuroQol Questionnaire (EQ-5D-3L) ........................................... 161 
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8.9.5. 
Patient Global Impression Items ................................................ 161 
9. 
STATISTICAL CONSIDERATIONS ...................................................................... 162 
9.1. 
Statistical Hypotheses............................................................................... 162 
9.2. 
Sample Size Determination ...................................................................... 162 
9.3. 
Data Analysis Considerations ................................................................... 164 
9.3.1. 
Analysis Sets ............................................................................. 164 
9.3.2. 
Interim Analysis ......................................................................... 164 
9.4. 
Key Elements of Analysis Plan ................................................................. 164 
9.4.1. 
Primary Safety Analyses ............................................................ 164 
9.4.2. 
Exploratory Efficacy Analyses .................................................... 165 
9.4.3. 
Other Analyses .......................................................................... 166 
9.4.4. 
Independent Data Monitoring Committee ................................... 166 
10. APPENDICES ...................................................................................................... 168 
10.1. 
Appendix 1: Exclusion of Participants Who Have Shown No 
Definitive Response to Preoperative Chemotherapy ................................. 168 
10.2. 
Appendix 2: Clinical Laboratory Tests ....................................................... 170 
10.3. 
Appendix 3: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria .......................................................... 172 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..................................... 175 
10.5. 
Appendix 5: Regulatory, Ethical, and Study Oversight 
Considerations .......................................................................................... 178 
10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................ 185 
10.7. 
Appendix 7: Eastern Cooperative Oncology Group Performance 
Status ....................................................................................................... 188 
10.8. 
Appendix 8: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ..................................... 189 
10.9. 
Appendix 9: Pregnancy Initial Notification Form ........................................ 197 
10.10. Appendix 10: Study pregnancy follow up form. ......................................... 199 
10.11. Appendix 11: Serious Adverse Event (SAE) Reporting Form .................... 201 
10.12. Appendix 12: Use/Analysis of DNA ........................................................... 205 
10.13. Appendix 13: Breast Cancer Staging Guidance ........................................ 206 
10.14. Appendix 14: Country-specific Requirements ........................................... 212 
10.14.1. France ....................................................................................... 212 
10.14.2. Germany .................................................................................... 215 
10.15. Appendix 15: Abbreviations and Specialist Terms .................................... 218 
10.16. Appendix 16: Protocol Amendment History ............................................... 224 

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11. REFERENCES ..................................................................................................... 257 

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LIST OF TABLES 
Table 1 
Objectives and Endpoints ....................................................................... 15 
Table 2 
Schedule of Activities – Prescreening .................................................... 39 
Table 3 
Schedule of Activities – Screening Period Through End of Study 
for All Cohorts ........................................................................................ 43 
Table 4 
Schedule of Activities: Prescreening for Participants Not Yet 
ctDNA-positive (i.e., ctDNA-negative) Under Protocol 
Amendment 03 ....................................................................................... 63 
Table 5 
Schedule of Activities Prescreening/Screening For Participants 
Currently ctDNA-positive and Not Yet Randomized as of Protocol 
Amendment 03 ....................................................................................... 65 
Table 6 
Schedule of Activities – For Previously Randomized Participants 
Continuing Under Protocol Amendment 03 and Protocol 
Amendment 04 Prior to the Data Cut-off and Transition to PACT 
Phase ..................................................................................................... 67 
Table 7 
PK Sampling Schedule for All Participants (Discontinued Under 
Protocol Amendment 03) ........................................................................ 71 
Table 8 
PK Sampling Schedule for Participants in the PK Substudy 
(Discontinued Under Protocol Amendment 03) ...................................... 72 
Table 9 
Summary of Risks and Mitigations for the Product ................................. 87 
Table 10 
Objectives and Endpoints ....................................................................... 91 
Table 11 
Summary of Patient Management Under Protocol 
Amendment 03 ....................................................................................... 94 
Table 12 
Summary of Patient Management Under Protocol 
Amendment 04 ....................................................................................... 95 
Table 13 
Prescreening Consent and ctDNA Testing Frequency ........................... 98 
Table 14 
Prescreening Stage, Consent, and Testing Window 
Requirements for Protocol Amendment 02 Participantsa ........................ 99 
Table 15 
Investigational Products ....................................................................... 122 
Table 16 
Recommended Initial Starting Dose ..................................................... 123 
Table 17 
Niraparib/Placebo Dose Reduction for Adverse Reactions ................... 127 
Table 18 
Dose Modifications for Nonhematologic Adverse Reactions ................. 127 

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Table 19 
Dose Modifications for Hematologic Adverse Reactions ....................... 127 
Table 20 
Required Data Collection and Safety Precautions for At-Home 
Nursing Visits ....................................................................................... 141 
Table 22 
Protocol required Safety Laboratory Tests ........................................... 170 
Table 23 
Evaluation of Overall Response for Participants with No 
Evidence of Disease at Baseline .......................................................... 173 
Table 24 
Timing of Contraception and Sperm Donationa ..................................... 175 
Table 25 
Contraceptives Allowed During the Studyc ........................................... 176 
Table 26 
Liver Chemistry Stopping Criteria and Required Follow up 
Assessments. ....................................................................................... 185 
Table 27 
Liver Chemistry Increased Monitoring Criteria with Continued 
Therapy ................................................................................................ 187 
Table 28 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status Grading ..................................................................................... 188 
Table 29 
Timing of Contraception and Sperm Donation in France ...................... 214 
Table 30 
Required Data Collection and Safety Precautions for At-Home 
Nursing Visits in Germany .................................................................... 215 
Table 31 
Contraceptives Allowed During the Study for Germany ........................ 217 
Table 32 
Abbreviations and Specialist Terms ..................................................... 218 
Table 33 
Glossary of terms ................................................................................. 222 
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LIST OF FIGURES 
Figure 2: 
Study Schema ........................................................................................ 35 
Figure 3: 
ctDNA Prescreening Testing Schedule .................................................. 36 
Figure 4 
Liver Chemistry Stopping and Increased Monitoring Algorithm for 
Participants with Entry Criteria ALT ≤2.5×ULN ..................................... 135 
Figure 5 
Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT ≥3×ULN but <8×ULN for Participants with Entry 
Criteria ALT ≤2.5×ULN ......................................................................... 136 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title 
A Randomized Phase 3 Double-Blinded Study Comparing the Efficacy and Safety of 
Niraparib to Placebo in Participants with Either HER2-Negative BRCA-Mutated or 
Triple-Negative Breast Cancer with Molecular Disease Based on Presence of Circulating 
Tumor DNA after Definitive Therapy (ZEST) 
Brief Title 
Efficacy and Safety Comparison of Niraparib to Placebo in Participants with 
HER2-Negative BRCAmut or Triple-Negative Breast Cancer with Molecular Disease 
Based on Presence of ctDNA 
Rationale 
Study 213831 was designed as a study of niraparib as treatment for participants with 
tumor breast cancer susceptibility gene mutated (tBRCAmut, which includes participants 
with germline BRCAmut [gBRCAmut] and/or somatic BRCAmut [sBRCAmut]) human 
epidermal growth factor receptor 2−negative (HER2−) breast cancer or tumor BRCA 
wild-type (tBRCAwt) triple-negative breast cancer (TNBC) who have molecular disease 
based on the presence of circulating tumor DNA (ctDNA) levels after completion of 
definitive therapy, including all of the following, if indicated: neoadjuvant treatment, 
surgery, adjuvant radiotherapy, and adjuvant chemotherapy; end of definitive therapy is 
defined as the date of completion of curative-intent surgery, adjuvant chemotherapy, or 
adjuvant radiotherapy, whichever was last. 
For patients with Stage I, II, IIIA, IIIB, or operable IIIC breast cancer, treatment includes 
surgical removal of the primary tumor, with lymph node dissection as required [Cardoso, 
2019; NCCN, 2020]. Although patient survival after surgery can be improved with 
adjuvant local and systemic therapy, the risk of recurrence in many patients with breast 
cancer remains high ([Steeg, 2016], reviewed in [Coakley, 2019]). Once definitive 
therapy is complete, there is no standard-of-care surveillance or treatment for patients 
with TNBC, beyond clinical monitoring, until metastatic disease presents. Similarly, for 
patients with hormone receptor positive (HR+)/HER2− breast cancer on adjuvant 
endocrine therapy, there is no standard of care surveillance or additional treatment until 
metastatic disease presents. Once the disease becomes metastatic, the 5-year survival 
rates are 11.5% for TNBC and 30.4% for HR+/HER2− breast cancer [SEER, 2019]. 
Current tumor markers to determine the risk of recurrence after definitive therapy, such 
as carcinoembryonic antigen, cancer antigen 27-29, and cancer antigen 15-3, lack 
sensitivity and are typically used only in the metastatic setting [Kokko, 2002; Lumachi, 
1999; Mariani, 2009]. To identify the patient population at high-risk of recurrence, 
current efforts are directed at identification of molecular detectable disease, as measured 
by the presence of ctDNA. Several studies in multiple cancer types, including breast 
cancer, have shown that molecular detectable disease can be identified using liquid 
biopsies by tracking tumor mutations in ctDNA and the presence of ctDNA has been 

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demonstrated to be predictive of clinical or radiological relapse [Coombes, 2019]. 
Currently, there is no standard of care for patients who have detectable ctDNA following 
their last intervention (surgery or adjuvant therapy) but who have not yet developed 
radiologic or clinically evident metastatic disease. 
The single-agent efficacy of 2 poly(ADP-ribose) polymerase (PARP) inhibitors, olaparib 
and talazoparib, has been demonstrated in patients with gBRCAmut HER2− breast 
cancer, including patients with gBRCAmut TNBC, in the locally advanced (talazoparib) 
and metastatic (olaparib and talazoparib) settings [Litton, 2018; Robson, 2017] and in 
patients with sBRCAmut metastatic breast cancer (olaparib) [Tung, 2020]. 
Studies in TNBC support homologous recombination deficiency (HRD) status as a 
predictor of response to treatment. HRD testing classifies tumors as either positive for a 
deficiency in homologous recombination DNA repair (homologous recombination 
deficient [HRd]) or without a defect in this pathway (homologous recombination 
proficient [HRp]). In patients with TNBC, including gBRCAwt TNBC, HRd disease is 
frequent [Chopra, 2020] and has been associated with improved response to anticancer 
treatment [Sharma, 2018; Staaf, 2019; Telli, 2016; Zhao, 2017]. Efficacy of PARP 
inhibitors has been observed in patients with HRd breast cancer. Patients with early HRd 
breast cancer treated with neoadjuvant olaparib in combination with paclitaxel had a 
pathological complete response rate of 55.1%, compared with 48.6% in patients treated 
with paclitaxel/carboplatin [Fasching, 2021]. In patients with HRd metastatic TNBC 
treated with veliparib plus cisplatin, longer progression-free survival was observed 
compared to treatment with cisplatin alone [Sharma, 2020]. In a study of olaparib as 
neoadjuvant treatment in patients with treatment-naïve TNBC, in which 18 of 32 patients 
obtained an objective response (56.3%), HRd TNBC was associated with response; 16 of 
18 responders (88.9%) had homologous recombination mutations and/or BRCA 
methylation compared with 4 of 14 nonresponders (28.6%) [Eikesdal, 2020]. In a study 
of neoadjuvant rucaparib in patients with untreated localized TNBC, 70% of whom had 
HRd cancers, HRDetect-high status was associated with ctDNA suppression [Chopra, 
2020]. 
Clinical activity of niraparib as neoadjuvant treatment in tBRCAmut HER2− breast 
cancer has been demonstrated [Han, 2019]. Additionally, niraparib has demonstrated 
antitumor efficacy in ovarian cancer beyond BRCAmut disease. Results from prior 
niraparib studies in ovarian cancer indicate a consistent continuum of clinical benefit 
across biomarker-defined subpopulations and that the benefit of niraparib treatment 
extends beyond patients with BRCAmut disease [Gonzalez-Martin, 2019; Mirza, 2016; 
Moore, 2019]. 
Based on these findings, Study 213831 will assess niraparib in participants with 
tBRCAmut HER2− breast cancer (including TNBC) or tBRCAwt TNBC who have 
molecular detectable disease, as determined by the presence of detectable ctDNA, until 
participants relapse with locally recurrent or metastatic disease. Given the substantial 
prevalence of HRd disease in TNBC and the expected particular sensitivity to PARP 
inhibition in these patients [Chopra, 2020], HRD status will be assessed in tumor tissue of 
tBRCAwt TNBC participants, and the primary efficacy analysis in tBRCAwt TNBC 
participants will be based on the HRd subpopulation, followed by testing of the overall 
cohort of tBRCAwt TNBC participants. As of the date of decision to stop enrollment in 
the ZEST study, this is no longer applicable. 

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Objectives and Endpoints and Estimands 
As a result of the decision to stop enrollment in the ZEST study, safety and tolerability of 
niraparib are being assessed as the primary endpoint and will use the Safety (SAF) 
Population; efficacy endpoints are considered exploratory. Estimands are not applicable 
for the primary endpoint. 
Table 1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Evaluation of safety and 
tolerability of niraparib 
The incidence of TEAEs, SAEs, and AESIs; TEAEs leading to death, 
TEAEs leading to dose modifications, and TEAEs leading to 
discontinuation will be assessed. Clinically relevant laboratory 
parameters, vital signs, ECOG performance status, and use of 
concomitant medications will be collected and evaluated as defined in 
the Statistical Analysis Plan (SAP). 
Exploratory 
Evaluation of the efficacy of 
niraparib relative to placebo as 
measured by disease-free 
survival (DFS) 
DFS is defined as the time until disease recurrence, measured from the 
time of randomization to the earliest date of assessment of disease 
recurrence or death by any cause, as assessed by Investigator using 
RECIST v1.1. 
Evaluation of distant recurrence-
free survival (DRFS) 
DRFS is defined as the time from randomization to the first detection of 
distant metastasis or death by any cause as assessed by Investigator 
using RECIST v1.1. 
Time to first subsequent therapy 
(TFST) 
TFST is defined as the time from randomization to the date of the first 
anticancer therapy used subsequent to the date of the endpoint DFS or 
death by any cause. 
Time to first subsequent 
chemotherapy 
Time to first subsequent chemotherapy is defined as the time from 
randomization to the date of the first systemic chemotherapy used 
subsequent to the date of the endpoint DFS or death by any cause. 
Time to symptomatic 
progression 
Time to symptomatic progression is defined as the time from 
randomization to the date of symptomatic progression, which either 
coincides with or is subsequent to the date of the endpoint DFS. 
Symptomatic progression includes any of the following:  
• 
Development of a skeletal-related event: pathologic fracture, 
spinal cord compression, or need for surgical intervention or 
radiation therapy (including palliative radiotherapy) to the bone 
• 
Initiation of a new systemic anticancer therapy for cancer pain 
progression or worsening of disease-related symptoms 
• 
Development of clinically significant symptoms due to loco-
regional tumor progression requiring surgical intervention or 
radiation therapy. 

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Objectives 
Endpoints 
Evaluation of the efficacy of 
niraparib relative to placebo as 
measured by invasive disease-
free survival (IDFS) 
IDFS will be assessed as per definition included in STEEP 2.0 [Tolaney, 
2021] (see Section 8.3.7 of the protocol). 
Evaluation of the efficacy of 
niraparib relative to placebo as 
measured by invasive breast 
cancer-free survival (IBCFS) 
IBCFS will be assessed as per definition included in STEEP 2.0 
([Tolaney, 2021]; See Section 8.3.8) 
Abbreviations: AE=adverse event; ctDNA=circulating tumor DNA; DFS=disease-free survival; 
DRFS=distant recurrence-free survival; ECOG=Eastern Cooperative Oncology Group; IBCFS=invasive 
breast cancer-free survival; IDFS=invasive disease-free survival; PD=progressive disease; 
PK=pharmacokinetic; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse 
event; TEAE=treatment-emergent adverse event; TFST=time to first subsequent therapy;
 
 
 
Overall Design 
Study 213831 was designed as a multicenter, multicohort, Phase 3, double-blinded, 
placebo-controlled study comparing the safety and efficacy of niraparib to placebo in 
participants who are 18 years and older with either HR+/HER2− tBRCAmut breast cancer 
or TNBC with any BRCA mutation status who have detectable ctDNA following 
completion of definitive therapy including all of the following, if indicated: neoadjuvant 
treatment, surgery, adjuvant radiotherapy, and adjuvant chemotherapy (as outlined in the 
inclusion/exclusion criteria). The study will include 2 separate cohorts: a tBRCAmut 
HER2− breast cancer (including TNBC) cohort (Cohort 1) and a tBRCAwt TNBC cohort 
(Cohort 2); end of definitive therapy is defined as the date of completion of curative-
intent surgery, adjuvant chemotherapy, or adjuvant radiotherapy, whichever was last.  
As a result of assessment of feasibility of study completion (i.e., the study was unable to 
randomize patients in the planned timeframe based on randomization projections as the 
study had lower-than-expected rates of ctDNA-positivity and a much higher-than-
expected proportion of patients with a ctDNA-positive [ctDNA+] test showing 
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radiographically detectable disease during screening assessments), a decision was made 
by the Sponsor to permanently stop enrollment into the ZEST study, which was 
communicated on 25 April 2023 (i.e., the date of decision to stop enrollment). As of the 
date of this communication, no further randomizations were approved by the Sponsor. 
A final data cut-off (DCO) date represents the end of data collection for the planned 
final analyses as described in the statistical analysis plan (SAP). Once the final DCO 
date has been reached, the clinical study database will be closed to new data. Before 
the DCO is reached all participants will continue assessments as per SOA Table 4, 
Table 5, and Table 6. Once the last participant consents to Protocol Amendment 04 
(or withdraws) or meets any protocol-defined stopping criteria (Section 7), the study 
will transition to PACT.  
Following the DCO date, Study 213831 will move to the PACT Phase, where the 
study will remain open for the following: 
1) Continued access to study treatment (niraparib) for participants who 
continue to derive clinical benefit from study treatment as judged by the 
Investigator and do not meet any protocol-defined study treatment stopping 
criteria (Section 7); participants may also choose to discontinue study 
treatment at any time and  
2) Surveillance scans for participants as outlined under Protocol Amendment 
04 until stopping criteria are met (Section 7).  
For more details regarding PACT, refer to Section 6.7.1. 
Although the clinical study database will be closed at the time of the final DCO date, 
the study remains open until the end of the study definition is reached. The end of 
study (EOS) is defined as the date of the last visit of the last participant in the study 
or last scheduled procedure for the last participant in the study. 
Participants on study as of the date of the decision to stop enrollment should be 
managed under Protocol Amendment 03 as outlined in Table 11 until Protocol 
Amendment 04 implementation. Upon implementation of Protocol Amendment 04, 
participants should be managed following Table 12. 
Participants randomized to treatment on the ZEST study may discontinue treatment and 
be offered scans above standard of care, while some previously specified assessments are 
now discontinued. As a result of stopping enrollment, Prescreening is stopped for new 
patients and study assessments should be discontinued with the exception of those 
outlined in Table 4 and Table 5 for those participants in prescreening as of the date of the 
decision to stop enrollment.  
Participants in Prescreening can no longer enter Screening and any participants currently 
in Screening as of the date of the decision to stop enrollment can no longer be 
randomized and should follow Table 12.  
For participants randomized in the ZEST study and on treatment as of the date of the 
decision to stop enrollment, the study was unblinded centrally and participants should be 
managed as outlined in Table 6. As of the date of the decision to stop enrollment, PK 
sample collection is also discontinued along with the PK substudy. 

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Participants will initially enter a Prescreening Period for confirmation of detectable 
ctDNA. For participants with detectable ctDNA, the Prescreening Period is followed by 
the Screening Period (Day -42 to Day -1) for completion of the remaining Screening 
assessments. It is recommended that the Screening Period start within 14 days of a 
confirmed ctDNA-positive result, provided all submitted prescreening tissue samples are 
of adequate quality per central review. 
Eligible participants in Cohorts 1 and 2 are then randomized to either niraparib or 
placebo. For Cohort 1, a Safety Run-in as well as a pharmacokinetic (PK) substudy will 
be performed. The Safety Run-in will include the first 40 randomized participants 
receiving concomitant endocrine therapy. The PK substudy will include at least the first 
40 randomized participants receiving endocrine therapy at sites participating in the PK 
substudy. Additional participants may be included in the PK substudy so that 
6 participants per endocrine therapy are included, if feasible. 
The Niraparib/Placebo Treatment Period is followed by an End of Treatment (EOT) Visit 
occurring within 7 days of last dose, a Safety Follow-up Visit 30 (+7) days after last 
dose, and Post-treatment Follow-up with assessments every 90 (±14) days for 2 years 
after the last dose and every 180 (±14) days thereafter. 
Patient-reported outcomes will be collected approximately every 28 days (aligned with 
the regular participant monitoring schedule) during the Treatment Period, at the EOT 
Visit, at the Safety Follow-up Visit, and at the first 2 Post-treatment Follow-up 
assessments. 
ctDNA Prescreening: 
Participants must sign a ctDNA Prescreening informed consent form (ICF) consenting to 
collection of tumor tissue samples for ctDNA assay design and tumor BRCA (tBRCA) and 
HRD testing as well as blood samples for ctDNA testing. Sufficient archival tumor tissue 
to establish the ctDNA platform and to perform tBRCA and HRd testing 
 
) is a requirement for 
study entry to enable this testing. This ctDNA Prescreening, utilizing the Signatera test 
for ctDNA, requires an archival tissue sample from the primary tumor, including 
pathology reports for all tumor tissue samples, a blood sample for whole exome 
sequencing (WES), and subsequent ctDNA blood samples, as described in Table 2 and 
Table 3. 
As a result of the decision to stop enrollment, prescreening procedures will be stopped, 
including ctDNA testing, except as outlined in Section 1.3, Table 4, and Table 5. 
Ongoing prescreen participants who are ctDNA-negative and <12 months from end of 
definitive therapy as of the date of the decision to stop enrollment may continue 
prescreening procedures as outlined above. Upon receiving a detectable ctDNA result by 
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the Signatera test, these participants will not receive further ctDNA tests and will proceed 
according to Table 4. Prescreen participants who are ctDNA+ as of the date of the 
decision to stop enrollment will follow Table 5. Participants who are deemed prescreen 
failures under previous versions of the protocol will not be reconsented and will not 
return for any prescreening procedures. 
Participants in prescreening will have ctDNA testing performed with a maximum of 
18 tests over a period of up to 6 years after end of definitive therapy for participants with 
a known BRCAmut (TNBC or HR+) and a maximum of 10 tests performed over a period 
of up to 2 years for participants with TNBC BRCAwt/unknown, as described in Table 13. 
Under Protocol Amendment 02, participants who are deemed prescreen failures under 
previous versions of the protocol due to negative ctDNA test results may have the 
opportunity to re-enter prescreening if they meet all eligibility criteria in this protocol 
amendment, meet staging criteria as outlined in Prescreening criterion P2, and remain 
within the prescreening testing duration windows described in Prescreening criterion P4 
(also see Table 14). 
Participants under ongoing Prescreening at the time of implementation of Protocol 
Amendment 02 are eligible for additional ctDNA testing provided they continue to meet 
all eligibility criteria in this protocol amendment and remain within the prescreening 
testing duration windows described in Prescreening criterion P4. (Also see Table 14)  
A participant can move to the Screening Period once detectable ctDNA is confirmed in 
Prescreening, provided all submitted prescreening tissue samples are of adequate quality 
per central review. ctDNA results will be blinded after randomization. 
BRCA Tumor Mutational Status Testing: 
During ctDNA Prescreening, tumor tissue samples from all participants will be collected 
for confirmatory central tBRCA testing for eligibility considerations using the 
 
 
Participants with HR+/HER2− breast cancer must have a known and documented 
deleterious or suspected deleterious tBRCAmut (either sBRCA or gBRCA positive) and 
meet all other prescreening eligibility criteria to qualify for ctDNA Prescreening and 
must have been on a stable regimen of endocrine therapy for a minimum of 3 months 
prior to randomization. Participants with HR+/HER2− breast cancer who have tBRCAmut 
confirmed by central testing will be eligible for Cohort 1; if central testing does not 
confirm a tBRCAmut in HR+/HER2− participants, they will not be eligible for the study. 
Participants with TNBC who have centrally confirmed tBRCAmut will be eligible for 
enrollment in Cohort 1, and those who are tBRCAwt or who have undetermined tBRCA 
status will be eligible for enrollment in Cohort 2. Note that the confirmatory central 
tBRCA test does not distinguish between somatic and germline BRCA mutations and does 
not replace standard germline testing. 
As a result of the decision to permanently stop enrollment, no further tBRCA testing 
 will be conducted for any participants, regardless of 
ctDNA status. All participants randomized prior to the date of the decision to stop 
enrollment have had confirmatory central tBRCA testing completed by 
 
 under previous versions of the protocol. 
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Tumor HRD Status Testing: 
Tumor tissue samples collected at Prescreening will be used for centralized testing using 
the 
 to classify participants in Cohort 2 by HRD status. 
As a result of the decision to permanently stop enrollment, no further HRD status 
assessment using the 
 will be conducted for any patient, 
regardless of ctDNA status. All participants randomized prior to the date of the decision 
to stop enrollment have had HRD assessment testing by 
 
 completed under previous versions of the protocol. 
Screening Period: 
As a result of the decision to permanently stop enrollment, participants can no longer 
enter screening. Participants currently in screening as of the date of the decision to stop 
enrollment that decide to remain on study will follow Table 5. 
During the Screening Period, participants will sign the main study ICF and complete all 
remaining assessments required to determine eligibility for the study. The Screening 
Period is within 6 weeks of Cycle 1/Day 1 and it is recommended to start within 14 days 
of a confirmed ctDNA-positive result, provided all submitted prescreening tissue samples 
are of adequate quality per central review. All screening criteria (unless otherwise 
specified in the Schedule of Activities [SOA]) are required to be repeated if they fall 
outside of 6 weeks prior to first dose. 
All participants are required to have documented presence of ctDNA, central 
confirmation of tBRCAmut status, and no evidence of overt recurrent/metastatic disease 
prior to being randomized 1:1 to either niraparib or placebo.  
Randomization and Stratification: 
As of the date of the decision to stop enrollment, no further randomizations were 
approved by the sponsor.  
Participants in Cohort 1 will be stratified based on the following factors: 
• 
Time from last intervention to randomization (<6 months versus ≥6 months). 
Time of last intervention is defined as the date of most recent oncological 
surgery, date of last adjuvant chemotherapy, or date of last radiotherapy fraction, 
whichever occurred later. 
• 
HR status (positive versus negative) 
• 
Prognostic Stage of breast cancer (Stage I/II versus Stage III) (see Appendix 13) 
Participants in Cohort 2 will be stratified based on the following factors: 
• 
Time from last intervention to randomization (<6 months versus ≥6 months). 
Time of last intervention is defined as the date of most recent oncological 
surgery, date of last adjuvant chemotherapy, or date of last radiotherapy fraction, 
whichever occurred later. 
• 
Prior use of adjuvant capecitabine (yes versus no) 
• 
Prognostic Stage of breast cancer (Stage I/II versus Stage III) (see Appendix 13) 
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Safety Run-in Period (Cohort 1): 
As of the date of the decision to stop enrollment, Safety Run-in is no longer applicable. A 
total of 40 participants were randomized in the study. 
A Safety Run-in Period will be conducted in the first 40 randomized participants in 
Cohort 1 who are taking endocrine therapy (anastrozole, letrozole, exemestane, and 
tamoxifen, with or without ovarian function suppressing agents). All participants 
receiving concomitant endocrine therapy need to have been on a stable regimen of 
endocrine therapy for a minimum of 3 months prior to randomization. While on study, 
the endocrine regimen can be interrupted or discontinued as clinically indicated. During 
the Treatment Period, the endocrine regimen may be exchanged for another regimen after 
discussion with the GSK Medical Monitor, but the regimen may not be changed during 
the Safety Run-in Period or the PK substudy.  
As of the date of the decision to stop enrollment, assessment by an IDMC is no longer 
needed due to enrollment being permanently stopped and the study being centrally 
unblinded. 
Study Conduct: 
As the date of the decision to stop enrollment, several study procedures described 
below are no longer applicable. As of Protocol Amendment 04, participants should 
be managed as outlined in Section 1.3 and Table 12. For participant management 
prior to DCO, refer to Section 1.3 for additional details. For participant 
management after DCO, please refer to Section 6.7. 
Participants who meet all eligibility criteria for study screening will have to sign the main 
ICF for this study before starting the screening assessments to participate in the study. 
Once all screening assessments are completed, eligible participants will be randomized in 
a 1:1 ratio to receive niraparib or placebo. 
Clinic visits will occur on Day 1 of each cycle (Table 3). Hematology laboratory values 
will be monitored weekly for the first 28-day cycle of the Niraparib/Placebo Treatment 
Period, and blood pressure (BP) and heart rate (pulse) will be monitored weekly for the 
first two 28-day cycles of the Niraparib/Placebo Treatment Period. If participants are 
unable to attend clinic visits on Cycle 1/Day 1 (postdose), Cycle 1/Day 15, and 
Cycle 2/Day 1 (postdose), they must have assessments for these visits performed through 
at-home nursing on the date the visit would have occurred. If participants are unable to 
attend clinic visits on Cycle 1/Day 8, Cycle 1/Day 22, Cycle 2/Day 8, Cycle 2/Day 15, 
and Cycle 2/Day 22, they must have the assessments for these visits performed either 
through a local laboratory/clinic or through at-home nursing on the date the visit would 
have occurred. As of the date of the decision to stop enrollment, at-home nursing services 
will no longer be offered. 
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All participants are required to undergo tumor imaging as provided below and all 
imaging data acquired with the purpose of tumor assessment must be submitted to the 
Imaging Vendor for Central Review. As of the date of the decision to stop enrollment, 
imaging does not need to be submitted to the imaging vendor for central review. Imaging 
will be conducted for ongoing participants as outlined in Section 1.3, Table 4, Table 5, 
and Table 6 The preferred imaging method is intravenous (IV) contrast-enhanced 
computed tomography (CT), and a bone scan. The same imaging method and anatomical 
coverage should be used throughout the study. 
• 
Baseline:  
• 
An IV contrast-enhanced-CT scan of the chest/abdomen/pelvis and a bone scan 
will be conducted within 42 days (6 weeks) prior to randomization (as outlined 
in Table 3). 
• 
If IV CT contrast cannot be used (e.g., sensitivity to CT contrast or contrast 
shortage): Noncontrast CT of the chest and IV contrast-enhanced magnetic 
resonance imaging (MRI) of abdomen/pelvis, and a bone scan.  
If both IV CT and IV MRI contrast cannot be used, or if renal insufficiency: 
noncontrast CT of chest/abdomen/pelvis and a bone scan. If MRI is performed 
at Baseline, it should be preferentially continued throughout the study. If brain 
metastasis is suspected, IV contrast-enhanced MRI is preferred over IV contrast-
enhanced CT for imaging of the brain. 
• 
On study: An IV contrast-enhanced CT scan of the chest, abdomen, and pelvis 
(or IV contrast-enhanced MRI of abdomen and pelvis and noncontrast CT of 
chest, if MRI performed at Baseline) will be conducted every 12 weeks 
(84±7 days) from date of randomization for the first 2 years and every 24 weeks 
(168±7 days) thereafter, or more frequently as clinically indicated 
(unscheduled), until Investigator assessment of disease recurrence using 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Bone scans 
should only be performed postbaseline if clinically indicated. If brain metastasis 
is suspected, IV contrast-enhanced MRI is preferred over IV contrast-enhanced 
CT for imaging of the brain. 
If a participant discontinues study treatment for any reason other than disease recurrence, 
death, withdrawal of consent, or loss to follow-up, then scans should continue at the 
specified intervals until disease recurrence is confirmed. 
Each participant will have an EOT Visit at the time of discontinuation from study 
treatment, a Safety Follow-up Visit 30 (+7) days after last dose, and Post-treatment 
Follow-up with assessments every 90 (±14) days for 2 years after the last dose and every 
180 (±14) days thereafter, which will continue until death or the end of study data 
collection (provided that this allows the opportunity for completion of all follow-up 
assessments). Information regarding subsequent anticancer treatments (including regimen 
and number of cycles), as well as the date of any subsequent progressive disease (ie, for 
determination of progression on next anticancer therapy), hospitalization, and other 
supportive care and procedures (eg, surgery or radiation), and survival status will be 
collected during these assessments. 

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Reporting of safety events will begin at the time of the ctDNA Prescreening ICF 
signature date only for events related to ctDNA and WES blood sample collection 
procedures. All adverse events (AEs) and serious adverse events (SAEs) will be collected 
and recorded for each participant from the day of signing the main study ICF until 
30 days after last dose of study treatment or start of new anticancer therapy. All AEs and 
SAEs experienced by a participant, irrespective of the suspected causality, will be 
monitored until the AE or SAE has resolved, until abnormal laboratory values have 
returned to baseline or normalized, until there is a satisfactory explanation for the 
changes observed, until the participant is lost to follow-up, or until the participant has 
died. All SAEs assessed by the Investigator as related to the study treatment and all AEs 
of special interest, regardless of causality, will be collected and reported until study 
closeout, or as otherwise indicated. Any pregnancies that occur within 180 days 
post-treatment will be reported. 
Participants will continue to receive their assigned treatment until disease recurrence as 
assessed by RECIST v1.1, death, withdrawal of consent, loss to follow-up, or until 
unacceptable toxicity. Those participants who have completed 39 cycles (approximately 
3 years) without evidence of recurrence will have the option to either continue treatment 
or stop treatment at that time. If available, participants continuing niraparib treatment at 
the time of final analysis may be offered the option to continue to receive niraparib 
treatment. Dose interruptions, reductions, and/or treatment discontinuation may be 
implemented at any time according to the dose modification guidelines in this protocol 
(Section 6.4) and under the discretion of the Investigator. As of the date of the decision to 
stop enrollment, this is no longer applicable.  
Biomarker Strategy 
As of the date of the decision to stop enrollment, sample collection for the purposes of 
exploratory biomarker analysis was stopped as outlined in Section 1.3. 
 
 
. 
In Cohort 1 (tBRCAmut/HER2−), participants with HR+ disease must have a known and 
documented deleterious or suspected deleterious tBRCAmut (either germline or somatic) 
to qualify for ctDNA Prescreening. All participants, including those with TNBC, will 
have their tBRCA status confirmed by a central laboratory prior to randomization. 
Participants with HR+/HER2− breast cancer must have a centrally confirmed tBRCAmut 
to be eligible for the study. 
Participants in Cohort 2 will have the HRD status of their tumor determined by 
centralized testing 
 
Participants in Cohorts 1 and 2 will be tested for ctDNA using blood samples at the 
following time points:  
• 
During ctDNA Prescreening: According to the schedule summarized in Table 2, 
Table 13, and Figure 3 
• 
At Cycle 1/Day 1: Predose 
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• 
During Niraparib/Placebo Treatment Period: Every 12 weeks from 
randomization until disease recurrence, to monitor niraparib efficacy and 
development of recurrence and/or metastasis. 
Exploratory biomarker analyses to identify factors important for niraparib therapy may be 
pursued. Blood samples for exploratory biomarker testing will be collected at the time 
points specified in Table 3. 
 
 
 
 
 
If a participant discontinues study treatment for any reason other than disease recurrence 
per RECIST v1.1, death, withdrawal of consent, or loss to follow-up, then ctDNA sample 
collection should continue at the specified intervals until disease recurrence is confirmed. 
Further Biomedical Research 
The Sponsor will conduct Further Biomedical Research on specimens and data collected 
during this study. This research may include genetic and genomic analyses, gene 
expression profiling, proteomics, metabolomics, and the measurement of other analytes 
after this study is completed. It may also include analysis of histological and/or clinical 
images and data. Such research is for biomarker testing to address emergent questions not 
described elsewhere in the protocol and will only be conducted on specimens from 
properly consented participants and as per local regulations. 
Pharmacokinetics 
As of the date of the decision to stop enrollment, sample collection for PK analysis is 
stopped. 
For all participants in Cohort 1 and Cohort 2, blood samples will be collected in the main 
study at Cycle 1/Day 1, Cycle 1/Day 15, Cycle 2/Day 1, Cycle 4/Day 1, and 
Cycle 8/Day 1, as specified in Table 7 for sparse PK sampling to characterize niraparib 
exposure in participants with breast cancer and to explore the relationship between 
exposure to niraparib and responses in efficacy and safety. 
A subset of participants in Cohort 1 will have additional blood samples collected in a PK 
substudy. The PK substudy will include at least the first 40 randomized participants 
receiving endocrine therapy at sites participating in the PK substudy. The samples 
collected in the PK substudy will be analyzed to characterize the steady-state PK of 
endocrine therapy and to assess any potential effect of niraparib on endocrine therapy 
exposure, as data permit. Based on the randomized nature of the study, it is assumed that 
approximately 20 participants in the PK substudy will be receiving endocrine therapy 
with niraparib, while the remaining participants will be receiving endocrine therapy with 
placebo, allowing for a comparison of endocrine therapy PK with or without niraparib 
co-administration. Additional participants may be included in the PK substudy if there 
are too few participants receiving any of the individual endocrine therapies to meet the 
objectives of the substudy; if feasible, 6 participants per endocrine therapy will be 
targeted. 
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In the PK substudy, participants will have blood samples collected at Cycle 1/Day 15, as 
specified in Table 8, at which time niraparib exposure will have reached steady state. 
Brief Summary 
The purpose of this study is to assess the efficacy and safety of niraparib in participants 
with either tBRCAmut HER2− breast cancer (including TNBC) or tBRCAwt TNBC with 
molecular detectable disease based on the presence of ctDNA following surgery or 
completion of adjuvant therapy. The study was originally designed as double-blind. As of 
the date of the decision to stop the study, the study was centrally unblinded. 
Study details include the following: 
As of the date of the decision to stop enrollment, the study will conclude when the last 
participant has completed their last study procedure (as outlined in Section 1.3). Study 
duration details outlined below are no longer applicable. 
• 
Study duration: 
• 
Treatment duration: Participants may continue study treatment until disease 
recurrence, death, withdrawal of consent, loss to follow-up, or until unacceptable 
toxicity. Those participants who have completed 39 cycles (approximately 3 years) 
with no evidence of recurrence will have the option to either continue treatment or 
stop treatment at that time (see Section 6.7). Participants on niraparib may continue 
treatment under Protocol Amendment 03 per protocol if they are considered by the 
Investigator to be deriving benefit. 
• 
Visit frequency: Weekly for Cycles 1 and 2 (participants have the option of local 
laboratory/clinic and/or at-home nursing visits for Cycle 1/Days 1 (postdose), 8, 15, 
and 22 and Cycle 2/Days 1 (postdose), 8, 15, and 22) and every 4 weeks thereafter; 
EOT Visit within 7 days after last dose; Safety Follow-up Visit 30 (+7) days after 
last dose; and Post-treatment Follow-up with assessments every 90 (±14) days for 
2 years after the last dose and every 180 (±14) days thereafter. See Section 1.3 for 
updated visits/frequencies as of the date of the decision to stop enrollment and 
Table 12 under Protocol Amendment 04. 
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Number of Participants 
Per the original study design, the number of participants was the following: 
• 
Cohort 1: A total of approximately 200 participants will be randomized. 
• 
Cohort 2: A total of approximately 600 participants will be randomized. 
A total of 40 participants were randomized in the study. 
Treatment Groups and Duration 
Following a confirmed detectable ctDNA test result, participants will be randomized 1:1 
to receive either niraparib or placebo and dosed with treatment. 
Niraparib will be supplied as 
. Placebo will be provided as 
 The starting dose will be based upon the participant’s hepatic function 
and baseline body weight and/or baseline platelet count. 
Participants with normal or mildly impaired hepatic function (as defined in Section 4.3 of 
the full protocol) and a baseline body weight ≥77 kg and baseline platelet count 
≥150,000/μL will be administered a niraparib starting dose of 300 mg orally once daily. 
Participants with normal or mildly impaired hepatic function and a baseline body weight 
<77 kg or baseline platelet count <150,000/μL will be administered a niraparib starting 
dose of 200 mg orally once daily. Participants with moderate hepatic impairment (defined 
as total bilirubin >1.5× and ≤3×upper limit of normal (ULN) and any level of aspartate 
aminotransferase elevation) will be administered a niraparib starting dose of 200 mg 
orally once daily, regardless of baseline body weight or baseline platelet count. 
Participants with severe hepatic impairment are excluded. 
Niraparib and placebo treatment will be blinded. As of date of the decision to stop 
enrollment, the study was centrally unblinded. For participant management, under 
Protocol Amendment 04, refer to Table 12. Prior to implementation of PACT, refer 
to Section 1.3, and once the PACT Phase begins, refer to Section 6.7.  
Note: All SAEs assessed as related by the Investigator continue to be reported for all 
study participants until study close out and all AEs of special interest (AESIs), 
regardless of causality, continue to be reported for all study participants until death 
or loss to follow up. 
Participant Selection Criteria 
Enrollment of new participants is permanently stopped due to Sponsor decision. 
Prescreening 
To qualify for Prescreening, participants must meet the following criteria: 
P1. 
Histologically confirmed Stage I to III non-metastatic primary invasive 
breast cancer that is one of the 2 following phenotypes: 
a. 
TNBC defined as: 
• 
Estrogen receptor (ER) and progesterone receptor (PgR) 
negative, defined as IHC nuclear staining <1%, and  
• 
HER2−  defined as follows: 
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• 
IHC 0, 1+ without ISH, or 
• 
IHC 2+ and ISH non-amplified as defined by 2018 ASCO-
CAP guidelines [Wolff, 2018]  
b. ER and/or PgR positive, HER2− breast cancer defined as follows: 
• 
ER and/or PgR positive defined as IHC nuclear staining ≥1%, 
and 
• 
HER2− defined as: 
• 
IHC 0, 1+ without ISH, or  
• 
IHC 2+ and ISH non-amplified as defined by 2018 ASCO-
CAP guidelines [Wolff, 2018]  
Participants with multifocal tumors are eligible provided that all lesions are 
within the same quadrant and have similar ER, PgR, and HER2 staining. 
Multicentric and synchronous bilateral breast cancers are not allowed. 
For participants who received neoadjuvant therapy and have discordant ER, 
PgR, and/or HER2 receptor results between the diagnostic biopsy 
(pretreatment) and surgical pathology (post neoadjuvant therapy), the receptor 
status of the pretreatment specimen determines eligibility. If the biopsy and the 
surgical specimens are discrepant in the adjuvant setting (i.e., participants had 
initial surgery), results from the surgical specimen define HR status. Those 
participants determined to be TNBC based on the pretreatment specimen 
should not subsequently receive tamoxifen or an aromatase inhibitor as part of 
their breast cancer treatment. 
Note: ER and PgR may be graded using the Allred scoring system, where 
TNBC is defined to be 0 out of 8 or 2 out of 8,or staining in <1% of cancer 
cells and HR+ is defined to be a score of ≥3 out of 8.  
P2. 
New participants joining the study (i.e., have not previously provided 
Prescreening consent prior to Protocol Amendment 02) must meet the 
following criteria: 
a. For participants who underwent initial surgery (Adjuvant 
approach): 
• 
TNBC participants must meet at least 1 of the following criteria:  
• 
Node-positive (≥pN1, any tumor size), or 
• 
Node-negative (pN0) or axillary node micro-metastasis (pN1mi) 
with invasive primary tumor ≥15 mm 
• 
HR+ participants must meet at least 1 of the following criteria: 
• 
Node-positive with ≥4 involved nodes (≥pN2, any tumor size), or 
• 
Node-negative (pN0) or axillary node micro-metastasis (pN1mi) 
with invasive primary tumor >5 cm (≥pT3), or 

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• 
Either node-positive with 1 to 3 involved nodes (pN1) OR node-
negative or axillary node micro-metastasis with invasive primary 
tumor >2 cm but ≤5 cm (pT2N0 or pT2N1mic). Invasive tumor 
must also meet 1 of the following: 
• 
Grade 3 
• 
Grade 1 or 2 with ER+/PgR- 
• 
Grade 1 or 2 with ER-/PgR+ 
b. For participants who underwent neoadjuvant chemotherapy 
followed by surgery (Neoadjuvant approach):  
• 
All participants must have shown a definitive response to preoperative 
chemotherapy by pathological, radiological, or clinical evaluation (see 
Appendix 1) 
• 
TNBC participants must have residual invasive breast cancer in the 
breast and/or resected lymph nodes (non-pCR) (any grade is allowed) 
• 
HR+ participants must have residual invasive breast cancer in the 
breast and/or resected lymph nodes (non-pCR), AND meet 1 of the 
following criteria: 
• 
Node-positive prior to or after neoadjuvant treatment (≥cN1 or 
≥pN1, any tumor size) 
• 
Invasive primary tumor size >2 cm prior to or after neoadjuvant 
treatment (≥cT2 or ≥pT2) 
c. For HR+ participants who underwent neoadjuvant endocrine-only 
therapy followed by surgery (Neoadjuvant approach, but without 
any preoperative chemotherapy)  
• 
All participants must have shown a definitive response to 
preoperative endocrine therapy by pathological, radiological, or 
clinical evaluation (see Appendix 1) 
• 
HR+ participants must have residual invasive breast cancer in the 
breast and/or resected lymph nodes (non-pCR), AND meet 1 of the 
following criteria: 
• 
Node-positive with ≥4 involved nodes (≥pN2, any tumor size), 
or 
• 
Node-negative (pN0) or axillary node micro-metastasis 
(pN1mi) with invasive primary tumor >5 cm (≥pT3), or 
• 
Either node-positive with 1 to 3 involved nodes (pN1) OR 
node-negative or axillary node micro-metastasis with invasive 
primary tumor >2 cm but ≤5 cm (pT2N0 or pT2N1mic). 
Invasive tumor must also meet 1 of the following: 
• 
Grade 3 

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• 
Grade 1 or 2 with ER+/PgR- 
• 
Grade 1 or 2 with ER-/PgR+ 
Participants who previously completed Prescreening under previous versions of 
the protocol and who are deemed to have been Prescreen failures due to negative 
ctDNA testing results on all allotted tests may re-enter Prescreening provided they 
are eligible to continue Prescreening testing as per protocol (see criterion P4) 
AND meet all staging criteria as defined above in criterion P2 a to c. 
Participants who are currently participating in ongoing Prescreening at the time of 
Protocol Amendment 02 consent, and who are eligible to continue Prescreening 
testing as per protocol (see criterion P4), must have Stage I to III non-metastatic 
primary invasive breast cancer as per criterion P1, but are not required to meet 
staging criteria as defined in criterion P2 a to c. As of the date of the decision to 
stop enrollment, participants who were deemed prescreen failures under previous 
versions of the protocol will not be reconsented and will not return for any 
prescreening procedures. 
P3. 
HR+ breast cancer participants must have a documented mutation in BRCA1 or 
BRCA2 that is predicted to be deleterious or suspected deleterious (known or 
predicted to be detrimental/lead to loss of function) identified through local 
testing. 
P4. 
Signed prescreening consent. 
New participants joining the study (i.e., have not previously provided 
Prescreening consent prior to Amendment 02) must sign consent within the 
following timepoints: 
a. 
For TNBC participants (tBRCAwt or tBRCA unknown): TNBC 
participants who have not been tested for tBRCA or have no mutation 
identified (tBRCAwt) must sign prescreening consent no later than within 
12 weeks from the end of definitive therapy. 
• NOTE: Participants receiving pembrolizumab must also consent to 
Prescreening within 12 weeks of completing definitive therapy (i.e., 
curative-intent surgery, chemotherapy, and/or radiation, whichever 
happens last). Pembrolizumab is NOT included in the definition of 
definitive therapy in this protocol, and participants may continue to 
receive pembrolizumab as per standard of care during the study, with 
ctDNA testing performed according to the schedule outlined in Table 2 
(footnote a). 
b. For known tBRCAmut TNBC or HR+ breast cancer participants: 
Participants who have a known and documented deleterious or suspected 
deleterious tBRCA mutation identified through local testing must sign 
prescreening consent no later than 5 years from end of definitive therapy 
(the first ctDNA test is recommended as soon as they are eligible after 
completing their last definitive therapy). 
Participants who are currently participating in ongoing Prescreening at the time of 
implementation of Protocol Amendment 02, or who completed Prescreening in 
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consent for additional ctDNA testing as per Protocol Amendment 02, but are not 
required to meet the consent timepoint windows as described in criterion P4 a to 
b. 
Participants who are eligible to either re-enter Prescreening or to continue 
ongoing Prescreening ctDNA testing are those who continue to meet other 
prescreening eligibility criteria and meet 1 of the following criteria at the time of 
consent for Protocol Amendment 02: 
• 
Participant is currently participating in ongoing Prescreening at the time of 
Protocol Amendment 02 implementation, has at least 1 additional ctDNA test 
left per the original testing schedule, and has not been deemed a Prescreen 
failure 
• 
Participant previously completed Prescreening under previous versions of the 
protocol and was deemed to have Prescreen-failed due to negative ctDNA 
testing results on all allotted tests, AND still remains within the defined testing 
duration window from end of definitive treatment at the time of reconsent: 
• 
Participants with TNBC (tBRCAwt or tBRCA unknown) may resume 
ctDNA testing so long as no more than 24 months has elapsed since the end 
of definitive treatment. 
• 
Participants with known tBRCAmut (either TNBC or HR+) may resume 
ctDNA testing so long as no more than 6 years has elapsed since the end of 
definitive treatment. 
Additional ctDNA testing for participants eligible to resume or continue 
Prescreening testing will occur according to the schedule outlined in Table 13, 
Table 14, and Figure 3. As of the date of the decision to stop enrollment, prior 
prescreen-fail patients (who had not already signed Protocol Amendment 02 
consent), are not allowed to be re-enrolled or reconsented and no further assessments 
or ctDNA testing are allowed. 
P5. Completed prior standard therapy for curative intent, including all of the following, 
if indicated: neoadjuvant treatment, surgery, adjuvant radiotherapy, and adjuvant 
chemotherapy. Participants with HR+HER2− tBRCAmut breast cancer may be 
receiving concurrent adjuvant endocrine therapy. Participants with TNBC may 
receive concurrent adjuvant pembrolizumab, if clinically indicated. All participants 
may receive concurrent bisphosphonates or denosumab. Participants are allowed and 
encouraged to enter Prescreening as soon as possible per protocol, and may be 
eligible to start the Prescreening process prior to the completion of adjuvant therapy 
(see Figure 1 , Table 2, and details of permitted concomitant medications outlined in 
Section 6.8). 
P6 An archival tumor tissue specimen of the primary tumor sufficient in quality and 
quantity for ctDNA assay design and tBRCA and HRD testing is required. As of the 
date of the decision to stop enrollment, no further tBRCA and HRD testing will be 
performed (see Section 1.3). 
NOTE: If the participant has a prior history of additional primary breast cancers, 
which appear eligible for prescreening in this ZEST trial (see exclusion criterion 12), 

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the lesion considered at highest risk for recurrence based on the investigator’s 
discretion will be used for ctDNA assay design.  
P7. Have a significant risk of disease recurrence as assessed by the Investigator. 
P8. Have no known or suspected locally recurrent or metastatic disease as assessed by 
the Investigator. 
P9. Have no known nonmodifiable conflicts with other inclusion and exclusion criteria 
listed in Section 5.1 and Section 5.2 of the full protocol, respectively. 
Screening for Inclusion in Cohort 1 and 2 
To be eligible for inclusion in Cohorts 1 and 2 of the study, participants must meet the 
prescreening criteria outlined above and in Section 5, as well as inclusion criteria outlined 
in Section 5.1, including, but not limited to, the following  
• 
Stage I to III breast cancer as outlined in Prescreening Criteria  
• 
Completed prior standard therapy for curative intent, including all of the 
following, if indicated: neoadjuvant treatment, surgery, adjuvant radiotherapy, 
and adjuvant chemotherapy. Participants with HR+HER2− tBRCAmut breast 
cancer may be receiving concurrent adjuvant endocrine therapy. Participants 
with TNBC may receive concurrent adjuvant pembrolizumab, if clinically 
indicated. All participants may receive concurrent bisphosphonates or 
denosumab (see Figure 1 , Table 2, and details of permitted concomitant 
medications outlined in Section 6.8). 
• 
Participants with HR+ breast cancer must be on a stable regimen of endocrine 
therapy, if indicated, for at least 3 months prior to randomization. Ovarian 
suppression, if indicated, must also have been started at least 3 months prior to 
randomization. 
• 
Participants must have detectable ctDNA as measured by central Signatera 
testing (refer to Table 2 for the timing of ctDNA testing). 
An archival tumor tissue specimen of the primary tumor sufficient in quality and 
quantity for ctDNA assay design and tBRCA and HRD is required. (See 
Prescreening criterion P6 for additional details.) 
Participants will be excluded from Cohorts 1 and 2 of the study if the following exclusion 
criteria are met, including, but not limited to (refer to Section 5.2 of the protocol for full 
listing of all exclusion criteria): 
• 
Current treatment with a CDK4/6 inhibitor or endocrine therapy other than 
anastrozole, letrozole, exemestane, and tamoxifen, with or without ovarian 
suppression. 
• 
Participants have any sign of metastasis or local recurrence after comprehensive 
assessment conducted per protocol.  
• 
Participants have shown no definitive response to preoperative chemotherapy by 
pathologic, radiological, or clinical evaluation, in cases where preoperative 
chemotherapy was administered (see Appendix 1). 

