Conditions: Neoplasms, Breast Carcinoma of Breast Human Epidermal Growth Factor 2 Negative Carcinoma of Breast BRCA1 Gene Mutation BRCA2 Gene Mutation Ovarian Neoplasms
Keywords: Human Epidermal Growth Factor 2 Negative Carcinoma of Breast BRCA1 Gene Mutation BRCA2 Gene Mutation PARP Inhibitor BRCA
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 216
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare progression-free survival (PFS) in patients with advanced/metastatic breast cancer who have a BRCA mutation when treated with niraparib as compared to those treated with physician's choice

Detailed description:
This is a phase III, randomized, open label, multicenter, controlled trial of niraparib versus physician's choice in previously-treated, HER2 negative, germline BRCA mutation-positive breast cancer patients. Niraparib is an orally active PARP inhibitor. Niraparib (in a 2:1 ratio) will be administered once daily continuously during a 21-day cycle. Physician's choice will be administered on a 21-day cycle. Health-related quality of life will be measured. The safety and tolerability will be assessed by clinical review of adverse events (AEs), physical examinations, electrocardiograms (ECGs), and safety laboratory values.

Arms:
arm 1: Physician may select from 4 active comparators arm 2: Patients will be randomized 2:1 to receive niraparib 300 mg (3x100 mg capsules) once daily for 21 continuous days

Interventions: intervention 1: niraparib intervention 2: Physician's choice
Intervention descriptions: intervention 1: 300 mg (3x100 mg capsules) once daily until progression or unacceptable toxicity develops intervention 2: Choice of 4 standard of care metastatic breast cancer chemotherapies, until progression or unacceptable toxicity develops

Protocol document:
Prot_002.pdf: 
Protocol Amendment 8
Study ID: 213551 
Official Title of Study:  A phase III, randomized, open label, multicenter, controlled trial of niraparib 
versus physician’s choice in previously-treated, HER2 negative, germline BRCA mutation-positive breast 
cancer patients. 
Other Identifier: NCT01905592  
Date of Document: 20-JAN-2017 (Document date has been redacted at Page 4 as it is handwritten text.) 


 
 
EORTC 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België – Belgique 
Tel: 
 
e-mail: 
 
www.eortc.org 
 
 
 
Intergroup Study (EORTC-1307-BCG) 
(BIG5-13) 
(TESARO PR-30-5010-C) 
 
(EudraCT number 2013-000684-85) 
(NCT01905592) 
(IND number # 117580) 
 
A phase III, randomized, open label, multicenter, controlled trial of 
niraparib versus physician’s choice in previously-treated, HER2 
negative, germline BRCA mutation-positive breast cancer 
patients. 
 
Co-Lead: 
Breast International Group (BIG) 
 
 
 
EORTC Breast Cancer Group 
 
Study Coordinator:  
 (BIG) 
Study Co-Coordinators: 
 (BIG) 
 
 
 
 
 
 (EORTC) 
 
 
 
 
 
 (Tufts Medical Center) 
 
Protocol 
version 
Date of PRC 
approval/notification 
Amendment reference 
N° 
Classification 
Outline 
June 28, 2013 
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1.0 
July 22, 2013 
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2.0 
August 28, 2013 
1 
Scientific  
3.0 
April 24, 2014 
3 
Scientific 
4.0 
May 04, 2015 
4 
Scientific 
5.0 
November 04, 2015 
5 
Scientific 
6.0 
January 13, 2017 
8 
Scientific 
 
Version 6.0 / January 13, 2017 
 
 
 
 
 
Copyright EORTC 2017 
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Contact addresses 
Executive Committee: 
Defined in the related study charter  
 
Writing Committee: 
 (EORTC, Statistician) 
 (EORTC, Study Co-coordinator) 
 (Tufts Medical Center) 
 (BIG, Scientific Director) 
 (BIG, Ass. Scientific Director) 
 (EORTC, Statistician) 
 (EORTC, Clinical Research Physician) 
 (BIG, Study Coordinator) 
 
Steering Committee: 
Defined in the related study charter 
 
 
 
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Contact addresses 
 
Study Coordinator: 
 
Phone: 
 
E-mail: 
 
Study Co-Coordinators: 
 
Phone: 
 
E-mail: 
 
 
 
Phone: 
 
E- mail: 
 
 
 
Phone: 
 ext 
 
E-mail: 
 
 
 
BIG Headquarters 
 
Scientific Director: 
 
 
Phone: 
 
E-mail: 
 
Associate Scientific Director: 
 
Phone: 
 
Email: 
  
Project Manager: 
 
Phone: 
 
E-mail: 
 
 
 
EORTC Headquarters 
 
Clinical Research Physician: 
 
Phone: 
 
E-mail: 
 
Project Manager: 
 
Phone: 
 
E-mail: 
 
Data Manager: 
 
Phone: 
 
E-mail: 
 
Statistician: 
 
Phone:  
 
E-mail: 
 
Pharmacovigilance Unit: 
Phone: 
 
Fax: 
 
E-mail: 
 
 
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Table of contents: 
Protocol summary 
10 
Trial organization 
18 
1 
Background and introduction 
19 
1.1 
Advanced/metastatic breast cancer with gBRCA mutation 
19 
1.2 
PARP and PARP inhibition 
19 
1.2.1 Niraparib: pre-clinical summary 
20 
1.2.2 Niraparib: clinical summary 
21 
1.2.3 Study rationale 
21 
2 
Objectives of the trial 
23 
2.1 
Primary objective 
23 
2.2 
Secondary objectives 
23 
2.2.1 Key secondary objective 
23 
2.2.2 Other secondary objectives 
23 
3 
Patient selection criteria 
23 
3.1 
Registration step 
24 
3.2 
Randomization step 
24 
4 
Trial design 
27 
4.1 
Overall study design 
27 
4.2 
Justification of study design and choice of endpoints 
29 
5 
Therapeutic regimens, expected toxicity, dose modifications 
30 
5.1 
Drug information 
30 
5.1.1 General information 
30 
5.1.2 Drug supply 
30 
5.1.3 Packaging, dispensing and storage 
30 
5.1.4 Drug reconciliation procedures 
31 
5.2 
Initial dose and schedule 
31 
5.3 
Treatment duration 
32 
5.4 
Withdrawal criteria 
32 
5.5 
Dose and schedule modifications 
33 
5.5.1 Niraparib- related dose modification for toxicity (hematologic and non- hematologic) 33 
5.5.2 Physician’s choice dose modification 
36 
5.6 
Concomitant treatments 
36 
5.6.1 Supportive care in case of toxicity 
36 
5.6.2 Other concomitant therapies 
36 
6 
Clinical evaluation, laboratory tests and follow-up 
37 
6.1 
Before Treatment 
37 


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6.1.1 Registration 
37 
6.1.2 Screening (day -28 to day 1) 
37 
6.2 
During treatment 
38 
6.2.1 Cycle 1, day 1 
39 
6.2.2 Cycle 2, day 1 
39 
6.2.3 Day 1, subsequent cycles 
40 
6.2.4 Study medication termination visit (within 28 days following the start of the last cycle)40 
6.2.5 Follow-up Visit 
41 
6.2.6 For those patients who discontinue treatment in the absence of progression 
41 
6.2.7 After progression, survival follow-up visits 
41 
6.3 
Summary table 
42 
7 
Criteria of evaluation 
48 
7.1 
Evaluation of efficacy 
48 
7.1.1 Measurability of tumor lesions at baseline 
48 
7.1.1.1 
Definitions 
48 
7.1.1.2 
Methods of measurements 
49 
7.1.2 Tumor response evaluation 
50 
7.1.2.1 
Frequency of tumor re-evaluation 
52 
7.1.2.2 
Date of progression 
52 
7.1.3 Reporting of tumor response 
52 
7.1.4 Response duration 
53 
7.1.5 Time to treatment failure 
53 
7.1.6 Progression Free Survival (PFS) 
53 
7.1.7 Overall Survival (OS) 
53 
7.2 
Evaluation of safety 
53 
7.2.1 Adverse events 
53 
7.2.2 General evaluation of adverse events 
54 
7.2.3 Serious adverse events 
54 
7.2.4 Toxic deaths 
54 
7.2.5 Evaluability for safety 
54 
8 
Statistical considerations 
55 
8.1 
Statistical design 
55 
8.1.1 Sample size 
55 
8.1.2 Randomization and stratifications 
56 
8.2 
Statistical analysis plan 
56 
8.2.1 Primary and secondary endpoints 
56 
8.2.2 Analysis populations 
57 


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8.2.3 Statistical methods 
57 
8.2.3.1 
Key Secondary Endpoint Analyses – Overall Survival 
58 
8.2.3.2 
Secondary Endpoints Analyses 
58 
8.2.4 Pre-planned sensitivity or exploratory analyses 
58 
8.2.5 Prognostic factor analyses 
59 
8.2.6 Post-treatment analyses 
59 
8.2.7 Data recoding and display 
59 
8.3 
Interim analysis 
59 
8.4 
End of study 
60 
9 
Data Monitoring 
60 
10 Quality of life assessment 
60 
10.1 
Rationale 
60 
10.2 
Objective 
61 
10.3 
HRQoL instrument 
61 
10.4 
Study design 
62 
10.4.1 
HRQoL schedule 
62 
10.5 
Statistical considerations 
63 
10.5.1 
Missing data 
64 
10.6 
Health Economics 
64 
11 Pharmacokinetics 
64 
12 Translational research 
65 
12.1 
BRCA 1/2 mutation analysis for patient enrolment 
65 
12.1.1 
Objective 
65 
12.1.2 
Material and methods 
65 
12.2 
Concordance of the companion diagnostic test for determination of germline BRCA 1/2 
mutations 
65 
12.2.1 
Objective 
65 
12.2.2 
Material and methods 
66 
12.3 
Evaluation of predictive biomarkers related to efficacy and safety of niraparib 
66 
12.3.1 
Tumor biomarkers 
66 
12.3.1.1 
Objective 
66 
12.3.1.2 
Material and methods 
66 
12.3.2 
Assessment of circulating plasma DNA 
67 
12.3.2.1 
Objective 
67 
12.3.2.2 
Material and methods 
67 
12.3.3 
Humoral immune response monitoring 
67 
12.3.3.1 
Objective 
67 
12.3.3.2 
Material and methods 
67 


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12.3.4 
Mutation profile screening test for selected myeloid- associated genes 
68 
12.3.5 
Summary of sample collection 
69 
12.4 
Routing and banking of human biological material 
70 
12.5 
General principles for human biological material (HBM) collection 
70 
12.6 
Data storage, transfer and development of statistical analysis plan 
70 
13 Publication policy 
71 
14 Investigator authorization procedure 
71 
15 Patient randomization procedure 
72 
15.1 
Registration procedure for screening (step 1) 
72 
15.2 
Eligibility checklist (step 2) 
72 
16 Forms and procedures for collecting data 
73 
16.1 
Case report forms and schedule for completion 
73 
16.2 
Data flow 
74 
17 Reporting of Serious Adverse Events 
74 
17.1 
Definitions 
74 
17.2 
Exceptions 
76 
17.3 
Severity assessment 
76 
17.4 
Causality assessment 
76 
17.5 
Expectedness assessment 
77 
17.6 
Reporting procedure for investigators 
77 
17.7 
Reporting responsibilities of the Sponsor 
78 
17.8 
Pregnancy reporting 
79 
18 Quality assurance 
79 
18.1 
Control of data consistency 
79 
18.2 
On-site quality control 
79 
18.3 
Audits 
80 
18.4 
External review of responses 
80 
18.4.1 
Tumor assessments 
80 
19 Ethical considerations 
81 
19.1 
Patient protection 
81 
19.2 
Subject identification 
81 
19.3 
Informed consent 
81 
20 Administrative responsibilities 
82 
20.1 
The study coordinator 
82 
20.2 
The EORTC Headquarters 
83 
20.3 
The BIG Headquarters 
83 
20.4 
The EORTC group 
83 


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21 Trial sponsorship and financing 
84 
22 Trial insurance 
84 
  
Table of appendices: 
Appendix A: References 
85 
Appendix B: Abbreviations 
88 
Appendix C: Common Terminology Criteria for Adverse Events 
91 
Appendix D: EORTC Quality of Life evaluation: guidelines for administration of questionnaires 
92 
Appendix E: NCCN guidelines version 1.2015 breast and/or ovarian cancer genetic assessment 
94 
Appendix F: European Quality of Life scale, 5-dimension 5 level (EQ-5D-5L) 
95 
Appendix G: Eastern Cooperative Oncology Group (ECOG) performance status 
97 
Appendix H: Drugs known to inhibit or induce CYP1A2 
98 
Appendix I: EORTC Quality of Life Questionnaire (EORTC QLQ-C30) 
99 
Appendix J: List of drugs that are substrates or inhibitors of P- glycoprotein 
102 
  


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Protocol summary 
Title of the Study 
A phase III, randomized, open label, multicenter, controlled trial of 
niraparib versus physician's choice in previously-treated, HER2 negative, 
germline BRCA mutation-positive breast cancer patients. 
Objective(s) 
Primary objective: To compare progression-free survival (PFS) as assessed 
by blinded, central review between patients randomized to niraparib versus 
physician’s choice.  
Key secondary objective: To compare overall survival between patients 
randomized to niraparib versus physician’s choice. 
Secondary objectives: 
1. Establish germline BRCA mutation status of screened patients using a 
centrally provided, validated test. Additional tests will be performed in 
order to determine concordance between tests for the purpose of developing 
a commercial companion diagnostic test. 
2. To evaluate safety and tolerability as measured by all AEs  
3. To compare PFS using investigator assessment of progression. 
4. To evaluate time to treatment failure (discontinuation of treatment for 
any reason). 
5. To compare response rate and duration of response. 
6. To compare time to deterioration of health-related quality of life: QLQ-
C30 and EQ-5D-5L. 
7. To describe subsequent therapies and potential relationships with 
outcomes. 
8. To assess genetic and non-genetic biomarkers relating to treatment 
efficacy. Germline and tumor mutations may be explored including somatic 
BRCA1 and 2 mutations, reversion mutations, loss of heterozygosity as well 
as genome landscape and transcriptional or functional measures of 
homologous recombination (HR) deficiency.  
9. To assess outcomes by germline mutation BRCA1 vs BRCA2. 
10. Descriptive summary statistics will be used to summarize post- 
treatment data (.i.e subsequent anticancer therapies and any new 
malignancy) 
Methodology 
Phase III - superiority study. Randomization will be conducted with 
stratification for visceral disease (yes or no), histology (TNBC vs ER/PR 
positive) and number of lines of prior cytotoxic chemotherapy (not 
including hormonal therapy) for advanced/metastatic disease (0-1 or 2).  
No crossover to niraparib is permitted following discontinuation from 
physician’s choice treatment. 


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Number of patients  
Number planed 
(Statistical design) 
Number analyzed 
Randomization will be 2:1 (treatment: control). At least 306 patients with 
germline BRCA mutations, as confirmed by the central test, will need to be 
randomized. Patients can also be randomized on the basis of a local test. 
The intent-to-treat population, defined as all randomized patients with a 
central confirmation of germline BRCA mutation, is the primary analysis 
population for the efficacy analysis. 
Diagnosis and 
main criteria for 
inclusion 
1. Histologically or cytologically confirmed HER2-negative metastatic or 
locally advanced breast cancer that is not amenable to resection or radiation 
with curative intent. 
2. Female and male patients age at least 18 years. 
3. Patients with a deleterious or suspected deleterious germline BRCA1 or 
BRCA2 mutation may be enrolled into the study and randomized based on 
either local or central laboratory testing of BRCA status (Myriad Genetic 
Laboratories, Salt Lake City, UT, USA). On- study central confirmation of 
BRCA status will be performed for those patients who were enrolled based 
on either a previous Myriad test or a local test. If after inclusion, based on a 
local test result or a previously done Myriad test, a patient turns out not to 
have a germline BRCA mutation per central laboratory results (Myriad 
Genetic Laboratories, Salt Lake City, UT, USA) the patient can still 
continue on study based on his/her physician discretion and his/her own 
preference. 
4. Measurable disease by RECIST v1.1 or non- measurable disease that is 
clinically evaluable (except sclerotic-only bone disease; bone-only disease 
that has a lytic component is allowed); there must evidence of disease 
progression within 3 months prior to enrollment without change of therapy. 
5. Patients must not have symptomatic uncontrolled brain metastases. To 
be considered controlled, central nervous system (CNS) disease must have 
undergone treatment (whole brain radiation, radiosurgery or equivalent) at 
least 1 month previously and the patient has no new or progressive signs or 
symptoms related to the CNS disease, and are off steroid therapy two 
weeks. A post- treatment brain CT/MRI obtained at least 7 days off of 
steroids that shows no evidence of progression is needed. 
6. Up to 2 prior cytotoxic regimens for advanced or metastatic breast 
cancer (not including adjuvant or neo-adjuvant therapy); patients with no 
prior cytotoxic regimens for advanced or metastatic disease will only be 
allowed if they relapsed during or within 12 months of (neo-) adjuvant 
cytotoxic therapy.  
7. Prior therapy should have included a taxane and/ or anthracycline 
(unless contraindication to those) in the neoadjuvant, adjuvant, or 
advanced/metastatic setting. 
a. Hormone receptor positive patients must also have hormone resistant 
disease; either relapsed while on adjuvant endocrine treatment, or within 
one year of completing adjuvant endocrine treatment, or progression on at 
least one line of endocrine treatment for advanced cancer. 
 
  


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8. Patients must not have received anticancer chemotherapy, radiotherapy 
(including palliative radiotherapy), hormonal therapy, biological therapy, or 
any other investigational therapy within 3 weeks prior to the start of study 
treatment. Patients with persistent toxicity (except alopecia) > grade 1 from 
prior cancer therapy will also be excluded. Bisphosphonate and denosumab 
is allowed. 
9. No prior treatment with a known or putative PARP inhibitor (except 
iniparib). No other anticancer agent (chemotherapy, hormonal therapy, or 
other agent) is to be permitted during the course of the study for any 
patient. 
10. Patients who have previously received platinum chemotherapy in the 
metastatic setting are allowed to enroll in the study as long as they did not 
progress while on or within 8 weeks from the day of the last platinum 
administration. Patients who received platinum in the (neo-) adjuvant 
setting are eligible, as long as they relapsed 12 months or more after the last 
dose of platinum.  
11. ECOG performance status 0-2 (Appendix G). 
12. Adequate organ function (assessed within 72 hours prior to the first 
dose): 
 
a. Absolute neutrophil count (ANC) ≥ 1,500 cells/μL 
 
b. Platelets ≥ 100,000 cells/μL 
 
c. Hemoglobin ≥ 9 g/dL 
 
d. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or ≥ 
50mL/min using Cockcroft-Gault equation  
 
e. Total bilirubin ≤ 1.5 × ULN  
 
f. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 
2.5 × ULN or < 5 × ULN with liver metastases 
13. Patients able to swallow and retain oral tablets 
14. Female patients must not be pregnant or breast feeding 
 
a. Female patient of childbearing potential must have a negative serum 
pregnancy test (β-human chorionic gonadotropin [β-hCG]) within 72 hours 
prior to the first dose). 
15. Patients of childbearing potential who are sexually active and their 
partners must agree to the use of a highly effective form of contraception 
throughout their participation during the study treatment and for 90 days 
after last dose of study treatment(s). These are: 
♦ combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation:  
♦ oral route  
♦ intravaginal route  
♦ transdermal route  
 


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♦ progestogen-only hormonal contraception associated with inhibition of 
ovulation  
♦ oral  
♦ injectable  
♦ implantable  
♦ intrauterine device (IUD)  
♦ intrauterine hormone-releasing system ( IUS)  
♦ bilateral tubal occlusion  
♦ Vasectomized partner  
♦ sexual abstinence, if the preferred and usual lifestyle of the subject 
a Note: For patients with ER and/or PR positive tumors avoidance 
of hormonal methods is highly recommended 
16. No known hypersensitivity to the components of niraparib or any of its 
analogs. 
17. No major surgery within 2 weeks prior to registration. Patients must 
have recovered from earlier major surgery before registration. 
18. No prior diagnosis of Stage IV ovarian cancer.  
Patients with history of Stage III ovarian cancer must have a 5-year disease-
free interval  
Patients with Stage I or II ovarian cancer must have a disease-free interval 
of 2 years  
Patients with a prior history of ovarian cancer who have peritoneal disease 
should have a normal serum CA-125. 
For patients with a prior history of ovarian cancer who have peritoneal 
disease and elevated serum carcinoma antigen CA- 125, a biopsy of the 
peritoneal disease is required to prove the breast cancer origin of the 
metastasis.  
19. No prior diagnosis, detection, or treatment of invasive cancer other than 
breast cancer within 2 years (except basal or squamous cell carcinoma of 
the skin that has been definitively treated) 
20. Patients must not be considered a poor medical risk due to a serious, 
uncontrolled medical disorder, non-malignant systemic disease, or active, 
uncontrolled infection. Examples include, but are not limited to 
uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial 
infarction, uncontrolled major seizure disorder, unstable spinal cord 
compression, superior vena cava syndrome, or any psychiatric disorder that 
prohibits obtaining informed consent. 
21. Absence of any psychological, familial, sociological or geographical 
condition potential hampering compliance with the study protocol and 
follow- up schedule; those conditions should be discussed with the patient 
before registration in the trial. 


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22. No immunocompromised patients (e.g., patients who are known to be 
serologically positive for human immunodeficiency virus [HIV]). 
23. No patients with known active Hepatitis B or C. 
24. Patients should acknowledge that they are at an increased risk of 
infection with conventional chemotherapy drugs and since the effects with 
niraparib are unknown they must accept that live virus and bacterial 
vaccines should not be administered to them for the duration of the study 
and for 3 months after last dose of study medication. 
25. If patients are blood donors they should accept not to donate blood 
during the study and for 3 months after the last dose of study drug. 
26. Patients must have voluntarily agreed to participate by given informed 
consent. 
27. If all of the comparator treatments are contraindicated the patient will 
not be included in the trial. 
28. Patients must not have received a platelet transfusion within 4 weeks of 
the first dose of study treatment and must not have had any known, 
persistent (>4 weeks) ≥ grade 3 hematological toxicity or fatigue from last 
cancer therapy. 
29. Patients must not have any known history of myelodysplastic syndrome 
(MDS). 
30. Patients must agree to peripheral blood samples during screening and at 
the end of treatment for mutational profile testing (for mutations of selected 
myeloid related genes) that will be performed only if the patient develops 
MDS or acute myeloid leukemia (AML) during the study or the post- 
treatment follow-up (a third sample will be collected in this case). 
Treatment 
Test product, dose 
and mode of 
administration 
Duration of 
treatment 
Group 1: niraparib 300 mg (3x100 mg niraparib capsules) will be 
administered orally QD continuously in an open- label fashion. The 
consumption of water and food is permissible. 
Group 2: Physician's choice of chemotherapy [amongst one of the 
following four single agents: eribulin, gemcitabine (both administered 
intravenously) capecitabine (administered orally) or vinorelbine 
(administered orally or intravenously) will be administered in 3 week 
cycles. The physician’s choice chemotherapy must be designated prior to 
randomization of each patient and the choice should be made according to 
the respective national available and approved treatment (Note: 
Gemcitabine will be administered as single agent as per NCCN guidelines. 
In France, gemcitabine is not allowed to be chosen as a treatment in the 
physician's choice arm). Patients will continue on study medication until 
disease progression as long as in the investigator's opinion they are 
benefiting from treatment and do not meet any other treatment 
discontinuation criteria. 


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Criteria for 
evaluation 
The primary objective of this study is to determine the efficacy of niraparib 
compared to physician's choice amongst four single agent chemotherapy 
agents (eribulin, vinorelbine, gemcitabine or capecitabine) in treatment of 
patients with germline BRCA mutation with advanced/ metastatic HER2 
negative breast cancer who have been treated with up to 2 prior lines of 
chemotherapy for advanced/ metastatic disease. This objective will be 
assessed by the primary endpoint of PFS as assessed by blinded, central 
review. 
Efficacy 
Safety 
Key secondary endpoint is evaluation of overall survival. 
Safety and tolerability will be described using frequency of AEs and AEs of 
CTCAE grade ≥3. Safety analyses will include all patients who have 
received at least one dose of study drug and will be evaluated descriptively. 
Statistical methods 
This is a phase III superiority trial of niraparib versus single agent 
chemotherapy (eribulin or vinorelbine or gemcitabine or capecitabine). The 
primary endpoint is PFS, which is defined as the time from the date of 
randomization to the date of first documentation of objective progression 
(by blinded central review) or death by any cause in the absence of 
documented objective progression whichever occurs first. 
The primary analysis population for efficacy constitutes all randomized 
patients who have a germline BRCA mutation per central laboratory 
(Myriad USA).The overall sample size for this study is based on the overall 
survival endpoint and is determined based on the alternative hypotheses 
that niraparib will result in an improvement in median survival of 9 to 13 
months (corresponding to a hazard ratio = 0.69). For a true hazard ratio of 
0.69, 265 deaths will provide 80% power (1-sided alpha = 0.025). 
Assuming 10 patients are enrolled per month in primary analysis population 
for efficacy, with 306 patients, 265 deaths are expected to occur 
approximately 54 months after the first patient enrolled.  
Assuming 40% of patients will be randomized on the basis of a local BRCA 
test and assuming that 15% of those patients will not be BRCA mutated per 
central test, it is estimated that an over-enrollment by 18 patients is needed 
to obtain the required 306 patients in the analysis population. The final PFS 
analysis is planned after 137 PFS events have occurred or end of 
recruitment, whichever occurs later. With 137 PFS events, there is 80 % 
power (1- sided alpha=0.025) to detect an HR 0.6 (equivalent to 3 to 5 
months).  
A gate-keeping strategy (i.e. sequential testing procedure) will be used to 
test PFS and OS. OS will be tested at a 1-sided alpha of 0.025 only if the 
final test on PFS is significant at a 1-sided alpha of 0.025.  
The primary analysis of PFS and OS will be performed using a stratified 
log-rank test, stratifying by the randomization strata. Stratified Cox 
proportional hazards models will be used to estimate the treatment hazard 
ratio and its 95% confidence interval. PFS and OS will be descriptively 
summarized using Kaplan-Meier methodology. 
An interim analysis for futility is planned after 93 PFS events. If the results 
cross the pre-specified futility boundary, the IDMC may recommend 
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Translational 
research 
1) A secondary endpoint of the trial is to establish germline BRCA mutation 
status of screened patients using a centrally provided, validated test.  
2) Additional tests will be performed for the purpose of developing a 
commercial companion diagnostic test. Concordance of the candidate 
companion diagnostic test with the centralized gBRCA mutation test with 
respect to identifying patients with gBRCA mutations will be evaluated on a 
separate blood sample collected at the same time that the blood sample for 
central testing is taken. The sensitivity and specificity (along with the 
corresponding 95% confidence bounds) of the candidate companion 
diagnostic test will be benchmarked to the centralized, validated test 
performed as an inclusion criterion. 
3) Archival tumor tissue (primary tumor or a metastatic lesion) will be 
collected with the intention to assessing markers of homologous 
recombination deficiency in the tumor genome landscape, (eg. HRD Score) 
assessment of LOH, somatic BRCA1 and BRCA2 mutations, reversion 
mutation analysis, methylation of alleles, transcriptional and protein 
expression profiles of DNA damage response (e.g. loss of 53BP1 
expression in BRCA carriers). 
4) Optional tumor biopsies (FFPE and snap frozen) will be collected at 
baseline and time of progression for assessment to validate markers of 
homologous recombination deficiency, HRD Score, assessment of LOH, 
mutation analysis, methylation of alleles, transcriptional and protein 
expression profiles of DNA damage response. The concordance between 
markers assessed on archival and optional baseline biopsy will be 
determined, and optional progression sample will be utilized to examine for 
mechanisms of acquired resistance to niraparib. 
5) Plasma at baseline, 6- weeks and progression with intention to study 
circulating free DNA (e.g. reversion mutations) and humoral immune 
response biomarkers. 
6) Blood sample at screening and treatment discontinuation will be 
collected to evaluate mutations for selected myeloid- associated genes if the 
patient develops MDS or acute myeloid leukemia during the study or the 
post- treatment follow- up (a third sample will be collected in this case). 
This test is a PCR- based next generation sequencing assay that screens 
DNA from leukocytes for the presence of mutations or insertions/deletion 
in commonly altered areas of 30 genes. Mutation profile before and after 
study treatment will be compared to determine whether any mutations were 
present prior to study treatment. These samples will be stored and analyzed 
if necessary for assessing niraparib related risk for MDS/AML 
development.  


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Quality of Life 
Patient reported outcomes will be collected via questionnaires (EORTC 
QLQ-C30 and EQ-5D-5L). These must be completed within 4 weeks 
before randomization and subsequent questionnaires are filled in every 2 
cycles (ie. 6 weeks) while on-treatment and every 3 months while in 
follow- up. Collection of HRQoL data is limited to the first 12 months after 
randomization. The primary HRQoL endpoint considered relevant for this 
study is time to HRQoL deterioration (TTQ). TTQ is defined as the time 
from randomization to death, progression or clinical relevant deterioration 
in pre-specified QLQ-C30 scales. 
PK – PD 
Blood samples for measurements of plasma levels of niraparib will be 
obtained in the experimental arm on cycle 1/ day 1 and on cycle 2/ day 1 at 
the following timepoints: 0 (predose within 30 minutes) and 2 hours post 
dose. In subsequent cycles, a blood sample for measurements of plasma 
levels of niraparib will be obtained on cycle 4/ day 1 predose (within 30 
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Trial organization 
This trial is an Intergroup Trial performed under the BIG umbrella, jointly conducted by several 
national/international cancer clinical research groups in different countries of European Union, North 
America and other countries.  
TESARO is the Sponsor in all participating countries. 
TESARO is responsible for the global management of the study set-up and execution.  
BIG is responsible for the study governance set-up and management. 
The EORTC centrally manages data collection and quality control of data and statistical analysis.  
Publication is managed by EORTC and BIG. 
TESARO (via PAREXEL) centrally manages the notification/submission of all necessary documents to the 
Competent Authorities and/or Ethics Committees and gets the confirmation of the review by IRB/IEC 
following applicable national laws. TESARO (via PAREXEL) also manages collection of essential 
documents, authorization of sites and sample logistics.  
This protocol is to be followed by all participating groups and sites. All chapters are fully applicable to all 
participants. 
The patient information sheet and informed consent templates are applicable for all participating groups 
and sites. Investigators will receive the translated and adapted Patient Information Sheet (PIS) & Informed 
Consents (ICs) directly from PAREXEL. 
Investigators who are members of the clinical cancer research groups participating to the trial should select 
one of these groups for the framework of this trial and include all patients through this group. In some 
cases, because of the national legal framework the choice may be imposed. For EORTC members, all 
patients will be accounted for the membership independently from the group they choose to participate 
through (see EORTC Policy 10).  
The investigational drug (niraparib) will be supplied by TESARO. 
This trial is fully supported by TESARO. 


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1 Background and introduction 
1.1 
Advanced/metastatic breast cancer with gBRCA mutation 
Breast malignancies typically arise from breast epithelium and are considered carcinomas, both non-
invasive and invasive carcinomas occur (Ref. 1). The 2012 incidence of invasive breast cancer in the 
United States (US) was 230,000 with a mortality rate of 40,000 (National Cancer Institute, 
www.cancer.gov/cancertopics/types/breast). Using the TNM classification, breast cancer is staged from I-
IV; patients with advanced (Stage III) and metastatic (Stage IV) breast cancers have a worse prognosis. 
Metastatic cancer is managed by various combinations of available treatments including surgery, radiation, 
chemotherapy, and targeted therapies. However, even with optimal treatment, 10-year survival rate is only 
about 10% (Ref. 2), and therefore a significant unmet medical need exists for new therapies to treat 
patients with advanced/metastatic breast cancer.  
Current approaches to the management of metastatic breast cancer select patients for endocrine or human 
epidermal growth factor receptor 2 (HER2) targeted therapy based on the expression of cell surface 
markers on breast tumors influencing the choice of treatment. Patients with estrogen receptor (ER) or 
progesterone receptor (PR) positive tumors often respond to hormonal therapy, including selective 
estrogen receptors modulators (tamoxifen, toremifene), aromatase inhibitors (exemestane, anastrazole, 
letrozole), an ER antagonist (fulvestrant) or progestins (megestrol acetate). Multiple lines of hormonal 
therapy are often given upon progression of disease prior to initiating chemotherapy. Patients with HER2-
positive disease are usually treated with HER2-targeting therapy (trastuzumab ± pertuzumab) along with 
chemotherapy. Upon progression, HER2-directed therapy (trastuzumab, lapatinib) may be continued along 
with different chemotherapy agents. Patients with ER-/PR-/HER2- triple negative breast cancer (TNBC) 
are usually treated with chemotherapy regimens involving either single agents or combinations. The most 
common single agents include: anthracyclines (doxorubicin, epirubicin, and pegylated liposomal 
doxorubicin), taxanes (paclitaxel, docetaxel, and albumin-paclitaxel), antimetabolites (capecitabine, 
gemcitabine) and antimitotics (vinorelbine, eribulin). The most common combinations include 
doxorubicin/epirubicin + cyclophosphamide (AC/EC), ±fluorouracil + AC (FAC/FEC), taxane + AC 
(anthracycline ± cyclophosphamide (AC/TAC), gemcitabine or capecitabine + taxane (GT or XT), and 
cyclophosphamide + methotrexate + F (CMF) (Ref. 3). 
Germline mutations of BRCA1 and BRCA2 genes are found in the majority of patients with hereditary 
breast or ovarian cancer. Individuals with these germline mutations are at markedly increased risk to 
develop cancer, particularly breast and ovarian cancers. Nevertheless, BRCA1/2 associated cancers are rare 
representing less than 5% of all breast cancer cases. Data regarding the impact of BRCA1/2 mutational 
status on treatment of breast cancer are currently inconclusive and thus these genes do not currently affect 
the decision making process regarding the type of systemic therapy (Ref. 4, Ref. 5, Ref. 6, Ref. 7). 
1.2 
PARP and PARP inhibition 
The Poly(ADP-ribose) polymerases (PARP) family of enzymes was first described over 40 years ago. 
PARP-1 and -2 are zinc-finger DNA-binding nuclear enzymes that play a crucial role in DNA repair. Upon 
formation of stalling DNA replication forks or single-strand DNA breaks, PARP binds DNA strands, a 
process which activates its enzymatic activity. Activated PARP catalyzes addition of long polymers of 
ADP-ribose on several proteins associated with chromatin, including histones and various DNA repair 
proteins including PARP itself. This results in chromatin relaxation, fast recruitment of DNA repair 
proteins and efficient repair of DNA breaks (Ref. 8). 
Normal cells repair up to 10,000 DNA defects daily and single strand breaks are the most common form of 
DNA damage. Cells that are unable to repair this burden of DNA damage, such as those with defects in the 
base excision repair (BER) pathway, or those treated with PARP inhibitors, are at risk for accumulating 


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multiple lesions that will ultimately trigger apoptosis. They enter S phase (DNA replication) of the cell 
cycle with unrepaired single strand breaks. Pre-existing single strand breaks are converted to double strand 
breaks (DSB) as the replication machinery passes. Accumulated double strand breaks present during S 
phase are repaired by homologous recombination (HR). Homologous recombination is the preferred repair 
pathway because it is associated with a much lower error rate than other forms of repair. Cells unable to 
perform DNA repair via HR (e.g., due to inactivation of genes required for HR, such as BRCA1 and 
BRCA2 mutated cells), are at risk for accumulating multiple lesions that will ultimately trigger apoptosis. 
These cells accumulate stalled replication forks during S phase and are more likely to use the error-prone 
non-homologous end joining (NHEJ) pathway to repair double strand breaks in DNA. Accumulation of 
errors in DNA by NHEJ contributes to the mutation burden that promotes the development of cancer. Pre-
clinical ex vivo and in vivo experiments suggested that PARP inhibitors are selectively cytotoxic for 
tumors with defects in the HR repair pathway, such as mutations in BRCA1 or BRCA2 genes. In normal or 
BRCA heterozygous cells, the lesion can be repaired and DNA replication and cell division continue. 
However in cells that lack functional DSB repair, loss of two DNA repair pathways causes 'synthetic 
lethality' and cell death (Ref. 9, Ref. 10). 
Human cancers exhibit genomic instability and an increased mutation rate due to underlying defects in 
DNA repair. These deficiencies render cancer cells more dependent on the remaining DNA repair 
pathways and targeting these pathways is expected to have a much greater impact on the survival of the 
tumor cells than on normal cells. There are several PARP inhibitors in clinical development. Treatment 
with PARP-1 and -2 inhibitors represents a novel opportunity to selectively kill a subset of cancer cell 
types by exploiting their deficiencies in DNA repair. The publication in 2005 of paired pre- clinical papers 
in Nature demonstrating hypersensitivity of BRCA- deficient cancer cells to single- agent PARP inhibitors, 
opened the door to clinical research into these agents, and provided a clear demonstration of a class effect 
(Ref. 9, Ref. 11).  
1.2.1 
Niraparib: pre-clinical summary 
Niraparib (formerly referred to as MK-4827) is a potent and selective PARP-1 and PARP-2 inhibitor with 
half maximal inhibitory concentration of control (IC50) of 3.8 and 2.1 nM, respectively, and is at least 
100-fold selective over other PARP-family members. Niraparib inhibits PARP activity stimulated as a 
result of DNA damage caused by addition of hydrogen peroxide in various cell lines with an IC50 and a 
90% inhibitory concentration of control (IC90) of about 4 and 50 nM, respectively (Ref. 12).  
Niraparib demonstrates selective anti-proliferative activity for cancer cell lines that have been silenced for 
BRCA1 or BRCA2 or carry BRCA1 or BRCA2 mutations as compared to their wild type counterparts. 
Niraparib demonstrates weak activity on normal human cells.  
Niraparib displayed strong antitumor activity in in vivo studies with BRCA1 mutant breast cancer (MDA-
MB-436), BRCA2 mutant pancreatic cancer (CAPAN-1), ATM-mutant mantle cell lymphoma (GRANTA-
519), serous ovarian cancer (OVCAR3), and colorectal cancer (HT29 and DLD-1) xenograft models and 
with patient-derived Ewing’s sarcoma mice models.  
Moreover, Murai et al demonstrated in 2012 that niraparib is the most potent amongst a series of 5 PARP 
inhibitors in trapping PARP (Ref. 13). 
Non clinical testing of niraparib did not indicate any untoward effects that would prevent clinical 
investigation in the human setting. 
Non clinical pharmacology studies with niraparib have generated sufficient data to support its clinical 
evaluation as a monotherapy for patients with advanced/metastatic breast cancer with gBRCA mutation. 
Details of the non clinical studies conducted with niraparib can be found in the current Investigator’s 
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1.2.2 
Niraparib: clinical summary 
To date, niraparib has been evaluated in a series of Phase 1 clinical trials in patients with solid tumors. As 
of 01 February 2013, 144 patients have been treated with niraparib at doses up to 400 mg once daily (QD). 
The dose limiting toxicity at the 400 mg QD dose was thrombocytopenia. At ASCO 2013, Michie et al, 
reported the final results of a phase I trial of niraparib in 100 patients (69 women, 31 men) with various 
solid tumors (49 ovarian, 23 CRPC, 12 breast and 16 others) (Ref. 14). The drug was given in pill form 
once a day and the researchers established the maximum tolerated dose at 300 mg a day. 
In these studies, niraparib was well tolerated, exhibited linear pharmacokinetics (PK), had evidence of 
target modulation, and had promising antitumor activity, especially in cancers with BRCA mutations. 
Recently, the results of NOVA study (Niraparib in ovarian cancer) have shown that among patients with 
platinum- sensitive, recurrent ovarian cancer, the median duration of progression- free survival was 
significantly longer among those receiving niraparib than among those receiving placebo, regardless of the 
presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity (Ref. 41). 
The results of this study are summarized below: 
1. BRCA mutated population: PFS (21 months niraparib vs 5.5 months placebo, HR= 0.27, P< 0.001) 
2. Population with no BRCA mutation but Homologous Recombination deficient (HRD) tumors (12.9 
months vs 3.8 months, HR= 0.38, P< 0.001) 
3. Overall non-gBRCA mutated population (9.3 months vs 3.9 months, HR= 0.45, P< 0.001) 
4. Non- BRCA mutated, Homologous Recombination Deficient negative population [exploratory] (6.9 
months vs 3.9 months, HR= 0.58, P= 0.022) 
Across these studies, the most commonly reported adverse events (AEs) during niraparib monotherapy 
(n=107) were nausea (57%), fatigue (55%), anemia (49%), vomiting (40%), constipation (39%), 
thrombocytopenia (34%), decreased appetite (33%), headache (24%), hyponatremia (24%), neutropenia 
(24%), cough (22%), diarrhea (22%), dyspnea (22%), and back pain (21%). 
Pharmacodynamic analyses conducted in the Phase 1 Study PN001 confirmed PARP inhibition at doses ≥ 
80 mg daily and antitumor activity was documented at doses ≥ 60 mg daily. Partial responses were 
observed in 7 (35%) of 20 ovarian cancer patients with BRCA1 and BRCA2 mutations receiving niraparib 
monotherapy. Two (50%) of 4 breast cancer patients with BRCA1 and BRCA2 mutations experienced 
partial responses. 
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have been observed in patients 
receiving treatment with olaparib, a PARP inhibitor; given the common mechanism of action, MDS and 
AML therefore represent a potential risk to patients receiving niraparib. Guidance on monitoring patients 
for new events of MDS/AML and the follow- up of patients with suspected MDS/AML is provided in 
section 5.5, section 6.2, section 12.3.4 and section 12.3.5. 
Details of the clinical studies conducted with niraparib can be found in the current Investigator's Brochure. 
1.2.3 
Study rationale 
This study is designed to compare the efficacy and safety of niraparib to current standard of care in the 
treatment of patients with HER2-negative germline BRCA1 or BRCA2 mutation (gBRCAmut) breast cancer 
who have received no more than 2 prior chemotherapy regimens for advanced/metastatic disease, 
including prior taxane and/or prior anthracycline therapy and for whom one of the physician's choice 
treatments would be indicated as standard of care. 
Individuals with gBRCAmut have a markedly increased risk of developing breast cancer. About 5% of 
patients with breast cancer have mutations in BRCA1 or BRCA2 (Ref. 15); thus , based on the 2012 
incidence of breast cancer in the US of 230,000, approximately 11,500 women develop breast cancer 


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annually in the US which harbor these mutations. Patients presenting with gBRCAmut breast cancer tend to 
be younger, and have larger tumor size and higher tumor grade at diagnosis and based on this, have a 
worse prognosis. There is anticipated to be a significant internationally prevalent burden of breast cancer 
bearing a specific biological pathway perturbation that may be targeted by a synthetic lethal strategy with 
PARP inhibition with expectation of improvement in therapeutic ratio with improved efficacy and greater 
tolerability. The investigation of effect in comparison to standard of care requires an international 
collaboration involving centers with significant prevalence of BRCA1 and BRCA2 carriers with breast 
cancer. 
Recent clinical studies have shown PARP inhibitors to be active in breast cancer. Clinical anticancer 
activity with PARP inhibitors has been seen in both patients with gBRCAmut and patients without 
gBRCAmut; however activity is more robust in patients with the germline mutation (Ref. 16, Ref. 17,  
Ref. 18, Ref. 19). 
Niraparib is a potent and selective PARP-1 and PARP-2 inhibitor that is at least 100-fold selective over 
other PARP-family members. To date, 12 breast cancer patients have been treated with niraparib in the 
Phase 1 Study PN001, 2 of whom had objective responses, both in patients with gBRCAmut (out of a total 
of 4 patients with known gBRCAmut). PARP inhibitors such as niraparib selectively kill tumor cells with 
gBRCA mutations and provide a novel approach to potentially improve the treatment of patients with 
advanced/metastatic gBRCAmut breast cancer (refer to investigator's brochure). 
Although the majority of BRCA1 mutant breast cancers are associated with the triple negative subtype, 25-
30% of BRCA1 mutant breast cancers are hormone-receptor positive. Furthermore, the majority of BRCA2 
mutant breast cancers are hormone-receptor positive (Ref. 20, Ref. 21). Given the data observed with 
olaparib, another PARP inhibitor, showing objective responses in patients with BRCA mutant/hormone 
receptor positive disease (Ref. 17), for this study, both hormone receptor positive and hormone receptor 
negative advanced/metastatic breast cancer patients with gBRCAmut will be enrolled. For patients with 
hormone-receptor positive disease, the disease must be hormone refractory (progression during at least one 
prior hormonal therapy) for which chemotherapy is indicated. 
It is known that PARP inhibitor responsiveness and platinum sensitivity correlate with the BRCAness 
phenotype in ovarian cancer (Ref. 22). This phenotype, which is similar to tumors with BRCA mutations, 
includes tumors with defects in the HR repair pathway caused by mutations in genes other than BRCA1 or 
BRCA2. Tumors with BRCAness phenotype are characterized by homologous recombination repair 
deficiency (HRD). Non clinical ex vivo and in vivo experiments suggest that PARP inhibitors are 
selectively cytotoxic for tumors with BRCAness. Furthermore, HRD correlates with platinum sensitivity 
and PARP inhibitor sensitivity (Ref. 23, Ref. 24). Clinical experience with olaparib in ovarian cancer also 
supports the correlation between platinum sensitivity and PARP inhibition responsiveness (Ref. 25). In the 
recent TNT study, advanced triple- negative breast cancer patients with germline BRCA mutations 
demonstrated significantly greater response and PFS when treated with carboplatin compared with 
docetaxel. Based on these data, the current study was amended to exclude advanced breast cancer patients 
with evidence of platinum resistance in the metastatic setting based on: 
♦ Progression during platinum therapy 
♦ Progression within 8 weeks from the end of platinum therapy (Ref. 26). 
 