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Independent Data Monitoring Committee 
As of the date of the decision to stop enrollment, an unblinded assessment by an IDMC is 
no longer needed due to the study being centrally unblinded. 
The IDMC will consist of 3 individuals, including 1 biostatistician and 2 physicians who 
are independent from the Sponsor. The membership, the key responsibilities of the 
IDMC, and the corresponding procedures will be defined in an IDMC Charter. 
Planned Statistical Analyses 
As a result of the decision to stop enrollment into the study, specific assessments 
such as collection of survival follow-up data, subsequent treatments, patient-
reported outcome (PRO) data, etc. will no longer be required (as outlined in 
Section 1.3).  
A final data cut-off (DCO) date represents the end of data collection for the planned final 
analyses as described in the statistical analysis plan (SAP). A final DCO date will be 
reached once the last participant consents to Protocol Amendment 04 (or withdraws) 
or meets any protocol-defined stopping criteria (Section 7) and the study will 
transition to PACT. Once the final DCO date has been reached, the clinical study 
database will be closed to new data. 
Safety and tolerability of niraparib are being assessed as the primary endpoint and 
will use the Safety Population. There is no formal hypothesis testing framework 
being implemented in this study. Estimands are not applicable for the primary 
endpoint.  
Any deviations from, or additions to, the original analysis plan described in this 
protocol will be documented in the SAP and final study report. 
1.2. 
Schema 
The ctDNA Prescreening process is described in the flow chart in Figure 1 . Participants 
are allowed, and encouraged, to start the Prescreening process (including consent and 
ctDNA assay design) as soon as possible in the postoperative setting, prior to the 
completion of adjuvant therapy.  
The overall study schema is presented in Figure 2. The ctDNA testing schedule is 
described in Figure 3. 
 
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Figure 2: 
Study Schema 
 
* HR+ participants in Cohort 1 will receive background endocrine therapy (anastrozole, letrozole, exemestane, and 
tamoxifen, with or without ovarian function suppressing agents). 
** Time of last intervention is defined as the date of most recent oncological surgery, date of last adjuvant 
chemotherapy, or date of last radiotherapy fraction, whichever occurred later. 
*** Participants with TNBC may receive concurrent adjuvant pembrolizumab, if clinically indicated. 
Abbreviations: BRCA=breast cancer susceptibility gene; ctDNA=circulating tumor DNA; DFS=disease-free survival; 
HER2=human epidermal growth factor receptor 2; HR=hormone receptor, R=randomization; tBRCAmut=tumor BRCA 
mutation (somatic or germline); tBRCAwt=tumor BRCA wild-type; TNBC=triple-negative breast cancer. 
As of 25 April 2023, study enrollment has been permanently stopped due to Sponsor decision. Participants will no 
longer be randomized, and the study was centrally unblinded. 
 
Upon Protocol Amendment 04 implementation at all sites, once the last participant consents to Protocol 
Amendment 04 (or withdraws) or meets any protocol-defined stopping criteria (Section 7), the study will 
transition to PACT.  
 
 

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1.3. 
Schedule of Activities 
The SOA for Prescreening is provided in Table 2. Prior to Prescreening, participants must 
meet the Prescreening criteria in Section 5 and have no known conflicts with the other 
inclusion and exclusion criteria listed in Section 5.1 and Section 5.2 of the full protocol, 
respectively. 
The SOA from the Screening Period to the end of the study is presented in Table 3; each 
treatment cycle is 4 weeks (28 days). The PK sampling schedule in the main study for all 
participants is presented in Table 7, and the PK sampling schedule for participants in the 
PK substudy is presented in Table 8. 
As a result of the date of the decision to permanently stop enrollment, no new patients are 
to be prescreened and/or screened onto the study. Participants in Prescreening can no 
longer enter screening and any participants in Screening can no longer be randomized. 
Participants randomized to treatment on the ZEST study may discontinue treatment and 
be offered scans above standard of care, while some previously specified assessments are 
now discontinued. Participants should be monitored under Protocol Amendment 03 as 
follows (also outlined in Table 11) 
• 
For participants Prescreening and ctDNA-negative as of the date of the decision to 
stop enrollment, see Table 4 for monitoring assessments. 
• 
For participants that are ctDNA+ as of the date of the decision to stop enrollment, 
but not yet randomized onto the study (includes participants in either Prescreening or 
Screening that are ctDNA+), see Table 5. 
• 
For those participants randomized in the ZEST study as of the date of the decision to 
stop enrollment, see Table 6. 
• 
All PK sampling is to be stopped. 
 
PACT Phase:  
Participants who continue to receive study treatment (niraparib) during the PACT 
Phase will be monitored and receive follow-up care in accordance with standard 
local clinical practice. Safety assessments will revert to the standard of care at a 
participant’s particular study site. SAEs, AESIs, AEs leading to discontinuation of 
study treatment, overdose and pregnancy reports will continue to be reported 
directly to the Sponsor via paper forms (or alternative reporting method as 
indicated by Sponsor, should one become available) through 30 days after the last 
dose of study treatment (see Section 10.9, Section 10.10, and Section 10.11). 
Participants receiving surveillance scans (as per Table 12) will continue to be 
offered scans above standard of care until stopping criteria are met (Section 7). For 
participants discontinuing treatment in the PACT Phase, an EOT Visit is not 
required. 
 
 

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Table 2 
Schedule of Activities – Prescreening 
Visit: 
Procedure: 
Prescreening 
Notes 
Informed consent for 
prescreening 
X 
A Prescreening informed consent specific to ctDNA testing will be issued ahead of the 
main informed consent. For new study participants, prescreening informed consent will be 
obtained no later than 5 years since the end of definitive therapy for TNBC or HR+ HER2- 
breast cancer patients with known and documented tBRCA mutation determined locally; for 
TNBC patients with unknown tBRCA status or tBRCAwt status, prescreening consent will 
be obtained no later than 12 weeks since the end of definitive therapy (after surgery if 
adjuvant treatment is not indicated or after adjuvant treatment). Note: In both cases, 
prescreening ICF may be obtained post-operatively and/or during adjuvant chemotherapy 
or radiation treatment. For prior participants who are resuming or continuing ctDNA 
testing, please see Prescreening criteria P2 and P4 for eligibility and consent details, and 
Table 13 and Table 14. As of the date of the decision to stop enrollment, prescreening of 
new patients on the study is discontinued unless outlined in Table 4 and Table 5 for 
ongoing participants. To continue in the study under Protocol Amendment 03, existing 
participants will be reconsented as outlined in Table 4 and/or Table 5. To continue in the 
study under Protocol Amendment 04, existing participants will be reconsented. See 
Table 12 for participant management under Protocol Amendment 04. 
Eligibility 
X 
As of the date of the decision to stop enrollment, prescreening of new patients on the study 
is discontinued unless outlined in Table 4 and Table 5 for ongoing participants. 
Demography 
X 
As of the date of the decision to stop enrollment, prescreening of new patients on the study 
is discontinued unless outlined in Table 4 and Table 5 for ongoing participants. 
Disease characteristics 
X 
Tumor characteristics to be collected include, but are not limited to, histologic tumor type, 
tumor grade, tumor stage (clinical prognostic, pathologic prognostic, and/or anatomic 
staging) as per AJCC 8th edition; (see Section 8.2.1/Appendix 13), and response to 
neoadjuvant chemotherapy (as applicable). Primary pathology reports will be collected 
from biopsy and all surgical resections characterizing ER status (with percent or Allred 
score if available), PgR (with percent or Allred score, if available), and HER2 status (with 
IHC ISH, if available), as well as tumor grade. If the participant's disease recurs during 
prescreening, scans/recurrence response/new tumor information will also be collected. As 
of the date of the decision to stop enrollment, prescreening of new patients on the study is 
discontinued unless outlined in Table 4 and Table 5 for ongoing participants. 

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Visit: 
Procedure: 
Prescreening 
Notes 
Anticancer, radiation 
therapies, and surgical 
procedures for current 
indication, including 
date of end of definitive 
therapy, prior to 
Screening 
X 
Includes cancer-related information, including medical, surgical, cancer (including 
genotyping), medication history, and end of definitive therapy date. Information about 
current or prior interventions should specifically be collected (as applicable): 
bisphosphonate/denosumab use, and PD-1/PD-L1 inhibitor use, ipsilateral breast/axillary 
surgery, contralateral breast/axillary surgery, and/or salpingo-oophorectomy.  
Note: End of definitive therapy is defined as the date of completing curative-intent surgery, 
adjuvant chemotherapy and/or adjuvant radiation, whichever happens last. Pembrolizumab 
is NOT included in the definition of definitive therapy in this protocol. 
As of the date of the decision to stop enrollment, prescreening of new patients on the study 
is discontinued unless outlined in Table 4 and Table 5 for ongoing participants. 
Tumor tissue for ctDNA 
assay design, BRCA 
status testing, and HRD 
testing 
X 
Tumor tissue sample from primary tumor. 
Tumor tissue will be obtained either after the participant’s last intervention (after surgery if 
adjuvant treatment is not indicated or after adjuvant treatment) or during adjuvant 
chemotherapy or radiation treatment. As of the date of the decision to stop enrollment, 
testing of new patients will be discontinued; however, BRCA results from testing already in 
progress (i.e., testing started prior to 25 April 2023) will be shared, per protocol. 
Pathology report 
submitted 
X 
Pathology reports will be submitted either after the participant’s last intervention (after 
surgery if adjuvant treatment is not indicated or after adjuvant treatment) or during adjuvant 
chemotherapy or radiation treatment. The report will accompany samples sent for testing. 
As of the date of the decision to stop enrollment, this assessment is discontinued for new 
patients; however, for any participant in prescreening at the time of the amendment, these 
may have already been submitted. 
Blood sample for WES 
testing (for ctDNA 
assay design) 
X 
Blood sample for ctDNA assay design (WES testing) will be obtained either after surgery 
if adjuvant treatment is not indicated or during/after chemotherapy or radiation adjuvant 
treatment. The sample may also be used for genetics and translational research (see 
Section 8.7 and Section 8.8 for details). As of the date of the decision to stop enrollment, 
this assessment is discontinued for new patients. 

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Visit: 
Procedure: 
Prescreening 
Notes 
Blood sample for 
ctDNA testing  
Initial ctDNA 
testa as soon as 
the participant 
is eligible, at 
least 4 weeks 
after surgery or 
as soon as 
possible after 
end of adjuvant 
treatment (see 
Figure 3). 
Participants 
receiving 
pembrolizumab 
should follow 
additional 
ctDNA 
assessment 
schedules 
outlined in 
footnote a. 
For TNBC with 
unknown tBRCA 
or tBRCAwt 
status, up to 
9 additional tests 
(10 total tests). 
For TNBC or 
HR+ breast 
cancer with 
known tBRCA 
mutation 
determined 
locally, up to 
18 total tests.  
See Figure 3 and 
Table 13. 
Final 
ctDNA 
test  
Suggested interval between ctDNA tests is approximately 8 weeks ±2 weeks for the first 6 
months from end of definitive therapy and then every 12 weeks thereafter (up to Month 24 
since the end of definitive therapy) as outlined in Figure 3 and Table 13. For TNBC or HR+ 
breast cancer patients with known tBRCA mutation, up to 8 more tests may be performed 
(~1 every 6 months) for up to 6 years (Month 72) from the end of definitive therapy. 
Initial ctDNA sample (for all new participants in any cohort) should be obtained no later 
than 4 weeks of signing prescreening consent or as soon as the participant is eligible for 
testing following end of definitive therapy. 
For participants with TNBC who are receiving adjuvant pembrolizumab following surgery, 
the first ctDNA test may occur during adjuvant pembrolizumab treatment provided that all 
adjuvant radiation and adjuvant chemotherapy have been completed (if indicated; see 
footnote a for further details). 
Participants with TNBC on adjuvant pembrolizumab who are found to have detectable 
ctDNA and who are otherwise eligible for the study will be allowed to start niraparib 
concurrently with the remaining cycles of adjuvant pembrolizumab. 
*HR+ participants in Cohort 1 should have started a stable regimen of endocrine therapy at 
least 6 weeks prior to the initial blood sample for ctDNA testing in order to allow for full 
study eligibility. In addition, CK4/6 inhibitors, if given, should be completed at least 
6 weeks prior to initial blood sample for ctDNA testing. 
As a result of the date of the decision to permanently stop enrollment, ctDNA testing was 
adjusted (as outlined in Table 4) for ctDNA-negative participants and discontinued (as 
outlined in Table 5 for ctDNA+ participants not yet randomized.  
Prior prescreen-fail patients (who had not already signed Protocol Amendment 02 consent), 
are not allowed to be re-enrolled or reconsented and no further assessments or ctDNA 
testing are allowed. 
Adverse events 
X 
Events related to ctDNA and WES blood sample collection procedures 
Abbreviations: AJCC=American Joint Committee on Cancer; BRCA=breast cancer susceptibility gene; ctDNA=circulating tumor DNA; ER= estrogen receptor; FFPE=formalin-fixed 
paraffin-embedded; HER2=human epidermal growth factor receptor 2; HR=hormone receptor; HRD=homologous recombination deficiency; IHC=immunohistochemistry; ISH= in situ 
hybridization; PD-1=programmed death protein 1; PD-L1=programmed cell death ligand 1; PgR=progesterone receptor; tBRCA=tumor breast cancer susceptibility gene; WES=whole 
exome sequencing. 
HR+ participants in Cohort 1 need to be on a stable regimen of endocrine therapy, if indicated, for a minimum of 3 months prior to randomization. Ovarian suppression, if indicated, 
must also have started at least 3 months prior to randomization. 
a 
Timing of initial ctDNA test in relation to pembrolizumab use: 

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1) Initial ctDNA test should occur at least 4 weeks after surgery, after completion of adjuvant treatment with radiation and/or chemotherapy (if indicated), or after at least 12 
weeks of pembrolizumab have been given in any setting, whichever happens last.  
2) If pembrolizumab is permanently discontinued prior to receiving at least 12 weeks, then the initial ctDNA test should occur at least 4 weeks after surgery, after completion of 
adjuvant treatment with radiation and/or chemotherapy (if indicated), or after at least 12 weeks from the first dose of pembrolizumab was given in any setting, whichever 
happens last. 
As of the date of the decision to stop enrollment, prescreening of new patients on the study is discontinued. Assessments for currently eligible ongoing participants in Prescreening 
under Protocol Amendment 03 are outlined in Table 4 and Table 5. 
 

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Table 3 
Schedule of Activities – Screening Period Through End of Study for All Cohorts 
Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Prescreening informed consent specific to ctDNA 
testing will be issued ahead of the main informed 
consent. 
To continue in the study under Protocol Amendment 03, 
existing participants will be reconsented as outlined in 
Table 5 and/or Table 6, as applicable. To continue in 
the study under Protocol Amendment 04, existing 
participants will be reconsented. See Table 12 for 
participant management. 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a participant recurs during Screening, scans, 
recurrence response, and new tumor information will be 
collected. 

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Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
Prior anticancer, 
radiation 
therapy, and 
surgical 
procedures for 
historical 
cancers 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes medical, surgical, cancer (including 
genotyping), and medication history. 
Information (as applicable) about current or prior 
interventions should specifically be collected: 
bisphosphonate/denosumab use, PD-1/PD-L1 inhibitor 
use, ipsilateral breast/axillary surgery, contralateral 
breast/axillary surgery, and/or salpingo-oophorectomy. 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes medical and cancer history (including 
genotyping), as well as family history. 
Substance use 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
As of the date of the decision to stop enrollment, 
discontinued for ctDNA+ participants not yet 
randomized (see Table 5 for assessments). 

TMF-17007234 
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45 
Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
Treatment 
assignment 
(randomization) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
As of the date of the decision to stop enrollment, 
randomization is discontinued. For participants that are 
ctDNA+ and not yet randomized at the time of the 
amendment see Table 5 for participant management. 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG does not need to be repeated if patient requires 
rescreening. As of the date of the decision to stop 
enrollment, ECGs are discontinued for ctDNA+ 
participants not yet randomized (see Table 5 for 
assessments). 
ECOG 
performance 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
 
As of the date of the decision to stop enrollment, 
ECOG assessment is discontinued for participants on 

TMF-17007234 
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Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
status 
placebo, and for ctDNA+ participants not yet 
randomized (see Table 5 for ctDNA+ participants). 
Physical 
examination 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Full physical examination should be performed at the 
time of Screening. Symptom-directed physical 
examinations may be performed thereafter. As of the 
date of the decision to stop enrollment, assessments are 
discontinued for participants on placebo, and for 
ctDNA+ participants not yet randomized (see Table 5 
for ctDNA+ participants). 

TMF-17007234 
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213831 
Protocol Amd 04 Final 
28 Nov 2023 
47 
Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height is not required after the Screening assessment. 
As of the date of the decision to stop enrollment, this is 
discontinued for ctDNA+ participants not yet 
randomized (see Table 5). 
Temperature, 
weight, and 
respiration rate 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Respiratory rate is required at Screening, and thereafter 
only if clinically indicated.  
As of the date of the decision to stop enrollment, 
assessment is discontinued for participants on placebo, 
and for ctDNA+ participants not yet randomized (see 
Table 5 for ctDNA+ participants). 

TMF-17007234 
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48 
Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
Blood pressure 
and heart rate 
monitoring  
X 
X* X* X* X* X* X* X* X* X 
X 
X 
X 
 
*Must be monitored weekly for the first 2 cycles 
(8 weeks), then on Day 1 of each subsequent cycle. If 
unable to attend the clinic visits, BP and heart rate 
(pulse) must be monitored at home-nursing visits or at a 
local laboratory/clinic for visits outlined in Section 4.1 
and Section 8.4.3 on the dates of these visits 
(recommended after remaining seated for 5 to 
10 minutes). 
Three readings of BP and heart rate are also 
recommended as outlined in Section 8.4.3.  
As of the date of the decision to stop enrollment, this 
assessment is discontinued for all participants on 
placebo. This assessment is discontinued at Screening 

TMF-17007234 
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213831 
Protocol Amd 04 Final 
28 Nov 2023 
49 
Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
for ctDNA+ participants not yet randomized (see 
Table 5). 
AE monitoring 
and review 
Reporting of safety events is to begin at the time of ctDNA Prescreening ICF signature date 
only for events related to ctDNA and WES blood sample collection procedures. All AEs 
and SAEs are required to be captured from the signing of the main study ICF through 30 
days after the last dose of study treatment or start of new anticancer therapy; whichever 
occurs first. SAEs assessed by the Investigator as related to study treatment, are to be 
collected until study closeout and all AESIs, regardless of causality, are to be collected 
until death or loss to follow up Any pregnancies in WOCBP participating in the study that 
occur within 180 days post-treatment discontinuation are to be captured. 
For France, see Section 10.14.1.1 for pregnancy 
reporting requirements. 
Concomitant 
 
X X X X X X X X X 
X 
X 
X 
 
Details regarding collection of endocrine therapy, 

TMF-17007234 
CONFIDENTIAL 
213831 
Protocol Amd 04 Final 
28 Nov 2023 
50 
Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
medication 
review 
ovarian suppression, bisphosphonate/denosumab 
treatment, and pembrolizumab are specified in the eCRF
completion guidelines.  
As of the date of the decision to stop enrollment, this 
assessment is discontinued for participants on placebo. 

TMF-17007234 
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213831 
Protocol Amd 04 Final 
28 Nov 2023 
51 
Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
Serum or highly 
sensitive urine 
pregnancy test 
(WOCBP only) 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
 
Pregnancy testing (serum or highly sensitive urine 
pregnancy test) must be conducted within 72 hours 
prior to the first dose of study treatment and then, 
starting in Cycle 2, within 72 hours of Day 1 of every 
cycle for the duration of the treatment period. Test 
result must be available and negative before the first 
dose of study treatment. Further details regarding 
pregnancy testing at Screening and during the study are 
provided in Section 5.1 and Section 8.4.6. 
Additional pregnancy testing may be necessary if 
required by local practices or regulations or if potential 
pregnancy is suspected. As of the date of the decision to 
stop enrollment, this assessment is discontinued for 
participants on placebo. 

TMF-17007234 
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213831 
Protocol Amd 04 Final 
28 Nov 2023 
52 
Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
HIV, hepatitis 
B, and hepatitis 
C screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
If participant was tested within 3 months prior to first 
dose of study treatment, testing at Screening is not 
required. 
As of the date of the decision to stop enrollment, this is 
discontinued for ctDNA+ participants not yet 
randomized (see Table 5). 
Hematology 
X 
X X X X X 
 
 
 
X 
X 
X 
X 
 
If dose interruption or modification is required at any 
point on study because of hematologic toxicity, weekly 
blood draws for CBC will be monitored until the AE 
resolves, and to ensure safety of the new dose, weekly 
blood draws for CBC will also be required for an 
additional 4 weeks after the AE has been resolved to 

TMF-17007234 
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Protocol Amd 04 Final 
28 Nov 2023 
53 
Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
the specified levels, after which monitoring every 
4 weeks may resume. On Cycle 1/Day 8, 
Cycle 1/Day 15, and Cycle 1/Day 22, samples for CBC 
can be drawn ± 1 day of the listed visit, as needed. For 
Cycle 2/Day 1 and Cycle (n)/Day 1, CBC blood draws 
may be up to 72 hours prior to the visit, as needed. 
See Appendix 2 for specific parameters to be measured. 
As of the date of the decision to stop enrollment, this 
assessment is discontinued for participants on placebo, 
and discontinued for ctDNA+ participants not yet 
randomized (see Table 5 for ctDNA+ participants). 
Clinical 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Serum/plasma chemistry parameters that will be 

TMF-17007234 
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213831 
Protocol Amd 04 Final 
28 Nov 2023 
54 
Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
chemistry 
measured are listed in Appendix 2. 
Samples for chemistry labs for Cycle 2/Day 1 and 
Cycle (n)/Day 1 visits may be drawn up to 72 hours 
prior to the visit, as needed. As of the date of the 
decision to stop enrollment, this is discontinued for 
participants on placebo, and for ctDNA+ participants 
not yet randomized (see Table 5 for ctDNA+ 
participants). 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specific coagulation factors will be evaluated as 
presented in Appendix 2. 

TMF-17007234 
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Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
As of the date of the decision to stop enrollment, this is 
discontinued for ctDNA+ participants not yet 
randomized (see Table 5). 

TMF-17007234 
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Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
Blood sample 
for ctDNA 
testing  
Please see 
Table 2 for 
ctDNA 
testing 
schedule for 
Prescreening
X 
Every 12 weeks (84±7 days) from 
randomization until disease 
recurrence. ctDNA screening should 
continue every 12 weeks if the 
participant stops treatment for any 
reason other than disease recurrence 
per RECIST v1.1, death, withdrawal 
of consent, or loss to follow-up. 
X 
 
 
Sample will be collected prior to niraparib 
administration on Cycle 1/Day 1. During the Treatment 
Period, samples will be collected every 12 weeks from 
randomization until disease recurrence. As of the date 
of the decision to stop enrollment, ctDNA testing is 
discontinued for all participants. 
Blood sample 
for 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
At time of 
disease 
recurrence 
 
 
Blood sample at Cycle 1/Day 1, at Cycle 3/Day 1, and 
at time of disease recurrence  
 
 
 
CCI
CCI

TMF-17007234 
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28 Nov 2023 
57 
Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
Optional tumor 
tissue sample 
upon disease 
recurrence 
 
 
 
 
 
 
 
 
 
 
 
At time of 
disease 
recurrence 
prior to 
subsequent 
anticancer 
therapy  
 
 
For exploratory analyses, submission of a fresh frozen 
tumor tissue specimen at time of disease recurrence is 
highly encouraged. 
Biopsy must be performed prior to initiation of 
subsequent anticancer therapy but does not need to 
occur within 7-days of last dose. As of the date of the 
decision to stop enrollment, this sample collection is 
discontinued for all participants. 
Blood samples 
for PK in main 
study  
See Table 7. As of the date of the decision to stop enrollment, collection of blood samples for PK is discontinued for all participants. 
Blood samples 
See Table 8. As of the date of the decision to stop enrollment, collection of blood samples for PK is discontinued for all participants. 

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Visit: 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post-treatment
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 
8 15 22 1 
1 
Within 
7 days of 
last dose (or
decision to 
discontinue)
30 (+7)
days 
after 
last 
dose 
Every 90 (±14)
days for 2 
years after last
dose and then 
every 
180 (±14) days 
All tests and procedures are required to be performed, 
and results evaluated, prior to dosing. Screening 
assessments completed within 7 days of the first dose do 
not need to be repeated. It is recommended that the 
Screening Period start within 14 days of confirmed 
detectable ctDNA (i.e., ctDNA+ status), provided all 
submitted prescreening tissue samples are of adequate 
quality per central review. All screening criteria (except 
as noted for specific assessments in this SOA) are 
required to be repeated if they fall outside of 6 weeks 
prior to first dose.  
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ±3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 
6. 
for PK substudy 
PRO 
collection: 
EORTC-QLQ-
C30, EQ-5D-
3L, 
FACT-GP5, 
PGIS/PGIC, 
and a subset of 
items from the 
PRO-CTCAE 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
First 2 Post-
treatment 
Follow-up 
assessments 
PROs should be completed on the assigned clinic visit 
day prior to any clinical procedures (see Section 8.9). 
PGIC only will be collected starting on Cycle 2/Day 1 
and every 28 days thereafter. 
As of the date of the decision to stop enrollment, PRO 
collection is discontinued for all participants. 
 

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Visit: 
 
Cycle: 
Screening Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or 
ED) 
Safety 
FUPa 
Post- 
treatment 
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 1 8 15 22 
1 
1 
Within 
7 days of 
last dose (or 
decision to 
discontinue) 
30 (+7) 
days 
after last 
dose 
Every 
90 (±14) 
days for 
2 years 
after last 
dose and 
then every 
180 (±14) 
days 
All tests and procedures are required to be performed, and results evaluated, prior to 
dosing. Screening assessments completed within 7 days of the first dose do not need 
to be repeated. It is recommended the Screening Period start within 14 days of 
confirmed detectable ctDNA (i.e., ctDNA+ status), provided all submitted 
prescreening tissue samples are of adequate quality per central review. All screening 
criteria (except as noted for specific assessments in this SOA) are required to be 
repeated if they fall outside of 6 weeks prior to first dose. 
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ± 3 days and weekly visits within ± 1 business 
day (relative to C1D1). 
As of the date of the decision to stop enrollment, randomization is stopped. 
Discontinued assessments are outlined in the table below and monitoring of 
participants previously randomized is outlined in Table 6. 
CT or MRI for 
DFS assessment 
X 
For CT or 
MRI 
falling out 
of 6 
weeks 
prior to 
first dose 
window, 
consult 
the 
medical 
monitor. 
Every 12 weeks (84±7 days) from date of randomization for the first 2 years 
(Year 1 Weeks 12, 24, 36, 48; Year 2, Weeks 60, 72, 84, 96) and every 
24 weeks (168±7 days) thereafter, or more frequently as clinically indicated 
(unscheduled), until Investigator assessment of disease recurrence using 
RECIST v1.1. 
Imaging should continue according to the specified window interval if the 
participant stops treatment for any reason other than disease recurrence per 
RECIST v1.1, death, withdrawal of consent, or loss to follow-up. 
IV contrast-enhanced CT scan of the chest, abdomen, and pelvis; IV contrast-
enhanced MRI of the abdomen and pelvis plus noncontrast CT of the chest should 
only be conducted if IV contrast-enhanced CT cannot be performed (eg, if 
participant is sensitive to IV CT contrast or contrast shortage). If MRI is performed 
at Baseline, it should be preferentially continued throughout the study. PET imaging 
is allowed if needed; refer to Appendix 3 for specific guidelines for use. The same 
imaging and anatomical coverage should be used throughout the study. If brain 
metastasis is suspected, IV contrast-enhanced MRI is preferred over IV contrast-
enhanced CT for imaging of the brain. 
It is important to adhere to the imaging schedule. If scans are performed outside of 
the specified window interval and the participant has not progressed, every attempt 
should be made to perform the subsequent scans at their scheduled time points. 
If an equivocal new lesion is observed on a postbaseline radiological assessment, a 
follow-up scan should be acquired at least 4 weeks later to reassess. On the follow-up
scan, if the equivocal new lesion becomes unequivocal, the date of progression is the 
date of the scan when the new lesion first appeared (refer to Appendix 3). Any lesion
assessed by the Investigator as representative of metastatic disease should be 
biopsied, if possible, to document disease recurrence histologically. 
All radiological images/scans, scheduled and unscheduled, must be submitted 
(preferably electronically) to a central imaging vendor for QC, storage, and analysis 
by BICR. As of the date of the decision to stop enrollment, scans are not to be 
submitted to a central imaging vendor. BICR analysis is no longer applicable.  
 

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Visit: 
 
Cycle: 
Screening 
Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or ED) Safety 
FUPa 
Post-treatment 
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 
15 22 
1 
8 
15 
22 
1 
1 
Within 
7 days of last 
dose (or 
decision to 
discontinue) 
30 (+7) 
days 
after 
last dose 
Every 90 (±14) 
days for 2 years 
after last dose 
and then every 
180 (±14) days 
All tests and procedures are required to be performed, and 
results evaluated, prior to dosing. Screening assessments 
completed within 7 days of the first dose do not need to be 
repeated. It is recommended the Screening Period start 
within 14 days of confirmed detectable ctDNA (i.e., 
ctDNA+ status), provided all submitted prescreening tissue 
samples are of adequate quality per central review. All 
screening criteria (except as noted for specific assessments 
in this SOA) are required to be repeated if they fall outside 
of 6 weeks prior to first dose. 
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ± 3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of participants 
previously randomized is outlined in Table 6. 
Bone scan 
X 
Bone scans performed between randomization and disease recurrence only if clinically indicated. Baseline bone scan will be performed within 42 days 
(6 weeks) of randomization. Bone scans do not need to be 
repeated if patient requires rescreening. 
Niraparib or 
placebo 
dispensed/ 
collected 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Missed doses will also be recorded as outlined in 
Section 6.4.1. If there is a change in weight from Screening 
to C1D1 to above or below the 77 kg threshold for dosing, 
then dosing of study drug should be based on weight from 
C1D1  
As a result of the date of the decision to stop enrollment, the
study was centrally unblinded and participants on placebo 
must immediately discontinue treatment. Placebo 
dispensation is also discontinued.  
For participants continuing on niraparib, see Table 6. 

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Visit: 
 
Cycle: 
Screening 
Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT (or ED) Safety 
FUPa 
Post-treatment 
FUPb 
Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 
15 22 
1 
8 
15 
22 
1 
1 
Within 
7 days of last 
dose (or 
decision to 
discontinue) 
30 (+7) 
days 
after 
last dose 
Every 90 (±14) 
days for 2 years 
after last dose 
and then every 
180 (±14) days 
All tests and procedures are required to be performed, and 
results evaluated, prior to dosing. Screening assessments 
completed within 7 days of the first dose do not need to be 
repeated. It is recommended the Screening Period start 
within 14 days of confirmed detectable ctDNA (i.e., 
ctDNA+ status), provided all submitted prescreening tissue 
samples are of adequate quality per central review. All 
screening criteria (except as noted for specific assessments 
in this SOA) are required to be repeated if they fall outside 
of 6 weeks prior to first dose. 
Treatment cycles are 28 (±3) days long. 
Monthly visits should occur within ± 3 days and weekly 
visits within ± 1 business day (relative to C1D1). 
As of the date of the decision to stop enrollment, 
randomization is stopped. Discontinued assessments are 
outlined in the table below and monitoring of participants 
previously randomized is outlined in Table 6. 
Anticancer 
therapy 
following study 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Anticancer therapy includes systemic therapy, radiation 
therapy, or surgical intervention. If new anticancer 
treatment is started before the Safety Follow-up Visit, it 
must be collected during this visit as outlined in the eCRF 
completion guidelines. As of the date of the decision to stop 
enrollment, this is discontinued for all participants. 
Disease 
progression on 
next anticancer 
therapy 
assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
As of the date of the decision to stop enrollment, this is 
discontinued for all participants. 
Follow-up status 
(survival 
assessment) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Survival status may be collected outside the protocol 
window on request, as per Section 4.1. 
As of the date of the decision to stop enrollment, this is 
discontinued for all participants. 
Abbreviations: AE=adverse event; AESI=AE of special interest; BICR=blinded independent central review; BMx=biomarker; BP=blood pressure; BRCA=breast cancer susceptibility gene; 
C=cycle; CBC=complete blood count; CRF=case report form; CT=computed tomography; ctDNA=circulating tumor DNA; ctDNA+=ctDNA -positive; D=day; ECG=electrocardiogram; 

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ECOG=Eastern Cooperative Oncology Group; ED=early discontinuation/withdrawal; EORTC-QLQ-C30=European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire 30-item Core Module; EOT=End of Treatment; EQ-5D-3L=EuroQoL 5-dimensional questionnaire 3-level version; FACT-GP5=Functional Assessment of Cancer Therapy-
General Population; FUP=Follow-up Period; HER2=human epidermal growth factor receptor 2; HIV=human immunodeficiency virus; ICF=informed consent form; IV=intravenous; 
MRI=magnetic resonance imaging; n=number of subsequent cycle; PD-1=programmed death protein 1; PD-L1=programmed cell death ligand 1; PET=positron emission tomography; 
PGIC=Patient Global Impression of Change; PGIS=Patient Global Impression of Severity; PK=pharmacokinetics; PRO=patient-reported outcome; PRO-CTCAE=Patient-Reported 
Outcomes Version of the Common Terminology Criteria for Adverse Events; QC=quality control; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event; 
SOA=Schedule of Activities; WES=whole exome sequencing; WOCBP=women of childbearing potential. 
a. 
As of the date of the decision to stop enrollment, the entire Safety FU Visit, and all associated assessments, are discontinued for participants on placebo at the time of unblinding. 
For participants on niraparib continuing on the study, see Table 6 or assessments. 
b. 
As of the date of the decision to stop enrollment, the entire Post-treatment FU Visit, and all associated assessments, are discontinued for all participants. 
 

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Table 4 
Schedule of Activities: Prescreening for Participants Not Yet ctDNA-positive (i.e., ctDNA-negative) Under 
Protocol Amendment 03 
Visit: 
Procedure: 
Prescreening/Monitoring 
Notes 
Assessments outlined in this table should be collected and/or continue as part of 
Prescreening for ctDNA-negative participants already in Prescreening as of the date of 
the decision to stop enrollment. 
Informed consent for 
prescreening 
X 
As of the date of the decision to stop enrollment, no new participants will be enrolled. 
Participants remaining on study must be reconsented under Protocol Amendment 03 
with a new ICF. Participants remaining on study must be reconsented under 
Protocol Amendment 04. 
Eligibility 
X 
Confirmation of eligibility to continue. As of the date of the decision to stop enrollment, no 
new participants will be enrolled. 
Demography 
X 
 
Disease characteristics 
X 
Tumor characteristics to be collected as outlined in Table 2. 
Anticancer, radiation 
therapies, and surgical 
procedures for current 
indication, including date of 
end of definitive therapy, prior 
to Screening 
X 
As outlined in Table 2. 
Blood sample for WES testing 
(for ctDNA assay design) 
X 
As outlined in Table 2. 
Samples prepared for Q2 are no longer required. 
Blood sample for ctDNA 
testing  
For Participants in Prescreening as of the date of the 
decision to stop enrollment and <12 months from end of 
definitive therapy: up to 2 additional ctDNA tests 
(excluding initial ctDNA test) until they reach 12 months 
from end of definitive therapy or final DCO is reached, 
whichever comes first. The frequency of these 2 
additional tests is at the discretion of the Investigator. 
As a result of the decision to stop enrollment, ctDNA-negative participants currently in 
Prescreening who are more than 12-months from end of definitive therapy as of the date 
of the decision to stop enrollment (25 April 2023) should have no further testing.  
Prior prescreen-fail patients (those that failed under previous versions of the protocol but 
who had not already signed Protocol Amendment 02 consent), are not allowed to be re-
enrolled or reconsented and no further assessments or ctDNA testing are allowed. 
Samples prepared for Q2 are no longer required. 
Adverse events 
X 
Events related to ctDNA and WES blood sample collection procedures should be 
reported as outlined in Section 8.5. 
CT or MRI scan 
X 
For participants who were ctDNA-negative as of the date of the decision to stop 
enrollment, but subsequently test ctDNA+, participants will be offered 1 scan for staging 
purposes.  

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Visit: 
Procedure: 
Prescreening/Monitoring 
Notes 
Assessments outlined in this table should be collected and/or continue as part of 
Prescreening for ctDNA-negative participants already in Prescreening as of the date of 
the decision to stop enrollment. 
Bone Scans 
X 
ctDNA-negative participants who were ctDNA-negative as of the date of the decision to 
stop enrollment, but subsequently test ctDNA+, participants will be offered 1 scan for 
staging purposes 
 
 

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Table 5 
Schedule of Activities Prescreening/Screening For Participants Currently ctDNA-positive and Not Yet 
Randomized as of Protocol Amendment 03 
Visit 
Procedure: 
Assessment 
Notes 
ctDNA+ participants must have had a positive test as of the date of the decision to stop enrollment (25 April 2023). If 
testing was started prior to the date of the decision was made to stop enrollment and the result is obtained after the date 
of the decision to stop enrollment, and was positive, the participant will be considered part of the ctDNA+ population and 
currently monitored accordingly.  
Prescreening 
Participants that are ctDNA+ in Prescreening on the date of the decision to stop enrollment should have completed 
collection of all Prescreening assessments outlined in this table. Participants in Prescreening but who have not 
proceeded to Screening as of the date of decision to stop enrollment should not proceed to Screening but can continue 
with Protocol Amendment 03 Monitoring Assessments if they consent to do so. 
Informed consent for prescreening 
X 
As outlined in Table 2.  
Eligibility 
X 
Confirmation of eligibility to continue. 
Demography 
X 
 
Disease characteristics 
X 
As outlined in Table 2.  
Anticancer, radiation therapies, and 
surgical procedures for current indication, 
including date of end of definitive therapy, 
prior to Screening 
X 
As outlined in Table 2.  
Tumor tissue for ctDNA assay design, 
BRCA status testing, and HRD testing 
 
As of the date of the decision to stop enrollment, this assessment is discontinued for all participants; however, if BRCA 
testing was already in progress as of the date of the decision to stop enrollment, BRCA results will be shared. Samples 
prepared for Q2 are no longer required. 
Blood sample for ctDNA testing  
 
As a result of the decision to stop enrollment, no further ctDNA testing should occur for participants who have tested 
ctDNA+. Samples prepared for Q2 are no longer required. 
Adverse events 
X 
Events related to ctDNA and WES blood sample collection procedures 
Screening 
For ctDNA+ participants in Screening as of the date of the decision to stop enrollment, Prescreening assessments as 
outlined above should have been completed and collected; Screening assessments outlined in this table should also be 
completed. 
Informed consent  
X 
As a result of the decision to stop enrollment, participants who wish to continue surveillance scans will need to provide 
consent under Protocol Amendment 03 by signing a new ICF. Participants remaining on study and entering PACT 
Phase must be reconsented under Protocol Amendment 04. 
Eligibility 
X 
As outlined in Table 3. 
Concomitant Medication Review 
X 
As outlined in Table 3. 

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Visit 
Procedure: 
Assessment 
Notes 
ctDNA+ participants must have had a positive test as of the date of the decision to stop enrollment (25 April 2023). If 
testing was started prior to the date of the decision was made to stop enrollment and the result is obtained after the date 
of the decision to stop enrollment, and was positive, the participant will be considered part of the ctDNA+ population and 
currently monitored accordingly.  
Medical History 
X 
As outlined in Table 3. 
Protocol Amendment 03 Monitoring 
For All ctDNA+ participants as of the date of the decision to stop enrollment (regardless of whether in Prescreening or 
Screening at the time).  
CT or MRI for DFS Assessments  
At the 
discretion of 
the 
Investigator 
All ctDNA+ participants as of the date of the decision to stop enrollment (regardless of whether in Prescreening or 
Screening at the time), will be offered the option of CT surveillance scans for assessment of disease as frequently as 
every 12 weeks, or less frequently at the discretion of the Investigator. Scans may continue until progressive 
disease/disease recurrence or participant withdrawal, in accordance with the judgment of the Investigator. 
Bone Scans 
At the 
discretion of 
the 
Investigator 
Bone scans will only be performed if clinically indicated. 
 
 
 

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Table 6 
Schedule of Activities – For Previously Randomized Participants Continuing Under Protocol Amendment 03 and 
Protocol Amendment 04 Prior to the Data Cut-off and Transition to PACT Phase 
As of the date of the decision to stop enrollment, all study treatment must be stopped for participants on placebo at the time of unblinding. 
Participants that were on placebo will be monitored for AEs and participants may remain on study to continue scans until disease 
progression or participant withdrawal, as outlined for participants on niraparib in the table below. Participants will be required to sign an 
ICF under Protocol Amendment 03 prior to continuing scans. 
Visit: 
 
Cycle: 
Screening 
Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT 
Safety FUP Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 
1 
8 
15 22 
1 
1 
Within 7 days 
decision to 
discontinue 
30 (+7) days 
after last 
dose 
All tests and procedures are required to be performed, and results 
evaluated, prior to dosing.  
Screening assessments outlined in this table should have been collected 
as part of Screening for these ctDNA+ participants already randomized at 
the time of the decision to stop enrollment. 
Treatment cycles are 28 (±3) days long. Monthly visits should occur 
within ±3 days and weekly visits within ± 1 business day (relative to 
C1D1). 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
A Prescreening informed consent specific to ctDNA testing will have been
issued ahead of the main informed consent. For participants who wish to 
remain on study, they must be reconsented under Protocol Amendment 
03. Participants remaining on study and entering PACT Phase must 
be reconsented under Protocol Amendment 04. 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
As outlined in Table 3. 
Prior anticancer, 
radiation 
therapy, and 
surgical 
procedures for 
historical 
cancers 
X 
 
 
 
 
 
 
 
 
 
 
 
 
As outlined in Table 3. 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
As outlined in Table 3. 

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Visit: 
 
Cycle: 
Screening 
Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT 
Safety FUP Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 
1 
8 
15 22 
1 
1 
Within 7 days 
decision to 
discontinue 
30 (+7) days 
after last 
dose 
All tests and procedures are required to be performed, and results 
evaluated, prior to dosing.  
Screening assessments outlined in this table should have been collected 
as part of Screening for these ctDNA+ participants already randomized at 
the time of the decision to stop enrollment. 
Treatment cycles are 28 (±3) days long. Monthly visits should occur 
within ±3 days and weekly visits within ± 1 business day (relative to 
C1D1). 
Substance use 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
performance 
status 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Physical 
examination 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
As outlined in Table 3. 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height is not required after the Screening assessment. 
Temperature, 
weight, and 
respiration rate 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Blood pressure 
and heart rate 
monitoring  
X 
X* X* X* X* X* X* X* X* 
X 
X 
X 
X 
*Must be monitored weekly for the first 2 cycles (8 weeks), then on Day 1 
of each subsequent cycle.  
Three readings of BP and heart rate are also recommended as outlined in
Section 8.4.3. 

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Visit: 
 
Cycle: 
Screening 
Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT 
Safety FUP Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 
1 
8 
15 22 
1 
1 
Within 7 days 
decision to 
discontinue 
30 (+7) days 
after last 
dose 
All tests and procedures are required to be performed, and results 
evaluated, prior to dosing.  
Screening assessments outlined in this table should have been collected 
as part of Screening for these ctDNA+ participants already randomized at 
the time of the decision to stop enrollment. 
Treatment cycles are 28 (±3) days long. Monthly visits should occur 
within ±3 days and weekly visits within ± 1 business day (relative to 
C1D1). 
AE monitoring 
and review 
Reporting of safety events is to begin at the time of ctDNA Prescreening ICF signature date
only for events related to ctDNA and WES blood sample collection procedures. All AEs and
SAEs are required to be captured from the signing of the main study ICF through 30 
days after the last dose of study treatment or start of new anticancer therapy; 
whichever occurs first. SAEs assessed by the Investigator as related to study 
treatment are to be collected until study closeout and all AESIs, regardless of 
causality, are to be collected until death or loss to follow up. Any pregnancies in 
WOCBP participating in the study that occur within 180 days post-treatment discontinuation
are to be captured. 
For France, see Section 10.14.1.1 for pregnancy reporting requirements. 
Concomitant 
medication 
review 
 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
As outlined in Table 3. 
Serum or highly 
sensitive urine 
pregnancy test 
(WOCBP only) 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
As outlined in Table 3. 
HIV, hepatitis B, 
and hepatitis C 
screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
As outlined in Table 3. 
Hematology 
X 
X 
X X 
X 
X 
 
 
 
X 
X 
X 
X 
As outlined in Table 3. 
Clinical 
chemistry 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
As outlined in Table 3. 

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Visit: 
 
Cycle: 
Screening 
Niraparib or Placebo Treatment Period 
(28-day cycles) 
EOT 
Safety FUP Notes 
C1 
C2 
C3 C(n) 
Day: 
Procedure: 
Up to 
6 weeks 
before D1 
1 
8 15 22 
1 
8 
15 22 
1 
1 
Within 7 days 
decision to 
discontinue 
30 (+7) days 
after last 
dose 
All tests and procedures are required to be performed, and results 
evaluated, prior to dosing.  
Screening assessments outlined in this table should have been collected 
as part of Screening for these ctDNA+ participants already randomized at 
the time of the decision to stop enrollment. 
Treatment cycles are 28 (±3) days long. Monthly visits should occur 
within ±3 days and weekly visits within ± 1 business day (relative to 
C1D1). 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI for 
DFS assessment 
X 
For CT or 
MRI falling 
out of 6 
weeks prior 
to first dose 
window, 
consult the 
medical 
monitor 
Every 12 weeks (84±7 days) from date of randomization for the first 2 years 
(Year 1 Weeks 12, 24, 36, 48; Year 2, Weeks 60, 72, 84, 96) and every 
24 weeks (168±7 days) thereafter, or more frequently as clinically indicated 
(unscheduled), until Investigator assessment of disease recurrence using 
RECIST v1.1. 
Imaging should continue according to the specified window interval if the 
participant stops treatment for any reason other than disease recurrence per 
RECIST v1.1, death, withdrawal of consent, or loss to follow-up. 
As of the date of the decision to stop enrollment, participants on niraparib or 
placebo at the time of unblinding may continue scans per protocol, or less 
frequently at the discretion of the Investigator, until disease progression. 
As outlined in Table 3. Note, as of the date of the decision to stop 
enrollment, scans are not to be submitted to a central imaging vendor. 
BICR analysis is no longer applicable.  
 
Note: scans may continue post-EOT until progressive disease/disease 
recurrence or participant withdraws. 
Bone scan 
X 
Bone scans performed between randomization and disease recurrence only if 
clinically indicated. 
As outlined in Table 3  
Niraparib 
dispensed/ 
collected 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
As outlined in Table 3.  
 
 

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Table 7 
PK Sampling Schedule for All Participants (Discontinued Under Protocol Amendment 03) 
Visit: 
 
Cycle: 
Niraparib or Placebo Treatment Period 
(28-day cycles) 
Notes 
 
C1 
C2 
C3 
C4 
C8 
As a result of Protocol Amendment 03, no further PK 
sampling will be performed. 
Day: 
Procedure: 
1 
8 
15 
22 
1 
1 
1 
1 
 
Blood samples for 
niraparib PK 
 
 
 
 
 
 
 
 
Blood samples for PK in the main study will be collected for all 
participants in Cohort 1 and Cohort 2. If participants are routinely 
taking their niraparib/placebo dose in the evening, they must be 
instructed to transition to niraparib/placebo morning dosing 1 
week before PK testing. 
   Predose (Up to 60 minutes 
prior to dosing) 
X 
 
X 
 
X 
 
X 
X 
Participants will be instructed to hold their dose of study treatment 
until the predose PK sample has been taken. 
For Cycle 4/Day 1 and Cycle 8/Day 1 samples, if a participant 
discontinues treatment before the scheduled blood draw, a blood 
draw for PK will be done at the EOT Visit. 
   3 hours postdose 
(±15 minutes) 
X 
 
X 
 
X 
 
 
 
Participants will be instructed to hold their dose of study treatment 
until the predose PK sample has been taken. 
Three-hour postdose sample is not required on Cycle 1/Day 15 for 
participants in the PK substudy. 
Abbreviations: C=cycle; EOT=End of Treatment; PK=pharmacokinetics. 

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Table 8 
PK Sampling Schedule for Participants in the PK Substudy (Discontinued Under Protocol Amendment 03) 
Visit: 
 
Procedure: 
Cycle 1, Day 15 
Notes 
Blood samples for PK substudy 
 
The PK substudy will include at least 40 participants receiving endocrine therapy in Cohort 1. 
Participants in the PK substudy will also have PK samples collected at the time points in Table 7 
, with the exception of the 3-hour postdose sample on Cycle 1/Day 15. 
Participants must be instructed to dose study treatment and endocrine therapy in the morning for 
1 and 2 weeks, respectively before PK sampling on Cycle 1/Day 15. 
As a result of decision to stop enrollment, no further PK sampling will be performed. 
   Predose (Up to 60 minutes prior to dosing) 
X 
Participants will be instructed to hold their dose of niraparib/placebo and endocrine therapy until 
the predose PK sample has been taken. Niraparib/placebo must be taken first and the endocrine 
therapy immediately after (within 5 minutes). 
   1 hour postdose (±15 minutes) 
X 
Participants in the PK substudy who vomit after taking their study treatment on a PK sampling day 
will need to return another time for their PK assessments. 
   2 hours postdose (±15 minutes) 
X 
   4 hours postdose (±15 minutes) 
X 
   6 hours postdose (±15 minutes) 
X 
   8 hours postdose (±15 minutes) 
X 
Abbreviations: PK=pharmacokinetics. 
 
 

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2. 
INTRODUCTION 
As of 25 April 2023, the decision was communicated by the Sponsor that enrollment in 
the ZEST study was permanently stopped due to feasibility of study completion (i.e., the 
study was unable to randomize participants in the planned timeframe based on 
randomization projections as the study had lower-than-expected rates of ctDNA-
positivity and a much higher-than-expected proportion of patients with a ctDNA-positive 
(ctDNA+) test showing radiographically detectable disease during screening 
assessments). There was no change in the benefit-risk and no safety concerns identified 
for participants in the study.  
 
2.1. 
Study Rationale 
Study 213831 was designed as a study of niraparib as treatment for participants with 
tumor breast cancer susceptibility gene mutated (tBRCAmut, which includes participants 
with germline BRCAmut [gBRCAmut] and/or somatic BRCAmut [sBRCAmut]) human 
epidermal growth factor receptor 2-negative (HER2−) breast cancer or tumor BRCA 
wild-type (tBRCAwt) triple-negative breast cancer (TNBC) who have molecular disease 
based on the presence of circulating tumor DNA (ctDNA) levels after completion of 
definitive treatment, including all of the following, if indicated: neoadjuvant treatment, 
surgery, adjuvant radiotherapy, and adjuvant chemotherapy; end of definitive therapy is 
defined as the date of completion of curative-intent surgery, adjuvant chemotherapy, or 
adjuvant radiotherapy, whichever was last. 
For patients with Stage I, II, IIIA, IIIB, or operable IIIC breast cancer, treatment includes 
surgical removal of the primary tumor, with lymph node dissection as required [Cardoso, 
2019; NCCN, 2020]. Although patient survival after surgery can be improved with 
adjuvant local and systemic therapy, the risk of recurrence in many patients with breast 
cancer remains high ([Steeg, 2016], reviewed in [Coakley, 2019]). Once definitive 
therapy is complete, there is no standard of care surveillance or treatment for patients 
with TNBC, beyond clinical monitoring, until metastatic disease presents. Similarly, for 
patients with hormone receptor positive (HR+)/HER2− breast cancer on adjuvant 
endocrine therapy, there is no standard of care surveillance or additional treatment until 
metastatic disease presents [NCCN, 2021]. Once the disease becomes metastatic, the 
5-year survival rates are 11.5% for TNBC and 30.4% for HR+/HER2− breast cancer 
[SEER, 2019]. 
Current tumor markers to determine the risk of recurrence after definitive therapy, such 
as carcinoembryonic antigen, cancer antigen 27-29, and cancer antigen 15-3, lack 
sensitivity and are typically used only in the metastatic setting [Kokko, 2002; 
Lumachi, 1999; Mariani, 2009]. To identify the patient population at high-risk of 
recurrence, current efforts are directed at identification of molecular detectable disease, 
as measured by the presence of ctDNA. Several studies in multiple cancer types, 
including breast cancer, have shown that molecular detectable disease can be identified 
using liquid biopsies by tracking tumor mutations in ctDNA and the presence of ctDNA 
has been demonstrated to be predictive of clinical or radiological relapse [Coombes, 

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2019]. Currently, there is no standard of care for patients who have detectable ctDNA 
following their last intervention (surgery or adjuvant therapy) but who have not yet 
developed radiologic or clinically evident metastatic disease. 
The single-agent efficacy of 2 poly(ADP-ribose) polymerase (PARP) inhibitors, olaparib 
and talazoparib, has been demonstrated in patients with gBRCAmut HER2− breast 
cancer, including patients with gBRCAmut TNBC, in the locally advanced(talazoparib) 
and metastatic (olaparib and talazoparib) settings [Litton, 2018; Robson, 2017] and in 
patients with sBRCAmut metastatic breast cancer (olaparib) [Tung, 2020]. 
Studies in TNBC support homologous recombination deficiency (HRD) status as a 
predictor of response to treatment. HRD testing classifies tumors as either positive for a 
deficiency in homologous recombination DNA repair (homologous recombination 
deficient [HRd]) or without a defect in this pathway (homologous recombination 
proficient [HRp]). In patients with TNBC, including gBRCAwt TNBC, HRd disease is 
frequent [Chopra, 2020] and has been associated with improved response to anticancer 
treatment [Sharma, 2018; Staaf, 2019; Telli, 2016; Zhao, 2017]. Efficacy of PARP 
inhibitors has been observed in patients with HRd breast cancer. Patients with early HRd 
breast cancer treated with neoadjuvant olaparib in combination with paclitaxel had a 
pathological complete response (pCR) rate of 55.1%, compared with 48.6% in patients 
treated with paclitaxel/carboplatin [Fasching, 2021]. In patients with HRd metastatic 
TNBC treated with veliparib plus cisplatin, longer progression-free survival (PFS) was 
observed compared to treatment with cisplatin alone [Sharma, 2020]. In a study of 
olaparib in patients with treatment-naïve TNBC, in which 18 of 32 patients obtained an 
objective response (56.3%), HRd TNBC was associated with response; 16 of 
18 responders (88.9%) had homologous recombination mutations and/or BRCA 
methylation compared with 4 of 14 nonresponders (28.6%) [Eikesdal, 2020]. In a study 
of neoadjuvant rucaparib in patients with untreated localized TNBC, 70% of whom had 
HRd cancers, HRDetect-high status was associated with ctDNA suppression [Chopra, 
2020]. 
Clinical activity of niraparib as neoadjuvant treatment in tBRCAmut HER2− breast 
cancer has been demonstrated [Han, 2019]. Additionally, niraparib has demonstrated 
antitumor efficacy in ovarian cancer beyond BRCAmut disease. Results from prior 
niraparib studies in ovarian cancer indicate a consistent continuum of clinical benefit 
across biomarker-defined subpopulations and that the benefit of niraparib treatment 
extends beyond patients with BRCAmut disease [Gonzalez-Martin, 2019; Mirza, 2016; 
Moore, 2019]. 
Based on these findings, Study 213831 will assess niraparib in participants with 
tBRCAmut HER2− breast cancer (including TNBC) or tBRCAwt TNBC who have 
molecular detectable disease, as determined by the presence of detectable ctDNA, until 
participants relapse with locally recurrent or metastatic disease. Given the substantial 
prevalence of HRd disease in TNBC and the expected particular sensitivity to PARP 
inhibition in these patients [Chopra, 2020], HRD status will be assessed in tumor tissue of 
tBRCAwt TNBC participants, and the primary efficacy analysis in tBRCAwt TNBC 
participants will be based on the HRd subpopulation, followed by testing of the overall 
cohort of tBRCAwt TNBC participants (see Section 9). As of the date of the decision to 
stop enrollment, this is no longer applicable. 