 


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2 Objectives of the trial 
2.1 
Primary objective 
The primary objective of this study is to compare progression-free survival (PFS), as assessed by blinded 
central review, of patients with advanced/metastatic HER2-negative gBRCAmut breast cancer when treated 
with niraparib as compared to those treated with physician’s choice single agent chemotherapy standards 
(eribulin, vinorelbine, gemcitabine or capecitabine). 
2.2 
Secondary objectives 
2.2.1 
Key secondary objective 
To compare overall survival of patients with advanced/metastatic HER2-negative gBRCAmut breast cancer 
when treated with niraparib as compared to those treated with physician’s choice single agent 
chemotherapy standards (eribulin, vinorelbine, gemcitabine or capecitabine). 
2.2.2 
Other secondary objectives 
1. To establish germline BRCA mutation status of screened patients using a centrally provided, validated 
test as well as future tests, and determine concordance between tests for the purpose of developing a 
commercial companion diagnostic test 
2. To evaluate safety and tolerability as measured by all AEs. 
3. To compare PFS using investigator assessment of progression 
4. To evaluate time to treatment failure (discontinuation of treatment for any reason) 
5. To compare response rate and duration of response 
6. To compare time to deterioration of health-related quality of life (HRQoL): European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and EuroQol 5 
Dimension 5 Level (EQ-5D-5L) (Appendices D, F, I ) 
7. To describe subsequent therapies and potential relationships with outcomes 
8. To assess genetic and non-genetic biomarkers relating to treatment efficacy. Germline and tumor 
mutations may be explored including somatic BRCA1 and 2 mutations, reversion mutations, loss of 
heterozygosity as well as genome landscape and transcriptional or functional measures of homologous 
recombination (HR) deficiency. 
9. To assess outcomes by germline mutation BRCA1 vs BRCA2. 
10. Descriptive summary statistics will be used to summarize post- treatment data (i.e subsequent 
anticancer therapies and any new malignancy). 
3 Patient selection criteria 
Patient enrollment will follow a two-step procedure as illustrated in chapter 4 and chapter 15 (registration 
and randomization steps). Patients must meet all of the criteria described in section 3 to be eligible. 
 
 


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3.1 
Registration step 
All patients will be registered in the trial as soon as possible after written informed consent signature. After 
this point, material must be sent for central BRCA mutation analysis from all the patients irrespective of 
whether they had done it either locally or in Myriad. Material for companion diagnostic testing must be 
sent in as well. 
1. Histologically or cytologically confirmed HER2-negative breast carcinoma with previously detected 
gBRCAmut or patients that meet one of the criteria for further genetic assessment according NCCN 
guidelines (Appendix E).  
2. Female and male patients age at least 18 years.  
From registration to randomization a maximum of 90 days is permitted  
3.2 
Randomization step 
1. Patients with a deleterious or suspected deleterious germline BRCA1 or BRCA2 mutation may be 
enrolled into the study and randomized based on either local or central laboratory testing of BRCA status 
(Myriad Genetic Laboratories, Salt Lake City, UT, USA). On- study central confirmation of BRCA status 
will be performed for those patients who were enrolled based on either a previous Myriad test or a local 
test. If after inclusion, based on a local test result or a previously done Myriad test, a patient turns out not 
to have a germline BRCA mutation per central laboratory results (Myriad Genetic Laboratories, Salt Lake 
City, UT, USA) the patient can still continue on study based on his/her physician discretion and his/her 
own preference . 
2. Metastatic or locally advanced disease that is not amenable to resection or radiation with curative 
intent. 
3. Measurable disease by RECIST v1.1 or non-measurable disease that is clinically evaluable (except 
sclerotic-only bone disease; bone-only disease that has a lytic component is allowed); there must be 
evidence of disease progression within 3 months prior to enrollment without change of therapy.  
4. Patients must not have symptomatic uncontrolled brain metastases. To be considered controlled, 
central nervous system (CNS) disease must have undergone treatment (whole brain radiation, radiosurgery 
or equivalent) at least 1 month previously and the patient has no new or progressive signs or symptoms 
related to the CNS disease, and are off steroid therapy two weeks. A post-treatment brain CT/MRI 
obtained at least 7 days off of steroids that shows no evidence of progression is needed. 
5. Up to 2 prior cytotoxic regimens for advanced or metastatic breast cancer (not including adjuvant or 
neo-adjuvant therapy); patients with no prior cytotoxic regimens for advanced or metastatic disease will 
only be allowed if they relapsed during or within 12 months of (neo-) adjuvant cytotoxic therapy.  
6. Prior therapy should have included a taxane and/or anthracycline (unless contraindication to those) in 
the neoadjuvant, adjuvant, or advanced/metastatic setting. 
a. Hormone receptor positive patients must also have hormone resistant disease; either relapsed while 
on adjuvant endocrine treatment or within one year of completing adjuvant endocrine treatment, 
or progression on at least one line of endocrine treatment for advanced cancer. 
7. Patients must not have received anticancer chemotherapy, radiotherapy (including palliative 
radiotherapy), hormonal therapy, biological therapy, or any other investigational therapy within 3 weeks 
prior to the start of study treatment. Patients with persistent toxicity (except alopecia) > grade 1 from prior 
cancer therapy will also be excluded. Bisphosphonate and denosumab are allowed. 


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8. No prior treatment with a known or putative PARP inhibitor (except iniparib). No other anticancer 
agent (chemotherapy, hormonal therapy, or other agent) is to be permitted during the course of the study 
for any patient. 
9.  Patients who have previously received platinum chemotherapy in the metastatic setting are allowed to 
enroll in the study as long as they did not progress while on or within 8 weeks from the day of the last 
platinum administration. Patients who received platinum in the (neo-) adjuvant setting are eligible, as long 
as they relapsed 12 months or more after the last dose of platinum.  
10. ECOG performance status 0-2 (Appendix G) 
11. Adequate organ function (assessed within 72 hours prior to first dose): 
 
a. Absolute neutrophil count (ANC) ≥ 1,500 cells/μL 
 
b. Platelets ≥ 100,000 cells/μL 
 
c. Hemoglobin ≥ 9 g/dL 
 
d. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or ≥ 50 mL/min using Cockcroft-Gault 
equation  
 
e. Total bilirubin ≤ 1.5 × ULN  
 
f. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN or < 5 × ULN with 
liver metastases 
12. Patients able to swallow and retain oral tablets 
13. Female patients must not be pregnant or breast feeding 
 
a. Female patient of childbearing potential must have a negative serum pregnancy test (β-human 
chorionic gonadotropin [β-hCG]) within 72 hours prior to first dose). 
14. Patients of childbearing potential who are sexually active and their partners must agree to the use of a 
highly effective form of contraception throughout their participation during the study treatment and for 90 
days after last dose of study treatment(s). These are: 
♦ combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation:  
♦ oral route  
♦ intravaginal route  
♦ transdermal route  
♦ progestogen-only hormonal contraception associated with inhibition of ovulation  
♦ oral  
♦ injectable  
♦ implantable  
♦ intrauterine device (IUD)  
♦ intrauterine hormone-releasing system ( IUS)  
♦ bilateral tubal occlusion  
♦ Vasectomized partner  
♦ sexual abstinence, if the preferred and usual lifestyle of the subject 


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Note: For patients with ER and/or PR positive tumors avoidance of hormonal methods is highly 
recommended 
15. No known hypersensitivity to the components of niraparib or any of its analogs. 
16. No major surgery within 2 weeks prior to registration. Patients must have recovered from earlier major 
surgery before registration. 
17. No prior diagnosis of Stage IV ovarian cancer.  
Patients with history of Stage III ovarian cancer must have a 5-year disease-free interval  
Patients with Stage I or II ovarian cancer must have a disease-free interval of 2 years  
Patients with a prior history of ovarian cancer who have a peritoneal disease should have normal serum 
carcinoma antigen CA-125. 
For patients with a prior history of ovarian cancer who have peritoneal disease and elevated serum 
carcinoma antigen CA- 125, a biopsy of the peritoneal disease is required to prove the breast cancer origin 
of the metastasis. 
18. No prior diagnosis, detection, or treatment of invasive cancer other than breast cancer within 2 years 
(except basal or squamous cell carcinoma of the skin that has been definitively treated)  
19. Patients must not be considered a poor medical risk due to a serious, uncontrolled medical disorder, 
non-malignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, 
uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major 
seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric 
disorder that prohibits obtaining informed consent. 
20. Absence of any psychological, familial, sociological or geographical condition potential hampering 
compliance with the study protocol and follow- up schedule; those conditions should be discussed with the 
patient before registration in the trial. 
21. No immunocompromised patients (e.g., patients who are known to be serologically positive for human 
immunodeficiency virus [HIV]). 
22. No patients with known active Hepatitis B or C. 
23. Patients should acknowledge that they are at an increased risk of infection with conventional 
chemotherapy drugs and since the effects with niraparib are unknown they must accept that live virus and 
bacterial vaccines should not be administered to them for the duration of the study and for 3 months after 
last dose of study medication. 
24. If patients are blood donors, they should accept not to donate blood during the study and for 3 months 
after the last dose of study drug. 
25. Patients must have voluntarily agreed to participate by given informed consent. 
26. If all of the comparator treatments are contraindicated the patient will not be included in the trial. 
27. Patients must not have received a platelet transfusion within 4 weeks of the first dose of study 
treatment and must not have had any known, persistent (>4 weeks) ≥ grade 3 hematological toxicity or 
fatigue from last cancer therapy. 
28. Patients must not have any known history of myelodysplastic syndrome (MDS).  
29. Patients must agree to peripheral blood samples during screening and at the end of treatment for 
mutational profile testing (for mutations of selected myeloid associated genes) that will be performed only 
if the patient develops MDS or acute myeloid leukemia (AML) during the study or the post- treatment 
follow-up (a third sample will be collected in this case).  


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4 Trial design 
4.1 
Overall study design 
This study is a randomized, open-label, multicenter, controlled trial to compare niraparib versus 
physician’s choice, amongst one of the following four single agents: eribulin, vinorelbine, gemcitabine or 
capecitabine, in patients with HER2-negative gBRCAmut breast cancer. Patients will be centrally registered 
at the EORTC Headquarters prior to the start of treatment, and after verification of the eligibility criteria, 
eligible patients will be randomized 2:1 to receive niraparib orally at a dose of 300 mg QD on a continuous 
dosing regimen or physician’s choice amongst one of the following four single agents (eribulin, 
vinorelbine, gemcitabine or capecitabine) according to the national available and approved treatment 
(Gemcitabine will be administered as single agent as per NCCN guidelines. In France, gemcitabine is not 
allowed to be chosen as a treatment in the physician's choice arm.). 
A schematic of the study design is provided in the following scheme. Screening assessments to determine 
patient eligibility for the study and to assess baseline disease status will be conducted within 28 days prior 
to the first dose (cycle 1/day 1). Clinic visits will be conducted at the beginning of every cycle (i.e., every 
3 weeks ± 3 days). Contrast enhanced computed tomography (CT) or magnetic resonance imaging (MRI) 
if CT is not feasible will be required at screening and every 2 cycles (6 weeks ± 7 days) for the first 12 
months, then every 3 cycles (9 weeks ± 7 days) until disease progression. Patients will continue on their 
assigned treatment until disease progression (determined by Response Evaluation Criteria in Solid Tumors 
[RECIST] v.1.1), unacceptable toxicity, death, withdrawal of consent, or they are lost to follow-up (please 
refer to chapter 5.3 and 5.4).  
Evaluation of CT scans and MRI, including determination of response to treatment and date of progression 
based on RECIST v.1.1, will be conducted by a central blinded review committee comprised of 2 
radiologists, with an arbiter as necessary. Results of the central blinded assessment will be used to 
determine the primary efficacy endpoint of PFS and will be conducted retrospectively. The study 
investigators also will assess response to treatment and date of progression based on RECIST v.1.1 during 
the conduct of the study. 
Patient reported outcomes (PROs) will be evaluated at screening, during the treatment period and after 
treatment discontinuation for a maximum period of up to 12 months after randomization. All patients 
randomized to niraparib will also undergo sparse blood sampling (predose and 2 hours postdose except for 
C4D1 that will be done only predose) at specified study visits for measurement of plasma levels of 
niraparib and translational protocol specified analyses. 
Safety will be evaluated throughout the study by AE monitoring and clinical laboratory assessments, 
(hematology, chemistry), vital signs, electrocardiograms (ECGs), physical examinations, and use of 
concomitant medications. 
After treatment discontinuation, information on subsequent anticancer therapy and survival (including new 
malignancy information) will be collected. If the patient discontinues prior to disease progression, tumor 
imaging, and assessment of PROs, will continue during the post-treatment phase at specified time intervals 
until disease progression or until the patient starts his/her subsequent anticancer therapy. No crossover to 
niraparib is permitted following discontinuation from physician’s choice treatment.  


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Figure 1: 
Study schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Metastatic or 
locally advanced 
taxane and/or 
antrhracycline 
pretreated HER2 
negative breast 
cancer patients 
that fulfil the 
NCCN criteria 
for genetic 
assessment or 
have a positive 
test for g BRCA 
mutation (local or 
Myriad) 
R 
E 
G 
I 
S 
T 
R 
A 
T 
I 
O 
N 
Patients 
positive for 
gBRCAmut 
(Locally or 
centrally 
assessed) 
R
Arm A: 
Niraparib 300 mg QD 
until PD 
Arm B: 
Physician choice* 
(eribulin or vinorelbine 
or gemcitabine or 
capecitabine) until PD 
No cross over 
is allowed 
Central 
testing of 
germline 
BRCA 
gene 
mutations 
for all 
patients  
*The treatment choice 
should be made 
according to the 
national available and 
approved treatment. 
Gemcitabine will be 
administered as single 
agent per NCCN 
guidelines. 
Gemcitabine is not 
allowed in France 
90 days maximally 
Screening phase 
(-28 to day1) 
Randomization 
2:1 (A: B) 
Max 2 weeks for 
sending of material 
and test result 


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An independent data monitoring committee (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 participating patients in the study. The membership, key responsibilities of the IDMC, and the 
corresponding procedures will be defined in an IDMC charter. 
4.2 
Justification of study design and choice of endpoints 
The key design features of the study include randomization and the use of an active control. Random 
assignment of patients avoids bias and helps ensure that both known and unknown risk factors are 
distributed evenly between treatment groups. Randomization is being conducted on a 2:1 basis to expose 
more subjects to niraparib allowing for the evaluation of safety of the compound in approximately 200 
patients. Randomization is being stratified by factors known to be prognostic for response, including 
presence or absence of visceral disease, histologic subtype, and number of lines of prior therapy. 
Due to the nature of the treatment regimens, specifically daily oral administration of niraparib versus 
various oral or intravenous regimens employed for the physician’s choice treatment arm, blinding is not 
possible. The primary evaluation of efficacy will be conducted by a central blinded review. 
Niraparib is to be administered orally at a dose of 300 mg daily. This dose was chosen based on the 
efficacy, pharmacokinetic / pharmacodynamics, safety and tolerability profiles of niraparib in early clinical 
testing.  
The comparator agents used in the trial – eribulin, vinorelbine, gemcitabine, or capecitabine – are widely 
available and approved for use or commonly used as single agents in the treatment of metastatic breast 
cancer. Regimens for all 4 agents conform to the 21-day cycle regimen should be planned for this protocol 
(Notes: 1. Gemcitabine will be administered as single agent as per NCCN guidelines. In France 
gemcitabine is not allowed to be chosen as a treatment in the physician's choice arm 2. A 28- day cycle 
regimen may apply to the intravenous administration of physician's choice vinorelbine). 
The primary endpoint in this trial – PFS – is a standard measure to assess the efficacy of treatment in 
cancer trials that is not confounded by subsequent therapy (Guidance for Industry: Clinical Trial Endpoints 
for the approval of Cancer Drugs and Biologics). Evaluation of this endpoint, including the assessment of 
tumor burden, response to treatment, and progression are based on established criteria in patients with 
solid tumors, specifically RECIST. The assessments will be conducted by an independent review 
committee based on RECIST who will be blinded to study medication. This central review will provide for 
standardization in the assessment of radiographs across all patients in this multicenter, multinational trial 
by radiologists with expertise in the evaluation of patients with solid tumors, including breast cancer. 
The key secondary endpoint of the trial is overall survival, which is an accepted direct measure of benefit. 
The study design includes long-term follow-up to capture subsequent anticancer therapy – including 
response to that therapy, as well as survival. New malignancy information will also be collected as part of 
this assessment. 
The patient population for this study, specifically patients with histologically or cytologically confirmed 
HER2-negative gBRCAmut metastatic or locally advanced breast cancer who have received up to 2 prior 
cytotoxic regimens, have very limited treatment options. 


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5 Therapeutic regimens, expected toxicity, dose 
modifications 
5.1 
Drug information 
5.1.1 
General information 
Niraparib ([3S]-3-[4-(7-(aminocarbonyl)-2H-indazol-2-yl) phenyl] piperidine [tosylate monohydrate salt]) 
is an orally available, potent, highly selective PARP-1 and -2 inhibitor. The crystalline tosylate 
monohydrate salt of niraparib is being developed as a monotherapy agent for tumors with defects in the 
HR DNA repair pathway and as a sensitizing agent in combination with cytotoxic agents and radiotherapy. 
This salt form is non-hygroscopic and comprised of agglomerated bundles of rod-like or columnar primary 
particles. Niraparib has an aqueous solubility of 0.77 mg/mL. Its molecular formula is C26H30N4O5S and 
its molecular weight is 510.617 daltons. It is formulated as a dry blend of niraparib and lactose lubricated 
with magnesium stearate. The active potency is 100 mg in size 0 gelatin capsules. 
Physician’s choice study medication will be eribulin, vinorelbine, gemcitabine, or capecitabine. All 
compounds are currently approved for the treatment of patients with breast cancer. However the choice 
should be made according to the national available and approved treatment. 
Important note: Gemcitabine will be administered as single agent as per NCCN guidelines. In France, 
gemcitabine is not allowed to be chosen as a treatment in the physician's choice arm. 
Study Medication 
Dosage Form 
Route 
Niraparib 
Capsule, 100 mg strength 
Oral 
Physician’s choice:  
♦ i.v eribulin, 
♦ i.v or oral vinorelbine 
♦ i.v gemcitabine  
♦ oral capecitabine 
Various 
IV or oral 
5.1.2 
Drug supply 
Niraparib will be provided free of charge by Tesaro. Practicalities for drug supply and re-supply will be 
detailed in separate guidelines. 
5.1.3 
Packaging, dispensing and storage 
Niraparib 100 mg capsules will be packed in high-density polyethylene (HDPE) bottles with child-resistant 
closures. Each dosing container will contain sufficient capsules for one cycle of treatment plus overage. 
Niraparib will be dispensed to patients on day 1 of every cycle (21 days) thereafter until the patient 
completes the study, withdraws from the study, or closure of the study. 
All niraparib study medication must be stored in accordance with the manufacturer’s instructions. Until 
dispensed to the patients, niraparib study medication will be stored in a suitable container at storage 
conditions specified by the Sponsor in a securely locked area, accessible to authorized personnel only. The 
pharmacist will dispense study drug for each patient according to the protocol and pharmacy manual, if 
applicable.  


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Physician’s choice treatments will be obtained from commercial supplies. Physician's choice treatments 
will be administered (dose, route, regimen) according to their respective product package insert or local 
practice. Gemcitabine as single agent will be administered per NCCN guidelines. In France gemcitabine is 
not allowed to be chosen as a treatment in physician's choice arm. 
5.1.4 
Drug reconciliation procedures 
Accountability of the investigational study drugs is under the responsibility of the investigator and can be 
delegated to an appropriately qualified person. 
Study drug accountability should be maintained by each site based on capsules dispensed versus returned 
to the clinic at each visit and the number days since last visit.  
Accountability records should include receipt date, lot numbers, expiry dates, patient number, use by 
subject, dispensing dates, quantities (lowest unit) and stock balance. Product returned to the pharmacy or 
site will be stored under the same conditions as products not yet dispensed but will be marked as 'returned' 
and kept separate from the products not yet dispensed. 
In addition to internal accountability documentation on site, study-specific accountability and drug 
destruction forms will be supplied for this purpose by TESARO (via PAREXEL), if site-specific forms are 
deemed not sufficiently detailed or do not provide enough information, according to PAREXEL quality 
assurance criteria. 
The drug accountability and destruction forms will be verified during monitoring visits. The study monitor 
will reconcile the drug accountability log with products stored in the pharmacy. 
At the end of study, when all patients have stopped protocol treatment, complete drug reconciliation per 
batch should be available at the site for verification by PAREXEL in order to allow drug destruction or 
return procedure. All dispensing and accountability records will be available for Sponsor review. After 
receiving Sponsor approval in writing, the investigational site is responsible for destruction of study drug 
according to local regulations. If a site does not have the capability for on- site destruction, Sponsor will 
provide a return for destruction service to a third party. 
Both the unused and expired study medication must be destroyed, upon authorization of the sponsor, 
according to local regulations and procedures, and a copy of the destruction form must be returned to 
PAREXEL.  
The medication provided for this trial is to be used only as indicated in this protocol and only for the 
patients entered in this study. 
5.2 
Initial dose and schedule 
Niraparib 300 mg (3 x 100 mg niraparib capsules) will be administered orally QD continuously in an open-
label fashion. Based on the results from the food effect study (Sub study of a phase 3 randomized double-
blind trial of maintenance with niraparib versus placebo in patients with platinum Sensitive Ovarian 
Cancer), patients are not required to fast before and after each daily dose of niraparib (refer to updated 
investigator's brochure). Patients will be instructed to take their dose at the same time each day, preferably 
in the morning. Patients must swallow and not chew all capsules. The consumption of water is permissible. 
The first dose will be administered at the site as well as on day 1 of cycles 2 and 4 (PK sub-study). All 
dose interruptions and reductions (including any missed doses), and the reasons for the 
reductions/interruptions, are to be recorded in the electronic case report forms (eCRF). 
Once the dose of study medication has been reduced, any re-escalation is not allowed. 
Administration of the drugs on the arm of physician's choice and the medical supervision will be managed 
according to the guidance provided by the holder of the marketing authorization for the licensed 
compounds and according to the national available and approved treatment (Note: gemcitabine will be 


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administered as a single agent as per NCCN guidelines. In France gemcitabine is not allowed to be chosen 
as a treatment in the physician's choice arm). 
5.3 
Treatment duration 
Treatment should be administered until documented disease progression, unacceptable toxicity, or patient 
refusal. Patients will continue on study medication until disease progression and as long as, in the 
Investigator’s opinion, they are benefiting from treatment and do not meet any other treatment 
discontinuation criteria. 
5.4 
Withdrawal criteria 
Whatever the disease status, the treatment will always be discontinued in case of: 
♦ Unacceptable toxicity, as judged by the local investigator, despite appropriate dose reduction and / or 
toxicity management. See section 5.5 for guidance on dose reductions.  
♦ Disease progression according to RECIST v.1.1  
♦ Risk to patients as judged by the Investigator  
♦ Risk to patients as judged by the Sponsor 
♦ Severe non-compliance with the protocol as judged by the Investigator  
♦ Severe non-compliance with the protocol as judged by the Sponsor 
♦ Patient request 
♦ The patient becomes pregnant 
♦ Withdrawal of consent for any reasons 
♦ Physician’s recommendation 
♦ Occurrence of a second malignancy 
The reason for withdrawal from study treatment must be documented in the electronic case report forms. 
Patients who discontinue from treatment will continue to receive follow-up assessments (treatment 
outcome with next therapy and overall survival including new malignancy information) as part of the study 
unless they are discontinued from the study by one of the following events: 
♦ Withdrawal of consent by the patient, who is at any time free to discontinue their participation in the 
study, without prejudice to further treatment 
♦ Patient lost to follow-up 
♦ Death from any cause 
Patients discontinuing therapy in the absence of progression should not receive any other cancer treatment 
before their disease progresses, unless this is clearly not in the interest of the patient. 
After progression, the treatment will be left to the discretion of the treating physician.  
Any anti-cancer therapy other than the study drug given as single agent will not be considered as part of 
the protocol treatment. 
Patients may be discontinued from treatment or from the study at any time. Patients who discontinue from 
the study will not be replaced. 


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5.5 
Dose and schedule modifications 
A three week interval of dosing will be considered as a “treatment period “or cycle of therapy. All adverse 
events caused by the drugs in the physician's choice treatment arm will be managed according to the 
guidance provided by the holder of the marketing authorization for the licensed compounds.  
5.5.1 
Niraparib- related dose modification for toxicity (hematologic and 
non- hematologic) 
Dose interruption and/or reduction may be implemented at any time for any grade toxicity considered 
intolerable by the patient. In addition, the following are protocol defined criteria for dose modification. 
Treatment must be interrupted for any treatment- related non-hematologic Common Terminology Criteria 
for Adverse Events v 4.0 (CTCAE), (Appendix C) grade 3 or 4 AE or serious AE (SAE) which the 
Investigator considers to be related to administration of niraparib. If the toxicity is resolved to baseline or ≤ 
grade 1 for non-hematological toxicities or above the lower limits defined in table 2 for hematologic 
toxicities (Hgb ≤ 9 g/dl, PLTs ≤ 100,000/µl, Neut≤1,500/ µl) within 28 days, the patient may restart 
treatment with niraparib, but with a dose level reduction unless prophylaxis is considered feasible (table 1). 
If the toxicity requiring dose interruption has not resolved completely or to NCI- CTCAE grade ≤ 1 for 
non- hematological toxicities or above the lower limit as defined in table 2 for hematologic toxicities (Hgb 
≤ 9 gr/ dl, PLTs ≤100, 000 / µl, Neutr≤ 1,500/ µl), during a maximum of 4 week (28 days) dose 
interruption period, and/ or the patient has already undergone a maximum of 2 dose reductions (to a 
minimum dose of 100 mg QD), the patient must permanently discontinue treatment with niraparib. At the 
investigator's discretion, following dose interruption (no longer than 28 days), patients may be considered 
for dose reductions, providing they have not already undergone the maximum number of 2 dose reductions 
allowed(no more than 2 dose reductions will be permitted). If upon re- challenging with the study 
treatment at the lowest allowable dose , any CTCAE Grade 3 or 4 adverse events (AEs) requiring dose 
interruption recur, the patient must be discontinued. Once niraparib dose has been reduced for a patient, all 
subsequent cycles must be administered at that dose, unless further dose reduction is required. For major 
surgery, up to 28 days of drug interruption is allowed. 
In case of dose interruptions, the next cycle will follow patient's original calendar schedule. Cycle 
timing will not be delayed for treatment interruptions and tumor assessment should occur according 
to this schedule regardless of whether study treatment is interrupted. Additional laboratory work- 
up prior to next treatment initiation should also be performed at the physician's discretion. Missed 
doses of niraparib (i.e. any dose that is not administered within the protocol defined administration 
window) will not be taken at a later date. 
 
 


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Table 1 
Niraparib dose reductions for non-hematologic toxicities 
Event 
Dose1 
Initial dose 
300 mg QD 
1st dose reduction for treatment-related CTCAE Grade 3 or 4 AE or 
SAE where prophylaxis is not considered feasible  
200 mg QD 
2nd dose reduction for treatment-related CTCAE Grade 3 or 4 AE or 
SAE where prophylaxis is not considered feasible  
100 mg QD 
Continued treatment-related CTCAE Grade 3 or 4 AE or SAE ≥ 28 
days  
Discontinue study medication 
1 
Dose not to be decreased below 100 mg daily 
Management of hematologic toxicities is described in Tables 2. For grade 3 or 4 neutropenia, 
thrombocytopenia, or anemia, treatment with niraparib must be interrupted with weekly blood counts 
monitored until recovery to ≤ grade 1. Niraparib should be resumed with a dose level reduction at that 
time. Cytokines (granulocyte colony stimulating factor [GCSF] may be administered as clinically indicated 
to manage febrile neutropenia according to local standard of care. Secondary prophylaxis should not be 
used for the niraparib arm but is allowed for the physician's choice arm.  
Thrombocytopenia is an expected event associated with the use of niraparib and is described in Version 1 
of the Investigator’s Brochure. Thrombocytopenia associated with the use of niraparib resolved upon 
treatment interruption and/or dose reduction. The occurrence of thrombocytopenia during cycle 1 requires 
additional patient monitoring in order to identify hematologic changes early and prevent higher grade 
thrombocytopenic events. A weekly monitoring of the complete blood count (CBC) during the first month 
is considered mandatory.  
If a patient completes the first cycle with no incidence of hematologic toxicity requiring dose interruption 
or modification, then CBC monitoring will proceed according to protocol every 3 weeks, thereafter. If dose 
interruption or modification is required at any point on study, weekly CBC will be required for another 4 
weeks after the adverse event has been resolved, to ensure safety of the new dose, after which monitoring 
every 3 weeks may resume.  
Any patient requiring transfusion of platelets or red blood cells (on two different occasions) or 
hematopoietic growth factor support must undergo a niraparib dose reduction upon recovery if study 
treatment is resumed. 
It is strongly recommended to refer the patient to the hematologist for further evaluation (1) if transfusions 
are required on more than two occasions in the absence of non- treatment related causes or (2) if the 
treatment- related hematologic toxicities have not recovered to allow retreatment with niraparib after 4 
weeks. If a diagnosis of MDS/AML is confirmed by a hematologist, the patient must permanently 
discontinue study treatment. 
 
 


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Table 2 Management of hematologic toxicities 
Platelet count 75,000-99,999 µL/ 
Study medications must be interrupted until platelet 
counts are equal to or greater than 100,000/µL with 
weekly blood counts for CBC monitored until 
recovery. Study medication may then be resumed at 
same dose or reduced dose based on clinical 
judgment 
Further occurrence of platelet count 75,000-99,999 
µL 
Study medications must be interrupted until platelet 
counts are equal to or greater than 100,000/µL with 
weekly blood counts for CBC monitored until 
recovery. Study medication may then be resumed at 
the same dose or reduced dose based on clinical 
judgment. Dose reduction should be made in case 
that new treatment interruption is needed in less 
than 3 weeks after resume of treatment. 
Platelet count <75,000* µL 
Study medications must be interrupted until platelet 
counts are equal to or greater than 100,000/ µL with 
weekly blood counts for CBC monitored until 
recovery. Study medication may then be resumed at 
the reduced dose. 
Neutrophil < 1,000/µL 
Study medications must be interrupted until 
neutrophil counts are equal to or greater than 
1,500/µL with weekly blood counts for CBC 
monitored until recovery. Study medication may 
then be resumed at the reduced dose. 
Hemoglobin < 8g/dL 
Study medications must be interrupted until Hb is 
equal to or greater than 9 g/dL with weekly blood 
counts for CBC monitored until recovery. Study 
medication may then be resumed at the reduced 
dose 
 
Note: If the hematologic toxicity has not recovered to the specified levels within 4 weeks of dose 
interruption and/or the patient has already undergone a maximum of 2 dose reductions then, the patient 
should be discontinued from study therapy. Specifically for thrombocytopenia, patients with a platelet 
count < 100,000/ µL (as AE of thrombocytopenia) must have the study medication interrupted and have 
weekly blood counts monitored until recovery ≥ 100,000 / µL. If the thrombocytopenia has not reverted to 
platelet count of ≥ 100,000 / µL within 4 weeks (28 days), the patient should be discontinued. 
*For patients with platelet count ≤ 10,000/µL prophylactic platelet transfusion per guidelines may be 
considered (Ref. 27, Ref. 28). Any patient requiring transfusion of platelets or red blood cells (on two 
different occasions) or hematopoietic growth factor support must undergo a niraparib dose reduction upon 
recovery if study treatment is resumed. The patient must be referred to a hematologist for further 
evaluation (1) if transfusions are required in more than 2 occasions in the absence of non- treatment related 
causes or (2) if the treatment- related hematologic toxicities have not recovered to allow re- treatment with 
niraparib after 4 weeks. For patients taking anticoagulation or antiplatelet drugs, consider the risk/benefit 
of interrupting these drugs and/or prophylactic transfusion at an alternate threshold, such as ≤ 20,000/µL. 


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5.5.2 
Physician’s choice dose modification 
Dose modifications for physician’s choice drugs will be according to the respective product package insert 
or local practice. Treatment interruptions longer than 28 days are not allowed. 
In case of dose interruptions, tumor assessment should occur according to the patient's original 
calendar schedule regardless of whether study treatment is interrupted. Additional laboratory work- 
up prior to next treatment initiation should also be performed at the physician's discretion.  
Important Note: Any patient requiring transfusion of platelets or red blood cells (on two different 
occasions) or hematopoietic growth factor support must undergo a study drug (physician's choice) dose 
reduction upon recovery if study treatment is resumed. 
It is strongly recommended to refer the patient to the hematologist for further evaluation (1) if transfusions 
are required in more than two occasions in the absence of non- treatment related causes or (2) if the 
treatment- related hematologic toxicities have not recovered to allow re- treatment with the study drug 
(physician's choice) after 4 weeks. If a diagnosis of MDS/AML is confirmed by a hematologist, the patient 
must permanently discontinue study treatment. 
5.6 
Concomitant treatments 
5.6.1 
Supportive care in case of toxicity 
Primary cytokine prophylaxis is not allowed. For patients on Physician's choice chemotherapy, secondary 
prophylactic treatment with cytokine (granulocyte colony- stimulating factor [GCSF] may be administered 
as clinically indicated according to local standard of care. For patients on niraparib GCSF prophylaxis is 
not considered appropriate and is not allowed. For patients on either niraparib or physician's choice 
chemotherapy GCSF may be administered as clinically indicated for the treatment of febrile neutropenia 
according to the local standard of care. Patients requiring hematopoietic growth factor support must 
undergo a niraparib dose reduction upon recovery if treatment is resumed. 
5.6.2 
Other concomitant therapies 
At screening, patients will be asked what medications they have taken during the last 30 days. At each 
subsequent study visit, patients will be asked what concomitant medications they are currently taking. 
Any medication the patient takes other than the study medication, including herbal and other alternative/ 
complementary remedies are considered concomitant medication. All concomitant medications must be 
recorded in the eCRF; information to be recorded for each concomitant medication includes generic name, 
route of administration, start date, stop date, dosage, and indication. Any changes in the dosage or regimen 
of a concomitant medication must be recorded in the eCRFs. 
Niraparib has potential to induce cytochrome P1A2 (CYP1A2) and its substrates. Therefore, caution 
should be used when drugs metabolized by CYP1A2 are administered concomitantly (Appendix H). 
Niraparib is a substrate for P-glycoprotein (P-gp); therefore, use caution with drugs that are inhibitors or 
substrates of P-gp (Appendix J). 
The niraparib safety profile includes risk for thrombocytopenia; therefore, patients should be advised to 
use caution with anticoagulation and antiplatelet drugs. 
For physician’s choice treatment, the product package insert will guide the use of concomitant 
medications.  


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6 Clinical evaluation, laboratory tests and follow-up 
6.1 
Before Treatment 
6.1.1 
Registration 
Registration must be done directly after specific for registration informed consent signature by the patient.  
Blood sample for centralized gBRCA mutation testing (can be done at any time prior to randomization). 
Patients that already have a positive test for g BRCA mutation previously done by Myriad or local 
laboratory at any time can proceed to the screening phase before the central result is available; however a 
new blood sample has to be drawn in the frame of this study. 
Additional blood sample to evaluate the concordance of a candidate companion diagnostic test with the 
centralized gBRCA mutation test with respect to identifying gBRCA mutated patients. 
The period between registration and randomization is defined for up to 90 days. In case that a patient is not 
randomized in this timeframe, randomization can be done at a period exceeding this time frame, after 
screening is repeated (The patient will be re- registered and a new Seq ID will be assigned). 
6.1.2 
Screening (day -28 to day 1) 
♦ At screening, the following procedures/tests will be performed: 
♦ Written main informed consent 
♦ Demographics (age, height, weight, race, ethnicity, sex) 
♦ Medical (including details of any prior invasive malignancy), surgical, medication history and breast 
cancer disease history which will include: Date of first diagnosis, tumor type, stage at time of initial 
diagnosis, histology and grade of disease at diagnosis and most recent biopsy if additional biopsy 
performed, date of start of first treatment, agents in first treatment, date of last dose of first treatment, 
dates of start of all subsequent treatments, agents in all subsequent treatments, dates of last dose of all 
subsequent treatments, best response for each prior treatment and date of recurrence for each treatment. 
♦ Formalin fixed paraffin embedded archival tumor sample(s) (primary or metastatic site) tumor block 
(preferred) or 20 slides of 5 micron thickness (they can be collected/sent during screening or after 
randomization [during Cycle 1]). 
♦ Optional tumor biopsy (FFPE and snap frozen cores) – a fresh tumor biopsy may be obtained using 
separate informed consent. 
♦ Sample collection (whole blood) for mutational profile testing (for mutations of selected myeloid 
associated genes) #.  
♦ Blood samples for plasma biomarker analysis and humoral immune response monitoring 
♦ Serum pregnancy test – required being negative within 72 hours prior to first dose of study drug for 
females of childbearing potential. 
♦ Physical examination 
♦ Vital signs (blood pressure, pulse, temperature) 
♦ ECOG performance status (Appendix G) 
♦ SAE monitoring from registration 
♦ Assessment of all adverse events according to CTCAE v4.0 


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♦ Collection of prior history (up to 1 year prior to enrollment) of myelosuppression (i.e. anemia, 
neutropenia, thrombocytopenia or leukopenia) 
♦ Cancer signs and symptoms 
♦ Concomitant medications 
♦ Hematology* (within 72 hours prior to first dose) (will include hemoglobin, platelets, mean 
corpuscular volume, white blood cells, differential white cell count, activated partial thromboplastin 
time and international normalized ratio) 
♦ Chemistry (within 72 hours prior to first dose) (will include sodium, potassium, calcium, magnesium, 
chloride, glucose, creatinine, total bilirubin, gamma glutamyltransferase, alkaline phosphatase, 
aspartate transaminase, alanine transaminase, urea or blood urea nitrogen, total protein, albumin, lactic 
dehydrogenase, and amylase) 
♦ For patients with peritoneal disease and a prior ovarian cancer: Serum CA-125 
♦ In case CA-125 is elevated: biopsy of the peritoneal disease  
♦ Urinalysis (within 72 hours prior to first dose): Specific gravity, leukocyte esterase, nitrite, blood, 
protein, glucose, ketones, urobilinogen, bilirubin. 
♦ 12-lead ECG  
♦ RECIST tumor assessment (chest, abdomen and pelvis CT or MRI scans)  
♦ HRQoL: QLQ-C30 and EQ-5D-5L to be completed within 4 weeks prior to randomization (chapter 10) 
♦ Randomization (within 72 hours prior to first dose). Note that physician’s choice treatment must be 
designated prior to randomization 
Tumor assessments (chest, abdomen and pelvis CT or MRI scans) that were done as part of standard of 
care due to progression of disease prior to receiving Myriad test results, do not need to be repeated but 
can be used for screening, provided that they were performed within 28- day screening timeframe. 
♦ Samples for mutational profile testing (mutations of selected myeloid associated genes) will be stored 
but they will be analyzed if necessary for assessing niraparib related risk for MDS/ AML development 
(e.g the patient develops MDS/ AMS during treatment or post- treatment follow-up). 
♦ Activated partial thromboplastin time (a PTT) and international normalized ratio (INR) will be done 
only at screening. 
6.2 
During treatment 
Visits should occur within ± 3 days of the scheduled visit, unless otherwise specified as outlined in Table 
6.3). All times should be recorded using the 24 hour clock (e.g., 23:20, not 11:20 PM).  
For a highly clinically suspected MDS/AML case reported while a patient is receiving treatment with the 
study drug, the patient should be referred to the local hematologist to confirm the diagnosis of MDS/AML. 
Testing with bone marrow aspirate and biopsy is strongly recommended in these cases. The study site must 
receive a copy of the hematologist's report of aspirate-biopsy findings which must include a classification 
according to World Health Organization (WHO) (Ref. 40). A whole blood sample will be also collected 
for mutational profile testing (mutations of selected myeloid- associated genes) for any highly clinically 
suspected MDS/AML case reported while a patient is receiving treatment. 


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6.2.1 
Cycle 1, day 1 
♦ On the day of the first dose of study medication, the following procedures will be performed (predose, 
unless otherwise specified): 
♦ Physical examination* 
♦ Vital signs (blood pressure, pulse, temperature, and weight) 
♦ ECOG performance status (Appendix G)* 
♦ Concomitant medications* 
♦ Hematology/chemistry*. The same tests as in screening phase will be performed (except activated 
partial thromboplastin time [a PTT] and international normalized ratio [INR]). 
♦ Niraparib arm only: 12-lead ECG predose and 2 hours postdose; the ECGs should be performed prior 
to blood draws for PK assessment. 
♦ Niraparib arm only: Blood samples for determination of niraparib levels predose (within 30 minutes) 
and 2 hours postdose. 
♦ First dose to be administered at the site 
*It does not need to be repeated if it was assessed at screening and within 72 hours of the cycle 1/day 1 
dose. Hematology tests (only CBCs esp. for platelet counts) need to be done weekly for the 1 month of 
treatment for patients receiving treatment in both arms. That means for the first cycle at D1#, D8# and 
D15# (Blood draw for CBC will also need to be done in D1 and D8 of the second cycle). Thereafter it is left 
at the discretion of the treating physician if he/she prefers to repeat hematology evaluation more often 
than what is described in the current protocol. The test can be performed at the most convenient 
laboratory (in accordance with local regulations) or the study site for the patient and the site must be 
informed of the result and keep a copy of it in the file of the patient. This data will be captured in the 
database. 
# It is strongly advised that these dates are followed.  
6.2.2 
Cycle 2, day 1 
♦ On cycle 2/day 1, the following procedures will be performed (predose, unless otherwise specified): 
♦ Physical examination 
♦ Vital signs (blood pressure, pulse, temperature, and weight) 
♦ ECOG performance status (Appendix G) 
♦ Assessment of all adverse events according CTCAE v 4.0 that have occurred since the previous visit  
♦ Concomitant medications 
♦ Hematology/chemistry (same tests as in screening phase except activated partial thromboplastin time [a 
PTT] and international normalized ratio [INR])*. 
♦ Niraparib arm only: 12-lead ECG, conducted predose and 2 hours postdose; the ECGs should be 
performed prior to blood draws for PK assessment. 
♦ Niraparib arm only: Plasma samples for determination of niraparib levels predose (within 30 minutes) 
and 2 hours postdose. 
* A blood draw only for CBC needs to be repeated at D8 of the second cycle to complete the first month of 
mandatory weekly hematological evaluation.  


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6.2.3 
Day 1, subsequent cycles 
♦ Cycle 3/day 1 only: blood samples for plasma biomarker analysis and humoral immune response 
monitoring 
♦ On day 1 of each subsequent cycle, the following procedures will be performed (predose, unless 
otherwise specified): 
♦ Physical examination 
♦ Vital signs (blood pressure, pulse, temperature, and weight) 
♦ ECOG performance status (Appendix G) 
♦ Assessment of all adverse events according CTCAE v 4.0 that have occurred since the previous visit 
♦ Concomitant medications 
♦ Hematology /chemistry (same tests as in screening phase except activated partial thromboplastin time 
[a PTT] and international normalized ratio [INR]). 
♦ 12-lead ECG to be conducted as clinically indicated 
♦ Cycle 4/Day 1 only: plasma samples for determination of niraparib levels predose (within 30 minutes). 
♦ RECIST tumor assessment (chest, abdomen, pelvis CTs or MRIs and CT or MRI scans of known sites 
of disease) conducted every 2 cycles (every 6 weeks ± 7 days) for the first 12 months and then every 3 
cycles (9 weeks ± 7 days) until disease progression  
♦ HRQoL: QLQ-C30 and EQ-5D-5L completed every 2 cycles (every 6 weeks ± 7 days) during the first 
12 months after randomization (chapter 10). 
Pregnancy testing will occur per site specific processes: please refer to the niraparib Investigator's 
Brochure for guidance.  
If patient is seen by local hematologists at any time during the conduct of the study, results of any 
additional tests performed to evaluate the bone marrow capacity should be reported accordingly in the e- 
CRF.  
6.2.4 
Study medication termination visit (within 28 days following the start 
of the last cycle) 
The following procedures should be conducted within 28 days following the start of the last cycle: 
♦ Physical examination 
♦ Vital signs (blood pressure, pulse, temperature, and weight) 
♦ ECOG performance status (Appendix G) 
♦ Assessment of all adverse events according CTCAE v 4.0 that have occurred since the previous visit  
♦ Concomitant medications 
♦ Hematology/ chemistry (same tests as in screening phase except activated partial thromboplastin time 
[a PTT] and international normalized ratio [INR]). 
♦ 12-lead ECG 
♦ Optional tumor biopsy (FFPE and snap frozen cores) at the point of treatment discontinuation for 
progression – a fresh tumor biopsy may be obtained using separate informed consent. 


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♦ Sample collection (whole blood) for mutational profile testing (mutations of selected myeloid- 
associated genes). These samples will be stored and analyzed if necessary for assessing niraparib 
related risk for MDS/AML development (for e.g the patient develops MDS/AML during treatment or 
post- treatment follow-up). 
♦ Blood samples for plasma biomarker analysis and humoral immune response monitoring (at 
termination due to progression or due to any other cause) 
♦ RECIST tumor assessment (chest, abdomen, pelvis CT or MRI and CT or MRI scans of known sites of 
disease, CT or MRI scans of known sites of disease) will continue on the study-specified schedule until 
disease progression or until the patient starts his/her subsequent anti- cancer therapy for patients 
terminating study for reasons other than PD. 
♦ Collect any unused study medication. 
If patient is seen by a local hematologist, results of any additional tests performed to evaluate the bone 
marrow capacity should be reported in the e- CRF [e.g bone marrow aspirate/ biopsy findings which 
must include a classification according to World Health Organization (WHO) (Ref. 40)].  
6.2.5 
Follow-up Visit 
All patients will be followed through 30 days post-treatment for assessment of adverse events. 
6.2.6 
For those patients who discontinue treatment in the absence of 
progression 
Patients who discontinue treatment without disease progression will undergo tumor assessments per the 
planned schedule: every 6 weeks ± 7 days during the first 12 months after randomization, and then every 9 
weeks ± 7 days until disease progression or until the start of subsequent anti-cancer therapy). New 
malignancy information will also be collected as part of this assessment. HRQoL (QLQ-C30 and EQ-5D-
5L) will be collected every 3 months during the first 12 months after randomization (chapter 10). 
6.2.7 
After progression, survival follow-up visits 
Once patients discontinue from study medication they will enter the survival follow-up phase for 
assessment of subsequent anticancer therapies and overall survival. Assessments will occur every 3 months 
(± 7 days). HRQoL (QLQ-C30 and EQ-5D-5L) will be collected every 3 months during the first 12 months 
after randomization (chapter 10). New malignancy information will also be collected as part of this 
assessment. For subsequent anticancer therapies, the following information will be collected: name and/or 
class, start date, dose- limiting toxicities, best response (CR, PR, SD, PD) and progression date. For a 
highly clinically suspected MDS/AML case reported while a patient is followed for post- treatment 
assessments, the patient should be referred to the local hematologist to confirm the diagnosis of 
MDS/AML. Testing with bone marrow aspirate and biopsy is strongly recommended in these cases. The 
study site must receive a copy of the hematologist's report of aspirate/ biopsy findings which must include 
a classification according to World Health Organization (WHO) (Ref. 40). A whole blood sample will be 
also collected for mutational profile testing (mutations of selected myeloid- associated genes) for any 
highly clinically suspected MDS/AML case reported during survival follow-up visits.


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6.3 
Summary table 
Cycle1 
Registration 
Screen 
C1 
C2 
Subse-
quent 
cycles2 
Study Medication 
Termination 
(to occur within 
28 days of start of 
Last cycle) 
Post- treatment follow-up 
30-Day 
Follow-
up 
Every 6 weeks 
± 7 days for 
the first 12 
months and 
then every 9 
weeks ± 7 
days until PD 
or subsequent 
treatment  
Follow-up  
every 3 months 
Day 
At any time 
prior to 
screening 
-28 to 
day 1 
D1 
D8 
D15 
D1 
D8 
Cycle n,  
Day 1 
 
 
 
 
Informed Consents 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical, surgical, 
cancer, medication 
history 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
gBRCA mutation 
analysis3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
companion 
diagnostic test4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Archival tumor 
samples5 
 
X 
X 
 
 
 
 
 
 
 
 
 
Optional tumor 
biopsy6 
 
X 
 
 
 
 
 
 
X6 
 
X6 
 
Pregnancy test7 
 
X7 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X8 
 
 
 
 
 
 
 
 
 
 


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Cycle1 
Registration 
Screen 
C1 
C2 
Subse-
quent 
cycles2 
Study Medication 
Termination 
(to occur within 
28 days of start of 
Last cycle) 
Post- treatment follow-up 
30-Day 
Follow-
up 
Every 6 weeks 
± 7 days for 
the first 12 
months and 
then every 9 
weeks ± 7 
days until PD 
or subsequent 
treatment  
Follow-up  
every 3 months 
Day 
At any time 
prior to 
screening 
-28 to 
day 1 
D1 
D8 
D15 
D1 
D8 
Cycle n,  
Day 1 
 
 
 
 
Physical 
examination 
 
X 
X 
 
 
X 
 
X 
X 
 
 
 
Vital signs, 
height9, weight 
 
X 
X 
 
 
X 
 
X 
X 
 
 
 
ECOG 
performance status 
 
X 
X 
 
 
X 
 
X 
X 
 
 
 
Adverse event 
monitoring 
X23 
X 
X 
 
 
X 
 
X 
X 
X 
 
 
Collection of prior 
history of 
myelosuppression 
(i.e. anemia, 
neutropenia, 
leukopenia and 
thrombocytopenia) 
 
X 
 
 
 
 
 
 
 
 
 
 
Serious adverse 
event monitoring 
X23 
 
X 
X 
 
 
X 
 
X 
X 
X 
 
 
Concomitant 
medications 
 
X 
X 
 
 
X 
 
X 
X 
 
 
 
Hematology (CBC 
only) 
 
X 
X10 
X 
X 
X 
X 
X 
X 
 
 
 


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Cycle1 
Registration 
Screen 
C1 
C2 
Subse-
quent 
cycles2 
Study Medication 
Termination 
(to occur within 
28 days of start of 
Last cycle) 
Post- treatment follow-up 
30-Day 
Follow-
up 
Every 6 weeks 
± 7 days for 
the first 12 
months and 
then every 9 
weeks ± 7 
days until PD 
or subsequent 
treatment  
Follow-up  
every 3 months 
Day 
At any time 
prior to 
screening 
-28 to 
day 1 
D1 
D8 
D15 
D1 
D8 
Cycle n,  
Day 1 
 
 
 
 
INR/aPTT 
 
X10 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry 
 
X 
X10 
 
 
X 
 
X 
X 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
 
X 
X11 
 
 
X11 
 
X12 
X 
 
 
 
Blood sample for 
biomarkers13 
 
X 
 
 
 
 
 
X13 
X 
 
 
 
Blood sample for 
pharmacokinetic 
analysis 
 
 
X14 
 
 
X14 
 
X15 
 
 
 
 
Tumor Assessment 
(RECIST v1.1) 
Chest, abdomen, 
pelvis CTs or 
MRIs.16 
 
X 
 
 
 
 
 
X16 
X16 
 
X16 
X16 
CA-125 
measurement in 
case of peritoneal 
disease and 
previously 
diagnosed ovarian 
cancer 
 
X 
 
 
 
 
 
 
 
 
 
 


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Cycle1 
Registration 
Screen 
C1 
C2 
Subse-
quent 
cycles2 
Study Medication 
Termination 
(to occur within 
28 days of start of 
Last cycle) 
Post- treatment follow-up 
30-Day 
Follow-
up 
Every 6 weeks 
± 7 days for 
the first 12 
months and 
then every 9 
weeks ± 7 
days until PD 
or subsequent 
treatment  
Follow-up  
every 3 months 
Day 
At any time 
prior to 
screening 
-28 to 
day 1 
D1 
D8 
D15 
D1 
D8 
Cycle n,  
Day 1 
 
 
 
 
HRQoL17 
 
X 
 
 
 
 
 
X17 
 
X17 
X17 
Niraparib capsules 
dispensed/collected 
or Physician’s 
choice treatment19 
 
 
X 
 
 
X 
 
X 
X19 
 
 
 
Sample collection 
(whole blood) for 
mutational profile 
testing20 
 
X20 
 
 
 
 
 
 
X20 
 
 
 
Additional tests to 
confirm the 
diagnosis of 
MDS/AML21 
 
 
 
 
 
 
 
 
X21 
 
 
 X21 
Anti-cancer 
therapies 
assessment 
 
 
 
 
 
 
 
 
 
 
 
X22 
Survival 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
X22 
 
 
 


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1 
Treatment cycles are 21 days (3 weeks) long, visits on Day 1 of each cycle, unless otherwise specified (A 28-day cycle regimen may apply to the intravenous administration of 
physician's choice vinorelbine) 
2 
Visits continue every 3 weeks until study medication termination visit. 
3 
Centralized germline BRCA mutation (gBRCAmut) testing of DNA. Patient blood sample may be drawn and performed at any time prior to randomization. Enrollment will be based 
on either central or local positive for germline BRCA mutation result.  
4 
A second blood sample will be archived for test bridging. 
5 
Formalin-fixed, paraffin-embedded tumor samples (primary or metastatic site; tumor blocks or 20 slides of 5 micron thickness). Genetic and non-genetic markers relating to DNA 
repair will be tested (alternatively can be done after randomization or during cycle 1). 
6 
A fresh tumor biopsy (FFPE and snap frozen cores) may be performed at screening and one time at progression using separate informed consent. Genetic and non-genetic markers 
relating to DNA repair and/or markers that predict efficacy and safety of PARP inhibitors will be tested. 
7 
Negative serum pregnancy test required within 72 hours prior to the first dose of study medication for females of childbearing potential. Pregnancy test will occur per site 
processes; please refer to the niraparib Investigator's Brochure for guidance.  
8 
Randomization should occur within 72 hours prior to first dose (Cycle 1, Day 1). Note that physician’s choice treatment must be designated prior to randomization. 
9 
Height obtained at screening only. 
10 If screening laboratory testing [hematology (CBC plus INR and aPTT), chemistry] was performed within 72 hours of Cycle 1, Day 1, repeat testing not required. Please note that 
during the first month of study treatment, it is mandatory to perform weekly blood draws for CBC for both treatment arms. INR and a PTT will be done only at screening. 
Also in case of a dose modification due to hematologic toxicity , weekly blood draws for CBC will be required for an additional 4 weeks after the adverse event has been resolved to 
baseline or grade 1, after which monitoring every 3 weeks may resume. 
11 For the niraparib arm only :12-lead ECG conducted, Cycle 1, Day 1 (predose and 2 hours post dose), Cycle 2, Day 1 (predose and 2 hours postdose), and cycle 1 and Cycle 2 Day 1 
assessments should be conducted prior to blood draws for PK assessments. 
12 12-lead ECG as clinically indicated in subsequent cycles. 
13 Blood samples will be taken at screening, at 6 weeks (Cycle 3/Day1) and at treatment termination (due to progression or due to any other cause). Analysis of circulating genetic and 
non-genetic markers relating to DNA repair and/or markers that predict efficacy and safety of PARP inhibitors will be tested. 
14 Blood samples for measurement of plasma levels of niraparib collected on Cycle 1, Day 1 and Cycle 2, Day 1 predose (within 30 minutes) and 2 hours post dose. 
15 Additional blood samples for plasma levels of niraparib collected on Cycle 4, Day 1 predose (within 30 minutes). 
16 Chest, abdomen and pelvis CT or MRI as well as CTs or MRIs scans of any other known sites of the disease are required at screening; thereafter every 6 weeks ±7 days (i.e. every 2 
cycles) for the first 12 months, then every 9 weeks ±7 days (i.e. every 3 cycles)until disease progression. Tumor assessments must continue on schedule if patients have dose delays. 
If the patient discontinues prior to disease progression, tumor imaging will continue at specified time intervals ( every 6 weeks ± 7 days during the first 12 months after randomization, 
and then every 9 weeks ± 7 days weeks) until progression or until the start of subsequent anti-cancer therapy.  
Patients without measurable disease at baseline are not excluded from this study. These patients should be followed with the same assessment schedule as those with measurable disease 
at baseline and throughout the study. 


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17 Questionnaires include EORTC QLQ-C30 and EQ-5D-5L (Appendix F and Appendix I). The time schedule is detailed in 10.4.1. The questionnaires must be filled within 4 weeks 
before randomization and subsequent questionnaires are filled in every 2 cycles (i.e., every 6 weeks ±7 days) for the first 12 months while on-treatment and every 3 months after study 
medication discontinuation. HRQoL forms will be collected regardless of progression status and will be limited to the first 12 months after randomization. 
18 Physician’s choice chemotherapy (eribulin, vinorelbine, gemcitabine, or capecitabine) to be administered according to product package insert or local standard of care. Gemcitabine 
will be administered as single agent as per NCCN guidelines. In France gemcitabine is not allowed to be chosen as a treatment in the physician's choice arm. 
19 No new study medication dispensed. 
20 Blood samples collected at screening and EOT (due to any cause including development of new MDS/AML)will be stored for evaluation if necessary for assessing niraparib- 
related risk for MDS/AML development (e.g if the patient develops MDS/AML during treatment or post- treatment follow- up). Mutation profile before and after study treatment will 
be compared to determine whether any mutations were present prior to study treatment. Additional details on sample collection and analysis can be found in Section 12.3.5. 
21 For a highly clinically suspected MDS/AML case reported while a patient is receiving treatment with the study drug or being followed for post- treatment assessments; the patient 
should be referred to the local hematologist to confirm the diagnosis of MDS/AML. Results of any additional tests performed by the hematologist should be reported as well in the e- 
CRF. Testing with bone marrow aspirate and biopsy is strongly recommended in these cases. The study site must receive a copy of the hematologist's report of aspirate/ biopsy findings 
which must include a classification according to World Health Organization (WHO) (Ref. 40). A whole blood sample will be also collected for mutational profile testing for any highly 
clinically suspected MDS/AML case reported during treatment. 
22 Assessments to occur every 3 months following study medication discontinuation. . In addition to survival, this assessment includes outcomes for subsequent anticancer therapies 
including any new malignancy information. 
23 From registration. Registration must be done directly after informed consent signature by the patient


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7 Criteria of evaluation 
7.1 
Evaluation of efficacy 
Objective tumor response and progression free survival will be measured according to the RECIST criteria 
(version 1.1) (Ref. 30).  
Response criteria are essentially based on a set of measurable lesions identified at baseline as target 
lesions, and – together with other lesions that are denoted as non-target lesions – followed until disease 
progression.  
The following paragraphs are a quick reference to the RECIST criteria (version 1.1). The complete criteria 
are included in the published RECIST document (Ref. 30) also available at http://www.eortc.be/RECIST).  
7.1.1 
Measurability of tumor lesions at baseline 
7.1.1.1 
Definitions 
♦ Measurable disease - the presence of at least one measurable lesion. If the measurable disease is 
restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
♦ Measurable lesions - tumor lesions that can be accurately measured in at least one dimension (longest 
diameter to be recorded as ≥ 10 mm with CT scan or clinical examination [using calipers]. Bone 
lesions are considered measurable only if assessed by CT scan and have an identifiable soft tissue 
component that meets these requirements (soft tissue component > 10 mm by CT scan). Malignant 
lymph nodes must be ≥ 15 mm in the short axis to be considered measurable; only the short axis will be 
measured and followed. All tumor measurements must be recorded in millimeters (or decimal fractions 
of centimeters) by use of a ruler or calipers. Tumor lesions situated in a previously irradiated area, or in 
an area subjected to other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  
♦ Non-measurable lesions - All other lesions (or sites of disease), including small lesions are considered 
non-measurable disease. Bone lesions without a measurable soft tissue component, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, lymphangitic involvement of lung or skin and abdominal masses followed by clinical 
examination are all non-measurable. Nodes that have a short axis <10 mm at baseline are considered 
non-pathological and should not be recorded or followed.  
♦ Target Lesions. When more than one measurable tumor lesion or malignant lymph node is present at 
baseline all lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) 
representative of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. Note that pathological nodes must meet the 
criterion of a short axis of ≥ 15 mm by CT scan and only the short axis of these nodes will contribute to 
the baseline sum. At baseline, the sum of the target lesions (longest diameter of tumor lesions plus 
short axis of lymph nodes: overall maximum of 5) is to be calculated and recorded. 


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♦ Non-target Lesions. All non-measurable lesions (or sites of disease) including pathological nodes 
(those with short axis ≥ 10 mm but < 15 mm), plus any measurable lesions over and above those listed 
as target lesions are considered non-target lesions. Measurements are not required but these lesions 
should be noted at baseline and should be followed as “present” or “absent”. 
All baseline evaluations should be performed as closely as possible to the beginning of treatment and never 
more than 4 weeks before the beginning of the treatment. 
7.1.1.2 
Methods of measurements 
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up. Assessments should be identified on a calendar schedule 
and should not be affected by delays in therapy, which may be treatment arm dependent. While on study, 
all target lesions recorded at baseline should have their actual measurements recorded on the CRF at each 
subsequent evaluation, even when very small (e.g. 2 mm). If it is the opinion of the radiologist that the 
lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned. For 
lesions which fragment/split add together the longest diameters of the fragmented portions; for lesions 
which coalesce, measure the maximal longest diameter for the “merged lesion”. 
♦ Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial and ≥ 
10 mm as assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by 
color photography including a ruler to estimate the size of the lesion is recommended. If feasible, 
imaging is preferred. 
♦ Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. CT, MRI. CT 
is the best currently available and reproducible method to measure lesions selected for response 
assessment. This guideline has defined measurability of lesions on CT scan based on the assumption 
that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in 
certain situations (e.g. for body scans). While PET scans are not considered adequate to measure 
lesions, PET-CT scans may be used providing that the measures are obtained from the CT scan and the 
CT scan is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast). 
♦ Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT should be obtained. 
♦ Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
♦ Tumor Markers. Tumor markers alone cannot be used to assess objective tumor response. If markers 
are initially above the upper normal limit, however, they must normalize for a patient to be considered 
in complete response. 


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♦ Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare cases if 
required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). When effusions are known to be a potential adverse effect 
of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the 
measurable tumor has met criteria for response or stable disease is advised to differentiate between 
response or stable disease and progressive disease. 
7.1.2 
Tumor response evaluation 
All patients will have their BEST RESPONSE from the start of study treatment until the end of treatment 
classified as outlined below: 
Complete Response (CR): disappearance of all target and non-target lesions and normalization of tumor 
markers. Pathological lymph nodes must have short axis measures < 10 mm (Note: continue to record the 
measurement even if < 10 mm and considered CR). Tumor markers must have normalized. Residual 
lesions (other than nodes < 10 mm) thought to be non-malignant should be further investigated before CR 
can be accepted.  
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for tumor lesions 
and short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Non 
target lesions must be non-PD.  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD 
taking as reference the smallest sum of diameters on study. 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions taking as 
references the smallest sum of diameters recorded on study (including baseline) AND an absolute increase 
of ≥ 5 mm. Appearance of new lesions will also constitute PD (including lesions in previously unassessed 
areas). In exceptional circumstances, unequivocal progression of non-target disease may be accepted as 
evidence of disease progression, where the overall tumor burden has increased sufficiently to merit 
discontinuation of treatment, for example where the tumor burden appears to have increased by at least 
73% in volume (which is the increase in volume when all dimensions of a single lesion increase by 20%). 
Modest increases in the size of one or more non-target lesions are NOT considered unequivocal 
progression. If the evidence of PD is equivocal (target or non-target), treatment may continue until the next 
assessment, but on further documentation, the earlier date must be used. 


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Table 5: Integration of target, non-target and new lesions into response assessment: 
Target Lesions Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
category also requires 
Patients with Target lesions ± non target lesions 
CR 
CR 
No 
CR 
Normalization of tumor 
markers, tumor nodes < 10 
mm 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all 
evaluated 
No 
PR 
SD 
Non-PD/ not all 
evaluated 
No 
SD 
Documented at least once ≥ 4 
wks. from baseline  
Not all 
evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Any  
PD 
 
Any 
PD 
Any 
PD 
 
Any 
Any 
Yes 
PD 
 
Patients with Non target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of tumor 
markers, all tumor nodes < 
10 mm 
No Target 
Non-CR/non-PD 
No 
Non-CR/ 
non-PD 
 
No Target 
Not all evaluated 
No 
NE 
 
No Target 
Unequivocal PD 
Any 
PD 
 
No Target 
Any 
Yes 
PD 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression [or evidence of unequivocal disease 
progression] at that time should be reported as “symptomatic deterioration”. This is a reason for 
stopping therapy, but is NOT objective PD. Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
In this trial where response is not the primary endpoint, complete or partial responses do not need 
confirmation to lead to best response.  


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7.1.2.1 
Frequency of tumor re-evaluation 
Subsequent tumor assessments of known sites of disease via CT or MRI scan will be required at the end of 
every 2 cycles (every 6 weeks ± 7 days) for the first 12 months and then every 3 cycles (9 weeks ± 7 days) 
until disease progression. In case of dose interruptions, the next cycle will follow patient's original 
calendar schedule. Cycle timing will not be delayed for treatment interruptions and tumor assessment 
should occur according to this schedule regardless of whether study treatment is interrupted. If the patient 
discontinues prior to disease radiological progression, tumor imaging will continue at the specified time 
intervals until progression or until the start of subsequent anti-cancer therapy. Disease progression 
assessments outside of the stated windows will not be disregarded for the purpose of establishing 
progression status. 
Patients without measurable disease at baseline are not excluded from this study. These patients should be 
followed with the same assessment schedule as those with measurable disease at baseline and throughout 
the study. Patients without measurable disease will be assessed for progression according to RECIST 
criteria based on non-target and/or new lesions. 
Radiological examinations performed in the conduct of this study will be submitted for blinded centralized 
review. The central review committee, who will determine response to treatment and date of progression 
of disease, will be comprised of 2 radiologists and an arbiter, if necessary. A separate charter and imaging 
manual will be provided that details the central blinded review and the procedures for submitting images to 
the central laboratory. Investigators will also assess response and date of progression. The date of 
progression as assessed by central review will be used for determination of PFS in the primary efficacy 
analysis; Investigator assessment for PFS is a secondary endpoint in this trial. 
The central review process is described in the independent review charter. 
7.1.2.2 
Date of progression 
This is defined as the first day when the RECIST (version 1.1) criteria for PD are met. Refer to section 7.1 
for further information on what constitutes early progression, assessment of progression of non-
target disease and new lesions.  
Further criteria to evaluate disease progression will be stated in the radiology charter. 
7.1.3 
Reporting of tumor response 
All patients must be assessed for response to treatment, even if there is a major protocol treatment 
deviation or if they are ineligible, or not followed/re-evaluated. Each patient will be assigned one of the 
following categories: complete response, partial response, stable disease, progressive disease, early death 
or not evaluable. 
Early death will be defined as death occurring within 90 days from randomization. Patients who die on 
treatment (= up to 30 days post treatment) will be reported in separate detail for safety.  
Patients’ response will be classified as "not evaluable" if insufficient data were collected to allow 
evaluation per these criteria. 
Refer to the table 5 in section 7.1. 
 
 


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7.1.4 
Response duration 
Response duration will be measured from the time measurement criteria for CR/PR (whichever is first 
recorded) are first met until the first date that recurrent or progressive disease is objectively documented. 
Patients without subsequent recurrence/progression will be censored at the same time as for the PFS 
endpoint. 
7.1.5 
Time to treatment failure 
Time to treatment failure is defined from the date of randomization to progression or discontinuation of 
treatment for any reason, including but not restricted to disease progression, treatment toxicity, and death. 
If progressive disease occurred earlier than treatment discontinuation, the date of progressive disease will 
be the date of treatment failure. At the time of analysis, patients who are continuing to receive 
treatment will be censored on the date of last contact. 
7.1.6 
Progression Free Survival (PFS) 
Primary endpoint: PFS per central review. 
Progression Free Survival (PFS) is calculated as the time from randomization to either the date of disease 
progression or the date of death. The date of first documented disease progression (as per central review) 
will be used as the date of event. Patients who die without prior documented disease progression will have 
a date of event on their death date. For the primary analysis, PFS will be censored according to FDA 
guidance on Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, appendix table A. 
The application of the guidance will be further detailed in the study Statistical Analysis Plan. 
Secondary endpoint: PFS per investigator. 
The definition is the same as for PFS per central review, using investigator reported PD dates instead of 
centrally reviewed PD dates. 
7.1.7 
Overall Survival (OS) 
Overall Survival (OS) is calculated as the time from randomization to the date of death (any cause). 
Patients still alive at the time of analysis are censored at the last time they are known to be alive. Early 
death will be defined as death occurring within 90 days from randomization. Patients who die on treatment 
(= up to 30 days post treatment) will be reported in separate detail for safety. 
7.2 
Evaluation of safety 
7.2.1 
Adverse events 
All AEs, including intercurrent illnesses, occurring from registration ICF signature until 30 days after last 
dose administration (or up to initiation of new anticancer therapy, whichever is earlier) will be documented 
in the eCRF. All adverse events must be followed until resolution or stabilization. Serious adverse events 
will be collected from registration till 30 days after last dose administration (or up to initiation of new 
anticancer therapy, whichever is earlier). Thereafter, only SAEs that are considered to be at least likely 
related to the protocol treatment will be collected. Survival follow-up visits will take place every three 
months following study medication discontinuation. New malignancy information will also be collected as 
part of this assessment.  
Deaths occurring 30 days beyond last dose administration will not be collected unless considered related to 
study treatment. Concomitant illnesses, which existed before entry into the study, will not be considered 
AEs unless they worsen during the treatment period. Pre-existing conditions will be recorded in the eCRF 
on the Medical History or appropriate page.  


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All AEs, regardless of the source of identification (e.g., physical examination, laboratory assessment, 
ECG, reported by patient), must be documented and recorded; the investigator will assess whether those 
events are drug related and this assessment will be recorded in the database for all adverse events.  
The AE should be recorded individually in patient's own words (verbatim) unless, in the opinion of the 
investigator, the AE constitute components of a recognized condition, disease, or syndrome. In the latter 
case, the condition, disease, or syndrome should be named rather than each individual symptom. All AEs 
will be coded using the CTCAE and recoded by the Sponsor in the Medical Dictionary for Regulatory 
Activities (MedDRA). The collection period of these AEs will start from registration. 
All adverse events must be followed until resolution or stabilization. 
7.2.2 
General evaluation of adverse events 
This study will use the International Common Terminology Criteria for Adverse Events (CTCAE) 
(Appendix C), version 4.0, for adverse event reporting. A copy of the CTCAE can be accessed from the 
EORTC home page www.eortc.org\investigators-area\ctc. 
The highest CTCAE grading per cycle and per patient will be computed at the EORTC HQ for analysis.  
Planned safety analysis and tabulations are described in the statistics section. 
The event of disease progression is an efficacy criterion and is therefore not considered an AE. If 
AEs/SAEs occur in relation to disease progression, the AEs/SAEs must be reported per AE/SAE reporting 
requirements described in Section 7.2.1 and Section 7.2.3. 
7.2.3 
Serious adverse events 
Serious adverse events are defined by the Good Clinical Practice Guideline. 
Serious adverse events should be immediately reported according to the procedure detailed in this 
PROTOCOL (see chapter on Reporting Serious Adverse Events) 
7.2.4 
Toxic deaths 
Toxic death is defined as death due to toxicity (defined as adverse events that are not confirmed as 
unrelated). The cause of death must be reported as "toxicity". The evaluation of toxic deaths is independent 
of the evaluation of response (patients can die from toxicity after a complete assessment of the response to 
therapy). 
7.2.5 
Evaluability for safety 
All patients who have started the treatment will be included in overall safety analyses. 
For hematological events, the medical review team may decide that blood counts have not been performed 
and/or reported according to the protocol and are therefore inadequate for the evaluation of one/several 
hematological parameters in some patients. 
Patients who have discontinued treatment because of toxicity will always be included in the safety 
analyses. 
 
 


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8 Statistical considerations 
The statistical analysis described below will be further detailed in a dedicated Statistical Analysis Plan 
(SAP). This plan will also further specify calculation of endpoints (as described in Chapter 7). 
A change to the data analysis methods described in the protocol will require a protocol amendment only if 
it alters a principal feature of the protocol (i.e. definition or analysis of primary or key secondary 
endpoint). Any changes to the methods described in the plan will be described and justified in the final 
clinical study report. 
8.1 
Statistical design 
8.1.1 
Sample size 
At least 306 gBRCAmut patients, confirmed by the centralized test, will need to be randomized as described 
in Section 12.1. 
The primary analysis population for efficacy (incl. primary PFS and OS analyses) constitutes all 
randomized patients who have a germline BRCA mutation per central laboratory results (Myriad USA) 
The overall sample size for this study is based on the overall survival endpoint and is determined based on 
the assumption that niraparib will result in an improvement of 4 months in median overall survival from 9 
to 13 months (corresponding to a hazard ratio= 0.69). For a true hazard ratio of 0.69, 265 deaths will 
provide 80% power at a 1-sided alpha of 0.025. Assuming 10 patients eligible for the primary analysis 
population for efficacy are enrolled per month, with 306 such patients, 265 deaths are expected to occur 
approximately 54 months after the first patient enrolled. At the time of the final analysis of PFS (primary 
endpoint) an interim analysis will be performed on OS, using an O'Brien-Fleming alpha spending function 
(see 8.3). 
Assuming 40% of patients will be randomized on the basis of a local BRCA test and assuming that 15% of 
those patients will be BRCA negative by the central test, it is estimated that we will need to randomize a 
total of 324 patients in order to obtain the required 306 patients in the analysis population. If the average 
enrollment rate is greater than 11 patients per month during the second year of enrollment, the sample size 
to achieve the required 265 events may be increased to up to 350 gBRCAmut patients in the primary 
analysis population for efficacy.  
PFS analysis in the original design of the BRAVO study was planned when 232 PFS events occur. 
Assuming the median PFS time is 3 months for physician choice and 6 months for niraparib 
(corresponding to a hazard ratio=0.50), with 232 PFS events, there would be 99.6% power (1-sided 
alpha=0.025) to detect a difference from 3 to 6 months in median PFS. Assuming a true PFS treatment 
hazard ratio of 0.64 (median PFS time of 3 months for physician's choice and 4.68 months for niraparib), 
the study would have approximately 80% power to detect a difference (1-sided alpha=0.025). 
The clinical relevance of the maximum significant HR of 0.759 that could be detected by 232 events was 
re-evaluated in the current treatment landscape. The assumptions needed to be revised in a way that the 
statistically significant HR observed in the study is also clinically relevant. Thus, PFS analysis is 
redesigned to give 80% power to detect an HR 0.6 (equivalent to 3 to 5 months) with a one-sided alpha of 
0.025, which will require approximately 137 PFS events to perform the final analysis.  
All patients should be recruited before the final PFS analysis is conducted, and therefore the final PFS 
analysis is to be conducted at approximately 137 events or end of recruitment, whichever occurs later. 
Patients should be continued to be followed until death even after the final analysis of PFS to assess long-
term effects of niraparib. 


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A gate-keeping strategy (i.e. sequential testing procedure) will be used to test PFS and OS. OS will be 
tested at a 1-sided alpha of 0.025 only if the final test on PFS is significant at a 1-sided alpha of 0.025. 
This is motivated by the fact that OS is defined as a key secondary endpoint and such approach allows 
control of the overall Type I error rate. Note that, as a result of the gatekeeping strategy, the power of the 
overall analysis of the trial, i.e to detect a HR = 0.6 for PFS and a HR = 0.69 for OS, will be lower than 
80%.  
One futility interim analysis on the primary endpoint of PFS is planned. This futility analysis will be 
performed after approximately 93 (68%) of the minimum required total number of PFS events have been 
recorded. A gamma family beta spending function with a non-binding gamma (γ = -5) stopping boundary 
will be used for the futility analysis. 
Overall survival (accounting for interim analysis performed at the time of final PFS analysis) and PFS 
(including futility analysis) sample size calculations were performed using PROC SEQDESIGN in SAS 
and confirmed with East software. 
8.1.2 
Randomization and stratifications 
Patients will be centrally randomized (for practical details, see chapter on registration / randomization 
procedure) in a 2:1 ratio (treatment: physician choice). Permuted block randomization will be used for 
random treatment allocation stratifying by visceral disease (yes vs no), histology (TNBC vs ER/PR 
positive) and number of lines of prior cytotoxic chemotherapy (not including hormonal therapy) for 
advanced/metastatic disease (0-1 or 2). 
8.2 
Statistical analysis plan 
8.2.1 
Primary and secondary endpoints 
Primary endpoint: progression-free survival (PFS) per central review. Refer to Chapter 7 for definition. 
Secondary endpoints:  
♦ Overall survival (key secondary efficacy endpoint). 
♦ Determine concordance between gBRCAmut tests for the purpose of developing a commercial 
companion diagnostic test.  
♦ Safety and tolerability, as documented by AEs and laboratory values 
♦ PFS using investigator assessment of progression 
♦ Time to treatment failure  
♦ Response rate and duration of response  
♦ Health-related quality of life: QLQ-C30 and EQ-5D-5L (see chapter 10). 
♦ Subsequent therapies and potential relationships with outcomes 
♦ To assess outcomes by germline mutation BRCA1 vs BRCA2 
 
 


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8.2.2 
Analysis populations 
♦ Intention-to-treat population: All randomized patients with centrally confirmed gBRCAmut will be 
analyzed in the arm they were allocated by randomization. 
♦ Per protocol population (PP): All patients with centrally confirmed gBRCAmut , who are eligible, have 
started their allocated treatment (at least one dose of the study drug(s) in chemotherapy trials) and who 
do not have protocol deviations that are believed a-priori to significantly impact the interpretation of 
efficacy results. The PP population will be further described in the SAP. 
♦ Safety population: All patients who have started their allocated treatment (at least one dose of the study 
medication received) 
A patient will be considered to be eligible if he/she did not have any deviation from the patient entry 
criteria listed in chapter 3 of the protocol. Potential eligibility problems will be assessed by the Clinical 
Research Physician at time of medical review. 
The ITT population is the primary analysis population for all efficacy analyses. For this analysis, patients 
will be analyzed as randomized. 
Efficacy will also be analyzed using the PP population.  
The safety population will be the primary analysis population for the safety analyses. Patients will be 
analyzed as treated, not necessarily by allocated treatment. 
8.2.3 
Statistical methods 
Descriptive statistics will be used to summarize demographics and baseline characteristics. 
Medical history, medications used prior to treatment and concomitant medications will be summarized by 
treatment group. 
Analyses of efficacy endpoints are described below. Further details will be provided in the SAP including 
any sensitivity analyses that may be performed. Primary efficacy analyses will be performed comparing 
the niraparib arm against the pooled physician’s choice arm. Descriptive statistics will also be presented 
for the individual single-agent therapies (eribulin, vinorelbine, gemcitabine or capecitabine) comprising 
the physician choice arm. 
Unless otherwise stated, statistical tests will be performed at the 1-sided 0.025 significance level. For 
estimation purposes, 2-sided 95% confidence intervals will be provided in final analyses. 
The primary PFS analysis will be performed using a stratified log-rank test for the difference in the 
distribution of PFS between the niraparib group and the control group (one-sided α-level of 0.025). 
Randomization factors will be used as the strata in the stratified log-rank test. The following hypothesis 
will be tested:  
H0: PFS(t)physician choice = PFS(t)niraparib 
Ha: PFS(t)physician choice < PFS(t)niraparib 
where PFS(t) represents the progression-free survivorship function at any time t. 
Kaplan-Meier estimates for median PFS and OS with the corresponding 2-sided (1-alpha) % confidence 
intervals will be presented. A non-stratified log-rank test will also be performed to assess the robustness of 
the primary result. The standard error of the Kaplan-Meier estimates will be computed using the 
Greenwood formula. Medians - if reached - will be presented with a 2-sided (1-alpha) % confidence 
interval based on the non-parametric method (Ref. 29). 
In addition, Cox proportional hazards model with a term for treatment group will be used to estimate the 
treatment hazard ratio and its 2-sided (1- alpha) % confidence interval. The settings (covariates, levels of 


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covariates, and method of covariate selection) of this Cox model will be further described in the dedicated 
SAP. 
8.2.3.1 
Key Secondary Endpoint Analyses – Overall Survival 
The primary analysis of overall survival will be performed using a stratified log-rank test, stratifying for 
the factors used for randomization. Kaplan-Meier estimates for median overall survival with the 
corresponding 95% confidence intervals will be presented. A non-stratified log-rank test will also be 
performed to assess the robustness of the primary result.  
In addition, Cox proportional hazards model with a term for treatment group will be used to estimate the 
treatment hazard ratio and its 2-sided 95% confidence interval.  
8.2.3.2 
Secondary Endpoints Analyses 
If it is determined that analytic validation alone is not sufficient for bridging between the central and 
proposed companion diagnostic test (i.e., in the example where the proposed companion diagnostic test is 
not the companion diagnostic test version of the centralized test), the following analyses will be 
performed. Concordance of the candidate companion diagnostic test with the centralized gBRCA mutation 
test with respect to identifying gBRCAmut patients will be evaluated using archived study samples. The 
sensitivity and specificity of the test compared to the centralized test with respect to gBRCA status will be 
determined along with the corresponding 2-sided 95% confidence interval. 
The best response (CR, PR, SD or PD) for each patient will be summarized by treatment arm. The overall 
response rate (ORR = CR+PR) will be summarized by treatment arm along with the corresponding exact 
2-sided 95% confidence interval. A chi-square test will be used to compare ORR between the treatment 
arms. Duration of response will be summarized for the subgroup of patients that obtained objective 
response (CR or PR) using the Kaplan-Meier method and be displayed graphically where appropriate. The 
median duration and 2-sided 95% confidence interval for the median will be provided for each treatment 
arm. 
Analyses of investigator-assessed PFS and time to treatment failure will be performed using the primary 
analysis methodology described above. Censoring rules will be further described in the SAP. 
The QLQ-C30 and the EQ-5D-5L will be utilized in this study. The analyses of these endpoints are 
detailed in chapter 10. 
Clinical laboratory parameters, vital signs, and ECGs will be summarized by treatment group and by study 
visits. Descriptive summary statistics in observed values as well as changes from baseline will be 
presented. In addition, thresholds of marked abnormalities will be predefined for specific safety 
parameters. Incidence of marked abnormalities and shift tables will be presented. 
8.2.4 
Pre-planned sensitivity or exploratory analyses 
Supportive analyses including additional sensitivity analyses of the primary endpoint (PFS) will be 
performed, the details of which will be provided in the SAP. 
Subgroups will also be explored for the primary efficacy endpoint based on: age, race, geographic region, 
ECOG performance status, visceral disease, histology, number of lines of prior cytotoxic chemotherapy 
(not including hormonal therapy) for advanced/metastatic disease, prior platinum treatment and germline 
mutation (BRCA1 vs BRCA2). 
 