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2.2. 
Background 
2.2.1. 
Overview of Breast Cancer 
Breast cancer is the most common cancer in women globally and makes up 
approximately 15% to 24% of all new cancer cases in women [Bray, 2018; SEER, 2019]. 
The incidence of breast cancer in men is approximately 70- to 100-fold lower than the 
incidence in women [American Cancer Society, 2020]. According to GLOBOCAN, the 
estimated number of new cases worldwide in women and men combined was 2,088,849 
in 2018 [Bray, 2018]. In the European Union-28, the estimated number of new cases in 
women that year was 404,920 [Cardoso, 2019]. 
There are 4 main breast cancer subtypes characterized by the expression status of 
hormone receptor (HR) status (estrogen receptor [ER] and progesterone receptor [PgR]), 
and the lack or presence of overexpression of the human epidermal growth factor 2 
(HER2): 
• HR positive, HER2 negative (HR+/HER2−) 
• HR negative, HER2 negative (HR−/HER2−; “triple-negative”) 
• HR positive, HER2 positive (HR+/HER2+) 
• HR negative, HER2 positive (HR−/HER2+) 
Studies show that the prevalence of the 4 main breast cancer subtypes is dependent on 
factors such as sex, age, and ethnicity. Male breast cancer is almost always HR+, and 
HER2 expression is uncommon [Cardoso, 2018a]. 
African American women are more likely to have TNBC with the highest prevalence in 
premenopausal African American women. These ethnic or menopausal differences are 
not seen in either the estrogen receptor positive (ER+)/HER2+ breast cancer subgroup or 
the ER+/HER2− subgroup [Carey, 2006]. 
For approximately 5% to 10% of patients with breast cancer, the breast cancer is 
hereditary [Baretta, 2016]. Up to 25% of hereditary breast cancers have been linked to 
specific germline mutations, with mutations in BRCA1 and BRCA2 making up 
approximately 20% [Balmana, 2011; Shiovitz, 2015]. BRCAmut breast cancer is 
characterized by a more aggressive phenotype than sporadic breast cancer: BRCAmut 
breast cancer is often of higher histological grade and is frequently triple-negative 
[Antoniou, 2003; Armes, 1998; Southey, 2011]. Although the prevalence of tBRCAmut in 
TNBC varies depending on factors such as age, ethnicity, and region, based on data from 
The Cancer Genome Atlas, the prevalence of tBRCAmut in TNBC is up to 25% 
[Belli, 2019]. 
Survival and recurrence are dependent on tumor stage and tumor subtype, as follows: 
• Patients with metastatic TNBC have a 5-year survival rate of only 11.5%; 
30.4% for patients with metastatic HR+/HER2− breast cancer; 36.8% for 
patients with metastatic HR−/HER2+ breast cancer; and 43.5% for patients 
with metastatic HR+/HER2+ breast cancer [SEER, 2019]. 

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• Patients with early stage TNBC have a very high 5-year recurrence rate (30% 
to 50%) compared to patients with other breast cancer subtypes [Azim, 2020; 
Dent, 2007]. 
• Patients with TNBC demonstrate a peak in the risk of recurrence 1 to 3 years 
after last intervention, while the risk of recurrence in patients with other types 
of breast cancer, including HR+/HER2− breast cancer, seems to be steady for 
at least 15 years [Dent, 2007]. 
• Patients with TNBC have a higher risk of distant recurrence than those with 
other breast cancer subtypes [Dent, 2007]. 
• Peak of recurrence is 12 months postsurgery in patients with TNBC and 
36 months postsurgery in patients with HR+/HER2− breast cancer [Park, 
2012]. 
The population selected for this study are participants with TNBC (HER2−/HR−) and 
HR+/HER2− breast cancer. Treatment of HER2+ breast cancer has evolved such that 
targeted therapies are the backbone for treatment in both the neoadjuvant/adjuvant and 
metastatic setting, regardless of BRCA status. There are also limited data on the use of 
PARP inhibitors and their effectiveness in BRCAmut HER2+ patients, and available data 
suggest that the proportion of patients with BRCAmut amongst patients with HER2+ 
breast cancer is low (1.5% to 3.3%) [Hu, 2020; Lang, 2017; Zhong, 2016]. Thus, patients 
with HER2+ breast cancer have been excluded from this study. 
2.2.2. 
Treatment Options for Patients with Operable HER2− Breast Cancer 
Treatment of patients with Stage I, II, IIIA, IIIB, or operable IIIC breast cancer includes 
surgical removal of the primary tumor, with lymph node dissection as required [Cardoso, 
2019; NCCN, 2020]. Surgery may be preceded by neoadjuvant therapy, particularly in 
patients with locally advanced disease, to reduce tumor size and improve the probability 
of achieving pCR [Cardoso, 2018b]. For HER2− breast cancer, including TNBC, 
doxorubicin/cyclophosphamide followed by paclitaxel or docetaxel/cyclophosphamide is 
the preferred neoadjuvant/adjuvant therapy. Paclitaxel/carboplatin or 
docetaxel/carboplatin may be used in select patients with operable TNBC [NCCN, 2020]. 
Addition of platinum can be considered in patients with TNBC or BRCAmut breast 
cancer [Cardoso, 2019]. 
In order to prevent recurrence and/or metastasis, surgery is often followed by adjuvant 
chemotherapy or radiation. For HR+/HER2− breast cancer, adjuvant endocrine therapy 
such as tamoxifen or an aromatase inhibitor is recommended worldwide [NCCN, 2021]; 
addition of adjuvant chemotherapy is only recommended for patients with high-risk 
disease [Cardoso, 2019; NCCN, 2020]. For patients with TNBC and residual disease after 
neoadjuvant therapy with taxane-, alkylator-, and anthracycline-based chemotherapy, 
capecitabine is recommended [Cardoso, 2019; NCCN, 2020]. Use of capecitabine in this 
patient population was shown to decrease mortality, although the 5-year mortality rate 
remains >20% [Masuda, 2017]. 
Based on the recent OlympiA study (NCT2032823; [Tutt, 2021]), the NCCN guidelines 
now also recommend the use of 1 year of adjuvant olaparib for high risk, Stage II to III 

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gBRCAmut HER2− breast cancer after completion of adjuvant chemotherapy [NCCN, 
2021]. 
Most recently, pembrolizumab received United States (US) FDA approval for 
neoadjuvant and adjuvant treatment in patients with TNBC based on results of the 
Phase 3 KEYNOTE-522 study, a randomized, placebo-controlled study in patients with 
untreated Stage II or Stage III TNBC that was newly diagnosed or previously untreated. 
Participants received pembrolizumab or placebo in combination with chemotherapy as 
neoadjuvant treatment. A pCR rate of 63% (95% CI: 59.5, 66.4) was reported for the 
pembrolizumab group compared with 56% (95% CI: 50.6, 60.6) in the placebo group. An 
event-free survival (EFS) event was reported in 123 (16%) participants in the 
pembrolizumab group and 93 (24%) in the placebo group (hazard ratio = 0.63; 95% 
confidence interval [CI]: 0.48, 0.82; p=0.00031) [Keytruda USPI, 2021]. 
2.2.3. 
HRD Status in TNBC 
In studies of TNBC, regardless of BRCA status, the percentage of patients with HRd 
tumors as assessed by 
 
 has been observed to range from 59% to 71% [Chopra, 2020; Mayer, 2020; 
Sharma, 2018; Staaf, 2019; Telli, 2018]. 
HRd, based on the 
, was associated with improved PFS in 
metastatic/recurrent TNBC patients treated with veliparib plus cisplatin versus cisplatin 
alone (hazard ratio=0.53 [95% CI: 0.31, 0.89], p=0.016) [Sharma, 2020]. Patients with 
HRd tumors had improved disease-free survival (DFS) compared to patients with HRp 
tumors in TNBC patients treated with adjuvant chemotherapy (hazard ratio=0.72 [95% 
CI: 0.51, 1.00], p=0.049), including in tBRCAwt patients (hazard ratio=0.64 [95% CI: 
0.43, 0.94], p=0.023) [Sharma, 2018]. HRd was also associated with pCR following 
neoadjuvant platinum-based chemotherapy in TNBC [Telli, 2018]. However, in other 
studies, no association has been observed between 
 
status and response to platinum-based chemotherapy in patients with TNBC [Mayer, 
2020; Tutt, 2018]. 
The presence of HRd tumors as determined by HRDetect (HRDetect-high status) was 
associated with improvement in invasive disease-free survival (IDFS) (hazard ratio=0.42 
[95% CI: 0.2, 0.87]) and distant relapse-free interval (hazard ratio=0.31 [95% CI: 0.13, 
0.76]) in patients with TNBC treated with adjuvant chemotherapy [Staaf, 2019] and was 
associated with extended median overall survival (OS; p=0.04) and total duration of 
therapy (p=0.00029) in patients with advanced breast cancer treated with platinum-based 
chemotherapy [Zhao, 2017]. In a study of neoadjuvant rucaparib in untreated localized 
TNBC, HRDetect-high status was associated with ctDNA suppression [Chopra, 2020]. 
Additionally, HRd tumors were associated with response in patients with treatment-naïve 
TNBC who were treated with olaparib as neoadjuvant treatment. Of 32 participants with 
TNBC, 18 had objective response (56.3%), while 16 of 18 responders (88.9%) had 
homologous recombination mutations and/or BRCA methylation compared with 4 of 
14 nonresponders (28.6%) [Eikesdal, 2020]. 
The collective evidence supports HRd disease as a predictor of response to treatment in 
BRCAwt TNBC. 
CCI
CCI
CCI

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2.2.4. 
PARP Inhibitors 
DNA repair is accomplished by several mechanisms in healthy cells, including but not 
limited to homologous recombination repair (HRR), nonhomologous end-joining 
(NHEJ), and base excision repair (BER). Some cells are incapable of HRR due to the 
inactivation of genes such as BRCA1 or BRCA2. In the absence of HRR, these cells must 
rely on alternative DNA repair mechanisms. 
PARP1 and PARP2 are zinc-finger DNA-binding proteins that detect damaged DNA and 
promote DNA repair by several mechanisms. For example, after detecting DNA damage, 
PARP activates the BER pathway via an intracellular signaling mechanism. Conversely, 
PARP inhibitors block DNA repair by the BER pathway. In cells incapable of HRR 
(eg, BRCA1 and BRCA2 mutations), PARP inhibition leads to irreparable double-strand 
DNA breaks, collapsed replication forks, and an increased use of the NHEJ pathway. 
These disruptions result in genomic instability and, ultimately, cell death. The synergy 
between cellular defect and drug-induced effect is referred to as synthetic lethality 
[Kaelin, 2005]. Treatment with PARP inhibitors represents an opportunity to selectively 
kill cancer cells with deficiencies in HRR and other DNA repair mechanisms. 
The rationale for employing PARP inhibitors to selectively eliminate cancer cells is 
supported by data derived from nonclinical ex vivo and in vivo experiments that 
demonstrate that PARP inhibitors are more potent cytotoxicity inducers in tumors with 
homozygous inactivation of BRCA1 or BRCA2 than in BRCA-replete counterparts. 
The single-agent efficacy of 2 PARP inhibitors, olaparib and talazoparib, has been shown 
in 2 separate Phase 3 randomized controlled studies in patients with gBRCAmut HER2− 
breast cancer who had received ≤3 prior lines of chemotherapy. Olaparib received 
approval for patients with gBRCAmut HER2− metastatic breast cancer based on the 
results of the OlympiAD study, and talazoparib received approval for the treatment of 
patients with gBRCAmut HER2− locally advanced or metastatic breast cancer based on 
the results of the EMBRACA study. In both studies, PFS was significantly longer in the 
PARP inhibitor group than in the standard therapy group (OlympiAD study: 7.0 months 
in the olaparib group versus 4.2 months in the standard therapy group; hazard ratio for 
disease progression or death=0.58 [95% CI: 0.43, 0.80], p<0.001; EMBRACA study: 
8.6 months in the talazoparib group versus 5.6 months in the standard therapy group; 
hazard ratio for disease progression or death=0.54 [95% CI: 0.41, 0.71], p<0.0001) 
[Litton, 2018; Robson, 2017]. The OlympiA trial also recently demonstrated that 1 year 
of adjuvant olaparib improved IDFS in patients with high-risk Stage II to III gBRCAmut 
HER2− breast cancer [Tutt, 2021]. A significant increase in IDFS was reported in with 
olaparib compared with placebo with a difference of 8.8% (95% CI: 4.5, 13.0; hazard 
ratio for invasive disease or death = 0.58; 99.5% CI: 0.41, 0.82; p<0.001). The results of 
the OlympiA trial provide a practice-changing advancement for the adjuvant treatment of 
gBRCAmut patients with high-risk breast cancer; however, there are many patients for 
whom the OlympiA results do not apply, including, but not limited to the following: 
• 
Those who achieved pCR; 
• 
TNBC patients who received adjuvant therapy and who have T1 and/or node-
negative disease; 

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• 
HR+HER2− patients who received adjuvant therapy and have either node-
negative disease or positive nodal disease with involvement of 1 to 3 nodes; 
• 
Those patients who already completed definitive therapy in the past and fall 
outside the traditional adjuvant 12-week window defined by OlympiA; and 
• 
Those with a sBRCAmut. 
Additionally, as noted in Section 2.2.3, evidence of efficacy for PARP inhibitors in HRd 
TNBC has been observed [Chopra, 2020; Eikesdal, 2020; Sharma, 2020]. 
2.2.5. 
Niraparib 
Niraparib is an orally available, potent, highly selective PARP-1 and -2 inhibitor that is 
dosed once daily. 
Niraparib is approved in multiple countries worldwide including the US, European 
Union, Switzerland, Australia, Canada, and Saudi Arabia as maintenance therapy for 
women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who 
are in complete response (CR) or partial response (PR) to platinum-based chemotherapy. 
ZEJULA (niraparib) is approved for the maintenance treatment of adult patients 
with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who 
are in a CR or PR to first-line platinum-based chemotherapy. ZEJULA is also 
approved for the maintenance treatment of adult patients with deleterious or 
suspected deleterious germline BRCA-mutated recurrent epithelial ovarian, 
fallopian tube, or primary peritoneal cancer who are in a complete or partial 
response to platinum-based chemotherapy. 
 
 
 
2.2.5.1. 
Efficacy of Niraparib in Maintenance Therapy Following Platinum-based 
Chemotherapy 
The efficacy results in the PRIMA study demonstrated a clinical benefit continuum 
defined by clinical and molecular biomarkers, with the greatest clinical benefit observed 
among participants with BRCAmut tumors. Furthermore, participants with HRd tumors, 
regardless of BRCA mutation status, had a similar clinical benefit. Median PFS was 
significantly longer in participants who received niraparib compared to those who 
received placebo, with correspondingly favorable hazard ratios. 
• The study met the primary endpoint in participants with HRd tumors (hazard 
ratio=0.43 [95% CI: 0.310, 0.588], p<0.0001). Median PFS based on 
Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) 
was 21.9 months in the niraparib arm and 10.4 months in the placebo arm. 
• The study met the primary endpoint for the overall population (hazard 
ratio=0.62 [95% CI: 0.502, 0.755], p<0.0001). Median PFS for participants 
randomized to niraparib was 13.8 months versus 8.2 months on placebo. 
• Participants benefitted from niraparib therapy regardless of tumor HRD test 
status. Median PFS for participants with HRp tumors randomized to the 
CCI

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niraparib arm was 8.1 months versus 5.4 months in the placebo arm (hazard 
ratio=0.68 [95% CI: 0.492, 0.944], p=0.0203). 
• In BRCAmut participants, a subset of participants with HRd tumors, treatment 
with niraparib prolonged median PFS by 11.2 months compared to placebo. 
Median PFS was 22.1 months in the niraparib arm versus 10.9 months in the 
placebo arm (hazard ratio=0.40 [95% CI: 0.265, 0.618], p<0.0001). 
• In the HRd/BRCAwt subgroup, treatment with niraparib prolonged median 
PFS by 11.4 months compared to placebo. Median PFS was 19.6 months in 
the niraparib arm and 8.2 months in the placebo arm (hazard 
ratio=0.50 [95% CI: 0.305, 0.831], p=0.0064). 
• Although immature, OS in the overall population numerically favored 
niraparib (hazard ratio=0.70 [95% CI: 0.442, 1.106], p=0.1238). 
The Phase 3 ENGOT-OV16/NOVA study, the first large, randomized study of niraparib, 
was a double-blind, randomized, placebo-controlled evaluation of participants with 
platinum-sensitive (defined as achieving a CR or PR and disease progression >6 months 
after completion of most recent platinum-based therapy) recurrent ovarian cancer. 
Participants must have received at least 2 platinum-based regimens and had either 
gBRCAmut disease or a tumor with high-grade serous or high-grade predominantly 
serous histology, but without such gBRCAmut (non-gBRCAmut). The study was 
conducted to assess the potential benefit of niraparib treatment in participants with 
demonstrated platinum responsiveness and aimed to define a molecular biomarker that 
could bifurcate the participant population into those who benefit from niraparib and those 
that do not. HRD testing was conducted in the non-gBRCAmut cohort to define tumors as 
either HRd or HRp. 
Data from NOVA demonstrated the magnitude of benefit from niraparib maintenance 
therapy, as measured by the primary endpoint of PFS, when compared with placebo in a 
platinum-responsive population. Treatment with niraparib significantly prolonged PFS, 
with the greatest benefit observed among participants with gBRCAmut tumors (hazard 
ratio=0.27), followed by participants with HRd non-gBRCAmut tumors (hazard 
ratio=0.38), and participants with HRp tumors (hazard ratio=0.58). Molecular biomarkers 
(BRCA mutation testing and homologous recombination status) were not useful for 
identifying a population that had no or little chance of deriving clinically meaningful 
benefit from niraparib treatment. 
In NOVA, the niraparib adverse event (AE) profile was manageable with dose 
adjustments. A dose modification approach that adjusted each participant to her 
appropriate dose in the first 3 cycles based on individual tolerance substantially reduced 
the incidence and severity of treatment-emergent adverse events (TEAEs) in participants, 
enabling them to continue on a sustained maintenance treatment. Owing to the 
implementation of this approach, at Cycle 12, of the 163 participants remaining on 
niraparib treatment in the NOVA study, only 37 (23%) remained on a daily dose of 
300 mg, with the remaining participants at either 200 mg (40%) or 100 mg (37%). 
Because of this, while Grade 3/4 thrombocytopenia was noted in approximately 36% of 
niraparib-treated participants during Month 1 with dose modifications, the rate of 
Grade 3/4 thrombocytopenia was less than 1% after Month 3. 

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In addition to PRIMA and NOVA, niraparib was studied in participants with advanced, 
relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal 
cancer with recurrent disease who had received at least 3 prior lines of therapy in 
QUADRA, a multicenter, open-label, single-arm Phase 2 study. Primary efficacy was 
determined by evaluation of Investigator-assessed confirmed objective response rate 
(ORR) as defined by RECIST v1.1 in patient populations with molecular biomarkers 
(deleterious BRCA mutations and other homologous recombination deficiencies) and the 
clinical biomarker of platinum sensitivity. 
The QUADRA study results demonstrated activity of niraparib in late-line participants 
with ovarian cancer [Moore, 2019]. A confirmed ORR of 24% (95% CI: 16%, 34%) was 
observed in participants with HRd, platinum-sensitive tumors, with median duration of 
response (DoR) of 8.3 months (95% CI: 6.5, non-evaluable). QUADRA showed a 
graduated continuum of clinical activity across a population of participant subgroups 
defined by clinical and molecular biomarkers, with the greatest activity observed in 
participants with BRCAmut platinum-sensitive tumors (ORR 39%), followed by 
participants with BRCAmut platinum-resistant tumors (ORR 33%) and participants with 
HRd/non-BRCAmut platinum-sensitive tumors (ORR 20%). ORR in participants with 
BRCAmut tumors independent of platinum sensitivity was 29%.  
The results from the PRIMA and NOVA studies, supported by the nonclinical data and 
the activity seen in later lines of treatment, indicate a consistent, durable benefit of 
niraparib treatment in advanced ovarian cancer patient population regardless of 
biomarkers. 
2.2.5.2. 
Efficacy of Niraparib in Breast Cancer 
Studies evaluating niraparib in participants with breast cancer include Study 3000-01-005 
(NEOADJUVANT), Study PR-30-5010-C (BRAVO), and Study 3000-PN162-01-001 
(TOPACIO/KEYNOTE-162). 
Study 3000-01-005 (NEOADJUVANT) Efficacy Data 
Study 3000-01-005 (NEOADJUVANT) was an open-label, single-arm pilot study 
evaluating the safety and efficacy of niraparib as neoadjuvant therapy in participants with 
HER2−, tBRCAmut (germline or somatic) resectable breast cancer (primary tumor 
≥1 cm) who had not received prior treatment for the current malignancy. Participants 
received niraparib 200 mg orally once daily for 28 days for at least 2 cycles. At the end of 
2 cycles, at their treating physician’s discretion, participants proceeded directly to 
surgery, received additional cycles of niraparib (maximum of 6 cycles), or received 
neoadjuvant chemotherapy. 
A total of 21 participants were enrolled and received niraparib [Han, 2019]. As of 
November 2019, as assessed by magnetic resonance imaging (MRI; primary endpoint), 
2 of 21 participants had a best overall response (BOR) of CR, 17 participants had a BOR 
of PR, and 2 participants had a BOR of stable disease (SD). No participant experienced 
progressive disease (PD) during the study period. The tumor response rate by MRI, 
defined as the proportion of participants with a ≥30% reduction in tumor volume from 
baseline, was 90%. The median decrease in tumor volume by MRI was 86%. These data 

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show promising antitumor activity in the neoadjuvant treatment of participants with 
localized HER2−, tBRCAmut breast cancer. 
Study PR-30-5010-C (BRAVO) Efficacy Data 
Study PR-30-5010-C (BRAVO) is an open-label, randomized Phase 3 study in 
participants with previously treated, HER2−, gBRCAmut advanced breast cancer that 
compared niraparib monotherapy to physician’s choice chemotherapy (ie, eribulin, 
vinorelbine, gemcitabine, or capecitabine). Participants may have received up to 2 prior 
courses of chemotherapy for advanced breast cancer (not including [neo]adjuvant 
therapy) or had relapsed within 12 months of adjuvant chemotherapy. Participants with 
HR+ breast cancer must have received at least 1 line of endocrine therapy and either 
progressed while receiving this therapy in the metastatic setting or relapsed during or 
within 1 year of completion of the adjuvant treatment. 
A total of 215 participants were randomized 2:1 between niraparib and physician’s choice 
chemotherapy. At the interim analysis, with 105 events of PD or death, recruitment was 
halted on the basis of futility. A high and imbalanced informative censoring rate was 
observed in the physician’s choice arm in the central review of data (28% physician’s 
choice arm versus 7% niraparib arm). When compared to the niraparib arm, the 
physician’s choice arm had an unusually high rate of discontinuations that occurred prior 
to the first scan (19% physician’s choice arm versus 11% niraparib arm), more 
participants who were lost to follow-up or never started study treatment (12% physician’s 
choice arm versus 5% niraparib arm), and a greater proportion of ineligible participants 
(19% physician’s choice arm versus 9% niraparib arm). It was concluded that further 
recruitment would not be productive in generating data that would be interpretable and 
therefore suitable for registration in this indication. 
After enrollment closure, the final analysis was carried out for the primary endpoint, with 
135 participants in the niraparib arm and 71 participants in the physician’s choice arm. 
The median follow-up duration was 19.9 months. The median PFS by central review was 
4.1 months in the niraparib arm versus 3.1 months in the physician’s choice arm 
(stratified log-rank p-value=0.58). The median time to OS was comparable between the 
niraparib arm and the physician’s choice arm (14.5 months versus 15.8 months). The 
ORR (CR+PR) in the centrally confirmed intent-to-treat (ITT) population with 
measurable disease based on central review for confirmed and unconfirmed responses 
was 21.4% and 31.0%, respectively, in the niraparib arm compared with 12.5% and 
23.4%, respectively, in the physician’s choice arm. The difference between the 
2 treatment arms was not statistically significant for either confirmed or unconfirmed 
response (p=0.3123 and 0.4296, respectively). 
Although there was evidence of niraparib’s activity in participants with advanced breast 
cancer and germline mutations in BRCA1 and BRCA2, the high degree of informative 
censoring in the physician’s choice chemotherapy arm prevented the accurate assessment 
of the study hypothesis that niraparib would be superior to the physician’s choice of 
therapy in this patient population. 

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Study 3000-PN162-01-001 (TOPACIO/KEYNOTE-162) Efficacy Data 
Study 3000-PN162-01-001 (TOPACIO/KEYNOTE-162) is an ongoing, multicenter, 
open-label, single-arm Phase 1/2 study to evaluate the safety and efficacy of niraparib 
plus pembrolizumab in enrolled women with advanced or metastatic TNBC or recurrent 
ovarian carcinoma, irrespective of BRCA mutation status. Participants received 200 mg of 
niraparib orally once daily and 200 mg of pembrolizumab intravenous (IV) on Day 1 of 
each 21-day cycle. 
A total of 55 participants were enrolled in the TNBC cohort in Phase 2 of the study 
[Vinayak, 2019]. 
In the full analysis population of this cohort (n=55), 5 participants had a BOR of 
confirmed CR, 5 had a BOR of confirmed PR, 13 had a BOR of SD, and 24 had a BOR 
of PD; 8 participants did not have an evaluable postbaseline scan. In the efficacy-
evaluable population (n=47), the confirmed ORR was 21% (90% CI: 12%, 33%), and the 
disease control rate (DCR) was 49% (90% CI: 36%, 62%). 
Although the prespecified statistical criterion for the primary objective was not met (null 
hypothesis of ORR ≤15%), combination treatment with niraparib and an 
anti-programmed cell death protein 1 (PD-1) antibody provided promising, durable 
clinical benefit. The median DoR in participants with a confirmed CR or PR had not been 
reached at the time of data cutoff. The DoR ranged from 4.6 to 15.9 months. Of the 
10 participants with confirmed CR or PR, 3 participants had a response duration longer 
than 1 year, 4 participants had a response duration of 9 to 12 months, and 2 participants 
had a response duration of 6 to 9 months. Four of the 13 participants with SD continued 
without disease progression for more than 6 months. The OS data were not mature at the 
time of the analysis. 
In the biomarker-defined evaluable population, 15 of the 47 participants (32%) were 
tBRCAmut, 27 participants (57%) were tBRCAwt, and the remaining 5 participants had 
unknown tBRCA status. 
The response rate was numerically higher in participants with tBRCAmut (n=15, 32%) 
than in those without confirmed tBRCAmut status (n=32, 68%). Among the 
15 participants with tBRCAmut status, the ORR was 47% (90% CI: 24%, 70%), and the 
DCR was 80% (90% CI: 56%, 94%). BOR was CR in 2 participants, PR in 5 participants, 
and SD in 5 participants. Among the 27 participants with tBRCAwt status, the ORR was 
11% (90% CI: 3%, 26%), and the DCR was 33% (90% CI: 19%, 51%). BOR was CR in 
3 participants and SD in 6 participants. 
Although clinical activity was more pronounced in participants with tBRCAmut disease, 
the combination treatment demonstrated clinical activity in participants irrespective of 
BRCA mutation status. The ORR of 21% in the efficacy-evaluable population was 
numerically higher than the single-digit ORRs reported for anti-PD-(L)1 agents in similar 
patient populations [Adams, 2019; Dirix, 2018; Emens, 2019]. The improvement in 
response rate did not appear to be driven entirely by stronger activity in the population 
with tBRCAmut because 3 participants with tBRCAwt status had CR, and 2 of these 
3 participants had no mutation in other HRR pathway genes. 

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Based on these data, participants on adjuvant pembrolizumab who are found to have 
detectable ctDNA and are otherwise eligible for the study will be allowed to start 
niraparib concurrently with the remaining cycles of adjuvant pembrolizumab. 
2.2.5.3. 
Niraparib and Endocrine Therapy 
In this study, participants in Cohort 1 with HR+/HER2− breast cancer may receive 
concomitant endocrine therapy. There is no expectation of a drug-drug interaction for 
concurrent niraparib and endocrine therapy from either pharmacokinetic (PK) or 
pharmacodynamic effects. Aromatase is an enzyme that belongs to the cytochrome P450 
(CYP) family. Aromatase inhibitors affect estrogen production from androgens by 
inhibiting the aromatase enzyme activity, which is a part of the estrogen pathway. 
Because niraparib neither inhibits nor induces any major CYP enzyme, and is not 
metabolized via this pathway, it is therefore unlikely to diminish effectiveness of 
aromatase inhibitors. 
A PK interaction is also not expected. Endocrine therapies, such as aromatase inhibitors 
(eg, anastrozole, exemestane, and letrozole) and tamoxifen, are mostly metabolized by 
CYP enzymes. Because niraparib neither inhibits nor induces any major CYP enzymes, it 
is unlikely to affect the exposure of endocrine therapies. 
2.2.5.4. 
Niraparib and Pembrolizumab 
In this study, participants with TNBC may receive concurrent adjuvant pembrolizumab 
therapy, as clinically indicated. The combination of niraparib and pembrolizumab has 
been broadly analyzed in a variety of cancers (see the Niraparib Investigator’s Brochure 
[IB] [GSK Document Number RPS-CLIN-014110]), with examination in breast cancer as 
outlined in the TOPACIO study (summarized above). No safety concerns have been 
identified [Konstantinopoulos, 2019; Vinayak; 2019]. 
2.2.6. 
Circulating Tumor DNA 
Despite improvement in patient survival after surgery with adjuvant and local systemic 
therapy, the risk of recurrence in many patients with breast cancer remains high ([Steeg, 
2016], reviewed in [Coakley, 2019]). The goal of adjuvant therapy is to treat patients who 
may have micrometastatic disease; however, it is not possible to reliably identify these 
patients. Thus, many patients receive treatment, often chemotherapy, that they may not 
need. In order to improve identification of the patient population at high risk of 
recurrence, current efforts are directed at identification of molecular detectable disease. 
Circulating free DNA was detected in the serum of patients with cancer as early as the 
1970s [Leon, 1977]. In the 1990s, Sorenson et al confirmed that the circulating free DNA 
observed in serum from patients with pancreatic adenocarcinoma originated from the 
tumor (ctDNA) [Sorenson, 1994]. Recent technological advances have demonstrated that 
the tumor mutational signature is reflected in the ctDNA, and new technologies have 
been developed to detect the ctDNA using minimally invasive procedures. Analysis of 
ctDNA in early stage cancer requires the ability to detect very low levels of ctDNA in 
plasma. Several studies have shown that molecular detectable disease can be identified 
using liquid biopsies in several cancer types, including breast cancer, by tracking tumor 

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mutations in ctDNA [Coombes, 2019; Garcia-Murillas, 2019; Garcia-Murillas, 2015; 
Olsson, 2015]. These studies demonstrated the clinical validity of ctDNA testing. 
Clinical Utility of ctDNA 
The clinical utility of ctDNA testing is currently being tested in several studies across 
different tumor types, including the following: 
• NRG-GI005 COBRA (NCT04068103) for FOLFOX in colon cancer 
sponsored by NRG Oncology 
• c-TRAK-TN (NCT03145961) for pembrolizumab in TNBC sponsored by the 
Institute of Cancer Research 
• NCT03311958 for nivolumab in diffuse large B-cell lymphoma sponsored by 
the Fox Chase Cancer Center 
• NCT04267237 for RO7198457 + atezolizumab versus atezolizumab in 
non-small cell lung cancer sponsored by Hoffman-La Roche 
• Imvigor010 study (NCT02450331) for atezolizumab as adjuvant monotherapy 
treatment in muscle invasive urothelial cancer sponsored by Hoffman-La 
Roche 
The presence of ctDNA has been demonstrated to be predictive of clinical or radiological 
relapse. In a study of 49 participants with primary breast cancer (enrolled after definitive 
therapy), ctDNA was detected using the Signatera test in 16 participants, all of whom 
experienced clinical relapse [Coombes, 2019]. The median lead time from ctDNA 
detection to clinical relapse was 266 days (8.9 months), with 301 days for HR+/HER2− 
breast cancer and 258 days for TNBC. No ctDNA was detected at any time point in any 
of the 31 patients who did not experience clinical relapse. 
In a study with 55 participants with early stage breast cancer treated with neoadjuvant 
chemotherapy before surgery, ctDNA was detected in 13 participants, 12 of whom 
experienced clinical relapse [Garcia-Murillas, 2015]. The median lead time from ctDNA 
detection to clinical relapse in this study was 7.9 months. No ctDNA was detected in 
24 of 25 participants who did not experience clinical relapse. The clinical relevance of 
ctDNA detection was also demonstrated: Clinical outcomes (including recurrence rate, 
DFS, and OS) were worse in participants who were ctDNA-positive after surgery than in 
participants who were ctDNA-negative. DFS was shorter in participants with ctDNA 
(6.5 months) than in participants without ctDNA (not reached), with a hazard ratio of 
25.1. 
In addition, a prospective study of 94 patients with advanced solid tumors (including 
TNBC) treated with pembrolizumab showed that a vast majority of patients with 
detectable ctDNA at baseline who ultimately achieved clearance of detectable ctDNA 
had done so after 3 to 12 weeks of immunotherapy treatment [Bratman, 2020]. Those 
patients with persistent detectable ctDNA after 12 weeks of pembrolizumab were highly 
unlikely to achieve ctDNA clearance despite additional pembrolizumab treatment. 
This new technology therefore provides an opportunity for early detection of tumor 
molecular recurrence prior to clinical recurrence; introducing therapy at this stage could 
potentially intercept and reverse disease progression while the disease burden is low, and 

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the patient has not yet developed radiologically evident metastatic disease. Currently, 
there is no standard of care for patients who have detectable ctDNA following their last 
intervention (surgery or adjuvant therapy) but have not yet developed radiologic or 
clinically evident metastatic disease. GSK therefore believes that the inclusion of 
participants with tBRCAmut HER2− breast cancer (including TNBC) or tBRCAwt TNBC 
who have molecular detectable disease, as determined by the presence of detectable 
ctDNA in the present study is appropriate and will allow the assessment of niraparib in 
representative populations with unmet medical need. 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of niraparib may be found in the current version of the 
Niraparib IB [GSK Document Number RPS-CLIN-014110]. 
2.3.1. 
Risk Assessment 
A summary of risks and mitigations for niraparib is provided in Table 9. 

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Table 9 
Summary of Risks and Mitigations for the Product 
Risks of Clinical Significance 
(Identified or Potential) 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Thrombocytopenia 
Anemia 
Leukopenia 
Neutropenia 
Pancytopenia 
Based on nonclinical and clinical 
observations as well as identified 
risk with PARP inhibitor, niraparib. 
Protocol has inclusion criteria that 
participants must have adequate organ and 
bone marrow function 
Protocol provides guidelines for monitoring 
hematologic laboratory parameters and 
adverse reactions. 
Protocol provides Investigator guidance for 
the clinical management of these events. 
Protocol provides guidance for dose 
modification and discontinuation of study 
treatment. 
Hypertension 
Cases reported with niraparib. 
Protocol includes exclusion criteria for 
participants who have systolic BP >140 
mmHg or diastolic BP >90 mmHg that has 
not been adequately treated or controlled. 
Protocol provides monitoring and stopping 
criteria for discontinuation of study treatment. 
Second primary malignancy 
Myelodysplastic 
syndrome/Acute myeloid 
leukemia 
Based on nonclinical and clinical 
observations as well as identified 
with PARP inhibitor, niraparib. 
Protocol provides monitoring and stopping 
criteria for discontinuation of study treatment. 
Embryofetal toxicity 
Based on nonclinical and clinical 
observations as well as identified 
with PARP inhibitor, niraparib. 
Protocol excludes participants who are 
pregnant or breastfeeding and provides 
detailed guidance on contraception. 
Posterior Reversible 
Encephalopathy Syndrome 
(PRES)a 
Cases reported with niraparib. 
Protocol provides monitoring, treatment, 
including control of hypertension, and 
stopping criteria for discontinuation of study 
treatment. 
Abbreviation: BP=blood pressure; PARP=poly(adenosine diphosphate-ribose) polymerase. 
a PRES, a treatable acute neurologic illness characterized by rapid onset headache, visual disturbance, altered 
consciousness, seizures, hypertension, imaging findings of white matter, parietal and posterior occipital, and 
vasogenic edema. 
2.3.2. 
Benefit Assessment 
Niraparib has demonstrated efficacy in participants with BRCAmut ovarian cancer in the 
NOVA and PRIMA studies, as well as clinical activity in advanced ovarian cancer. The 
NOVA study (Study PR-30-5011-C) was a Phase 3, double-blind, randomized, placebo-
controlled study in participants with platinum-sensitive (defined as achieving a CR or PR 
and disease progression >6 months after completion of most recent platinum-based 
therapy) recurrent ovarian cancer. Participants must have received at least 2 platinum-
based regimens. Participants had either a gBRCAmut or a non-gBRCAmut tumor with 
high-grade serous or high-grade predominantly serous histology. Treatment with 
niraparib significantly prolonged median PFS compared to treatment with placebo, with 
the greatest benefit observed among participants with gBRCAmut tumors (hazard 
ratio=0.27 [95% CI: 0.173, 0.410], p<0.0001). The treatment effect of niraparib observed 
in participants with gBRCAmut tumors was comparable to that observed in participants 

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with sBRCAmut tumors (subgroup of participants with HRd/non-gBRCAmut tumors) 
(hazard ratio=0.27 [95% CI: 0.081, 0.903], p=0.0248). 
Niraparib also showed treatment activity in QUADRA, a Phase 2, multicenter, 
open-label, single-arm study in participants with advanced, relapsed, high-grade serous 
epithelial ovarian, fallopian tube, or primary peritoneal cancer with recurrent disease who 
had received ≥3 prior lines of therapy (Section 2.2.5.1). In this difficult-to-treat patient 
population, participants with BRCAmut tumors demonstrated an ORR of 29%. 
In PRIMA, a Phase 3, double-blind, randomized, placebo-controlled study of niraparib as 
maintenance treatment in participants with advanced ovarian cancer who were in CR or 
PR to first-line platinum-based chemotherapy, niraparib showed benefit in participants 
with HRd tumors (hazard ratio=0.43 [95% CI: 0.310, 0.588], p<0.0001), in the overall 
population (hazard ratio=0.62 [95% CI: 0.502, 0.755], p<0.0001), and in BRCAmut 
participants (a subset of participants with HRd tumors; hazard ratio=0.40 [95% CI: 0.265, 
0.618], p<0.0001). 
Preliminary evidence of clinical activity of niraparib in tBRCAmut HER2− breast cancer 
comes from Study 3000-01-005, an open-label, single-arm pilot study evaluating the 
safety and efficacy of niraparib as neoadjuvant therapy in participants with HER2− 
tBRCAmut resectable breast cancer (primary tumor ≥1 cm) who had not received prior 
treatment for the current malignancy. A total of 21 participants were enrolled and 
received niraparib [Han, 2019]. As of November 2019, as assessed by MRI (primary 
endpoint), 2 of 21 participants had a BOR of CR, 17 participants had a BOR of PR, and 
2 participants had a BOR of SD. No participant experienced PD during the study period. 
The tumor response rate, defined as the proportion of participants with a ≥30% reduction 
in tumor volume from baseline, by MRI was 90%. The median decrease in tumor volume 
by MRI was 86%. 
Additional information regarding the safety and efficacy data that supported the approval 
of niraparib for these indications can be found in the current version of the IB and the 
locally approved product label. The efficacy of PARP inhibitors has also been 
demonstrated in participants in high risk breast cancers such as HER2− and gBRCAmut 
breast cancer compared with placebo in the OlympiA trial (see Section 2.2.4) with no 
new safety findings resulting from olaparib treatment [Tutt, 2021]. 
Additionally, the potential overlapping toxicities between niraparib and anastrozole, 
letrozole, exemestane, and tamoxifen, with or without ovarian function suppressing 
agents, include hypertension (anastrozole), nausea, musculoskeletal pain/arthralgia, 
insomnia, headache, and dyspnea [Arimidex SmPC, 2017; Arimidex USPI, 2019; 
Aromasin SmPC, 2018; Aromasin USPI, 2019; Femara SmPC, 2019; Femara USPI, 
2020; Soltamox SmPC, 2018; Soltamox USPI, 2019; Zejula SmPC, 2020; Zejula USPI, 
2020]. There is a low risk of drug-drug interaction for the combination of niraparib and 
the proposed background endocrine therapies. No interaction is expected at the level of 
endocrine therapy exposure, as niraparib is not an inhibitor or inducer of the CYP 
pathways, which drive the elimination of many endocrine agents.  
Based on data from studies with niraparib in combination with pembrolizumab 
[Niraparib, IB], no interaction is expected with exposure for participants taking 
concurrent adjuvant pembrolizumab. Additionally, initiation of ctDNA prescreening 

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during adjuvant pembrolizumab and subsequent enrollment for those patients with 
detectable ctDNA may also be of benefit to patients. As referenced in Section 2.2.6, 
recent data suggests that if ctDNA has not cleared in patients after 12 weeks of 
pembrolizumab therapy, then ctDNA is very unlikely to clear at all despite additional 
treatment with pembrolizumab [Bratman, 2020]. Delaying enrollment onto the trial until 
after adjuvant pembrolizumab is complete may in turn delay an opportunity for the 
patient to intervene on expected progressive disease. Therefore, allowing TNBC patients 
to pursue concurrent pembrolizumab (as clinically indicated) with enrollment onto the 
trial allows participants earlier access to a potentially effective intervention in a situation 
where the data suggest potential poor outcome, i.e., with lack of ctDNA clearance after 
12 weeks, despite continued immunotherapy. 
2.3.3. 
Overall Benefit/Risk Conclusion 
As of communication sent on 25 April 2023, the Sponsor permanently stopped 
enrollment the ZEST study due to assessment of feasibility to complete the study (i.e., the 
study was unable to randomize participants in the planned timeframe based on 
randomization projections as the study had lower-than-expected rates of ctDNA-
positivity and a much higher-than-expected proportion of patients with a ctDNA+ test 
showing radiographically detectable disease during screening assessments) and not due to 
any safety concerns. There are no changes in the assessment of benefit-risk resulting from 
this decision. 
Niraparib, as a once daily oral treatment, prolonged the effect of platinum-based 
chemotherapy, substantially improved PFS, and significantly reduced the risk of 
recurrence or death in a broad ovarian cancer population of patients, thereby enabling a 
delay in disease recurrence and the need for additional platinum-based or other 
chemotherapy with its associated cumulative toxicities, as demonstrated in multiple 
pivotal clinical studies. In addition to the demonstrated efficacy of niraparib in BRCAmut 
ovarian cancer (Section 2.3.2), results from clinical studies indicate a consistent 
continuum of niraparib treatment across biomarker-defined subpopulations and that the 
benefit of niraparib treatment extends beyond patients with BRCAmut disease 
(Section 2.2.5.1). 
The AE profile of niraparib consisted of AEs that are commonly managed in the patient 
population of advanced cancer. The key safety concerns included hematological 
toxicities, hypertension, and myelodysplastic syndrome (MDS)/acute myeloid leukemia 
(AML) and a potential risk of second primary malignancies. Common AEs including 
Grade 3 and higher AEs were generally manageable with dose modification and clinical 
treatment, most of which resolved without discontinuation of study treatment. 
The benefit/risk profile of niraparib is anticipated to be favorable in the populations in 
this study with utilization of the risk mitigation strategies as outlined in the study 
protocol. Allowance of concurrent adjuvant pembrolizumab with niraparib as described 
in the protocol does not alter the overall benefit/risk assessment. 

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Based on the observed efficacy of niraparib in ovarian tumors, including BRCAmut and 
BRCAwt disease, the preliminary clinical activity of niraparib as neoadjuvant therapy in 
tBRCAmut HER2− breast cancer, and the observed efficacy of other PARP inhibitors in 
metastatic gBRCAmut breast tumors independent of HR status, GSK believes that 
niraparib will demonstrate efficacy in patients with HER2− breast cancer.  
 

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3. 
OBJECTIVES AND ENDPOINTS AND ESTIMANDS 
As of the date of the decision to stop enrollment, safety and tolerability are being 
assessed as the primary endpoint and will use the Safety (SAF) Population. Estimands are 
not applicable for the primary endpoint. 
Table 10 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Evaluation of safety and tolerability of niraparib 
The incidence of TEAEs, SAEs, and AESIs; TEAEs 
leading to death, TEAEs leading to dose 
modifications, and TEAEs leading to discontinuation 
will be assessed. Clinically relevant laboratory 
parameters, vital signs, ECOG performance status, 
and use of concomitant medications will be collected 
and evaluated as defined in the Statistical Analysis 
Plan (SAP). 
Exploratory 
Evaluation of the efficacy of niraparib relative to 
placebo as measured by DFS 
DFS is defined as the time until disease recurrence, 
measured from the time of randomization to the 
earliest date of assessment of disease recurrence 
or death by any cause, as assessed by Investigator 
using RECIST v1.1. 
Evaluation of distant recurrence-free survival 
(DRFS) 
DRFS is defined as the time from randomization to 
the first detection of distant metastasis or death by 
any cause as assessed by Investigator using 
RECIST v1.1. 
Time to first subsequent therapy (TFST) 
TFST is defined as the time from randomization to 
the date of the first anticancer therapy used 
subsequent to the date of the endpoint DFS or 
death by any cause. 
Time to first subsequent chemotherapy 
Time to first subsequent chemotherapy is defined as 
the time from randomization to the date of the first 
systemic chemotherapy used subsequent to the 
date of the endpoint DFS or death by any cause. 

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Objectives 
Endpoints 
Time to symptomatic progression 
Time to symptomatic progression is defined as the 
time from randomization to the date of symptomatic 
progression, which either coincides with or is 
subsequent to the date of the endpoint DFS. 
Symptomatic progression includes any of the 
following:  
• 
Development of a skeletal-related event: 
pathologic fracture, spinal cord compression, or 
need for surgical intervention or radiation therapy 
(including palliative radiotherapy) to the bone 
• 
Initiation of a new systemic anticancer therapy 
for cancer pain progression or worsening of 
disease-related symptoms  
• 
Development of clinically significant symptoms 
due to loco-regional tumor progression requiring 
surgical intervention or radiation therapy. 
Evaluation of the efficacy of niraparib relative to 
placebo as measured by invasive disease-free 
survival (IDFS) 
IDFS will be assessed as per definition included in 
STEEP 2.0 ([Tolaney, 2021] see Section 8.3.7). 
Evaluation of the efficacy of niraparib relative to 
placebo as measured by invasive breast cancer-free 
survival (IBCFS) 
IBCFS will be assessed as per definition included in 
STEEP 2.0 ([Tolaney, 2021]; see Section 8.3.8) 
Abbreviations: AE=adverse event; ctDNA=circulating tumor DNA; DFS=disease-free survival; DRFS=distant 
recurrence-free survival; ECOG=Eastern Cooperative Oncology Group; IBCFS=invasive breast cancer-free survival; 
IDFS=invasive disease-free survival; OS=overall survival; PD=progressive disease; PK=pharmacokinetic; 
RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event; SAP=Statistical Analysis Plan; 
SOA=Schedule(s) of Activities; TEAE=treatment-emergent adverse event; TFST=time to first subsequent therapy; 
 
 
CCI
CCI

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
Study 213831 was designed as a multicenter, multicohort, Phase 3, double-blinded, 
placebo-controlled study comparing the safety and efficacy of niraparib to placebo in 
participants who are 18 years and older with either HR+/HER2− tBRCAmut breast cancer 
or TNBC with any BRCA mutation status who have detectable ctDNA following 
completion of definitive therapy, including all of the following, if indicated: neoadjuvant 
treatment, surgery, adjuvant radiotherapy, and adjuvant chemotherapy; end of definitive 
therapy is defined as the date of completion of curative-intent surgery, adjuvant 
chemotherapy, or adjuvant radiotherapy, whichever was last. The study will include 
2 separate cohorts: a tBRCAmut HER2− breast cancer (including TNBC) cohort 
(Cohort 1) and a tBRCAwt TNBC cohort (Cohort 2). 
As a result of assessment of feasibility of study completion (i.e., the study was unable to 
randomize patients in the planned timeframe based on randomization projections as the 
study had lower-than-expected rates of ctDNA-positivity and a much higher-than-
expected proportion of patients with a ctDNA+ test showing radiographically detectable 
disease during screening assessments), a decision was made by the Sponsor to 
permanently stop enrollment into the ZEST study, which was communicated on 
25 April 2023 (i.e., the date of the decision to stop enrollment). As of the date of this 
communication no further randomizations were approved by the Sponsor. 
Participants on study as of the date of the decision to discontinue enrollment should be 
managed under Protocol Amendment 03 as outlined in Table 11. 
As of Protocol Amendment 04, participants should be managed as outlined in Table 
12. Once the last participant consents to Protocol Amendment 04 (or withdraws) or 
meets any protocol-defined stopping criteria (Section 7), the study will transition to 
PACT (see Section 6.7.1 for details).  
Data collection for the planned final analysis will end once the final data cut-off 
(DCO) date is reached. Once the final DCO date has been reached, the clinical study 
database will be closed to new data. Before the DCO is reached all participants will 
continue assessments as per SOA Table 4, Table 5, and Table 6. 
The end of study is defined in Section 6.7. 

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Table 11 
Summary of Patient Management Under Protocol Amendment 03 
 
Prescreen fail 
participants 
eligible for 
Prescreening 
under Protocol 
Amendment 02 
Participants in Prescreening/Screeninga,b 
Randomized Participantsa 
Participants 
<12 months 
since end of 
definitive 
therapy 
Participants 
≥12 months 
since end of 
definitive 
therapy 
Participants 
ctDNA+ not yet 
randomizedc 
Participants 
on niraparib 
Participants on 
placebo 
Status Under 
Protocol 
Amendment 03 
Not eligible to 
join Protocol 
Amendment 03 
Eligible to 
continue under 
Protocol 
Amendment 03 
Not eligible to 
continue under 
Protocol 
Amendment 03 
Eligible to 
continue under 
Protocol 
Amendment 03 
Eligible to 
continue under 
Protocol 
Amendment 03 
Eligible to 
continue under 
Protocol 
Amendment 03 
SOA Table 
NA 
Table 4  
NA 
Table 5  
Table 6  
Table 6  
a. 
Participants in Prescreening, Screening, or Randomized as of the date of decision to stop enrollment 
(25 April 2023) 
b. 
Screening only applies to ctDNA+ participants. 
c. 
If ctDNA testing was started prior to the date of the decision was made to stop enrollment and the result was 
obtained after the date of the decision to stop enrollment, and was positive, the participant will be considered part 
of the ctDNA+ population and currently monitored accordingly. 
 