 


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8.2.5 
Prognostic factor analyses 
Cox models will be constructed for PFS and OS, using a backward stepwise method, with a two-sided 0.10 
cutoff for selection, and forcing treatment arm to stay in the model. 
Evaluation of the prognostic value of biomarkers will initially be performed using univariate Cox 
proportional hazards and Kaplan-Meier analyses, followed by multivariate Cox proportional hazard 
models. Additional exploratory analyses may be performed. 
8.2.6 
Post-treatment analyses 
Descriptive summary statistics will be used to summarize post- treatment data (i.e subsequent anticancer 
therapies and any new malignancy). 
8.2.7 
Data recoding and display 
Frequency tables will be tabulated (by treatment group or otherwise) for all categorical variables by the 
levels of the variables as they appear on the CRF (with %). Categories with a text field specification will 
be tabulated as categories and then supplemented by a listing with the following information for the 
patients fulfilling the condition for the specification (patient id, institution, treatment group, value of the 
item and text field contents). 
Dates relating to events prior to entry will be presented as the delay in days (or weeks, months, or years) 
between the past event and the date of entry (date of randomization – date of past event + 1) and presented 
using the median and range. For example, on the randomization checklist, the date of last administration of 
prior treatment (or the date of first diagnosis of the cancer) will be presented as the time elapsed (in days, 
weeks, months or years, as appropriate) since the day of the last administration and the date of entry on 
study (date of randomization – last administration/diagnosis +1). 
Other delays (eg. re-treatment delays) are presented as continuous variables using the median and range. 
Continuous variables for which a coding system exists (such as for laboratory data) will be recoded into 
categories (for adverse events, the grading scale specified in the protocol will be used). Whenever no 
specific scale exists, lab data will be categorized based on the normal range: for example, below the lower 
normal limit (when appropriate), within the normal range, above the upper normal limit (ULN) and the 
degree to which it is above the ULN (for example > 2.5 x ULN, > 5 x ULN, > 10 x ULN). For laboratory 
data, the nadir is generally displayed. The nadir in a given cycle is the lowest laboratory value in that 
cycle; the overall nadir for a patient is the lowest laboratory value among all cycles. 
Other continuous variables (for example age, dose …) will be presented using the median and range 
(minimum, maximum).  
Dose intensity calculations will be performed according to specification in the dedicated SAP. 
If appropriate, continuous data may also be presented in categories (for example, age may also be grouped 
in decades) 
8.3 
Interim analysis 
As outlined in Section 8.1.1, one interim futility analysis is planned for the PFS endpoint. The purpose of 
this interim analysis is to allow early stopping of the study for futility based on PFS data and to assess the 
safety of the niraparib regimen. The interim analysis is planned after 93 PFS events (68%) have been 
documented. It is anticipated that at this time, approximately 164 patients will have been randomized.  
A gamma family beta-spending function with a non-binding gamma (γ=-5) stopping boundary based on 
the actual number of PFS events at the time of interim analysis data cutoff will be used for the interim 
futility analysis of PFS. Non-binding for futility implies that the futility boundary is constructed in such a 


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way that it can be overruled without inflating the Type I error. There is no intention of stopping early for 
efficacy at these interim analyses therefore no alpha spending is incorporated. 
An interim analysis of overall survival is planned at the time of the final PFS analysis. The interim analysis 
will utilize O’Brien-Fleming type boundaries derived from the Lan DeMets alpha spending function based 
on the actual number of deaths observed at the time of the interim analysis. 
8.4 
End of study 
End of study occurs when all of the following criteria have been satisfied: 
1. Thirty days after all patients have stopped protocol treatment 
2. The trial is mature for the analysis of overall survival as defined in the protocol 
3. The database has been fully cleaned and frozen for this analysis 
9 Data Monitoring 
Safety data are reviewed within the EORTC Headquarters on a regular basis as part of the Medical Review 
process. Problems which are identified will be discussed with the Study Coordinators and the Sponsor who 
will take appropriate measures. Safety information will also be included in trial status reports which serve 
as a basis of discussion during Group meetings. These reports will be made available to investigators 
participating in the study. 
An independent data monitoring committee (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 participating patients in the study. The IDMC will be comprised of at least 3 independent 
individuals, including one biostatistician and 2 physicians. The IDMC is tasked with making a 
recommendation to the Sponsor based on their assessment of efficacy and safety information to continue 
or stop the trial. A futility analysis is planned after 93 PFS events (see Section 8.3). If the results cross the 
prespecified futility boundary, the IDMC may recommend stopping the study. The membership, key 
responsibilities of the IDMC, and the corresponding procedures will be defined in an IDMC charter. 
The Independent Data Monitoring Committee (IDMC) will review all safety problems identified by the 
EORTC Headquarters for which an advice is sought. In principle, no access to outcome data is necessary 
for safety reviews. However, the IDMC will also provide recommendations as an initial step in phase III 
trials to advise if a full review of all study data and endpoints is needed. 
No efficacy results will be presented at EORTC/BIG Group meetings or elsewhere before the trial is 
closed to recruitment and the data are mature for the analysis of the primary endpoint, unless 
recommended otherwise by the IDMC. 
10 Quality of life assessment 
10.1 Rationale 
Health related quality of life (HRQoL) is a multidimensional construct, which can be defined as a state of 
general well-being reflecting physical, psychological, and social well-being and the impact of the disease 
and/or treatment related symptoms on daily-life functioning. The patient’s subjective perspective is an 
inherent component of HRQoL and is therefore best assessed via self-administration. 
Reducing mortality and morbidity is still the most important factor in cancer clinical research. 
Nevertheless, issues such as reducing side effects, symptom relief and improving patients’ satisfaction 
have also become relevant parameters in the evaluation of medical strategies. Cancer treatments may 


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produce adverse effects and diminish a patient’s quality of life even when survival is extended. Progress in 
the acceptance of new cancer therapies is sometimes critically dependent on their HRQoL consequences. 
Given the poor overall prognosis of the study population, improvement of the well-being during the 
remaining (progression-free) survival is an important factor for the patient. 
10.2 Objective 
In the present study, HRQoL is a secondary endpoint. The hypothesis is that Niraparib will result in 
improved progression-free survival and overall survival compared to the standard arm which may result in 
a beneficial effect on HRQoL. 
It is expected that deterioration in HRQoL (both symptoms and functioning) is inevitable in almost all 
patients eventually due to the metastatic disease. The primary working hypothesis is that Niraparib will 
cause a later occurrence of the deterioration. Therefore the endpoint will be to compare the time to HRQoL 
deterioration between the both arms. 
The specific HRQoL domains of interest for HRQoL deterioration are: 
♦ Specific symptoms: fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation 
and diarrhea. 
♦ Specific functionality: physical functioning, role functioning, social functioning and emotional 
functioning. 
♦ General health. 
Time to HRQoL deterioration defined in section 10.5 will be compared between the two treatment arms. 
Secondary HRQoL hypotheses of interest are: 
♦ Niraparib will lead to less severe side effects. 
♦ Niraparib will lead to less patients experiencing a clinical relevant HRQoL deterioration. 
10.3 HRQoL instrument 
HRQoL will be assessed with various instruments to capture the various HRQoL domains as specified 
above. 
General quality of life domains will be assessed via the EORTC Quality of Life Questionnaire (QLQ-C30) 
version 3. This instrument is composed of multi-item and single-item scales. These include five functional 
scales (physical, role, emotional, social, and cognitive), three symptom (fatigue, nausea and vomiting and 
pain) and a global health status/QoL scale and six single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea and financial difficulties). All scales and single items meet the standards for 
reliability. The reliability and validity of the questionnaire is highly consistent across different language-
cultural groups (Ref. 31). The average time to complete the questionnaire is approximately 10 minutes. 
The EORTC QLQ-C30 version 3 has been translated in over 50 languages according to a standardized 
translation procedure.  
The domains of interest as specified in the previous paragraph are covered by the QLQ-C30. 
A breast cancer specific module (BR23) to complement the QLQ-C30 exists. It is meant for use among 
breast cancer patients varying in disease stage and treatment modality (i.e. surgery, chemotherapy, 
radiotherapy and hormonal treatment). However, as the module relates mainly to symptoms and 
functionality related to surgery and hormonal treatment, it does not fit the study objectives and is therefore 
not included (Ref. 32). 


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English versions of the HRQoL Instrument(s) and the EORTC “Guidelines for administration of 
questionnaires” are included in Appendix D, Appendix F and Appendix I.  
10.4 Study design 
HRQoL questionnaires must be filled out at the hospital when patients come for a scheduled visit 
according to the EORTC “Guidelines for administration of questionnaires” (see Appendix D). The pre-
treatment questionnaires must be filled within 4 weeks before randomization. Subsequent questionnaires 
are filled in every 2 cycles (i.e., every 6 weeks ± 7 days) for the first 12 months while on-treatment and 
every 3 months while off-treatment. The on-treatment schedule coincides with the imaging schedule. 
Collection of HRQoL data will be limited to the first 12 months after randomization. Beyond that time, the 
absolute number of patients available is expected to be too low to allow reliable analyses and therefore 
data collection is no longer justified.  
Master copies of the HRQoL questionnaires will be sent to the institutions. Additional copies or 
translations can be provided upon request via the EORTC contact person. The clinical report forms will 
include a question whether the HRQoL forms have been filled in, and if not, the reason why. The 
questionnaire will be handed out to the patients by the investigator or a study nurse prior to seeing the 
doctor for clinical evaluations. The patient should complete the questionnaires by her/himself in her/his 
own language during the visit to the outpatient clinic as completely and accurately as possible. It is 
recommended that a key person (e.g. research nurse) at each center should be responsible for questionnaire 
data collection in order to optimize the compliance of the patient and to ensure the completeness of the 
data. 
During the study, compliance with completing questionnaires will be investigated at each time point. The 
compliance of the HRQoL assessments will also be reviewed twice a year and will be part of the 
descriptive report. 
10.4.1 
HRQoL schedule 
The time windows for eligible HRQoL assessments will be as follows: 
 
Assessment 
Time window  
Baseline 
Can be completed before or on the day of randomization 
itself but no earlier than 4 weeks before. 
On protocol treatment: every 2 
cycles (i.e., every 6 weeks). 
To be completed every 2 cycles (i.e., every 6 weeks ± 7 days 
from randomization) while on protocol treatment 
irrespective of treatment delays. Eligible time window is up 
to 1 week before or 1 week after the target assessment date. 
Off protocol treatment: every 
three months 
To be completed every 3 months after end of protocol 
treatment. Eligible time window is up to 1 month before or 1 
month after the target assessment date. 
 
 Important note: HRQoL forms will be collected regardless of progression status. HRQoL data 
collection will be limited to the first 12 months after randomization. 


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10.5 Statistical considerations 
Data from the EORTC QLQ-C30 will be scored according to the algorithm described in the EORTC 
scoring manual. All scales and single items are scored on categorical scales and linearly converted to 0-
100 scales. 
The primary HRQoL endpoint considered relevant for this study is time to HRQoL deterioration (TTQ). 
TTQ is defined as the time from randomization to the first observed of the following events: 
♦ Death 
♦ Progression 
♦ Deterioration in any of the following QLQ-C30 scales: fatigue, nausea/vomiting, pain, dyspnea, 
insomnia, appetite loss, constipation, diarrhea, physical functioning, role functioning, social 
functioning and emotional functioning or global health/QoL scale. Patients are considered to have 
deteriorated for a given scale if a worsening of 10 points at any time point after baseline is 
observed. A change of 10 points or more is considered to be clinically relevant (Ref. 33). 
Patients who have not experienced an event at the time of analysis will be censored at the time of the last 
completed HRQoL assessment. All patients who have a baseline and at least one follow- up HRQoL 
assessment will be included in the TTQ analysis.  
TTQ will be calculated using Kaplan–Meier method and compared using the two-sided log-rank test across 
the randomized arms. TTQ will be described using medians and hazard ratio with 95% confidence 
intervals (CIs). 
In order to assess the robustness of the results the following sensitivity variants to the TTQ endpoint will 
be investigated: 
♦ TTQ1 – time from randomization to death, treatment discontinuation or deterioration in any of the 
selected QLQ-C30 scores. (treatment discontinuation instead of progression) 
♦ TTQ2 – time from randomization to death or deterioration in any of the selected QLQ-C30 scores. 
(excluding progression as event) 
♦ TTQ3 – time from randomization to deterioration in any of the selected QLQ-C30 scores. 
(excluding both death and progression) 
♦ TTQ4 – time from randomization to death, progression or deterioration in any of the following 
QLQ-C30 scores: fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, 
diarrhea. (limit only to symptom deterioration). 
These alternative formulations serve only to investigate the robustness of the main results. They do not 
replace the primary endpoint. In case a significant difference is found in TTQ, the endpoint will be split up 
in its various events (death, progression and the selected scales) in order to investigate the treatment effect 
on each of these components. 
In addition the following summary statistics per patient will be calculated for the secondary objectives as 
sensitivity analyses and to complement the interpretation of the time-to-event model: 
♦ average change from baseline during the on protocol treatment period. 
♦ average change from baseline during the off protocol treatment period. 
♦ 10 point worsening from baseline during the on protocol treatment period (y/n). 
♦ 10 point worsening from baseline during the off protocol treatment period (y/n). 
These statistics will be compared between the two groups using non-parametric Wilcoxon rank test (for the 
summary statistics based on average change) or Fisher exact test (for the summary statistics based on 10 


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point worsening). Results will be summarized by the appropriate statistic estimation and corresponding 
95% CI interval. For the two binary summary statistics, missing data due to attrition will be imputed as 
worsening for sensitivity purposes. 
All available scales from the QLQ-C30 will be summarized per treatment arm on an exploratory basis. 
10.5.1 
Missing data 
Missing data is a potential major source of bias in HRQoL assessment. 
In order to check the potential impact in the study, the compliance mechanism will be investigated prior to 
initiating the HRQoL analysis. HRQoL compliance at a certain assessment time Ti will be defined as the 
ratio of the number of valid forms received over the number of forms expected at that time:  
[
]
i
i
i
i
T
at
expected
QoL
U
L
within
forms
QoL
valid
T
Compliance
,
)
(
=
 
where Li and Ui are the lower and upper bound of the time windows associated with Ti. HRQoL forms will 
be considered as invalid if no validated completion date was provided, the completion date falls outside of 
the time windows, mulitple HRQoL forms were received during the time window (the form closest to the 
assessment date will be kept), a wrong version or wrong translation of questionnaire was used or the form 
was filled out by an unauthorized person. QoL forms are expected at Ti for each patient that was within the 
QoL assessment schedule; ie. alive at time Ti. Reasons for non-completion if an assessment was missed 
will be collected via the CRFs. Characteristics of patients with and without valid HRQoL data will be 
compared and trends over time per dropout pattern will be investigated. Model building will be used in 
order to investigate whether the compliance mechanism is linked to selected prognostic variables. 
Once the main analysis is completed, sensitivity analyses will be undertaken to verify the robustness of the 
results vis-à-vis the missing data.  
In case overall compliance is deemed too low (< 50%), only an exploratory analysis will be performed in 
lieu of the main analysis. 
10.6 Health Economics 
In addition, the EQ-5D-5L will be administered at same times as the HRQoL instruments. The EQ-5D-5L 
is a general health status and health utility measure (Ref. 34). It measures 5 dimensions of health state: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression each assessed by a single 
question on a five-point ordinal scale. It also includes a visual analogue scale (VAS) to measure health 
state. The EQ-5D-5L will be included in this study for the purpose of the computation of utilities that can 
be used in health economic studies. This instrument has been used extensively in cancer studies and 
published results from these studies support its validity and reliability (Ref. 35). In addition, validated 
translations for this instrument are available for a number of countries and languages. 
The outcomes of the EQ-5D-5L will be used to define distinct health states with corresponding utilities for 
use in economic modeling evaluations. 
11 Pharmacokinetics 
5 ml blood samples into EDTA tube for measurements of plasma levels of niraparib will be obtained on 
cycle 1/day 1 and on cycle 2/day 1 at the following time points: 0 (predose within 30 minutes) and 2 hours 
post dose. In subsequent cycles, a blood sample for measurements of plasma levels of niraparib will be 
obtained on cycle 4/day 1 predose (within 30 minutes) only. 
The time of last dose prior to PK blood draw should be recorded. 


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Model predicted AUCs will be derived. Parameters of interest include AUC, Cmin, Cmax, CL/F, Vz/F, 
AUCss, Cminss, Cmaxss.  
Complete instructions for collection, processing, shipping, and handling are detailed in the Laboratory 
Manual, which will be provided to the sites prior to authorization.  
12 Translational research 
12.1 BRCA 1/2 mutation analysis for patient enrolment 
12.1.1 
Objective 
Before randomization, patients will be screened centrally for germline BRCA mutation status. Patients with 
BRCA1 or BRCA2 mutation that is considered deleterious or suspected deleterious (include those 
mutations or translocations termed "deleterious" or "suspected deleterious" according to Myriad reporting) 
by analysis at an either local or central laboratory will be deemed eligible to enter the trial. On study 
central confirmation of BRCA status will be performed for those patients who were enrolled based on 
either a previous Myriad test or a local test. 
12.1.2 
Material and methods 
7 mL of whole blood will be collected in EDTA tube. 
Central testing under the context of this protocol may be performed at any time prior to randomization.  
BRCA DNA mutation  analysis will be performed centrally by certified Myriad Genetic Laboratories 
(Myriad Genetic Laboratories, Salt Lake City, UT, USA) by using the validated, sequencing-based, 
BRACAnalysis® test. Patients who have a prior test done by Myriad or any other local test may enroll in 
the study but on study central confirmation of BRCA status will be performed at Myriad Genetic 
Laboratories , Salt Lake City, UT, USA . 
Further details on the test, including definition of "deleterious” or “suspected deleterious" mutations, 
analytical specificity and sensitivity, can be found in the publicly available "BRACAnalysis® Technical 
Specifications" and will be included in the final statistical analysis plan. 
12.2 Concordance of the companion diagnostic test for 
determination of germline BRCA 1/2 mutations 
12.2.1 
Objective 
Additional mutation analysis testing will be performed for the purpose of developing a commercial 
companion diagnostic test. 
The concordance of the candidate companion diagnostic test with the centralized gBRCA mutation test 
with respect to identifying gBRCA mutated patients will be evaluated using a separate blood sample. 
The sensitivity and specificity of the companion diagnostic test to the centralized validated test with 
respect to gBRCA status will be determined along with the corresponding 95% confidence intervals. 
Assuming the true sensitivity is 95%, with 306 samples, there is 99% probability that the width of the 95% 
confidence interval is within 5%. Assuming the true specificity is 95%, with at least 125 samples, there is 
90% probability that the width of the 95% confidence interval is within 5%.  
In addition, the effect of treatment on PFS will be evaluated by cohort (as identified by the candidate 
companion diagnostic test) using the analysis methodology described for the primary PFS analysis. If a 
companion diagnostic is not needed or it is determined that analytic validation is sufficient for bridging the 


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centralized test to the candidate companion diagnostic test, the above mentioned sensitivity, specificity and 
PFS analyses may not be performed.  
12.2.2 
Material and methods 
7 mL of whole blood will be collected in EDTA tube at the same time that the blood sample for central 
testing is taken. 
Further analytical and methodological details will be included in the final statistical analysis plan. 
12.3 Evaluation of predictive biomarkers related to efficacy and 
safety of niraparib 
The overall aim is to explore molecular mechanisms mediating response and resistance to niraparib. Such 
an approach will be through the analysis of DNA and mRNA alterations. 
12.3.1 
Tumor biomarkers 
12.3.1.1 
Objective 
Mutation of germline BRCA leads to malignancies deficient in BRCA and homologous recombination 
capabilities, and appears to be a predictive marker for responsiveness to niraparib and other PARP 
inhibitors. Changes independent of BRCA mutation within malignancies are known to cause phenotype of 
homologous recombination deficiency. This study will look at somatic markers of DNA repair. Other 
biomarkers that are postulated to be related to efficacy of niraparib will also be evaluated in the context of 
this trial. 
12.3.1.2 
Material and methods 
♦ 1 Formalin-fixed, paraffin-embedded (FFPE) tumor block (preferred) or 20 slides of 5 micron 
thickness from archival primary tumor or a metastatic lesion will be collected at the screening visit 
prior to enrollment or after randomization (during cycle1). 
♦ Optional: for patients with accessible metastatic lesions, repeat biopsies at baseline and at progression 
are requested as an option.  
♦ The following material shall be submitted: 
♦ 1-2 FFPE cores 
♦ Frozen tumor tissue: 2-4 snap frozen cores embedded in optimal temperature cutting (OCT) 
compound 
A minimum of 1-2 frozen and 1-2 FFPE cores using a 14-gauge or smaller diameter spring-loaded biopsy 
needle will be taken. Two biopsies are the minimum number with at least one frozen and one FFPE and 
then the next priority should be a frozen sample. 
For new tumor tissue biopsies and archival samples (primary tumor and metastatic lesions), evaluation of 
genome landscape scoring measures of homologous recombination deficiency such as homologous 
recombination deficiency (HRD) score, assessment of loss of heterozygosity (LOH), reversion mutation 
analysis, methylation of alleles, transcriptional and protein expression profiles of DNA damage response 
(e.g. loss of 53BP1 expression in BRCA1 carriers) will be studied. 
Tumor samples (both primary and metastatic) may be deep sequenced to look at clonal evolution, co-
existent mutations and mutation profiles using next generation sequencing technologies. 


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Serial biopsies will be assayed for the changes that occur during progression and resistance to the 
niraparib. These will be also compared with the primary tumor or prior sample collected. 
If enough RNA can also be extracted, gene expression of these tumors may be evaluated using a genome-
wide, deep sequencing technology or by alternative methods. 
Significant alterations identified with these technologies can also evaluated using circulating plasma DNA. 
Further analytical and methodological details will be included in the final statistical analysis plan. 
12.3.2 
Assessment of circulating plasma DNA 
12.3.2.1 
Objective 
Plasma of cancer patients sometimes contains cell-free tumor DNA that can carry information on tumor 
mutations and tumor burden. This information may be useful as a minimally-invasive way of monitoring 
advanced disease using cancer genetic alterations (mutations, rearrangements) that are specific to the 
individual’s tumor. This information may allow us to track and monitor tumor dynamics during the disease 
course as well emergence of new clones (ie resistance mechanisms). The aim of the correlative deep 
sequencing is to understand the molecular landscape (mutations, rearrangements and copy number 
changes) associated with BRCA mutant tumors as well as response or resistance to the study therapy.  
12.3.2.2 
Material and methods 
10 mL whole blood will be collected in an EDTA tube for plasma preparation at baseline, 6-weeks (cycle 
3/day 1) and at study termination (due to progression or any other reason). 
Individual mutations may be assessed using technologies such as Sequenom Mass Spectrometry or deep 
sequencing. 
Further analytical and methodological details will be included in the final statistical analysis plan. 
12.3.3 
Humoral immune response monitoring 
12.3.3.1 
Objective 
There is significant evidence of increase in both humoral and cell mediated immune response and 
circulating tumor antigen expression in highly genome unstable triple negative (Ref. 36) and BRCA 
mutation (Ref. 37) associated breast cancer, in particular where the immune infiltrated medullary and 
atypical medullary variants of breast cancer are enriched (Ref. 38). There is also evidence reviewed in that 
immunogenic cell death can be responsible for a significant proportion of the therapeutic effect of agents 
that impact the DNA damage response in breast cancer (Ref. 39). 
The objective is to understand the drivers of immunogenic cell death in a disease with significant evidence 
of cancer antigen and immune cell up-regulation and how this might affect the response to PARP inhibitor. 
12.3.3.2 
Material and methods 
Aliquots of serial plasma samples collected at baseline, 6-weeks and at study termination (due to 
progression or any other reason) (see section 12.3.2.2) will be assessed for humoral immune markers. 
Further analytical and methodological details will be included in the final statistical analysis plan. 
 
 


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12.3.4 
Mutation profile screening test for selected myeloid- associated 
genes 
At Screening and treatment discontinuation as well as for any suspected MDS/AML case, blood samples 
(5 ml EDTA) will be collected to evaluate mutations for selected myeloid- associated genes. This test is a 
PCR- based next generation sequencing assay that screens DNA from leukocytes for the presence of 
mutations or insertion/deletion in commonly altered areas of 30 genes. The panel includes genes that are 
associated with AML, MDS or myeloproliferative neoplasias, including ASXL1, CEBPA, DMNT3A 
FLT3, IDH1, IDH2, NPM1, RUNX1, TET2 and TP53. These samples for mutation screening test will be 
stored for evaluation (of the selected myeloid- associated genes mutations) if necessary for assessing 
niraparib- related risk for MDS/AML (e.g the patient develops MDS/ AML). Mutation profile before and 
after study treatment will be compared to determine whether any mutations were present prior to study 
treatment. 
Details on blood sample collection can be found in the Laboratory Manual. 
 
 


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12.3.5 
Summary of sample collection 
Type of 
sample 
Local storage 
conditions 
Amount of 
sample 
Collection time 
points 
Purpose 
Mandatory  
 
Blood 
Room 
temperature 
7mL 
Any time prior to 
randomization 
Central BRCA 1/2 
mutation analysis 
Blood 
Room 
temperature 
7mL 
Any time prior to 
randomization 
Concordance of 
companion diagnostic 
test 
FFPE tumor 
tissue 
Room 
temperature 
Archival block 
or 20 unstained 
slides 
Screening 
Predictive biomarkers 
Blood 
Room 
temperature 
5 ml 
Any time prior to 
randomization, end 
of treatment and for 
any highly clinically 
suspected 
MDS/AML case 
during treatment or 
follow- up period.  
Mutations of selected 
myeloid- associated 
genes. 
Blood 
Frozen at -
80°C(or store 
short term at -
20°C for max. 3 
months prior to 
transfer to -
80°C for long 
term)  
10mL 
Screening, 6 weeks 
and at study 
termination (due to 
progression or any 
other reason). 
Circulating plasma DNA 
and humoral immune 
response 
Optional 
 
FFPE tumor 
tissue 
Room 
temperature 
1-2 core needle 
biopsies 
Screening and at 
progression 
Predictive biomarkers 
Snap frozen 
tumor tissue 
embedded in 
OCT 
Frozen at -80°C 
2-4 core needle 
biopsies 
Screening and at 
progression  
Predictive biomarkers 
 
 
 


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12.4 Routing and banking of human biological material 
Blood samples taken for the central testing will be sent to Myriad Genetic Laboratories (USA) prior to 
randomization. 
Blood samples taken for myeloid neoplasm mutational screening will be shipped to and stored at QUEST 
Laboratories (USA). 
Other samples will be shipped to central repositories (based in USA for US sites and in Europe for 
European sites) as promptly as feasible on day of draw or 6-monthly. 
From here, samples will be redistributed to other laboratories performing the research described above (see 
chapter 12.5 on General Principles for HBM collection). 
If tumor blocks are provided, they will be promptly and diligently returned after sections are cut (assuming 
sufficient remaining tissue in block) to the originating pathology department upon request. 
Complete instructions for collection, processing, shipping, and handling are detailed in the Laboratory 
Manual.  
12.5 General principles for human biological material (HBM) 
collection 
Human biological material (HBM) collection involves the collection and storage of biological material, 
residual biological material or derivatives in compliance with ethical and technical requirements.  
Biobanking refers to the chain of procedures that encompass the life cycle of the biological material, e.g. 
from collection, shipping to long term storage and use, and may also be subject to local regulation and/or 
national/international legislation. 
In this study, biological material will be centralized and stored in central repositories (based in USA for 
US sites and in Europe for European sites). From here, the biological material will be used or distributed to 
the other research laboratories involved in the translational research (TR) projects specified in this protocol 
or defined in the future.  
Collection, storage and access to HBM for use in research shall be in accordance with the specific policy 
and charter developed for the study. 
Translational research proposals not outlined in this protocol will be assessed by the study steering 
committee (as defined in the related study charter) for merit and feasibility. Academic and sponsor 
proposals to access the data to explore hypotheses will also be considered by the study steering committee. 
12.6 Data storage, transfer and development of statistical analysis 
plan  
The translational projects will be the result of the work of TESARO, the collaborating groups and central 
laboratories. Statistical analysis plan will be written before starting any analysis of samples and will 
specify the analytical and methodological details. Clinical and patient-reported outcome data will be 
collected and stored in the EORTC clinical database and biological investigational data will remain with 
each party conducting the research. Transfer of data will be realized according to applicable study policy 
and charter for access to study data and biological material. 
 
 


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13 Publication policy 
Publications and oral presentations of any results from the study shall be in accordance with accepted 
scientific practice, academic standards and customs and in accordance with the specific dedicated policy 
developed for the study. This policy will be made available to all investigators/sites and groups 
participating in the study. 
The final publication of the main trial results will be written by the Study Coordinators on the basis of the 
final analysis performed at the EORTC Headquarters and published in a major scientific journal. 
14 Investigator authorization procedure 
Investigators will be authorized to register and/or randomize patients in this trial only once they have 
returned the required documents to PAREXEL. Documents might include, but are not limited to the 
following: 
♦ The updated signed and dated Curriculum Vitae of the Principal Investigator 
♦ The (updated) list of the normal ranges, for their own institution signed and dated by the head of the 
laboratory. Please make sure normal ranges are provided also for those tests required by the protocol 
but not routinely done at the investigator’s institution. 
♦ A Study Agreement between the sponsor and Principal Investigator, stating that the investigator will 
fully comply with the protocol and including a statement on any conflict of interest that may arise due 
to trial participation. This may include an estimate of yearly accrual. 
♦ A copy of the favorable opinion of the local or national (whichever is applicable) ethics committee 
mentioning the documents that were reviewed (including the version numbers and version dates of all 
documents). A list of all members of the ethics committee is also requested. 
♦ A copy of the translated and adapted (according to all national requirements) Patient Information / 
Informed Consent sheet. Version numbers and dates must be clearly stated on each page. 
♦ The signature log-list of the staff members with a sample of each authorized signature and the 
indication of the level of delegations. 
♦ The full name, address, phone numbers and e-mail address of the local pharmacist who will be 
responsible for the trial medication. 
♦ An accreditation, a certification, an established quality control / external quality assessment or another 
validation should be provided for the own laboratory. 
The center specific applicable list of required documents will be included in the protocol activation 
package, with proper instructions as required by this protocol, your group and / or the applicable national 
law. 
The new investigator will be added to the “authorization list”, and will be allowed to register/randomize 
patients in the trial as soon as 
♦ All the applicable documents are available at PAREXEL. 
♦ All applicable national legal and regulatory requirements are fulfilled. 
Patient registration/randomization from centers not (yet) included on the authorization list will not be 
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15 Patient randomization procedure 
Patient randomization will only be accepted from authorized investigators (see chapter on “investigator 
authorization procedure"). 
A patient can only be randomized after verification of eligibility. Both the eligibility check and 
randomization must be done before the start of the protocol treatment. 
Patients should be registered directly on the EORTC online randomization system (ORTA = online 
randomized trials access), accessible 24 hours a day, 7 days a week, through the internet. To access the 
interactive randomization program, the investigator needs a username and a password (which can be 
requested at http://orta.eortc.be/). 
In case of problems investigators can phone the EORTC Headquarters from 9.00 am to 5.00 pm (Belgian 
local time) from Monday through Friday to randomize patients via the EORTC call center. Randomization 
via the phone is not available on Belgian holidays. A list of these holidays is available on the EORTC web 
site (http://orta.eortc.be/) and it is updated annually. 
Through Internet: 
 
 
http://orta.eortc.be/ 
In case of problems randomization by phone:  
 
 
15.1 Registration procedure for screening (step 1) 
STANDARD INFORMATION REQUESTED: 
♦ EORTC institution number  
♦ EORTC protocol number  
♦ step number: 1 
♦ name of the responsible investigator  
♦ patient's code (maximum 4 alphanumerics)  
♦ patient's birth date (day/month/year)  
PROTOCOL SPECIFIC QUESTIONS: 
♦ confirmed HER2-negative breast carcinoma 
♦ date of written informed consent (day/month/year) 
At the end of the procedure, a patient sequential identification (SeqID) number will be assigned. This 
number will allow the identification of the patients in the VISTA/Remote Data Capture system 
(VISTA/RDC) that will be used to complete the Case Report Forms. 
15.2 Eligibility checklist (step 2) 
Patient randomization will only be accepted after patient has been registered (step 1). 
A patient can only be randomized after verification of eligibility. Randomization must be done before the 
start of the protocol treatment. 
An exhaustive list of questions to be answered during the randomization procedure is included in the 
eligibility checklist, which is part of the case report forms. 
 
 
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STANDARD INFORMATION REQUESTED: 
♦ EORTC institution number  
♦ EORTC protocol number 
♦ step number: 2 
♦ name of the responsible investigator 
♦ patient's code (maximum 4 alphanumerics)  
♦ patient's birth date (day/month/year)  
PROTOCOL SPECIFIC QUESTIONS: 
♦ all eligibility criteria will be checked  
♦ stratification factors 
♦ physician's choice of intended treatment for control arm 
♦ date foreseen for protocol treatment start 
Once eligibility has been verified, the treatment arm will be randomly (2:1) allocated to the patient. 
16 Forms and procedures for collecting data 
16.1 Case report forms and schedule for completion 
Data will be reported on the electronic CRFs specifically designed by the EORTC Headquarters for 
this study, with the exception of the Quality of Life form (EORTC QLQ-C30), Health questionnaire form 
(EQ-5D-5L), the SAE form and the Pregnancy notification form which are paper CRFs.  
Copies of the Quality of Life and Health questionnaire forms should be sent directly to the EORTC 
Headquarters by one of the following means: 
♦ By regular post to the EORTC Headquarters: 
Breast Group Data Manager 
EORTC Headquarters 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België - Belgique 
 
SERIOUS ADVERSE EVENTS AND PREGNANCY NOTIFICATION FORMS SHOULD BE 
IMMEDIATELY REPORTED ACCORDING TO THE PROCEDURE DETAILED IN THIS 
PROTOCOL (see chapter on Reporting Serious Adverse Events). 
A. Before the treatment starts: 
♦ The patient must be registered and randomized through your data center. 
♦ The electronic CRFs, to be completed for a patient, are available on the VISTA/RDC website one day 
after the registration on http://rdc.eortc.be/ or on http://www.eortc.org in the section for investigators. 
The paper CRF(s) will be made available to the institution at the time the institution is authorized. 
 
 


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B. During/after treatment 
The list of forms to be completed for this study and their submission schedule are available on the 
VISTA/RDC website and are also described in the "guidelines for completion of case report forms" that 
are provided to each participating investigator.  
ALL Forms must be electronically approved and sent by the responsible investigator  
or one of his/her authorized staff members with the exception of the paper Quality of Life and Health 
questionnaire form (no signature needed). 
16.2 Data flow 
The case report forms must be completed electronically, with the exception of the paper forms (the Quality 
of Life forms, Health questionnaire, SAE form and pregnancy notification form if applicable), dated and 
signed by the investigator or one of his/her authorized staff members as soon as the requested information 
is available. 
The list of staff members authorized to sign case report forms (with a sample of their signature) must be 
sent to the EORTC Headquarters by the responsible investigator before the start of the study. To enter the 
RDC system, the investigator or authorized staff member needs to use the same username and password 
that are used to access the interactive randomization program (ORTA). 
In all cases, it remains the responsibility of the principal investigator to check that data are entered as soon 
as possible and that the (electronic) forms are filled out completely and correctly. The EORTC data 
manager will subsequently apply the corrections into the database. 
The EORTC Headquarters will perform extensive consistency checks on the CRFs and issue queries in 
case of inconsistent data. The queries for the electronic forms will appear in the VISTA/RDC system and 
must be answered there directly. 
If an investigator (or an authorized staff member) needs to modify a CRF after the form has been 
electronically sent to the EORTC Headquarters, he/she should create a request for data correction in the 
VISTA/RDC system. 
The data corrections will appear in the VISTA/RDC system and the EORTC data manager will 
subsequently apply the corrections into the database. 
When satellite institutions are involved all contacts are done exclusively with the primary institution, for 
purposes of data collection and all other study related issues. 
More details on the data flow and related monitoring activities can be found in the Guidelines for 
completion of Case Report Forms. 
17 Reporting of Serious Adverse Events 
ICH GCP and the EU Directive 2001/20/EC require that both investigators and sponsors follow specific 
procedures when notifying and reporting adverse events/reactions in clinical trials. These procedures are 
described in this section of the protocol.  
17.1 Definitions 
These definitions reflect the minimal regulatory obligations; specific protocol requirements might apply in 
addition. 
AE: An Adverse Event is defined as “any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment”. An adverse event can therefore be any unfavorable and unintended 


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signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal laboratory 
finding (including results of blood tests, x-rays or scans) or a disease temporarily associated with the use of 
the protocol treatment, whether or not considered related to the investigational medicinal product. 
AR: An Adverse reaction of an investigational medicinal product is defined as “any noxious and 
unintended response to a medicinal product related to any dose administered”. 
All adverse events judged by either the reporting investigator or the sponsor as having a reasonable causal 
relationship to a medicinal product qualify as adverse reactions. The expression reasonable causal 
relationship means to convey in general that there is evidence or argument to suggest a causal relationship. 
UAR: An Unexpected Adverse Reaction is “any adverse reaction, the nature, or severity of which is not 
consistent with the applicable product information" (e.g. investigator's brochure for an unapproved 
investigational product or summary of product characteristics (SmPC) for a marketed product). 
When the outcome of the adverse reaction is not consistent with the applicable product information this 
adverse reaction should be considered as unexpected. 
Severity: The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate or severe, or as described in CTC grades); the event itself, however, may be of relative minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based on 
patient/event outcome or action criteria usually associated with events that pose a threat to patient’s life or 
functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.  
SAE: A Serious Adverse Event is defined as any untoward medical occurrence or effect in a patient, 
whether or not considered related to the protocol treatment, that at any dose: 
♦ results in death 
♦ is life-threatening (i.e. an event in which the subject was at risk of death at the time of event; it does not 
refer to an event which hypothetically might have caused death if it was more severe) 
♦ requires inpatient hospitalization or prolongation of existing patient hospitalization 
♦ results in persistent or significant disability or incapacity 
♦ is a congenital anomaly or birth defect 
♦ is a medically important event or reaction (i.e. important adverse reactions that are not immediately life 
threatening or do not result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed above ). NOTE: Any new malignancy will be 
monitored and must be reported as serious adverse event regardless of the treatment arm the subject is 
in. This includes any new malignancy occurring at any time for the duration of the study. 
Documentation on the diagnosis of the new malignancy must be provided at the time of reporting as a 
serious adverse event (e.g., any confirmatory histology or cytology results, X-rays, CT scans, radiology 
reports with the conclusions summary in English, etc.). Additionally, new malignancy should also be 
reported on the eCRF.  
♦ Medical and scientific judgment should be exercised in deciding whether other situations should be 
considered. Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
SAR: A Serious Adverse Reaction is defined as any SAE which is considered related to the protocol 
treatment.  
SUSAR: Suspected Unexpected Serious Adverse Reaction.  


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SUSARs occurring in clinical investigations qualify for expedited reporting to the appropriate Regulatory 
Authorities within the following timeframes: 
♦ Fatal or life-threatening SUSARs within 7 calendar days 
♦ Non-fatal or non-life-threatening SUSARs within 15 calendar days 
Inpatient hospitalization: a hospital stay equal to, or greater than, 24 hours. 
Second primary malignancy is one unrelated to the treatment of a previous malignancy (and is NOT a 
metastasis from the previous malignancy).  
Secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered 
a metastasis of the previous malignancy. 
17.2 Exceptions 
The following situations do not need to be reported as SAEs:  
♦ Elective hospitalization for pre-existing conditions that have not been exacerbated by trial treatment. 
♦ A hospitalization which was planned before the patient consented for study participation and where 
admission did not take longer than anticipated. 
♦ A hospitalization planned for protocol related treatment or protocol related procedure as per 
institutional standard timelines. 
♦ Social and/or convenience admission to a hospital. 
♦ Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that leads to the 
procedure is an (S)AE . 
♦ Situations where an untoward medical occurrence did not occur (palliative care, rehabilitation, 
overdose without occurrence of an adverse event). 
♦ 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. 
By EORTC convention, clinical events related to the primary cancer being studied or to the primary cancer 
progression are not to be reported as SAEs, even if they meet any of the seriousness criteria from the 
standard SAE definition, unless the event is more severe than expected and therefore the investigator 
considers that their clinical significance deserves reporting.  
17.3 Severity assessment 
The severity of all AEs (serious and non-serious) in this trial should be graded using CTCAE v4.0 
www.eortc.org\investigators-area\ctc 
17.4 Causality assessment 
The Investigator will assess the causality/relationship between the study drug and the AE. One of the 
following categories should be selected based on medical judgment, considering the definitions and all 
contributing factors:  
♦ Related: A clinical event, including laboratory test abnormality, occurs in a plausible time relationship 
to treatment administration, and which concurrent disease or other drugs or chemicals cannot explain. 
The response to withdrawal of the treatment should be clinically plausible.  


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♦ Likely related: A clinical event, including laboratory test abnormality, with a reasonable time sequence 
to administration of the treatment, unlikely to be attributed to concurrent disease or other drugs or 
chemicals.  
♦ Unlikely to be related: A clinical event, including laboratory test abnormality, with a temporal 
relationship to treatment administration which makes a causal relationship improbable, or in which 
other drugs, chemicals or underlying disease provide likely explanations.  
♦ Unrelated: A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration. Typically explained by extraneous factors (e.g., 
concomitant disease, environmental factors or other drugs or chemicals).  
The investigator will use clinical judgment to determine the relationship. Alternative causes, such as 
natural history of the underlying diseases, medical history, concurrent conditions, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the protocol treatment will be considered 
and investigated. 
The decision will be recorded on the SAE form and if necessary the reason for the decision will also be 
recorded.  
17.5 Expectedness assessment 
The expectedness assessment is the responsibility of the sponsor of the study. The expectedness 
assessment will be performed against the following reference documents: 
♦ Niraparib: Investigator's Brochure. 
♦ Eribulin: Summary of Product Characteristics  
♦ Vinorelbine: Summary of Product Characteristics  
♦ Gemcitabine: Summary of Product Characteristics  
♦ Capecitabine: Summary of Product Characteristics  
17.6 Reporting procedure for investigators 
This procedure applies to all Serious Adverse Events (SAEs) occurring from the time a subject is 
registered until 30 days after last protocol treatment administration (or up to initiation of new anticancer 
therapy, whichever is earlier) and to any SAE that occurs outside of the SAE detection period (after the 30-
days period/initiation of new anticancer therapy), if it is considered to be at least likely related to the 
protocol treatment or study participation. 
Registration till 30 days after last protocol treatment 
administration(or up to initiation of new anticancer therapy, 
whichever is earlier): 
All SAEs 
From day 31 after last protocol treatment 
administration/initiation of new anticancer therapy, 
(whichever is earlier): 
Only related SAEs 
Any new malignancy should also be reported in expedited way on a SAE form with the appropriate 
seriousness criteria! 
Initial reports of SAEs must be followed later with detailed descriptions, including clear photocopies of 
other documents as necessary (e.g., hospital reports, consultant reports, autopsy reports etc.), with the 
patient’s personal identifiers removed. All relevant information obtained by the Investigator through 
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In order to be compliant with regulatory reporting requirements, all initial SAE reports should always 
include the following minimal information: 
♦ Name of person sending the report (i.e., name, address of Investigator) 
♦ Patient identification (screening/randomization number, initials, NOT patient name) 
♦ Protocol number 
♦ Description of SAE 
♦ Causality assessment, if possible 
All points on the SAE form should be covered in the initial report. In addition, all events must be 
documented in the AE eCRF. 
All reporting must be done by the principal investigator or authorized staff member (i.e. on the signature 
list) to confirm the accuracy of the report. 
All SAE data must be collected on the study-specific SAE form. 
All SAEs must be reported immediately and no later than 24 hours from the time the investigator or staff 
became aware of the event.  
All SAE-related information needs to be provided in English. 
All additional documents in local language must be accompanied by a translation in English, or the 
relevant information must be summarized in a follow-up SAE report form. 
Investigators must fax or e-mail (scan) all SAE-related information to: 
 
EORTC Pharmacovigilance Unit: 
 
Fax No. 
 
 
Email: 
 
Complete information requested on the SAE form of any reported serious adverse event must be returned 
within 7 calendar days of the initial report. If the completed form is not received within this deadline, the 
EORTC Pharmacovigilance Unit will make a written request to the investigator. 
Queries sent out by the EORTC Pharmacovigilance Unit need to be answered within 7 calendar days. 
All forms need to be dated and signed by the principal investigator or any authorized staff member (i.e. on 
the signature list). 
17.7 Reporting responsibilities of the Sponsor 
The EORTC Pharmacovigilance Unit will forward all SAE reports to the appropriate persons within the 
EORTC Headquarters and to the pharmacovigilance contact at the pharmaceutical company. 
After receipt of the initial report, the sponsor will review the information and, if necessary, contact the 
Investigator, to obtain further information for assessment of the event. The Sponsor will evaluate the 
seriousness and the causal relationship of the event to study medication. In addition, the Sponsor will 
evaluate the expectedness according to the reference documents (see above). Based on the Investigator and 
Sponsor’s assessment of the event, a decision will be made concerning the need for further action. 
The EORTC Pharmacovigilance Unit and the Company have outlined the reporting of SUSARs in a 
pharmacovigilance agreement. 
The EORTC Pharmacovigilance Unit will provide a six-monthly summary which will be added in the Trial 
Status Report and which will be accessible to all participating investigators.  
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17.8 Pregnancy reporting 
Pregnancy occurring during a patient’s participation in this trial, although not considered an SAE, must be 
notified to the EORTC Pharmacovigilance Unit within the same timelines as an SAE (within 24 hours) on 
a Pregnancy Notification Form. The outcome of a pregnancy should be followed up carefully and any 
adverse outcome to the mother or the child should be reported. This also applies to pregnancies in female 
partners of a male patient participating in this trial. 
♦ Any pregnancy in a female subject or in a female partner of a male subject diagnosed during the 
treatment period or within 30 days after last protocol treatment administration must be reported to the 
EORTC Pharmacovigilance Unit  
♦ This must be reported within 24 hours of first becoming aware of the event by fax or e-mail (scan), to 
the Pharmacovigilance Unit on a Pregnancy Notification Form  
♦ All outcomes of pregnancy must be reported on the same form within 30 days after he/she has gained 
knowledge of the normal delivery or elective abortion. 
♦ Any SAE that occurs during pregnancy must be recorded on the SAE report form (e.g., maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, congenital 
anomaly, birth defect) and reported within 24 hours in accordance with the procedure for reporting 
SAEs (see above). 
18 Quality assurance 
18.1 Control of data consistency  
Data forms will be electronically sent to the EORTC Headquarters database by the VISTA/RDC (Remote 
Data Capture) system. Computerized and manual consistency checks will be performed on newly received 
forms; queries will be issued in case of inconsistencies. Consistent forms will be validated by the data 
manager. Inconsistent forms will be kept "pending" until resolution of inconsistencies. 
18.2 On-site quality control 
PAREXEL will perform on-site monitoring visits according to the monitoring plan. 
The aim of these site visits will be: 
♦ to verify that the site facilities remain adequate for performing the trial 
♦ to verify that the principal investigator and site staff involved in the trial are working in compliance 
with GCP and protocol requirements  
♦ to assess the consistency of data reported on the case report forms with the source data 
♦ to check that Serious Adverse Events have been properly reported and that follow-up information or 
queries are correctly fulfilled 
♦ to assist the site in resolving any outstanding queries 
♦ to control the drug accountability process 
The retention of archived study documentation is determined by the national regulatory requirements and 
will be defined by contractual agreement(s) between the study site(s) and the Sponsor (or Sponsor's 
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18.3 Audits 
The EORTC Quality Assurance and Control Unit (QA&C), BIG, TESARO or TESARO's designee will 
conduct audits of institutions participating in this protocol. Audits will be coordinated such that PAREXEL 
will have primary responsibility for routine audits of the sites (according to audit plan), while EORTC, 
BIG, TESARO or TESARO's designee will perform additional audits whenever needed. These audits are 
performed to provide assurance that the rights, safety and wellbeing of subjects are properly protected, to 
assess compliance with the protocol and IMP handling, processes and agreements, ICH GCP standards and 
applicable regulatory requirements, and to assess the quality of data. 
The investigator, by accepting to participate in this protocol, agrees that EORTC, TESARO, BIG, any third 
party (e.g. a CRO) acting on behalf of them, or any domestic or foreign regulatory agency, may come at 
any time to audit or inspect their site and all subsites, if applicable.  
This audit consists of interviews with the principal investigator and study team, review of documentation 
and practices, review of facilities, equipment, IMP storage and source data verification. 
The investigator will grant direct access to all paper and/or electronic documentation pertaining to the 
clinical study (e.g. CRFs, source documents such as hospital patient charts and investigator study files) and 
for inspection of the IMP, to these authorized individuals. All site facilities related to the study conduct 
could be visited during an audit (e.g. pharmacy, laboratory, archives, etc). The investigator agrees to co-
operate and provide assistance at reasonable times and places with respect to any auditing activity, 
including timely follow-up to observations noted and corrective and preventive actions that may be 
required to address such observations. 
If a regulatory authority inspection is announced, the investigator must inform the EORTC Headquarters 
QA&C Unit, BIG and TESARO immediately (contact at: 
 
In this way EORTC and BIG can provide support in preparing and/or facilitating the inspection in their 
institution. EORTC representatives/delegates may also attend the inspection. 
18.4 External review of responses 
In accordance with the recommendations of the RECIST v.1.1 criteria, all responses will be reviewed by 
an expert or experts independent of the study. 
18.4.1 
Tumor assessments 
Radiological examinations performed during the conduct of this study will be submitted for blinded central 
review. The central review committee, who will determine response to treatment and date of progression 
of disease, will be comprised of 2 radiologists and an arbiter, if necessary. A separate charter and imaging 
manual will be provided that details the central blinded review and the procedures for submitting images to 
the central laboratory. Investigators will also assess response and date of progression. The date of 
progression as assessed by central review will be used for determination of PFS in the primary efficacy 
analysis; Investigator assessment for PFS is a secondary endpoint in this trial. 
Best response to treatment (CR, PR, SD, and PD) also will be determined based on RECIST v.1.1 by both 
central blinded review and site Investigator review as secondary endpoints. 
The central review process will be conducted as follows: 
♦ When the patient discontinues treatment and/or the Investigator determines that the patient has 
progressed, all imaging data will be submitted for central review. 
♦ The scans will undergo central radiology review based on RECIST v.1.1. 
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19 Ethical considerations 
19.1 Patient protection 
The responsible investigator will ensure that this study is conducted in agreement with either the 
Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) 
and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. 
The protocol has been written, and the study will be conducted according to the ICH Harmonized 
Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pd
f). 
The protocol must be approved by the competent ethics committee(s) as required by the applicable 
national legislation. 
19.2 Subject identification 
The name of the patient will neither be asked for nor recorded at the EORTC Headquarters. A sequential 
identification number will be automatically allocated to each patient registered in the trial. This number 
will identify the patient and will be included on all case report forms. In order to avoid identification 
errors, the patient’s code (maximum of 4 alphanumerics) and date of birth will also be reported on the case 
report forms. 
19.3 Informed consent 
All patients will be informed about 
♦ the aims of the study 
♦ the possible adverse events 
♦ the procedures and possible hazards to which the patient will be exposed 
♦ the mechanism of treatment allocation 
♦ strict confidentiality of any patient data 
♦ medical records possibly being reviewed for trial purposes by authorized individuals other than their 
treating physician 
The template of the patient’s informed consent statement is given as a separate document dated and 
version controlled to this protocol. 
An adapted translation of the PIS/PIC will be provided by EORTC Headquarters and it is the responsibility 
of the Coordinating investigators for this trial (sometimes called National Coordinators) to adapt it to 
national/local requirements where necessary. 
The translated informed consent documents are to be submitted to ethics committees for approval. The 
competent ethics committee for each institution must approve the informed consent documents before the 
center can join the study. It is the responsibility of the competent ethics committee to ensure that the 
translated informed documents comply with ICH-GCP guidelines and all applicable national legislation. 
It is emphasized in the patient information sheet that participation is voluntary and that the patient is free to 
refuse further participation in the protocol whenever he/she wants to. This will not have any impact on the 
patient’s subsequent care. Documented informed consent must be obtained for all patients included in the 
study before they are registered and/or randomized at the EORTC Headquarters. The written informed 


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21 Trial sponsorship and financing 
TESARO is the Sponsor in all participating countries and is fully supporting the study. 
Sponsor contact details: 
 
Medical Director 
TESARO 
1000 Winter Street North #3300 
Waltham 
MA 02451 
United States of America 
Phone:  
 
Fax: 
 
 
E-mail:  
 
22 Trial insurance 
A clinical trial insurance has been taken out according to the laws of the countries where the study will be 
conducted. An insurance certificate will be made available to the participating sites at the time of study 
initiation.  
Clinical trial insurance is only valid in centers authorized by TESARO (via PAREXEL). For details please 
refer to the chapter on investigator authorization. 
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Appendix A: References 
Ref. 1 
Gonzalez-Angulo AM, Sahin A, Krishnamurthy S, et al.: Biologic markers in axillary node-
negative breast cancer: differential expression in invasive ductal carcinoma versus invasive 
lobular carcinoma. Clin Breast Cancer 7:396-400, 2006 
Ref. 2 
Hortobagyi GN, Smith TL, Legha SS, et al.: Multivariate analysis of prognostic factors in 
metastatic breast cancer. J Clin Oncol 1:776-786, 1983 
Ref. 3 
Cardoso F, Harbeck N, Fallowfield L, et al.: Locally recurrent or metastatic breast cancer: ESMO 
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 23 Suppl 7:vii11-
vii19, 2012 
Ref. 4 
Chen JJ, Silver D, Cantor S, et al.: BRCA1, BRCA2, and Rad51 operate in a common DNA 
damage response pathway. Cancer Res 59:1752s-1756s, 1999 
Ref. 5 
Frankish H: BRCA1 has a pivotal role in repairing DNA. Lancet 357:1678, 2001 
Ref. 6 
Le PF, Randrianarison V, Marot D, et al.: BRCA1 and BRCA2 are necessary for the 
transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. Cancer Res 
60:5548-5552, 2000 
Ref. 7 
Lakhani SR, Gusterson BA, Jacquemier J, et al.: The pathology of familial breast cancer: 
histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2. 
Clin Cancer Res 6:782-789, 2000 
Ref. 8 
Curtin NJ: DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 
12:801-817, 2012 
Ref. 9 
Bryant HE, Schultz N, Thomas HD, et al.: Specific killing of BRCA2-deficient tumours with 
inhibitors of poly(ADP-ribose) polymerase. Nature 434:913-917, 2005 
Ref. 10 Patel AG, Sarkaria JN, Kaufmann SH: Nonhomologous end joining drives poly(ADP-ribose) 
polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc Natl 
Acad Sci U S A 108:3406-3411, 2011 
Ref. 11 Farmer H, McCabe N, Lord CJ, et al.: Targeting the DNA repair defect in BRCA mutant cells as a 
therapeutic strategy. Nature 434:917-921, 2005 
Ref. 12 Jones P, Altamura S, Boueres J, et al.: Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-
indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor 
efficacious in BRCA-1 and -2 mutant tumors. J Med Chem 52:7170-7185, 2009 
Ref. 13 Murai J, Huang SY, Das BB, et al.: Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. 
Cancer Res 72:5588-5599, 2012 
Ref. 14 Michie C, Sandhu S, Schelman W: Final results of the phase I trial of niraparib (MK4827), a 
poly(ADP)ribose polymerase (PARP) inhibitor incorporating proof of concept biomarker studies 
and expansion cohorts involving BRCA1/2 mutation carriers, sporadic ovarian, and castration 
resistant prostate cancer (CRPC)., in (ed 2013 ASCO annual meeting) 
Ref. 15 Wooster R, Bignell G, Lancaster J, et al.: Identification of the breast cancer susceptibility gene 
BRCA2. Nature 378:789-792, 1995 
Ref. 16 Fong PC, Boss DS, Yap TA, et al.: Inhibition of poly(ADP-ribose) polymerase in tumors from 
BRCA mutation carriers. N Engl J Med 361:123-134, 2009 
Ref. 17 Tutt A, Robson M, Garber JE, et al.: Oral poly(ADP-ribose) polymerase inhibitor olaparib in 
patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. 
Lancet 376:235-244, 2010 


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Ref. 18 Gelmon KA, Tischkowitz M, Mackay H, et al.: Olaparib in patients with recurrent high-grade 
serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, 
multicentre, open-label, non-randomised study. Lancet Oncol 12:852-861, 2011 
Ref. 19 Kummar S, Ji J, Morgan R, et al.: A phase I study of veliparib in combination with metronomic 
cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin Cancer Res 
18:1726-1734, 2012 
Ref. 20 Atchley DP, Albarracin CT, Lopez A, et al.: Clinical and pathologic characteristics of patients 
with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 26:4282-4288, 2008 
Ref. 21 Foulkes WD: Re: Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and 
BRCA2 mutation carriers. J Natl Cancer Inst 95:1344, 2003 
Ref. 22 Konstantinopoulos PA, Spentzos D, Karlan BY, et al.: Gene expression profile of BRCAness that 
correlates with responsiveness to chemotherapy and with outcome in patients with epithelial 
ovarian cancer. J Clin Oncol 28:3555-3561, 2010 
Ref. 23 Kang J, D'Andrea AD, Kozono D: A DNA repair pathway-focused score for prediction of 
outcomes in ovarian cancer treated with platinum-based chemotherapy. J Natl Cancer Inst 
104:670-681, 2012 
Ref. 24 McCabe N, Turner NC, Lord CJ, et al.: Deficiency in the repair of DNA damage by homologous 
recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 66:8109-
8115, 2006 
Ref. 25 Fong PC, Yap TA, Boss DS, et al.: Poly(ADP)-ribose polymerase inhibition: frequent durable 
responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 
28:2512-2519, 2010 
Ref. 26 Tutt A , Ellis P, Kilburn L, et al: TNT: A randomized phase III trial of carboplatin compared with 
docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA 1/2 
breast cancer,SABCS 2014, Abstract S3-01 
Ref. 27 Schiffer CA, Anderson KC, Bennett CL, et al. (2001). "Platelet transfusion for patients with 
cancer: clinical practice guidelines of the American Society of Clinical Oncology." J Clin Oncol 
19(5): 1519-1538.  
Ref. 28 Slichter SJ (2007). Evidence-based platelet transfusion guidelines. Hematology Am Soc Hematol 
Educ Program:172-178. 
Ref. 29 Brookmeyer, R., and Crowley, J. (1982), ‘‘A Confidence Interval for the Median Survival Time, 
Biometrics, 38, 29–41. 
Ref. 30 Eisenhauer EA, Therasse P, Bogaerts J, et al.: New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247, 2009 
Ref. 31 Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst 1993 Mar 3,85(5), 365-376. 
Ref. 32 Sprangers MA, Groenvold M, Arraras JI, et al. The European Organization for Research and 
Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from 
a three-country field study. J Clin Oncol 1996 Oct,14(10), 2756-2768. 
Ref. 33 Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-
related quality-of-life scores. J Clin Oncol 1998 Jan,16(1), 139-144. 
Ref. 34 Rabin R, de CF. EQ-5D: a measure of health status from the EuroQol Group. Ann Med 2001 
Jul,33(5), 337-343. 


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Ref. 35 Pickard AS, Wilke CT, Lin HW, Lloyd A. Health utilities using the EQ-5D in studies of cancer. 
Pharmacoeconomics 2007,25(5), 365-384. 
Ref. 36 Grigoriadis A, Caballero OL, Hoek KS, et al. CT-X antigen expression in human breast cancer. 
Proc Natl Acad Sci U S A 2009 Aug 11,106(32), 13493-13498. 
Ref. 37 Adams S, Greeder L, Reich E, et al. Expression of cancer testis antigens in human BRCA-
associated breast cancers: potential targets for immunoprevention? Cancer Immunol Immunother 
2011 Jul,60(7), 999-1007. 
Ref. 38 Mavaddat N, Barrowdale D, Andrulis IL, et al. Pathology of breast and ovarian cancers among 
BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers 
of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 2012 Jan,21(1), 134-147. 
Ref. 39 Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu 
Rev Immunol 2013,31, 51-72. 
Ref. 40 Vardiman J, Thiele J, Arber D " The 2008 revision of the World Health Organization (WHO) 
classification of myeloid neoplasms and acute leukemia: rationale and important 
changes"BLOOD July 2009, Volume 114, Number 5. 
Ref. 41 Mirza MR, Bradley JM, Herrstedt J, et al.: Niraparib Maintenance Therapy in Platinum-Sensitive, 
Recurrent Ovarian Cancer. N Engl J Med 375 (22), 2154-2164, 2016.  


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Appendix B: Abbreviations 
 
ADL 
Activities of Daily Living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
AML 
Alanine transaminase 
Acute Myeloid Leukemia 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate transaminase 
β-HCG 
β-human chorionic gonadotropin 
BER 
Base excision repair 
BOR 
Best overall response 
BRCA1, BRCA2 
Breast cancer 1, 2 gene 
BUN 
Blood urea nitrogen 
CA125 
Carcinoma antigen 125 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CR 
Complete response 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP1A2 
Cytochrome P1A2 
DNA 
DSB 
Deoxyribonucleic acid 
Double strand break 
ECG 
Electrocardiograms 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EE 
Ethinyl estradiol 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer quality of life 
questionnaire – Core 30 
EQ-5D-5L 
EuroQoL 5 Dimension 5 Level 
ER 
Estrogen receptor 


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FISH 
Fluorescent in- situ hybridization 
gBRCAmut 
Germline BRCA mutation 
GCP 
Good Clinical Practice 
GCSF 
Granulocyte colony-stimulating factor 
GGT 
Gamma glutamyltransferase 
HDPE 
High-density polyethylene 
HER2 
Human epidermal growth factor receptor 2 
HIV 
Human immunodeficiency virus 
HR 
Homologous recombination 
HRD 
Homologous recombination repair deficiency 
IC50 
Half maximal inhibitory concentration of control 
IC90 
90% inhibitory concentration of control 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
DMC 
data monitoring committee 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IWRS 
Interactive web response system 
LDH 
Lactic dehydrogenase 
MCV 
Mean corpuscular volume 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NCCN 
National Comprehensive Cancer Network 
NE 
Non evaluable 
NHEJ 
Non-homologous end joining 
ORR 
Overall response rate 
PARP 
Poly(ADP-ribose) polymerase 
PD 
Progressive disease 
PFS 
Progression-free survival 


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P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
PP 
Per-protocol 
PR 
Progesterone receptor; partial response 
PRO 
Patient reported outcome 
QD 
Once daily 
QoL 
Quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TNBC 
Triple negative breast cancer 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cells 


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Appendix C: Common Terminology Criteria for 
Adverse Events 
In the present study, adverse events and/or adverse drug reactions will be recorded according to the  
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. 
At the time this protocol was issued, the full CTC document was available on the NCI web site, at the 
following address:     http://ctep.cancer.gov/reporting/ctc.html. 
The EORTC Headquarters web site   www.eortc.org\investigators-area\ctc   provides a link to the 
appropriate CTC web site. This link will be updated if the CTC address is changed. 


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Appendix D: EORTC Quality of Life evaluation: 
guidelines for administration of questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
EORTC Quality of Life evaluation: guidelines for administration of questionnaires 
The instructions given below are intended to provide some general guidelines for collecting quality of life 
(QOL) data in EORTC studies. These instructions apply for all types of questionnaires. 
1. Who is the responsible person (RP) for QOL data collection? 
In each institution, the principal investigator is the responsible for the local organization of QoL data 
collection. This can be delegated to a physician, data manager, (research) nurse or a psychologist. Such a 
person should have the full protocol at his/her disposal as well as the questionnaire(s). This person would 
also be the intermediate contact point in case of any necessary clarification asked by the EORTC 
Headquarters. 
2. Who should fill out the questionnaire? 
In principle it is the patient who has to complete the QOL forms and preferably without help from others. 
In the case where a patient is too sick to fill out the questionnaire by him/herself or if the patient is not able 
to complete the questionnaire for such reasons as forgetting his/her glasses, another person could read the 
questions without making any suggestions and report the answers on the forms. It is not allowed for 
another person to fill in the questionnaire as if (s)he was the patient (proxy assessment) unless specifically 
allowed by the protocol. 
3. What instructions should be given to the patient? 
At entry in a study, the RP should give the patient an explanation of the objective of the study and 
instructions for completing the questionnaires. 
The patient should be informed that participation in the QOL protocol is voluntary and that the information 
provided is confidential (identification is only for administrative purposes and includes date of birth and 
today’s date (completion date)). 
The following issues should be explained to the patient: 
♦ The schedule of assessments. 
♦ The questionnaire is a self administered questionnaire that should be completed by the patient 
him(her)self. The patient can ask for aid in reading or writing but should not let another person provide 
the answers. 
♦ The patient should   circle   the choice that best corresponds to his/her situation. 
♦ There is no right or wrong answer to any of these questions. The answers will not influence any 
medical decision making. 
♦ All questions should be answered.  
♦ The patient will be given a questionnaire in the default language(s) of the hospital. If desired, the 
patient may request another language. The RP will then contact the EORTC Headquarters for the 
appropriate translation. 
The RP should make sure that the patient understands the instructions. 


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At each subsequent assessment as defined by the protocol, the patient should receive the questionnaire 
from the RP or from other appropriate staff if the RP is unavailable. 
4. Where should the patient complete the questionnaire? 
The patient should complete the questionnaire at the clinic, and, ideally in a quiet, private room. If this is 
not possible, the waiting room is an acceptable alternative. In general it does not take long to complete the 
questionnaire, but patients should be given the time they need to answer all questions. 
5. When should they complete the questionnaire? 
The timing of the planned QoL assessments is detailed in the protocol. When a QOL assessment is 
planned, the questionnaire should be given to the patient preferably before the meeting with the physician, 
ensuring that the patient has enough time to complete the questionnaire. If the patient is to receive a 
therapy, the questionnaire should be filled out before administration of the treatment (unless indicated 
otherwise in the protocol). The questionnaire should not be taken home and/or mailed (unless indicated 
otherwise in the protocol). 
6. Review of the completed questionnaire 
After the patient has completed the questionnaire, the person handling the questionnaire should: 
♦ Complete the “Hospital Staff” specific data box. 
♦ Check that the completion date is correctly filled in by the patient. 
♦ Screen the questionnaire for omissions. 
If this is the case: 
♦ Please ask the patient the reason for omissions. It may be that patient forgot to flip a page or did not 
understand a question. The patient should not be forced to provide an answer if (s)he does not wish to 
do so. 
♦ Additional explanation may be provided, but the questions should not be rephrased. 
7. Missing forms 
If for some reason the patient is unable or does not wish to complete a quality of life questionnaire the 
reason and the date of visit should be documented on the corresponding CRF (case report form).  
8. Mailing to EORTC Headquarters 
A copy of the questionnaires should be sent to EORTC Headquarters as soon as possible, while the 
original source document should be kept on site. As it is impossible to retrospectively collect missing 
quality of life data, please make sure the patient completes the questionnaire at the time-point when he/she 
is supposed to complete it. 
Copies of the Quality of Life and Health questionnaire forms should be sent directly to the EORTC 
Headquarters by one of the following means: 
♦ By fax, to the attention of Breast Group Data Manager: 
 
♦ By scanning and e-mailing the forms (see CRF guidelines) 
♦ By post to the EORTC Headquarters: 
Breast Group Data Manager 
EORTC Headquarters 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België - Belgique 
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Appendix G: Eastern Cooperative Oncology Group 
(ECOG) performance status 
 
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, i.e., light house work, 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 
 


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Appendix H: Drugs known to inhibit or induce 
CYP1A2 
 
 
Inhibitors of CYP1A2 
Strong  
≥5-fold increase in 
AUC or >80% 
decrease in CL 
Moderate  
≥2 but <5-fold increase in AUC or 50-
80% decrease in CL 
Weak  
≥1.25 but <2-fold increase in AUC or 
20-50% decrease in CL 
Ciprofloxacin, 
enoxacin, fluvoxamine  
 
Methoxsalen, mexiletine, oral 
contraceptives, phenylpropanolamine, 
thiabendazole, vemurafenib, zileuton  
 
Acyclovir, allopurinol, 
caffeine, cimetidine, Daidzein, 
disulfiram, Echinacea, famotidine, 
norfloxacin, propafenone, 
propranolol, terbinafine, 
 ticlopidine, verapamil 
Inducers of CY1A2 
Strong 
80% decrease in AUC 
Moderate 
50-80% decrease in AUC 
Weak  
20-50% decrease in AUC 
 
Montelukast, 
phenytoin, smokers 
versus non-smokers 
Moricizine, 
omeprazole, 
phenobarbital 
Substrates of CYP1A2 
Sensitive substratesa 
Substrates with narrow therapeutic 
rangeb 
Alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, 
tizanidine  
Theophylline, tizanidine, Warfarin 
Guidance for Industry, Drug Interaction Studies, February 2012 
Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to increase 5-fold or 
higher when co-administered with a known CYP inhibitor or AUC ratio in poor metabolizers vs. extensive 
metabolizers is greater than 5-fold. 
CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship 
indicates that small increases in their exposure levels by the concomitant use of CYP inhibitors may lead 
to serious safety concerns (e.g., Torsades de Pointes).  
 


EORTC-1307-BCG / BIG5-13 / TESARO PR-30-5010-C 
Niraparib in BRCA germline mutated MBC 
Version 6.0 
99 / 102 
January 13, 2017 
Appendix I: EORTC Quality of Life Questionnaire 
(EORTC QLQ-C30) 
 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party copyright laws
and therefore have been excluded.


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Niraparib in BRCA germline mutated MBC 
Version 6.0 
102 / 102 
January 13, 2017 
Appendix J: List of drugs that are substrates or 
inhibitors of P- glycoprotein 
 
Substrates 
Inhibitors 
Aliskiren 
Amiodarone 
Ambrisentan 
Azithromycin 
Colchicine 
Captopril 
Dabigatran etexilate 
Carvedilol 
Digoxin 
Clarithromycin 
Everolimus 
Conivaptan 
Fexofenadine 
Cyclosporine 
Imatinib 
Diltiazem 
Lapatinib 
Dronedarone 
Maraviroc 
Erythromycin 
Nilotinib 
Felodipine 
Posaconazole 
Itraconazole 
Ranolazine 
Ketoconazole 
Saxagliptin 
Lopinavir and Ritonavir 
Sirolimus 
Quercetin 
Sitagliptin 
Quinidine 
Talinolol 
Ranolazine 
Tolvaptan 
Ticagrelor 
Topotecan 
Verapamil 
Source: Guidance for Industry, Drug Interaction Studies, February 2012 

SAP_003.pdf: 
Statistical Analysis Plan
Study ID:  213551 
Official Title of Study: A phase III, randomized, open label, multicenter, controlled trial 
of niraparib versus physician’s choice in previously-treated, HER2 negative, germline 
BRCA mutation-positive breast cancer patients.  
Date of Document: 11 Aug 2020 


Niraparib 
PR-30-5010-C (BRAVO) - 16.1.9  Documentation of Statistical Methods 
Confidential 
  Page 1 of 1 
Table 1: 
List of SAPs 
SAP Version 
Number 
SAP Title 
Sponsor 
Protocol 
Version 
Date of Approval 
1.0 
Statistical 
Analysis Plan 
TESAROa 
6.0 
11 August 2020 
1.0 
Statistical 
Analysis Plan 
EORTC 
6.0 
24 January 2017 
Abbreviations:  EORTC= European Organisation for Research and Treatment of Cancer 
a TESARO is a wholly owned subsidiary of GlaxoSmithKline Company 


STATISTICAL ANALYSIS PLAN 
A phase III, randomized, open label, multicenter, controlled trial of  
niraparib versus physician’s choice in previously-treated, HER2 negative, 
germline BRCA mutation-positive breast cancer patients 
Protocol Number: 
PR-30-5010-C 
Protocol Version and Date: 
v6.0 January 13, 2017 
v5.0 November 04, 2015 
v4.0 May 04, 2015 
v3.0 April 24, 2014 
v2.0 August 28, 2013 
v1.0 July 22, 2013 
Outline January 28, 2013 
Study Drug Name: 
Niraparib and Physician’s Choice (Eribulin, 
Vinorelbine, Gemcitabine and Capecitabine) 
Phase: 
Phase III 
Sponsor: 
TESARO, Inc. (a Glaxo Smith Kline Company) 
Analysis Plan Date: 
August 11, 2020 
Analysis Plan Version: 
Version 1.0 
Confidentiality Statement 
All information contained in this document is privileged and confidential to TESARO. 
Any distribution, copying, or disclosure is strictly prohibited without prior written 
approval by TESARO. 


TESARO Inc. 
 
Statistical Analysis Plan 
Protocol No:  PR-30-5010-C 
Confidential 
 
Page 2 of 36 
 
 
SPONSOR SIGNATURE PAGE 
 
Protocol Title: 
A phase III, randomized, open label, multicenter, 
controlled trial of niraparib versus physician’s choice in 
previously-treated, HER2 negative, germline BRCA 
mutation-positive breast cancer patients 
 
Protocol Number: 
PR-30-5010-C  
Sponsor:  
TESARO, Inc., a Glaxo Smith Kline Company 
1000 Winter Street 
Waltham MA 02451 
 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with the 
statistical methodology described in the protocol, clinical development plan, and all applicable 
regulatory guidance and guidelines. 
 
_________________________ 
 
Yongqiang Tang  
 
 
 
 
 
Date 
Director, Biostatistics 
TESARO, Inc.  
 
 
_________________________ 
 
Ilker Yalcin 
 
 
 
 
    
             Date 
Vice President, Biostatistics 
TESARO, Inc.  
 
 
PPD
PPD


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TABLE OF CONTENTS 
 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY DESIGN OVERVIEW ...................................................................................9 
2.1. 
Overall Study Design ....................................................................................................9 
2.2. 
Sample Size ................................................................................................................14 
2.3. 
Randomization and Stratification ...............................................................................14 
3. 
STUDY OBJECTIVES ..............................................................................................15 
3.1. 
Primary Objective .......................................................................................................15 
3.2. 
Secondary Objectives .................................................................................................15 
3.2.1. 
Key Secondary Objective ...........................................................................................15 
3.2.2. 
Other Secondary Objectives .......................................................................................15 
4. 
STUDY ENDPOINTS AND EVALUATION ...........................................................16 
4.1. 
Efficacy Endpoints ......................................................................................................16 
4.1.1. 
Primary Efficacy Endpoints ........................................................................................16 
4.1.2. 
Key Secondary Efficacy Endpoints ............................................................................16 
4.1.2.1. 
Other Secondary Efficacy Endpoints ..........................................................................16 
4.2. 
Safety Evaluations ......................................................................................................16 
4.3. 
Demographics and Baseline Characteristics ...............................................................16 
4.3.1. 
Pharmacokinetics Evaluations ....................................................................................17 
4.4. 
Quality of Life Assessment ........................................................................................17 
4.5. 
Translational Research ................................................................................................17 
5. 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .........................19 
5.1. 
Definition of Baseline .................................................................................................19 
5.2. 
Definition of Treatment Period ...................................................................................19 
5.3. 
Definition of Relative Study Days ..............................................................................19 
5.4. 
Analysis Visit Window ...............................................................................................19 
5.4.1. 
Safety Analysis Visit Window ....................................................................................19 
5.4.2. 
Efficacy Analysis Visit Window ................................................................................19 
5.5. 
Safety Data Handling ..................................................................................................19 
5.5.1. 
Handling of Repeated Clinical Laboratory Tests .......................................................19 


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5.5.2. 
Handling of Partial Dates for Adverse Events ............................................................20 
5.5.3. 
Handling of Partial Dates for Medications .................................................................20 
6. 
PLANNED ANALYSIS .............................................................................................21 
6.1. 
Changes from Planned Analyses in the Protocol ........................................................21 
6.2. 
Interim Analysis ..........................................................................................................21 
6.3. 
Final Analyses and Reporting .....................................................................................21 
7. 
ANALYSIS POPULATION AND APPLICATION..................................................22 
7.1. 
Screening Population ..................................................................................................22 
7.2. 
Centrally Confirmed ITT Population ..........................................................................22 
7.3. 
Full ITT Population ....................................................................................................22 
7.4. 
Safety Population ........................................................................................................22 
7.5. 
Analysis Populations Application...............................................................................22 
8. 
STATISTICAL CONSIDERATION ..........................................................................23 
8.1. 
General Statistical Procedures ....................................................................................23 
8.2. 
Enrollment and Disposition ........................................................................................23 
8.2.1. 
Patients Enrollment .....................................................................................................23 
8.2.2. 
Patients Disposition ....................................................................................................23 
8.3. 
Protocol Deviations ....................................................................................................23 
8.4. 
Demographics and Baseline Characteristics ...............................................................24 
8.4.1. 
Patients Demographics and Baseline Characteristics .................................................24 
8.4.2. 
Medical History ..........................................................................................................25 
8.4.3. 
Disease History ...........................................................................................................25 
8.4.4. 
Prior and Concomitant Medications ...........................................................................26 
8.5. 
Efficacy Analysis ........................................................................................................27 
8.5.1. 
Primary Efficacy Endpoint Analysis ..........................................................................27 
8.5.1.1. 
PFS per Central Review ..............................................................................................27 
8.5.1.2. 
Sensitivity Analyses ....................................................................................................28 
8.5.1.3. 
Homogeneity of Results across Subgroups ................................................................29 
8.5.2. 
Secondary Efficacy Endpoints Analysis .....................................................................29 
8.5.2.1. 
Overall Survival ..........................................................................................................29 
8.5.2.2. 
PFS Per Investigator Assessment ...............................................................................29 
8.5.2.3. 
Best Overall Response ................................................................................................30 
8.5.2.4. 
Duration of Response .................................................................................................31 


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8.5.2.5. 
Time to Treatment Failure ..........................................................................................32 
8.6. 
Interim Analysis ..........................................................................................................32 
8.7. 
Safety Analysis ...........................................................................................................33 
8.7.1. 
Adverse Events ...........................................................................................................33 
8.7.2. 
Extent of Treatment Exposure ....................................................................................34 
8.7.3. 
Clinical Laboratory Tests ...........................................................................................35 
8.7.4. 
Physical Examination Findings ..................................................................................35 
8.7.5. 
Vital Signs ..................................................................................................................35 
8.7.6. 
ECOG performance status ..........................................................................................36 
8.7.7. 
Electrocardiogram (ECG) ...........................................................................................36 
8.8. 
Additional Data Presentation as Listing .....................................................................36 
APPENDIX 1. EUROPEAN ORGANIZATION FOR THE RESEARCH AND 
TREATMENT OF CANCER: PR-30-5010-C STATISTICAL ANALYSIS 
PLAN ..........................................................................................................................37 
 
LIST OF TABLES 
Table 1: Summary Table ................................................................................................................11 
Table 2: Application of Populations on Tables, Listings, and Figures ..........................................22 
Table 3: Censoring Rules for PFS Per Central Review .................................................................28 
Table 4: Censoring Rules for PFS Per Investigator Assessment ...................................................30 
Table 5: Censoring Rules Used for Duration of Response Analysis .............................................32 
 
LIST OF FIGURES 
Figure 1: Study Schema .................................................................................................................10 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Explanation  
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Plasma or Serum Concentration 
AUCss 
Area Under the Plasma or Serum Concentration at Steady State 
BMI 
Body Mass Index 
CI 
Confidence Interval  
CL/F 
Clearance After Oral Administration 
Cmax 
Maximum Observed Plasma or Serum Concentration 
Cmax, ss 
Maximum Observed Plasma or Serum Concentration at Steady State 
Cmin 
Minimum Observed Plasma or Serum Concentration 
Cmin, ss 
Minimum Observed Plasma or Serum Concentration at Steady State 
CR  
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of Response  
ECG 
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
EQ-5D-5L 
Euroqol 5 Dimension 5 Level  
ER 
Estrogen Receptor                                                                              
GSK 
Glaxo Smith Kline 
HER-2 
Human Epidermal Growth Factor Receptor 2                                                       
HRQoL 
Health-Related Quality of Life 
ID 
Identifier 
ITF 
Time to Treatment Failure  
ITT 
Intent-To-Treat 
IV 
Intravenous(ly) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NCCN 
National Comprehensive Cancer Network 
ORR 
Overall Response Rate 
OS 
Overall Survival                                                                               


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PD 
Progressive Disease                                                                            
PDV 
Important or Significant Protocol Deviation 
PFS 
Progression Free Survival 
PRO 
Patient Reported Outcomes  
PT 
Preferred Term                                                              
QD 
Quaque Die (Once Daily) 
QLQ-C30 
Quality of Life Questionnaire C30 
QoL 
Quality of Life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event                                                                          
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class                                                                             
STD  
Standard Deviation 
TEAE 
Treatment Emergency Adverse Event 
Vz/F 
Volume of Distribution After Oral Administration 
WHO 
World Health Organization  
 
 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) is designed to outline the statistical methods for evaluating 
the safety and efficacy of investigational drug niraparib for TESARO study protocol PR-30-
5010-C: A phase III, randomized, open label, multicenter, controlled trial of niraparib versus 
physician’s choice in previously-treated, HER2 negative, germline BRCA mutation-positive 
breast cancer patients. 
 
This document has been prepared based on study protocol version 6.0 dated January 13, 2017. 
This SAP is intended to supplement but not supersede the core SAP issued by the European 
Organization for the Research and Treatment of Cancer (EORTC), approved on  
January 24, 2017 (Appendix 1). 
 
 
 


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2. 
STUDY DESIGN OVERVIEW 
2.1. 
Overall Study Design 
This study is a randomized, open-label, multicenter, controlled trial to compare niraparib versus 
physician’s choice, amongst one of the following 4 single agents: eribulin, vinorelbine, 
gemcitabine or capecitabine, in patients with HER2-negative gBRCAmut breast cancer. Patients 
will be centrally registered at the EORTC Headquarters prior to the start of treatment, and after 
verification of the eligibility criteria, eligible patients will be randomized 2:1 to receive niraparib 
orally at a dose of 300 mg QD on a continuous dosing regimen or physician’s choice amongst 
one of the following four single agents (eribulin, vinorelbine, gemcitabine, or capecitabine) 
according to the national available and approved treatment (gemcitabine will be administered as 
single agent as per NCCN guidelines. In France, gemcitabine is not allowed to be chosen as a 
treatment in the physician's choice arm).  
The study schema is presented Figure 1. 
Screening assessments to determine patient eligibility for the study and to assess baseline disease 
status will be conducted within 28 days prior to the first dose (cycle 1/day 1). Clinic visits will be 
conducted at the beginning of every cycle (i.e., every 3 weeks ± 3 days). Contrast enhanced 
computed tomography (CT) or magnetic resonance imaging (MRI) if CT is not feasible will be 
required at screening and every 2 cycles (6 weeks ± 7 days) for the first 12 months, then every 3 
cycles (9 weeks ± 7 days) until disease progression. Patients will continue their assigned 
treatment until disease progression (determined by Response Evaluation Criteria in Solid Tumors 
[RECIST] v.1.1), unacceptable toxicity, death, withdrawal of consent, or they are lost to follow-
up.  
Evaluation of CT scans and MRI, including determination of response to treatment and date of 
progression based on RECIST v.1.1, will be conducted by a central blinded review committee 
comprised of 2 radiologists, with an arbiter as necessary. Results of the central blinded 
assessment will be used to determine the primary efficacy endpoint of PFS and will be conducted 
retrospectively. The study investigators also will assess response to treatment and date of 
progression based on RECIST v.1.1 during the conduct of the study.  
Patient reported outcomes (PROs) will be evaluated at screening, during the treatment period and 
after treatment discontinuation for a maximum period of up to 12 months after randomization. 
All patients randomized to niraparib will also undergo sparse blood sampling (predose and 2 
hours postdose except for cycle 4, day 1 that will be done only predose) at specified study visits 
for measurement of plasma levels of niraparib and translational protocol specified analyses.  
 
Safety will be evaluated throughout the study by adverse event (AE) monitoring and clinical 
laboratory assessments (hematology, chemistry), vital signs, electrocardiograms (ECGs), 
physical examinations, and use of concomitant medications.  