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Table 12 
Summary of Patient Management Under Protocol Amendment 04 
 
Participants in Prescreening/Screening
a,b 
Randomized Participants
a 
Participants <12 
months since end 
of definitive 
therapy 
Participants ≥12 
months since 
end of definitive 
therapy 
Participants 
ctDNA+ not yet 
randomized
c 
Participants on 
niraparib 
Participants on 
placebo 
Status Under 
Protocol 
Amendment 04 
prior to DCOd 
Eligible to 
continue under 
Protocol 
Amendment 04 
SOA Table 4 with 
final ctDNA test 
drawn prior to 
DCOd or 
participant 
reaches 
12 months since 
end of definitive 
therapy, 
whichever comes 
first. 
Not eligible to 
continue under 
Protocol 
Amendment 04  
Eligible to 
continue under 
Protocol 
Amendment 04 
as per SOA 
Table 5 until 
DCOd 
Eligible to 
continue under 
Protocol 
Amendment 04 
as per SOA 
Table 6 until 
DCOd 
Eligible to 
continue under 
Protocol 
Amendment 04 as 
per SOA Table 6 
until DCOd 
Status Under 
Protocol 
Amendment 04 
after DCOd 
Not eligible to 
continue under 
Protocol 
Amendment 04 
after DCOd 
Not eligible to 
continue under 
Protocol 
Amendment 04  
Eligible to 
continue under 
Protocol 
Amendment 04 
after DCOd and 
enter PACT to 
receive 
surveillance 
scans
e until 
stopping 
criteria are metf 
Eligible to 
continue under 
Protocol 
Amendment 04 
after DCOd and 
enter PACT to 
receive 
niraparib, SOC 
assessments, 
and surveillance 
scans
e until 
stopping criteria 
are met f g 
Eligible to 
continue under 
Protocol 
Amendment 04 
after DCOd and 
enter PACT to 
receive 
surveillance 
scans
euntil 
stopping criteria 
are metf 
a. 
Participants in prescreening, screening, or randomized as of the date of decision to stop enrolment 
(25 April 2023)  
b. Screening only applies to ctDNA+ participants. 
c. 
If ctDNA testing was started prior to the date of the decision was made to stop enrollment and the result 
was obtained after the date of decision to stop enrollment, and was positive, the participant will be 
considered part of the ctDNA+ population and currently monitored accordingly. 
d. DCO is defined as the end of data collection for the planned final analyses as described in the SAP. Once 
the final DCO date has been reached, the clinical study database will be closed to new data. 
e. 
Participants may continue surveillance scans per protocol, or less frequently at the discretion of the 
Investigator, until progressive disease/disease recurrence or participant withdraws. 
f. 
For protocol-defined stopping criteria, please refer to Section 7.  
g. SAEs, AESIs, AEs leading to discontinuation of study treatment, overdose and pregnancy reported will 
continue to be reported directly to the sponsor via paper form through 30 days after the last dose of study 
treatment. All SAEs assessed as related by the Investigator continue to be reported for all study 
participants until study close out and all AESIs, regardless of causality, continue to be reported for all 
study participants until death or loss to follow up. 
 

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Participants randomized to treatment on the ZEST study may discontinue treatment and 
be offered scans above standard of care, while some previously specified assessments are 
now discontinued. As a result of stopping enrollment, Prescreening is stopped for new 
patients and study assessments should be discontinued with the exception of those 
outlined in Table 4 and Table 5 for those participants in prescreening as of the date of the 
decision to stop enrollment.  
Participants in Prescreening can no longer enter Screening and any participants currently 
in Screening as of the date of the decision to stop enrollment can no longer be 
randomized and should follow those outlined in Table 5.  
For participants randomized in the ZEST study and on treatment as of the date of the 
decision to stop enrollment, the study was unblinded centrally and participants should be 
managed as outlined in Table 6. As of the decision to stop enrollment, PK sample 
collection is also discontinued along with the PK substudy.  
Participants will initially enter a Prescreening Period for confirmation of detectable 
ctDNA (Table 2). For participants with detectable ctDNA, the Prescreening Period is 
followed by the Screening Period (Day -42 to Day -1) for completion of the remaining 
Screening assessments. It is recommended that the Screening Period start within 14 days 
of a confirmed ctDNA-positive result, provided all submitted prescreening tissue samples 
are of adequate quality per central review (Table 3). Eligible participants in Cohorts 1 
and 2 are then randomized to either niraparib or placebo. For Cohort 1, a Safety Run-in as 
well as a PK substudy will be performed. The Safety Run-in will include the first 
40 randomized participants receiving concomitant endocrine therapy. The PK substudy 
will include at least the first 40 randomized participants receiving endocrine therapy at 
sites participating in the PK substudy. Additional participants may be included in the PK 
substudy so that 6 participants per endocrine therapy are included, if feasible. 
The Niraparib/Placebo Treatment Period is followed by an End of Treatment (EOT) Visit 
occurring within 7 days of last dose, a Safety Follow-up Visit 30 (+7) days after last 
dose, and Post-treatment Follow-up with assessments every 90 (±14) days for 2 years 
after the last dose and every 180 (±14) days thereafter. 
Patient-reported outcomes (PROs), including the 30-question European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire 30-item Core Module 
(EORTC-QLQ-C30), 6-question EuroQoL 5-dimensional questionnaire 3-level version 
(EQ-5D-3L), single-item Patient Global Impression of Severity (PGIS)/Patient Global 
Impression of Change (PGIC), and Functional Assessment of Cancer Therapy-General 
Population (FACT-GP5), as well as a subset of approximately 15 questions from the 
Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE), will be collected approximately every 28 days (aligned with the 
regular participant monitoring schedule) during the Treatment Period, at the EOT Visit, at 
the Safety Follow-up Visit, and at the first 2 Post-treatment Follow-up assessments. 

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ctDNA Prescreening: 
Participants must sign a ctDNA Prescreening informed consent form (ICF) consenting to 
collection of tumor tissue samples for ctDNA assay design and tBRCA and HRD testing 
as well as blood samples for ctDNA testing. Sufficient archival tumor tissue to establish 
the ctDNA platform and to perform tBRCA and HRd testing using the 
 
is a requirement for study entry to enable this testing. This ctDNA 
Prescreening, utilizing the Signatera test for ctDNA, requires an archival tissue sample 
from the primary tumor, including pathology reports for all tumor tissue samples, a blood 
sample for whole exome sequencing (WES), and subsequent ctDNA blood samples, as 
described in Table 2 and Table 3. 
As a result of the decision to stop enrollment, prescreening procedures will be stopped, 
including ctDNA testing, except as outlined in Section 1.3, Table 4, and Table 5. 
Ongoing prescreen participants who are ctDNA-negative and <12 months from end of 
definitive therapy on the date of the decision to stop enrollment may continue 
prescreening procedures as outlined above. Upon receiving a detectable ctDNA result by 
the Signatera test, these participants will not receive further ctDNA tests and will proceed 
according to Table 4. Prescreen participants who are ctDNA+ as of the date of the 
decision to stop enrollment will follow Table 5. Participants who are deemed prescreen 
failures under previous versions of the protocol will not be reconsented and will not 
return for any prescreening procedures. 
The Prescreening ICF can be signed either after the participant’s last intervention (after 
surgery if adjuvant treatment is not indicated or after adjuvant treatment) and/or during 
chemotherapy and radiation adjuvant treatment. The timing of tumor tissue and blood 
sample collection in Prescreening is outlined in Table 2. It is recommended that initial 
testing for ctDNA is conducted as close to the end of adjuvant therapy as possible.  
Participants in prescreening will have ctDNA testing performed with a maximum of 
18 tests over a period of up to 6 years after end of definitive therapy for participants with 
a known BRCAmut (TNBC or HR+) and a maximum of 10 tests performed over a period 
of up to 2 years for participants with TNBC BRCAwt/unknown, as described in Table 13. 
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Table 13 
Prescreening Consent and ctDNA Testing Frequency 
 
Known BRCAmut (TNBC or HR+) 
TNBC BRCAwt/unknown 
Time of entry since 
completion of end of 
definitive therapy (only for 
new patients under Protocol 
Amendment 02) 
Anytime within 5 years 
Consent within 12 weeks 
First ctDNA test within 16 weeks  
Maximum number of ctDNA 
tests 
Up to 18 tests over up to 6 years post-end of 
definitive therapy, until ctDNA-positive result 
or study end, whichever happens first 
Up to 10 tests over up to 2 years 
post-end of definitive therapy, until 
ctDNA-positive result or study end, 
whichever happens first 
Frequency of Testing (relative to end of definitive therapy) 
Month 0 to Month 6 
Every 8 weeks ±2 weeksa 
Month 6 to Month 24 
Every 12 weeks ±4 weeks 
Month 24 to 6 years 
Every 6 months (±4 weeks) 
Not applicable 
a. 
Participants who are either under ongoing Prescreening at the time of implementation of Protocol Amendment 02, 
or who are re-entering prescreening should resume ctDNA testing at the time of consent to Protocol 
Amendment 02 and continue testing with the frequency and duration defined by the time relative to end of 
definitive therapy. For example, a TNBC BRCAwt patient re-entering prescreening at 21 months from the end of 
definitive therapy may test for ctDNA at 21 months and 24 months, then stop. 
As of the date of the decision to stop enrollment in the ZEST study, this is no longer applicable due to changes in 
ctDNA testing frequency for remaining participants on study (see Section 1.3). 
 
Under Protocol Amendment 02, participants who were deemed prescreen failures under 
previous versions of the protocol due to negative ctDNA test results may have the 
opportunity to re-enter prescreening if they meet all eligibility criteria in this protocol 
amendment, meet staging criteria as outlined in Prescreening criterion P2, and remain 
within the prescreening testing duration windows described in Prescreening criterion P4 
(also see Table 14).  
Participants under ongoing Prescreening at the time of implementation of Protocol 
Amendment 02 are eligible for additional ctDNA testing provided they continue to meet 
all eligibility criteria in this protocol amendment and remain within the prescreening 
testing duration windows described in Prescreening criterion P4. (Also see Table 14) 

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Table 14 
Prescreening Stage, Consent, and Testing Window Requirements for 
Protocol Amendment 02 Participantsa 
 
New Patients (enrolled in 
Amendment 02) 
Current Patients in Ongoing 
Prescreening at the Time of 
Protocol Amendment 02 
Implementation 
Prior Prescreen failure 
Participants Re-entering the 
Study Under Protocol 
Amendment 02 
Stage 
Must meet Prescreening 
eligibility criteria for Protocol 
Amendment 02: Prescreening 
criterion P2 a,b,c 
Must have Stage I-III non-
metastatic primary invasive 
breast cancer as per 
Prescreening criterion P1. 
Must meet Prescreening 
eligibility criteria for Protocol 
Amendment 02: Prescreening 
criterion P2 a,b,c 
Protocol 
Amendment 02 
Consent Window 
TNBC tBRCAwt/unk: Must 
sign no later than 12 weeks 
from end of definitive therapy 
 
Known tBRCAmut (HR+ and 
TNBC): Must sign no later 
than 5 years from end of 
definitive therapy 
Not applicable 
Not applicable 
ctDNA Testing 
Window 
TNBC tBRCAwt/unk: Must 
start ctDNA testing no later 
than 16 weeks from end of 
definitive therapy 
 
 
Known tBRCAmut (HR+ and 
TNBC): Must start no later 
than 5 years from end of 
definitive therapy 
TNBC tBRCAwt/unk: May 
continue ctDNA testing so long 
as no more than 24 months has 
elapsed since the end of 
definitive treatment. 
 
Known tBRCAmut (HR+ and 
TNBC): May continue ctDNA 
testing so long as no more than 
6 years has elapsed since the 
end of definitive treatment. 
TNBC tBRCAwt/unk: May 
resume ctDNA testing so long 
as no more than 24 months has 
elapsed since the end of 
definitive treatment. 
 
Known tBRCAmut (HR+ and 
TNBC): May resume ctDNA 
testing so long as no more than 
6 years has elapsed since the 
end of definitive treatment. 
Additional 
Requirements 
Not applicable 
To be considered “ongoing”, 
participant must have at least 1 
additional ctDNA test left per 
the previous testing schedule 
and has not yet been deemed a 
Prescreen fail. 
Not applicable 
a. 
Participants must also meet all other Prescreening eligibility criteria (P1 to P9; see Section 5) as per protocol in 
order to be eligible for ctDNA prescreening testing. 
As of the date of the decision to stop enrollment, this is no longer applicable as there will be no new prescreening 
participants and prior prescreen failure participants are not allowed to re-enter the study. 
 
The ctDNA testing will be reserved to participants who, from the Investigator’s 
perspective, are at a significant risk of disease recurrence and do not present radiological 
or clinical signs of disease recurrence. 
For participants with TNBC who are receiving adjuvant pembrolizumab following 
surgery, the first ctDNA test may occur during adjuvant pembrolizumab treatment 
provided that all adjuvant radiation and adjuvant chemotherapy have been completed (if 
indicated), and according to the schedule outlined in Table 2 (footnote a). Participants on 
adjuvant pembrolizumab who are found to have detectable ctDNA and are otherwise 
eligible for the study will be allowed to start niraparib concurrently with the remaining 
cycles of adjuvant pembrolizumab. 

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A participant can move to the Screening Period once detectable ctDNA is confirmed in 
Prescreening, provided all submitted prescreening tissue samples are of adequate quality 
per central review. ctDNA results will be blinded after randomization. 
BRCA Tumor Mutational Status Testing: 
During ctDNA Prescreening, tumor tissue samples from all participants will be collected 
for confirmatory central tBRCA testing for eligibility considerations using the 
 
 
Participants with HR+/HER2− breast cancer must have a known and documented 
deleterious or suspected deleterious tBRCAmut (either sBRCA or gBRCA positive) and 
meet all other prescreening eligibility criteria to qualify for ctDNA Prescreening and 
must have been on a stable regimen of endocrine therapy for a minimum of 3 months 
prior to randomization. Participants with HR+/HER2− breast cancer who have tBRCAmut 
confirmed by central testing will be eligible for Cohort 1; if central testing does not 
confirm a tBRCAmut in HR+/HER2− participants, they will not be eligible for the study. 
Participants with TNBC who have centrally confirmed tBRCAmut will be eligible for 
enrollment in Cohort 1, and those who are tBRCAwt or who have undetermined tBRCA 
status will be eligible for enrollment in Cohort 2. Note that the confirmatory central 
tBRCA test does not distinguish between somatic and germline BRCA mutations and does 
not replace standard germline testing. 
As a result of the decision to permanently stop enrollment, no further tBRCA testing 
using 
 will be conducted for any participants, regardless of 
ctDNA status. All participants randomized prior to the date of the decision to stop 
enrollment have had confirmatory central tBRCA testing completed by the 
 
 assay under previous versions of the protocol. 
Tumor HRD Status Testing 
Tumor tissue samples collected at Prescreening will be used for centralized testing using 
 to classify participants in Cohort 2 by HRD status. 
As a result of the decision to permanently stop enrollment, no further HRD status 
assessment using the 
 will be conducted for any patient, 
regardless of ctDNA status. All participants randomized prior to the date of the decision 
to stop enrollment have had HRD assessment testing by 
 
assay completed under previous versions of the protocol. 
Screening Period: 
As a result of the decision to permanently stop enrollment, participants can no longer 
enter Screening. Participants currently in Screening as of the date of the decision to stop 
enrollment that decide to remain on study will follow Table 5. 
During the Screening Period, participants will sign the main study ICF and complete all 
remaining assessments required to determine eligibility for the study. The Screening 
Period is within 6 weeks (42 days) of Cycle 1/Day 1 and is recommended to start within 
14 days of a confirmed ctDNA-positive result, provided all submitted prescreening tissue 
samples are of adequate quality per central review. All screening criteria (unless 
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otherwise specified in Table 3) are required to be repeated if they fall outside of 6 weeks 
prior to first dose. 
All participants are required to have documented presence of ctDNA, central 
confirmation of tBRCAmut status, and no evidence of overt recurrent/metastatic disease 
prior to being randomized 1:1 to either niraparib or placebo.  
Randomization and Stratification: 
As of the date of the decision to stop enrollment, participants can no longer be 
randomized. 
Participants in Cohort 1 will be stratified based on the following factors: 
• Time from last intervention (defined in Section 6.3.2) to randomization 
(<6 months versus ≥6 months) 
• HR status (positive versus negative) 
• Prognostic Stage of breast cancer (Stage I/II versus Stage III) (Appendix 13) 
Participants in Cohort 2 will be stratified based on the following factors: 
• Time from last intervention (defined in Section 6.3.2) to randomization 
(<6 months versus ≥6 months) 
• Prior use of adjuvant capecitabine (yes versus no) 
• Prognostic Stage of breast cancer (Stage I/II versus Stage III) (Appendix 13) 
Safety Run-in Period (Cohort 1): 
As of the date of the decision to stop enrollment, Safety Run-in is no longer applicable. A 
total of 40 participants were randomized in the study. 
A Safety Run-in Period will be conducted in the first 40 randomized participants in 
Cohort 1 who are taking endocrine therapy (anastrozole, letrozole, exemestane, and 
tamoxifen, with or without ovarian function suppressing agents). All participants 
receiving concomitant endocrine therapy need to have been on a stable regimen of 
endocrine therapy for a minimum of 3 months prior to randomization. While on study, 
the endocrine regimen can be interrupted or discontinued as clinically indicated. During 
the Treatment Period, the endocrine regimen may be exchanged for another regimen after 
discussion with the GSK Medical Monitor, but the regimen may not be changed during 
the Safety Run-in Period or the PK substudy.  
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As of the date of the decision to stop enrollment, assessment by an IDMC is no longer 
needed due to enrollment being permanently stopped and the study being centrally 
unblinded. 
Study Conduct: 
As of the date of the decision to stop enrollment, several study procedures described 
below are no longer applicable. As of Protocol Amendment 04, participants should be 
managed as outlined in Table 12 and Section 1.3. Once PACT Phase is implemented, 
participants will be managed as per Section 6.7.1. 
Participants who meet all eligibility criteria will be randomized in a 1:1 ratio to receive 
niraparib or placebo.  
Clinic visits will occur on Day 1 of each cycle (Table 3). Hematology laboratory values 
will be monitored weekly for the first 28-day cycle of the Niraparib/Placebo Treatment 
Period, and blood pressure (BP) and heart rate (pulse) will be monitored weekly for the 
first two 28-day cycles of the Niraparib/Placebo Treatment Period. If participants are 
unable to attend clinic visits on Cycle 1/Day 1 (postdose), Cycle 1/Day 15, and 
Cycle 2/Day 1 (postdose), they must have assessments for these visits performed through 
at-home nursing on the date the visit would have occurred. If participants are unable to 
attend clinic visits on Cycle 1/Day 8, Cycle 1/Day 22, Cycle 2/Day 8, Cycle 2/Day 15, 
and Cycle 2/Day 22, they must have the assessments for these visits performed either 
through a local laboratory/clinic or through at-home nursing on the date the visit would 
have occurred. At-home nursing services are to be used as per investigator discretion for 
COVID-related accommodations where needed, and/or to reduce frequent visit burden 
for participants. Further details are outlined in Section 8.1.1. As of the date of the 
decision to stop enrollment, at-home nursing services will no longer be offered. 
All participants are required to undergo tumor imaging as provided below and all 
imaging data acquired with the purpose of tumor assessment must be submitted to the 
Imaging Vendor for Central Review. As of the date of the decision to stop enrollment, 
imaging does not need to be submitted to the imaging vendor for central review. Imaging 
will be conducted for ongoing participants as outlined in Section 1.3, Table 4, Table 5, 
and Table 6. The preferred imaging method is IV contrast-enhanced CT, and a bone scan. 
The same imaging method and anatomical coverage should be used throughout the study. 
• Baseline:  
• 
An IV contrast-enhanced CT scan of the chest/abdomen/pelvis and a bone scan 
will be conducted within 42 days (6 weeks) prior to randomization (as outlined 
in Table 3). 
• 
If IV CT contrast cannot be used (e.g., sensitivity to CT contrast or contrast 
shortage): Noncontrast CT of the chest and IV contrast-enhanced magnetic 
resonance imaging (MRI) of abdomen/pelvis, and a bone scan.  
If both IV CT and IV MRI contrast cannot be used, or if renal insufficiency: 
noncontrast CT of chest/abdomen/pelvis, and a bone scan. If MRI is performed at 
Baseline, it should be preferentially continued throughout the study. If brain 
metastasis is suspected, IV contrast-enhanced MRI is preferred over IV contrast-
enhanced CT for imaging of the brain. 

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• On study: An IV contrast-enhanced CT scan of the chest, abdomen, and pelvis (or 
IV contrast-enhanced MRI of abdomen and pelvis and noncontrast CT of chest, if 
MRI performed at Baseline) will be conducted every 12 weeks (84±7 days) from 
date of randomization for the first 2 years and every 24 weeks (168±7 days) 
thereafter, or more frequently as clinically indicated (unscheduled), until 
Investigator assessment of disease recurrence using RECIST v1.1. Bone scans 
should only be performed postbaseline if clinically indicated. If brain metastasis is 
suspected, IV contrast-enhanced MRI is preferred over IV contrast-enhanced CT 
for imaging of the brain. 
If a participant discontinues study treatment for any reason other than disease recurrence, 
death, withdrawal of consent, or loss to follow-up, then scans should continue at the 
specified intervals until recurrence is confirmed. 
Each participant will have an EOT Visit at the time of discontinuation from study 
treatment, a Safety Follow-up Visit 30 (+7) days after last dose, and Post-treatment 
Follow-up with assessments every 90 (±14) days for 2 years after the last dose and every 
180 (±14) days thereafter, which will continue until death or the end of study data 
collection (provided that this allows the opportunity for completion of all follow-up 
assessments). Information regarding subsequent anticancer treatments (including regimen 
and number of cycles), as well as the date of any subsequent PD (ie, for determination of 
progression on next anticancer therapy), hospitalization, and other supportive care and 
procedures (eg, surgery or radiation), and survival status will be collected during these 
assessments. 
GSK may request that updated survival data be collected on all treated/randomized 
participants outside the protocol window noted in the Schedule of Activities (SOA) 
(Table 3). At the time of the request, the site will determine survival status for each 
participant by the method agreed with the participant, unless the participant has 
withdrawn consent from the study. 
Reporting of safety events will begin at the time of ctDNA Prescreening ICF signature 
date only for events related to ctDNA and WES blood sample collection procedures. All 
AEs and serious adverse events (SAEs) will be collected and recorded for each 
participant from the day of signing the main study ICF until 30 days after last dose of 
study treatment or start of new anticancer therapy. All AEs and SAEs experienced by a 
participant, irrespective of the suspected causality, will be monitored until the AE or SAE 
has resolved, until abnormal laboratory values have returned to baseline or normalized, 
until there is a satisfactory explanation for the changes observed, until the participant is 
lost to follow-up, or until the participant has died. All SAEs assessed by the Investigator 
as related to the study treatment and all adverse events of special interest (AESIs), 
regardless of causality, will be collected and reported until study closeout, or as otherwise 
indicated. Any pregnancies that occur within 180 days post-treatment will be reported.  
Participants will continue to receive their assigned treatment until disease recurrence as 
assessed by RECIST v1.1, death, withdrawal of consent, loss to follow-up or until 
unacceptable toxicity. Those participants who have completed 39 cycles (approximately 
3 years) with no evidence of recurrence will have the option to either continue treatment 
or stop treatment at that time. If available, participants continuing niraparib treatment at 
the time of final analysis may be offered the option to continue to receive niraparib 

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treatment. Dose interruptions, reductions, or treatment discontinuation may be 
implemented at any time according to the dose modification guidelines in this protocol 
(Section 6.4) and under the discretion of the Investigator. 
For all participants in Cohort 1 and Cohort 2, blood samples will be collected in the main 
study at Cycle 1/Day 1, Cycle 1/Day 15, Cycle 2/Day 1, Cycle 4/Day 1, and 
Cycle 8/Day 1, as specified in Table 7 for sparse PK sampling to characterize niraparib 
exposure in participants with breast cancer and to explore the relationship between 
exposure to niraparib and responses in efficacy and safety. 
A subset of participants in Cohort 1 will have additional blood samples collected in a PK 
substudy. The PK substudy will include at least the first 40 randomized participants 
receiving endocrine therapy at sites participating in the PK substudy. The samples 
collected in the PK substudy will be analyzed to characterize the steady-state PK of 
endocrine therapy and to assess any potential effect of niraparib on endocrine therapy 
exposure, as data permit. Based on the randomized nature of the study, it is assumed that 
approximately 20 participants in the PK substudy will be receiving endocrine therapy 
with niraparib, while the remaining participants will be receiving endocrine therapy with 
placebo, allowing for a comparison of endocrine therapy PK with or without niraparib 
co-administration. Additional participants may be included in the PK substudy if there 
are too few participants receiving any of the individual endocrine therapies to meet the 
objectives of the substudy; if feasible, 6 participants per endocrine therapy will be 
targeted. The samples for the PK substudy will be collected at Cycle 1/Day 15 as 
specified in Table 8, at which time niraparib exposure will have reached steady state. 
4.2. 
Scientific Rationale for Study Design 
Despite recent advances made in the treatment of TNBC and HR+/HER2− breast cancer, 
an urgent unmet medical need exists for effective therapeutic options to delay metastatic 
breast disease following definitive therapy. This study will include the following cohorts: 
• Cohort 1: participants with HER2− breast cancer (independent of HR status) 
who have tumors that are tBRCAmut and have detectable ctDNA 
• Cohort 2: participants with TNBC who have tumors that are tBRCAwt and 
have detectable ctDNA 
For Cohort 1, the decision to enroll all participants with tBRCAmut HER2− breast cancer 
to a single cohort, despite differences in HR status, is based on the observed efficacy of 
niraparib in BRCAmut ovarian tumors, preliminary clinical activity of niraparib as 
neoadjuvant in tBRCAmut HER2− breast cancer, and the observed efficacy of other 
PARP inhibitors in metastatic gBRCAmut breast tumors independent of HR status. 
Efficacy analyses will be stratified by HR status to determine the effect of niraparib on 
each participant population. 
Cohort 2 will enroll participants with tBRCAwt TNBC who have detectable ctDNA 
following completion of definitive therapy. The unmet medical need for antitumor 
therapy in participants with TNBC is independent of tBRCA status. The results from the 
NOVA and PRIMA studies of niraparib indicate a consistent continuum of clinical 
benefit across biomarker-defined subpopulations and that the benefit of niraparib 
treatment extends beyond participants with BRCAmut disease (Section 2.2.5.1). This 

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observation is not limited to niraparib or ovarian cancer. In Study 3000-PN162-01-001 
(TOPACIO/KEYNOTE-162), combination treatment with niraparib and pembrolizumab 
demonstrated clinical activity in participants with TNBC, irrespective of BRCA mutation 
status, with the greatest activity observed in participants with tBRCAmut tumors 
(Section 2.2.5.2). Studies demonstrating the activity of other PARP inhibitors in TNBC 
are summarized in Section 2.1. 
The following aspects of the study design are discussed in more detail below: 
• The choice of placebo as the comparator arm 
• Justification for tBRCA/HRD assay 
• The ctDNA method 
• Justification of enrichment of Stage II to III and non-pCR patients 
• Justification of ctDNA testing frequency and timing 
Justification of Comparator Arm 
Placebo was chosen as the comparator arm as there is currently no available standard-of-
care therapy for patients who have detectable ctDNA following their last intervention 
(surgery or adjuvant therapy). Ongoing long-term hormonal therapies as backbone 
therapy in HR+ participants are allowed (eg, aromatase inhibitors, tamoxifen) in 
Cohort 1. 
A conceptually similar approach has led to regulatory approval of drugs delaying the 
onset of radiologically detectable metastasis in biochemically recurrent (=low disease 
burden) non-metastatic castration-resistant prostate cancer where placebo was also used 
as the comparator arm and participants continued to receive backbone hormonal ablation 
therapy in both treatment arms [Fizazi, 2019; Smith, 2018]. 
While results from the OlympiA trial noted in Section 2.2.4 demonstrated improved IDFS 
with adjuvant olaparib treatment in patients with high-risk Stage II to III gBRCAmut 
HER2− breast cancer, those eligible for Cohort 1 in this study are a subset of patients 
with BRCAmut that are not eligible for treatment with olaparib due to one or more of the 
following criteria: 
• 
TNBC patients who received adjuvant therapy and who have T1 and/or 
node-negative disease; 
• 
Those patients who already completed definitive therapy in the past and fall 
outside the traditional adjuvant 12-week window defined by OlympiA; and 
• 
Those with a sBRCAmut, and 
• 
Those who do not otherwise meet criteria for adjuvant olaparib treatment per 
local guidelines 
In these settings, enrollment into this ZEST study remains an appropriate option for 
patients and, given the absence of any standard of care alternatives, the use of placebo in 
the comparator arm is medically justified. 

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Justification for tBRCA/HRD Assay 
 
 
 
. This assay has been analytically validated in 
breast cancer and is CE marked, which supports its use in investigational studies of 
PARP inhibitors. 
Justification of ctDNA Method 
The Signatera test, the method chosen for use in this study, requires an archival tissue 
sample of the primary tumor, including pathology reports for all tumor tissue samples, 
and blood samples from each participant. The tumor tissue sample and a blood sample 
are used for WES to identify tumor-specific somatic variants by comparing the WES 
profile of the primary tumor (somatic DNA) with that of matched white blood cells 
(germline DNA). To determine whether observed somatic variants are found in all tumor 
cells or a subset of tumor cells, clonality inference is performed as described by 
McGranahan et al [McGranahan, 2015]. 
 
 
 
 The risk of recurrence for patients with TNBC is 
CCI
CCI
CCI
CCI

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highest during the first 2 to 3 years following the completion of standard therapy for 
curative intent [Cortazar, 2014]. The main period of screening for ctDNA covers a 
24-month period following the end of therapy for curative intent. The ctDNA test is 
expected to identify molecular detectable disease on average approximately 9 months 
ahead of clinical or radiologic progression; therefore, 24 months should allow for 
identification of a large proportion of participants with risk of recurrence. A more distant 
time point from the end of the curative intent therapy is also included to capture some 
participants who would progress later, particularly participants with HR+ disease, who 
are known to have a slower rate of recurrence over time. In cases where surgery is the last 
step of curative intent therapy, a minimum 4-week interval is proposed to allow elevated 
circulating free DNA that is released from surgical trauma to normalize [Henriksen, 
2020]. For participants receiving pembrolizumab, the schedule of ctDNA assessment is 
outlined in Table 2 (footnote a) based on data from Bratman et al [Bratman, 2020] to 
allow for adequate opportunity for ctDNA nadir to occur with adjuvant pembrolizumab. 
Justification for Enrichment of Stage II to III and non-pCR Patients  
The eligible population for ZEST prescreening has been amended in the current protocol 
amendment to enrich for participants most likely to develop detectable ctDNA, which are 
those participants with higher stage disease at the time of diagnosis and those participants 
who did not achieve a pCR following neoadjuvant therapy. Several recent studies have 
shown that the detection rate of ctDNA in breast cancer patients differs significantly 
across tumor stages [Riva, 2017; Cavallone, 2020; Molinero, 2022; Yoshinami, 2020]. In 
a study of 46 patients with TNBC, the ctDNA detection rate at diagnosis was 0%, 77%, 
and 100% in patients with Stage I, II, and III disease, respectively [Riva, 2017]. Another 
study reported 0.01% in Stage I, 1.15% in Stage II, and 9.73% in Stage III [Cavallone, 
2020].  
Another clinicopathological feature related to ctDNA incidence is presence or lack of 
residual disease after neoadjuvant therapy. In a cohort of 84 high-risk early breast cancer 
patients in the neoadjuvant chemotherapy I-SPY 2 trial using the Signatera ctDNA assay, 
authors demonstrated that after NAC, all patients who achieved pCR were ctDNA-
negative (n=17, 100%). For those who did not achieve pCR (n=43), ctDNA-positive 
patients (14%) had a significantly increased risk of metastatic recurrence (hazard 
ratio=10.4; 95% CI: 2.3 to 46.6). Patients who did not achieve pCR but were 
ctDNA-negative (86%) had an excellent outcome, similar to those who achieved pCR 
(hazard ratio=1.4; 95% CI: 0.15 to 13.5) [Magbanua, 2021]. 
In short, the literature to date suggests that ctDNA detectability appears to mirror classic 
“high-risk” features for breast cancer recurrence, such as higher stage at diagnosis and 
non-pCR following neoadjuvant therapy. These findings support the decision to modify 
the prescreening population for future prescreening participants in the ZEST trial.  
Justification of ctDNA Testing Frequency and Timing in Prescreening 
Under Protocol Amendment 02, the timepoints for starting ctDNA testing and the 
frequency of testing are outlined in Table 13 and Figure 3. For new study participants 
with HR+/HER2- BRCAmut breast cancer and TNBC BRCAmut (BRCAmut [TNBC or 
HR+]; Cohort 1), ctDNA surveillance can start up to 5 years from the end of definitive 
therapy, while new participants with TNBC that do not carry BRCA mutation or where 

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local BRCA test was not performed (TNBC BRCAwt/unknown; Cohort 2) are required to 
sign the prescreening informed consent within 12 weeks from the end of definitive 
therapy. The reason for restricting the time from the end of definitive therapy for TNBC 
BRCAwt/unknown (Cohort 2) is to identify fast molecular progressors early on, post 
completion of curative-intent treatment, and before radiological relapse is detected. 
However, a wider window of enrollment is allowed for Cohort 1 (BRCAmut [TNBC or 
HR+]); for several reasons. Most importantly, patients with a BRCA mutation that fall 
beyond 12 weeks of completion of definitive therapy, as based on the OlympiA study, 
would not be eligible for Lynparza (olaparib) treatment, and are a population with an 
unmet medical need [Tutt, 2021]. To that end, the ZEST study design offers ctDNA 
testing to patients with a BRCA mutation that have been identified past the time of 
eligibility for the OlympiA trial, and therefore, are not eligible for olaparib treatment 
beyond this 12-week window. Enrollment is allowed for up to 5 years since end of 
definitive therapy to allow ample time for identification of BRCAmut patients who may 
have previously been treated but are more recently found to carry a mutation as standard-
of-care genetic testing practices evolve. Further, it has recently been shown that 
development of ctDNA detectability among HR+/HER2− patients may be delayed for 
several years after diagnosis [Lipsyc-Sharf, 2022], which also supports the prolonged 
recruitment window. The number of tests a participant is being offered in the ZEST trial 
is a maximum of 10 tests for patients with TNBC and tBRCAwt/unknown or up to 
18 tests for TNBC or HR+ breast cancer patients with tBRCAmut but for up to 6 years 
since end of definitive therapy, ctDNA-positive result, or end of study, whichever occurs 
first. The frequency of tests is outlined in Figure 3. 
The revised testing schedule in Protocol Amendment 02 applies to participants newly 
referred for prescreening and to ongoing participants in prescreening, but also may be 
offered to previously prescreened participants that tested negative for ctDNA and who 
meet Prescreening criteria P2 and P4, and all the other prescreening eligibility criteria. 
The rationale for additional testing is derived from the literature data suggesting ctDNA 
prevalence in patients tested more than 18 months since definitive therapy is 3% in 
TNBC and ranges between 4% and 25% in HR+/HER2− breast cancer [Olsson, 2015; 
Garcia-Murillas, 2019; Coombes, 2019; Turner, 2021].  
In line with maximizing early detection of ctDNA+ patients, prior to radiological relapse 
in participants receiving pembrolizumab treatment, ctDNA testing is recommended to 
start within 12 weeks from first pembrolizumab dose in any setting. Data from Magbanua 
et al. [Magbanua, 2021], summarized above, provide confidence that ctDNA status post 
neoadjuvant chemotherapy is a good predictor of outcome. To that end, additional 
12 weeks of treatment with pembrolizumab in the adjuvant setting is not required prior to 
testing for ctDNA. 
4.3. 
Justification for Dose 
The starting dose of niraparib is based upon the participant’s hepatic function and 
baseline body weight and/or baseline platelet count. Normal or mildly impaired hepatic 
function is defined as either AST >ULN and total bilirubin ≤ULN; or any AST and total 
bilirubin >1.0× to 1.5× upper limit of normal (ULN). Moderately impaired hepatic 
function is defined as total bilirubin >1.5× and ≤3×ULN and any level of AST elevation. 

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In participants with normal or mildly impaired hepatic function, the niraparib starting 
dose is 300 mg orally once daily in participants with a baseline body weight ≥77 kg and 
baseline platelet count ≥150,000/μL and 200 mg orally once daily in participants with a 
baseline body weight <77 kg or baseline platelet count <150,000/μL. The dose is based 
on observations from previous niraparib studies that identified body weight and platelet 
count as clinical factors associated with Grade 3/4 thrombocytopenia events. These 
observations were confirmed in the PRIMA study, in which an individualized starting 
dose (200 mg in participants <77 kg or with a baseline platelet count <150,000/μL; 
300 mg in participants with ≥77 kg and a platelet count ≥150,000/μL) allowed 
participants to achieve comparable efficacy with a substantially lower incidence of 
thrombocytopenia and anemia. 
In participants with moderate hepatic impairment, the niraparib starting dose is 200 mg 
orally once daily in all participants, regardless of baseline body weight or baseline 
platelet count. This recommendation is based on results of a study of niraparib in 
participants with normal hepatic function and moderate hepatic impairment (Study 3000-
01-003). Due to the expected effect of hepatic impairment on niraparib disposition, the 
starting dose is reduced from 300 mg to 200 mg once daily for participants with moderate 
hepatic impairment, weight ≥77 kg, and platelet count ≥150,000/μL in order to minimize 
the risk of thrombocytopenia while still maintaining niraparib exposures in a range 
associated with efficacy in the PRIMA study. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities for the last participant in the study. As a result of the decision to 
permanently stop enrollment, the study will conclude when the last participant has 
completed their last study procedure (as outlined in Section 1.3). 
Participants will remain on study until discontinuation/withdrawal from the study or the 
end of study data collection. (Reasons for participant discontinuation/withdrawal are 
provided in Section 7.2.) If a participant dies, the cause of death should be documented in 
the electronic case report form (eCRF). A participant will be considered to have 
withdrawn from the study if the participant has not died and is lost to follow-up, has 
withdrawn consent, is no longer being followed at the Investigator’s discretion, or if the 
study is closed/terminated. 

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The end of study (EOS) is defined as the date of the last visit of the last participant 
in the study or last scheduled procedure for the last participant in the study. Note: 
Participants are considered ctDNA+ if the result of ctDNA testing was positive as of 
the date of the decision to stop enrollment in the ZEST study. If ctDNA testing was 
started prior to the date of the decision was made to stop enrollment and the result 
is obtained after the date of the decision to stop enrollment, and was positive, the 
participant will be considered part of the ctDNA+ population and currently 
monitored accordingly. For any additional ctDNA samples taken/tested after the 
date of the decision to stop enrollment, the testing process outlined in Table 12 
should be followed. For participant management under Protocol Amendment 04, 
refer to Table 12. Once the last participant consents to Protocol Amendment 04 (or 
withdraws) or meets any protocol-defined stopping criteria (Section 7), the study 
will transition to PACT. 

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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. Enrollment of new 
participants is permanently stopped due to Sponsor decision. 
Prescreening 
To qualify for Prescreening, participants must meet the following criteria: 
P1. 
Histologically confirmed Stage I to III non-metastatic primary invasive breast 
cancer that is one of the 2 following phenotypes: 
a. 
TNBC defined as:  
• 
ER and PgR negative, defined as IHC nuclear staining <1%, and 
• 
HER2− defined as follows: 
o IHC 0, 1+ without ISH, or 
o IHC 2+ and ISH non-amplified as defined by 2018 ASCO-CAP 
guidelines [Wolff, 2018] 
b. ER and/or PgR positive, HER2− breast cancer defined as follows: 
• 
ER and/or PgR positive, defined as IHC nuclear staining ≥1%, and 
• 
HER2−  defined as follows: 
o ICH 0, 1+ without ISH, or 
o IHC 2+ and ISH non-amplified as defined by 2018 ASCO-CAP 
guidelines [Wolff, 2018] 
Participants with multifocal tumors are eligible provided that all lesions are within 
the same quadrant and have similar ER, PgR, and HER2 staining. Multicentric 
and synchronous bilateral breast cancers are not allowed. 
For participants who received neoadjuvant therapy and have discordant ER, PgR, 
and/or HER2 receptor results between the diagnostic biopsy (pretreatment) and 
surgical pathology (post neoadjuvant therapy), the receptor status of the 
pretreatment specimen determines eligibility. If the biopsy and the surgical 
specimens are discrepant in the adjuvant setting (i.e., participants had initial 
surgery), results from the surgical specimen define HR status. Those participants 
determined to be TNBC based on the pretreatment specimen should not 
subsequently receive tamoxifen or aromatase inhibitor as part of their breast 
cancer treatment. 
Note: ER and PgR may be graded using the Allred scoring system, where TNBC 
is defined to be 0 out of 8 or 2 out of 8, or staining in <1% of cancer cells and 
HR+ is defined to be a score of ≥3 out of 8. 

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P2. 
New participants joining the study (i.e., have not previously provided 
Prescreening consent prior to Protocol Amendment 02) must meet the following 
criteria: 
a. 
For participants who underwent initial surgery (Adjuvant approach):  
• 
TNBC participants must meet at least 1 of the following criteria: 
• Node-positive (≥pN1, any tumor size), or 
• Node-negative (pN0) or axillary node micro-metastasis (pN1mi) 
with invasive primary tumor ≥15 mm 
• 
HR+ participants must meet at least 1 of the following criteria: 
• Node-positive with ≥4 involved nodes (≥pN2, any tumor size), or 
• Node-negative (pN0) or axillary node micro-metastasis (pN1mi) 
with invasive primary tumor >5 cm (≥pT3), or 
• Either node-positive with 1 to 3 involved nodes (pN1) OR node-
negative or axillary node micro-metastasis with invasive primary 
tumor >2 cm but ≤5 cm (pT2N0 or pT2N1mic). Invasive tumor 
must also meet 1 of the following: 
• 
Grade 3 
• 
Grade 1 or 2 with ER+/PgR- 
• 
Grade 1 or 2 with ER-/PgR+ 
b. 
For patients who underwent neoadjuvant chemotherapy followed by 
surgery (Neoadjuvant approach): 
• 
All participants must have shown a definitive response to preoperative 
chemotherapy by pathological, radiological, or clinical evaluation (see 
Appendix 1) 
• 
TNBC participants must have residual invasive breast cancer in the 
breast and/or resected lymph nodes (non-pCR) (any grade is allowed) 
• 
HR+ participants must have residual invasive breast cancer in the 
breast and/or resected lymph nodes (non-pCR), AND meet 1 of the 
following criteria:  
• Node-positive prior to or after neoadjuvant treatment (≥cN1 or 
≥pN1, any tumor size),  
• Invasive primary tumor size >2 cm prior to or after neoadjuvant 
treatment (≥cT2 or ≥pT2),  
c. 
For HR+ participants who underwent neoadjuvant endocrine-only 
therapy, followed by surgery (Neoadjuvant approach, but without 
any preoperative chemotherapy) 

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• 
All participants must have shown a definitive response to preoperative 
endocrine therapy by pathological, radiological, or clinical evaluation 
(see Appendix 1) 
• 
HR+ participants must have residual invasive breast cancer in the 
breast and/or resected lymph nodes (non-pCR), AND meet 1 of the 
following criteria: 
• Node-positive with ≥4 involved nodes (≥pN2, any tumor size), or 
• Node-negative (pN0) or axillary node micro-metastasis (pN1mi) 
with invasive primary tumor >5 cm (≥pT3), or 
• Either node-positive with 1 to 3 involved nodes (pN1) OR node-
negative or axillary node micro-metastasis with invasive primary 
tumor >2 cm but ≤5 cm (pT2N0 or pT2N1mic). Invasive tumor 
must also meet 1 of the following: 
• 
Grade 3 
• 
Grade 1 or 2 with ER+/PgR- 
• 
Grade 1 or 2 with ER-/PgR+ 
Participants who previously completed Prescreening under previous versions of 
the protocol and who are deemed to have been Prescreen failures due to negative 
ctDNA testing results on all allotted tests may re-enter Prescreening provided they 
are eligible to continue Prescreening testing as per protocol (see criterion P4) 
AND meet all staging criteria as defined above in criterion P2 a to c. 
Participants who are currently participating in ongoing Prescreening at the time of 
Protocol Amendment 02 consent, and who are eligible to continue Prescreening 
testing as per protocol (see criterion P4), must have Stage I to III non-metastatic 
primary invasive breast cancer as per criterion P1, but are not required to meet 
staging criteria as defined in criterion P2 a to c. As of the date of the decision to 
stop enrollment, prior prescreen-fail patients (who had not already signed 
Protocol Amendment 02 consent), are not allowed to be re-enrolled or 
reconsented and no further assessments or ctDNA testing are allowed. 
P3. 
HR+ breast cancer participants must have documented mutation in BRCA1 or 
BRCA2 that is predicted to be deleterious or suspected deleterious (known or 
predicted to be detrimental/lead to loss of function) identified through local 
testing. 
P4. 
Signed prescreening consent. 
New participants joining the study (i.e., that have not previously provided 
Prescreening consent prior to Amendment 02) must sign consent within the 
following timepoints: 
a. 
For TNBC participants (tBRCAwt or tBRCA unknown): TNBC 
participants who have not been tested for tBRCA or have no mutation 
identified (tBRCAwt) must sign prescreening consent no later than within 
12 weeks from the end of definitive therapy 

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• 
Note: Participants receiving pembrolizumab must also consent to 
Prescreening within 12 weeks of completing definitive therapy (i.e., 
curative-intent surgery, chemotherapy, and/or radiation, whichever 
happens last). Pembrolizumab is NOT included in the definition of 
definitive therapy in this protocol, and participants may continue to 
receive pembrolizumab as per standard of care during the study, with 
ctDNA testing performed according to the schedule outlined in Table 2 
(footnote a) 
b. For known tBRCAmut TNBC or HR+ breast cancer participants: 
Participants who have a known and documented deleterious or suspected 
deleterious tBRCA mutation identified through local testing must sign 
prescreening consent no later than 5 years from end of definitive therapy 
Participants who are currently participating in ongoing Prescreening at the time of 
implementation of Protocol Amendment 02, or who completed Prescreening in 
the past under previous versions of the protocol, must provide Prescreening 
consent for additional ctDNA testing as per Protocol Amendment 02, but are not 
required to meet the consent timepoint windows as described in criterion P4 a to 
b. 
Participants who are eligible to either re-enter Prescreening or to continue 
ongoing Prescreening ctDNA testing are those who continue to meet other 
prescreening eligibility criteria and meet 1 of the following criteria at the time of 
consent for Protocol Amendment 02:  
• 
Participant is currently participating in ongoing Prescreening at the time of 
Protocol Amendment 02 implementation, has at least 1 additional ctDNA test 
left per the original testing schedule, and has not been deemed a Prescreen 
failure. 
• 
Participant previously completed Prescreening under previous versions of the 
protocol and was deemed to have Prescreen-failed due to negative ctDNA 
testing results on all allotted tests, AND still remains within the defined testing 
duration window from end of definitive treatment at the time of reconsent: 
• Participants with TNBC (tBRCAwt or tBRCA unknown) may resume 
ctDNA testing so long as no more than 24 months has elapsed since the end 
of definitive treatment. 
• Participants with known tBRCAmut (either TNBC or HR+) may resume 
ctDNA testing so long as no more than 6 years has elapsed since the end of 
definitive treatment. 
Additional ctDNA testing for participants eligible to resume or continue 
Prescreening testing will occur according to the schedule outlined in Table 13, 
Table 14, and Figure 3. As of the date of the decision to stop enrollment, prior 
prescreen-fail patients (who had not already signed Protocol Amendment 02 
consent), are not allowed to be re-enrolled or reconsented and no further 
assessments or ctDNA testing are allowed. 

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P5. 
Completed prior standard therapy for curative intent, including all of the 
following, if indicated: neoadjuvant treatment, surgery, adjuvant radiotherapy, 
and adjuvant chemotherapy. Participants with HR+HER2− tBRCAmut breast 
cancer may be receiving concurrent adjuvant endocrine therapy. Participants with 
TNBC may receive concurrent adjuvant pembrolizumab, if clinically indicated. 
All participants may receive bisphosphonates or denosumab. Participants are 
allowed and encouraged to enter Prescreening as soon as possible per protocol, 
and may be eligible to start the Prescreening process prior to the completion of 
adjuvant therapy (see Figure 1 , Table 2, and Section 6.8 for further details of 
permitted concomitant medications). 
P6. 
An archival tumor tissue specimen of the primary tumor sufficient in quality and 
quantity for ctDNA assay design and tBRCA and HRD testing is required. As of 
the date of the decision to stop enrollment, no further tBRCA and HRD testing 
will be performed (see Section 1.3). 
NOTE: If the participant has a prior history or additional primary breast cancers, 
which appear eligible for prescreening in this ZEST trial (see exclusion 
criterion 12), the lesion considered at highest risk for recurrence based on the 
investigator’s discretion will be used for ctDNA assay design.  
P7. 
Have a significant risk of disease recurrence as assessed by the Investigator. 
P8. 
Have no known or suspected locally recurrent or metastatic disease as assessed by 
the Investigator. 
P9. 
Have no known nonmodifiable conflicts with other inclusion and exclusion 
criteria listed in Section 5.1 and Section 5.2, respectively. 
To be eligible for randomization in the study, participants must meet the full inclusion 
and exclusion criteria presented in Section 5.1 and Section 5.2, respectively. 
5.1. 
Inclusion Criteria 
Participants must meet all prescreening criteria to be included in the study. Participants 
are eligible to be included in Cohorts 1 and 2 of the study only if all of the following 
criteria are met: 
1. Stage I to III breast cancer per AJCC for breast cancer staging criteria 8th edition 
(see Section 8.2.1) with surgical resection of the primary tumor that is confirmed to 
be either: 
• TNBC, or 
• HR+/HER2− breast cancer with a known and documented deleterious or 
suspected deleterious tBRCA mutation  
Note: TNBC is defined as outlined in P1. ER and PgR may be graded using the 
Allred scoring system, where TNBC is defined to be 0 out of 8 or 2 out of 8, or 
staining in <1% of cancer cells and HR+ is defined to be a score of ≥3 out of 8. 
2. Completed prior standard therapy for curative intent, including all of the following, 
if indicated: neoadjuvant treatment, surgery, adjuvant radiotherapy, and adjuvant 
chemotherapy. Participants with HR+HER2− tBRCAmut breast cancer may be 

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receiving concurrent adjuvant endocrine therapy. Participants with TNBC may 
receive concurrent adjuvant pembrolizumab, if clinically indicated. All participants 
may receive concurrent bisphosphonates or denosumab (see Figure 1, Table 2, and 
Section 6.8 for further details of permitted concomitant medications). 
3. Participants with HR+ breast cancer must be on a stable regimen of endocrine 
therapy, if indicated, for at least 3 months prior to randomization. Ovarian 
suppression, if indicated, must also have been started at least 3 months prior to 
randomization. 
4. Detectable ctDNA as measured by central Signatera testing (refer to Table 2 for the 
timing of ctDNA testing). As of the date of the decision to stop enrollment, sample 
collection was stopped as outlined in Section 1.3.  
5. An archival tumor tissue specimen of the primary tumor sufficient in quality and 
quantity for ctDNA assay design and tBRCA and HRD testing is required. (Archival 
tissue must have been sent during Prescreening.) (See Prescreening criterion P6 for 
additional details.) 
6. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
7. Must be ≥18 years of age. 
8. Must have adequate organ and bone marrow function, as defined below.  
Absolute neutrophil count: 
≥1,500/μL 
Platelets: 
≥100,000/μL 
Hemoglobin: 
≥9 g/dL or 5.6 mmol/L 
Renal function: 
Calculated creatinine clearance ≥30 mL/min  
Total bilirubin: 
≤3 × ULN 
ALT 
≤2.5 × ULN 
Note: complete blood count (CBC) should be obtained without transfusion or receipt 
of colony-stimulating factors within 4 weeks prior to obtaining the sample. Creatinine 
clearance should be determined as per the Cockcroft-Gault formula. 
Participants with current active liver or biliary disease are excluded (with the 
exception of Gilbert’s syndrome or asymptomatic gallstones or otherwise stable 
chronic liver disease per Investigator assessment). Participants with mild hepatic 
impairment are allowed, defined as either AST >ULN and total bilirubin ≤ULN; any 
AST and total bilirubin >1.0× to 1.5× ULN. Participants with moderate hepatic 
impairment are allowed, defined as total bilirubin >1.5× to ≤3× ULN and any level of 
AST elevation. All participants must also have ALT ≤2.5xULN in order to be eligible 
for the study. 
9. Participants with toxicity from prior cancer therapy must have recovered to Grade 1. 
(A participant with Grade 2 neuropathy or any grade of alopecia is an exception to 
this criterion and may qualify for this study.)  
10. Must be able to swallow and retain orally administered study treatment. 
11. A female participant is eligible if she is not pregnant or breastfeeding, and at least 1 
of the following conditions applies:  
• 
Is not a woman of childbearing potential (WOCBP), as defined in Appendix 4. 