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Figure 1: Study Schema  
 
 
After treatment discontinuation, information on subsequent anticancer therapy and survival 
(including new malignancy information) will be collected. If the patient discontinues prior to 
disease progression, tumor imaging, and assessment of PROs, will continue during the post-
treatment phase at specified time intervals until disease progression or until the patient starts 
his/her subsequent anticancer therapy. No crossover to niraparib is permitted following 
discontinuation from physician’s choice treatment.  
 
The study schedule is summarized in Table 1.  
 
 


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Table 1: Summary Table 
Cycle1 
Registration 
Screen 
C1 
C2 
Subsequ
ent  
cycles2 
Study 
Medication 
Termination 
(to occur 
within 28 
days of start 
of Last 
cycle) 
Post- treatment follow-up 
30-
Day 
Follo
w- up 
Every 6 weeks ± 
7 days for the 
first 12 months 
and then every 9 
weeks ± 7 days 
until PD or 
subsequent 
treatment 
Follow-up 
every 3 
months 
Day 
At any time 
prior to  
screening 
-28 to 
day 1 
D1 
D8 
D15 
D1 
D8 
Cycle n, 
 
Day 1 
Informed Consents 
X 
X 
Demographics 
X 
Medical, surgical, cancer, medication 
history 
X 
Blood sample for gBRCA mutation 
analysis3 
X 
Blood sample for companion diagnostic 
test4 
X 
Archival tumor samples5 
X 
X 
Optional tumor biopsy6 
X 
X6 
X6 
Pregnancy test7 
X7 
Randomization 
X8 
Physical examination 
X 
X 
X 
X 
X 
Vital signs, height9, weight 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
Adverse event monitoring 
X23 
X 
X 
X 
X 
X 
X 
Collection of prior history of 
myelosuppression (i.e. anemia, 
neutropenia, leukopenia and 
thrombocytopenia) 
X 
Serious adverse event monitoring 
X23 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
Hematology (CBC only) 
X 
X10 
X 
X 
X 
X 
X 
X 
INR/aPTT 
X10 
Serum Chemistry 
X 
X10 
X 
X 
X 
Urinalysis 
X 


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12-lead ECG 
X 
X11 
X11 
X12 
X 
Blood sample for biomarkers13 
X 
X13 
X 
Blood sample for pharmacokinetic 
analysis 
X14 
X14 
X15 
Tumor Assessment (RECIST v1.1) 
Chest, abdomen, pelvis CTs or MRIs.16 
X 
X16 
X16 
X16 
X16 
CA-125 measurement in case of 
peritoneal disease and previously 
diagnosed ovarian cancer 
X 
HRQoL17 
X 
X17 
X17 
X17 
Niraparib capsules dispensed/collected 
or Physician’s choice treatment18 
X 
X 
X 
X19 
Sample collection (whole blood) for 
mutational profile testing20 
X20 
X20 
Additional tests to confirm the diagnosis 
of MDS/AML21 
X21 
X21 
Anti-cancer therapies assessment 
X22 
Survival Assessment 
X22 
1 Treatment cycles are 21 days (3 weeks) long, visits on Day 1 of each cycle, unless otherwise specified (A 28-day cycle regimen may apply to the intravenous administration of 
physician's choice vinorelbine)  
2 Visits continue every 3 weeks until study medication termination visit.  
3 Centralized germline BRCA mutation (gBRCAmut) testing of DNA. Patient blood sample may be drawn and performed at any time prior to randomization. Enrollment will be 
based on either central or local positive for germline BRCA mutation result.  
4 A second blood sample will be archived for test bridging.  
5 Formalin-fixed, paraffin-embedded tumor samples (primary or metastatic site; tumor blocks or 20 slides of 5 micron thickness). Genetic and non-genetic markers relating to 
DNA repair will be tested (alternatively can be done after randomization or during cycle 1).  
6 A fresh tumor biopsy (FFPE and snap frozen cores) may be performed at screening and one time at progression using separate informed consent. Genetic and non-genetic 
markers relating to DNA repair and/or markers that predict efficacy and safety of PARP inhibitors will be tested.  
7 Negative serum pregnancy test required within 72 hours prior to the first dose of study medication for females of childbearing potential. Pregnancy test will occur per site 
processes; please refer to the niraparib Investigator's Brochure for guidance.  
8 Randomization should occur within 72 hours prior to first dose (Cycle 1, Day 1). Note that physician’s choice treatment must be designated prior to randomization.  
9 Height obtained at screening only.  
10 If screening laboratory testing [hematology (CBC plus INR and aPTT), chemistry] was performed within 72 hours of Cycle 1, Day 1, repeat testing not required. Please note 
that during the first month of study treatment, it is mandatory to perform weekly blood draws for CBC for both treatment arms. INR and a PTT will be done only at screening.  
Also in case of a dose modification due to hematologic toxicity, weekly blood draws for CBC will be required for an additional 4 weeks after the adverse event has been resolved 
to baseline or grade 1, after which monitoring every 3 weeks may resume.  
11 For the niraparib arm only :12-lead ECG conducted, Cycle 1, Day 1 (predose and 2 hours post dose), Cycle 2, Day 1 (predose and 2 hours postdose), and cycle 1 and Cycle 2 
Day 1 assessments should be conducted prior to blood draws for PK assessments.  
12 12-lead ECG as clinically indicated in subsequent cycles.  
13 Blood samples will be taken at screening, at 6 weeks (Cycle 3/Day1) and at treatment termination (due to progression or due to any other cause). Analysis of circulating 
genetic and non-genetic markers relating to DNA repair and/or markers that predict efficacy and safety of PARP inhibitors will be tested.  
14 Blood samples for measurement of plasma levels of niraparib collected on Cycle 1, Day 1 and Cycle 2, Day 1 predose (within 30 minutes) and 2 hours post dose.  
15 Additional blood samples for plasma levels of niraparib collected on Cycle 4, Day 1 predose (within 30 minutes).  


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16 Chest, abdomen and pelvis CT or MRI as well as CTs or MRIs scans of any other known sites of the disease are required at screening; thereafter every 6 weeks ±7 days (i.e. 
every 2 cycles) for the first 12 months, then every 9 weeks ±7 days (i.e. every 3 cycles) until disease progression. Tumor assessments must continue on schedule if patients have 
dose delays.  
If the patient discontinues prior to disease progression, tumor imaging will continue at specified time intervals (every 6 weeks ± 7 days during the first 12 months after 
randomization, and then every 9 weeks ± 7 days weeks) until progression or until the start of subsequent anti-cancer therapy.  
Patients without measurable disease at baseline are not excluded from this study. These patients should be followed with the same assessment schedule as those with measurable 
disease at baseline and throughout the study.  
17 Questionnaires include EORTC QLQ-C30 and EQ-5D-5L (protocol, Appendix F and Appendix I). The time schedule is detailed in the protocol, Section 10.4.1. The 
questionnaires must be filled within 4 weeks before randomization and subsequent questionnaires are filled in every 2 cycles (i.e., every 6 weeks ±7 days) for the first 12 months 
while on-treatment and every 3 months after study medication discontinuation. HRQoL forms will be collected regardless of progression status and will be limited to the first 12 
months after randomization.  
18 Physician’s choice chemotherapy (eribulin, vinorelbine, gemcitabine, or capecitabine) to be administered according to product package insert or local standard of care. 
Gemcitabine will be administered as single agent as per NCCN guidelines. In France gemcitabine is not allowed to be chosen as a treatment in the physician's choice arm.  
19 No new study medication dispensed.  
20 Blood samples collected at screening and EOT (due to any cause including development of new MDS/AML) will be stored for evaluation if necessary for assessing niraparib- 
related risk for MDS/AML development (e.g if the patient develops MDS/AML during treatment or post- treatment follow- up). Mutation profile before and after study treatment 
will be compared to determine whether any mutations were present prior to study treatment. Additional details on sample collection and analysis can be found in protocol Section 
12.3.5.  
21 For a highly clinically suspected MDS/AML case reported while a patient is receiving treatment with the study drug or being followed for post- treatment assessments; the 
patient should be referred to the local hematologist to confirm the diagnosis of MDS/AML. Results of any additional tests performed by the hematologist should be reported as 
well in the e- CRF. Testing with bone marrow aspirate and biopsy is strongly recommended in these cases. The study site must receive a copy of the hematologist's report of 
aspirate/ biopsy findings which must include a classification according to World Health Organization (WHO) . A whole blood sample will be also collected for mutational profile 
testing for any highly clinically suspected MDS/AML case reported during treatment.  
22 Assessments to occur every 3 months following study medication discontinuation. In addition to survival, this assessment includes outcomes for subsequent anticancer 
therapies including any new malignancy information.  
23 From registration. Registration must be done directly after informed consent signature by the patient 


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2.2. 
Sample Size 
At least 306 gBRCAmut patients, confirmed by the centralized test, will need to be randomized.  
The overall sample size for this study is based on the overall survival endpoint and is determined 
based on the alternative hypotheses that niraparib will result in an improvement of 4 months in 
median survival of 9 to 13 months (corresponding to a hazard ratio = 0.69). For a true hazard 
ratio of 0.69, 265 deaths will provide 80% power (1-sided alpha = 0.025). Assuming 10 patients 
eligible for the primary analysis population for efficacy are enrolled per month in, with 306 
patients, 265 deaths are expected to occur approximately 54 months after the first patient 
enrolled.  
Assuming 40% of patients will be randomized on the basis of a local BRCA test and assuming 
that 15% of those patients will not be BRCA mutated per central test, it is estimated that an over-
enrollment by 18 patients is needed to obtain the required 306 patients in the analysis population. 
The final PFS analysis is planned after 137 PFS events have occurred or end of recruitment, 
whichever occurs later. With 137 PFS events, there is 80% power (1- sided alpha=0.025) to 
detect an HR 0.6 (equivalent to 3 to 5 months).  
2.3. 
Randomization and Stratification 
Patients will be centrally randomized in a 2:1 ratio (treatment: physician’s choice). Permuted 
block randomization will be used for random treatment allocation stratifying by visceral disease 
(yes vs no), histology (TNBC vs ER/PR positive) and number of lines of prior cytotoxic 
chemotherapy (not including hormonal therapy) for advanced/metastatic disease (0-1 or 2).  


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3. 
STUDY OBJECTIVES 
3.1. 
Primary Objective 
The primary objective of this study is to compare progression-free survival (PFS), as assessed by 
blinded central review, of patients with advanced/metastatic HER2-negative gBRCAmut breast 
cancer when treated with niraparib as compared to those treated with physician’s choice single 
agent chemotherapy standards (eribulin, vinorelbine, gemcitabine or capecitabine). 
3.2. 
Secondary Objectives 
3.2.1. 
Key Secondary Objective 
To compare overall survival (OS) of patients with advanced/metastatic HER2-negative 
gBRCAmut breast cancer when treated with niraparib as compared to those treated with 
physician’s choice single agent chemotherapy standards (eribulin, vinorelbine, gemcitabine or 
capecitabine) 
3.2.2. 
Other Secondary Objectives 
• To establish germline BRCA mutation status of screened patients using a centrally 
provided, validated test as well as future tests, and determine concordance between 
tests for the purpose of developing a commercial companion diagnostic test  
• To evaluate safety and tolerability as measured by all AEs  
• To compare PFS using investigator assessment of progression  
• To evaluate time to treatment failure (discontinuation of treatment for any reason)  
• To compare response rate and duration of response  
• To compare time to deterioration of health-related quality of life (HRQoL): European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
(EORTC QLQ-C30) and EuroQol 5 Dimension 5 Level (EQ-5D-5L)  
• To describe subsequent therapies and potential relationships with outcomes  
• To assess genetic and non-genetic biomarkers relating to treatment efficacy. Germline 
and tumor mutations may be explored including somatic BRCA1 and 2 mutations, 
reversion mutations, loss of heterozygosity as well as genome landscape and 
transcriptional or functional measures of homologous recombination (HR) deficiency.  
• To assess outcomes by germline mutation BRCA1 vs BRCA2 
• Descriptive summary statistics will be used to summarize post- treatment data (i.e 
subsequent anticancer therapies and any new malignancy). 
 
 


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4. 
STUDY ENDPOINTS AND EVALUATION 
4.1. 
Efficacy Endpoints  
4.1.1. 
Primary Efficacy Endpoints 
PFS per blinded central review, defined as the time from randomization to the earliest date of 
death or disease progression (PD).  
4.1.2. 
Key Secondary Efficacy Endpoints 
Overall survival (OS), defined as the time from randomization to the date of death of any causes. 
4.1.2.1. 
Other Secondary Efficacy Endpoints 
• Progression-free survival (PFS) using investigator assessment of progression, defined 
as the time from randomization to the earliest date of death or date of disease 
progression (PD) as reported by investigator.   
• Overall response rate (ORR), defined as percentage of patients who achieved CR or 
PR to treatment evaluated using RECIST v1.1      
• Duration of response (DOR), defined from the time measurement criteria for CR or 
PR (whichever is first recorded) are first met until the first date that recurrent or 
progressive disease is objectively documented. 
• Time to treatment failure (TTF), defined as the date of randomization to 
discontinuation of treatment for any reason, including but not restricted to disease 
progression, treatment toxicity and death.   
4.2. 
Safety Evaluations 
• Treatment emergent adverse events (TEAEs) 
• Clinical laboratory assessment 
- Hematology (CBC only) 
- Biochemistry  
- Urinalysis at baseline 
- Serum pregnancy testing at baseline 
• Physical examination findings 
• Vital signs including weight  
• ECOG performance status 
• ECG findings 
4.3. 
Demographics and Baseline Characteristics 
• Demographics and baseline characteristics 
• Medical history 


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− Medical history 
− History of myelosuppression 
• Disease history 
− Initial diagnosis and primary/adjuvant treatment 
− Treatment of the current breast cancer in the metastatic setting 
− Ovarian cancer 
− Other invasive malignancies 
• Previous and concomitant medications 
4.3.1. 
Pharmacokinetics Evaluations 
Blood samples for measurements of plasma levels of niraparib will be obtained in the 
experimental arm on cycle 1/ day 1 and on cycle 2/ day 1 at the following timepoints: 0 (pre-dose 
within 30 minutes) and 2 hours post dose. In subsequent cycles, a blood sample for 
measurements of plasma levels of niraparib will be obtained on cycle 4/ day 1 pre-dose (within 
30 minutes) only. 
The plasma concentration-time data is analyzed by non-compartmental analysis using 
WinNonlin version 6.2.1 or higher.  
PK evaluations include:  
• Plasma concentrations 
• Pharmacokinetic parameters 
A PK analysis was not conducted and will not be described in a separate analysis plan. 
4.4. 
Quality of Life Assessment 
Health related quality of life (HRQoL) is used to evaluate patients’ quality of life associated with 
the medical strategies on cancer treatment. 
Patients’ life quality evaluation includes: 
• Time to deterioration of health-related quality of life assessed by QLQ-C30  
• Time to deterioration of health-related quality of life assessed by EQ-5D-5L  
Here, time is defined as the time of randomization to the first observed events of death, 
progression, or deterioration. An HRQoL analysis was not conducted and will be not addressed 
in a separate analysis plan. 
4.5. 
Translational Research 
The translational research evaluations include: 
• Concordance between gBRCAmut tests  
• Subsequent therapies and potential relationships with outcomes  
• Genetic and non-genetic biomarkers relating to treatment efficacy 


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• Outcomes by germline mutation BRCA1 vs BRCA2 
A translational research analysis was not conducted and will not be described in a separate 
analysis plan. 
 
 


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5. 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
5.1. 
Definition of Baseline 
For all evaluations unless otherwise noted, baseline is defined as the most recent non-missing 
measurement prior to or on the first administration of study drug. Baseline can be the same date 
as first dose, given the measurement is expected prior to first dose when only date information is 
available. 
5.2. 
Definition of Treatment Period 
Treatment period is defined as the time from the first dose of study treatment through 30 days 
after last dose of study treatment. 
5.3. 
Definition of Relative Study Days 
Unless otherwise noted, relative study days (Rel Days) of an evaluation are defined as number of 
days relative to the first dose date of study drug which is designated as Day 1, and the preceding 
day is Day -1, the day before that is Day -2, etc. Relative study days are calculated as an 
evaluation date minus first dose date of study drug, and plus 1 day if evaluation date is on or 
after first dose date.   
Relative study days take negative values if evaluation date occurs prior to first dose date and take 
positive values if evaluation date occurs on or after first dose date of study drug. 
5.4. 
Analysis Visit Window 
5.4.1. 
Safety Analysis Visit Window 
For safety parameters as described in Section 4.2, measurements collected from unscheduled 
visits will not be included in the by-visit summary tables but will be included in the listings. 
Early termination visits for safety measurements will not be mapped to any scheduled post-
baseline visit but will be used as the last assessment during treatment period.  
5.4.2. 
Efficacy Analysis Visit Window 
For efficacy assessment, all records including unscheduled visit will be included in the analysis. 
5.5. 
Safety Data Handling 
For all safety data, only observed data will be used for analyses, and missing data will not be 
imputed. 
5.5.1. 
Handling of Repeated Clinical Laboratory Tests 
For repeated tests, the highest or lowest laboratory result reported at the visit will be recorded in 
the summary table.. Lab results beyond the detectable limits will be reported as detectable limits 
for calculating descriptive statistics.  
All the laboratory test results will be included in the data listings as reported. 


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5.5.2. 
Handling of Partial Dates for Adverse Events   
When determining the treatment emergent AE, partial dates will be handled as follows.  
• If the day of the month is missing, the onset day will be set to the first day of the 
month unless it is the same month and year as first dose date. In this case, the onset 
date will be assumed to be the first date of treatment. 
• If the onset day and month are both missing, the day and month will be assumed to be 
January 1, unless the event occurred in the same year as the study treatment. In this 
case, the event onset will be coded to the day of treatment to conservatively report the 
event as treatment-emergent.  
• A missing onset date will be coded as the day of treatment. If the resulting onset date 
is after a reported date of resolution, the onset date will be set equal to the date of 
resolution.   
• Imputation of partial dates is used only to determine whether an event is treatment-
emergent; data listings will present the partial date as recorded in the eCRF. 
5.5.3. 
Handling of Partial Dates for Medications  
When determining prior or concomitant medications, partial start dates of prior and concomitant 
medications will be assumed to be the earliest possible date consistent with the partial date. 
Partial stop dates of prior and concomitant medications will be assumed to be the latest possible 
date consistent with the partial date. In the case of completely missing stop date, medication will 
be assumed to be ongoing. In the case of complete missing start date, medication will be 
assumed to be prior medication. 
 
 


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6. 
PLANNED ANALYSIS 
6.1. 
Changes from Planned Analyses in the Protocol 
Changes from planned analyses described in the Protocol are as follows: 
• The per protocol patient population and derived analyses (sensitivity and efficacy) 
were eliminated  
• Results from analyses of PK evaluations, PROs, and translational research will not be 
reported.  
• Predefined incidence and thresholds of marked abnormalities for specific safety 
parameters such as clinical laboratory parameters, vital signs, and ECGs will not be 
reported  
• Descriptive statistics for the individual single-agent therapies (eribulin, vinorelbine, 
gemcitabine or capecitabine) comprising the physician’s choice arm will not be reported. 
6.2. 
Interim Analysis 
There will be interim analysis for futility for PFS per central review and for overall survival 
which will be performed using the centrally confirmed intent to treat (ITT) population.  
Interim analysis for futility for PFS per central review will be done based on an estimate of when 
the required 93 events will be reached. A gamma family beta-spending function with a non-
binding gamma (γ=-5) stopping boundary based on the actual number of PFS events at the time 
of interim analysis data cutoff and the minimum total target number of events of 137 will be used 
for the interim futility analysis of PFS, i.e. the information fraction for futility analysis is equal to 
the number of events observed at the interim analysis divided by 137. The futility boundary will 
be assessed by the EAST 6 software. 
The interim analysis for overall survival will be performed using the locked database for the final 
analysis report. The analysis will utilize O’Brien-Fleming type boundaries derived from the Lan 
DeMets alpha spending function based on the actual number of events observed at the time of the 
interim analysis. 
6.3. 
Final Analyses and Reporting 
All final planned analyses per protocol and this SAP will be performed only after database lock. 
 
 
 


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7. 
ANALYSIS POPULATION AND APPLICATION 
7.1. 
Screening Population  
The Screening Population includes all screened and registered patients who sign an informed 
consent form and will be used for the patient disposition, protocol deviation, and inclusion or 
exclusion analysis. 
7.2. 
Centrally Confirmed ITT Population  
The Centrally Confirmed ITT Population includes all randomized patients with centrally 
confirmed germline gBRCA mutation. The Centrally Confirmed ITT population is the primary 
analysis population for all efficacy analyses. Analyses involving the ITT population will group 
patients by the randomized treatment arm, which does not necessarily correspond to the 
treatment they received.  
7.3. 
Full ITT Population  
The Full ITT population includes all randomized patients. Analyses involving the ITT 
Population will group patients by the randomized treatment arm, which does not necessarily 
correspond to the treatment they received. 
7.4. 
Safety Population  
The Safety population (SP) includes all patients who started their allocated treatment (receive at 
least one dose of allocated drug). The SP will be the primary analysis population for the safety 
analyses. Analyses involving the SP population will group patients by the treatment they actually 
received. 
7.5. 
Analysis Populations Application 
Unless otherwise noted, the analysis populations that will be used for creating the summary 
table(s) and listings of each type is provided in Table 2. 
Table 2: Application of Populations on Tables, Listings, and Figures 
Type 
Screening 
Safety 
Centrally confirmed ITT 
Full ITT 
Enrollment 
X 
X 
X 
X 
Disposition 
 
X 
X 
 
Protocol deviations 
 
 
X 
 
Demographics and baseline characteristics 
 
X 
X 
 
Medical history 
 
 
X 
 
Disease history 
 
 
X 
 
Prior and concomitant medications 
 
X 
 
 
Safety evaluations 
 
X 
 
 
Treatment exposure  
 
X 
 
 
Efficacy analysis  
 
 
X 
 
Sensitivity analysis for PFS 
 
 
X 
 


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8. 
STATISTICAL CONSIDERATION 
All summaries and statistical analysis will be performed by SAS v9.3 or later.  
8.1. 
General Statistical Procedures 
Frequency distributions for categorical variables will be provided as number of patients with a 
response in the category and the percentages of the total number of patients in that column.  
Percentages will be based on number of patients in the given population as noted. Percentages 
will be reported to one decimal place.  
A 2-sided 95% confidence interval (CI) for categorical variables without multiplicity adjustment 
will be provided where appropriate for efficacy analysis. When comparison of test is required, p-
value will be reported as < 0.001 if it is smaller 0.001, otherwise it will be report to 3 decimal 
places. 
The descriptive statistics for continuous variables will be number of patients, mean, standard 
deviation (STD), median, minimum and maximum.   Mean and median will be reported to 1 
more decimal place than the raw data, while the STD will be reported to 2 more decimal places 
than the raw data. Minimum and maximum will be reported the same as the original data.  
Time-to-event analyses will be performed using Kaplan-Meier methods and a Cox proportional 
hazard model. 
If stated, relative study day (Rel days) which is defined as number of days relative to the first 
dose date of study drug (see Section 5.3 for details) will be included in the data listing. 
In general, all listings will be ordered by patient ID, treatment arm and visit for available data 
unless otherwise specified in the text.   
Safety and efficacy analysis visit windows, safety data handling (repeated laboratory tests, partial 
dates of AEs and medications) are described in Section 5.4 and Section 5.5.  
8.2. 
Enrollment and Disposition  
8.2.1. 
Patients Enrollment 
Patients enrollment will be summarized for each treatment arm. The number of patients in each 
analysis population will be presented by treatment arm and overall. 
Enrollment information will be provided in a data listing. 
8.2.2. 
Patients Disposition 
Study status including primary reasons for discontinuation from treatment will be tabulated using 
frequency distribution by treatment arm.  
Discontinued patients from treatment will be provided in a data listing. 
8.3. 
Protocol Deviations 
Important or significant protocol deviations (PDVs) will be assessed by sponsor personnel 
following Protocol Deviation Guideline outlined in Clinical Management Plan.  


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A PDV is classified as important if there is the potential to impact the completeness, accuracy, 
and/or reliability of the study data, or affect a patient’s rights, safety, or well-being. An important 
PDV is subclassified as significant if it is confirmed to adversely impact the completeness, 
accuracy, and/or reliability of the study data, or affect a patient’s rights, safety, or well-being. All 
PDVs will be identified and finalized prior to database lock and documented.   
Number and percentage of patients with a significant or important PDV will be tabulated by type 
of deviation.  
All protocol deviations will be listed.  
8.4. 
Demographics and Baseline Characteristics 
8.4.1. 
Patients Demographics and Baseline Characteristics 
Demographic and baseline (see Section 5.1 for definition) characteristics will be tabulated using 
descriptive statistics by treatment arm. The following variables will be included in the tables:  
• The demographic data are: 
− Age at screening (years) 
− Age at randomization and category (years) and in categories 18-64, 65-74, ≥ 65, ≥ 
75 
− Sex 
− Race 
− Ethnicity 
• Baseline characteristics include: 
− Height (cm) 
− Weight (kg) 
− body mass index (BMI) (BMI kg/m2, calculated as weight (kg) / height (m)2) 
− ECOG performance status  
− Previous BRCA mutation 
− Central BRCA mutation (positive, BRCA1+ only, BRCA2+ only, rearrangement 
only, BRCA1 & BRCA2, BRCA1+ & rearrangement, BRCA2+ & 
rearrangement) 
− Estrogen receptor (ER) status 
− Progesterone receptor (PR) status 
− HER2 status 
− Hormone receptor (HR) status 
− Presence of bone metastases 
− Presence of brain metastases 


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− Visceral disease 
− Histology 
− Number of lines of prior cytotoxic chemotherapy (not including hormonal 
therapy) for advanced/metastatic disease (0, 1-2, or >2)  
Conversions for height and weight are as follows: 
Weight (kg) = Weight (lb) x 0.4536 
Height (m) = Height (cm) x 0.1 
Demographics and baseline characteristics will be listed. 
8.4.2. 
Medical History 
The medical history will be coded using the current version of Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary. The frequency count and percentage of patients 
experiencing any medical conditions will be tabulated by system organ classifications (SOC) and 
preferred term (PT) of MedDRA for each treatment arm.   
Prior myelosuppression history will be summarized using frequency distribution for each 
treatment arm. 
A data listing of medical history and disease history will be provided. 
8.4.3. 
Disease History 
Disease history will be tabulated using descriptive data by treatment arm for the following parts. 
Summary of initial diagnosis and primary/adjuvant treatment of the current breast cancer:   
• Time from first diagnosis to date of randomization (months) 
• Tumor stage at initial diagnosis 
• T status at initial diagnosis 
• N status at initial diagnosis 
• M status at initial diagnosis 
• Histology at initial diagnosis 
• Grade at initial diagnosis  
• Additional biopsy performed for metastatic/recurrent disease 
− Histology after biopsy 
− Grade after biopsy 
• Surgery performed for primary tumor 
• (Neo-)adjuvant therapy received  
• (Neo-)adjuvant endocrine therapy received 


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• (Neo-)adjuvant  radiotherapy received 
• Number of chemotherapy regimens in metastatic setting   
• Total duration of chemotherapy in metastatic setting 
• Endocrine therapy regimens in metastatic setting 
• Any radiotherapy given in metastatic setting 
• Other systemic therapy in metastatic setting 
• Prior platinum treatment 
• Prior diagnosis of malignancy other than breast/ovarian cancer 
• Prior diagnosis of ovarian cancer 
8.4.4. 
Prior and Concomitant Medications  
All medications as documented by the Investigator will be coded using Anatomical Therapeutic 
Chemical (ATC) classification based on the World Health Organization (WHO) Drug Dictionary 
(WHO-DD Sept 2016).  
The count and percentage of patients who took prior and concomitant medications will be 
provided WHO Drug ATC level 3 and preferred term (PT) for each treatment arm. For the 
summary tables, if a patient has taken a prior or concomitant medication more than once, the 
patient will be counted only once for the medication. 
Prior medications are defined as any medications, other than study treatment, medications for 
cancer treatment and pre-medications for study treatment, which ended prior to the first dose 
date of study treatment. 
Concomitant medications are medications other than study treatments, being taken on or after the 
initial study treatment dosing date through 30 days after the last dose or until the start of 
subsequent antitumor therapy.  
The use of prior medications, that includes prior anticancer regimens and concomitant 
medications will be provided in a by-patient data listing. 
 
 
 


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8.5. Efficacy Analysis 
RECIST v1.1 will be used by  central review as the primary measure for assessment of tumor 
response, date of disease progression. Tumor response will be assessed every 6 weeks ±7 days 
(i.e. every 2 cycles) for the first 12 months, then every 9 weeks ±7 days (i.e. every 3 cycles) until 
disease progression.  
Primary efficacy analysis for PFS per central review will be evaluated using stratified log-rank 
test. Kaplan-Meier estimates for PFS and OS with the corresponding 2-sided 95% confidence 
intervals will be presented. A non-stratified log-rank test will also be performed to assess the 
robustness of the primary result.  
In addition, Cox proportional hazards model with a term for treatment arm will be used to 
estimate the treatment hazard ratio and its 2-sided 95% confidence interval.  
Assessment at unscheduled visit will also be included in the analysis (see Section 5.4.2). 
8.5.1. 
Primary Efficacy Endpoint Analysis 
8.5.1.1. 
PFS per Central Review 
The primary efficacy analysis is to compare the progression free survival (PFS) per central 
review between niraparib treatment arm and physician’s choice arm.  
A log-rank test stratified on randomization factors (see Section 8.4.1 for definition) will be used 
to assess the difference of PFS between two arms at 1-sided α-level of 0.025 for the following 
hypothesis:  
H0: PFS(t)physician’s choice = PFS(t)niraparib   
Ha: PFS(t)physician’s choice < PFS(t)niraparib 
where PFS(t) represents the PFS function at any time (t). 
The PFS per central review is defined as the time from randomization to the earliest date of 
disease progression (PD) or the date of death. PFS in months will be calculated as:  
(Earlier date of PD or death – Date of randomization + 1) / 30.4375.  
If the patient did not experience an event, patient will be censored. The detailed censoring and 
event rules according to FDA guidance on Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics are described in Table 3.  
 


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Table 3: Censoring Rules for PFS Per Central Review 
Condition 
Date of event /censoring 
Censoring 
Event 
No baseline radiologic tumor assessments 
Date of randomization 
Yes 
No 
Documented Progression  
Date of radiologic tumor assessment 
showing disease progression 
No  
Yes  
No documented progression, no death 
Date of last documented central tumor 
assessment 
Date of randomization if only baseline 
radiologic tumor assessments are 
available,  
Yes 
No 
Treatment discontinuation for 
undocumented progression, or toxicity, or 
any other reason (apart from documented 
progression) 
Date of last documented central 
radiologic tumor assessment 
 
Yes 
No 
New anticancer treatment started 
Date of last documented radiologic 
tumor assessment before initiation of 
new anti-cancer treatment 
Yes 
No 
Death before first PD assessment 
Date of death 
No 
Yes 
Death in between 2 adequate assessment 
visits * 
Date of death 
No 
Yes 
Death or progression after more than 1 
missed adequate assessment visit * 
Date of last documented central 
radiologic tumor assessment before the 
missed visits 
Yes 
No 
* Adequate on-protocol imaging requires an assessment every 6 week (± 7 days) for the first 12 months, and then 
every 9 weeks (± 7 days) thereafter, from start of study treatment until progression or start of subsequent 
anticancer treatment. 
8.5.1.2. 
Sensitivity Analyses 
The following sensitivity analysis will be performed to assess the robustness of the primary 
result:  
• Repeat the same for Centrally Confirmed ITT Population 
• Perform non-stratified log-rank test 
• Perform univariate Cox model (non-stratified) adjusting for potential prognostic factors 
and potential imbalances therein 
- Niraparib treatment 
- Age (55-70, >70) using age < 55 as reference group 
- ECOG performance status (1-2) using ECOG=0 as reference group 
- Visceral disease (yes, no) as NO as reference group 
- Histology (ductal, lobular, other) using ductal Other as reference group 
- Number of lines of prior cytotoxic chemotherapy (not including hormonal therapy) 
for advanced/metastatic disease (0 vs. 1-2) using 0 as reference group 
- Prior platinum treatment (no vs yes) using NO as reference group 
- Germline mutation (BRCA-1 only, BRCA-2 only) using both as reference group 
 


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Cases with missing values for 1 of the above factors are excluded from the model when the 
factor is included in multivariate Cox model. 
Hazard ratio with 95% 2-sided Wald CI will be reported for each factor in univariate and final 
multivariate Cox model.  
8.5.1.3. 
Homogeneity of Results across Subgroups   
Subgroup analyses will be performed for the following baseline factors by means of Cox models 
(with Breslow ties) including the factor of interest and the randomized treatment if the subgroup 
contains at least 10% of the patients of the centrally confirmed ITT population:  
• Age 55-70, >70) 
• ECOG performance status (0 vs 1-2) 
• Visceral disease positive 
• Histology (ductal, lobular) 
• Number of lines of prior cytotoxic chemotherapy (not including hormonal therapy) 
for advanced/metastatic disease, (1-2) 
• Prior platinum treatment  
The subgroup analyses will be reported as a forest plot containing the treatment effect hazard 
ratios and 95% 2-sided Wald CIs in each subgroup originating from the Cox model. 
8.5.2. 
Secondary Efficacy Endpoints Analysis 
8.5.2.1. 
Overall Survival  
Overall survival (OS) is defined as the time from randomization to the date of death of any 
causes. If the patient did not experience an event, he/she will be censored at the last follow-up date. 
Analysis of OS will be examined as described in Section 8.5.1.1 for centrally confirmed 
population.  A KM plot will be provided.  
8.5.2.2. 
PFS Per Investigator Assessment  
PFS using investigator assessment of progression is defined as the time from randomization to 
the earliest date of death or date of disease progression (PD) as reported by investigator.  
PFS in months will be calculated as 
(Earlier date of death or PD reported by investigator – First dose date + 1) / 30.4375 
If the patient did not experience an event, patient will be censored. The detailed censoring and 
event rules according to FDA guidance on Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics are described in  Table 4. 
 
 
 


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 Table 4: Censoring Rules for PFS Per Investigator Assessment 
Condition 
Date of event /censoring 
Censoring Event 
No baseline radiologic tumor 
assessments 
Date of randomization 
Yes 
No 
No documented progression, no death 
Date of last documented radiologic tumor 
assessment 
In the event that only baseline radiologic 
tumor assessments are available, the date of 
randomization 
Yes 
No 
Documented Progression  
Date of radiological tumor assessment 
showing disease progression  
No  
Yes  
Treatment discontinuation for 
undocumented progression, or Toxicity 
or any other reason (apart from 
documented progression) 
Date of last documented radiologic tumor 
assessment 
Yes 
No 
New anti-cancer treatment started 
Date of last documented radiologic tumor 
assessment before initiation of new anti-
cancer treatment 
Yes 
No 
Death before first PD assessment 
Date of death 
No 
Yes 
Death in between 2 adequate 
assessment visits * 
Date of death 
No 
Yes 
Death or progression after more than 
one missed adequate assessment visits * 
Date of last documented radiologic tumor 
assessment before the missed visits 
Yes 
No 
* Adequate on-protocol imaging requires an assessment every 6 week (± 7 days) until Month 12 and every 9 weeks (± 7 days) 
thereafter, from start of protocol treatment until progression or start of subsequent anticancer treatment. 
The median duration and 2-sided 95% confidence interval for the median will be provided for 
each treatment arm.  
8.5.2.3. 
Best Overall Response  
The best overall response to treatment (CR, PR, SD, Non-CR/Non-PD,  PD, or Not Evaluable) 
and objective response rate (CR + PR),and disease control rate (CR + PR + SD) for each patient 
will be summarized by treatment arm.  Response rates by prognostic factors between central 
review assessment and investigator review assessment will be tabulated using frequency 
distribution.    
8.5.2.3.1. Best Overall Response when confirmation is not required 
For each patient, the unconfirmed best overall response (uBOR) is defined as the best time-point 
overall response that are recorded from the date of randomization until the date of first 
documented progression/recurrence, or the date of subsequent anti-cancer therapy, or the date of 
study discontinuation, whichever occurs first. Comparison of overall response rate (ORR) 
between treatment arms will be performed using Cochran–Mantel–Haenszel (CMH) test 
adjusting for randomization stratification factors. 
8.5.2.3.2. Best Overall Response when confirmation is required 
To confirm CR or PR response, tumor imaging may be performed at the earliest 4 weeks after 
the first indication of response or at the next scheduled scan, whichever is clinically indicated. 


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Tumor imaging for confirmation of response occurred less than 4 weeks after the first indication 
of response of CR or PR may be used for clinical decision, but it will NOT be used for 
determination of BOR. Confirmed BOR of each patient will be determined per medical review 
according to RECIST v.1.1.  
ORR is defined as percentage of patients who achieved CR or PR to treatment evaluated using 
RECIST v1.1. Response rate per central review and by Investigational assessment for each 
treatment arm will be provided with 95% exact confidence interval. Comparison of overall 
response rate (ORR) between treatment arms will be performed using Cochran–Mantel–Haenszel 
(CMH) test adjusting for randomization stratification factors. P-value will be reported. 
8.5.2.4. 
Duration of Response 
Unconfirmed DOR (uDOR) per central review is defined as the time from first CR or PR 
whichever comes first until the time of disease progression by RECIST v1.1 or death by any 
cause.  
Confirmed DOR per central review is defined as the time from first documentation of response 
(confirmed CR or PR) until the time of first documentation of disease progression by RECIST 
v1.1 or death by any cause.  
Bothe uDOR and confirmed DOR will be calculated only for patients who responded to the 
study treatment using the censoring rules specified in  Table 5.   
uDOR in months is defined as: 
 (Date of Event or Censoring – Date of first CR or PR + 1)/30.4375  
Confirmed DOR in months is defined as:  
(Date of Event or Censoring – Date of first confirmed CR or PR + 1)/30.4375 
DOR will be summarized using the Kaplan-Meier method and be displayed graphically where 
appropriate. The median duration and 2-sided 95% confidence interval for the median will be 
provided for each treatment arm. 
 
 


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Table 5: Censoring Rules Used for Duration of Response Analysis 
Situation 
Date of Event or Censoring 
Outcome 
Start of subsequent anti-cancer therapy 
without a prior documented progression 
or death 
Date of last evaluable radiologic tumor 
assessment prior to or on the date of 
initiation of the subsequent anti-cancer 
therapy 
Censored 
No documented radiologic progression 
and no subsequent anti-cancer therapy 
started 
Date of last evaluable radiologic tumor 
assessment  
Censored 
Documented radiologic progression or 
death after two or more consecutive 
missing radiologic assessments 
Date of last evaluable radiologic tumor 
assessment before the missed tumor 
assessments 
Censored 
Documented radiologic progression or 
death 
Earliest date of documented radiologic 
progression or death 
Event 
8.5.2.5. 
Time to Treatment Failure  
Time to Treatment Failure is defined as the date of randomization to discontinuation of treatment 
for any reason, including but not restricted to disease progression, treatment toxicity, and death.  
If the patient does not experience an event, he/she will be censored at the last dose date or last 
tumor assessment date whichever occurs later. Patients who never started any protocol treatment 
will be censored at time of randomization 
The median duration and 2-sided 95% confidence interval for the median will be provided for 
each treatment arm.  
8.6. 
Interim Analysis 
This interim analysis will be performed for futility for PFS per central review and for overall 
survival using centrally confirmed ITT population.  
PFS by central independent review will be analyzed as specified in Section 8.5.1.1 and overall 
survival interim analysis will be performed as specified in Section 8.5.2.1.  
  
 


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8.7. 
Safety Analysis 
8.7.1. 
Adverse Events 
AEs will be coded using MedDRA v20.0 or later and will be classified by SOC and PT of 
MedDRA. Severity of AEs will be assessed by investigators according to CTCAE (v4.0).   
A treatment-emergent AE (TEAE) will be defined as any new AE that begins, or any preexisting 
condition that worsens in severity during the treatment period.  For the determination of the 
TEAEs during the treatment period, AEs with the greatest severity before the baseline will be 
used as the benchmark for the comparison of the AEs occurring within 30 days after last dose 
date or until the start of subsequent antitumor treatment.  
AEs that have a possible or definite relationship to study drug will be defined to be related to the 
drug while others will be defined as “not related”. Any TEAEs for which the relationship to 
study treatment is missing will be considered as related to study treatment. TEAEs with the 
closest relationship to study treatment will be used for summary.    
The number and percentage of patients who experienced an AE will be summarized by treatment 
arm.  
The following types of summaries will be provided for each study treatment: 
• Overview of TEAEs  
• TEAEs by SOC and PT  
• TEAEs by PT in decreasing frequency 
• Non-Serious TEAEs (PT >= 5%) by PT in decreasing frequency  
• Drug-related TEAEs by PT in descending frequency  
• Drug-related TEAEs by SOC and PT  
• TEAEs by SOC, PT, and Maximum CTCAE toxicity grade  
• TEAEs by SOC, PT, and Maximum CTCAE toxicity grade ≥ 3  
• Drug-related TEAEs by SOC, PT and Maximum CTCAE toxicity grade  
• Serious TEAEs by SOC and PT  
• Drug-related serious AEs by SOC and PT  
• TEAEs leading to study drug discontinuation by SOC and PT  
• TEAEs leading to dose reduction or interruption by SOC and PT  
• Death and primary reasons causing death  
For physician’s choice arm, drug-related AEs refer to all AEs considered related to the 
administered treatment.  
If a preferred term (PT) or system organ class (SOC) was reported more than once for a patient, 
the patient would only be counted once in the incidence for that preferred term or system organ 
class.  