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OR 
• 
Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), as described in Appendix 4 (for France, see 
Section 10.14.1.2 and for Germany see Section 10.14.2.3), during the Treatment 
Period and for at least 180 days (except in France, see Section 10.14.1.1) after 
the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for 
the purpose of reproduction during this period. The Investigator should evaluate 
the effectiveness of the contraceptive method in relationship to the first dose of 
study treatment. 
• 
A WOCBP must have a negative pregnancy test (highly sensitive urine test or 
serum test as required by local regulations) within 72 hours before the first dose 
of study treatment. 
• 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be excluded 
from participation if the serum pregnancy result is positive. 
• 
Additional requirements for pregnancy testing during and after study treatment 
are described in Section 8.4.6. 
• 
The Investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
See Appendix 4 for a list of acceptable birth control methods (for France see 
Section 10.14.1.2 and for Germany see Section 10.14.2.3). Information must be 
captured appropriately within the site’s source documents. 
12. Male participants are eligible if they agree to the following during the Treatment 
Period and for at least 90 days (except France, see Section 10.14.1.1) after the last 
dose of study treatment (see Appendix 4 for a list of acceptable birth control 
methods; for France see Section 10.14.1.2 and for Germany see Section 10.14.2.3): 
• 
Be abstinent from intercourse as their preferred and usual lifestyle (abstinent on 
a long-term and persistent basis) and agree to remain abstinent 
OR 
• 
Must agree to use contraception/barrier as detailed below: 
• 
Agree to use a male condom (and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception as a 
condom may break or leak)  
PLUS 
• 
Male participants must refrain from donating sperm for at least 90 days 
after the last dose of study treatment (except in France, see 
Section 10.14.1.1) 
13. Must be able to understand the study procedures and agree to participate in the study 
by providing written informed consent (as described in Appendix 5), which includes 

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compliance with the requirements and restrictions listed in the ICF and in this 
protocol. 
5.2. 
Exclusion Criteria 
Participants are excluded from Cohorts 1 and 2 of the study if any of the following 
criteria are met: 
1. Prior treatment with a PARP inhibitor. 
2. Current treatment with a CDK4/6 inhibitor or endocrine therapy other than 
anastrozole, letrozole, exemestane, and tamoxifen, with or without ovarian 
suppression. 
3. Participants have any sign of metastasis or local recurrence after comprehensive 
assessment conducted per protocol. 
4. Participants have shown no definitive response to preoperative chemotherapy by 
pathologic, radiological, or clinical evaluation, in cases where preoperative 
chemotherapy was administered (see Appendix 1). 
5. Participants have systolic BP >140 mmHg or diastolic BP >90 mmHg that has not 
been adequately treated or controlled. 
6. Participants have any clinically significant gastrointestinal abnormalities that may 
alter absorption such as malabsorption syndrome or major resection of the stomach 
and/or bowels. 
7. Participants have received colony-stimulating factors (eg, granulocyte macrophage 
colony-stimulating factor or recombinant erythropoietin) within 4 weeks prior to the 
first dose of study treatment. 
8. Participants have previously or are currently participating in a treatment study of an 
investigational agent within 4 weeks of the first dose of therapy preceding the study. 
9. Participants have received live vaccine within 30 days of planned start of study 
randomization. Study participants can be vaccinated against Corona virus disease 
2019 (COVID-19) using vaccines authorized via the appropriate regulatory 
mechanisms (i.e. Emergency Use Authorization, Conditional Marketing 
Authorization or Marketing Authorization Application). Note: messenger ribonucleic 
acid (mRNA) and adenoviral-based COVID-19 vaccines are considered nonlive. If 
COVID-19 vaccine is administered at any time, the date, name of the COVID-19 
vaccine anatomic location, etc. as outlined in Section 6.8, must be entered in the 
eCRF. Refer to Appendix 3 for further information regarding COVID-19 vaccination 
timing and recommendations. 
10. Participants have known hypersensitivity to the components of niraparib, placebo, or 
their formulation excipients. 
11. Participants have undergone major surgery within 4 weeks of starting the first dose 
of study treatment or have not recovered from any effects of any major surgery. 
12. Participants have a second primary malignancy. Exceptions are the following: 

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• 
Adequately treated nonmelanoma skin cancer, curatively treated in situ cancer 
of the cervix, ductal carcinoma in situ (DCIS) of the breast, Stage I Grade 1 
endometrial carcinoma. 
• 
Other solid tumors and lymphomas (without bone marrow involvement) 
diagnosed ≥5 years prior to randomization and treated with no evidence of 
disease recurrence and for whom no more than 1 line of chemotherapy was 
applied 
13. Participants have current active pneumonitis or any history of pneumonitis requiring 
steroids (any dose) or immunomodulatory treatment within 90 days of planned start 
of the study. 
14. Participants have any clinically significant concomitant disease or condition (such as 
transfusion-dependent anemia or thrombocytopenia) that could interfere with, or for 
which the treatment might interfere with, the conduct of the study or that would, in 
the opinion of the Investigator, pose an unacceptable risk to the participants in this 
study. 
15. Participants have any psychological, familial, sociological, or geographical condition 
potentially hampering compliance with the study requirements and/or follow-up 
procedures. Those conditions should be discussed with the participants before study 
entry. 
16. Participants have high medical risk due to a serious, uncontrolled medical disorder; 
nonmalignant systemic disease; or active, uncontrolled infection (including 
COVID-19). Examples include, but are not limited to, uncontrolled ventricular 
arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure 
disorder, unstable spinal cord compression, superior vena cava syndrome, active 
uncontrolled coagulopathy, bleeding disorder, or any psychiatric disorder that 
prohibits obtaining informed consent. 
17. Participant is pregnant, breastfeeding, or expecting to conceive children while 
receiving study treatment and/or for up to 180 days after the last dose of study 
treatment (except France, see Section 10.14.1.1). 
18. Participants have presence of hepatitis B surface antigen or a positive hepatitis C 
antibody test result at Screening or within 3 months prior to first dose of study 
treatment. Participants with presence of hepatitis B core antibody should also be 
excluded. NOTE: Participants with chronic hepatitis B virus (HBV) infection, who 
meet the criteria for anti-HBV therapy may be eligible if the participant is on a 
suppressive antiviral therapy prior to initiation of cancer therapy. 
NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled only if a confirmatory negative Hepatitis C RNA PCR is obtained. 
Also, participants with a history of Hepatitis C infection may be eligible if they have 
both: completed curative therapy, have an HCV viral load <quantifiable limit. 
19. Participant is immunocompromised. Participants with splenectomy are allowed. 
Participants with known human immunodeficiency virus (HIV) are allowed if they 
meet the following criteria: 
a. 
Cluster of differentiation 4 ≥350/µL and viral load <400 copies/mL 

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b. No history of acquired immunodeficiency syndrome-defining opportunistic 
infections within 12 months prior to enrollment. 
c. 
No history of HIV-associated malignancy for the past 5 years. 
d. Concurrent antiretroviral therapy as per the most current National Institutes of 
Health (NIH) Guidelines for the Use of Antiretroviral Agents in Adults and 
Adolescents Living with HIV [NIH, 2021] started >4 weeks prior to study 
enrollment. 
20. Participants have a known history of MDS or AML. 
5.3. 
Lifestyle Considerations 
Not applicable for this study.  
5.4. 
Prescreen Failures and Screen Failures 
Participants will undergo prescreening followed by screening for eligibility in the study 
as outlined in Section 1.3 and Section 5. Prescreen failures are defined as participants 
who consent to participate in the clinical study but are not subsequently eligible for 
screening. Participants who do not meet ctDNA criteria due to insufficient tissue may 
submit additional tissue. Additionally, participants may be tested multiple times for the 
presence of ctDNA (up to 10 times over 2 years or up to 18 times over a maximum of 
6 years since end of definitive therapy, depending on the cohort; see Table 2, Table 13, 
and Figure 3).  
A screen failure occurs when a participant who consents to participate in the clinical 
study and successfully completes prescreening is not subsequently randomized. 
Individuals who meet the prescreening criteria to enter into screening but do not meet the 
Screening criteria for participation in this study may be rescreened. Participants should 
not be rescreened more than twice. Participants who are rescreened are required to sign a 
new ICF and should be assigned a new participant number for every 
Screening/Rescreening event. Rescreened participants will not be required to complete 
prescreening procedures. All screening criteria (with the exception of those outlined in 
the SOA; Table 3) are required to be repeated if they fall outside of 6 weeks prior to first 
dose. 
Participants that were deemed prescreen failures under previous versions of the protocol 
due to negative ctDNA test results may have the opportunity to re-enter prescreening and 
be offered additional tests (as outlined in Table 2 and Figure 3) if they are within the 
window for testing and meet all the prescreening eligibility criteria, including but not 
limited to Prescreening criteria P2 and P4, once Protocol Amendment 02 is implemented. 
These participants must sign the prescreening ICF again. As of the date of the decision to 
stop enrollment, prior prescreen-fail patients (who had not already signed Protocol 
Amendment 02 consent), are not allowed to be re-enrolled or reconsented and no further 
assessments or ctDNA testing are allowed. 
A minimal set of prescreen or screen failure information is required to ensure transparent 
reporting of prescreen or screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
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failure details, eligibility criteria, disease characteristics, and prior therapy and surgeries 
(as per the SOA; Section 1.3), information from any previous trials with the same 
investigational medicinal product (IMP), any protocol deviations, and any SAEs. 

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6. 
STUDY TREATMENTS AND CONCOMITANT THERAPY 
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
Study treatments to be administered in this study are summarized in Table 15 and 
Section 6.1.1. For further details, refer to the Pharmacy Manual and/or the product label. 
6.1. 
Study Treatments Administered 
Details about the investigational products are provided in Table 15. As of the date of the 
decision to stop enrollment, the study was centrally unblinded and participants in the 
placebo arm are to stop administration of placebo. 
Table 15 
Investigational Products  
 
Investigational Product 
Treatment name 
Niraparib 
Placebo 
Type 
Drug 
Drug 
Dose formulation 
Unit dose strength 
Route of 
administration 
Use 
Sourcing 
Provided centrally by the Sponsor 
Provided centrally by the Sponsor 
Packaging and 
Labeling 
 
 
Each bottle will be labeled as required 
per country requirements. 
 
 
Each bottle will be labeled as required 
per country requirements. 
Manufacturer 
GSK 
GSK 
Abbreviation: NA=not applicable. 
6.1.1. 
Niraparib 
Niraparib ([3S]-3-[4-[7-(aminocarbonyl)-2H-indazol-2-yl] phenyl] piperidine [tosylate 
monohydrate salt]) is an orally available, potent, and highly selective PARP1 and PARP2 
inhibitor. The excipients for niraparib are lactose monohydrate and magnesium stearate. 
Niraparib will be supplied as 
. Niraparib tablets will be packaged in high-
density polyethylene bottles with child-resistant closures. Participants will be provided 
enough tablets to accommodate 28 days of dosing plus up to 3 days for visit flexibility.  
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Table 16 
Recommended Initial Starting Dose 
Hepatic Function 
Baseline Criteria 
Starting Dose 
Normal or mildly 
impaired hepatic 
functiona 
Weight <77 kg, platelets 
<150,000/μL, or both 
200 mg once daily (two 100-mg tablets) 
Weight ≥77 kg and platelets 
≥150,000/μL 
300 mg once daily (three 100-mg tablets) 
Moderate hepatic 
impairmentb 
Weight <77 kg, platelets 
<150,000/μL, or both 
200 mg once daily (two 100-mg tablets) 
Weight ≥77 kg and platelets 
≥150,000/μL 
200 mg once daily (two 100-mg tablets) 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal.  
a. 
Mildly impaired hepatic function is defined as either AST >ULN and total bilirubin ≤ULN; or any AST and total 
bilirubin >1.0× to 1.5× ULN  
b. 
Moderate hepatic impairment is defined as total bilirubin >1.5× and ≤3× ULN and any level of AST elevation.  
Participants will be instructed to take their niraparib dose at approximately the same time 
each day, except on clinic visit days. On these days, participants should hold their 
niraparib dose until their visit; it will be taken at the site. Participants must swallow and 
not chew 
 If a participant vomits or misses a dose of niraparib, a replacement 
dose should not be taken. Bedtime administration may be a potential method for 
managing nausea. Niraparib may be taken with or without food or water. 
Dose adjustments are described in Section 6.4. Once initial starting dose has been 
assigned, dose escalation is not allowed. 
The label text of the study treatments will comply with Good Manufacturing Practice and 
national legislation to meet the requirements of the participating countries. Blinded 
niraparib study treatment will be provided to participants on niraparib treatment 
only. Open-label supplies will be provided to those participants upon transition to 
the PACT Phase. Participants on placebo treatment will not receive further study 
treatment.  
 
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6.2. 
Preparation, Handling, Storage, and Accountability 
Preparation 
The Pharmacy Manual contains instructions for administration as well as complete 
instructions for collection, processing, shipping, and handling. A pharmacist, 
Investigator, or designee will dispense study treatment for each participant according to 
the protocol and the Pharmacy Manual. 
Handling and Storage (Including Disposal) 
1. The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
2. Only participants randomized in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the Investigator and authorized site staff. 
3. Precaution will be taken to avoid direct contact with the study treatment. A Material 
Safety Data Sheet describing occupational hazards and recommended handling 
precautions will be provided to the Investigator. In the case of unintentional 
occupational exposure, notify the monitor, GSK Medical Monitor, and/or GSK study 
contact. 
4. At the end of the study, when all participants have stopped protocol treatment, 
complete drug reconciliation per batch should be available at the site for verification 
in order to allow drug destruction or return procedure. After receiving Sponsor 
approval in writing, the investigational site is responsible for destruction of study 
treatment according to local regulations. If a site does not have the capability for 
onsite destruction, the Sponsor will provide a return for destruction service through a 
third party. Both the unused and expired study treatment must be destroyed, upon 
authorization of the Sponsor, according to local regulations and procedures, and a 
copy of the destruction form must be filed in the study binder. 
5. The treatment provided for this study is to be used only as indicated in this protocol 
and only for the participants entered in this study. 
6. Further guidance and information for the final disposition of unused study treatment 
are provided in the Pharmacy Manual. 
Accountability 
1. The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
2. Details of maintaining drug accountability, including information on the 
accountability log, will be provided in the Pharmacy Manual. 
 

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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Randomization 
All participants will be centrally randomized using 
 
 
 of the date of the decision to stop enrollment, no 
additional randomizations were approved by the sponsor. 
In Cohort 1, participants with confirmed detectable ctDNA and confirmation of 
tBRCAmut status will be randomized 1:1 to either niraparib or placebo. 
In Cohort 2, participants with confirmed detectable ctDNA and confirmation of tBRCAwt 
status or with undetermined tBRCA status will be randomized 1:1 to either niraparib or 
placebo. 
6.3.2. 
Stratification 
In Cohort 1, randomization of participants will be stratified based on the following 
factors: 
• Time from last intervention to randomization (<6 months versus ≥6 months). 
Time of last intervention is defined as the date of most recent oncological 
surgery, date of last adjuvant chemotherapy, or date of last radiotherapy 
fraction, whichever occurred later. 
• HR status (positive versus negative) 
• Prognostic Stage of breast cancer (Stage I/II versus Stage III) (Appendix 13) 
In Cohort 2, randomization of participants will be stratified based on the following 
factors:  
• Time from last intervention to randomization (<6 months versus ≥6 months). 
Time of last intervention is defined as the date of most recent oncological 
surgery, date of last adjuvant chemotherapy, or date of last radiotherapy 
fraction, whichever occurred later. 
• Prior use of adjuvant capecitabine (yes versus no) 
• Prognostic Stage of breast cancer (Stage I/II versus Stage III) (Appendix 13) 
6.3.3. 
Blinding and Breaking the Blind 
As of the date of the decision to stop enrollment, the study was centrally unblinded to 
allow participants on active treatment to have the option to continue treatment with 
niraparib if considered in the participants best interest by the Investigator, and properly 
documented. Administration of placebo must be stopped for participants in the placebo 
arm. 
The identity of the treatments will be concealed by the use of study treatments that are all 
identical in appearance, packaging, labeling, and schedule of administration. 
The participant, Investigator, blinded study staff, and the blinded Sponsor study team and 
its representatives will be blinded to the participant’s assigned treatment from the time of 
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randomization until database lock. For participants who are ongoing on treatment at the 
end of the study, the study blind may be lifted to enable continuation of niraparib 
treatment, if needed. Study treatment assignment will be available to the Investigator 
upon request for post-study treatment planning. 
If an individual’s role on the study requires information about treatment assignment 
(eg, an individual is involved in emergency unblinding), procedures will be used to 
ensure all other personnel remain blinded. 
In the event unblinding has occurred, the circumstances necessitating unblinding (ie, date 
and details about the situation leading to unblinding) must be documented promptly, and 
the Sponsor Medical Monitor notified as soon as possible. Only the Principal Investigator 
or delegate should be unblinded to the respective participant’s code. Study site personnel 
and Sponsor personnel directly associated with the conduct of the study should not be 
unblinded. In the event of inadvertent participant unblinding, the participant must 
discontinue study intervention, but would be offered the option to continue receiving 
niraparib (if applicable) using another vehicle, if available. 
GSK’s Global Clinical Safety and Pharmacovigilance staff may unblind the treatment 
assignment for any participant with an SAE. If the SAE requires that an expedited 
regulatory report be sent to 1 or more regulatory agencies, a copy of the report, 
identifying the participant’s treatment assignment, may be sent to the Investigators in 
accordance with local regulations and/or GSK policy. 
6.4. 
Planned Dose Adjustments 
6.4.1. 
Dose Levels and Dose Adjustment 
To manage adverse reactions, Investigators may consider interruption of treatment, dose 
reduction, or discontinuation, consistent with the following guidance. The severity of 
AEs will be graded utilizing the National Cancer Institute Common Toxicity Criteria for 
Adverse Events (NCI-CTCAE), Version 5.0. Guidelines for dose modifications and 
interruptions for management of common toxicities associated with the study treatment(s) 
are provided in Table 17, Table 18, and Table 19. Participants who are on treatment with 
niraparib/placebo, as well as standard of care therapies such as endocrine therapy in 
Cohort 1 or concurrent adjuvant pembrolizumab therapy, should have decisions regarding 
dose interruptions/reductions of niraparib/placebo and standard of care therapies made 
independently, according to investigator-assessed causality. 
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Once a dose is reduced, the participant must remain at the reduced dose for the study; 
even if the AE resolves, the dose should not be re-escalated. 
Table 17 
Niraparib/Placebo Dose Reduction for Adverse Reactions 
Dose Level 
Initial Dose: 300 mg/day 
Initial Dose: 200 mg/day 
Starting dose 
300 mg/day (three 100-mg tablets) 
200 mg/day (two 100-mg tablets) 
First dose reduction 
200 mg/day (two 100-mg tablets) 
100 mg/day (one 100-mg tablet) 
Second dose reduction 
100 mg/day (one 100-mg tablet) 
NA or discontinuation of niraparib 
Abbreviation: NA=not applicable. 
Table 18 
Dose Modifications for Nonhematologic Adverse Reactions 
Nonhematologic NCI-CTCAE Grade ≥3 adverse 
reaction where prophylaxis is not considered feasible 
or adverse reaction event persists despite treatment 
Withhold niraparib/placebo until resolution of 
adverse reaction and/or for a maximum of 28 days. 
Resume niraparib/placebo at a reduced dose per 
Table 17.  
NCI CTCAE Grade ≥3 treatment-related adverse 
reaction event lasting more than 28 days while the 
participant is administered niraparib/placebo 
100 mg/day 
Discontinue medication. 
Abbreviation: NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events. 
Table 19 
Dose Modifications for Hematologic Adverse Reactions 
Weekly blood draws for CBC will be monitored until the adverse reaction resolves, and to ensure the safety 
of the new dose, weekly blood draws for CBC will also be required for an additional 4 weeks after the 
adverse reaction has been resolved to the specified levels, after which monitoring every 4 weeks may 
resume. 
Platelet count <100,000/µL 
First occurrence: 
• 
Withhold niraparib/placebo for a maximum of 28 days and monitor 
blood counts weekly until platelet counts return to ≥100,000/µL. 
• 
Resume niraparib/placebo at the same or reduced dose per Table 
17. 
• 
If nadir platelet count was <75,000/µL, resume at a reduced dose 
after recovery. 
Second or third occurrence: 
• 
Withhold niraparib/placebo for a maximum of 28 days and monitor 
blood counts weekly until platelet counts return to ≥100,000/µL. 
• 
Resume niraparib/placebo at a reduced dose per Table 17. 
• 
Discontinue niraparib/placebo if the platelet count has not returned 
to acceptable levels within 28 days of the dose interruption period or 
if the participant has already undergone dose reduction to
g 
once daily.a 
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Neutrophil <1,000/µL or  
Hemoglobin <8 g/dL 
• 
Withhold niraparib/placebo for a maximum of 28 days and monitor 
blood counts weekly until neutrophil counts return to ≥1,500/µL or 
hemoglobin returns to ≥9 g/dL. 
• 
Resume niraparib/placebo at a reduced dose per Table 17. 
• 
Discontinue niraparib/placebo if neutrophil or hemoglobin level has 
not returned to acceptable levels within 28 days of the dose 
interruption period, or if the participant has already undergone dose 
reduction to
mg once daily.a 
Hematologic adverse 
reaction requiring RBC 
and/or platelet transfusion 
• 
For participants with platelet count ≤10,000/μL, platelet transfusion 
should be considered. If there are other risk factors such as 
coadministration of anticoagulation or antiplatelet drugs, consider 
interrupting these drugs and/or transfusion at a higher platelet count. 
• 
RBC transfusion is at the discretion of the Investigator. 
• 
Resume niraparib/placebo at a reduced dose. 
Abbreviations: AML=acute myeloid leukemia; CBC=complete blood count; MDS=myelodysplastic syndrome; RBC=red 
blood cell. 
a If MDS/AML is confirmed, discontinue niraparib/placebo. 
 
6.5. 
Study Treatment Compliance 
When participants self-administer study treatment at home, compliance with niraparib 
will be assessed by counting returned 
 during the site visits and will be documented 
in the source documents and relevant form. Deviation(s) from the prescribed dosage 
regimen should be recorded. 
A record of the quantity of niraparib dispensed to and administered by each participant 
must be maintained and reconciled with study treatment and compliance records. 
Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions, will also be recorded. 
6.6. 
Treatment of Overdose 
For this study, a dose of niraparib/placebo greater than indicated in this protocol within 
the specified administration window will be considered an overdose. 
The Investigator should contact the GSK Medical Monitor immediately upon learning of 
an overdose and should do the following: 
1. Closely monitor the participant for AE/SAE and laboratory abnormalities.  
2. Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF. Refer to Section 10.8. 
Decisions regarding overdose management, monitoring duration, dose interruptions, or 
dose modifications will be made by the Investigator in consultation with the GSK 
Medical Monitor based on the clinical evaluation of the participant. 
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6.7. 
Treatment After the End of the Study 
At the time of study closure, participants who are experiencing therapeutic benefit from 
treatment and an acceptable tolerability profile may have the option to continue treatment 
with niraparib after the end of the study. For those participants that may continue 
receiving niraparib after the end of the study, they may continue to be followed for safety 
until disease progression, unacceptable toxicity, initiation of new anticancer therapy, 
withdrawal of consent, or discontinuation for any other reason. 
As of the date of the decision to stop enrollment, upon discontinuation from assigned 
study treatment, participants may receive additional (non-protocol) therapy at the 
discretion of the treating physician. For participants who discontinue study treatment, any 
poststudy intervention will not be provided as part of the protocol unless otherwise 
specified in Section 1.3 (Table 4, Table 5, and Table 6).  
The Investigator is responsible for ensuring that consideration has been given to the 
poststudy care of the participant’s medical condition, whether or not GSK is providing 
specific poststudy treatment. 
The EOS is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure for the last participant in the study. 
6.7.1. 
Continued Access to Study Intervention  
Participants receiving study treatment (niraparib) at the time of the final analysis 
DCO date may continue to receive niraparib if, in the opinion of their treating 
physician, they are benefiting from continued treatment, and they do not meet any 
protocol-defined treatment discontinuation criteria (Section 7). Niraparib will 
continue until a discontinuation criterion, as assessed by the Investigator, has been 
met.  
Participants who continue niraparib in the PACT Phase will be cared for in 
accordance with local standard clinical practice at a participant’s particular site, in 
addition to surveillance scans.  
Participants will continue to be monitored for all SAEs, AEs leading to treatment 
discontinuation, overdoses, and pregnancy and AESIs while receiving niraparib. 
With the exception of SAEs, AEs leading to treatment discontinuation, overdoses 
and pregnancy cases and AESIs that must continue to be reported to GSK, 
information relating to participant care will be recorded on participant medical 
records and will not otherwise be reported for the purposes of this study. 
Investigators must continue to report all SAEs, AESIs, AEs leading to treatment 
discontinuation, overdose and pregnancy reports until 30 days after the 
participant’s last dose of study treatment in accordance with Section 10.8.  
Post final analysis DCO date, reporting and follow up of SAEs, AESIs, AEs leading 
to discontinuation, overdose and pregnancy reports will be done via paper forms (or 
alternative reporting method as indicated by Sponsor, should one become available) 
(see Section 10.9, Section 10.10, and Section 10.11 for details). For dispensing of 
niraparib and maintaining niraparib accountability in the PACT Phase, please refer 
to Section 6, as well as the Pharmacy Manual. Surveillance scans for disease 

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progression and/or recurrence will be provided per protocol. All other assessments 
will revert to standard of care at their site. 
Note: All SAEs assessed as related by the Investigator must continue to be reported 
for all study participants until study close out. All AESIs, regardless of causality, 
must continue to be reported for all study participants until death or loss to follow 
up. 
Participants currently in prescreening for ctDNA testing must have their final 
ctDNA test drawn prior to DCO and will not be eligible to continue on study once 
DCO is reached. After DCO is reached, participants eligible for surveillance scans 
(i.e., participants randomized to placebo and participants who were ctDNA+ve prior 
to date of decision to stop enrollment), as outlined in Table 12, may continue 
receiving surveillance scans until disease progression and/or recurrence or a 
stopping criterion is met as listed in Section 7. 
6.8. 
Concomitant Medications and Nondrug Therapies 
Participants should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, as appropriate. 
Participants will be instructed to inform the Investigator prior to starting any new 
medications from the time of first dose of study treatment until the Safety Follow-up 
Visit occurring 30 days after end of study treatment. Any concomitant medication(s), 
including nonprescription medication(s) and herbal product(s), taken during the study 
will be recorded in the eCRF. The minimum requirement is that drug name, dose, and the 
dates of administration are to be recorded. Additionally, a complete list of all prior 
anticancer therapies will be recorded in the eCRF. Past and current endocrine therapies, 
ovarian suppressive agents, antiresorptive therapies such as bisphosphonates or 
denosumab, and pembrolizumab should be recorded in the study database. 
The COVID vaccine given at any time should be recorded as a concomitant medication; 
the date of vaccination, name of the vaccine, dose number (1st/2nd/booster injection), 
injection site (anatomic location), and injection side (laterality) must be entered into the 
eCRF. Refer to Appendix 3 for further information regarding COVID-19 vaccination 
timing and recommendations. 
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification. 
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file. Any such changes 
will be communicated to the investigative sites in the form of a letter. 
6.8.1. 
Prohibited Medications and Nondrug Therapies 
Known prior medications that exclude a participant from participating in the study are 
described in the exclusion criteria (Section 5.2). 

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Participants are prohibited from receiving the following therapies during the Screening 
and Treatment Periods of this study: 
• Systemic anticancer or anticancer biological therapy; however, biological 
therapy for the treatment of COVID-19 and other non-oncologic conditions is 
permitted. Concurrent endocrine therapy is permitted, if indicated. Concurrent 
adjuvant pembrolizumab is permitted, if clinically indicated, and as specified 
in the Schedule of Activities (Table 2 footnote a, Table 3, and see Figure 1 ). 
• Chemotherapy. 
• Investigational agents other than niraparib. 
• Prophylactic cytokines (eg, granulocyte colony-stimulating factor) should not 
be administered in the first cycle of the study but may be administered in 
subsequent cycles according to local guidelines. 
• Live vaccines within 30 days prior to the first dose of study treatment and 
while participating in this clinical study. 
An increased risk of infection by the administration of live virus and bacterial 
vaccines has been observed with conventional chemotherapy drugs. Effects 
with niraparib are unknown; therefore, live virus and bacterial vaccines should 
not be administered to participants in the study. Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, 
chicken pox, yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid 
(oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed. Study participants can be vaccinated against 
COVID-19 as outlined in Section 5.1 and Section 6.8. Intranasal influenza 
vaccines (eg, FluMist) are live attenuated vaccines and are not allowed. 
The niraparib safety profile includes risk for thrombocytopenia; therefore, participants 
should be advised to use caution when taking anticoagulants (eg, warfarin) and 
antiplatelet drugs (eg, aspirin). In addition, given the reported small risk of 
thrombocytopenia with non-mRNA-based COVID-19 vaccinations, whenever possible, a 
28-day window should be allowed between administration of non-mRNA COVID-19 
vaccination and initiation of niraparib therapy. 
Even though inhibition of CYP3A4 in the liver is not expected, the potential to inhibit 
CYP3A4 at the intestinal level has not been established at relevant niraparib 
concentrations. Therefore, caution is recommended when niraparib is combined with 
active substances the metabolism of which is CYP3A4-dependent and, notably, those 
having a narrow therapeutic range (eg, ciclosporin, tacrolimus, alfentanil, ergotamine, 
pimozide, quetiapine, and halofantrine). 
Neither niraparib nor the primary circulating metabolite, M1, is a CYP3A4 inducer in 
vitro. In vitro, niraparib weakly induces CYP1A2 at high concentrations, and the clinical 
relevance of this effect could not be completely ruled out. M1 is not a CYP1A2 inducer. 
Therefore, caution is recommended when niraparib is combined with active substances 
the metabolism of which is CYP1A2-dependent and, notably, those having a narrow 
therapeutic range (eg, clozapine, theophylline, and ropinirole). 

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Niraparib is not an inhibitor of bile salt export pump (BSEP). In vitro, niraparib inhibits 
P-glycoprotein (P-gp) very weakly and breast cancer resistance protein (BCRP) with a 
half-maximal inhibitory concentration (IC50)=161 µM and 5.8 µM, respectively. 
Therefore, a clinically meaningful interaction related to an inhibition of these efflux 
transporters, although unlikely, cannot be excluded. Caution is then recommended when 
niraparib is combined with substrates of BCRP (eg, irinotecan, rosuvastatin, simvastatin, 
atorvastatin, and methotrexate). 
Niraparib is an inhibitor of multidrug and toxin extrusion protein (MATE)1 and -2 with 
IC50 of 0.18 µM and ≤0.14 µM, respectively. Increased plasma concentrations of 
co-administered medicinal products that are substrates of these transporters 
(eg, metformin) cannot be excluded. 
In vitro, niraparib weakly inhibits the organic cation transporter 1 (OCT1) with an 
IC50=34.4 µM. Caution is recommended when niraparib is combined with active 
substances that undergo an uptake transport by OCT1 such as metformin. 
Physicians should follow the current versions of the niraparib IB for information on the 
general management of participants. 
6.8.2. 
Other Study Restrictions 
Participants who are blood donors should not donate blood during the study and for 
90 days after the last dose of study treatment. 
Participants should maintain a normal diet, unless modifications are required to manage 
an AE such as diarrhea, nausea, or vomiting. 

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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Discontinuation of specific sites or of the study as a whole are detailed in Appendix 5. 
7.1. 
Withdrawal/Stopping Criteria 
Participants will continue to receive their assigned treatment or assigned assessments 
(e.g., participants not on study treatment and receiving surveillance scans) until 
disease recurrence as assessed by RECIST v1.1, death, withdrawal of consent, loss to 
follow-up, or until unacceptable toxicity, including meeting stopping criteria for liver 
chemistry defined in Section 7.1.1. Note that disease recurrence excludes all in situ 
cancer events (see Section 8.3.1). Those participants who have completed 39 cycles 
(approximately 3 years) with no evidence of recurrence will have the option to either 
continue treatment or stop treatment at that time. 
In addition, study treatment may be permanently discontinued for any of the following 
reasons, unless otherwise specified below: 
• AE 
− If a participant has any treatment-related NCI-CTCAE v5.0 Grade 3 or 4 
AEs (see Table 19 on separate guidelines for platelet count) that have not 
reverted to NCI-CTCAE v5.0 Grade 1 or better within 28 days of dose 
interruption. 
− If upon re-challenge with study treatment at the lowest allowable dose any 
NCI-CTCAE v5.0 Grade 3 or 4 AEs recur, the participant must be 
discontinued from niraparib treatment. 
• Must be permanently discontinued for MDS or AML 
• Additional primary malignancy other than MDS or AML may require 
discontinuation. To be assessed by the treating physician in agreement with 
the Sponsor. 
• Must be permanently discontinued for Posterior Reversible Encephalopathy 
Syndrome (PRES) 
• Risk to the participant as judged by the Investigator, Sponsor, or both 
• Severe noncompliance with protocol as judged by the Investigator, Sponsor, 
or both. 
• Must be permanently discontinued for pregnancy. 
• Must be permanently discontinued for withdrawn consent. 
• Inadvertent participant unblinding 
• Lost to follow-up. 
• Study is closed or terminated. 

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If a participant with any of the above criteria is allowed to continue study treatment, the 
Investigator must contact the GSK Medical Monitor. 
The primary reason that study treatment was permanently discontinued must be 
documented in the participant’s medical records and eCRF. 
If the participant voluntarily discontinues from treatment due to toxicity, “adverse event 
(AE)” will be recorded as the primary reason for permanent discontinuation on the eCRF. 
Once a participant has permanently discontinued from study treatment, the participant 
will not be allowed to be re-treated on study but would be offered the option to continue 
receiving niraparib (if applicable). 
All participants must be followed for survival, up to the end of study as defined in this 
protocol. Discontinuation of study intervention does not impact participation in the study. 
Participants who discontinue from study treatment will continue to receive follow-up 
assessments as specified in the Schedule of Activities (Table 3) and described in 
Section 4.1, and data collection should continue. 
If the participant does not agree to continue in-person visits during the follow-up period, 
a modified follow-up must be arranged to ensure the collection of endpoints and safety 
information. This could be a telephone contact with the participant, contact with a 
relative or treating physician, or collecting information from medical records. The 
approach taken should be recorded in the medical records. A participant who agrees to 
modified follow-up is not considered to have withdrawn consent or to have withdrawn 
from the study. 
Under Protocol Amendment 03, on the date of the decision to stop enrollment, all 
randomization to study treatment is discontinued. All participants on study are centrally 
unblinded and those on placebo will stop the study intervention immediately, as outlined 
in Table 6. Participants on niraparib may continue treatment until disease recurrence at 
the discretion of the Investigator if they are deriving benefit from treatment. Participants 
will be managed as outlined in Table 11. Participants discontinued from study 
intervention will have follow-up assessments as outlined in Table 6. See Table 5 for end 
of study assessments for participants that are ctDNA+ and not yet randomized.  
Following PACT implementation, all recruited participants who no longer receive 
study treatment, should be managed as per Section 6.7.1. 
 
7.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
ensure participant safety and evaluate liver event etiology. 
Discontinuation of study treatment for abnormal liver tests is required when the following 
occurs: 
• A participant meets one of the conditions outlined in the Liver Chemistry 
Stopping and Increased Monitoring Algorithms ( Figure 4 and Figure 5 ) 
OR 

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• In the presence of abnormal liver chemistry not meeting protocol-specified 
stopping rules, if the Investigator believes that it is in the best interest of the 
participant. 
 
 
 
Figure 4 
Liver Chemistry Stopping and Increased Monitoring Algorithm for 
Participants with Entry Criteria ALT ≤2.5×ULN 
 
 
Abbreviations: ALT=alanine aminotransferase; INR=international normalized ratio; SAE=serious adverse 
event; ULN=upper limit of normal. 
The Liver Safety Required Actions and Follow-up Assessments section can be found in 
Appendix 6. 

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Figure 5 
Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT ≥3×ULN but <8×ULN for Participants with Entry 
Criteria ALT ≤2.5×ULN  
 
Abbreviations: ALT=alanine aminotransferase; bili=bilirubin; INR=international normalized ratio; 
SAE=serious adverse event; ULN=upper limit of normal. 
The Liver Safety Required Actions and Follow-up Assessments section can be found in 
Appendix 6. 
7.1.1.1. 
Restart/Rechallenge After Liver Stopping Criteria Met 
Study intervention restart/rechallenge after liver chemistry stopping criteria are met is 
allowed in this study. If participant meets liver chemistry stopping criteria, do not 
restart/rechallenge participant with study treatment unless all of the following occurs: 
• GSK Medical Governance approval is granted. 
AND 
• Ethics and/or Institutional Review Board (IRB) approval is obtained, if 
required. 
AND 
• Separate consent for treatment restart/rechallenge is signed by the participant, 
and the participant is informed of any associated risks. 
• Refer to Appendix 6 for details on the restart/rechallenge process. 

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• If GSK Medical Governance approval to restart/rechallenge participant with 
study treatment is not granted, then the participant must permanently 
discontinue study treatment and should continue in the study for protocol-
specified follow up assessments. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
Specific reasons for discontinuing from the study include the following: 
• Withdrawal of consent by the participant, who is at any time free to 
discontinue participation in the study, without prejudice to further treatment 
• Lost to follow-up 
• Death from any cause 
• Sponsor’s decision to terminate study 
• Investigator’s decision 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
Documentation of participant consent for Further Biomedical Research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified will 
be destroyed. If a participant withdraws from the study, he/she may request destruction of 
samples taken and not tested, and the Investigator must document this in the site study 
records. Terms and conditions for participant withdrawal will be fully detailed in the ICF. 
If the participant withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. 
As of the date of the decision to stop enrollment, participants found to be on placebo 
must stop study intervention immediately. Participants deriving benefit from niraparib, as 
determined by the Investigator, will continue to receive treatment until disease 
recurrence. For participants randomized onto the study, participants will be considered to 
have completed the study when they have completed their last study procedure (as 
outlined in Section 1.3). 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible, counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether the participant wishes to 
and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the participant (where possible, 

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3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including 
those who did not get study treatment. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented, and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 
7.3.1. 
Further Biomedical Research Maintaining Confidential Participant 
Information 
The Sponsor will conduct Further Biomedical Research on specimens and data collected 
during this study. This research may include genetic and genomic analyses, gene 
expression profiling, proteomics, metabolomics, and the measurement of other analytes 
after the study is completed. It may also include analysis of histological and/or clinical 
images and data. Such research is for biomarker testing to address emergent questions not 
described elsewhere in the protocol and will only be conducted on specimens from 
properly consented participants and per local regulations. 
In an effort to optimize the research that can be conducted with Further Biomedical 
Research specimens, it is essential to link the study participant’s clinical study data with 
Further Biomedical Research test results. The clinical study data allow specific analyses 
to be conducted. Knowing participant characteristics like sex, age, medical history, 
treatment type, and treatment outcomes are critical to understanding the clinical context 
of Further Biomedical Research analytical results. 
To maintain privacy of information collected from specimens obtained for Further 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) E15 guidelines, Definitions for 
Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories [ICH E15, 2007]. 
At the clinical study site, unique codes will be placed on the Further Biomedical 
Research specimens for transfer to the storage facility. This first code is a random 
number that does not contain any personally identifying information embedded within it 
in order to maintain participant privacy. The link (or key) between participant identifiers 
and this first unique code will be held at the study site. No personal identifiers will appear 
on the specimen tube. 
Participants may withdraw their consent for Further Biomedical Research and have their 
specimens and all derivatives destroyed. Participants may withdraw consent at any time 
by contacting the Investigator. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
General Guidelines 
• Study procedures and their timing are summarized in the Schedule of 
Activities (Table 3). As a result of the decision to permanently stop 
enrollment, assessments are discontinued as outlined in Section 1.3 and 
assessments for participants in Prescreening, Screening, or randomized onto 
the ZEST study as of the date of the decision to stop enrollment are outlined 
in Table 4, Table 5, and Table 6.  
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately 
upon occurrence or awareness to determine whether the participant should 
continue or discontinue study treatment. 
• Adherence to the study design requirements, including those specified in the 
SOA, is essential and required for study conduct. 
• All Screening evaluations must be completed and reviewed by the Investigator 
and/or site study team to confirm that potential participants meet all eligibility 
criteria. The Investigator will maintain a Screening log to record details of all 
participants screened and to confirm eligibility or record reasons for Screening 
failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management 
(eg, blood count) and obtained before signing of ICF may be utilized for 
Screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the timeframe defined in the SOA. 
• Results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 
• Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples. 
8.1.1. 
General Guidance for Treatment Continuity When Participants Are 
Unable to Come into the Clinic 
As of the date of the decision to stop enrollment, at-home nursing services will no longer 
be offered.  
Due to the significant challenges that currently face the healthcare system and 
participants due to COVID-19 as well as the potential for enduring or additional 
quarantine measures or other unforeseen circumstances, the following guidance is being 
provided in this protocol. In the spirit of global diversity in the COVID-19 pandemic and 
its impact on healthcare in each individual country as well as the recently issued guidance 
by several regulatory authorities, the autonomy of each investigative site to assess the 
benefit/risk for their participants participating in the niraparib clinical studies should be 
maintained.  

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Prior to utilization of any of the measures outlined in this section, discussion and 
approval must be obtained from the Sponsor/contract research organization (CRO). 
It is expected that sites participating in niraparib clinical studies will make every effort to 
ensure proper monitoring and well-being of enrolled participants by adhering to safety 
monitoring as outlined in the protocol SOA. The use of local laboratories/clinics and 
local radiology centers or of home nursing to reduce the need for the participant to come 
into the hospital are supported, if deemed necessary for the well-being of the participant. 
These local facilities should be added to regulatory documents, as required. Utilization of 
home nursing should be as follows: 
The Sponsor has retained an in-home nursing vendor to provide aspects of a traditional 
site visit in the participant’s own home, allowing for consistency, continuity, and quality 
of care throughout the study when a participant may be unable to travel. This service can 
be utilized for participants who do not wish to travel to the study site or if it was 
determined not to be in the best interest of the participant to report to the study site. 
If sites opt to utilize this service, they must inform the participant that the service will be 
provided their name, address, and telephone number. Participants must also be told that 
this information will not be shared with the Sponsor. This conversation must be 
documented in the source documents. An ICF addendum describing this process is 
available for use, dependent on local regulations. 
The home nursing service may perform the following functions: 
• Measurement of vital signs 
• Collection of PK samples 
• Local hematology and central laboratory assessment sample collection, including 
blood, as outlined in Table 20 (for Germany, see Table 30) 
• Submission to the participant’s site for processing and analysis of laboratory 
assessments 
• Processing and submission of the central laboratory assessment to appropriate 
vendors 
• Review/documentation of AEs, SAEs, concomitant medications, and 
questionnaires to supplement the Investigator. 
• Completion of visit documentation 
Additionally, regulatory guidance issued in response to the COVID-19 pandemic 
supports the use of central and remote monitoring programs to maintain oversight of 
clinical sites. Any restrictions in place at the site that will impact monitoring and/or 
participant access to the site and care providers should be communicated to the Sponsor 
and CRO. 
The following are general rules for participants with limited possibility to travel (see 
Table 20; for Germany, see Table 30) 
• If possible, replace in-person visits with phone contact or alternative location 
for assessment, such as local laboratories, clinics, and imaging centers. 

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• In instances where it is desired to reduce participant exposure in clinic, 
in-person visits every other cycle are acceptable if there are no ongoing AEs 
or new AEs. At this time, these missed visits will be considered protocol 
deviations. 
• Delay in oral niraparib/placebo treatment for up to 28 days is acceptable if the 
participants do not have access to local laboratories and whereby the site’s 
pharmacy will not dispense the study treatment unless participant is cleared 
with laboratory tests by the Principal Investigator per the institution’s standard 
operating procedure (SOP). 
− If an interruption longer than 28 days is required, contact the GSK 
Medical Monitor around Day 28 of interruption. This will be reviewed, 
and recommendations will be made on a case-by-case basis. 
• Drug dispensation for niraparib/placebo is possible for multiple cycles, with a 
maximum of 2 bottles dispensed at once to participants who have not 
experienced an SAE related to the study treatment within the last 3 months 
(=no ongoing “related” SAE). 
Table 20 
Required Data Collection and Safety Precautions for At-Home 
Nursing Visits 
Assessment 
Recommendation 
Follow-up assessment 
Contact participant by phone. This discussion should include 
assessment of new therapies and overall survival. 
Hematology 
Assessments may be performed through at-home nursing or at 
local laboratory. Arrangements for at-home nursing or the use of a 
local laboratory should be made by the site including the reporting 
of results to the PI for review.  
Vital signs 
Assessments may be performed through at-home nursing or at 
local laboratory or clinic. Arrangements for at-home nursing or the 
use of a local laboratory/clinic should be made by the site 
including the reporting of results to the PI for review. 
Adverse events 
• 
Ongoing AEs and SAEs – reviewed by phone 
• 
If hematologic AE are ongoing, a local CBC is desirable 
• New AEs/SAEs – may be assessed by phone (please 
remember to submit SAE documentation within 24 hours of 
learning of the event) (For Germany, see Section 10.14.2) 
Concomitant medications 
Reviewed by phone and via medical record review 
PK 
Blood samples for PK may be collected through at-home nursing. 
Arrangements for at-home nursing should be made by the site. 
Abbreviations: AE=adverse event; CBC=complete blood count; CT=computed tomography; ctDNA=circulating tumor 
DNA; EC=Ethics Committee; IRB=Institutional Review Board; MRI=magnetic resonance imaging; PI=Principal 
Investigator; PK=pharmacokinetic; PRO=patient-reported outcome; RECIST=Response Evaluation Criteria in Solid 
Tumors; SAE=serious adverse event. 
As of the date of the decision to stop enrollment, at-home nursing services will no longer be offered. 
 

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8.1.1.1. 
Direct to Participant Investigational Medicinal Product Shipments 
IRB/Ethics Committee approvals must be obtained as required by local requirements 
prior to shipping IMP (ie, niraparib/placebo) directly to participants. 
If sites opt to utilize delivery of niraparib/placebo from the clinical site to the 
participant’s home, they must inform the participant that a courier will be provided their 
name, address, and phone number to deliver the medication. They must also be told that 
this information will not be shared with the Sponsor. This conversation must be 
documented in source documents. 
The courier has mitigations for sites that are not allowing external vendors into the 
clinics; the Sponsor/CRO must be informed of any site-specific barriers so that adequate 
arrangements can be made prior to shipment of any materials. 
For sites that do not wish to utilize the GSK courier service, the following requirements 
must be met: 
• The site must provide either the SOP outlining the transportation process, if 
available, or documentation of site transport policies for GSK/CRO review. 
• Once the site SOP and/or documentation of site procedures has been reviewed 
and approved by GSK/CRO, the site may transport niraparib/placebo per their 
institutional standards. At a minimum, sites must adhere to the following 
guidelines when transporting niraparib/placebo: 
− The primary packing container must be packed in a way that will maintain a 
temperature of 15°C to 30°C.* 
− A temperature monitor must be included with the shipment and placed next to 
the primary packing container. 
− The temperature monitor must be able to record maximum/minimum 
temperature as well as the duration. If the temperature monitor cannot record 
this information, the site must record time and temperature at which it was 
stored prior to transport as well as time and temperature at conclusion of 
transport on the Investigational Product Transfer Log for external transport. 
** 
Sites receiving the transported investigational product must record if the alarm is 
triggered on the monitor on the Investigational Product Transfer Log and file in the 
pharmacy binder to be reviewed during Independent Drug Monitoring Visits (IDMVs). 
** 
Sites must complete the Investigational Product Transfer Log (or equivalent) for each 
transfer instance, which will be maintained in the pharmacy binder for review during 
IDMVs. 
Sites must report any temperature excursions of the investigational product as soon as 
identified. Please refer to the In-transit Temperature Excursion section of the Pharmacy 
Manual for instructions on how to proceed if a temperature excursion occurs. If no 
alarm, the monitors can be discarded. ** 

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*Validated Shipper must meet International Safe Transit Association 7e or 7d certified 
qualification. 
**We ask that sites use a courier who can check the temperature monitoring device upon 
receipt at the participant’s home and report back the results to the site. If this is not 
feasible, the participants should be instructed not to dose until the site can contact the 
participant by phone and confirm that the investigational product shipment was received 
in good condition and stayed within the limits of the temperature monitor. This follow-up 
must be documented in the participant’s source notes. 
8.2. 
Screening and Baseline Assessments 
8.2.1. 
Baseline Assessments at Screening 
Refer to the SOA (Table 3) for the full list of assessments collected during Screening. 
Prior to entering the Screening Period, it must be confirmed in Prescreening (Table 2) 
that participants have detectable ctDNA (see Section 8.8), and all submitted prescreening 
tissue samples are of adequate quality per central review. For participants on study as of 
the date of the decision to stop enrollment, please refer to Table 4, Table 5, and Table 6 
for Prescreening and Screening assessments. 
Tumor characteristics to be collected during Screening include, but are not limited to, 
histologic tumor type, tumor grade, tumor stage (clinical prognostic, pathologic 
prognostic, and/or anatomic staging as per the AJCC 8th edition [Hortobagyi, 2007]; also 
see Appendix 13), and response to neoadjuvant chemotherapy (as applicable). Primary 
pathology reports will be collected from biopsy and all surgical resections characterizing 
ER status (with percent or Allred score, if available), PgR (with percent or Allred score, 
if available), and HER2 status (with immunohistochemistry and in situ hybridization, if 
available), as well as tumor grade. 
The stage of breast cancer at Baseline will be determined as follows: 
• Baseline staging for participants who received neoadjuvant treatment prior to 
surgery will be based on pretreatment clinical prognostic staging, per AJCC 
for breast cancer staging criteria 8th edition (Appendix 13), as assessed by the 
Investigator based on radiological and/or clinical assessment. 
• Baseline staging for participants who underwent initial surgery and did not 
receive neoadjuvant treatment will be based on post-surgical pathological 
prognostic staging (see Appendix 13), per AJCC for breast cancer staging 
criteria 8th edition, as assessed by the Investigator based on pathologic 
assessment. 
8.2.2. 
Baseline CT/MRI and Bone Scan 
An IV contrast-enhanced-CT scan of the chest, abdomen, and pelvis (preferred imaging 
method) and a bone scan will be conducted within 42 days (6 weeks) prior to 
randomization (as outlined in Table 3; as of the date of the decision to stop enrollment, 
please refer to Table 5 or Table 6 for assessment details for ctDNA+ participants 
remaining on study). An IV contrast-enhanced MRI of the abdomen and pelvis plus 
noncontrast CT of the chest should only be conducted if clinically indicated (eg, if 

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participant is sensitive to IV CT contrast or shortage of contrast). If brain metastasis is 
suspected, IV contrast-enhanced MRI is preferred over IV contrast-enhanced CT for 
imaging of the brain. The same imaging modality, method, and anatomical coverage 
should be used throughout the study. 
8.3. 
Efficacy Assessments 
8.3.1. 
Postbaseline Imaging and Tumor Assessment 
The efficacy of study treatment will be evaluated by assessment of disease recurrence by 
the Investigator using RECIST v.1.1 (Appendix 3) [Eisenhauer, 2009]. As of the date of 
the decision to stop enrollment, refer to Table 6 for frequency/timing of assessments for 
randomized participants, on study at the time of implementation of the amendment. 
Central review of scans is discontinued, and scans do not need to be sent to the 
central imaging vendor.  
• Disease assessment modalities may include imaging (eg, CT scan, MRI), 
physical examination (as indicated for palpable/superficial lesions), and 
histopathology. Bone scans should only be performed postbaseline if 
clinically indicated. If brain metastasis is suspected, IV contrast-enhanced 
MRI is preferred over IV contrast-enhanced CT for imaging of the brain. 
• Postbaseline disease assessments are scheduled every 12 weeks (84±7 days) 
from the date of randomization for the first 2 years and every 24 weeks 
(168±7 days) thereafter, or more frequently as clinically indicated 
(unscheduled), until the Investigator’s assessment of disease recurrence using 
RECIST v1.1 (Table 3). The date of disease recurrence will be the earliest 
date that recurrence is assessed by the Investigator, whether by radiology or 
histopathology. Radiological assessments must be performed on a calendar 
schedule and should not be affected by dose interruptions/delays. 
• It is important to adhere to the imaging schedule. If scans are performed 
outside of the specified window interval and the participant has not 
progressed, every attempt should be made to perform the subsequent scans at 
their scheduled time points. 
• All radiological images/scans at the time points specified in Table 3, as well 
as any unscheduled images/scans, must be submitted (preferably 
electronically) to a central imaging vendor for quality control, storage, and 
analysis by blinded independent central review (BICR). As of the date of the 
decision to stop enrollment, central review of scans is discontinued and scans 
do not need to be sent to the central imaging vendor. Analysis by BICR is no 
longer applicable. 
• For postbaseline assessments, a window of 7 days is permitted to allow for 
flexible scheduling. 
• If an equivocal new lesion is observed on a postbaseline radiological 
assessment, a follow-up scan should be acquired at least 4 weeks later to 
reassess. On the follow-up scan, if the equivocal new lesion becomes 
unequivocal, the date of progression is the date of the scan when the new 