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In tabulation by severity (i.e., CTCAE toxicity grade),  
• For a given PT, only the most severe PT for each patient will be included.   
• For a given SOC, only the most severe SOC for each patient will be included.   
Similarly, in tabulation by relationship, 
• For a given PT, the highest ranked relationship to treatment for each patient will be 
included.  
• For a given SOC, the most closely related SOC to the study drug for each patient will 
be included.  
The following tables presented as listings will be provided: 
• Deaths 
• Serious AEs 
All AEs will be listed.  
8.7.2. 
Extent of Treatment Exposure  
Dose modifications for physician’s choice drugs will be done according to the respective product 
package insert or local practice. Therefore, calculated dose reductions/interruptions and dose 
intensities will not be reported for the physician’s choice arm. 
Duration of treatment will be summarized by treatment arm and each study drug for following 
variables:  
• Number of exposure cycles started as a continuous variable 
• Number and percentage of patients treated by cycles 1 to >10 
• Duration of exposure (days) 
• Average cycle duration (weeks) 
− as a continuous variable 
− in categories: <2, 2-<2.5, 2.5-<3.5, 3.5-<4, ≥4 weeks 
• Maximum cycle duration (weeks) 
− as a continuous variable 
− in categories: <2, 2 -<2.5, 2.5-<3.5, 3.5-<4, ≥4 weeks 
The cycle duration is calculated as the difference between the start dates of 2 subsequent 
treatment cycles.  
For IV drugs, the treatment duration (in days) will be calculated as:  
first dose of last cycle – date of first dose + 21 – date of randomization + 1 
For oral drugs, the treatment duration (in days) will be calculated as:  
last dose administration - first dose administration + 1  


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Dose modification and relative dose intensity for niraparib arm will include:  
• Number of patients with dose reduction or interruptions combined 
• Duration of exposure (days) 
• Actual cumulative dose (mg), defined as sum of all doses actually administered  
• Actual dose intensity (mg/day), defined as actual cumulative dose (mg) divided by the 
duration of exposure (days)  
• Relative dose intensity (%), defined as actual dose intensity (mg/day) divided by the 
intended dose intensity (mg/day) 
- as a continuous variable 
- in categories: ≤70%, 70-≤90%,90-≤110%, 110-≤120%, >120%. 
Details of study treatment administration and accountability will be listed by treatment arm for 
Safety Population. 
8.7.3. 
Clinical Laboratory Tests 
All laboratory parameters collected at each center’s local laboratory will be converted from 
original values and  units if supplied and converted to SI values and units to be classified as 
normal, low, or high based on normal ranges and units of measurement.  
For hematology (CBC only) and serum chemistry laboratory parameters which are normalized in 
SI units, descriptive summary tables for observed values and changes from baseline will be 
provided by visit and treatment arm for Safety Population.  
As the raw data lacks values to determine NCI CTCAE v4.0 toxicity grades and laboratory 
normal ranges, summary and change from baseline for hematology and chemistry tables will not 
be reported.  
Separate listings will be provided for urinalysis, and pregnancy testing by visit, treatment arm 
and patient ID for Safety Population.   
8.7.4. 
Physical Examination Findings 
Physical examination will be listed.  
8.7.5. 
Vital Signs 
Vital signs (systolic and diastolic blood pressure (mmHg), heart rate (bmp), temperature (0C), 
height (cm), and weight (kg) will be summarized and change from baseline by visit and 
treatment arm.  Observed vital signs and changes from baseline will be provided for each 
parameter.  
Conversion of temperature is as following: 
Temperature (ºC) = (Temperature (ºF) – 32) x 5/9 
A patient-detailed listing of vital signs (including weight) will be provided.  


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8.7.6. 
ECOG performance status  
The ECOG shift from baseline toxicity grade to worst (highest) post-baseline toxicity grade 
during the on-treatment period (see Section 5.3 for definition) will be summarized for Safety 
Population.  
Listings will be presented by treatment arm. 
8.7.7. 
Electrocardiogram (ECG) 
The following analyses will be performed on Safety Population for each applicable ECG 
parameters (Heart Rate [HR], RR, PR interval, QRS interval, QT interval, and QTcF interval) for 
each study treatment, during the on-treatment period (see Section 5.2 for definition). For each of 
continuous ECG parameters, descriptive statistics at baseline, at each post-baseline time point 
and changes from baseline at each post-baseline time point. If there are multiple measurements at 
a time point, the average of the replicate measurements should be taken at each time point. 
- Frequency (number and percentage) of patients with notable ECG values according to 
the following categories:   QTcF increase from baseline > 30 ms, > 60 ms 
- QTcF > 450 ms, > 480 ms, > 500 ms 
- HR ≤ 50 bpm and decrease from baseline ≥ 20 bpm 
- HR ≥ 120 bpm and increase from baseline ≥ 20 bpm 
- PR ≥ 220 ms and increase from baseline ≥ 20 ms 
- QRS ≥ 120 ms 
QTcF which is corrected QT interval is calculated using Fridericia's formula as QT/(RR).  
Patients with notable ECG interval values and qualitative ECG abnormalities will be listed for 
each patient and time point and the corresponding notable values and abnormality findings will 
be included in the listings. 
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in assessing 
the minimum and maximum of all visits and in the analysis of notable post-baseline abnormal 
ECG results. Listings will be presented for ECG.  
8.8. Additional Data Presentation as Listing   
• Subsequent anticancer treatment 
 


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APPENDIX 1. EUROPEAN ORGANIZATION FOR THE RESEARCH 
AND TREATMENT OF CANCER: PR-30-5010-C 
STATISTICAL ANALYSIS PLAN 
 


24/01/2017
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EORTC protocol 1307 
(EudraCT number 2013-000684-85) 
 A phase III, randomized, open-label, multicenter, controlled trial of 
A phase III, randomized, open-label, multicenter, controlled trial of niraparib versus physician’s choice in previously treated, HER2-negative, 
niraparib versus physician’s choice in previously treated, HER2-negative, germline BRCA mutation-positive breast cancer patients 
germline BRCA mutation-positive breast cancer patients 
 
 
 Study Coordinator: 
, Royal Marsden Hospital and Institute of Cancer Research, United Kingdom, 
Breast International Group (BIG) 
 
 
Statistical Analysis Plan 
Version 1.0 
Date  
24 01 2017 
 
 
 prepared by: 
, biostatistician EORTC 
 with the collaboration of: 
, biostatistician EORTC 
, clinical research physician EORTC 
 reviewed by: 
, 
 EORTC 
, 
 
, 
,  
 
The contents of this Statistical Analysis Plan are confidential. 
 
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Table of Contents 
 
List of abbreviations .................................................................................................................. 4 
1
time to HRQoL deterioration ............................................................................................................. 5 
upper limit of normal ......................................................................................................................... 5 
white blood cell .................................................................................................................................. 5 
 
Background ................................................................................................................................ 6 
2
2.1 
Scope ................................................................................................................................... 6 
2.2 
Trial design [as in protocol version 6, January 13, 2017] ................................................... 6 
2.3 
Sample size [as in protocol version 6, January 13, 2017] ................................................... 7 
2.4 
Objectives of the trial [as in protocol version 6, January 13, 2017] ................................... 8 
2.4.1 
Primary objective ........................................................................................................... 8
2.4.2 
Secondary objectives ..................................................................................................... 8
 
Study conduct........................................................................................................................... 10 
3
 
Quality assurance ..................................................................................................................... 10 
4
 
Conventions ............................................................................................................................. 10 
5
5.1 
Data Display ...................................................................................................................... 10 
5.2 
Data cleaning ..................................................................................................................... 11 
5.3 
Notations in this SAP ........................................................................................................ 11 
 
Statistical analyses ................................................................................................................... 11 
6
6.1 
Implementation of clinical cut-off date and data selection ............................................... 11 
6.2 
Patient availability ............................................................................................................. 12 
6.2.1 
Accrual ......................................................................................................................... 12
6.2.2 
Follow-up ..................................................................................................................... 13
6.2.3 
Eligibility ..................................................................................................................... 13
6.2.4 
Patient populations ....................................................................................................... 13
6.4 
Study Flow Chart .............................................................................................................. 15 
6.5 
Baseline characteristics ..................................................................................................... 16 
6.5.1 
Baseline patient and tumor characteristics ................................................................... 16
6.5.2 
Stratification factors ..................................................................................................... 16
6.5.3 
Medical history ............................................................................................................ 17
6.5.4 
Disease history ............................................................................................................. 17
6.6 
Compliance to the protocol ............................................................................................... 18 
6.6.1 
Central medical review of compliance to protocol ...................................................... 18
6.6.2 
Compliance to treatment allocation ............................................................................. 18
6.6.3 
Other compliance measures ......................................................................................... 19
6.7 
Exposure to treatment........................................................................................................ 19 
6.7.1 
Protocol therapy ........................................................................................................... 19
6.7.2 
Further anti-tumor treatment (after stop of protocol treatment) .................................. 21


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6.8 
Safety evaluations ............................................................................................................. 21 
6.8.1 
Hematology .................................................................................................................. 21
6.8.2 
Biochemistry ................................................................................................................ 22
6.8.3 
Adverse Events ............................................................................................................ 22
6.8.4 
Serious Adverse Events ............................................................................................... 22
6.9 
Reasons for stopping treatment ......................................................................................... 25 
6.10 Disease status .................................................................................................................... 25 
6.11 Statistical inference on efficacy endpoints ........................................................................ 26 
6.11.1 Definitions.................................................................................................................... 26
6.11.2 Primary endpoint: Progression-free Survival by independent central review ............. 27
6.11.3 Secondary efficacy endpoints ...................................................................................... 29
6.12 Interim analysis for futility for progression free survival ................................................. 32 
6.13 Interim analysis for overall survival.................................................................................. 32 
6.14 Quality of Life ................................................................................................................... 32 
 
Overview table for the 4 analysis reports ................................................................................ 35 
7
 
Bibliography ............................................................................................................................ 37 
8
 
Appendix 1: List of case report forms (CRFs)......................................................................... 38 
9
 Appendix 2: Tables and listing to be provided to IDMC for safety review ............................ 39 
10
 
 
 
 
 
 
 
 


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List of abbreviations 
1
AE 
adverse event                                                                                  
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CCD 
clinical cut-off date                                                                          
CI 
confidence interval 
CR 
complete response 
CRF(s) 
case report form(s)                                                                            
CT 
contrast-enhanced computed tomography (CT)                                                     
CTC 
common terminology criteria 
CTCAE 
common terminology criteria for adverse events 
ECG 
electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EORTC 
European Organisation for Research and Treatment of Cancer 
ER 
estrogen receptor                                                                              
FAR 
final analysis report                                                                      
FDA 
Food and Drug Administration 
FU 
follow-up 
GGT 
gamma glutamyltransferase 
HR 
hormone receptor                                                                               
HRQoL 
Health-related quality of life 
HER-2 
human epidermal growth factor receptor 2                                                       
IDMC-PFS 
Independent Data Monitoring Committee report for the interim analysis for futility for PFS 
IDMC-OS 
IDMC report for the interim analysis for OS                                                
INR 
international normalized ratio 
ITT 
Intent-to-treat 
IQR 
interquartile range                                                                        
IV 
intravenous(ly)                                                                                
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
MedDRA 
medical dictionary for regulatory activities 
MRI 
magnetic resonance imaging                                                                     


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MRP 
medical review plan                                                                            
ORR 
overall response rate 
OS 
overall survival                                                                               
OS-AR 
analysis report for the final analysis of the overall survival endpoint (OS-AR)                
PD 
progressive disease                                                                            
PT 
preferred term (AE term)                                                                       
aPTT 
activated partial thromboplastin time 
PTT 
partial thromboplastin time 
PR 
progesterone receptor                                                                          
PRO 
patient-reported outcomes                                                                      
PFS 
progression-free survival                                                                      
QD 
quaque die (once daily) 
QLQ-C30 
quality of life questionnaire C30 
QoL 
quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors                                               
SAE 
serious adverse event                                                                          
SAP 
statistical analysis plan 
SAR 
serious adverse reaction                                                                    
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
System Organ Class                                                                             
SUSAR 
suspected unexpected serious adverse reaction                                                  
TTQ 
time to HRQoL deterioration 
ULN 
upper limit of normal 
WBC 
white blood cell  


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Background 
2
2.1 
Scope 
This Statistical Analysis Plan (SAP) describes the statistical analyses that will be performed for: 
- 
the Independent Data Monitoring Committee (IDMC) report for the interim analysis on futility for 
progression-free survival (IDMC-PFS) 
- 
the final analysis report (FAR)  
- 
the IDMC report for the interim analysis for overall survival (IDMC-OS) 
- 
the analysis report for the final analysis of the overall survival endpoint (OS-AR)  
of the intergroup European Organization for the Research and Treatment of Cancer (EORTC)-1307-BCG, 
BIG5-13, TESARO PR-30-5010-C protocol, titled “A phase III, randomized, open-label, multicenter, 
controlled trial of niraparib versus physician’s choice in previously treated, HER2-negative, germline BRCA 
mutation-positive breast cancer patients.” Section 7 provides an overview table documenting which of the 
analyses described in Section 6 will be performed for which report.  
 
The reports will be prepared by the EORTC according to EORTC standard operating procedures and 
Policies. The FAR will include all results needed to prepare publication of the primary results. A separate 
SAP will be made for the translational research analyses. 
 
The FAR and OS-AR will be programmed and prepared by the EORTC study statistician and statistical 
analyst (if applicable). The IDMC-PFS and IDMC-OS will be prepared and presented to the IDMC by the 
reporting statistician. The IDMC-PFS and IDMC-OS reports are confidential documents, the contents of 
which will only be accessible to the IDMC, IDMC administrator, and the EORTC reporting statistician, until 
the end of the trial.  
The specifications detailed in the present analyses plan will supplement but never supersede the key 
specifications in the protocol, (namely the sections on “analysis of primary or key secondary endpoints” 
“analysis population” and “method”). Any change with respect to the specifications in the protocol will be 
explicitly mentioned and justified. 
2.2 
Trial design [as in protocol version 6, January 13, 2017] 
This is a Phase III, randomized, two-arm, open-label, multicenter, superiority study to compare niraparib 
with physician’s treatment choice in patients with HER2-negative gBRCAmut breast cancer. After registration, 
eligible patients will be randomized 2:1 to: 
Arm 1: niraparib orally at a dose of 300 mg daily (QD) on a continuous dosing regimen 
Arm 2: physician’s choice amongst one of the following 4 single agents (intravenous [IV] eribulin, IV or oral 
vinorelbine, IV gemcitabine, or oral capecitabine), according to the nationally available and approved 
treatment (Gemcitabine will be administered as single agent as per National Comprehensive Cancer Network 
[NCCN] guidelines. In France, gemcitabine is not allowed as a treatment in the physician's choice arm.) 
Patients will continue on study medication until disease progression, as long as, in the investigator’s opinion, 
they are benefitting from treatment and do not meet any other treatment discontinuation criteria. 
See also the trial scheme in Figure 1. 
Clinic visits will be conducted at the beginning of every cycle (ie, every 3 weeks ± 3 days). 
Contrast-enhanced computed tomography (CT), or magnetic resonance imaging (MRI) if CT is not feasible, 
will be required at screening and every 6 weeks ± 7 days for the first 12 months, then every 9 weeks ± 7 days 
until disease progression. Patients will continue on their assigned treatment until disease progression 
(determined by Response Evaluation Criteria in Solid Tumors [RECIST] v.1.1), unacceptable toxicity, death, 
withdrawal of consent, or they are lost to follow-up.  
Evaluation of CT scans and MRI, including determination of response to treatment and date of progression 
based on RECIST v.1.1, will be conducted by a central blinded review committee comprised of 
2 radiologists, with an arbiter as necessary. Results of the central blinded assessment will be used to 
determine the primary efficacy endpoint of PFS and will be conducted retrospectively. The study 
investigators also will assess response to treatment and date of progression, based on RECIST v.1.1, during 
the conduct of the study. 


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Patient-reported outcomes (PROs) will be evaluated at screening, during the treatment period, and after 
treatment discontinuation, for a maximum period of up to 12 months after randomization.  
Safety will be evaluated throughout the study by AE monitoring and clinical laboratory assessments, 
(hematology, chemistry), vital signs, electrocardiograms (ECGs), physical examinations, and use of 
concomitant medications. 
After treatment discontinuation, information on subsequent anticancer therapy and survival (including new 
malignancy information) will be collected. If the patient discontinues prior to disease progression, tumor 
imaging and assessment of PROs will continue during the post-treatment phase at specified time intervals 
until disease progression or until the patient starts his/her subsequent anticancer therapy. No crossover to 
niraparib is permitted following discontinuation from physician’s choice treatment.  
The IDMC was 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 patients participating in the study. The 
membership, key responsibilities of the IDMC, and the corresponding procedures were defined in an IDMC 
charter. 
2.3 
Sample size [as in protocol version 6, January 13, 2017] 
At least 306 gBRCAmut patients, confirmed by the centralized test, will need to be randomized.  
The primary analysis population for efficacy (including primary PFS and OS analyses) constitutes all 
randomized patients who have a germline BRCA mutation per central laboratory results (Myriad Genetics, 
Inc., USA, hereafter referred to as “Myriad”) 
The overall sample size for this study is based on the overall survival endpoint, and is determined based on 
the assumption that niraparib will result in an improvement of 4 months in median overall survival, from 9 to 
13 months (corresponding to a hazard ratio= 0.69). For a true hazard ratio of 0.69, 265 deaths will provide 
80% power at a 1-sided alpha of 0.025. Assuming 10 patients who are eligible for the primary analysis 
population for efficacy are enrolled per month, with 306 such patients, 265 deaths are expected to occur 
approximately 54 months after the first patient enrolled. At the time of the final PFS analysis (primary 
endpoint), an interim analysis will be performed on OS, using an O'Brien-Fleming alpha spending function 
(protocol Section 8.3). 
Assuming 40% of patients will be randomized on the basis of a local BRCA test, and assuming that 15% of 
those patients will be BRCA-negative by the central test, it is estimated that 324 patients will need to be 
randomized to obtain the required 306 patients in the analysis population. If the average enrollment rate is 
greater than 11 patients per month during the second year of enrollment, the sample size to achieve the 
required 265 events may be increased up to 350 gBRCAmut patients in the primary efficacy analysis 
population.  
The PFS analysis is designed to give 80% power to detect an HR 0.6 (equivalent to 3 to 5 months) with a 
one-sided alpha of 0.025, which will require approximately 137 PFS events to perform the final analysis. All 
patients should be recruited before the final PFS analysis is conducted, and therefore the final PFS analysis is 
to be conducted at approximately 137 events or end of recruitment, whichever occurs later. If final analysis is 
done by the end of enrollment, all PFS events occurred by the end of enrollment will be included in the 
analysis. Patients should be continued to be followed until death even after the final analysis of PFS to assess 
long-term effects of niraparib. 
A gate-keeping strategy (i.e. sequential testing procedure) will be used to test PFS and OS. OS will be tested 
at a 1-sided alpha of 0.025 only if the final test on PFS is significant at a 1-sided alpha of 0.025. This is 
motivated by the fact that OS is defined as a key secondary endpoint and such approach allows control of the 
overall Type I error rate. One futility interim analysis on the primary endpoint of PFS is planned. This 
futility analysis will be performed after approximately 93 (68%) of the minimum required total number of 
PFS events have been recorded. A gamma family beta spending function with a non-binding gamma (γ = -5) 
stopping boundary will be used for the futility analysis.  
An interim analysis of overall survival is planned at the time of the final PFS analysis. The interim analysis 
will utilize O’Brien-Fleming type boundaries derived from the Lan DeMets alpha spending function based 
on the actual number of deaths observed at the time of the interim analysis. 


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Overall survival (accounting for interim analysis performed at the time of final PFS analysis) and PFS 
(including futility analysis) sample size calculations were performed using PROC SEQDESIGN in SAS and 
confirmed with East software. 
2.4 
Objectives of the trial [as in protocol version 6, January 13, 2017] 
2.4.1 
Primary objective 
The primary objective of this study is to compare progression-free survival (PFS), as assessed by blinded 
central review, of patients with advanced/metastatic HER2-negative gBRCAmut breast cancer when treated 
with niraparib as compared to those treated with physician’s choice single agent chemotherapy standards 
(eribulin, vinorelbine, gemcitabine or capecitabine). 
2.4.2 
Secondary objectives 
2.4.2.1 
Key secondary objective 
To compare overall survival of patients with advanced/metastatic HER2-negative gBRCAmut breast cancer 
when treated with niraparib as compared to those treated with physician’s choice single agent chemotherapy 
standards (eribulin, vinorelbine, gemcitabine or capecitabine). 
2.4.2.2 
Other secondary objectives 
1. To establish germline BRCA mutation status of screened patients using a centrally provided, validated test 
as well as future tests, and determine concordance between tests for the purpose of developing a commercial 
companion diagnostic test 
2. To evaluate safety and tolerability as measured by all AEs. 
3. To compare PFS using investigator assessment of progression 
4. To evaluate time to treatment failure (discontinuation of treatment for any reason) 
5. To compare response rate and duration of response 
6. To compare time to deterioration of health-related quality of life (HRQoL): European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and EuroQol 5 
Dimension 5 Level (EQ-5D-5L) (Appendices D, F, I ) 
7. To describe subsequent therapies and potential relationships with outcomes 
8. To assess genetic and non-genetic biomarkers relating to treatment efficacy. Germline and tumor 
mutations may be explored including somatic BRCA1 and 2 mutations, reversion mutations, loss of 
heterozygosity as well as genome landscape and transcriptional or functional measures of homologous 
recombination (HR) deficiency. 
9. To assess outcomes by germline mutation BRCA1 vs BRCA2. 
10. Descriptive summary statistics will be used to summarize post- treatment data (i.e subsequent anticancer 
therapies and any new malignancy). 


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Figure 1: Study Scheme 
 
NCCN: National Comprehensive Cancer Network, QD: quaque die (once daily),  PD: Progressive disease, gBRCAmut, germline BRCA mutation.


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Study conduct 
3
Safety data will be reviewed on a regular basis by the medical review team, as documented in the medical 
review plan (version 1.1, June 4, 2015).  
The medical review team includes EORTC representatives (clinical research physician, pharmacovigilance 
manager), as well as a clinical representative from the sponsor (TESARO) and the study coordinator. The 
medical review plan (MRP) describes the procedures and practices to be conducted by the medical team for 
this study, to ensure that the medical data generated from the trial are valid and reliable and that early 
recognition, identification, and reporting of events that affect patient safety are maintained during the trial. 
Additionally, an IDMC will process a systematic, periodic review of all the safety data in the study. This 
process is documented in the study’s IDMC charter (version 1.0, February 17, 2015). The medical review 
team can also request an additional IDMC review in the event that safety problems are identified for which 
independent advice is sought. 
No outcome data is included in any of the safety reviews, apart from an overview of the secondary 
malignancies and deaths and their causes. See Appendix 2 for an overview of the information provided to 
IDMC for the safety review.  
No efficacy results will be presented before the data are mature for the primary analysis according to 
EORTC policy 009 (version 4.2, March 3, 2015).  
The FAR will contain a summary of all important amendments, a summary of the first interim analysis for 
futility, as well as any important issues related to the study conduct.   
 
 
Quality assurance 
4
The primary analysis of the FAR will undergo an independent validation by a statistician from EORTC. 
He/she will independently program the primary efficacy endpoint and the centrally confirmed intent-to-treat 
(ITT) population, based on the information provided in this SAP. The calculated variables are compared on 
the basis of a one-to-one comparison, and discrepancies are resolved. 
The following analyses will undergo an independent EORTC validation: 
- 
IDMC-PFS: PFS per central review assessment and the centrally confirmed ITT population 
- 
IDMC-OS: the OS endpoint and the centrally confirmed ITT population 
- 
OS-AR: the OS endpoint and the centrally confirmed ITT population 
 
Conventions 
5
5.1 
Data Display 
Unless explicitly mentioned otherwise, the following data display settings will be applied. 
- 
Listings will always include: the patient id, the patient’s institution, and the randomized treatment 
arm. Additional variables will be added on a case-by-case basis.  
- 
Frequency tables will be tabulated by the randomized treatment arm. For all categorical 
variables, the levels of the variables as they appear on the case report form (CRF) will be 
reported (with %). Categories with a text field specification will be tabulated as categories and then 
supplemented by a listing with the following information for patients fulfilling the specific 
condition: value of the item and text field contents). 
- 
Delays: Dates relating to events prior to study enrollment will be presented as the delay in days (or 
weeks, months, or years) between the past event and the date of entry (date of randomization – date 
of past event + 1), and will be presented using the median, interquartile range (IQR), and range. For 
example, on the randomization checklist, the date of first cancer diagnosis will be presented as the 
time elapsed (in days, weeks, months, or years, as appropriate) since the day of the first diagnosis 
and the date of entry on study (date of randomization – last administration/diagnosis +1). Other 
delays (eg,. retreatment delays) are presented as continuous variables using the median, IQR, and 
range. 


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- 
Continuous variables for which a coding system exists (such as for laboratory data) will be recoded 
into categories (for AEs, the grading scale specified in the protocol will be used).  
- 
Other continuous variables (for example age or dose) will be presented using the median, IQR, and 
range (minimum, maximum).   
- 
If appropriate, continuous data may also be presented in categories (for example, age may also be 
grouped in decades). 
- 
To convert a time interval from days to months, the interval will be divided by 30.5. To convert a 
time interval from days to years, the interval will be divided by 365.25.  
- 
When the value of a variable is missing on formcrg1 or formcrg2, but is provided on formrg1 or 
formrg2, the corresponding data entry on the rg1 or rg2 form will be reported. For each variable, the 
applicable cases will be listed. 
- 
When for some patients the value of a variable is unknown or missing, these patients will be 
classified in a separate category, “missing,” for that variable. 
- 
To facilitate the reading process, long listings may be included in the appendix of the FAR. They 
will then be referred to in the corresponding section of the FAR. 
 
5.2 
Data cleaning 
- 
Patients who had a positive test by both Myriad (central laboratory) and another laboratory will be 
coded as having a BRCA mutation by Myriad on formrg2 and formcrg2. 
- 
In the event of an unknown date, where a timeframe is known between for the event, the date in the 
middle of that timeframe will be entered. If the timeframe is not known,  a query will be issued. 
 
See the Conventions List for EORTC study 1307-BCG (version 1.0, May 26, 2014) for additional data 
cleaning conventions.  
 
5.3 
Notations in this SAP 
- 
Variable names on the case report forms (CRFs) will be displayed in italic. 
- 
The study CRFs will be referred to by either their SAS form code or the form name. See Appendix 1 
for an overview of the SAS form codes and form names of the CRFs that are used in this SAP.  
- 
Variables names containing a “-” refer to a sequence of variables, e.g., dtsptrtn1-6 refers to 
dtsptrtn1, dtsptrtn2, dtsptrtn3, dtsptrtn4, dtsptrtn5 and dtsptrtn6. 
 
Statistical analyses  
6
6.1 
Implementation of clinical cut-off date and data selection 
For the IDMC-AR and the FAR, the clinical cut-off date (CCD) will be determined as the date when the 
number of required events is estimated to be reached, using the frequency of the events for PFS per central 
review.  
 
For the OS-AR, the CCD will be determined as the date when the number of required events is estimated to 
be reached, on the basis of events of overall survival in the centrally confirmed ITT population.  
 
A CCD will be applied removing forms containing patient visit data after the CCD. This will be 
implemented as follows: 
 
- 
Screening failure form: 
The form is removed when “date of screening failure (dtsf) > CCD.” 
 
- 
The following forms are removed when the patient was randomized after the CCD: 


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formrg2, formcrg2, disease history form, medical history form, medical review form, initial 
measurements form, physical examination form at screening, myelosuppression history form. 
These forms are removed when “dor2 > CCD”. 
 
- 
Previous and concomitant medication form: 
The form is removed when “date of visit (dtvisitpcm) > CCD”. 
 
- 
Biochemistry form: 
The form is removed when “date of visit (dtbio) > CCD.” 
 
- 
Hematology form: 
The form is removed when “date of visit (dthem) > CCD.” 
 
- 
Follow-up measurements form: 
The form is removed when “date of visit (dtassfm) > CCD.” 
 
- 
Protocol Treatment forms: 
The form is removed when the last treatment-related date > CCD 
The last treatment-related date for formtrtc = dtsptrtc 
The last treatment-related date for formtrte = the maximum of dtadme1-2 
The last treatment-related date for formtrtg = the maximum of dtadmg1-3 
The last treatment-related date for formtrtn = the maximum of dtsptrt and dtsptrtn1-6 
The last treatment-related date for formtrtviv = the maximum of dtadmv1-3 
The last treatment-related date for formtrtvo = dtsptrtv 
 
- 
Adverse events form: 
The form is removed when “start date (aestdtc) > CCD.” 
 
- 
End of treatment form:  
The form is removed when “date of last treatment administration (dtlast) > CCD.” 
 
- 
Follow-up form:  
The form is removed when “date of visit (dtassfu) > CCD,” except for the survival section.  
The survival section is removed when “date last known to be alive/date of death (dtssfu) > CCD.” 
 
- 
Quality of life form: 
The form is removed when “today’s date (Q331) > CCD.” 
 
- 
Health economics questionnaire: 
The form is removed when “date completed by patient (Q527) > CCD.” 
 
- 
Independent central review: 
The records in the rs dataset from the central review data export are removed when “Date/Time of 
Response Assessment (RSDTC) > CCD.” 
 
6.2 
Patient availability 
6.2.1 
Accrual 
The following information concerning accrual will be reported: 
- 
Recruitment rate (accrual over time): A graph displaying the cumulative accrual over time and the 
expected accrual will be presented. A separate graph will be produced to report the number of 
patients registered and the number randomized in the study.   
- 
A table with the total number of patients and percentage of patients recruited, by institution and by 
group, will be presented, ordered by descending volume of accrual. 


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6.2.2 
Follow-up 
The following information on the duration of follow-up (FU) in the full ITT population (Section 6.2.4) will 
be reported. The follow-up reporting will be repeated in the centrally confirmed ITT population (Section 
6.2.4) in the appendix of the analysis report. 
- 
FU duration by treatment arm and overall estimated by the inverse Kaplan-Meier method (Schemper 
& Smith, 1996): patients who died are censored on their death date (Section 6.11.1) and other 
patients have an event on their last follow-up date as defined below:  
The last follow-up date is calculated as the maximum of the following dates (if available): 
- 
End of treatment form: date of last treatment administration (dtlast), date last known to be 
alive/death (dtssof)  
- 
Follow-up form: date of visit (dtassfu), date last known to be alive/death (dtssfu) 
- 
Follow-up measurements form: date of visit (dtassfm) 
- 
Initial measurements form: date of visit (dtassim) 
- 
Treatment forms: last treatment-related date (Section 6.1) 
- 
AE forms: start date of event (aestdtc), stop date of event (aeendtc) if available 
- 
ECG form: date of visit (dtecg) if number of ECG performed at this visit (nrecg) > 0 
- 
Biochemistry form: date of visit (dtbio) if analysis was performed (nybio =1) 
- 
Hematology form: date of visit (dthem) if analysis was performed (nyhem =1) 
- 
Physical examination form: date of physical examination (dtpe) if performed (nype =1) 
- 
Date of randomization (dor2) 
- 
Date of screening (dor) 
 
6.2.3 
Eligibility 
The following information on eligibility in the full ITT population (Section 6.2.4) will be reported. The 
eligibility reporting will be repeated in the centrally confirmed ITT population (Section 6.2.4) in the 
appendix of the analysis report. 
- 
Table with eligibility status (formDM01: nyeligteam) and main reason for ineligibility (formDM01 
eligr, for nyeligteam=0) by randomized treatment arm, as assessed by the medical review team  
- 
Listing of ineligible patients together with main reason for ineligibility (formDM01: eligr, txeligr, 
for patients with nyeligteam=0) 
- 
Listing of patients who entered with a waiver on some eligibility criteria (formDM01: eligr, txeligr, 
nyeligteam, for patients with nyeligdev =1) 
- 
Listing or table of patients with deviation(s) to some eligibility criteria that are declared as eligible 
by the medical review team (formDM01: eligr, txeligr, for patients with nyelig =1 and 
nyeligteam=1) 
6.2.4 
Patient populations 
The following patient populations will be used in the analyses: 
- 
Screening population: all screened/registered patients. Tables for the screening population will 
contain 4 columns:  
- column 1:  patients who were screened, not randomized, and declared a screening failure 
- column 2:  patients who were screened, not (yet) randomized, and not (yet) declared a 
screening failure  
- column 3: patients who were randomized to physician choice  
- column 4: patients who were randomized to niraparib.  


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- 
Centrally confirmed ITT population: all randomized patients with a centrally confirmed germline 
BRCA mutation. Analyses involving the ITT population will group patients by the randomized 
treatment arm, which does not necessarily correspond to the treatment they received. 
Patients are considered to have a centrally confirmed germline BRCA mutation when on the 
CENBRCA form either   
o a “Variant in BRCA 1 (NYBRCA1CEN = 1)” is reported which is either “Positive for a 
deleterious mutation” or “Genetic variant, suspected deleterious” (INTER1CEN in (1,2)),  
o a “Variant in BRCA 2 (NYBRCA2CEN = 1)” is reported which is either “Positive for a 
deleterious mutation” or “Genetic variant, suspected deleterious” (INTER2CEN in (1,2)), or  
o a “BRCA1 and/or BRCA2 rearrangement found (BRCAREARRCEN = 1)” is reported which 
is either “Positive for a deleterious mutation” or “Genetic variant, suspected deleterious” 
(INTERREARRCEN in (1,2)). 
Note that this population corresponds to the ITT population specified in the protocol, which is the 
primary analysis population for all efficacy analyses. 
- 
Full ITT population: all randomized patients. Analyses involving the ITT population will group 
patients by the randomized treatment arm, which does not necessarily correspond to the treatment 
they received. 
Note that the distinction is made between full and centrally confirmed ITT population to ensure that 
those patients who were randomized, but were not confirmed centrally to have a germline BRCA 
mutation after randomization, are still accounted for in this report. 
- 
Per-protocol population: all patients in the centrally confirmed ITT population who are eligible 
according to medical review (Section 6.2.3) and started on their randomized treatment (received at 
least 1 dose of the allocated drug). Analyses involving the per-protocol population will group 
patients by the randomized treatment arm, which corresponds to the treatment they actually received. 
- 
Safety population: all randomized patients who started on their allocated treatment (received at least 
1 dose of the allocated drug). Analyses involving the safety protocol population will group patients 
by the randomized treatment arm, which corresponds to the treatment they actually received. 
A table will document the number of patients included/excluded in each of the analysis populations (by 
treatment arm, if applicable). Also, the main reason for exclusion from each analysis population will be 
documented, eg, for the full ITT population, the reason for exclusion is the main reason for screening failure 
(formsf: sf1, txsf1).  
 
 


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6.4 
Study Flow Chart 
The following study flow chart will be completed in the FAR. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Population 
 
                                  
Screening  population 
 
 
 
Centrally confirmed ITT population 
 
 
 
 
 
 
Full ITT population 
Screened patients 
(N=) 
Screening Failures (N=) 
Main reason for screening 
failure 
Median follow-up duration 
Main efficacy results 
Niraparib 
N= (%) 
Distribution of stratification factors 
Randomized based on: 
- Myriad BRCA test N= (%) 
- other BRCA test N= (%) 
Ineligibe patients N= (%) 
Main reason for ineligibility 
Physician’s treatment choice 
N= (%) 
Distribution of stratification factors 
Randomized based on: 
- Myriad BRCA test N= (%) 
- other BRCA test N= (%) 
Ineligibe patients N= (%) 
Main reason for ineligibility 
Median follow-up duration 
Main efficacy results 
 
Treatment 
Allocation 
Randomized patients 
(N=) 
Registration/ 
Screening 
Started on 
Physician’s 
treatment choice 
Randomization 
Central 
BRCA 
testing 
Centrally 
confirmed  
N= (%) 
Centrally 
confirmed  
N = (%) 
Compliance to 
treatment 
allocation 
Started on  
Niraparib 
N= (%) 


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6.5 
Baseline characteristics 
All baseline characteristics will be reported in the full ITT population unless explicitly specified otherwise. 
The baseline characteristics reporting will be repeated in the centrally confirmed ITT population, the safety 
population and the per protocol population in the appendix of the analysis report. 
6.5.1 
Baseline patient and tumor characteristics  
6.5.1.1 
Baseline patient and tumor characteristics at screening/registration 
The following characteristics will be reported in the screening population: 
- 
Gender (sex, formcrg1) 
- 
Age at screening (median, IQR, range, by decades). dor1 (on formcrg1) – dob (on patient form)) 
- 
Patient meets one of the criteria for further genetic assessment according NCCN guidelines 
(formcrg1: nygenass) 
- 
Previously detected (prior to screening/registration) germline BRCA mutation? (formcrg1: 
nyprevmut) 
- 
HER2 status (formcrg1: nyhistbc) 
- 
Physician's choice of intended treatment for control arm (formrg1: physchoicerg1) 
6.5.1.2 
Baseline patient and tumor characteristics at randomization 
- 
Ethnicity (formmh: eth) 
- 
Race (formmh: race) 
- 
Gender (sex, formcrg1) 
- 
Age at randomization (median, IQR, range, by decades). dor1 (on formcrg1) – dob (on patient form) 
- 
Germline BRCA1 or BRCA2 mutation (at randomization)? (formcrg2: nybrcamut)  
- 
Estrogen receptor (ER) status (formcrg2: er) 
- 
Progesterone receptor (PR) status (formcrg2: pr) 
- 
HER2 status (formcrg1: nyhistbc) 
- 
Hormone receptor (HR) status. The HR status is calculated from the ER and PR status. It will be 
reported as positive when the ER status and/or the PR status is positive. It will reported as negative 
when both the ER and PR status are negative.  
- 
Visceral disease? (formcrg2: nyviscel) 
- 
Presence of bone metastases? (formim: boneinvim=1, 2 or 3)  
- 
Presence of brain mets? (formim: braininvim=1, 2 or 3) 
- 
Eastern Cooperative Oncology Group (ECOG) performance status (formph: ecog for visitpe = 0) 
6.5.2 
Stratification factors 
- 
A table with the value of the stratification factors as entered at time of randomization 
o visceral disease: yes vs no (formrg2: qval211)  
o histology: triple negative versus ER/PR positive  (formrg2: the maximum of qval23 and 
qval24) 
o number of lines of prior cytotoxic chemotherapy for advanced/metastatic disease: 0-1 or 2 
(formrg2: qval212)  
- 
Listing of patients (and corresponding stratification factors) for whom there are inconsistencies 
between the values declared during randomization versus those updated prior to the database lock 
date for the report. 


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6.5.3 
Medical history 
- 
History of myelosuppression (formmh: nymyh). In the event that a patient has a history of 
myelosuppresion, the information on the myelosuppression history form will be listed (formmyh: 
myhevent, myhgrade, dtstmyh, dtspmyh, txregimpyh, txtrtmyh).  
6.5.4 
Disease history 
Related to the initial diagnosis and primary/adjuvant treatment of the current breast cancer (per disease 
history form): 
- 
Time interval between first pathological diagnosis of breast cancer and date of randomization 
(median, IQR, range)  
- 
Stage at initial diagnosis (formdh: stageinit) 
- 
T status at initial diagnosis (formdh: tstage) 
- 
N status at initial diagnosis (formdh: nstage) 
- 
M status at initial diagnosis (formdh: mstage) 
- 
Histology at initial diagnosis (formdh: thist, txthist) 
- 
Grade at initial diagnosis (formdh: tgrad) 
- 
Additional biopsy performed for metastatic/recurrent disease (for patients who were M0 at 
diagnosis)? (formdh: nyaddbx) If yes, histology and grade after biopsy (formdh: thistbx, txthistbx, 
tgradbx) 
- 
Surgery performed for primary tumor? (formdh: nysurgproc)   
- 
(Neo-)adjuvant chemotherapy received? (formdh: setadj)  If yes, the regimen, time interval between 
initial diagnosis and first progression (formdh: regimadj, txregimadj, dtrecadj- dtdiag) 
- 
Endocrine therapy given? (formdh: nyendoadj) If yes, the regimen (formdh: txendoadj) 
- 
Radiotherapy given? (formdh: nyrxadj) 
 
Related to treatment of the current breast cancer in the metastatic setting: 
- 
Number of chemotherapy regimens given for the current breast cancer in the metastatic setting 
(formdh: nrregimmet) 
For patients who received at least 1 regimen: the type of first regimen, the duration of treatment, and 
the response to this treatment (formdh: regim1, txregim1, dtspregim1-dtstregim1, respregim1) 
For patients who received at least 2 regimens: the type of second regimen, the duration of treatment, 
and the response to this treatment (formdh: regim2, txregim2, dtspregim2-dtstregim2, respregim2) 
- 
Total duration of chemotherapy given for the current breast cancer in the metastatic setting (formdh: 
the sum of [dtspregim2-dtstregim2] and [dtspregim1-dtstregim1]) 
- 
Endocrine therapy given? (formdh: nyendomet) If yes, the regimen (formdh: txendomet) 
- 
Radiotherapy given? (formdh: nyrtmet) If yes, a listing of the type (formdh: txrtmet) 
- 
Other systemic therapy (not entered above)? If yes, a listing of the type, the response to this 
treatment, the last administration date, and the date of randomization (in the current study) 
 
Related to ovarian cancer, for female patients only: 
- 
Prior diagnosis of ovarian cancer? (formdh: nypriorovdh) If yes, stage (formdh: stageovdh) 
 
Related to other invasive malignancies: 
- 
Cancer history other than metastatic breast cancer or ovarian cancer? (formdh: nycanchist) If 
yes, a listing of the type, the date of diagnosis of the malignancy, last treatment for the 
malignancy (formdh: txcanc, dtdiagcanc, dtsptrtcanc). 
6.5.4.1 
BRCA testing 
The following variables will be tabulated 3 times, in 3 different populations:  
- 
the screening population  


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- 
the full ITT population  
- 
the centrally confirmed ITT population, restricted to those patients who were randomized after a 
germline BRCA mutation detected at a different lab than Myriad (formcrg2: nybrcamutnot=2): 
BRCA testing before screening: 
- 
Previously detected germline BRCA mutation (formcrg1: nyprevmut) 
BRCA testing before randomization: 
- 
germline BRCA1 or BRCA 2 mutation? (formcrg2: nybrcamutnot) 
Central BRCA testing results: 
Were results from central BRCA mutation testing received? (yes, if formcenbrca is received). If yes: 
- 
Variant in BRCA 1 or 2? (1, 2, both 1 and 2, neither 1 nor 2) (formcenbrca: nybrca1cen and 
nybrca2cen) 
- 
If variant in BRCA 1 or both: specify the interpretation (formcenbrca: inter1cen) 
- 
If variant in BRCA 2 or both: specify the interpretation (formcenbrca: inter2cen) 
Previous BRCA testing results: 
Was a second BRCA mutation test performed outside the context of this protocol? (yes, if  
 
formothbrca is received). If yes: 
- 
Location of BRCA mutation test? (formothbrca: locbrca) 
- 
Variant in BRCA 1 or 2? (1, 2, both 1 and 2, neither 1 nor 2) (formothbrca: nybrca1loc and 
nybrca2loc) 
- 
If variant in BRCA 1 or both: specify the interpretation (formothbrca: inter1loc) 
- 
If variant in BRCA 2 or both: specify the interpretation (formothbrca: inter2loc) 
 
6.6 
Compliance to the protocol 
Compliance will be reported in the full ITT population, and repeated in the centrally confirmed ITT 
population in the appendix of the analysis report. 
6.6.1 
Central medical review of compliance to protocol 
- 
Were there protocol treatment deviations as described in the MRP? (formdm01: devia) If yes, the 
type of violation (formdm01: violev) 
- 
Were there protocol treatment deviations as described in the MRP that were judged as severe 
violations by the medical review team? (formdm01: nydeviateam) If yes, the type of violation 
(formdm01: violev) 
6.6.2 
Compliance to treatment allocation 
Definitions: 
- 
A patient is defined to have started on niraparib if at least 1 dose is reported on the niraparib 
treatment form during cycle 1 (formtrtn: max(dosen, dose1n, dose2n, dose3n, dose4n, dose5n, 
dose6n) > 0 for cycletrn =1) 
- 
A patient is defined to have started on capecitabine if at least 1 dose is reported on the capecitabine 
treatment form during cycle 1 (formtrtc: max(dosec, dose1c, dose2c, dose3c, dose4c, dose5c) > 0 for 
cycletrc =1) 
- 
A patient is defined to have started on eribulin if at least 1 dose is reported on the eribulin treatment 
form during cycle 1 (formtrte: max(dosee1, dosee2) > 0 for cycletre =1) 
- 
A patient is defined to have started on gemcitabine if at least 1 dose is reported on the gemcitabine 
treatment form during cycle 1 (formtrtg: max(doseg1, doseg2, doseg3) > 0 for cycletrg =1) 


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- 
A patient is defined to have started on intravenous (IV) vinorelbine if at least 1 dose is reported on 
the IV vinorelbine treatment form during cycle 1 (formtrtviv: max(dosev1, dosev2, dosev3) > 0 for 
cycletrv =1) 
- 
A patient is defined to have started on oral vinorelbine if at least 1 dose is reported on the oral 
vinorelbine treatment form during cycle 1 (formtrtvo: max(dosev, dose1v, dose2v, dose3v, dose4v, 
dose5v) > 0 for cycletrvo =1) 
- 
A patient is defined to have started on physician’s treatment choice if he/she started on capecitabine, 
eribulin, gemcitabine, IV vinorelbine, or oral vinorelbine. 
The following information regarding treatment compliance will be reported: 
- 
Treatment actually started (niraparib, physician’s treatment choice, other, no information available) 
(using the definition above). If the patient did not start the allocated treatment, the reason why 
(formdm01: txdevia).  
- 
For patients who started on another treatment or for whom no treatment information is available in 
the database, a listing will be provided, including any additional information concerning the 
treatment actually received (stored in the medical review form textboxes). (formdm01: txdevia, 
txdmisrev ) 
6.6.3 
Other compliance measures 
Related to the timing of the tumor measurements: 
- 
average difference between 2 successive tumor measurement of the same patient (median, IQR, 
range) (formfum: dtassfm – dtassfm[-1], where the formfum forms are sorted by patient in 
ascending order on dtassfm, and with dtassfm[-1] being the previous value of dtassfm for the same 
patient)  
- 
Histogram of the difference between 2 successive tumor measurement of the same patient (all 
patients, all time points). Bar width will be 3 days. (formfum: dtassfm – dtassfm[-1]) 
- 
Histogram of the timing of all the tumor measurements (all patients, all time points) relative to the 
theoretical measurement dates as set from start of treatment (per protocol). Bar width will be 5 
days. (formfum: dtassfm – [closest theoretical date of per protocol schedule]) 
Related to the assessment of the hematologic toxicity: 
- 
Did the patient receive weekly blood tests during first month from start of treatment? (yes/no).  
Availability of a hematology form (formlbhem: nyhem=1, dthem) for the following 4 dates: start of 
treatment + 7 days (± 3 days), start of treatment + 14 (± 3 days), start of treatment + 21 (± 3 days), 
start of treatment + 28 (± 3 days) 
 
- 
Did the patient receive weekly blood tests for 1 month following the first dose reduction for 
hematologic toxicity? (yes/no).  
For patients with a dose reduction due to a hematologic toxicity (investigator reported on the 
treatment form), availability of a hematology form (formlbhem: nyhem=1, dthem) for the following 
4 dates: date of first dose reduction due to hematological toxicity + 7 days (± 3 days), date of first 
dose reduction due to hematological toxicity + 14 (± 3 days), date of first dose reduction due to 
hematological toxicity + 21 (± 3 days), date of first dose reduction due to hematological toxicity + 28 
(± 3 days). 
 