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lesion first appeared (refer to Appendix 3). Any lesion assessed by the 
Investigator as representative of metastatic disease should be biopsied if 
possible to document disease recurrence histologically. In the event that 
disease recurrence occurs without any radiologic correlate, the date of disease 
recurrence is the date of biopsy with histopathologic confirmation of recurrent 
breast cancer. 
• For this study, disease recurrence will exclude all in situ cancer events 
(ipsilateral or contralateral DCIS, ipsilateral or contralateral lobular carcinoma 
in situ [LCIS], and all in situ cancers of nonbreast sites). 
• If a participant discontinues study treatment for any reason other than disease 
recurrence per RECIST v1.1, death, withdrawal of consent, or loss to 
follow-up, then scans and ctDNA sample collection should continue at the 
specified intervals until disease recurrence is confirmed per RECIST v1.1. 
• In the case of contralateral invasive breast cancer, ipsilateral or contralateral 
DCIS, or second primary nonbreast invasive cancer, scans and ctDNA sample 
collection will continue until participants meet the criteria for DFS (as defined 
in Section 8.3.2). 
• To ensure comparability between the baseline and subsequent radiological 
assessments, the same method of assessment and the same technique should 
be used throughout the study. 
8.3.2. 
Exploratory Efficacy Endpoint: Disease-Free Survival 
As of the date of the decision to stop enrollment, DFS is being evaluated as an 
exploratory endpoint. 
DFS as the exploratory endpoint is defined as the time until disease recurrence, measured 
from the time of randomization to the earliest date of assessment of disease recurrence or 
death by any cause. Disease recurrence will be assessed by the Investigator using 
RECIST v1.1. 
The definition of DFS used in this study is same as the definition of recurrence-free 
survival used in Hudis et al [Hudis, 2007]. DFS events includes the following: 
• Ipsilateral invasive breast tumor recurrence (IIBTR): invasive breast cancer 
involving the same breast parenchyma as the original primary. 
• Regional invasive breast cancer recurrence: invasive breast cancer in the 
axilla, regional lymph nodes (including ipsilateral axillary, ipsilateral 
infraclavicular, ipsilateral internal mammary, and ipsilateral supraclavicular 
nodes), chest wall, and skin of the ipsilateral breast. 
• Distant recurrence: metastatic disease - breast cancer that has either been 
biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer. 
• Death attributable to any cause, including breast cancer, nonbreast cancer, or 
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For this study, disease recurrence will exclude all in situ cancer events (ipsilateral or 
contralateral DCIS, ipsilateral or contralateral LCIS and all in situ cancers of nonbreast 
sites). 
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8.3.3. 
Exploratory Efficacy Endpoint: Distant Recurrence-Free Survival 
DRFS as an exploratory endpoint in this study will be evaluated based on the 
Investigator’s assessment using RECIST v1.1 and is defined as the time from 
randomization to the first detection of distant metastasis or death by any cause. 
DRFS events include the following: 
• Distant recurrence: metastatic disease - breast cancer that has either been 
biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer. 
• Death attributable to any cause, including breast cancer, nonbreast cancer, or 
unknown cause. 
8.3.4. 
Exploratory Efficacy Endpoint: Time to First Subsequent Therapy 
Time to first subsequent therapy (TFST) is defined as the time from randomization to the 
date of the first anticancer therapy used subsequent to the date of the endpoint DFS or 
death by any cause. 
Anticancer therapy includes systemic therapy, radiation therapy, or surgical intervention. 
8.3.5. 
Exploratory Efficacy Endpoint: Time to First Subsequent Chemotherapy 
Time to first subsequent chemotherapy is defined as the time from randomization to the 
date of the first systemic chemotherapy used subsequent to the date of the endpoint DFS 
or death by any cause. 
8.3.6. 
Exploratory Efficacy Endpoint: Time to Symptomatic Progression 
Time to symptomatic progression is defined as the time from randomization to the date of 
symptomatic progression, which either coincides with or is subsequent to the date of the 
endpoint DFS. Symptomatic progression includes any of the following:  
• Development of a skeletal-related event: pathologic fracture, spinal cord 
compression, or need for surgical intervention or radiation therapy (including 
palliative radiotherapy) to the bone 
• Initiation of a new systemic anticancer therapy for cancer pain progression or 
worsening of disease-related symptoms 
• Development of clinically significant symptoms due to loco-regional tumor 
progression requiring surgical intervention or radiation therapy 
8.3.7. 
Exploratory Efficacy Endpoint: Invasive Disease-Free Survival 
IDFS will be assessed per the definition included in STEEP 2.0 [Tolaney, 2021] 
(Table 21), which defines IDFS as including the following events: 
• IIBTR: invasive breast cancer involving the same breast parenchyma as the 
original primary. 
• Regional invasive breast cancer recurrence: invasive breast cancer in the 
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infraclavicular, ipsilateral internal mammary, and ipsilateral supraclavicular 
nodes), chest wall, and skin of the ipsilateral breast. 
• Distant recurrence: metastatic disease - breast cancer that has either been 
biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer. 
• Death attributable to any cause, including breast cancer, nonbreast cancer, or 
unknown cause. 
• Contralateral invasive breast cancer. 
• Second primary nonbreast invasive cancer. 
IDFS specifically excludes all in situ cancer events (ipsilateral or contralateral DCIS, 
ipsilateral or contralateral LCIS, and all in situ cancers of nonbreast sites). 
8.3.8. 
Exploratory Efficacy Endpoint: Invasive Breast Cancer-Free Survival 
• IBCFS will be assessed per the definition included in STEEP 2.0 [Tolaney, 2021] 
(Table 21), which defines IBCFS as including the following events: 
• IIBTR: invasive breast cancer involving the same breast parenchyma as the 
original primary. 
• Regional invasive breast cancer recurrence: invasive breast cancer in the axilla, 
regional lymph nodes (including ipsilateral axillary, ipsilateral infraclavicular, 
ipsilateral internal mammary, and ipsilateral supraclavicular nodes), chest wall, 
and skin of the ipsilateral breast. 
• Distant recurrence: metastatic disease - breast cancer that has either been biopsy 
confirmed or clinically diagnosed as recurrent invasive breast cancer. 
• Death attributable to any cause, including breast cancer, nonbreast cancer, or 
unknown cause. 
• Contralateral invasive breast cancer. 
IBCFS specifically excludes all in situ cancer events (ipsilateral or contralateral DCIS, 
ipsilateral or contralateral LCIS, and all in situ cancers of nonbreast sites). 
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8.4. 
Safety Assessments 
Planned timepoints for all safety assessments for Cohort 1 (tBRCAmut/HER2−) and 
Cohort 2 (tBRCAwt/TNBC) are presented in Table 3. As of the date of the decision to 
stop enrollment, refer to Table 6 for frequency/timing of safety assessments for 
randomized participants on study. Safety assessments for participants in Prescreening and 
Screening as of the date of the decision to stop enrollment are outlined in Table 4 and 
Table 5. 
8.4.1. 
Physical Examinations 
A full physical examination will include assessments of the cardiovascular, respiratory, 
gastrointestinal, and neurological systems. Height (at Screening only) and weight will 
also be measured and recorded. Full physical examinations will be conducted at 
Screening. 
Symptom-directed physical examinations will include assessments based on participants’ 
current symptoms and will be performed at subsequent visits as summarized in Table 3. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.4.2. 
ECOG Performance Status 
Performance status will be assessed using the ECOG performance status scale 
(Appendix 7) as specified in Table 3. The same observer should assess performance 
status each time, if possible. 
8.4.3. 
Vital Signs 
Vital sign measurements are recommended to be measured after remaining seated for 5 to 
10 minutes. Vital sign measurements will include temperature, systolic and diastolic BP, 
heart rate (pulse), and respiratory rate. Vital signs will be assessed at designated study 
visits as specified in Table 3.  
If participants are unable to attend the clinic visits on Cycle 1/Day 1 (postdose), 
Cycle 1/Day 15, and Cycle 2/Day 1 (postdose), they must have assessments for these 
visits performed through at-home nursing on the date the visit would have occurred. If 
participants are unable to attend clinic visits on Cycle 1/Day 8, Cycle 1/Day 22, 
Cycle 2/Day 8, Cycle 2/Day 15, and Cycle 2/Day 22, they may have the assessments for 
these visits performed either through a local laboratory/clinic or through at-home nursing 
on the date the visit would have occurred. As of the date of the decision to stop 
enrollment, at-home nursing services will no longer be offered. 
Three readings of BP and pulse rate are recommended. In cases where 3 readings are 
taken, the first reading should be rejected and the second and third readings averaged to 
get the measurement to be recorded in the eCRF. 
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Vital signs will be measured more frequently if warranted by the clinical condition of the 
participant. On days where vital signs are measured multiple times, temperature does not 
need to be repeated unless clinically indicated. 
8.4.4. 
Electrocardiograms 
Participants will undergo 12-lead electrocardiogram (ECG) at Screening as specified in 
Table 3. Participants will be supine and rested for approximately 2 minutes before ECGs 
are recorded.  
8.4.5. 
Clinical Safety Laboratory Tests 
See Appendix 2 for the list of clinical laboratory tests to be performed and the SOA 
(Table 3) for the timing and frequency of these tests. All protocol-required laboratory 
tests must be conducted in accordance with the Study Laboratory Manual. Clinical 
laboratory assessments will be performed by the local laboratory at the investigational 
site. If allowed by country regulation/ethics, clinical safety laboratory sampling may be 
conducted remotely in-home nursing services. As of the date of the decision to stop 
enrollment, at-home nursing services will no longer be offered. 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. 
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant, unless judged by the Investigator to be more severe than expected 
for the participant’s condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study treatment should 
be repeated until the values return to normal/baseline or are no longer considered 
significantly abnormal by the Investigator or GSK Medical Monitor. 
• If clinically significant values do not return to normal/baseline within a period 
of time judged reasonable by the Investigator, the etiology should be 
identified, and the Sponsor should be notified. 
If laboratory values from non-protocol-specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded. 
Hematologic, blood chemistry, and coagulation factor testing may occur more frequently 
than is specified in the SOA, if medically indicated per the Investigator’s judgment or if 
the event meets the criteria for study treatment dose modification (see Section 6.4). 
Additional tests may be performed at a laboratory facility other than the study site, but 
the test results must be reported to the study site, the study site must keep a copy of test 
results with the participant’s study file, and the results must be entered into the eCRF. 
Any suspected case of MDS/AML reported while a participant is receiving treatment or 
followed for post-treatment assessments must be referred for evaluation to a local 
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site must receive a copy of the hematologist’s report of aspirate/biopsy findings, which 
must include a classification according to the World Health Organization, and other 
sample testing reports related to MDS/AML. Report data will be entered in the 
appropriate eCRF pages, and the site must keep a copy of all reports with the 
participant’s study file. If a diagnosis of MDS/AML is confirmed by a hematologist, the 
participant must permanently discontinue study treatment. 
Any suspected case of secondary cancer (new malignancies other than MDS/AML) 
reported while a participant is receiving treatment or followed for post-treatment 
assessments must be investigated, including obtaining and documenting a histological 
diagnosis. Testing completed as part of standard of care is sufficient as long as the 
methods are deemed acceptable after consultation with the GSK Medical Monitor. 
8.4.6. 
Pregnancy Testing 
• Refer to Section 5.1 Inclusion Criteria for pregnancy testing study entry 
criteria. 
• Pregnancy testing (serum or highly sensitive urine pregnancy test) must be 
conducted for WOCBP within 72 hours prior to the first dose of study 
treatment and then, starting in Cycle 2, within 72 hours of Day 1 of every 
cycle for the duration of the Treatment Period. Test results must be available 
and negative before the first dose of study treatment. 
• Additional serum or highly sensitive urine pregnancy tests may be performed, 
as determined necessary by the Investigator or required by local regulation, to 
establish the absence of pregnancy at any time during the participant’s 
participation in the study. 
• Any pregnancies that occur within 180 days (for France, see 
Section 10.14.1.1) post-treatment are to be reported as described in 
Section 8.5.5. 
8.5. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The definitions of AEs, SAEs, and other safety events can be found in Appendix 8. 
AESIs are defined in Section 8.5.8. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, or 
surrogate). 
The Investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and remain responsible for 
following up all events. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 8. 

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8.5.1. 
Time Period and Frequency for Collecting AE and SAE Information 
• Reporting of safety events is to begin at the time of ctDNA Prescreening ICF 
signature date only for events related to ctDNA and WES blood sample 
collection procedures (Table 2). 
• All AEs and SAEs will be collected and recorded for each participant from the 
day of signing the main study ICF until 30 days after last dose of study 
treatment or the start of new anticancer therapy, as shown in the SOA 
(Table 3). However, any SAEs assessed as related to study participation (eg, 
study treatment, protocol-mandated procedures, invasive tests, or change in 
existing therapy) or related to niraparib will be recorded from the time a 
participant consents to participate in the study until study closeout as specified 
in the SOA. 
• All AESIs, regardless of causality, will be collected and reported from the 
signing of the main study ICF until study closeout at the time points specified 
in the SOA and as described in Section 8.5.8. 
• Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent for the main study will be recorded as medical 
history/current medical conditions and not as AEs. 
• All SAEs will be recorded and reported to the Sponsor or designee 
immediately and under no circumstance should this exceed 24 hours, as 
indicated in Appendix 8. The Investigator will submit any updated SAE data 
to the Sponsor within 24 hours of it being available. (For Germany, see 
Section 10.14.2.2.) 
• Investigators are not obligated to actively seek information on AEs or SAEs 
after conclusion of the study participation. However, if the Investigator learns 
of any SAE, including a death, at any time after a participant has been 
discharged from the study, and he/she considers the event to be reasonably 
related to the study treatment or study participation, the Investigator must 
promptly notify the Sponsor. 
• For participants in PACT Phase, SAEs, AESIs, AEs leading to treatment 
discontinuation, overdose and pregnancy reports including follow-up 
reports will continue to be reported directly to GSK via paper forms (or 
alternative reporting method as indicated by Sponsor, should one become 
available) through 30 days after last dose of study. See Section 10.8, 
Section 10.9, Section 10.10, and Section 10.11 for details.  
• All SAEs assessed as related by the Investigator continue to be reported 
for all participants (not only participants in PACT Phase) until study 
close out and all AESIs, regardless of causality, continue to be reported 
for all participants (not only participants in PACT Phase) until death or 
loss to follow up.  
• Additionally, any SAEs that are ongoing at the time of the final DCO 
must be followed up to resolution unless the event is considered by the 
Investigator unlikely to resolve, or the patient is lost to follow-up or dies. 

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GSK retains the right to request additional information for any patient 
with ongoing AE(s)/SAE(s) at EOS, if judged necessary. 
8.5.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. 
8.5.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs and SAEs will be followed until the 
event is resolved, stabilized, otherwise explained, the participant is lost to follow-up (as 
defined in Section 7.3), or until the participant has died. Further information on follow-up 
procedures is given in Appendix 8. 
8.5.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of an SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 
• The Sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The Sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRBs/Independent Ethics Committees (IECs), and Investigators. 
• An Investigator who receives an Investigator safety report describing an SAE 
or other specific safety information (eg, summary or listing of SAEs) from the 
Sponsor will review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements. 
• Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions according to local regulatory requirements and Sponsor 
policy and forwarded to Investigators as necessary. 
8.5.5. 
Pregnancy 
• Details of all pregnancies in female participants and, if indicated, female 
partners of male participants who receive study treatment will be collected 
after the start of study treatment and until 180 days after the last dose of study 
treatment in female participants and 90 days after the last dose of study 
treatment for female partners of male participants. (For France, see 
Section 10.14.1.1.) 
• If a pregnancy is reported, the Investigator will record pregnancy information 
on the appropriate form and submit it to GSK within 24 hours of learning of 
the pregnancy of the female participant or female partner of male participant 
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partner). While pregnancy itself is not considered to be an AE or SAE, any 
pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an AE or SAE. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, and ectopic pregnancy) are considered SAEs 
and will be reported as such. 
• The participant/pregnant female partner will be followed to determine the 
outcome of the pregnancy. The Investigator will collect follow-up information 
on the participant/pregnant female partner and the neonate, and the 
information will be forwarded to the Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the 
study treatment by the Investigator will be reported to the Sponsor as 
described in Section 8.5.4. While the Investigator is not obligated to actively 
seek this information in former study participants/pregnant female partners, he 
or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study 
will discontinue study treatment. 
8.5.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 8 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular and Death sections of the eCRF will be 
required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and noncardiovascular death. 
The cardiovascular-related eCRFs are presented as queries in response to reporting of 
certain cardiovascular Medical Dictionary for Regulatory Activities (MedDRA) terms. 
The cardiovascular information should be recorded in the specific cardiovascular section 
of the eCRF within 1 week of receipt of a cardiovascular event data query prompting its 
completion. 
The death-related eCRF is available at all times under Common Forms and should be 
completed within 1 week of when the death is reported. Initial and follow-up reports 
regarding death must be completed within 1 week of when the death is reported. 
For death unequivocally due to disease under study, record death in the Death eCRF. For 
death due to reasons other than the disease under study, record death in the Death eCRF 
and Death Details eCRF as outlined in the eCRF completion guidelines. 
8.5.7. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying 
as SAEs 
An event that is part of the natural course of the disease under study (ie, disease 
recurrence or hospitalization due to disease recurrence) does not need to be reported as an 
SAE. Death due to disease under study is to be recorded on the Death eCRF. 

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8.5.8. 
Adverse Events of Special Interest  
An AESI is any AE (serious or nonserious) that is of scientific and medical concern 
specific to niraparib for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor is warranted. These events must be recorded as such on the 
eCRF. Serious AESIs must be reported to the Sponsor within 24 hours of the Investigator 
becoming aware of them. (For Germany, see Section 10.14.2.2.) 
The AESIs for niraparib are as follows: 
• MDS and AML 
• Second primary cancers (new malignancies other than MDS or AML) 
These AESIs for niraparib should be reported to the Sponsor until death or loss to 
follow-up. 
8.6. 
Pharmacokinetics 
As of the date of the decision to stop enrollment, collection of blood samples for PK 
analysis and the PK substudy are discontinued. 
For all participants in Cohort 1 and Cohort 2, sparse blood samples will be collected to 
characterize niraparib exposure in participants with breast cancer and to explore the 
relationship between exposure to niraparib and responses in efficacy and safety. Blood 
samples will be collected predose (up to 60 minutes prior to dosing) and 3 hours postdose 
(±15 minutes) at Cycle 1/Day 1, Cycle 1/Day 15, and Cycle 2/Day 1 and predose (up to 
60 minutes prior to dosing) at Cycle 4/Day 1 and Cycle 8/Day 1, as specified in Table 7. 
If participants are routinely taking their niraparib/placebo dose in the evening, they must 
be instructed to transition to niraparib/placebo morning dosing 1 week before the PK 
sampling day. If participants are unable to attend the clinic visits on Cycle 1/Day 1 
(postdose), Cycle 1/Day 15, and Cycle 2/Day 1 (postdose), these visits may be performed 
through at-home nursing (see Section 8.1.1) at which blood samples for PK will be 
collected on the date the visit would have occurred. 
A subset of participants in Cohort 1 will have additional blood samples collected in a PK 
substudy. The PK substudy will include at least the first 40 randomized participants 
receiving endocrine therapy in Cohort 1 at sites participating in the PK substudy. The 
samples collected in the PK substudy will be analyzed to characterize the steady-state PK 
of endocrine therapy and to assess any potential effect of niraparib on endocrine therapy 
exposure, as data permit. Based on the randomized nature of the study, it is assumed that 
approximately 20 participants in the PK substudy will be receiving endocrine therapy 
with niraparib, while the remaining participants will be receiving endocrine therapy with 
placebo, allowing for a comparison of endocrine therapy PK with or without niraparib 
co-administration. Additional participants may be included in the PK substudy if there 
are too few participants receiving any of the individual endocrine therapies to meet the 
objectives of the substudy; if feasible, 6 participants per endocrine therapy will be 
targeted. 
Blood samples will be collected from participants in the PK substudy predose (up to 
60 minutes prior to dosing) and 1, 2, 4, 6, and 8 hours postdose on Cycle 1/Day 15 for the 
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tamoxifen (N-DMT) and niraparib, as appropriate. These time points were selected based 
on the PK properties of the endocrine therapies and the length of time it takes to reach 
niraparib steady state, allowing for the parameters’ minimum plasma concentration at 
steady state (Cmin,ss), maximum plasma concentration at steady state (Cmax,ss), and area 
under the plasma concentration-time curve over the dosing interval at steady state 
(AUCss) to be determined reliably for the endocrine therapies and niraparib. 
Participants in the PK substudy who vomit after taking their study treatment on a PK 
sampling day will need to return another time for their PK assessments. 
On the PK sampling day, participants should withhold both the endocrine therapy and 
niraparib/placebo dose until the predose PK sample has been taken. At the clinic, 
niraparib/placebo should be administered first, and the endocrine therapy should be 
administered immediately after (within 5 minutes) to align with the sampling scheme. 
Participants must be instructed to dose study treatment and endocrine therapy in the 
morning for 1 and 2 weeks, respectively before PK sampling on Cycle 1/Day 15 (as 
outlined in Table 8). 
A blood sample for measuring niraparib concentration may be collected for a liver event 
[see Appendix 6]. 
Samples may be analyzed for the relevant analyte using validated analytical methods. 
Samples collected from participants randomized to niraparib treatment will be analyzed 
for niraparib concentrations using a validated liquid chromatography-tandem mass 
spectrometry method. 
For all PK samples, instructions for the collection and handling of biological samples will 
be provided by the Sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded. 
Samples collected for analyses of niraparib plasma concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study. 
Genetic analyses will not be performed on these blood samples unless consent for this 
was included in the informed consent. Participant confidentiality will be maintained. 
Treatment concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
8.7. 
Genetics 
See Section 10.12 for information regarding the use/analysis of DNA including for WES 
testing. Details on processes for collection and shipment and destruction of these samples 
can be found in the Study Laboratory Manual. 
8.8. 
Translational Research 
Translational research may include research using DNA derived from tumor tissue or 
blood (see Section 10.12). All participants will undergo ctDNA Prescreening, utilizing 
the Signatera test for ctDNA. For the Signatera test, all participants must provide an 
archival tumor tissue specimen of the primary tumor, including pathology reports for all 
tumor tissue samples. Tissue sample requirements are outlined in the Study Reference 
Manual. For participants in both Cohorts 1 and 2, a blood sample is also required for 

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WES, and subsequent blood samples for the ctDNA testing will be collected according to 
the schedule summarized in Table 2 and according to the schedule shown in the SOA 
(Table 3) during the Treatment Period. As of the date of the decision to stop enrollment, 
refer to Section 1.3, and Table 4, Table 5, and Table 6 for changes to ctDNA testing for 
participants in Prescreening, Screening, and/or randomized onto the ZEST study. 
During ctDNA Prescreening, tumor tissue samples from all participants will be collected 
for confirmatory central tBRCA testing using the 
. Participants 
with HR+/HER2− breast cancer must have a known and documented tBRCAmut to 
qualify for ctDNA Prescreening. All participants, including those with TNBC, will have 
their tBRCA status confirmed by a central laboratory prior to randomization. Note that the 
confirmatory central tBRCA test does not distinguish between somatic and germline 
BRCA mutations and does not replace standard germline testing. 
Participants in Cohort 2 will have the HRD status of their tumor determined by 
. Incidental non-BRCA tumor 
mutation findings will be released to the Investigator as recommended per NCCN 
Guidelines [NCCN, 2021]. 
Participants are required to have ctDNA testing performed predose on Cycle 1/Day 1 and 
then every 12 weeks (84±7 days) from randomization until disease recurrence, as 
specified in the SOA (Table 3).  
If a participant discontinues study treatment for any reason other than disease recurrence 
per RECIST v1.1, death, withdrawal of consent, or loss to follow-up, then ctDNA sample 
collection should continue at the specified intervals until disease recurrence is confirmed. 
Exploratory biomarker analysis to identify factors important for niraparib therapy may be 
pursued. Blood samples for exploratory biomarker testing will be collected at the time 
points specified in the SOA (Table 3).
 
 
 
 
 
For participants who experience disease recurrence, an optional tumor tissue sample at 
the time of recurrence is also highly encouraged. 
All samples will be collected and managed centrally, when possible, and distributed 
either directly or subsequently to designated translational research laboratories for 
biomarker testing. Details on tissue and blood sample collection, processing, storage, 
shipping, and handling instructions can be found in the Study Laboratory Manual. 
Remaining tumor tissue samples and tumor-derived samples such as DNA and remaining 
blood and/or blood-derived samples such as plasma and DNA may be stored for potential 
further biomarker testing in cancer-related research and may be used for the development 
of companion diagnostic tests. 
8.8.1. 
Tumor Tissue Collection at Time of Disease Recurrence 
Data from these investigations may contribute to the understanding of the tumor 
microenvironment, including, but not limited to, tumor characteristics and gene and 
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protein expression and how they relate to niraparib clinical activity. Research biopsies at 
the time of disease recurrence are optional and apply only to those participants who are 
planning to undergo a biopsy of a visceral site (ie, nonbony lesion) as part of standard 
clinical care. Biopsies must be performed prior to initiating new anticancer therapy (see 
Table 3). It is preferred that for tumor biopsies that are not simply incisional or 
excisional, a 16-gauge core biopsy needle is used; however, a smaller bore needle may be 
used if considered necessary for the participant’s safety. Four core needle biopsies need 
to be obtained. Fine needle biopsies are not recommended for this study. It is 
recommended that participants undergoing tumor biopsy have a prothrombin 
time/activated partial thromboplastin time <1.5 × ULN. Details regarding tumor tissue 
sample collection and management are provided in the Study Laboratory Manual. 
As of the date of the decision to stop enrollment, collection of tumor tissue at time of 
disease recurrence is discontinued. 
8.9. 
Patient-Reported Outcome Measures 
PROs (including the 30-question EORTC-QLQ-C30, 6-question EQ-5D-3L, single-item 
PGIS/PGIC, and FACT-GP5, as well as a subset of approximately 15 questions from the 
PRO-CTCAE) will be used to measure the patient-reported assessment of treatment 
throughout study participation as specified in the SOA (Table 3). Summaries of each 
PRO instrument are provided below. 
PRO questionnaires should be collected prior to dosing or clinical procedures during the 
Treatment Period on the assigned clinic visit day. After the Treatment Period, PRO 
assessments are conducted at the EOT Visit, the Safety Follow-up Visit, and the first 2 
Post-treatment Follow-up assessments. They may be administered by telephone during 
follow-up if the participant is no longer actively returning to the site. 
The questionnaires will be administered to participants in different regions based on the 
availability of translated versions. 
Participants will be instructed on the completion of the questionnaires by site personnel 
who have been trained on their implementation. 
As of the date of the decision to stop enrollment, collection of PROs is discontinued. 
8.9.1. 
EORTC-QLQ-C30 
The change from baseline in EORTC-QLQ-C30 will be assessed as a secondary 
endpoint. The EORTC-QLQ-C30 was developed to assess the quality of life of patients 
with cancer, and it is the most widely used cancer-specific health-related quality-of-life 
(HRQoL) instrument. 
The EORTC-QLQ-C30 is a 30-item questionnaire used to measure HRQoL in 
participants with cancer; it has been translated and validated in over 100 languages and 
has been used in more than 3,000 studies worldwide (http://groups.eortc.be/qol/eortc-qlq-
c30). The EORTC-QLQ-C30 is composed of both multi-item scales and single-item 
measures. These include 5 functional scales (Physical functioning, Role functioning, 
Emotional functioning, Cognitive functioning, and Social functioning), 3 symptom scales 
(Fatigue, Nausea and vomiting, and Pain), 6 single items (Dyspnea, Insomnia, Appetite 
loss, Constipation, Diarrhea, and Financial difficulties), and a global health 

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status/HRQoL scale. The EORTC-QLQ-C30 uses a 1-week recall period for all items and 
a 4-point scale for the functional and symptom scales/items with response categories of 
“Not at all,” “A little,” “Quite a bit,” and “Very much.” The 2 items assessing global 
health status/quality of life utilize a 7-point scale ranging from 1 (“Very Poor”) to 7 
(“Excellent”) [Aaronson, 1993]. 
8.9.2. 
PRO-CTCAE 
Descriptive data will be presented using items from the PRO-CTCAE as a secondary 
endpoint. The PRO-CTCAE is a PRO measure developed to evaluate symptomatic 
toxicity in participants of cancer clinical studies [Basch, 2014]. The PRO-CTCAE was 
designed to be used as a companion to the Common Terminology Criteria for Adverse 
Events (CTCAE), the standard lexicon for AE reporting in cancer studies. The 
PRO-CTCAE includes an item library of 124 items representing 78 symptomatic 
toxicities drawn from the CTCAE. PRO-CTCAE provides a systematic yet flexible tool 
for descriptive reporting of symptomatic treatment side effects in cancer clinical studies. 
In the present study, a selection of items from the PRO-CTCAE Version 1.0 Item Library 
will be administered to participants. 
A subset of items from the PRO-CTCAE will be assessed. Symptoms for inclusion in the 
PRO-CTCAE are the following: 
• Dry mouth 
• Mouth or throat sores 
• Problems with tasting food or drink 
• Abdominal pain 
• Cough 
• Palpitations 
• Rash 
• Numbness or tingling in hands or feet 
• Dizziness 
• Headache 
• Aching muscles 
• Aching joints 
8.9.3. 
FACT-GP5 
The change from baseline in the FACT-GP5 will be assessed as a secondary endpoint. 
The Functional Assessment of Cancer Therapy - General (FACT-G) (now in Version 4) 
is a 27-item compilation of general questions divided into 4 primary quality-of-life 
domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and 
Functional Well-Being [Cella, 1993]. It is considered appropriate for use with 
participants with any form of cancer and has also been used and validated in other 

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chronic illness conditions (eg, HIV/AIDS and multiple sclerosis) and in the general 
population (using a slightly modified version). 
The FACT-GP5 item is a single item from the FACT-G, which assesses how bothersome 
the side effects of treatment are for patients with cancer. The recall period is the past 
7 days, and the item has a 5-category response scale ranging from “0=Not at all” to 
“4=Very much.” This item is being included to assess the overall tolerability of treatment 
from the participant’s perspective. 
8.9.4. 
EuroQol Questionnaire (EQ-5D-3L) 
The change from baseline in EQ-5D-3L will be assessed as an exploratory endpoint. The 
EQ-5D-3L is a standardized instrument for use as a measure of health utility. It is 
designed for self-completion or interview administration and is cognitively simple, taking 
only a few minutes to complete. 
The EQ-5D-3L self-assessment questionnaire has 2 parts. The first part consists of 
5 items covering 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression). Each dimension is measured by a 3-point Likert scale (no problems, 
some or moderate problems, and unable or extreme problems). Participants are asked to 
choose 1 level that reflects their “own health state today” for each of the 5 dimensions. 
Participants can be then classified into 1 of 243 distinct health states. The second part is a 
20-cm visual analogue scale (EQ-VAS) that has endpoints labelled “best imaginable 
health state” and “worst imaginable health state” anchored at 100 and 0, respectively. 
The EQ-5D-3L will provide data for use in economic models and analyses including 
developing health utilities or quality-adjusted life-years. The EQ-5D-3L will be 
completed by participants last after completing all other PRO assessments. 
8.9.5. 
Patient Global Impression Items 
PGIS and PGIC will be assessed as exploratory endpoints. The PGIS assesses global 
impression of symptom severity at baseline and subsequent time points. The second 
question, the PGIC, serves to rate the global change in symptoms at subsequent time 
points as outlined in Table 3. In addition to evaluating symptom severity and change, 
these questions serve as anchors to establish thresholds of clinically meaningful change 
for the questionnaires in the study [Guy, 1976]. 
 

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9. 
STATISTICAL CONSIDERATIONS 
As of the date of the decision to permanently stop enrollment into the study, specific 
assessments such as collection of survival follow-up data, subsequent treatments, PRO 
data, etc. will no longer be required (as outlined in Section 1.3). Safety and tolerability of 
niraparib are being assessed as the primary endpoint and will use the SAF Population. 
Estimands are not applicable. Any deviations from, or additions to, the original analysis 
plan described in this protocol will be documented in the SAP and final study report. 
9.1. 
Statistical Hypotheses 
As of the date of the decision to stop enrollment, there is no formal hypothesis testing 
framework being implemented in this study. 
9.2. 
Sample Size Determination 
The sample size determinations were based on the original ZEST study design and 
endpoints. A total of 40 participants were randomized in the study.  
The placebo median DFS is expected to be approximately 9 months from randomization. 
This is based on the published data from 49 patients with primary breast cancer 
monitored longitudinally using serial plasma for up to 4 years after surgery and adjuvant 
chemotherapy [Coombes, 2019]. Plasma ctDNA was detected ahead of clinical or 
radiological relapse (disease recurrence) in 16 of the 18 relapsed patients. The median 
time from detection of ctDNA presence to disease recurrence was 8.9 months. 
The placebo median OS is expected to be approximately 30 months from randomization. 
This is based on the estimated sum of the median DFS (9 months) and the median OS 
from Phase 3 studies with approved therapies in either advanced or metastatic TNBC 
(IMpassion130 study: 21 months [Schmid, 2018]) or advanced or metastatic gBRCAmut 
HER2− breast cancer (OlympiAD study: 19 months [Robson, 2017]; EMBRACA study: 
22 months [Litton, 2018]. 
Cohort 1 (tBRCAmut/HER2−) 
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Cohort 2 (tBRCAwt/TNBC) 
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9.3. 
Data Analysis Considerations 
9.3.1. 
Analysis Sets 
The analysis populations are defined as follows: 
• ITT Population: All participants randomized into the study. The ITT 
population is the primary analysis population for the efficacy analysis. For this 
analysis, participants will be analyzed as randomized. 
• Safety (SAF) Population: All randomized participants who receive at least 
1 dose of study treatment (niraparib or placebo). Participants will be analyzed 
as treated. 
The ITT Population is the analysis population for the efficacy analysis. The SAF 
population will be the primary analysis population for the safety analyses. 
Additional analysis populations may be defined in the SAP. 
9.3.2. 
Interim Analysis 
9.4. 
Key Elements of Analysis Plan 
Data will be listed and summarized according to the GSK reporting standards, where 
applicable. Complete details will be documented in the SAP. Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the SAP and final study report. 
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis. 
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment. 
As the duration of treatment for a given participant will depend on efficacy and 
tolerability, the duration of follow-up will vary between participants. Consequently, there 
will be no imputation for missing data. 
Demographic and baseline characteristics will be summarized. 
9.4.1. 
Primary Safety Analyses 
The SAF Population will be used for the analysis of safety data. All serially collected 
safety endpoints (e.g., laboratory tests, vital signs) will be summarized according to the 
scheduled nominal visit at which they were collected and across all on-treatment time 
points. Complete details of the safety analyses will be provided in the SAP. 
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9.4.1.1. 
Extent of Exposure 
The number of participants administered study treatment will be summarized according 
to the duration of therapy. 
9.4.1.2. 
Adverse Events 
AEs will be coded using the standard MedDRA and grouped by system organ class. AEs 
will be graded by the Investigator according to the NCI-CTCAE (version 5.0). 
Events will be summarized by frequency and proportion of total participants, by system 
organ class, and preferred term. Separate summaries will be given for all AEs, treatment-
related AEs, SAEs, AEs leading to dose reduction, interruption, and/or discontinuation of 
study treatment, and AESIs. 
AEs, if listed in the NCI-CTCAE (Version 5.0), will be summarized by maximum grade. 
Otherwise, the AEs will be summarized by maximum intensity. 
The incidence of deaths and the primary cause of death will be summarized. 
Further details will be provided in the SAP. 
9.4.1.3. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluation: The evaluation of clinical laboratory tests will focus on 
selected laboratory analytes from the hematology and blood chemistry panel. 
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE (Version 5.0). Laboratory test results outside the 
reference ranges that do not have an associated NCI-CTCAE criteria will be summarized 
using proportions. 
Descriptive statistics (mean, standard deviation, median, and range) will be used to 
summarize change from baseline in observed value at each scheduled visit. 
The worst-case toxicity grade in hematology and chemistry results during treatment will 
be summarized. 
Further details will be provided in the SAP. 
9.4.1.4. 
Other Safety Measures 
Data for vital signs will be summarized based on predetermined criteria identified to be 
of potential clinical concern. 
Data for physical examinations, ECOG performance status, and concomitant medications 
will also be summarized. 
Further details will be provided in the SAP. 
9.4.2. 
Exploratory Efficacy Analyses 
The following exploratory efficacy endpoints will be evaluated: 
• DFS 
• DRFS 

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• TFST 
• Time to first subsequent chemotherapy 
• Time to symptomatic progression 
• IDFS 
• IBCFS 
9.4.3. 
Other Analyses 
9.4.3.1. 
Exploratory Biomarker Analyses 
9.4.3.2. 
Genetic Analyses 
Further details on genetic analyses will be addressed in the genetic SAP. 
9.4.4. 
Independent Data Monitoring Committee 
As of the date of the decision to stop enrollment, assessment by an IDMC is no longer 
needed due to study enrollment being permanently discontinued and the study being 
centrally unblinded. 
An IDMC will be established to provide independent review and assessment of the 
efficacy and safety data in a systematic manner and to safeguard the interest and safety of 
the participants in the study. 
The IDMC will consist of 3 individuals, including 1 biostatistician and 2 physicians who 
are independent from the Sponsor. The membership, the key responsibilities of the 
IDMC, and the corresponding procedures will be defined in an IDMC Charter. 
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10. 
APPENDICES 
10.1. 
Appendix 1: Exclusion of Participants Who Have Shown No 
Definitive Response to Preoperative Chemotherapy 
Participants who have shown no definitive response to preoperative chemotherapy by 
pathologic, radiological, or clinical evaluation, in cases where preoperative chemotherapy 
was administered, will be excluded from the study. 
For study eligibility, determination of no definitive response to preoperative 
chemotherapy should be evaluated pathologically whenever possible. 
• Radiological and/or clinical evaluation of response to preoperative 
chemotherapy should be used only when response cannot be determined 
pathologically. 
• Source documentation of preoperative therapy response, including pathology 
reports and/or imaging reports, should be collected whenever possible. 
In short, participants who demonstrate any objective sign of response to therapy by either 
pathologic, radiographic, or clinical assessment would be allowed to move forward with 
further eligibility assessment for the study. 
Pathologic Evaluation 
No definitive response to preoperative chemotherapy by pathologic evaluation is 
considered to include at least one of the following: 
• CAP/AJCC System: Treatment effect in the breast: No definite response to 
presurgical therapy in the invasive carcinoma; or 
• RCB System: RCB-III: Extensive residual disease; or 
• Miller-Payne System: Grade 1: No change or some alteration to individual 
malignant cells, but no reduction in overall cellularity; or 
• Japanese Breast Cancer Society System: Grade 0: Little change with treatment 
was observed in invasive cancer tissue. 
If none of the above systems are routinely used at the site, other standard of care 
pathological assessment systems may be used to determine lack of response to 
postoperative chemotherapy but should be reviewed with the Medical Monitor on a case-
by-case basis. 
Radiological and Clinical Evaluation 
If response to preoperative chemotherapy cannot be determined pathologically by the 
Investigator, then response should be determined radiologically and/or clinically. 
No definitive response to preoperative chemotherapy by radiological and/or clinical 
evaluation is considered to include at least one of the following: 

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• Progressive disease (PD) defined as the development of new, previously 
undetected lesions, or an increase in the size of the primary lesion as assessed 
by the Investigator; or 
• Stable disease (SD) defined as no decrease in size of the primary lesion, as 
assessed by the Investigator. 
Assessment should be based on a comparison of imaging or clinical exam performed 
before initiation and after completion of preoperative chemotherapy. 
Imaging modalities for comparison can include either mammogram, ultrasound, or 
magnetic resonance imaging, but the same modality must be used for both pre- and post-
chemotherapy assessments. 
Sources: [Fitzgibbons, 2018; Ogston, 2003; Symmans, 2007] 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
Screening Only Testing 
The tests detailed below will be performed by the local laboratory at investigational site. 
• HIV and hepatitis B and C testing performed at Screening (or within 3 months 
prior to first dose of study treatment) only; laboratory tests for: 
− HIV-1 and HIV-2 antibodies 
− Hepatitis B surface antigen, hepatitis B core antibody, and hepatitis C 
antibodies 
• Follicle-stimulating hormone and estradiol (in women of non-childbearing 
potential <60 years of age) 
Continuous Laboratory Assessments 
The tests detailed in Table 22 will be performed by the local laboratory at the 
investigational site. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or as required by local regulations. 
Table 22 
Protocol required Safety Laboratory Tests 
Laboratory Assessment 
Parameters 
Hematology 
• 
White blood cell count – total and differential 
• 
Hemoglobin 
• 
Hematocrit 
• 
Platelet counta 
• 
Absolute neutrophil count 
• 
Absolute lymphocyte countf 
Coagulation factorsb 
• 
PT/INR 
• 
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Laboratory Assessment 
Parameters 
Clinical chemistryc 
• 
Alanine aminotransferase 
• 
Albuminf 
• 
Alkaline phosphatased 
• 
Aspartate aminotransferase 
• 
Bilirubin (total) 
• 
Bilirubin, directf 
• 
Blood urea nitrogen or ureae,f 
• 
Calciumf 
• 
Chloridef 
• 
CO2 or bicarbonatef 
• 
Creatinine 
• 
Glucosef 
• 
Potassiumf 
• 
Sodiumf 
• 
Total proteinf 
Urinalysis 
• 
Local standard of care urine dipsticks and/or urine laboratory 
parameters may be used to assess for urinary tract infection. 
Pregnancy test 
• 
Serum or highly sensitive urine hCG pregnancy test on 
WOCBP only. 
Abbreviations: ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; BUN=blood urea nitrogen; 
hCG=human chorionic gonadotropin; IEC=Independent Ethics Committee; INR=international normalized ratio; 
IRB=Institutional Review Board; PT=prothrombin time; PTT=partial thromboplastin time; WOCBP=women of 
childbearing potential; ULN=upper limit of normal. 
a Mean platelet volume is optional but encouraged, especially for participants with high-grade thrombocytopenia. 
b Coagulation factors (PT/INR and aPTT/PTT) should be tested as part of the Screening procedures for all participants 
in accordance with local standard of care. Any participant receiving anticoagulant therapy should have coagulation 
factors monitored closely throughout the study. If PTT/aPTT is not part of standard of care in the participant’s region, 
then the test does not need to be performed. 
c Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1 and Appendix 6. All events of ALT ≥3× ULN and total bilirubin ≥2× ULN 
(>35% direct bilirubin) or ALT ≥3× ULN and INR >1.5, if INR measured, which may indicate severe liver injury 
(possible Hy's law), must be reported to GSK in an expedited manner (excluding studies of hepatic impairment or 
cirrhosis). 
d If alkaline phosphatase is elevated, consider fractionating. 
e BUN is preferred; if not available, urea may be tested. 
f If these items are not done as part of standard of care in the participant’s region, then these tests do not need to be 
performed. All other laboratory assessments are considered essential. 
 
Investigators must document their review of each laboratory safety report. 

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10.3. 
Appendix 3: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria  
RECIST v1.1 Assessment Guidelines [Eisenhauer, 2009] 
Imaging Modality Specifications 
The full Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) 
guidelines [Eisenhauer, 2009] are described below; note that the outcome of interest for 
this study is the assessment of new lesions. 
Please note the following: 
• The same diagnostic method, including use of contrast when applicable, must 
be used throughout the study per participant to evaluate a tumor lesion. 
Contrast agents must be used in accordance with the Image Acquisition 
Guidelines. 
• All measurements should be taken and recorded in millimeters (mm), using a 
ruler or calipers. 
• Ultrasound is not a suitable modality of disease assessment. If new lesions are 
identified by ultrasound, confirmation by computed tomography (CT) or 
magnetic resonance imaging (MRI) is required. 
• Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is generally 
not suitable for ongoing assessments of disease. However, FDG-PET can be 
useful in confirming new sites of disease where a positive FDG-PET scans 
correlates with the new site of disease present on CT/MRI or when a baseline 
FDG-PET was previously negative for the site of the new lesion. FDG-PET 
may also be used in lieu of a standard bone scan providing coverage allows 
interrogation of all likely sites of bone disease and FDG-PET is performed at 
all assessments. 
• If PET/CT is performed, then the CT component can only be used for standard 
response assessments if performed to diagnostic quality, which includes the 
required anatomical coverage and prescribed use of contrast. The method of 
assessment should be noted as CT on the case report form (CRF). 
CT and MRI: IV contrast-enhanced-CT with up to 5-mm contiguous slices is the 
preferred imaging modality except for imaging of the brain (IV contrast-enhanced MRI 
preferred). Whenever possible the same scanner should be used. 
X-ray: In general, X-ray should not be used for lesion measurements owing to poor 
lesion definition. Lesions on chest X-ray may be considered new lesions if they are 
clearly defined and surrounded by aerated lung; however, chest CT is preferred over 
chest X-ray to assess thoracic lesions. 
Bone Scan (typically bone scintigraphy): If a bone scan is performed and a new 
lesion(s) is equivocal, then correlative imaging (ie, X-ray, CT, or MRI) is required to 
demonstrate malignant characteristics of the lesion(s).  

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Note: PET (FDG or fluoride) may be used in lieu of a standard bone scan providing 
coverage allows interrogation of all likely sites of bone disease and PET is performed at 
all assessments. 
Guidelines for Evaluation of Disease 
New Lesions 
All participants in the current study have detectable circulating tumor ctDNA (ctDNA), 
and it is assumed that they all have tumors not yet recognizable by imaging. For disease-
free survival (DFS) assessment and participant management, the protocol emphasizes 
specific RECIST v1.1 guidance on the appearance of new lesions. According to 
RECIST v1.1, the appearance of an unequivocal new lesion is required to trigger an 
assessment of progressive disease. The appearance of equivocal new lesions and how to 
deal with this with respect to identifying a date of progression is guided as follows: if an 
equivocal new lesion appears in the images, the Investigators are encouraged to continue 
treatment and to collect a follow-up scan at least 4 weeks later. If a previously equivocal 
new lesion coverts to an unequivocal new lesion at the follow-up scan, then the date of 
progression is designated by when the new lesion first appeared. Following this new 
lesion guidance should limit the number of premature radiological calls of progressive 
disease. 
Evaluation of overall response 
Table 23 presents the overall response at an individual time point for all possible 
combinations of tumor responses for participants with non-measurable only disease at 
baseline. 
Table 23 
Evaluation of Overall Response for Participants with No Evidence of 
Disease at Baseline 
New Lesions 
Overall Response 
No 
NED 
NE 
NE 
Yes 
PD 
Abbreviations: NE=not evaluable; NED=no evidence of disease; PD=progressive disease. 
 
Note: 
• Participants with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression 
at that time should be classified as having “symptomatic deterioration.” 
Objective response status is determined by evaluations of disease burden. 
Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
• Overall RECIST v1.1 response options for this study will be limited to No 
Evidence of Disease, Not Evaluable, or Progressive Disease because 
participants are expected to have no radiographic evidence of disease at 
enrollment. 

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Lymphadenopathy After COVID-19 Vaccination and Tumor Assessments 
Case reports of new lymphadenopathy within days to weeks after COVID-19 vaccination, 
local to the side of vaccine administration, have been published [Becker, 2021; 
Cohen, 2021; Eshet, 2021; Keshavarz, 2021]. This reactive lymphadenopathy is 
indistinguishable from malignant lymphadenopathy on medical images and has the 
potential to confound radiological tumor assessments, particularly in indications with a 
propensity to metastasize to local axillary lymph nodes, such as breast cancer. 
Lymphadenopathy after COVID-19 vaccination is transient (appears within days and 
subsides within days/weeks after vaccination), local (predominantly axillary lymph node 
and less frequently in supraclavicular/lower cervical nodes, when administered into the 
deltoid muscle of upper arm), and ipsilateral to the vaccination site (e.g., right axillary 
lymph node if administered to right deltoid muscle). Lymphadenopathy after COVID-19 
vaccination has been observed on anatomical images (CT/MRI scans) as mildly swollen 
(10 to 20 mm short-axis diameter) and more frequently on PET scans with elevated 
uptake of 18F-FDG. 
Vaccination information (name, date, dose number [1st/2nd/booster], injection site, and 
laterality) collected in the Concomitant Medications COVID-19 Vaccination eCRF will 
be available to site and/or central radiologists to supplement their tumor assessments. 
If there is suspicion of lymphadenopathy after COVID-19 vaccination during tumor 
assessment, caution should be applied before classifying affected lymph nodes as 
unequivocal new lesions and the assignment of progressive disease. Consider imaging 
follow-up and/or tissue diagnosis in those recently vaccinated patients at higher risk of 
local malignant lymphadenopathy. 
Additional COVID-19 vaccination/imaging guidance may be found in Becker et al and 
from the Society of Breast Imaging recommendations (SBI) [Becker, 2021; SBI, 2021]. 
Please contact the GSK study team for more information. 

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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
Niraparib is known to have properties that require participants to use contraception. For 
details on niraparib, refer to the niraparib Investigator’s Brochure [GSK Document 
Number RPS-CLIN-014110]. Based on its mechanism of action, niraparib may cause 
teratogenicity and/or embryo-fetal death when administered to a pregnant woman. (For 
France and Germany, please see Section 10.14 for Contraceptive and Barrier Guidance.) 
Participants who are women of childbearing potential (WOCBP) (see WOCBP 
definition) may only be enrolled if they have a negative pregnancy test (serum or highly 
sensitive urine test) within 72 hours prior to taking study treatment. Participants must 
agree to abstain from activities that could result in pregnancy from Screening through 
180 days after the last dose of study treatment, be willing to use a highly effective 
contraception (see Table 25; for Germany Table 31), or be considered women of 
non-childbearing potential (WONCBP) (see WONCBP definition).  
Participants should be informed that taking the study treatment may involve unknown 
risks to the fetus if pregnancy were to occur during the study. To participate in the study, 
they must adhere to the contraception requirements described below. If there is any 
question that a participant will not reliably comply with the requirements for 
contraception, that participant should not be enrolled in the study. 
Male participants may only be enrolled if they agree to use a male condom (and should 
also be advised of the benefit for a female partner to use a highly effective method of 
contraception, as a condom may break or leak), or be abstinent from intercourse as their 
preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to 
remain abstinent. Male participants must use an adequate method of contraception and 
not donate sperm according to the timeframe in Table 24. 
 
Table 24 
Timing of Contraception and Sperm Donationa 
Parameter 
Timeframe 
Contraception use, 
female participants 
Starting with the Screening Visit through 180 days after the last dose of study 
treatment 
Contraception use, 
male participants 
Starting with the first dose of study treatment through 90 days after the last dose 
of study treatment 
Sperm donation 
Starting with the first dose of study treatment through 90 days after the last dose 
of study treatment 
a. 
For France, see Section 10.14.1.2; for Germany, see Section 10.14.2.2. 

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Table 25 
Contraceptives Allowed During the Studyc 
CONTRACEPTIVES a ALLOWED DURING THE STUDY INCLUDE THE FOLLOWING: 
Highly Effective b Methods that Have Low User Dependency (Failure rate of <1% per year when used 
consistently and correctly) 
• 
IUD (nonhormonal only) 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
− 
Azoospermia is a highly effective contraceptive method, provided that the partner is the 
sole sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, 
then an additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 90 days. 
Note: Documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or medical 
history interview. 
Highly Effectiveb Methods that Are User Dependent (Failure rate of <1% per year when used 
consistently and correctly) 
• 
Sexual abstinence 
− 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant. Periodic abstinence 
(calendar, symptom-thermal, and postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method are not acceptable methods of 
contraception. 
• 
Barrier methods of contraception 
− 
Acceptable barrier methods of contraception include the following: male condom with 
either cap, diaphragm, or sponge with spermicide (double-barrier methods). The use of 
double-barrier methods should always be supplemented with the use of a spermicide to 
result in a failure rate of <1%. Female condom and male condom should not be used 
together. 
Abbreviations: IUD=intrauterine device; WOCBP=woman of childbearing potential. 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly. 
c For Germany, see Section 10.14.2.3, Table 31. 

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Definition of WOCBP 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming postmenopausal unless permanently 
sterile (see Notes below) 
Definition of WONCBP 
Women in the following categories are considered WONCBP (not fertile): 
1. Premenopausal female with permanent infertility due to 1 of the following (for the 
purpose of this study): 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
2. Postmenopausal female 
Notes: 
• A postmenopausal state is defined as ≥60 years of age or <60 years of age 
with no menses for 12 months without an alternative medical cause. 
− Follicle-stimulating hormone (FSH) and plasma estradiol levels in the 
postmenopausal range should be obtained to confirm a postmenopausal 
state in women <60 years of age not using hormonal contraception or 
hormone replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than 1 FSH 
measurement is required. 
− Females on HRT and whose menopausal status is in doubt will be required 
to use 1 of the non-estrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment. 
• For individuals with permanent infertility due to an alternate medical cause 
other than those previously listed, (eg, Mullerian agenesis, androgen 
insensitivity, gonadal dysgenesis), Investigator discretion should be applied 
when determining study entry. 
• If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a 
menstrual cycle cannot be confirmed before first dose of study treatment, 
additional evaluation should be considered. 
• Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
 

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10.5. 
Appendix 5: Regulatory, Ethical, and Study Oversight 
Considerations 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
− Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) international ethical 
guidelines 
− Applicable ICH Good Clinical Practice (GCP) guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, informed consent form (ICF), 
Investigator’s Brochure [GSK Document Number RPS-CLIN-014110], and 
other relevant documents (eg, advertisements) must be submitted to an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the 
Investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 
• Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate 
an immediate hazard to study participants. 
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC 
− Notifying the IRB/IEC of serious adverse events (SAEs) or other 
significant safety findings as required by IRB/IEC procedures. 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), European Medical Device Regulation 2017/745 for clinical 
device research (if applicable), and all other applicable local regulations 
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Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions 
regarding the study. 
• Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and 
data protect requirements, where applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent 
was obtained before the participant was enrolled in the study and the date the 
written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) 
during their participation in the study. 
• A copy of the ICF(s) must be provided to the participant. 
• Participants who are rescreened are required to sign a new ICF 
• GSK (alone or working with others) may use participant’s coded study data 
and samples and other information to carry out this study; understand the 
results of this study; learn more about the study treatments or about the study 
disease; publish the results of these research efforts; and work with 
government agencies or insurers to have the study treatments approved for 
medical use or approved for payment coverage. 
• The ICF contains a separate section that addresses the use of participant data 
and remaining samples for further research. The Investigator or authorized 
designee will inform each participant of the possibility of further research not 
related to the study/disease. Participants will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. A separate signature will be required to 
document a participant's agreement to allow any participant data and/or 
remaining leftover samples to be used for further research not related to the 
study/disease. Participants who decline further research will tick the 
corresponding “No” box. 
Data Protection 
• Participants will be assigned a unique identifier by the Sponsor. Any 
participant records or datasets that are transferred to the Sponsor will contain 
the identifier only; participant names or any information which would make 
the participant identifiable will not be transferred. 
• The participant must be informed that his/her personal study-related data will 
be used by the Sponsor in accordance with local data protection law. The level 
of disclosure must also be explained to the participant who will be required to 
give consent for their data to be used as described in the informed consent. 

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• The participant must be informed that his/her medical records may be 
examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the Sponsor, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities. 
• The contract between sponsor and study sites specifies responsibilities of the 
parties related data protection, including handling of data security breaches and 
respective communication and cooperation of the parties. 
• Information technology systems used to collect, process, and store study-related 
data are secured by technical and organizational security measures designed to 
protect such data against accidental or unlawful loss, alteration, or unauthorized 
disclosure or access. 
 
Committees Structure 
An Independent Data Monitoring Committee (IDMC) will be established to ensure 
participants’ safety during this study and will consist of 3 individuals, including 
1 biostatistician and 2 physicians who are independent from the Sponsor. The 
membership, the key responsibilities of the IDMC, and the corresponding procedures will 
be defined in an IDMC charter. 
Dissemination of Clinical Study Data 
• Where required by applicable regulatory requirements, an Investigator 
signatory will be identified for the approval of the CSR. The Investigator will 
be provided reasonable access to statistical tables, figures, and relevant reports 
and will have the opportunity to review the complete study results at a GSK 
site or other mutually-agreeable location. 
• GSK will also provide all Investigators who participated in the study with a 
summary of the study results and will tell the Investigators what treatment 
their participants received. The Investigator(s) is/are encouraged to share the 
summary results with the study participants, as appropriate. 
• GSK will also provide the Investigator with clinically relevant Clinical 
Laboratory Improvement Amendments (CLIA)-validated tumor genetic 
results from
 test to be shared, as applicable, 
with their specific participants. 
• Under the framework of the SHARE initiative, GSK intends to make 
anonymized participant-level data from this study available to external 
researchers for scientific analyses or to conduct further research that can help 
advance medical science or improve patient care. This helps ensure the data 
provided by study participants are used to maximum effect in the creation of 
knowledge and understanding. Requests for access may be made through 
www.clinicalstudydatarequest.com. 
• GSK will provide the Investigator with the randomization codes for their site 
only after completion of the full statistical analysis. 
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• The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study 
will be in accordance with GSK Policy. 
• GSK intends to make anonymized participant-level data from this study 
available to external researchers for scientific analyses or to conduct further 
research that can help advance medical science or improve patient care. This 
helps ensure the data provided by study participants are used to maximum 
effect in the creation of knowledge and understanding. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or 
electronic CRFs unless transmitted to the Sponsor or designee electronically 
(eg, laboratory data). The Investigator is responsible for verifying that data 
entries are accurate and correct by physically or electronically signing the 
CRF. 
• Guidance on completion of CRFs will be provided in Case Report Form 
Completion Guidelines. 
• Quality tolerance limits (QTLs) will be predefined in the Study Reference 
Manual to identify systematic issues that can impact participant safety and/or 
reliability of study results. These predefined parameters will be monitored 
during and at the end of the study, and all deviations from the QTLs and 
remedial actions taken will be summarized in the CSR. As of the date of the 
decision to stop enrollment under Protocol Amendment 03, the study had 
not enrolled enough participants to define or monitor QTLs. The QTLs 
are no longer applicable. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to source 
data documents. 
• Monitoring details describing strategy including definition of study critical 
data items and processes (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based 
monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the monitoring plan. 
• The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Detailed information about study data 
collection and management process, including systems used, can be found in 
the study Data Management Plan. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, contract research organizations). 
• Records and documents, including signed ICF, pertaining to the conduct of 
this study must be retained by the Investigator for 25 years from the issue of 
the final CSR/equivalent summary unless local regulations or institutional 

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policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records 
may be transferred to another location or party without written notification to 
the Sponsor.  
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at 
the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The Investigator may need to request 
previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• Source Data Per the ICH E6 Guideline (Section 1.52) source 
documentation is defined as “Original documents, data, and records (e.g., 
hospital records, clinical and office charts, laboratory notes, memoranda, 
participants’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-
rays, patient files, and records kept at the pharmacy, at the laboratories, 
and at medico-technical departments involved in the clinical trial).” The 
Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
• The sponsor or designee will perform monitoring to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
• Copies of documents are shared with external third parties contracted by 
GSK for review by a central reader mechanism (e.g., endpoint 
adjudication committee; expert reader). The non-exhaustive list of 
documents shared to inform the central reader may include, discharge 
summaries, imaging reports, ECG reports etc. Participant names or any 
information which would make the participant identifiable or is not 
essential for the central reader mechanism will be redacted by the 
Investigator sites prior to transfer. Details of the list of documents and 
the redaction procedure are provided in the site manual or equivalent. 
These documents will be used by the third party solely for the purpose 
indicated within this protocol.  
 

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• Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
Study/Site Termination 
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. 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: 
For study termination: 
• Discontinuation of further study treatment development 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of 
the IRB/IEC or local health authorities, the Sponsor's procedures, or GCP 
guidelines 
• Inadequate or no recruitment of participants (evaluated after a reasonable 
amount of time) by the Investigator 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. 
If this is foreseen, the Investigator agrees to submit all manuscripts or 
abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments. 

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• The Sponsor will comply with the requirements for publication of study 
results. In accordance with standard editorial and ethical practice, the Sponsor 
will generally support publication of multicenter studies only in their entirety 
and not as individual site data. In this case, a coordinating Investigator will be 
designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 
 

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10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
Table 26 
Liver Chemistry Stopping Criteria and Required Follow up 
Assessments. 
Liver Chemistry Stopping Criteria –Liver Stopping Event 
Participant with entry criteria ALT≤2.5 × ULN 
ALT-absolute 
ALT 8 × ULN 
ALT Increase 
ALT 5 × ULN but <8 × ULN persists for 2 weeks 
ALT 3 × ULN but <5 × ULN persists for 4 weeks 
Bilirubina,b 
ALT 3 × ULN and bilirubin  2 × ULN (>35% direct bilirubin)  
INRb  
ALT 3 × ULN and INR>1.5, if INR measured 
Cannot Monitor 
ALT 5 × ULN but <8 × ULN and cannot be monitored weekly for 
2 weeks 
ALT 3 × ULN but <5 × ULN and cannot be monitored weekly for 
4 weeks 
Symptomaticc 
ALT 3 × ULN associated with symptoms (new or worsening) believed to 
be related to liver injury or hypersensitivity 
 
Required Actions and Follow-up Assessments following ANY Liver Stopping Event 
Actions 
Follow-up Assessments 
• 
Immediately discontinue study treatment  
• 
Report the event to GSK within 24 hours 
• 
Complete the liver event CRF and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAEb 
• 
Perform liver event follow-up assessments  
• 
Monitor the participant until liver 
chemistries resolve, stabilize, or return to 
within baseline (see MONITORING 
below) 
• 
Do not restart/rechallenge participant with 
study treatment unless allowed per 
protocol and GSK Medical Governance 
approval is granted 
• 
If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
treatment and may continue participant in 
the study for any protocol-specified 
follow-up assessments  
• 
Viral hepatitis serologyd 
• 
Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and hepatitis 
delta antibody.e 
• 
Blood sample for PK analysis, obtained 
within 3 hours (±15 minutes) after last dosef 
• 
Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH). 
• 
Fractionate bilirubin, if total bilirubin 
2 × ULN 
• 
Obtain complete blood cell count with 
differential to assess eosinophilia 
• 
Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• 
Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications. 

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Required Actions and Follow-up Assessments following ANY Liver Stopping Event 
Actions 
Follow-up Assessments 
MONITORING: 
For bilirubin or INR criteria:  
• 
Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow-up assessments 
within 24 hrs 
• 
Monitor participants twice weekly until 
liver chemistries resolve, stabilize, or 
return to within baseline 
• 
A specialist or hepatology consultation is 
recommended 
For all other criteria:  
• 
Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow-up assessments 
within 24 to 72 hrs 
• 
Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• 
Record alcohol use on the liver event 
alcohol intake case report form 
For bilirubin or INR criteria: 
• 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins). 
• 
Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use in 
the preceding week [James, 2009]). NOTE: 
Not required where test is not available per 
local standard-of-care 
• 
Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and/or liver biopsy to evaluate liver disease; 
complete Liver Imaging and/or Liver 
Biopsy CRF forms. 
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
CRF=case report form; HPLC=high-performance liquid chromatography; IgM=immunoglobulin M; 
INR=international normalized ratio; PCR=polymerase chain reaction; PK=pharmacokinetic; SAE=serious 
adverse event; ULN=upper limit of normal. 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation 
is not immediately available, discontinue study treatment for that participant if ALT 
3 × ULN and 
bilirubin 2 × ULN. Additionally, if serum bilirubin fractionation testing is unavailable, record presence 
of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver 
injury.  
b All events of ALT 3 × ULN and bilirubin  2× ULN (>35% direct bilirubin) or ALT 
3 × ULN and 
INR >1.5, if INR measured which may indicate severe liver injury (possible “Hy’s Law”), must be 
reported as an SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not 
required and the threshold value stated will not apply to participants receiving anticoagulants. 
c New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as 
fever, rash, or eosinophilia). 
d Includes: Hepatitis A IgM antibody, hepatitis B surface antigen and hepatitis B core antibody (IgM), 
hepatitis C RNA, cytomegalovirus IgM antibody, Epstein-Barr viral capsid antigen IgM antibody (or if 
unavailable, obtain heterophile antibody or monospot testing), and hepatitis E IgM antibody.  
e If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA 
virus (where needed) [Le Gal, 2005]. 
f Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment 
prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK 
sample cannot be collected in the time period indicated above, do not obtain a PK sample.  

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Table 27 
Liver Chemistry Increased Monitoring Criteria with Continued 
Therapy  
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
Participant with entry criteria 
ALT≤2.5 × ULN 
ALT 5 × ULN and <8 × ULN and 
bilirubin <2 × ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be monitored 
weekly for 2 weeks. 
OR 
ALT 3 × ULN and <5 × ULN and 
bilirubin <2 × ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be monitored 
weekly for 4 weeks. 
• 
Notify the GSK medical monitor within 
24 hours of learning of the abnormality to 
discuss participant safety. 
• 
Participant can continue study treatment 
• 
Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return 
to within Baselinea  
• 
If at any time participant meets the liver 
chemistry stopping criteria, proceed as 
described above 
For participant with entry criteria 
ALT≤2.5 × ULN 
• 
If ALT decreases from ALT 5 × ULN and 
<8 × ULN to ≥3 × ULN but <5 × ULN, 
continue to monitor liver chemistries weekly. 
• 
If, after 4 weeks of monitoring, ALT 
<3 × ULN and bilirubin <2 × ULN, 
monitor participants twice monthly until 
liver chemistries normalize or return to 
within baseline. 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of 
normal. 
a For the purpose of these guidelines, “baseline” refers to laboratory assessments performed closest and 
prior to first dose of study treatment. 

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10.7. 
Appendix 7: Eastern Cooperative Oncology Group 
Performance Status 
Table 28 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Grading 
Description 
Grade 
Fully active, able to carry on all pre-disease performance without restriction. 
0 
Restricted in physically strenuous activity, but ambulatory and able to carry out work 
of a light or sedentary nature (ie, light housework, office work). 
1 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
2 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
3 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
4 
Source: [Oken, 1982]  
 

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10.8. 
Appendix 8: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
Adverse Event (AE) Definition 
• An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study treatment, whether or not considered 
related to the study treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention. 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (ie, not related 
to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/ SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
• Events that occur as a result of protocol-mandated procedures (i.e., invasive 
procedures, modification of participant’s previous therapeutic regimen). 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
 

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Events NOT Meeting the AE Definition  
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
• Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed before signing the informed consent) that did not worsen from baseline. 
 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 

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An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
influenza, and accidental trauma (eg, sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect in the offspring of a study participant 
f. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) 
g.  Other situations: 
• Possible Hy’s Law case: ALT≥3×ULN AND total bilirubin ≥2×ULN 
(>35% direct bilirubin) or international normalized ratio (INR) >1.5 must be 
reported as SAE. 
• Medical or scientific judgment should be exercised by the Investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
 
Definition of Treatment-Emergent Adverse Event (TEAE) 
TEAE Definition 
• A TEAE is defined as any new AE that begins, or any pre-existing condition that 
worsens in severity, after at least 1 dose of study treatment has been 
administered. 
Definition of an Adverse Event of Special Interest (AESI) 
An AESI is any AE (serious or nonserious) that is of scientific and medical concern 
specific to the study treatment, for which ongoing monitoring and rapid communication 
by the Investigator to the Sponsor is appropriate. 
Niraparib AESIs 
AESIs for niraparib are the following: 
• myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) 
• second primary cancers (new malignancies [other than MDS or AML]) 

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Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 
 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK required form. 
• There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
 
Assessment of Intensity 
The Investigator will make an assessment of intensity (severity) for each AE and SAE 
reported during the study. 
The severity of AEs will be graded according to Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0; National Institutes of Health (NIH), National Cancer 
Institute (NCI). The CTCAE severity Grades 1 through 5 provide unique clinical 
descriptions of severity of each AE. The CTCAE v5.0 is available on the NCI/NIH 
website. 

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Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study treatment 
and each occurrence of each AE/SAE. The Investigator will use clinical judgment 
to determine the relationship. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• For causality assessment, the Investigator will also consult the IB and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the Investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to GSK. 
• The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Assessment of Outcomes 
The Investigator will assess the outcome of all serious and nonserious unsolicited AEs 
recorded during the study as: 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered with sequelae/resolved with sequelae 
• 
Fatal (SAEs only). 

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Follow-up of AEs, SAEs, AESIs, pregnancies, and any other events of interest  
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• New or updated information will be recorded in the originally submitted documents. 
• 
The Investigator will submit any updated SAE data to GSK within 24 hours of receipt 
of the information. (For reporting in Germany, see Section 10.14.2.2). 
• After the initial AE/SAE/AESI/pregnancy or any other event of interest, the 
Investigator is required to proactively follow each participant at subsequent 
visits/contacts. All SAEs, and nonserious AESI (as defined in the Section 8.5.8), will 
be followed until the event is resolved, stabilized, otherwise explained, or the 
participant is lost to follow-up. 
Follow-up of pregnancies 
Pregnant participants will be followed to determine the outcome of the pregnancy. At the 
end of the pregnancy, whether full-term or premature, information on the status of the 
mother and child will be forwarded to GSK using the reporting procedures outlined for 
the study. Generally, the follow-up period does not need to be longer than 6 to 8 weeks 
after the estimated date of delivery. 
Regardless of the reporting period for SAEs in this study, if the pregnancy outcome is an 
SAE, it should always be reported as such. 
• 
Furthermore, the Investigator must report any SAE occurring as a result of a post-
study pregnancy that is considered by the Investigator to be reasonably related to the 
study intervention, to GSK as described in the section below. 
 
Updating of SAE, AESI and pregnancy information after removal of write access to 
the participant’s eCRF 
When additional SAE, AESI or pregnancy information is received after write access to 
the participant’s eCRF is removed, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the Investigator. The 
updated report should be sent to the Study contact for reporting SAEs (refer to 
Section 8.5.3). 

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Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool (until DCO) 
• The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool until DCO is met. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. ** 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the GSK Medical Monitor or the SAE Coordinator by telephone. 
• If the site during the course of the study becomes aware of any serious, nonserious 
AEs, pregnancy exposure, related to any GSK non-IMP they will report these events 
to GSK or to the concerned competent authority via the national spontaneous 
reporting system. These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE reporting can be found in the local study contact document. 
** 
For reporting in Germany, see Section 10.14.2.2. 
 
SAE/AESIs/AEs leading to treatment discontinuation/Overdose/Pregnancy Reporting to 
GSK via Paper Data Collection Tool/paper forms (only if electronic system unavailable 
and/or in PACT Phase) 
• Email/Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the GSK Medical Monitor or the SAE 
Coordinator. 
• In rare circumstances and in the absence of email/facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE data collection tool within the designated reporting time 
frames. 
• For PACT Phase: 
• 
SAEs/AESIs/AE leading to discontinuation/Overdose/Pregnancy reports 
need to be reported within 24 hours of becoming aware of the event.  
• 
Initial and follow up SAEs, AESIs, Overdose and AEs leading to 
discontinuation will be submitted to Sponsor on a paper SAE form. 
• 
Alternative reporting methods may become available during the PACT 

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SAE/AESIs/AEs leading to treatment discontinuation/Overdose/Pregnancy Reporting to 
GSK via Paper Data Collection Tool/paper forms (only if electronic system unavailable 
and/or in PACT Phase) 
Phase. Details for these methods and preferred reporting processes will be 
provided separately by the Sponsor, if/when applicable. 
• 
Pregnancy cases will be submitted to Sponsor on a paper pregnancy initial 
or paper pregnancy follow up form.  
• 
In case sites need to discuss the event please contact the GSK Medical 
Monitor and your local CRA. 
• 
Details about SAE/AE reporting can be found on the paper form (Refer to 
Section 10.9, Section 10.9, and Section 10.11) 
 

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10.9. 
Appendix 9: Pregnancy Initial Notification Form 
 

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10.10. 
Appendix 10: Study pregnancy follow up form. 
 
 

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10.11. 
Appendix 11: Serious Adverse Event (SAE) Reporting Form 
 

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10.12. 
Appendix 12: Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study treatment, 
susceptibility, severity, and progression of disease. Variable response to study 
treatment may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; 
disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and Institutional Review 
Board/Independent Ethics Committee allow, a blood sample will be collected 
for DNA analysis. 
• DNA (derived from tumor or blood specimens) samples will be used for 
research related to niraparib or breast cancer and related diseases. They may 
also be used to develop tests/assays (including diagnostic tests) related to 
niraparib (monotherapy or combination therapy, or study treatments of this 
drug class) and breast cancer (or related cancer indications). Genetic research 
may consist of the analysis of one or more candidate genes or the analysis of 
genetic markers throughout the genome (as appropriate). 
• Additional analyses of DNA samples may be conducted if it is hypothesized 
that this may help further understand the clinical data. 
• The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to niraparib (monotherapy or combination 
therapy) or study treatments of this class to understand the study disease or 
related conditions.  
• The results of genetic analyses may be reported in a CSR or in a separate 
study summary. 
• The Sponsor will store the DNA samples in a secure storage space with 
adequate measures to protect confidentiality. 
• The samples will be retained while research on niraparib (or study treatments 
of this class) continues but no longer than 15 years after the last participant’s 
last visit or other period as per local requirements. 
 

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10.13. 
Appendix 13: Breast Cancer Staging Guidance 
 

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10.14. 
Appendix 14: Country-specific Requirements 
10.14.1. 
France 
The following sections outline France-specific changes from the main protocol.  
10.14.1.1. Contraceptive Requirements 
Contraception requirements were adjusted in alignment with recommendations by 
ANSM. 
• Any pregnancies that occur within 194 days (6.5 months) post-treatment are to 
be reported as described in Section 8.5.5. 
• Details of all pregnancies in female participants and, if indicated, female 
partners of male participants who receive study treatment will be collected 
after the start of study treatment and until 194 days (6.5 months) after the last 
dose of study treatment in female participants and 104 days (3.5 months) after 
the last dose of study treatment for female partners of male participants. 
Inclusion Criteria (criteria #11 and #12) 
11 A female participant is eligible if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies: 
• Is not a woman of childbearing potential (WOCBP), as defined in 
Section 10.14.1.2. 
OR 
• Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), as described in Section 10.14.1.2, during the 
Treatment Period and for at least 194 days (6.5 months) after the last dose of 
study treatment and agrees not to donate eggs (ova, oocytes) for the purpose 
of reproduction during this period. The Investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of 
study treatment. 
• A WOCBP must have a negative pregnancy test (highly sensitive urine test or 
serum test as required by local regulations) within 72 hours before the first 
dose of study treatment. 
• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive. 
• Additional requirements for pregnancy testing during and after study 
treatment are described in Section 8.4.6. 
• The Investigator is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a 
woman with an early undetected pregnancy. 

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See Section 10.14.1.2 for a list of acceptable birth control methods. Information must be 
captured appropriately within the site’s source documents. 
12 Male participants are eligible if they agree to the following during the Treatment 
Period and for at least 104 days (3.5 months) after the last dose of study treatment 
(see Section 10.14.1.2 for a list of acceptable birth control methods): 
• Be abstinent from intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent 
OR 
• Must agree to use contraception/barrier as detailed below: 
− Agree to use a male condom (and should also be advised of the benefit for 
a female partner to use a highly effective method of contraception as a 
condom may break or leak)  
• PLUS 
• Male participants must refrain from donating sperm for at least 104 days 
(3.5 months) after the last dose of study treatment 
Exclusion Criteria (criterion #17) 
17 Participant is pregnant, breastfeeding, or expecting to conceive children while 
receiving study treatment and/or for up to 194 days (6.5 months) after the last 
dose of study treatment. 
10.14.1.2. Contraceptive and Barrier Guidance for France 
Niraparib is known to have properties that require participants to use contraception. For 
details on niraparib, refer to the niraparib Investigator’s Brochure. Based on its 
mechanism of action, niraparib may cause teratogenicity and/or embryo-fetal death when 
administered to a pregnant woman. 
Participants who are women of childbearing potential (WOCBP) (see WOCBP 
definition) may only be enrolled if they have a negative pregnancy test (serum or highly 
sensitive urine test) within 72 hours prior to taking study treatment. Participants must 
agree to abstain from activities that could result in pregnancy from Screening through 
194 days (6.5 months) after the last dose of study treatment, be willing to use a highly 
effective contraception (see Table 25), or be considered women of non-childbearing 
potential (WONCBP) (see WONCBP definition). 
Participants should be informed that taking the study treatment may involve unknown 
risks to the fetus if pregnancy were to occur during the study. To participate in the study, 
they must adhere to the contraception requirements described below. If there is any 
question that a participant will not reliably comply with the requirements for 
contraception, that participant should not be enrolled in the study. 
Male participants may only be enrolled if they agree to use a male condom (and should 
also be advised of the benefit for a female partner to use a highly effective method of 
contraception, as a condom may break or leak), or be abstinent from intercourse as their 

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preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to 
remain abstinent. Male participants must use an adequate method of contraception and 
not donate sperm according to the timeframe in Table 29. 
 
Table 29 
Timing of Contraception and Sperm Donation in France 
Parameter 
Timeframe 
Contraception use, 
female participants 
Starting with the Screening Visit through 194 days (6.5 months) after the 
last dose of study treatment 
Contraception use, 
male participants 
Starting with the first dose of study treatment through 104 days 
(3.5 months) after the last dose of study treatment 
Sperm donation 
Starting with the first dose of study treatment through 104 days 
(3.5 months) after the last dose of study treatment 
 

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10.14.2. 
Germany 
The following sections outline German specific changes from the main protocol 
regarding at-home nursing visits, SAE reporting, and contraceptive and barrier guidance. 
As of the date of the decision to stop enrollment, at-home nursing services will no 
longer be offered. 
10.14.2.1. General Guidance for Treatment Continuity When Participants Are 
Unable to Come into the Clinic in Germany 
Table 30 
Required Data Collection and Safety Precautions for At-Home 
Nursing Visits in Germany 
Assessment 
Recommendation 
Follow-up assessment 
Contact participant by phone. This discussion should 
include assessment of new therapies and overall survival. 
Hematology 
Assessments may be performed through at-home nursing or 
at local laboratory. Arrangements for at-home nursing or 
the use of a local laboratory should be made by the site 
including the reporting of results to the PI for review.  
Vital signs 
Assessments may be performed through at-home nursing or 
at local laboratory or clinic. Arrangements for at-home 
nursing or the use of a local laboratory/clinic should be 
made by the site including the reporting of results to the PI 
for review. 
Adverse events 
• 
Ongoing AEs and SAEs - reviewed by phone 
• 
If hematologic AE are ongoing, a local CBC is 
desirable 
• 
New AEs/SAEs - may be assessed by phone (please 
remember to submit SAE documentation immediately 
when learning of the event) 
Concomitant medications 
Reviewed by phone and via medical record review 
PK 
Blood samples for PK may be collected through at-home 
nursing. Arrangements for at-home nursing should be made 
by the site. 
Abbreviations: AE=adverse event; CBC=complete blood count; CT=computed tomography; ctDNA=circulating tumor 
DNA; EC=Ethics Committee; IRB=Institutional Review Board; MRI=magnetic resonance imaging; PI=Principal 
Investigator; PK=pharmacokinetic; PRO=patient-reported outcome; RECIST=Response Evaluation Criteria in Solid 
Tumors; SAE=serious adverse event. 
As of the date of the decision to stop enrollment, at-home nursing services will no longer be offered. 
10.14.2.2. Time Period and Frequency for Collecting AE, AESI, and SAE 
Information for Germany 
• All SAEs will be recorded and reported to the Sponsor or designee 
immediately, as indicated below. The Investigator will submit any updated 
SAE data to the Sponsor immediately it becomes available. 

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• An AESI is any AE (serious or nonserious) that is of scientific and medical 
concern specific to niraparib for which ongoing monitoring and rapid 
communication by the Investigator to the Sponsor is warranted. These events 
must be recorded as such on the eCRF. Serious AESIs must be reported to the 
Sponsor immediately the Investigator becomes aware of them. 
 
Follow-up of AEs, SAE, AESIs, pregnancies, and any other events of interest 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• New or updated information will be recorded in the originally submitted 
documents. 
• The Investigator will submit any updated SAE data to GSK immediately on receipt 
of the information. 
 
Reporting of SAE to GSK (Germany) 
SAE Reporting to GSK via Electronic Data Collection Tool 
• The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event immediately. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the GSK Medical Monitor or the SAE Coordinator by telephone. 
• If the site during the course of the study becomes aware of any serious, nonserious 
AEs, pregnancy exposure, related to any GSK non-IMP they will report these events 
to GSK or to the concerned competent authority via the national spontaneous 
reporting system. These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE reporting can be found in the local study contact document.  
 

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10.14.2.3. Contraceptive and Barrier Guidance for Germany 
Table 31 
Contraceptives Allowed During the Study for Germany 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE THE 
FOLLOWING: 
Highly Effectiveb Methods that Have Low User Dependency (Failure rate of <1% per year 
when used consistently and correctly) 
• 
IUD (nonhormonal only) 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
− 
Azoospermia is a highly effective contraceptive method, provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, then an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: Documentation of azoospermia for a male participant can come from the 
site personnel’s review of the participant’s medical records, medical 
examination, or medical history interview. 
Highly Effectiveb Methods that Are User Dependent (Failure rate of <1% per year when used 
consistently and correctly) 
• 
Sexual abstinence 
− 
Sexual abstinence is considered a highly effective method only if defined as 
refraining from intercourse during the entire period of risk associated with the 
study treatment. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant. Periodic abstinence (calendar, symptom-thermal, and postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method are not acceptable methods of contraception. 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b Failure rate of <1% per year when used consistently 
 

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10.15. 
Appendix 15: Abbreviations and Specialist Terms 
The following abbreviations and specialist terms are used in this study protocol. 
Table 32 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
AESI 
adverse event of special interest 
AJCC 
American Joint Committee on Cancer 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
AST 
aspartate aminotransferase 
BCRP 
breast cancer resistance protein 
BER 
base excision repair 
BOR 
best overall response 
BP 
blood pressure 
BSEP 
bile salt export pump 
BRCA 
breast cancer susceptibility gene 
BRCAmut 
breast cancer susceptibility gene mutation 
CBC 
complete blood count 
CE 
conformité européenne (European Conformity) 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CLIA 
Clinical Laboratory Improvement Amendments 
COVID-19 
Corona virus disease 2019 
CR 
complete response 
CRO 
contract research organization 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
ctDNA+ 
ctDNA-positive 
CV 
Cardiovascular 
CYP 
cytochrome P450 
DCIS 
ductal carcinoma in situ 
DCO 
data cut-off 

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Abbreviation or Specialist Term 
Explanation 
DCR 
disease control rate 
DFS 
disease-free survival 
DoR 
duration of response 
DRFS 
distant recurrence-free survival 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EFS 
event-free survival 
EORTC-QLQ-C30 
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire 30-item Core Module 
EOS 
End of the study 
EOT 
End-of-Treatment 
EQ-5D-3L 
EuroQoL 5-Dimensional Questionnaire 3-Level Version 
ER+ 
estrogen receptor positive 
ER 
estrogen receptor 
E-R 
exposure-response 
FACT-GP5 
Functional Assessment of Cancer Therapy-General 
Population 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FFPE 
formalin-fixed paraffin-embedded 
FISH 
fluorescence in situ hybridization 
FSH 
follicle-stimulating hormone 
gBRCAmut 
a deleterious or suspected deleterious germline mutation in 
the BRCA gene 
GCP 
Good Clinical Practice 
GIS 
genome instability score 
H0 
null hypothesis 
H1 
alternative hypothesis 
hCG 
human chorionic gonadotropin 
HER2 
human epidermal growth factor 2 
HER2− 
human epidermal growth factor 2 negative 
HER2+ 
human epidermal growth factor 2 positive 
HIV 
human immunodeficiency virus 
HPLC 
high-performance liquid chromatography 
HR 
hormone receptor 
HR− 
hormone receptor negative 
HR+ 
hormone receptor positive 

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Abbreviation or Specialist Term 
Explanation 
HRD 
homologous recombination deficiency 
HRd 
homologous recombination deficient 
HRp 
homologous recombination proficient 
HRQoL 
health-related quality of life 
HRR 
homologous recombination repair 
IB 
Investigator’s Brochure 
IBCFS 
invasive breast cancer-free survival 
IC50 
half-maximal inhibitory concentration 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ICF 
informed consent form 
IDFS 
invasive disease-free survival 
IDMC 
Independent Data Monitoring Committee 
IDMV 
Independent Drug Monitoring Visit 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IIBTR 
ipsilateral invasive breast tumor recurrence 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISH  
in situ hybridization 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IV 
intravenous 
IWRS 
interactive web response system 
LCIS 
lobular carcinoma in situ 
MATE 
multidrug and toxin extrusion protein 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid 
MRI 
magnetic resonance imaging 
MTM 
mean tumor molecule 
NCCN 
National Comprehensive Cancer Network 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
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Abbreviation or Specialist Term 
Explanation 
N-DMT 
N-desmethyl tamoxifen 
NED 
no evidence of disease 
NHEJ 
nonhomologous end-joining 
NIH 
National Institutes of Health 
OCT1 
organic cation transporter 1 
ORR 
objective response rate 
OS 
overall survival 
PACT 
post-analysis continued treatment 
PARP 
poly(ADP-ribose) polymerase 
pCR 
pathological complete response 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death ligand 1 
PET 
positron emission tomography 
P-gp 
P-glycoprotein 
PgR 
progesterone receptor 
PFS 
progression-free survival 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PR 
partial response 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PRO 
patient-reported outcome 
PRO-CTCAE 
Patient-reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events 
QTL 
quality tolerance limit 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAF 
Safety (analysis population) 
SAP 
Statistical Analysis Plan 
SBI 
Society of Breast Imaging 
sBRCAmut 
somatic mutation in the BRCA gene 
SD 
stable disease 
SNV 
single nucleotide variant 
SOA 
schedule of activities 

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Abbreviation or Specialist Term 
Explanation 
SOP 
standard operating procedure 
STEEP 
Standardized Definitions for Efficacy EndPoints 
tBRCA 
tumor BRCA 
tBRCAmut 
tumor mutation in the BRCA gene 
tBRCAwt 
tumor BRCA wild-type 
TEAE 
treatment-emergent adverse event 
TFST 
time to first subsequent therapy 
TNBC 
triple-negative breast cancer 
ULN 
upper limit of normal 
US 
United States 
WES 
whole exome sequencing 
WOCBP 
woman of childbearing potential 
WONCBP 
woman of non-childbearing potential 
 
Table 33 
Glossary of terms 
Term 
Definition 
Comparator  
Any product used as a reference (including placebo, 
marketed product, GSK or non-GSK) for an 
investigational product being tested in a clinical trial. 
This is any product that is being used to assess the 
safety, efficacy, or other measurable value against the 
test product (IMP). 
Investigational Product 
A pharmaceutical form of an active substance or 
placebo being tested or used as a reference in a clinical 
trial, including products already with a marketing 
authorization but used or assembled (formulated or 
packaged) in a way different from the authorized 
form, or when used for an unauthorized indication, or 
when used to gain further information about the 
authorized form. 
Placebo 
An inactive substance or treatment that looks the same 
as, and is given in the same way as, an active drug or 
intervention/treatment being studied. 
Standard of Care 
Medicine(s) for a specific indication, or a component of 
the standard care for a particular medical indication, 
based on national and/or international consensus; 
there is no regulatory significance to this term. 
• 
Products/regimens considered standard of care 
may differ country to country, depending on 
consensus in individual countries.  
 
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TRADEMARK INFORMATION 
Trademarks of the GSK group of 
companies 
 
Trademarks not owned by the GSK group 
of companies 
Zejula 
 
Arimidex 
 
 
Aromasin 
 
 
EAST 
 
 
EORTC-QLQ-C30 
 
 
EQ-5D-3L 
 
 
FACT-GP5 
 
 
Femara 
 
 
FluMist 
 
 
Keytruda 
 
 
Lynparza 
 
 
MedDRA 
 
 
 
 
PRO-CTCAE 
 
 
Signatera 
 
 
Soltamox 
 
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10.16. 
Appendix 16: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 03 02 June 2023 
This amendment is considered substantial based on the criteria defined set forth in Article 
10(s) of Directive 2001/20/EC of the of the European Parliament and the Council of the 
European Union because it significantly impacts the scientific value of the study. 
Overall Rationale for the Amendment  
Amendment 03 applies to all study sites. The changes are based on the Sponsor decision 
to permanently stop all enrollment into the ZEST
 
 
 
 
 
 
 
t has completed their last study 
procedure (as outlined in the Schedule of Activities). 
List of main changes in the protocol and their rationale: 
Section # and title 
Description of Change 
Brief Rationale 
Synopsis 
Section 1.2 (Schema) 
Section 1.3 (Schedule of 
Activities) 
Section 2 (Introduction) 
Section 2.3.3 (Overall 
Benefit/Risk Conclusion) 
Section 4.1 (Overall 
Design) 
Section 4.4 (End of study 
definition) 
Section 5 (Study 
Population) – throughout, 
as applicable 
Section 6.1 (Study 
Treatments Administered) 
Section 6.3 (Measures to 
Minimize Bias: 
Randomization and 
Blinding) – throughout 
Section 6.7 (Treatment 
After End of Study) 
Section 7.1 
(Withdrawal/Stopping 
Criteria) 
Section 7.2 (Participant 
Updates to indicate enrollment in the 
study is closed and study was centrally 
unblinded. Participants on placebo were 
stopped. 
Requirement for specific protocol 
assessments and follow-up visits 
removed and updates to assessment 
(including discontinuation and/or 
adjusted frequency) for managing 
participants in Prescreening, Screening, 
and/or randomized in the study at the 
time of stopping enrollment. Participants 
randomized to treatment on the ZEST 
study may discontinue treatment and be 
offered scans above standard of care, 
while some previously specified 
assessments are now discontinued. 
Table 2 and Table 3 updated with 
footnotes indicating 
discontinued/adjusted assessments. 
New table summarizing participant 
management under Protocol 
Amendment 03 added (Table 11) and 
new schedule of assessments tables 
outlining expected assessments 
(Table 4, Table 5, Table 6). All 
pharmacokinetic (PK) sample collection 
Due to this amendment stemming from the 
decision to permanently stop enrollment 
(outlined above), changes were made to 
outline the necessary assessments and 
management of participants in Prescreening, 
Screening, and/or randomized in the ZEST 
study at the time of implementation of the 
amendment, including monitoring of 
participants who are deriving clinical benefit 
from niraparib and remain on study. 
 
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Section # and title 
Description of Change 
Brief Rationale 
Discontinuation/Withdraw
al from Treatment) 
Section 8 (Study 
Assessments and 
Procedures) – throughout 
Section 10.5 (Regulatory, 
Ethical, and Study 
Oversight Considerations) 
Section 10.11.2 Germany 
(Country-specific 
Appendix) 
is stopped.  
Requirement for central review of scans 
(BICR) removed, along with ctDNA 
testing requirements. 
Text surrounding timing of sharing 
genetic results relative to analyses 
(primary endpoint/interim) removed. 
End of study definition updated. 
At-home nursing visits will no longer be 
offered. 
Synopsis 
Section 3 (Objectives and 
Endpoints and Estimands) 
Section 8 (Study 
Assessments and 
Procedures) – throughout 
Section 9 (Statistical 
Considerations) – 
throughout 
Section 5 (prescreening) 
Minor updates to incorporate country-
specific correction/wording. 
Minor updates to consolidate country-specific 
agency requested changes. 
Throughout 
Editorial, administrative, and document 
formatting revisions 
Minor changes for consistency, clarifications, 
and corrections to text, and/or necessary 
updates in line with current template or 
company style guide. 
 
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Amendment 02 FRA-1 13 Feb 2023 
This amendment is considered substantial based on the criteria defined in EU Clinical 
Trial Regulation No 536/2014 of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment:  
Amendment 02 FRA-1 is a country-specific version of global Amendment 2.0 in which 
changes implemented in this protocol 
 
 
 
 
 
List of main changes in the protocol and their rationale: 
Section # and title 
Description of Change 
Brief Rationale 
Throughout 
Editorial, administrative, and document 
formatting revisions 
Minor changes to align with required 
changes in Sponsor’s updated 
template, style guide, and ways of 
working, consistency, as well as 
additional minor editorial changes and 
clarifications. 
Synopsis 
Section 1.2 Schema  
Section 4.1 Overall Design 
Section 4.2 Scientific 
Rationale for Study Design 
Section 5 Study Population 
(Prescreening) 
Section 6.3.2 Stratification 
Appendix 10 Breast Cancer 
Staging 
Synopsis 
Section 1.2 Schema 
(Figure 1, Figure 3) 
Section 1.3 Schedule of 
Activities (Table 2) 
Section 4.1 Overall Design 
Section 4.2 Scientific 
Rationale for Study Design 
Section 5 Study Population 
(Prescreening) 
Section 5.4 Prescreen 
Failures and Screen 
Failures 
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Section # and title 
Description of Change 
Brief Rationale 
Synopsis 
Section 5 Study Population 
(Prescreening) 
Prescreening Criterion P3 added to outline 
documentation of BRCA mutation 
Updated for study conduct. 
Section 2.2.5.1 Efficacy of 
Niraparib in Maintenance 
Therapy Following 
Platinum-based 
Chemotherapy 
Section 2.3.2 Benefit 
Assessment 
Section 4.2 Scientific 
Rationale for Study Design 
Synopsis 
Section 5 Study Population 
(Prescreening) 
Criterion P3 updated to P6 with addition of 
new criterion and text updated to clarify 
archival tissue requirements. 
Clarification for study conduct. 
Synopsis 
Section 1.3 Schedule of 
Activities (Table 3) 
Section 4.1 Overall Design 
Screening period updated to within 
6 weeks (42 days) of Day 1 and 
clarification this is only recommendation to 
start within 14 days of a confirmed positive 
ctDNA result. 
Clarification in study conduct 
Section 4.3 Justification for 
Dose 
Section 5.1 Inclusion 
Criteria 
Section 6.1.1 Niraparib 
(Table 12) 
Mild and moderate hepatic impairment 
definitions updated. Gilbert’s syndrome 
text removed from sections other than 
inclusion/exclusion criteria for clarification 
to more accurately reflect the definitions of 
hepatic impairment in the study for 
niraparib 
Language alignment across sections 
and clarification in study conduct. 
Section 5.2 Exclusion 
Criteria 
Exclusion criterion 18 update to reflect 
FDA guidance. 
Exclusion criterion 19 corrected for 
typographical error. 
For clarification in study conduct to 
align with FDA guidance and ensuring 
participant safety. 
Section 5.1 Inclusion 
Criteria 
Appendix 4: Contraceptive 
and Barrier Guidance 
Inclusion criterion #12 language and 
Appendix 4 text updated regarding male 
condom use and sexual intercourse  
A revision of the protocol wording for 
use of male condoms by subjects is 
being made for consistency with 
guidance provided in the Investigator 
Brochure and is not a consequence of 
new safety information. Highly 
effective contraceptive methods that 
are user dependent updated as 
requested by ANSM. 
Section 1.3 Schedule of 
Activities (Table 3) 
Section 6.1.1 Niraparib 
Details added regarding dosing based on 
screening weight if there is a change in 
weight prior to Cycle 1/Day 1 dosing. 
Clarification for study conduct 
Section 1.3 Schedule of 
Updated language regarding timing of 
Clarification for study conduct 
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Section # and title 
Description of Change 
Brief Rationale 
Activities (Table 3) 
Section 8.4.6 Pregnancy 
Testing 
pregnancy tests for Screening and 
subsequent cycles. 
Section 6.4.1 Dose Levels 
and Dose Adjustment 
Clarification included that dose cannot be 
re-escalated once reduced 
Alignment with expected conduct 
during the study. 
Section 4.1 Overall Design 
Section 7.1 Withdrawal/ 
Stopping Criteria 
Updated language included regarding 
survival follow-up, definition of 
discontinuation of study intervention, and 
conduct of follow-up period visits. 
Clarification for study conduct 
Section 8.1.1 General 
Guidance for Treatment 
Continuity When 
Participants Are Unable to 
Come into the Clinic 
(Table 16)  
Appendix 11 Country-
specific Requirements 
(Table 28) 
Updated assessments to be performed by 
the home health services (HHS) vendor.  
Clarification for study conduct to align 
with agreed upon assessments 
performed by contracted HHS vendor. 
Appendix 2 Clinical 
Laboratory Tests  
Appendix 4 Contraceptive 
and Barrier Guidance 
Updated FSH requirements for WONCBP 
to be <60 years 
Clarification for study conduct 
Synopsis  
Section 1.2 Schema 
(Figure 1) 
Section 4.1 Overall Design 
Section 5.1 Inclusion 
Criteria 
Section 8.2.1 Baseline 
Assessments at Screening 
Inclusion criterion 1 text adjusted to clarify 
staging criteria. 
Clarifications also included throughout the 
protocol for the following: local tBRCA 
mutation can be somatic or germline 
positive, tumor staging based on clinical 
prognostic, pathologic prognostic, and/or 
anatomic staging, and Allred score 
included. 
Clarification for study conduct  
Section 1.3 Schedule of 
Activities (Table 3) 
Note added to Table 3 indicating ECG 
does not need to be repeated if a patient is 
rescreening.  
ECG is obtained for baseline 
documentation only and repeat is not 
medically indicated. 
Synopsis  
Section 2.1 Study Rationale 
Section 4.1 Overall Design 
Included definition for end of definitive 
therapy 
Clarification for consistency in study 
conduct 
Section 2.3.1 Risk 
Assessment (Table 6) 
Section 5.1 Inclusion 
Criteria 
Inclusion criteria 8 and 9, as well as 
Table 6 updated to remove 3-week delay 
in randomization and treatment for criteria 
to be met. 
Administrative change for clarification; 
text not required  
Synopsis,  
Section 1.3 Schedule of 
Activities (Table 3) 
Section 4.1 Overall Design  
Appendix 3 Guidelines for 
Assessment of Disease, 
Disease Progression and 
Response Criteria 
Imaging text update for clarification. 
Clarification for study conduct. 
Synopsis 
Study duration updated to included overall 
study duration of approximately 8 years. 
Editorial change for clarification 
regarding study conduct. 
Synopsis 
Section 9.1 Statistical 
Clarification to align language in the 
protocol. 
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Section # and title 
Description of Change 
Brief Rationale 
Hypotheses 
 
Synopsis 
Section 9.4.7 Independent 
Data Monitoring Committee 
Text updated regarding timing of safety 
review of Cohort 1 
Clarification for study conduct 
Synopsis 
Section 4.1 Overall Design 
Section 6.7 Treatment After 
the End of the Study 
Update text surrounding potential 
continuation of niraparib post-end of study. 
Editorial 
Section 6.3.3 Blinding and 
Breaking the Blind 
Updated text surrounding breaking the 
blind for those who may continue niraparib 
treatment at the end of the study 
Clarification for study conduct 
Section 8.6 
Pharmacokinetics 
Clarification for study conduct 
Section 9.3.2 Interim 
Analysis 
Updated text to include HRD cutoff GIS of 
42 for Cohort 2 (tBRCAwt/TNBC) 
Clarification for study conduct. 
Appendix 2 Clinical 
Laboratory Tests (Table 20) 
Footnotes added to Table 20 to outline 
required laboratory tests and those to be 
provided if performed per standard of care. 
Clarification for study conduct. 
Appendix 8 AEs and SAEs: 
Definitions and Procedures 
for Recording, Evaluating, 
Follow-up, and Reporting 
Updates to safety reporting language 
Updated to include updated template 
language 
 
Amendment 02 05 Oct 2022 
This amendment is considered substantial based on the criteria defined in EU Clinical 
Trial Regulation No 536/2014 of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment:  
Amendment 2.0 changes implemented in this protocol aim 
 
 
 
 
 
List of main changes in the protocol and their rationale: 
Section # and title 
Description of Change 
Brief Rationale 
Throughout 
Editorial, administrative, and document 
formatting revisions 
Minor changes to align with required 
changes in Sponsor’s updated 
template, style guide, and ways of 
working, consistency, as well as 
additional minor editorial changes and 
clarifications. 
Synopsis 
Section 1.2 Schema  
Section 4.1 Overall Design 
Section 4.2 Scientific 
Rationale for Study Design 
Section 5 Study Population 
(Prescreening) 
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Section # and title 
Description of Change 
Brief Rationale 
Section 6.3.2 Stratification 
Appendix 10 Breast Cancer 
Staging 
Synopsis 
Section 1.2 Schema 
(Figure 1, Figure 3) 
Section 1.3 Schedule of 
Activities (Table 2) 
Section 4.1 Overall Design 
Section 4.2 Scientific 
Rationale for Study Design 
Section 5 Study Population 
(Prescreening) 
Section 5.4 Prescreen 
Failures and Screen 
Failures 
Synopsis 
Section 5 Study Population 
(Prescreening) 
Section 2.2.5.1 Efficacy of 
Niraparib in Maintenance 
Therapy Following 
Platinum-based 
Chemotherapy 
Section 2.3.2 Benefit 
Assessment 
Section 4.2 Scientific 
Rationale for Study Design 
Synopsis 
Section 5 Study Population 
(Prescreening) 
Criterion P3 updated to P6 with addition of 
new criterion and text updated to clarify 
archival tissue requirements. 
Clarification for study conduct. 
Synopsis 
Section 1.3 Schedule of 
Activities (Table 3) 
Section 4.1 Overall Design 
Screening period updated to within 
6 weeks (42 days) of Day 1 and 
clarification this is only recommendation to 
start within 14 days of a confirmed positive 
ctDNA result. 
Clarification in study conduct 
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Section # and title 
Description of Change 
Brief Rationale 
Section 4.3 Justification for 
Dose 
Section 5.1 Inclusion 
Criteria 
Section 6.1.1 Niraparib 
(Table 12) 
Section 5.2 Exclusion 
Criteria 
Exclusion criterion 18 update to reflect 
FDA guidance. 
Exclusion criterion 19 corrected for 
typographical error. 
For clarification in study conduct to 
align with FDA guidance and ensuring 
participant safety. 
Section 5.1 Inclusion 
Criteria 
Appendix 4: Contraceptive 
and Barrier Guidance (and 
Appendix 11, where 
applicable) 
Inclusion criterion #12 language and 
Appendix 4 text updated regarding male 
condom use and sexual intercourse 
(Appendix 11 updated, where applicable) 
A revision of the protocol wording for 
use of male condoms by subjects is 
being made for consistency with 
guidance provided in the Investigator 
Brochure and is not a consequence of 
new safety information. 
Section 1.3 Schedule of 
Activities (Table 3) 
Section 6.1.1 Niraparib 
Details added regarding dosing based on 
screening weight if there is a change in 
weight prior to Cycle 1/Day 1 dosing. 
Clarification for study conduct 
Section 1.3 Schedule of 
Activities (Table 3) 
Section 8.4.6 Pregnancy 
Testing 
Updated language regarding timing of 
pregnancy tests for Screening and 
subsequent cycles. 
Clarification for study conduct 
Section 6.4.1 Dose Levels 
and Dose Adjustment 
Clarification included that dose cannot be 
re-escalated once reduced 
Alignment with expected conduct 
during the study. 
Section 4.1 Overall Design 
Section 7.1 Withdrawal/ 
Stopping Criteria 
Updated language included regarding 
survival follow-up, definition of 
discontinuation of study intervention, and 
conduct of follow-up period visits. 
Clarification for study conduct 
Section 8.1.1 General 
Guidance for Treatment 
Continuity When 
Participants Are Unable to 
Come into the Clinic 
(Table 16)  
Appendix 11 Country-
specific Requirements 
(Table 28) 
Updated assessments to be performed by 
the home health services (HHS) vendor.  
Clarification for study conduct to align 
with agreed upon assessments 
performed by contracted HHS vendor. 
Appendix 2 Clinical 
Laboratory Tests  
Appendix 4 Contraceptive 
and Barrier Guidance 
Updated FSH requirements for WONCBP 
to be <60 years 
Clarification for study conduct 
Synopsis  
Section 1.2 Schema 
(Figure 1) 
Section 4.1 Overall Design 
Section 5.1 Inclusion 
Criteria 
Section 8.2.1 Baseline 
Assessments at Screening 
Inclusion criterion 1 text adjusted to clarify 
Clarification for study conduct  
Section 1.3 Schedule of 
Activities (Table 3) 
Note added to Table 3 indicating ECG 
does not need to be repeated if a patient is 
rescreening.  
ECG is obtained for baseline 
documentation only and repeat is not 
medically indicated. 
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Section # and title 
Description of Change 
Brief Rationale 
Synopsis  
Section 2.1 Study Rationale 
Section 4.1 Overall Design 
Included definition for end of definitive 
therapy 
Clarification for consistency in study 
conduct 
Section 2.3.1 Risk 
Assessment (Table 6) 
Section 5.1 Inclusion 
Criteria 
Inclusion criteria 8 and 9, as well as 
Table 6 updated to remove 3-week delay 
in randomization and treatment for criteria 
to be met. 
Administrative change for clarification; 
text not required  
Synopsis,  
Section 1.3 Schedule of 
Activities (Table 3) 
Section 4.1 Overall Design  
Appendix 3 Guidelines for 
Assessment of Disease, 
Disease Progression and 
Response Criteria 
Imaging text update for clarification. 
Clarification for study conduct. 
Synopsis 
Study duration updated to included overall 
study duration of approximately 8 years. 
Editorial change for clarification 
regarding study conduct. 
Synopsis 
Section 9.1 Statistical 
Hypotheses 
Clarification to align language in the 
protocol. 
Synopsis 
Section 9.4.7 Independent 
Data Monitoring Committee 
Text updated regarding timing of safety 
review of Cohort 1 
Clarification for study conduct 
Synopsis 
Section 4.1 Overall Design 
Section 6.7 Treatment After 
the End of the Study 
Update text surrounding potential 
continuation of niraparib post-end of study. 
Editorial 
Section 6.3.3 Blinding and 
Breaking the Blind 
Updated text surrounding breaking the 
blind for those who may continue niraparib 
treatment at the end of the study 
Clarification for study conduct 
Section 8.6 
Pharmacokinetics 
Updated to include sample collection for 
liver events. 
Clarification for study conduct 
Section 9.3.2 Interim 
Analysis 
Clarification for study conduct. 
Appendix 2 Clinical 
Laboratory Tests (Table 20) 
Footnotes added to Table 20 to outline 
required laboratory tests and those to be 
provided if performed per standard of care. 
Clarification for study conduct. 
Appendix 8 AEs and SAEs: 
Definitions and Procedures 
for Recording, Evaluating, 
Follow-up, and Reporting 
Updates to safety reporting language 
Updated to include updated template 
language 
Appendix 11 Country-
specific Requirements 
New appendix outlining country-specific 
requirements 
New appendix per protocol template 
outlining country-specific difference 
previously outlined in country-specific 
amendments. 
 
 
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Amendment 01: 22 Feb 2022 
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. 
Overall Rationale for the Amendment: 
Amendment 01 FRA is a country-specific version of global Amendment 01, 
 
 
 
 
Section # and Name 
Description of Change 
Brief Rationale 
Headers, cover page, Synopsis, 
Section 3, Section 5.4, Section 7, 
Section 8.5.6, Section 8.7, 
Appendix 2, Appendix 5, 
Appendix 8 AEs and SAEs, 
Appendix 10 Protocol 
Amendment Summary of 
Changes, Section 11, and 
throughout the document. 
Headers and cover page were 
updated with new version 
number. Protocol Amendment 
Summary of Changes section 
was added to include rationale 
for this amendment. Formatting 
adjustments made throughout. 
References added, as needed, to 
support changes. 
Editorial changes and formatting updates 
to align with the Sponsor’s updated 
standard protocol template and ways of 
working, including description of 
estimands described in the SAP. 
Section 1.1 Synopsis 
Section 1.3 Schedule of 
Activities, Table 3 
Section 4.1 Overall Study Design
Section 5.1 Inclusion Criteria 
(criteria #11 and #12) 
Section 5.2 Exclusion Criteria 
(criterion #17) 
Section 8.4.6 Pregnancy Testing 
Section 8.5.5 Pregnancy 
Appendix 4 Contraceptive and 
Barrier Guidance, Table 20 
Synopsis 
Section 5 Study Population 
Section 5.1 Inclusion Criteria 
(Criterion #1) 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
Section 1.2, Figure 2 (Study 
Schema) 
Section 1.3, Table 2 
(Prescreening) 
Section 5 Study Population 
Section 5.1 Inclusion Criteria 
(criterion #2) 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 Schema, Figure 1 
Section 1.3 Schedule of 
Activities, Table 2 (Prescreening)
Section 4.1 Overall Design 
(ctDNA prescreening) 
Section 1.3 Schedule of 
Activities, Table 3  
Section 6.4.1 Dose Levels and 
Dose Adjustments 
Section 6.8 Concomitant 
Medications and Nondrug 
Therapies  
Section 6.8.1 Prohibited 
Medication and Drug Therapies 
Concomitant medications 
clarified to reference eCRF 
completion guidelines regarding 
collection of additional therapies 
(endocrine therapy, ovarian 
suppression, 
bisphosphonates/denosumab, 
and pembrolizumab). 
Updated to indicate concurrent 
pembrolizumab use is permitted 
and remove immunotherapies. 
Guidance provided that for 
participants on concurrent that 
endocrine or pembrolizumab 
decisions regarding dose 
interruptions/modifications 
should be made independently. 
Clarification for study conduct 
surrounding permitted therapies and 
collection of concomitant medications 
including endocrine therapy, ovarian 
suppression, 
bisphosphonates/denosumab, and 
pembrolizumab use. 
The Sponsor has provided clarifying 
language in the protocol to allow 
Investigators flexibility with needed dose 
adjustments for those breast cancer 
treatment medications not directly 
administered by the protocol, i.e., 
endocrine therapies and pembrolizumab. 
Section 5.1 Inclusion Criteria 
(criterion #5) 
Updated to remove details of 
specimen handling and only 
refer to Study Reference Manual 
and added clarification that 
Clarification for inclusion criteria. 
While adequate quality and quantity of 
tumor tissue remains an important 
eligibility requirement for study 
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Description of Change 
Brief Rationale 
archival tissue refers to 
prescreening archival tissue. 
enrolment, the Sponsor has been able to 
provide increased flexibility for tissue 
requirements, and anticipate further 
improvements to technology over the 
course of the study. Therefore, specific 
parameters have been removed from the 
protocol in the best interest of the 
participants. 
Section 5.1 Inclusion Criteria 
(criterion #8) 
Creatinine clearance added to 
eligibility criteria instead of 
serum creatinine, as well as 
clarification notes regarding 
adequate renal function, hepatic 
impairment, and creatinine 
clearance. 
Creatinine clearance was changed to align 
with other niraparib studies. 
An upper limit of ALT was added for 
participant safety. 
Section 5.2 Exclusion Criteria 
(criterion #9) 
Section 6.8 Concomitant 
Medications and Nondrug 
Therapies 
Section 6.8.1 Prohibited 
Medications and Nondrug 
Therapies 
Appendix 3 Guidelines for 
Assessment of Disease, Disease 
Progression and Response 
Criteria 
Updated language surrounding 
COVID-19 vaccine, 
recommendations, timing, and 
information to be entered in the 
eCRF. 
Guidance regarding 
thrombocytopenia associated 
with mRNA vaccines included. 
Guidance included surrounding 
lymphadenopathy after 
COVID-19 vaccinations and 
tumor assessments. 
Updated based on Sponsor guidance 
regarding the COVID-19 vaccines 
reflecting current evolving medical 
practice, tumor assessments, and for 
study conduct to record the data, as 
effects of concomitant COVID-19 
vaccine used with niraparib are not 
known. 
Section 5.2 Exclusion Criteria 
(criterion #19) 
Exclusion criterion updated 
allowing immunocompromised 
participants. 
Amended criteria to allow 
immunocompromised participants with 
HIV. 
Based on accumulated safety data for 
niraparib and immunocompromised 
participants, and precedent set by other 
niraparib studies. Patients with well-
controlled HIV may be eligible for 
enrollment onto the ZEST study. 
Section 1.3 Schedule of 
Activities Table 3 
Section 8.4.3 Vital signs 
Updated notes and text to clarify 
that 3 readings for blood 
pressure measurements are only 
recommendations and vital signs 
may be taken at a local 
laboratory/clinic or at-home 
nursing visits for specific visits. 
Clarification for study conduct that 3 
blood pressure readings are not required. 
As per clinical standard-of-care, a single 
blood pressure measurement is sufficient 
for safety monitoring. Because it is 
important for participant safety to ensure 
that blood pressure is recorded weekly for 
the first 8 weeks, the Sponsor has 
provided flexibility in terms of options 
for where the participant may complete 
these assessments. 
Section 1.3 Schedule of 
Activities, Table 4 (PK Sampling 
for All Participants) 
Section 1.3 Schedule of 
Activities, Table 5 (PK Sampling 
for PK Substudy) 
Section 8.6 Pharmacokinetics 
Updated notes/text to indicate 
participants must switch to 
morning niraparib dosing 
1 week prior to PK testing. 
Updated footnotes/text 
regarding blood samples to 
include the transition of morning 
dosing 1 week prior to PK 
Clarification in study conduct. 
PK analysis is an important aspect of the 
ZEST study. As such, the timing of 
niraparib and endocrine therapy dosing 
should align with the timing of planned 
PK sampling. Clarifying language has 
been added to the protocol to ensure that 
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Section # and Name 
Description of Change 
Brief Rationale 
testing for niraparib and 2 weeks 
prior to PK testing for endocrine 
therapy at Cycle 1/Day 15. 
accurately interpreted to ensure the safety 
of the participants. 
Section 8.8 Translational 
Research 
Appendix 5 Regulatory, Ethical, 
and Study Oversight 
Considerations 
Included text regarding 
incidental tumor mutation 
findings released to the 
Investigator and timing. 
Appendix 2 Clinical Laboratory 
Tests, Table 18 
List of laboratory parameters 
updated including addition of 
total and direct bilirubin, and 
removal of amylase, 
magnesium, phosphorus, and 
uric acid from clinical chemistry 
parameters. Urinalysis 
parameter removed and text 
updated. 
Clarification for study conduct as 
amylase is not necessary for monitoring 
pancreatitis during niraparib treatment. 
Bilirubin specification added for liver 
toxicity monitoring. Unnecessary 
laboratory assessments removed, and 
clarification in study conduct pertaining 
to urinalysis to accommodate local 
standard of care. 
Bilirubin had been erroneously omitted 
from the Table, and so, has been added 
for participant safety. Other deleted 
laboratory parameters were those deemed 
unnecessary for safety monitoring of 
participants and were therefore, removed 
or modified. Amylase, magnesium, 
phosphorus, and uric acid are not 
typically included in standard-of-care 
clinical chemistry panels and niraparib 
has not been shown to specifically cause 
abnormalities in these parameters. 
Similarly, specific urinalysis parameters 
were removed to allow local standard-of-
care evaluation for the presence of 
baseline urinary infection. 
Appendix 4, Contraceptive and 
Barrier Guidance, Table 21 
Updated to specify only 
nonhormonal IUDs permitted. 
Added barrier methods of 
contraception. 
Clarification for study conduct and to 
include acceptable user-dependent, highly 
effective contraceptive options to be 
consistent with current standard of care in 
breast oncology clinical practice. This 
change supports patient safety and is an 
important additional option for 
participants. 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 6 Liver Safety Require 
Actions and Follow-up 
Assessments, Table 22 
Added clarification surrounding 
HPLC for serum acetaminophen 
is only required as per local 
standard of care. 
Clarification in study conduct to 
accommodate local standard of care. 
While this laboratory assessment may be 
helpful in determining the cause of liver 
injury, it is not strictly essential in the 
evaluation and may not be available in all 
study locations. 
Synopsis 
Section 1.3 Schedule of 
Activities Table 3 
Section 3 Objectives and 
Endpoints 
Section 4.1 Overall design 
Section 8.2.2 Baseline CT/MRI 
and Bone Scan 
Section 8.3.1 Postbaseline 
Imaging and Tumor Assessment 
Section 8.3.11 Exploratory 
Efficacy Endpoint (Time to Brain 
Progression) 
Section 9.4.3 Exploratory 
Efficacy Analyses 
Appendix 3 Guidelines for 
Assessment of Disease, Disease 
Progression and Response 
Criteria - adapted from RECIST 
v1.1 
Addition of new exploratory 
endpoint regarding time to brain 
progression including 
clarification that IV contrast-
enhanced MRI is preferred for 
brain imaging if brain metastasis
suspected. 
New exploratory endpoint exploring 
brain metastasis and clarification for 
study conduct as IV contrast is more 
sensitive for detection of brain metastasis. 
Synopsis, Objectives and 
Endpoints 
Section 3 Objectives and 
Endpoints 
Section 8.3.2 Primary Efficacy 
Endpoint, Table 15 Definitions o
Efficacy Endpoints 
Section 8.3.10 Exploratory 
Efficacy Endpoint (IBCFS) 
Section 9.4.3 Exploratory 
Efficacy Analyses 
Synopsis, Objectives and 
Endpoints 
Section 3 Objectives and 
Endpoints 
Section 8.3.9 Exploratory 
Efficacy Endpoint (IDFS) 
. 
Synopsis, Objectives and 
Endpoints 
Section 3 Objectives and 
Endpoints 
Adjusted wording of safety 
endpoints and removed physical 
examinations and analyses will 
be conducted as outlined in the 
SAP. 
Clarification for analysis; physical 
examination data are not collected on 
eCRFs for analysis. 
This clarification regarding the physical 
exam was to ensure alignment with the 
eCRF. 
Synopsis 
Section 1.3 Schedule of 
Activities, Table 2 Prescreening,  
Section 4,1 Overall Design 
Section 5.1 Inclusion Criteria 
Updated start of endocrine 
therapy for eligible participants 
to 3 months prior to 
randomization. 
Editorial change. Protocol clarification; 
“prior to enrollment” is unclear. Original 
intent was 3 months prior to starting 
niraparib. 
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Section # and Name 
Description of Change 
Brief Rationale 
(criterion #3) 
Synopsis 
Section 1.2 Schema, Figure 1 
Section 1.3 Schedule of 
Activities, Table 3 
Section 4.1 Overall Design 
Section 8.2.1 Baseline 
Assessments at Screening 
Updated text regarding start of 
Screening Period with respect to 
confirmation of detectable 
ctDNA and quality of 
prescreening tissue samples. 
Editorial change to clarify start of 
Screening period for study conduct. 
Synopsis 
Section 1.2 Schema, Figure 2 
Section 4.1 Overall Design 
Section 6.3.2 Stratification 
Added text, as well as a footnote 
to Figure 2 to indicate time of 
last intervention is defined as the 
date of most recent oncological 
surgery, date of last adjuvant 
chemotherapy, or date of last 
radiotherapy fraction, whichever 
occurred later. 
Editorial change to clarify time of last 
intervention. 
Synopsis 
Clarified that main ICF should 
be signed before screening 
starts. 
Clarification statement to comply with 
GCP. 
Synopsis 
Section 5 Study Population 
Section 5.4 Prescreen Failures 
and Screen Failures 
Prescreening criteria numbered 
and incorporated prescreen 
failures along with screen 
failures in renamed section. 
Formatting change to align Prescreening 
criteria with eCRFs 
Section 5.1 Inclusion Criteria 
Specified that participants must 
meet prescreening criteria to be 
included in the study 
Editorial change for clarification 
regarding participants’ inclusion in the 
study. 
Synopsis 
Section 1.2 Schema 
Section 5 Study Population 
Prescreening (criterion #P2) 
Added text indicating 
prescreening should be started 
as soon as possible, prior to 
completion of adjuvant therapy. 
Editorial changes for clarification in 
study conduct. 
Section 5.2 Exclusion Criteria 
(criterion #2) 
Added text regarding ovarian 
suppression treatment as a 
permitted medication. 
Editorial change for consistency with rest 
of protocol. 
Synopsis 
Section 5.2 Exclusion Criteria 
(criterion #4) 
Appendix 1 Exclusion of 
Participants Who Have Shown 
No Definitive Response to 
Preoperative Chemotherapy 
Clinical evaluation added as 
criteria for evaluation of no 
definitive response and 
additional information added for 
evaluation of no definitive 
response criteria 
Clarification for study conduct. Text 
updated to clarify methods for assessment 
of no definitive response with no impact 
on participant safety, study conduct, or 
study interpretation. 
Section 1.2 Study Schema, 
Figure 2 
Key eligibility criteria updated 
Administrative change to align with 
protocol text. 
Section 1.2 Schema, Figure 1 
Section 1.3 Schedule of 
Activities, Table 2 Prescreening 
Section 4.1 Overall Design 
Changed "final cycle" for 
initiation of prescreening 
platform to "last 6 weeks of 
chemotherapy and radiation 
adjuvant treatment" in 
notes/footnotes. 
Editorial change to provide clarification 
with a measurable time definition for 
specific adjuvant treatment. 
Section 1.3 Schedule of 
Activities Table 2 (Prescreening) 
Section 1.3 Schedule of 
Activities, Table 3 
Included note regarding regimen 
stability for HR+ participants in 
Cohort 1 on endocrine therapy. 
Updated note for pathology 
report to indicate it will 
accompany samples sent for 
testing. 
Formatting/editorial clarification for 
study conduct to align with protocol text 
and intended data collection for screening 
versus prescreening periods, and analysis. 
There is no change to the information 
collected as part of the clinical study; this 
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Section # and Name 
Description of Change 
Brief Rationale 
Assessments added to 
Prescreening activities 
(eligibility; demography; disease 
characteristics; anticancer, 
radiation therapies; surgical 
procedures for current indication 
prior to Screening; and AEs). 
Similarly, activities related to 
Demography, disease 
characteristics, and tumor 
characteristics removed from 
Table 3, anticancer therapies 
updated to clarify only prior 
anticancer therapies for 
historical cancers, and notes 
updated. 
Medical history notes updated to 
outline information to be 
captured. 
when the data are collected, i.e., no 
impact on safety and no significant 
impact on study conduct, or study 
interpretation. 
Section 1.3 Schedule of 
Activities, Table 3 
Section 8.4.6 Pregnancy Testing 
Appendix 2 Clinical Laboratory 
Tests, Table 18 
Appendix 4 Contraceptive and 
Barrier Guidance  
Notes and text requiring serum 
pregnancy testing adjusted and 
footnote removed in Table 18 
(previously Table 17). 
Clarification for consistency in study 
conduct regarding pregnancy testing 
requirements. 
Section 1.3 Schedule of 
Activities, Table 3 
Section 8.8.1 Tumor Tissue 
Collection at Time of Disease 
Recurrence 
Added footnote and text 
indicating optional biopsies 
must be performed before 
initiating new anticancer therapy 
and do not need to occur within 
7-days of last dose. 
Editorial change to provide clarification 
for study conduct. 
Section 1.3 Schedule of 
Activities, Table 3 
Section 8.9 Patient Reported 
Outcome Measures 
Section 8.9.5 Patient Global 
Impression Items 
Updated note for PRO collection 
to be completed on the assigned 
clinic visit day and for PGIC to 
indicate it will be collected 
starting on Cycle 2/Day 1 and 
every 28 days thereafter. 
Editorial change to provide clarification 
for study conduct. 
Section 1.3 Schedule of 
Activities Table 2 (Disease 
Characteristics)  
Table 3 (Eligibility) 
Included note regarding 
recurrence during 
prescreening/screening and 
information to be collected. 
Editorial change to provide clarification 
for study conduct. 
Section 1.3 Schedule of 
Activities Table 3 
Updated notes to specify 
difference in visit windows for 
monthly versus weekly visits. 
Editorial clarification for study conduct. 
Section 1.3 Schedule of 
Activities Table 3 
Section 8.3.1 Postbaseline 
Imaging and Tumor Assessment 
Text regarding CT or MRI for 
DFS updated to include: (Year 1 
Weeks 12, 24, 36, 48; Year 2, 
Weeks 60, 72, 84, 96) and notes 
updated regarding PET scan, 
and that imaging should 
continue within the defined 
interval windows. 
Editorial clarification for the Investigator. 
Section 1.3 Schedule of 
Activities Table 3  
Note added to anticancer 
therapy following study 
Administrative change for omission in the 
original protocol for the evaluation of the 

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Brief Rationale 
treatment indicating any new 
anticancer treatment started 
before the Safety Follow-up 
Visit must be collected during 
this visit as outlined in eCRF 
completion instructions. 
safety of niraparib in this population. 
Section 1.3 Schedule of 
Activities, Table 3 
Hematology and clinical 
chemistry blood draw visit 
windows for specific visits 
Editorial clarification for study conduct 
providing flexibility in blood draws. 
Section 1.3 Schedule of 
Activities, Table 3 
Editorial change to align with protocol 
text. 
Section 1.3 Schedule of 
Activities, Table 3 (Niraparib or 
placebo dispensed/collected) 
Note added regarding recording 
missed doses. 
Editorial change to align with data 
collection in eCRFs. 
Section 1.3 Schedule of 
Activities, Table 4 PK Sampling 
Schedule for All Participants 
Removed text regarding holding 
dose 1 day prior to 
Cycle 2/Day 1 
Administrative change to correct error in 
original protocol. 
Synopsis 
Section 4.1 Overall design 
Section 4.2 Overall Rationale for 
Study Design 
Sections 8.8 Translational 
Research 
Section 9.3.2 Interim Analysis 
Included name of assay for 
tumor BRCA/HRD testing. 
Administrative change for clarification 
for study conduct and for 
regulatory/ethics approval of the assay as 
part of the current protocol and any 
necessary reporting requirements related 
to assay use in this study. 
Section 6.8 Concomitant 
Medications and Nondrug 
Therapies 
Concomitant medication follow-
up corrected to indicate that it 
continues until the Safety 
follow-up visit after end of 
treatment and not until end of 
study. 
Administrative change to provide 
clarification for study conduct. 
Section 4.1 Overall Design 
Section 8.1.1 General Guidance 
for Treatment Continuity When 
Participants Are Unable to Come 
into the Clinic, Table 14 
Section 8.6 Pharmacokinetics 
Updated to include at-home 
nursing services (or local 
laboratory/clinic) and 
clarification of study days for 
these visits if participants are 
unable to attend clinic visits. 
Administrative change to provide 
clarification for participants' safety during 
the COVID-19 pandemic. 
Section 1.3 Schedule of 
Activities, Table 2 Prescreening 
Section 8.8 Translational 
Research 
Adjusted protocol text to refer to 
Study Reference Manual for 
details. 
Editorial change to provide clarification 
of tissue requirements per vendor 
performing the analysis outlined in the 
study reference manual. 
Section 2.2.2 Treatment Options 
for Patients with Operable 
HER2− Breast Cancer 
Section 2.2.4 PARP Inhibitors 
Section 2.2.5.2 Efficacy of 
Niraparib in Breast Cancer 
(Study 3000-PN162-01-001 
TOPACIO) 
Section 2.2.5.4 Niraparib and 
Pembrolizumab 
Section 2.2.6 Circulating Tumor 
DNA 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.3.2 Benefit Assessment
Section 2.3.3 Overall 
Benefit/Risk Conclusion 
Section 4.2 Scientific Rationale 
for Study Design 
Section 4.3 Justification for Dose Amended language for niraparib 
dosing in participants with 
moderate hepatic impairment. 
Administrative change to align with the 
IB. 
Section 6 Study Treatments and 
Concomitant Therapy 
Updated references to Pharmacy 
Manual to Study Reference 
Manual 
Administrative change to correction text 
throughout protocol as study does not 
have a Pharmacy Manual. 
Section 6.1.1 Niraparib 
Text corrected regarding t
 
provided for dosing with up to 
3 days flexibility. 
Administrative change to correction text 
and align with Table 3 visit window. 
Section 6.1.1 Niraparib, Table 10 Updated footnotes regarding 
hepatic impairment definitions. 
Editorial change to provide clarification 
for participant safety. 
Section 6.1.1 Niraparib 
Included text that dose 
escalation not permitted once 
initial starting dose is assigned. 
Editorial change for clarification of study 
conduct. 
Section 6.3.1 Randomization 
Removed IVRS and reference to 
phone numbers. 
Editorial change to correction align 
protocol text regarding randomization 
procedures being used in the study. 
Section 6.3.3 Blinding and 
Breaking the Blind 
Deleted text regarding unblinded
third party not relevant to the 
study.  
Editorial change to correct text to align 
with study. 
Synopsis 
Section 4.1 Overall Design 
Section 7.1 Withdrawal/Stopping 
Criteria 
Updated text regarding duration 
of treatment. 
Editorial clarification for study conduct. 
Section 7.1 Withdrawal/Stopping 
Criteria 
Updated text regarding 
withdrawal of participants with 
additional primary malignancies 
other than MDS and AML and 
regarding possibility of 
continued niraparib treatment if 
participants are discontinued. 
Editorial change for clarification  
Synopsis 
Section 7.3.1 Further Biomedical 
Research Maintaining 
Confidential Participant 
Information 
Clarification that Further 
Biomedical Research is after 
study completion. 
Administrative change to align with ICF 
text. 
Synopsis 
Section 8.8 Translational 
Research 
Appendix 9 Use/Analysis of 
DNA 
Clarification regarding possible 
use of tumor tissue and blood 
samples for exploratory 
research. 
Appendix heading updated and 
clarified DNA samples can be 
Editorial changes for clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
derived from tumor or blood 
specimens. 
Section 8.1.1 General Guidance 
for Treatment Continuity When 
Participants Are Unable to Come 
into the Clinic 
Section 8.1.1, Table 14 
Removed text pertaining to 
global telemedicine and updated 
Table 14 (previously Table 13) 
table title for clarification. 
Editorial changes for Clarification that 
Sponsor not providing global 
telemedicine services; sites to engage 
their own local platform. 
Section 8.1.1.1 Direct to 
Participant Investigational 
Medicinal Product Shipments 
Revised text to remove drug 
supply vendor name. 
Administrative correction. 
Section 8.5 Adverse Events, 
Serious Adverse Events, and 
Other Safety Reporting 
Appendix 5 Regulatory, Ethical, 
and Study Oversight 
Considerations 
Removed mention of LAR. 
Administrative change to align with 
inclusion criterion 13. 
Section 8.5.6 Cardiovascular and 
Death Events 
Clarification regarding the 
recording of death information 
in eCRFs. 
Administrative change to provide 
clarification for collection of death 
information aligned with eCRFs. 
Section 8.7 Genetics 
Updated section heading and 
language regarding WES 
testing. 
Administrative change to provide 
clarification in protocol text. 
Section 9.4.5.1 Pharmacokinetic 
Parameters 
Clarifications in PK language 
and GSK analysts access to PK 
datasets. 
Administrative change to align with PK 
and Exposure-Response Analysis Plan as 
per regulatory agency recommendation 
and for clarification on access to data. 
Appendix 3 Guidelines for 
Assessment of Disease, Disease 
Progression and Response 
Criteria 
Updated criteria for participants 
with no evidence of disease at 
baseline. 
Editorial changes to provide clarification 
for study conduct. 
 
Amendment DEU-4: 07 January 2022 
This amendment is considered to be non-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 because it neither significantly impacts the safety or physical/mental 
integrity of participants nor the scientific value of the study. 
Overall Rationale for the Amendment: 
Amendment DEU-4 is a country-specific protocol amendment of country-specific 
Amendment 01/DEU-3, 
 
 
. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1.1 General 
Guidance for Treatment 
Continuity When 
Participants Are Unable to 
Come into the Clinic 
‘Limited physical examination 
including symptom-directed physical 
examinations’ has been removed from 
the list of functions home nursing 
services may perform. 
German specific requirements have 
been applied, as physical examinations 
can only be performed by a physician, 
implemented at the request of BfArM. 
Section 10.4, Appendix 4: 
Contraceptive and Barrier 
The following text has been removed 
from the “Highly Effective Methods 
German specific requirements have 
been applied with regards to 
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Section # and Name 
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Brief Rationale 
Guidance  
that Are User Dependent” section of 
Table 21: 
• Barrier methods of contraception 
- Acceptable barrier methods of 
contraception include the 
following: male condom with 
either cap, diaphragm, or sponge 
with spermicide (double barrier 
methods). The use of double-
barrier methods should always be 
supplemented with the use of a 
spermicide to result in a failure rate 
of <1%. Female condom and male 
condom should not be used 
together. 
contraceptives allowed during the 
study, implemented at the request of 
BfArM. 
 
Amendment 01/DEU-3: 07 October 2021 
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. 
Overall Rationale for the Amendment: 
Amendment 01 is a global protocol amendment 
 
 
 
 
Section # and Name 
Description of Change 
Brief Rationale 
Headers, cover page, Synopsis, 
Section 3, Section 5.4, Section 7, 
Section 8.5.6, Section 8.7, 
Appendix 2, Appendix 5, 
Appendix 8 AEs and SAEs, 
Appendix 10 Protocol 
Amendment Summary of 
Changes, Section 11, and 
throughout the document. 
Headers and cover page were 
updated with new version 
number. Protocol Amendment 
Summary of Changes section 
was added to include rationale 
for this amendment. Formatting 
adjustments made throughout. 
References added, as needed, to 
support changes. 
Editorial changes and formatting updates 
to align with the Sponsor’s updated 
standard protocol template and ways of 
working, including description of 
estimands described in the SAP. 
Synopsis 
Section 5 Study Population 
Section 5.1 Inclusion Criteria 
(Criterion #1) 
Added definition for TNBC (ER 
and progesterone receptor <1% 
and HER2 negative by FISH or 
IHC staining 0 or 1+). Included 
details to clarify eligibility for 
participants with multifocal 
tumors and clarify that 
multicentric and bilateral breast 
cancers are not allowed. 
Important clarification for participant 
eligibility. This revision was made to the 
protocol to specifically define the 
parameters for TNBC, as definitions can 
vary across countries and local practices. 
Because assignment to a TNBC status 
versus a HR+ status can have significant 
implications for treatment selection, it 
was important for study conduct to clarify 
the eligible TNBC population for the 
ZEST study. In addition, the sponsor 
needed to clarify the acceptability of 
multifocal tumors with similar histology 
but exclusion of multicentric and bilateral 
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breast cancers to ensure ctDNA results 
are reflective of a single breast cancer 
entity. This is to ensure accurate 
interpretation of the study endpoints 
because the bespoke ctDNA platform 
may vary across different tumors. 
Multifocal disease is usually defined as 
involvement of several areas within a 
breast quadrant, which typically 
represents a single disease entity 
occurring along an entire duct. In 
contrast, multicentric disease involves 
multiple areas within different quadrants, 
typically representing involvement of 
multiple ducts with potentially distinct 
index tumors. 
Synopsis 
Section 1.2, Figure 2 (Study 
Schema) 
Section 1.3, Table 2 
(Prescreening) 
Section 5 Study Population 
Section 5.1 Inclusion Criteria 
(criterion #2) 
Added regarding participants 
with HR+HER2− tBRCAmut 
breast cancer may be receiving 
concurrent adjuvant endocrine 
therapy, all participants may be 
receiving concurrent adjuvant 
bisphosphonates or adjuvant 
pembrolizumab, if clinically 
indicated. 
Figure footnote updated to 
indicate concurrent adjuvant 
pembrolizumab is permitted.  
Clarification that endocrine, 
bisphosphonates or denosumab, and 
pembrolizumab therapies are allowed. 
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Brief Rationale 
Section 1.2 Schema, Figure 1 
Section 1.3 Schedule of 
Activities, Table 2 (Prescreening) 
Section 4.1 Overall Design 
(ctDNA prescreening) 
Section 1.3 Schedule of 
Activities, Table 3  
Section 6.4.1 Dose Levels and 
Dose Adjustments 
Section 6.8 Concomitant 
Medications and Nondrug 
Therapies  
Section 6.8.1 Prohibited 
Medication and Drug Therapies 
Concomitant medications 
clarified to reference eCRF 
completion guidelines regarding 
collection of additional therapies 
(endocrine therapy, ovarian 
suppression, 
bisphosphonates/denosumab, 
and pembrolizumab). 
Updated to indicate concurrent 
pembrolizumab use is permitted 
and remove immunotherapies. 
Guidance provided that for 
participants on concurrent that 
endocrine or pembrolizumab 
decisions regarding dose 
interruptions/modifications 
should be made independently. 
Clarification for study conduct 
surrounding permitted therapies and 
collection of concomitant medications 
including endocrine therapy, ovarian 
suppression, 
bisphosphonates/denosumab, and 
pembrolizumab use. 
The Sponsor has provided clarifying 
language in the protocol to allow 
Investigators flexibility with needed dose 
adjustments for those breast cancer 
treatment medications not directly 
administered by the protocol, i.e., 
endocrine therapies and pembrolizumab. 
Section 5.1 Inclusion Criteria 
(criterion #5) 
Updated to remove details of 
specimen handling and only 
refer to Study Reference Manual 
Clarification for inclusion criteria. 
While adequate quality and quantity of 
tumor tissue remains an important 
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and added clarification that 
archival tissue refers to 
prescreening archival tissue. 
eligibility requirement for study 
enrolment, the Sponsor has been able to 
provide increased flexibility for tissue 
requirements, and anticipate further 
improvements to technology over the 
course of the study. Therefore, specific 
parameters have been removed from the 
protocol in the best interest of the 
participants. 
Section 5.1 Inclusion Criteria 
(criterion #8) 
Creatinine clearance added to 
eligibility criteria instead of 
serum creatinine, as well as 
clarification notes regarding 
adequate renal function, hepatic 
impairment, and creatinine 
clearance. 
Creatinine clearance was changed to align 
with other niraparib studies. 
An upper limit of ALT was added for 
participant safety. 
Section 5.1 Inclusion Criteria 
(criterion #12) 
Appendix 4 Contraceptive and 
Barrier Guidance, Table 20 
Recommendations for duration 
of contraception use for male 
participants was updated to 
continue for 90 days, rather than 
180 days, after the last dose of 
study treatment. 
Clarification for participant safety in 
alignment with the current IB. 
Section 5.2 Exclusion Criteria 
(criterion #9) 
Section 6.8 Concomitant 
Medications and Nondrug 
Therapies 
Section 6.8.1 Prohibited 
Medications and Nondrug 
Therapies 
Appendix 3 Guidelines for 
Assessment of Disease, Disease 
Progression and Response 
Criteria 
Updated language surrounding 
COVID-19 vaccine, 
recommendations, timing, and 
information to be entered in the 
eCRF. 
Guidance regarding 
thrombocytopenia associated 
with mRNA vaccines included. 
Guidance included surrounding 
lymphadenopathy after 
COVID-19 vaccinations and 
tumor assessments. 
Updated based on Sponsor guidance 
regarding the COVID-19 vaccines 
reflecting current evolving medical 
practice, tumor assessments, and for 
study conduct to record the data, as 
effects of concomitant COVID-19 
vaccine used with niraparib are not 
known. 
Section 5.2 Exclusion Criteria 
(criterion #19) 
Exclusion criterion updated 
allowing immunocompromised 
participants. 
Amended criteria to allow 
immunocompromised participants with 
HIV. 
Based on accumulated safety data for 
niraparib and immunocompromised 
participants, and precedent set by other 
niraparib studies. Patients with well-
controlled HIV may be eligible for 
enrollment onto the ZEST study. 
Section 1.3 Schedule of 
Activities Table 3 
Section 8.4.3 Vital signs 
Updated notes and text to clarify 
that 3 readings for blood 
pressure measurements are only 
recommendations and vital signs 
may be taken at a local 
laboratory/clinic or at-home 
nursing visits for specific visits. 
Clarification for study conduct that 3 
blood pressure readings are not required. 
As per clinical standard-of-care, a single 
blood pressure measurement is sufficient 
for safety monitoring. Because it is 
important for participant safety to ensure 
that blood pressure is recorded weekly for 
the first 8 weeks, the Sponsor has 
provided flexibility in terms of options 
for where the participant may complete 
these assessments. 
Section 1.3 Schedule of 
Updated notes/text to indicate 
Clarification in study conduct. 

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Activities, Table 4 (PK Sampling 
for All Participants) 
Section 1.3 Schedule of 
Activities, Table 5 (PK Sampling 
for PK Substudy) 
Section 8.6 Pharmacokinetics 
participants must switch to 
morning niraparib dosing 
1 week prior to PK testing. 
Updated footnotes/text 
regarding blood samples to 
include the transition of morning 
dosing 1 week prior to PK 
testing for niraparib and 2 weeks 
prior to PK testing for endocrine 
therapy at Cycle 1/Day 15. 
PK analysis is an important aspect of the 
ZEST study. As such, the timing of 
niraparib and endocrine therapy dosing 
should align with the timing of planned 
PK sampling. Clarifying language has 
been added to the protocol to ensure that 
the samples drawn for PK analysis can be 
accurately interpreted to ensure the safety 
of the participants. 
Section 8.8 Translational 
Research 
Appendix 5 Regulatory, Ethical, 
and Study Oversight 
Considerations 
Included text regarding 
incidental tumor mutation 
findings released to the 
Investigator and timing. 
Clarification for study conduct. 
Appendix 2 Clinical Laboratory 
Tests, Table 18 
List of laboratory parameters 
updated including addition of 
total and direct bilirubin, and 
removal of amylase, 
magnesium, phosphorus, and 
uric acid from clinical chemistry 
parameters. Urinalysis 
parameter removed and text 
updated. 
Clarification for study conduct as 
amylase is not necessary for monitoring 
pancreatitis during niraparib treatment. 
Bilirubin specification added for liver 
toxicity monitoring. Unnecessary 
laboratory assessments removed, and 
clarification in study conduct pertaining 
to urinalysis to accommodate local 
standard of care. 
Bilirubin had been erroneously omitted 
from the Table, and so, has been added 
for participant safety. Other deleted 
laboratory parameters were those deemed 
unnecessary for safety monitoring of 
participants and were therefore, removed 
or modified. Amylase, magnesium, 
phosphorus, and uric acid are not 
typically included in standard-of-care 
clinical chemistry panels and niraparib 
has not been shown to specifically cause 
abnormalities in these parameters. 
Similarly, specific urinalysis parameters 
were removed to allow local standard-of-
care evaluation for the presence of 
baseline urinary infection. 
Appendix 4, Contraceptive and 
Barrier Guidance, Table 21 
Updated to specify only 
nonhormonal IUDs permitted. 
Added barrier methods of 
Clarification for study conduct and to 
include acceptable user-dependent, highly 
effective contraceptive options to be 
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contraception. 
consistent with current standard of care in 
breast oncology clinical practice. This 
change supports patient safety and is an 
important additional option for 
participants. 
Appendix 6 Liver Safety Require 
Actions and Follow-up 
Assessments, Table 22 
Added clarification surrounding 
HPLC for serum acetaminophen 
is only required as per local 
standard of care. 
Clarification in study conduct to 
accommodate local standard of care. 
While this laboratory assessment may be 
helpful in determining the cause of liver 
injury, it is not strictly essential in the 
evaluation and may not be available in all 
study locations. 
Synopsis 
Section 1.3 Schedule of 
Activities Table 3 
Section 3 Objectives and 
Endpoints 
Section 4.1 Overall design 
Section 8.2.2 Baseline CT/MRI 
and Bone Scan 
Section 8.3.1 Postbaseline 
Imaging and Tumor Assessment 
Section 8.3.11 Exploratory 
Efficacy Endpoint (Time to Brain 
Progression) 
Section 9.4.3 Exploratory 
Efficacy Analyses 
Appendix 3 Guidelines for 
Assessment of Disease, Disease 
Progression and Response 
Criteria - adapted from RECIST 
v1.1 
Addition of new exploratory 
endpoint regarding time to brain 
progression including 
clarification that IV contrast-
enhanced MRI is preferred for 
brain imaging if brain metastasis 
suspected. 
New exploratory endpoint exploring 
brain metastasis and clarification for 
study conduct as IV contrast is more 
sensitive for detection of brain metastasis. 
Synopsis, Objectives and 
Endpoints 
Section 3 Objectives and 
Endpoints 
Section 8.3.2 Primary Efficacy 
Endpoint, Table 15 Definitions of
Efficacy Endpoints 
Section 8.3.10 Exploratory 
Efficacy Endpoint (IBCFS) 
Section 9.4.3 Exploratory 
Efficacy Analyses 
Synopsis, Objectives and 
Endpoints 
Section 3 Objectives and 
Endpoints 
Section 8.3.9 Exploratory 
Efficacy Endpoint (IDFS) 
Synopsis, Objectives and 
Endpoints 
Section 3 Objectives and 
Endpoints 
Adjusted wording of safety 
endpoints and removed physical 
examinations and analyses will 
be conducted as outlined in the 
SAP. 
Clarification for analysis; physical 
examination data are not collected on 
eCRFs for analysis. 
This clarification regarding the physical 
exam was to ensure alignment with the 
eCRF. 
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Brief Rationale 
Synopsis 
Section 1.3 Schedule of 
Activities, Table 2 Prescreening,  
Section 4,1 Overall Design 
Section 5.1 Inclusion Criteria 
(criterion #3) 
Updated start of endocrine 
therapy for eligible participants 
to 3 months prior to 
randomization. 
Editorial change. Protocol clarification; 
“prior to enrollment” is unclear. Original 
intent was 3 months prior to starting 
niraparib. 
Synopsis 
Section 1.2 Schema, Figure 1 
Section 1.3 Schedule of 
Activities, Table 3 
Section 4.1 Overall Design 
Section 8.2.1 Baseline 
Assessments at Screening 
Updated text regarding start of 
Screening Period with respect to 
confirmation of detectable 
ctDNA and quality of 
prescreening tissue samples. 
Editorial change to clarify start of 
Screening period for study conduct. 
Synopsis 
Section 1.2 Schema, Figure 2 
Section 4.1 Overall Design 
Section 6.3.2 Stratification 
Added text, as well as a footnote 
to Figure 2 to indicate time of 
last intervention is defined as the
date of most recent oncological 
surgery, date of last adjuvant 
chemotherapy, or date of last 
radiotherapy fraction, whichever 
occurred later. 
Editorial change to clarify time of last 
intervention. 
Synopsis 
Clarified that main ICF should 
be signed before screening 
starts. 
Clarification statement to comply with 
GCP. 
Synopsis 
Section 5 Study Population 
Section 5.4 Prescreen Failures 
and Screen Failures 
Prescreening criteria numbered 
and incorporated prescreen 
failures along with screen 
failures in renamed section. 
Formatting change to align Prescreening 
criteria with eCRFs 
Section 5.1 Inclusion Criteria 
Specified that participants must 
meet prescreening criteria to be 
included in the study 
Editorial change for clarification 
regarding participants’ inclusion in the 
study. 
Synopsis 
Section 1.2 Schema 
Section 5 Study Population 
Prescreening (criterion #P2) 
Added text indicating 
prescreening should be started 
as soon as possible, prior to 
completion of adjuvant therapy. 
Editorial changes for clarification in 
study conduct. 
Section 5.2 Exclusion Criteria 
(criterion #2) 
Added text regarding ovarian 
suppression treatment as a 
permitted medication. 
Editorial change for consistency with rest 
of protocol. 
Synopsis 
Section 5.2 Exclusion Criteria 
(criterion #4) 
Appendix 1 Exclusion of 
Participants Who Have Shown 
No Definitive Response to 
Preoperative Chemotherapy 
Clinical evaluation added as 
criteria for evaluation of no 
definitive response and 
additional information added for 
evaluation of no definitive 
response criteria 
Clarification for study conduct. Text 
updated to clarify methods for assessment 
of no definitive response with no impact 
on participant safety, study conduct, or 
study interpretation. 
Section 1.2 Study Schema, 
Figure 2 
Key eligibility criteria updated 
Administrative change to align with 
protocol text. 
Section 1.2 Schema, Figure 1 
Section 1.3 Schedule of 
Activities, Table 2 Prescreening 
Section 4.1 Overall Design 
Changed "final cycle" for 
initiation of prescreening 
platform to "last 6 weeks of 
chemotherapy and radiation 
adjuvant treatment" in 
notes/footnotes. 
Editorial change to provide clarification 
with a measurable time definition for 
specific adjuvant treatment. 
Section 1.3 Schedule of 
Activities Table 2 (Prescreening) 
Included note regarding regimen 
stability for HR+ participants in 
Formatting/editorial clarification for 
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Section 1.3 Schedule of 
Activities, Table 3 
Cohort 1 on endocrine therapy. 
Updated note for pathology 
report to indicate it will 
accompany samples sent for 
testing. 
Assessments added to 
Prescreening activities 
(eligibility; demography; disease 
characteristics; anticancer, 
radiation therapies; surgical 
procedures for current indication 
prior to Screening; and AEs). 
Similarly, activities related to 
Demography, disease 
characteristics, and tumor 
characteristics removed from 
Table 3, anticancer therapies 
updated to clarify only prior 
anticancer therapies for 
historical cancers, and notes 
updated. 
Medical history notes updated to 
outline information to be 
captured. 
and intended data collection for screening 
versus prescreening periods, and analysis. 
There is no change to the information 
collected as part of the clinical study; this 
change only represents a clarification of 
when the data are collected, i.e., no 
impact on safety and no significant 
impact on study conduct, or study 
interpretation. 
Section 1.3 Schedule of 
Activities, Table 3 
Section 8.4.6 Pregnancy Testing 
Appendix 2 Clinical Laboratory 
Tests, Table 18 
Appendix 4 Contraceptive and 
Barrier Guidance  
Notes and text requiring serum 
pregnancy testing adjusted and 
footnote removed in Table 18 
(previously Table 17). 
Clarification for consistency in study 
conduct regarding pregnancy testing 
requirements. 
Section 1.3 Schedule of 
Activities, Table 3 
Section 8.8.1 Tumor Tissue 
Collection at Time of Disease 
Recurrence 
Added footnote and text 
indicating optional biopsies 
must be performed before 
initiating new anticancer therapy 
and do not need to occur within 
7-days of last dose. 
Editorial change to provide clarification 
for study conduct. 
Section 1.3 Schedule of 
Activities, Table 3 
Section 8.9 Patient Reported 
Outcome Measures 
Section 8.9.5 Patient Global 
Impression Items 
Updated note for PRO collection 
to be completed on the assigned 
clinic visit day and for PGIC to 
indicate it will be collected 
starting on Cycle 2/Day 1 and 
every 28 days thereafter. 
Editorial change to provide clarification 
for study conduct. 
Section 1.3 Schedule of 
Activities Table 2 (Disease 
Characteristics)  
Table 3 (Eligibility) 
Included note regarding 
recurrence during 
prescreening/screening and 
information to be collected. 
Editorial change to provide clarification 
for study conduct. 
Section 1.3 Schedule of 
Activities Table 3 
Updated notes to specify 
difference in visit windows for 
monthly versus weekly visits. 
Editorial clarification for study conduct. 
Section 1.3 Schedule of 
Activities Table 3 
Section 8.3.1 Postbaseline 
Imaging and Tumor Assessment 
Text regarding CT or MRI for 
DFS updated to include: (Year 1 
Weeks 12, 24, 36, 48; Year 2, 
Weeks 60, 72, 84, 96) and notes 
updated regarding PET scan, 
Editorial clarification for the Investigator. 

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Brief Rationale 
and that imaging should 
continue within the defined 
interval windows. 
Section 1.3 Schedule of 
Activities Table 3  
Note added to anticancer 
therapy following study 
treatment indicating any new 
anticancer treatment started 
before the Safety Follow-up 
Visit must be collected during 
this visit as outlined in eCRF 
completion instructions. 
Administrative change for omission in the 
original protocol for the evaluation of the 
safety of niraparib in this population. 
Section 1.3 Schedule of 
Activities, Table 3 
Hematology and clinical 
chemistry blood draw visit 
windows for specific visits 
added to notes. 
Editorial clarification for study conduct 
providing flexibility in blood draws. 
Section 1.3 Schedule of 
Activities, Table 3 
Clarified that assessments for 
ctDNA 
 
 
 
Editorial change to align with protocol 
text. 
Section 1.3 Schedule of 
Activities, Table 3 (Niraparib or 
placebo dispensed/collected) 
Note added regarding recording 
missed doses. 
Editorial change to align with data 
collection in eCRFs. 
Section 1.3 Schedule of 
Activities, Table 4 PK Sampling 
Schedule for All Participants 
Removed text regarding holding 
dose 1 day prior to 
Cycle 2/Day 1 
Administrative change to correct error in 
original protocol. 
Synopsis 
Section 4.1 Overall design 
Section 4.2 Overall Rationale for 
Study Design 
Sections 8.8 Translational 
Research 
Section 9.3.2 Interim Analysis 
Included name of assay for 
tumor BRCA/HRD testing. 
Administrative change for clarification 
for study conduct and for 
regulatory/ethics approval of the assay as 
part of the current protocol and any 
necessary reporting requirements related 
to assay use in this study. 
Section 6.8 Concomitant 
Medications and Nondrug 
Therapies 
Concomitant medication follow-
up corrected to indicate that it 
continues until the Safety 
follow-up visit after end of 
treatment and not until end of 
study. 
Administrative change to provide 
clarification for study conduct. 
Section 4.1 Overall Design 
Section 8.1.1 General Guidance 
for Treatment Continuity When 
Participants Are Unable to Come 
into the Clinic, Table 14 
Section 8.6 Pharmacokinetics 
Updated to include at-home 
nursing services (or local 
laboratory/clinic) and 
clarification of study days for 
these visits if participants are 
unable to attend clinic visits. 
Administrative change to provide 
clarification for participants' safety during 
the COVID-19 pandemic. 
Section 1.3 Schedule of 
Activities, Table 2 Prescreening 
Section 8.8 Translational 
Research 
Adjusted protocol text to refer to 
Study Reference Manual for 
details. 
Editorial change to provide clarification 
of tissue requirements per vendor 
performing the analysis outlined in the 
study reference manual. 
Section 2.2.2 Treatment Options 
for Patients with Operable 
HER2− Breast Cancer 
Section 2.2.4 PARP Inhibitors 
Section 2.2.5.2 Efficacy of 
Niraparib in Breast Cancer 
(Study 3000-PN162-01-001 
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TOPACIO) 
Section 2.2.5.4 Niraparib and 
Pembrolizumab 
Section 2.2.6 Circulating Tumor 
DNA 
Section 2.3.2 Benefit Assessment
Section 2.3.3 Overall 
Benefit/Risk Conclusion 
Section 4.2 Scientific Rationale 
for Study Design 
Section 4.3 Justification for Dose Amended language for niraparib 
dosing in participants with 
moderate hepatic impairment. 
Administrative change to align with the 
IB. 
Section 6 Study Treatments and 
Concomitant Therapy 
Updated references to Pharmacy 
Manual to Study Reference 
Manual 
Administrative change to correction text 
throughout protocol as study does not 
have a Pharmacy Manual. 
Section 6.1.1 Niraparib 
Text corrected regarding tablets 
provided for dosing with up to 
3 days flexibility. 
Administrative change to correction text 
and align with Table 3 visit window. 
Section 6.1.1 Niraparib, Table 10 Updated footnotes regarding 
hepatic impairment definitions. 
Editorial change to provide clarification 
for participant safety. 
Section 6.1.1 Niraparib 
Included text that dose 
escalation not permitted once 
initial starting dose is assigned. 
Editorial change for clarification of study 
conduct. 
Section 6.3.1 Randomization 
Removed IVRS and reference to 
phone numbers. 
Editorial change to correction align 
protocol text regarding randomization 
procedures being used in the study. 
Section 6.3.3 Blinding and 
Breaking the Blind 
Deleted text regarding unblinded
third party not relevant to the 
study.  
Editorial change to correct text to align 
with study. 
Synopsis 
Section 4.1 Overall Design 
Section 7.1 Withdrawal/Stopping 
Criteria 
Updated text regarding duration 
of treatment. 
Editorial clarification for study conduct. 
Section 7.1 Withdrawal/Stopping 
Criteria 
Updated text regarding 
withdrawal of participants with 
additional primary malignancies 
other than MDS and AML and 
regarding possibility of 
continued niraparib treatment if 
participants are discontinued. 
Editorial change for clarification  
Synopsis 
Section 7.3.1 Further Biomedical 
Research Maintaining 
Confidential Participant 
Information 
Clarification that Further 
Biomedical Research is after 
study completion. 
Administrative change to align with ICF 
text. 
Synopsis 
Clarification regarding possible Editorial changes for clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.8 Translational 
Research 
Appendix 9 Use/Analysis of 
DNA 
use of tumor tissue and blood 
samples for exploratory 
research. 
Appendix heading updated and 
clarified DNA samples can be 
derived from tumor or blood 
specimens. 
Section 8.1.1 General Guidance 
for Treatment Continuity When 
Participants Are Unable to Come 
into the Clinic 
Section 8.1.1, Table 14 
Removed text pertaining to 
global telemedicine and updated 
Table 14 (previously Table 13) 
table title for clarification. 
Editorial changes for Clarification that 
Sponsor not providing global 
telemedicine services; sites to engage 
their own local platform. 
Section 8.1.1.1 Direct to 
Participant Investigational 
Medicinal Product Shipments 
Revised text to remove drug 
supply vendor name. 
Administrative correction. 
Section 8.5 Adverse Events, 
Serious Adverse Events, and 
Other Safety Reporting 
Appendix 5 Regulatory, Ethical, 
and Study Oversight 
Considerations 
Removed mention of LAR. 
Administrative change to align with 
inclusion criterion 13. 
Section 8.5.6 Cardiovascular and 
Death Events 
Clarification regarding the 
recording of death information 
in eCRFs. 
Administrative change to provide 
clarification for collection of death 
information aligned with eCRFs. 
Section 8.7 Genetics 
Updated section heading and 
language regarding WES 
testing. 
Administrative change to provide 
clarification in protocol text. 
Section 9.4.5.1 Pharmacokinetic 
Parameters 
Clarifications in PK language 
and GSK analysts access to PK 
datasets. 
Administrative change to align with PK 
and Exposure-Response Analysis Plan as 
per regulatory agency recommendation 
and for clarification on access to data. 
Appendix 3 Guidelines for 
Assessment of Disease, Disease 
Progression and Response 
Criteria 
Updated criteria for participants 
with no evidence of disease at 
baseline. 
Editorial changes to provide clarification 
for study conduct. 
 
Amendment DEU-2: (10 Sep 2021) 
Overall Rationale for the Amendment 
Amendment DEU-2 is a country-specific protocol amendment in response to Health 
Authority feedback to align protocol text with country regulatory requirements as 
outlined below. 
Summary of Changes for Amendment DEU-2: 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1.1 General 
Guidance for Treatment 
Continuity When 
Participants Are Unable to 
Come into the Clinic 
Section 8.5 Adverse Events, 
Serious Adverse Events, 
Removed ’24 hours’ from the 
definition of immediate reporting 
of SAEs 
To align with the German GCP regulation 
(Section 12 (4)) which states that the 
Investigator must inform the sponsor 
immediately of the occurrence of a serious 
adverse event without mention of an 
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Section # and Name 
Description of Change 
Brief Rationale 
and Other Safety Reporting 
Appendix 8 AEs And 
SAEs: Definitions And 
Procedures For Recording, 
Evaluating, Follow-Up, 
And Reporting 
 
Amendment DEU-1: (26 Jul 2021) 
Overall Rationale for the Amendment 
Amendment DEU-1 is a country-specific protocol amendment in response to Health 
Authority feedback to align protocol text with country regulatory requirements as 
outlined below. 
Summary of Changes for Amendment DEU-1: 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.5 
Appendix 5 Regulatory, 
Ethics, and Study 
Oversight Considerations 
Removed mention of legally 
authorized representative (LAR). 
To align with inclusion criterion 13 and 
regulatory feedback (LAR not permitted 
under the German Medicines Act). 
 
Amendment GBR-1: (30 Apr 2021) 
Overall Rationale for the Amendment 
Amendment GBR-1 is a country-specific amendment to the original version of the 
protocol and was produced to amend protocol language pertaining specifically to 
COVID-19 vaccination and contraceptive use as noted during Health Authority review. 
Summary of Changes for Amendment GBR-1: 
Section # and Name 
Description of Change 
Brief Rationale 
Headers, cover page, 
Protocol Amendment 
Summary of Changes, and 
throughout 
Headers and cover page were 
updated with new version 
number; headers were updated 
with new document number; 
Protocol Amendment Summary 
of Changes section was updated 
to include rationale for this 
amendment. Editorial changes 
made throughout. 
Editorial changes to align with the 
Sponsor’s standard protocol template and 
ways of working and inclusion of specific 
language noted during Health Authority 
review 
Section 5.1 (Inclusion 
criteria number 12); 
Appendix 4, Table 19 
Recommendations for duration 
of contraception use for male 
participants was updated to 
continue for 90 days, rather than 
180 days, after the last dose of 
study treatment. 
Protocol has been amended to align with the 
niraparib Investigator’s Brochure. 

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Brief Rationale 
Section 5.2 (Exclusion 
criteria number 9); Section 
6.8.1 (Prohibited 
medications) 
Deleted language: The use of 
live Corona virus disease 2019 
(COVID-19) adenoviral vaccines 
within 30 days of randomization 
must be discussed with the GSK 
Medical Monitor. 
Added language: Study 
participants can be vaccinated 
against COVID-19 using 
vaccines authorized via the 
appropriate regulatory 
mechanisms (i.e. Emergency 
Use Authorization, Conditional 
Marketing Authorization or 
Marketing Authorization 
Application). Note: mRNA and 
adenoviral-based COVID-19 
vaccines are considered nonlive. 
Updated recommendation on use of 
COVID-19 vaccines based on GSK 
Guidance to reflect current evolving 
medical practice. 

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