6.7 
Exposure to treatment 
The exposure will be reported in the safety population. 
6.7.1 
Protocol therapy 
Protocol therapy consists of niraparib or physician’s treatment choice among IV eribulin, IV or oral 
vinorelbine, IV gemcitabine, or oral capecitabine. Dose modifications for physician’s choice drugs will be 
done according to the respective product package insert or local practice. Therefore, calculated dose 
reductions/interruptions and dose intensities will not be reported for the physician’s choice arm. 


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Niraparib, capecitabine, and oral vinorelbine are oral drugs with a daily administration schedule. The cycles 
for these drugs were defined as 3 week time-intervals, irrespective of interruptions. The other drugs have an 
IV administration route, with normal cycle duration of 3 weeks. Cycle duration will be longer in the event 
that the next cycle needs to be delayed, eg, due to toxicity. 
For IV. drugs, the treatment duration (in days) will be calculated as:  
(first dose of last cycle +21 - first dose of first cycle) + 1 
For oral drugs, the treatment duration (in days) will be calculated as:  
(last dose administration - first dose administration) + 1 
6.7.1.1 
Treatment received  
- 
The frequency of patients who received at least 1 dose of niraparib will be presented. 
- 
The frequency of patients who received at least 1 dose of physician’s treatment choice will be 
presented, including the type of regimen. 
- 
A table showing the planned versus received regimen for patients randomized to the physician’s 
treatment choice arm will be presented. 
6.7.1.2 
Duration of treatment 
The following data will be displayed: 
- 
Number of patients who have stopped protocol treatment and who are still on protocol treatment. 
- 
Number of cycles of protocol therapy received (until database lock) (the maximum of: totcyc 
[formeot], cycletrc [formtrtc], cycletre [formtrte], cycletrn [formtrtn], cycletrg [formtrtg], cycletrvo 
[formtrtvo] and cycletrv [formtrtviv]). This will be reported separately for patients who have stopped 
protocol treatment and who are still on protocol treatment.  
- 
Duration of protocol therapy (until database lock, in months) (Section 6.7.1). This will be reported 
separately for patients who have stopped protocol treatment and who are still on protocol treatment. 
Average cycle duration in weeks (median, IQR, range, and in categories: <2, 2 - <2.5, 2.5 - 3.5, >3.5 
- 4, >4 weeks). Cycle duration calculated as the difference between the start dates of 2 subsequent 
treatment cycles  
- 
Maximum cycle duration in weeks - (median, IQR, range, and in categories: <2, 2 - <2.5, 2.5 - 3.5, 
>3.5 - 4, >4 weeks). Cycle duration as calculated above. 
6.7.1.3 
Relative dose intensity for the Niraparib arm 
The observed dose intensity is calculated as the total dose received divided by the duration of protocol 
therapy in days. For the definition of the duration of protocol therapy, see Section 6.7.1. 
The relative dose intensity is calculated as the observed dose intensity (in days) divided by the theoretical 
dose intensity (in days), eg, for niraparib, the theoretical daily dose intensity equals 100 mg.  
Relative dose intensity will be reported as median, IQR, and range, and in the following categories: ≤70%, 
>70-90%, >90-110%, >110-120%, >120% 
6.7.1.4 
Dose reductions and interruptions (calculated) for the niraparib arm 
A dose reduction is defined as any dose administration of ≤ 90% of the theoretical dose for any of the 
protocol drugs. Dose interruptions are not reported as dose reductions, but are reported separately. 
A dose interruption is defined as any dose administration of 0 for any of the protocol drugs prior to stopping 
protocol treatment. In the event that a dose of 0 is reported in the last cycle and there is no end treatment 
form available for this patient (at time of database lock), this case will count as a dose interruption and the 
patient is assumed to still be on treatment. 
- 
Frequency of patients with a dose reduction of niraparib. In the event of dose reduction, the cycle 
and reason of first dose reduction 


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- 
Frequency of patients with a dose interruption of niraparib. In the event of an interruption, the cycle 
and reason of first dose interruption 
6.7.2 
Further anti-tumor treatment (after stop of protocol treatment) 
The following variables will be reported in the group of patients who stop protocol treatment and for whom 
follow-up information is available for at least 2 months after stopping protocol treatment (to allow for 
sufficient survival/follow-up to have started a new treatment).  
Additionally, the analyses will include the next line of treatment following disease progression. This will be 
reported in a subgroup, specifically those patients with progressive disease on protocol treatment.  
- 
Any chemotherapy administration? (formfu: maximum of nyctxfu) 
- 
Any radiotherapy? (formfu: maximum of nyrtfu) 
- 
Any surgery? (formfu: maximum of nysurgfu) 
- 
Any hormonal therapy? (formfu: maximum of nyhorfu) 
- 
Any targeted agents? (formfu: maximum of nytarfu) If yes, specification of the first new targeted 
therapy given following the end of protocol treatment (formfu: txtarfu) 
- 
Any other treatment? (formfu: maximum of nyothfu) If yes, specification of the first new other 
therapy given following the end of protocol treatment (formfu: txothfu)  
- 
Niraparib given in compassionate use program? (formfu: the maximum of nircompuse) 
The molecularly targeted treatments and other treatment might be further categorized into meaningful drug 
classes based on medical review.  
6.8 
Safety evaluations 
All safety and tolerability evaluations based on the clinical database will be reported in the safety population. 
AE grading will be described according to CTC version 4.0. 
For the reporting in this section, “during protocol treatment” is defined as: 
- 
The Adverse Events: The time period from start of treatment up to (and including) 30 days after the 
last protocol treatment administration date, as reported on the end of treatment form (formeot: 
dtlast). In the event that there is no end of treatment form received at time of database lock, all 
AEs/laboratory results from start of treatment will be reported.  
- 
For hematology and biochemistry: The time period from start of treatment up to the study 
medication termination visit (formlbhem: visithem=1,2,3 or 4, formlbbio: visitbio=1 or 2).  
6.8.1 
Hematology 
The category “missing” means that the corresponding laboratory test was never performed during treatment. 
When the laboratory test was performed at least once, but the required normal ranges were not provided, this 
is reported as “upper limit of normal [ULN] not reported” or “lower limit of normal [LLN] not reported.” 
Certain laboratory results are reported both on the hematology form and on the AE form. These variables 
will be reconciled during database cleaning.  
- 
The worst grade during protocol treatment will be tabulated for the following laboratory tests/ 
preferred terms: 
Hematology form: white blood cell (WBC) count, neutropenia, lymphopenia, thrombocytopenia, 
anemia 
AE form: febrile neutropenia, anemia, neutrophil count decreased, lymphocyte count decreased, 
neutrophil count decreased, platelet count decreased, white blood cell decreased 
- 
Listing of the grade ≥ 3 AEs that meet these criteria. This listing will include the baseline laboratory 
value and corresponding grade.  


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6.8.2 
Biochemistry 
The category “missing” means that the corresponding laboratory test was never performed during treatment. 
When the laboratory test was performed at least once, but the required normal ranges were not provided, this 
is reported as “ULN not reported” or “LLN not reported”.  
Certain laboratory results are reported both on the biochemistry form and on the AE form. These variables 
will be reconciled during database cleaning. 
- 
The worst grade during protocol treatment will be tabulated for the following laboratory tests/ 
preferred terms: 
Biochemistry 
form: 
hypoalbuminemia, 
alkaline 
phosphatase, 
SGPT, 
amylase, 
SGOT, 
hyperbilirubinemia, blood urea nitrogen (BUN) abnormality, hypercalcemia, hypocalcemia, serum 
creatinine, gamma glutamyltransferase (GGT), hyperglycemia, hypoglycemia, hyperkalemia, 
hypokalemia, lactate dehydrogenase (LDH) abnormality, lymphopenia, hypermagnesemia, 
hypomagnesemia, hypernatremia, hyponatremia, hyperbilirubinemia. 
AE form: hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, 
hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, 
serum amylase increased, GGT increased, alanine aminotransferase (ALT) increased, alkaline 
phosphatase (ALP) increased, aspartate aminotransferase (AST) increased, blood bilirubin increased, 
creatinine increased. 
- 
Listing of the grade ≥ 3 AEs that meet these criteria. This listing will include the baseline laboratory 
value and corresponding grade.  
6.8.3 
Adverse Events 
Adverse events will be tabulated by preferred term within the System Organ Class (SOC); however, for the 
following SOCs, AEs will be pooled across the preferred terms: Eye disorders (EYE), Hepatobiliary 
disorders (HEP), Immune system disorders (IMM), Injury, poisoning and procedural complications (INJ), 
Musculoskeletal and connective tissue disorders (MUS), Pregnancy, puerperium and perinatal conditions 
(PRE), Skin and subcutaneous tissue disorders (SKI), Social circumstances, Surgical and medical procedures 
(SUR). 
The preferred term will always be included in the listings. The report will include: 
- 
Table containing the worst grade of all reported AEs classified under the specific SOC/preferred 
during protocol treatment. 
- 
Listing of all AEs during protocol treatment. The listing will include the preferred term, the date of 
randomization, the date of event onset, the stop date of the event, whether this event is serious, the 
relationship to protocol treatment, and the action that was taken with respect to the protocol 
treatment. This listing will be organized by the treatment received and the SOC. Within those 
sections, the items will be sorted by the grade and preferred term.    
- 
Table containing the worst grade of all reported AEs classified under the specific SOC/preferred 
term during protocol treatment that are reported to be related or likely related to the protocol 
treatment. 
6.8.4 
Serious Adverse Events 
Tables of the serious adverse events (SAEs) will be provided by the EORTC pharmacovigilance department. 
Unlike the data presented in other sections of the report, SAE data are based on the safety database. The 
safety database will be reconciled with the clinical database prior to database lock.  
The following tables will be reported: 
- 
Study safety overview per treatment arm 
Randomized Treatment arm 
# SAE 
terms 
# SAR 
terms 
# SUSAR 
terms 
# Deaths 
# Toxic 
deaths 
Niraparib 
 
 
 
 
 
Physician’s choice 
 
 
 
 
 


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SAE = serious adverse event; SAR = serious adverse reaction; SUSAR = suspected, unexpected, serious 
adverse reaction; Toxic death = cases with at least one SAR term with fatal outcome, ie, a death judged by 
either the reporting investigator or the sponsor as having a reasonable causal relationship to the study 
treatment. The study safety overview table lists the number of reported SAE terms, SAR terms and 
SUSAR terms per treatment received and the number of reported death and toxic death cases. There 
can be multiple reported terms within one case, but as a patient can only die once, it is the numbers 
of deaths and toxic death cases which are listed (instead of terms). 
The column # SAE terms displays a count of all SAEs; all events which are reported as ‘serious’ 
(ie,1 seriousness criterion) regardless of relationship to the study treatment. This implies that the 
number of SAE terms also includes the number of SAR terms (and SUSAR, deaths, and toxic deaths 
terms). 
The column # SAR terms displays a count of all SARs; all SAEs judged by either the reporting 
investigator or the sponsor as having a reasonable causal relationship to the study treatment. This 
implies that the number of SARs also includes the number of SUSAR and toxic deaths terms. 
The column # SUSAR terms displays a count of all SUSARs; all SARs which are considered as 
unexpected.  
The column # Deaths displays a count of all cases with at least 1 SAE term with fatal outcome, 
regardless of relationship to study treatment. This implies that the number of death cases also 
includes the number of toxic death cases. 
The column # Toxic deaths displays a count of all cases with at least one SAR term with fatal 
outcome, ie,. a death judged by either the reporting investigator or the sponsor as having a reasonable 
causal relationship to the study treatment. Note, a toxic death can also be a SUSAR and vice versa, 
but this is not always the case. 
- 
Suspected Unexpected Serious Adverse Reactions (SUSARs) by SOC and preferred term 
Identification 
Number 
Randomized 
Treatment arm 
SOC 
Preferred term 
Count by 
Preferred term 
 
 
 
 
 
 
- 
Toxic deaths by SOC and preferred term 
 
Identification 
Number 
Randomized 
Treatment arm 
SOC 
Preferred term 
Count by 
Preferred term 
 
 
 
 
 


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- 
Line Listings of Serious Adverse Reactions (SAR) 
Randomized 
Treatment 
arm 
Institution 
identifier 
 
Patient 
ID 
case ID 
(for internal 
reference) 
Seriousness 
Criteria 
Reported 
Term 
(verbatim 
term) 
Grade 
(CTCv4.0) 
Event Start Date  Event Stop Date 
Outcome 
Treatment 
Relationship 
to Treatment 
Niraparib 
 
 
 
 
 
 
 
 
 
 
 
Physician’s 
choice 
 
 
 
 
 
 
 
 
 
 
 
 


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- 
Cumulative Summary Tabulation of Serious Adverse Events (SAE) 
SOC 
Preferred term 
Events in 
Niraparib 
arm 
Events in 
Physician’s 
choice arm 
Total number of events 
Blood and lymphatic system disorders 
Febrile bone marrow 
aplasia 
 
 
 
Febrile neutropenia 
 
 
 
Neutropenia 
 
 
 
Blood and lymphatic system disorders Total 
 
 
 
Gastrointestinal disorders 
Abdominal pain 
 
 
 
Diarrhoea 
 
 
 
Nausea 
 
 
 
Vomiting 
 
 
 
Gastrointestinal disorders Total 
 
 
 
… 
 
 
 
Grand Total 
 
 
 
 
- 
Cumulative Summary Tabulations of Serious Adverse Reactions (SAR) 
SOC 
Preferred term 
Events in 
Niraparib 
arm 
Events in 
Physician’s 
choice arm 
Total number of events 
Blood and lymphatic system 
disorders 
Febrile bone marrow 
aplasia 
 
 
 
Febrile neutropenia  
 
 
Neutropenia 
 
 
 
Blood and lymphatic system disorders Total 
 
 
 
… 
 
 
 
Grand Total 
 
 
 
 
6.9 
Reasons for stopping treatment 
Reasons for stopping treatment will be reported in the full ITT population. The reporting will be repeated in 
the centrally confirmed ITT population in the appendix of the analysis report. 
- 
Is patient still on protocol treatment? (end of treatment form) 
If not: 
- 
Reason for stopping protocol therapy (end of treatment form) 
6.10 
Disease status  
Disease status will be reported in the full ITT population, and entails the tabulation of the following event 
frequency. The reporting will be repeated in the centrally confirmed ITT population, the safety population 
and the per protocol population in the appendix of the analysis report. 
- 
Disease progression, type of first event. This variable will be categorized as follows: 
1. Progressive disease (PD) both per investigator assessment and central independent review 
2. PD per investigator assessment, not confirmed by review 
3. PD per central independent review, not reported by the investigators 
4. Start of new anticancer treatment in absence of PD (by central review or investigator 
reported) 
5. No PD 


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Patients will be classified in one of these 5 categories based on their status at the time of 
evaluation. For the definitions of the aforementioned dates, see Section 6.11.1. When dates do not 
differ by more than 7 days, the corresponding events are considered to have happened 
instantaneously for the above classification. 
 
For patients classified as “Start of new anticancer treatment,” #4 above, the frequency of patients for 
whom clinical progression (not radiologically confirmed) was reported by the investigator prior to 
the start of new anticancer therapy, will be reported. 
 
- 
Death. The patient is reported to have died if ssof=2 (formeot) or ssfu=2 (formfu); otherwise the 
patient is considered alive. In the event that the patient died, the main cause of death will be 
provided:  rdeadfof, txrdeadof in case ssof=2 (formeot) or rdeadfu txrdeadfu in case ssfu=2 (formfu)  
- 
Listing of early death, defined as death occurring within 90 days from randomization.  
- 
Listing of patients who die on treatment (= up to 30 days post protocol treatment stop). Second 
primary malignancy. The patient is reported to have a second primary malignancy if nynew=1 
(formfu) or dtnewof is reported (formeot). If yes, a listing of the site/type: txnew in case nynew=1 
(formfu) or txnewof in case dtnewof is reported (formeot).  
 
6.11 
Statistical inference on efficacy endpoints 
Efficacy analyses will be reported in the centrally confirmed ITT population, unless explicitly mentioned 
otherwise. The following analyses will be provided as supplementary statistics to the primary test for each 
efficacy endpoint. The primary test itself will be covered in the subsection for each endpoint. 
- 
Kaplan-Meier curves by randomized treatment arm will be shown. Medians - if reached - will be 
presented with a 2-sided 95% confidence interval (CI) based on the nonparametric method 
(Brookmeyer & Crowley, 1982).  
- 
A univariate Cox proportional hazards model with the randomized treatment as a factor and stratified 
by the randomization factors will be used to estimate the treatment hazard ratio and its 2-sided 95% 
CI. The proportional hazards assumption will be assessed by means of the graphical and numerical 
method based on cumulative sums of martingale-based residuals  (Lin, Wei, & Ying, 1993). The 
method will be implemented using the ‘asses’ statement in the ‘phreg’ procedure of SAS, using the 
default settings. In the event that the proportional hazards assumption does not hold, how the hazard 
ratio changes over time will be explored by means of models involving treatment interaction with (a 
function of) time. The results will be displayed graphically.  
6.11.1 
Definitions 
The following definitions for the death date, disease progression date by independent central review, and 
disease progression date per investigator assessment will be applied throughout the report: 
- 
Death date 
If the patient died (according to the definition in Section 6.10), the death date is calculated as the 
minimum of: dtssof if ssof=2 (formeot) and dtssfu for follow-up forms with ssfu=2 (formfu); 
otherwise the date of death is empty. 
 
- 
Disease progression date by independent central review 
The progression date is calculated from the independent central review data export, in the form rs, as 
the minimum of RSDTC for those patients for whom RSACPTFL = "Y" and RSTEST="Overall 
Response" and RSORRES="PD". If the date is missing, the patient is considered to not have a 
disease progression by independent central review 
 
- 
Disease progression date per investigator assessment 
The progression date is calculated as the minimum of: dtprfm (formfum), dtpdof (formeot) and 
dtpdradfu (formfu).  If the date is missing, the patient is considered to not have a disease progression 
per investigator assessment. Note that this definition implies that if the patient stops protocol 
treatment due to a non-radiologic (clinical) progression, this will not count as a disease progression.  


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- 
Clinical disease progression (non-radiologic) date per investigator assessment 
The clinical progression date is calculated as the minimum of: dtcpdof (formeot) and dtpdclinfu 
(formfu).  
 
- 
Date of start of new anticancer treatment 
The minimum of dtctxfu, dtrtfu, dtsurgfu, dthorfu, dttarfu, dtothfu (formfu). If the date is missing, 
the patient is considered to not have started a new anticancer treatment. 
Any date relating to an anticancer treatment identified by medical review on the concomitant 
medication form will be taken into account in the calculation of this date. 
6.11.2 
Primary endpoint: Progression-free Survival by independent central review 
This endpoint is defined as the time from randomization until the minimum of the date of death (Section 
6.11.1) and the date of disease progression per independent central review. The independent central review 
process is documented in the Independent Review Charter (version 1.0, November 27, 2013) 
For the primary analysis, PFS will be censored according to Food and Drug Administration (FDA) guidance 
on Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, appendix table A. The 
application of the guidance will be detailed below: 
This endpoint considers the following as events: 
- 
death (Section 6.10) 
- 
disease progression per independent central review  
If the patient did not experience an event, he/she will be censored. See table 1 below for more detailed 
censoring and event rules for this endpoint.  
A documented central independent radiologic assessment is defined as the independent central radiologic 
review for a radiologic (CT or MRI) disease assessment, taking place before the start of the new anticancer 
treatment (Section 6.11.1), if applicable.  
Table 1: Censoring rules for the endpoint of progression-free survival by independent central review 
Condition 
Date of event /censoring 
Censoring 
Event 
No baseline tumor assessments 
Date of randomization 
Yes 
No 
Documented Progression  
Date of radiological assessment showing 
disease progression 
No  
Yes  
No documented progression, no death 
Date of last documented central 
independent radiologic assessment 
In the event that only baseline tumor 
assessments are available, the date of 
randomization 
Yes 
No 
Treatment discontinuation for undocumented 
progression, or toxicity, or any other reason 
(apart from documented progression) 
Date of last documented central 
independent radiologic assessment 
 
Yes 
No 
New anticancer treatment started 
Date of last documented central 
independent radiologic assessment before 
initiation of new anti-cancer treatment 
Yes 
No 
Death before first PD assessment 
Date of death 
No 
Yes 
Death in between 2 adequate assessment 
visits * 
Date of death 
No 
Yes 
Death or progression after more than 1 missed 
adequate assessment visit * 
Date of last documented central 
independent radiologic assessment 
before the missed visits 
Yes 
No 


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* Adequate on-protocol imaging requires an assessment every 6 weeks (± 7 days) until Month 12, and every 9 weeks  
(± 7 days) thereafter, from start of protocol treatment until progression or start of subsequent anticancer treatment. 
The primary test will be performed at the 1-sided 0.025 significance level. The primary PFS analysis will be 
performed using a stratified log-rank test for the difference in the distribution of PFS between the niraparib 
group and the control group (one-sided α-level of 0.025). The randomization factors will be used as the strata 
for this test. The following hypothesis will be tested:  
H0: PFS(t)physician choice = PFS(t)niraparib 
Ha: PFS(t)physician choice < PFS(t)niraparib 
where PFS(t) represents the progression-free survivorship function at any time (t). 
The aforementioned analysis on the primary endpoint will undergo an independent validation by an EORTC 
statistician. The independent EORTC statistician will independently program the analysis, based on the 
information provided in this SAP. The output of this analysis will be compared and discrepancies will be 
resolved. 
Sensitivity analyses 
- 
The analysis mentioned above will be repeated in the per protocol population, to assess the 
robustness of the primary result.  
- 
The analysis mentioned above will be repeated in the full ITT population, to assess the robustness of 
the primary result when including patients who were not centrally confirmed to be BRCA-positive.  
- 
A non-stratified log-rank test will also be performed to assess the robustness of the primary result. 
- 
A multivariate Cox model will be fitted to assess the robustness of the treatment effect when 
adjusting for (potential) prognostic factors and (potential) imbalances therein. The Cox model (with 
Breslow ties) will be constructed based on a backward stepwise selection method, with a two-sided 
0.10 cutoff for selection, and forcing treatment arm to stay in the model. The following factors will 
be considered for inclusion in the model:  
- 
Age (< 55,55-70,>70) 
- 
ECOG performance status (0 vs 1-2) 
- 
visceral disease (yes, no) 
- 
histology (ductal, lobular, other) 
- 
number of lines of prior cytotoxic chemotherapy (not including hormonal therapy) for 
advanced/metastatic disease (0, 1-2)  
- 
prior platinum treatment (no vs yes) 
- 
germline mutation (BRCA-1 vs BRCA-2 vs both) 
Cases with missing values for 1 of the above factors are excluded from the model (when the factor is 
included in that model). 
The reporting of this analysis will contain in 1 table: 
- the fitted univariate Cox models for each of the factors (Hazard ratio for each factor and 95% 
2-sided Wald CI) 
- the fitted full multivariate Cox model (Hazard ratio for each factors and 95% 2-sided Wald 
CI) 
- the multivariate Cox model after model selection as described above (hazard ratio for each 
factor and 95% 2-sided Wald CI, Type III test p-value for each factor) 
Homogeneity of results across subgroups 
Subgroup analyses will be performed for the following baseline factors by means of Cox models (with 
Breslow ties) including the factor of interest and the randomized treatment if the subgroup contains at least 
10% of the patients of the centrally confirmed ITT population:  
- 
Age (< 55,55-70,>70) 


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- 
Race (Ashkenazi Jewish descendant, White or Caucasian, Black, Native Hawaiian or Other Pacific 
Islander, Asian, American Indian or Alaska Native, Other) 
- 
geographic region (US, Europe, Israel) 
- 
ECOG performance status (0 vs 1-2) 
- 
visceral disease (yes, no) 
- 
histology (ductal, lobular, other) 
- 
number of lines of prior cytotoxic chemotherapy (not including hormonal therapy) for 
advanced/metastatic disease, (0, 1-2) 
- 
prior platinum treatment (no vs yes) 
- 
germline mutation (BRCA-1 vs BRCA-2 vs both) 
These subgroup analyses will be reported as forest plots containing the treatment effect hazard ratios and 
95% 2-sided Wald CIs in each subgroup originating from the Cox model. 
Two key subgroup analyses are defined: those by prior platinum treatment and the subgroups by BRCA 
mutation type. These two subgroup analyses will be supplemented with Kaplan-Meier curves by randomized 
treatment in each subgroup separately, as well as a stratified logrank test (97.5% 1-sided significance level) 
within each subgroup. 
The subgroup analysis by BRCA mutation was already identified as a secondary endpoint in the protocol 
(Section 2.2.2). The key subgroup analysis for prior platinum treatment is added in this SAP, after the 
eligibility criteria related to prior platinum treatment have been weakened in amendment 4.0. 
6.11.3 
Secondary efficacy endpoints 
6.11.3.1 Overall survival (OS) (key secondary endpoint) 
This endpoint considers the following as events: 
- 
death (Section 6.10) 
This endpoint is defined as the time from randomization until the date of death (Section 6.11.1), if the patient 
died. If the patient did not experience an event, he/she will be censored at the last follow-up date (Section 
6.2.2).  
The primary analysis of this endpoint will be performed using a stratified log-rank test, performed at the 1-
sided 0.025 significance level, in the OS-AR. The randomization factors will be used as the strata for this 
test. 
Sensitivity analyses 
- 
The analysis mentioned above will be repeated in the per protocol population, to assess the 
robustness of the primary result  
- 
The analysis mentioned above will be repeated in the full ITT population, to assess the robustness of 
the primary result when including patients who were not centrally confirmed to be BRCA positive.  
- 
A non-stratified log-rank test will also be performed to assess the robustness of the primary result.  
- 
A multivariate Cox model will be fitted to assess the robustness of the treatment effect when 
adjusting for (potential) prognostic factors and (potential) imbalances therein. The Cox model (with 
Breslow ties) will be constructed based on a backward stepwise selection method, with a two-sided 
0.10 cutoff for selection, and forcing treatment arm to stay in the model. The following factors will 
be considered for inclusion in the model:  
- 
Age (< 55,55-70,>70) 
- 
ECOG performance status (0 vs 1-2) 
- 
visceral disease (yes, no) 
- 
histology (ductal, lobular, other) 
- 
number of lines of prior cytotoxic chemotherapy (not including hormonal therapy) for 
advanced/metastatic disease (0, 1-2)  
- 
prior platinum treatment (no vs yes) 
- 
germline mutation (BRCA-1 vs BRCA-2 vs both) 


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Cases with missing values for 1 of the above factors are excluded from the model (when the factor is 
included in that model). 
The reporting of this analysis will contain in 1 table: 
- the fitted univariate Cox models for each of the factors (Hazard ratio for each factor and 95% 
2-sided Wald CI) 
- the fitted full multivariate Cox model (Hazard ratio for each factors and 95% 2-sided Wald 
CI) 
- the multivariate Cox model after model selection as described above (hazard ratio for each 
factors and 95% 2-sided Wald CI, Type III test p-value for each factor) 
6.11.3.2 Progression-free Survival (PFS) per investigator assessment of progression 
This endpoint is defined as the time from randomization until the minimum of the date of death (Section 
6.11.1) and the date of disease progression, as reported by the investigator.  
For the primary analysis, per protocol, the definition for investigator reported PFS is the same as for PFS per 
central review, using investigator-reported PD dates instead of centrally reviewed PD dates. This is detailed 
below: 
This endpoint considers the following as events: 
- 
death (Section 6.10) 
- 
disease progression as reported by the investigator (Section 6.11.1)  
If the patient did not experience an event, he/she will be censored. See table 2 below for more detailed 
censoring and event rules for this endpoint.  
A documented radiological assessment is defined as the radiologic (CT or MRI) disease assessment taking 
place before the start of the new anticancer treatment (Section 6.11.1), if applicable.  
Table 2: Censoring rules for the endpoint of progression-free survival per investigator assessment 
Condition 
Date of event /censoring 
Censoring 
Event 
No baseline tumor assessments 
Date of randomization 
Yes 
No 
No documented progression, no death 
Date of last documented radiologic assessment 
In the event that only baseline tumor 
assessments are available, the date of 
randomization 
Yes 
No 
Documented Progression  
Date of radiological assessment showing 
disease progression  
No  
Yes  
Treatment discontinuation for 
undocumented progression, or Toxicity 
or any other reason (apart from 
documented progression) 
Date of last documented radiologic assessment 
Yes 
No 
New anti-cancer treatment started 
Date of last documented radiologic assessment 
before initiation of new anti-cancer treatment 
Yes 
No 
Death before first PD assessment 
Date of death 
No 
Yes 
Death in between 2 adequate assessment 
visits * 
Date of death 
No 
Yes 
Death or progression after more than one 
missed adequate assessment visits * 
Date of last documented radiologic assessment 
before the missed visits 
Yes 
No 
* Adequate on-protocol imaging requires an assessment every 6 weeks (± 7 days) until Month 12 and every 9 weeks (± 
7 days) thereafter, from start of protocol treatment until progression or start of subsequent anticancer treatment. 


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The main analysis of this endpoint will be performed using a stratified log-rank test, performed at the 1-sided 
0.025 significance level. The randomization factors will be used as the strata for this test. 
Sensitivity analyses 
- 
The analysis mentioned above will be repeated in the per protocol population, to assess the 
robustness of the primary result.  
- 
The analysis mentioned above will be repeated in the full ITT population, to assess the robustness of 
the primary result when including patients who were not centrally confirmed to be BRCA positive.  
- 
A non-stratified log-rank test will also be performed to assess the robustness of the primary result.  
6.11.3.3 
Response to treatment 
Response to treatment will be reported for all patients in the centrally confirmed ITT population by 
randomized treatment arm:  
- 
Tabulation of the best overall response to treatment (complete response [CR], partial response, stable 
disease [SD], disease progression [PD], early death, not assessable/evaluable) by medical review 
(formdm01: respev). 
- 
Tabulation of overall response rate (CR or partial response) by medical review (formdm01: 
respev=1,2 versus respev=3,4,5,8); for each treatment arm, the response rate if supplemented by a 2-
sided 95% CI (Pearson-Clopper method). The Pearson’s chi-square test for association will be 
performed to compare the overall response rate (ORR) between treatment arms and the 
corresponding p-value will be displayed. 
Duration of response to treatment will be reported in the efficacy population, restricted to those patients who 
obtained a response (CR or partial response) by medical review (formdm01: respev=1,2), by randomized 
treatment arm. 
- 
The duration of response is calculated as the time from response until the first event of 
investigator-reported disease progression or death whichever occurs earlier (Section 6.11.3.2).  
The same censoring rules as for investigator-reported disease progression apply (Section 
6.11.3.2).  The duration of response will be reported using the Kaplan-Meier method. Kaplan-
Meier curves by randomized treatment arm will be shown. Medians - if reached - will be 
presented with a 2-sided 95% CI, based on the nonparametric method (Brookmeyer & Crowley, 
1982).  
6.11.3.4 Time to treatment failure  
Time to treatment failure considers the following as events: 
- 
End of protocol treatment for any reason (including death) (formeot: dtlast) 
- 
Disease progression as reported by the investigator (Section 6.11.1) 
Time to treatment failure is defined as the time from randomization until the date of the first event (date of 
last treatment administration on end of treatment form). If the patient does not experience an event, he/she 
will be censored at the last dose date or last tumor assessment date whichever occurs later (Section 6.2.2).  
Patients that never started any protocol treatment will be censored at time of randomization.  
The main analysis of this endpoint will be performed using a stratified log-rank test, performed at the 1-sided 
0.025 significance level. The randomization factors will be used as the strata for this test. 
Sensitivity analyses 
- 
The analysis mentioned above will be repeated in the per-protocol population, to assess the 
robustness of the primary result  
- 
The analysis mentioned above will be repeated in the full ITT population, to assess the robustness of 
the primary result when including patients who were not centrally confirmed to be BRCA-positive.  
- 
A non-stratified log-rank test will also be performed to assess the robustness of the primary result.  


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6.12 
Interim analysis for futility for progression free survival 
This interim analysis will be reported in the centrally confirmed ITT population. 
PFS by central independent review will be analyzed as specified in Section 6.11.2. 
A CCD for the interim analysis will be determined based on an estimate of when the required 93 events will 
be reached. At time of database lock, the true number of observed events can be slightly more or less than 
93. A gamma family beta-spending function with a non-binding gamma (γ=-5) stopping boundary based on 
the actual number of PFS events at the time of interim analysis data cutoff and the minimum total target 
number of events of 137 will be used for the interim futility analysis of PFS (i.e. the information fraction for 
futility analysis is equal to the number of events observed at the interim analysis divided by 137). The futility 
boundary will be assessed by the EAST 6 software).  
Based on the accrual rate and PFS median assumptions, the enrollment will be done after 137th event and the 
final PFS analysis will be done at the end of enrollment. The information fraction calculated based on 137 
events will be larger than the information fraction calculated based on the total number of events at the end 
of enrollment. This larger information fraction will yield a smaller hazard ratio futility boundary which 
allows the trial to be stopped more easily if the experiment drug is not efficacious. 
In order to fully evaluate the interim data, the projected numbers of PFS and OS events by the end of 
enrollment will be provided in the IDMC reports. The projections will be done using the interim data based 
on the following: 
1. Past accrual and projected future accrual 
2. Observed PFS rates and assumptions going forward 
3. Observed death rates and assumptions going forward. 
 
6.13 
Interim analysis for overall survival 
An interim analysis for overall survival will be reported in the centrally confirmed ITT population at the time 
of the final PFS analysis. 
This interim analysis will be performed using the locked database for the FAR. OS will be analyzed as 
specified in Section 6.11.3.1. 
The interim analysis rule for early efficacy will be assessed using the EAST 6 software, using the original 
design (i.e. target number of events) as implemented in the protocol (version 6, January 13, 2017). The 
interim analysis will utilize O’Brien-Fleming type boundaries derived from the Lan DeMets alpha spending 
function based on the actual number of events observed at the time of the interim analysis. 
6.14 
Quality of Life 
Before the database lock for the FAR, the database will be checked for compliance to the HRQoL schedule 
detailed in Section 10.4.1 of the protocol (version 6, January 13, 2017). The following considerations are 
subject to the outcome of this compliance review and will be detailed in a separate SAP which will be 
finalized before the database lock. 
Statistical considerations 
Data from the EORTC quality of life questionaire-C30 (QLQ-C30) will be scored according to the algorithm 
described in the EORTC scoring manual. All scales and single items are scored on categorical scales, and are 
linearly converted to 0-100 scales. 
The primary health-related quality of life (HRQoL) endpoint considered relevant for this study is time to 
HRQoL deterioration (TTQ). TTQ is defined as the time from randomization to the first observed of the 
following events: 
- 
death (Section 6.10) 
- 
disease progression (Section 6.11.1) 
- 
deterioration in any of the following QLQ-C30 scales: fatigue, nausea/vomiting, pain, dyspnea, 
insomnia, appetite loss, constipation, diarrhea, physical functioning, role functioning, social 
functioning and emotional functioning or global health/quality-of-life (QoL) scale. Patients are 


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considered to have deteriorated for a given scale if a worsening of 10 points at any time point 
after baseline is observed. A change of 10 points or more is considered to be clinically relevant. 
Patients who have not experienced an event at the time of analysis will be censored at the time of the last 
completed HRQoL assessment. All patients who have a baseline and at least one follow- up HRQoL 
assessment will be included in the TTQ analysis.  
TTQ will be calculated using Kaplan–Meier method and compared using the two-sided log-rank test across 
the randomized arms. TTQ will be described using medians and hazard ratio with 95% CIs. 
To assess the robustness of the results, the following sensitivity variants to the TTQ endpoint will be 
investigated: 
- 
TTQ1 – time from randomization to death, treatment discontinuation, or deterioration in any of 
the selected QLQ-C30 scores (treatment discontinuation instead of progression) 
- 
TTQ2 – time from randomization to death or deterioration in any of the selected QLQ-C30 
scores (excluding progression as event) 
- 
TTQ3 – time from randomization to deterioration in any of the selected QLQ-C30 scores 
(excluding both death and progression) 
- 
TTQ4 – time from randomization to death, disease progression, or deterioration in any of the 
following QLQ-C30 scores: fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, 
constipation, diarrhea (limit only to symptom deterioration). 
These alternative formulations serve only to investigate the robustness of the main results. They do not 
replace the primary endpoint. In the event that a significant difference is found in TTQ, the endpoint will be 
split up by its various events (death, disease progression, and the selected scales) to investigate the treatment 
effect on each of these components. 
In addition, the following summary statistics per-patient will be calculated for the secondary objectives as 
sensitivity analyses and to complement the interpretation of the time-to-event model: 
- 
average change from baseline during the on-protocol treatment period 
- 
average change from baseline during the off-protocol treatment period 
- 
10-point worsening from baseline during the on-protocol treatment period (y/n) 
- 
10-point worsening from baseline during the off-protocol treatment period (y/n) 
These statistics will be compared between the 2 groups using non-parametric Wilcoxon rank test (for the 
summary statistics based on average change) or Fisher exact test (for the summary statistics based on 
10-point worsening). Results will be summarized by the appropriate statistical estimation and corresponding 
95% CI. For the 2 binary summary statistics, missing data due to attrition will be imputed as worsening for 
sensitivity purposes. 
All available scales from the QLQ-C30 will be summarized per treatment arm on an exploratory basis. 
Missing data 
Missing data is a potential major source of bias in HRQoL assessment. 
To check the potential impact of missing HRQoL data in the study, the compliance mechanism will be 
investigated prior to initiating the HRQoL analysis. HRQoL compliance at a certain assessment time (Ti) will 
be defined as the ratio of the number of valid forms received over the number of forms expected at that time: 


i
i
i
i
T
at
expected
QoL
U
L
within
forms
QoL
valid
T
Compliance
,
)
(

  
where Li and Ui are the lower and upper bound of the time windows associated with Ti. HRQoL forms will 
be considered as invalid if no validated completion date was provided, the completion date falls outside of 
the time windows, multiple HRQoL forms were received during the time window (the form closest to the 
assessment date will be kept), a wrong version or wrong translation of questionnaire was used, or the form 
was filled out by an unauthorized person. QoL forms are expected at Ti for each patient who was within the 
QoL assessment schedule, ie, alive at time Ti. Reasons for non-completion if an assessment was missed will 
be collected via the CRFs. Characteristics of patients with and without valid HRQoL data will be compared, 


Study 1307 
 
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and trends over time per dropout pattern will be investigated. Model building will be used to investigate 
whether the compliance mechanism is linked to selected prognostic variables. 
Once the main analysis is completed, sensitivity analyses will be undertaken to verify the robustness of the 
results vis-à-vis the missing data.  
In the event that overall compliance is deemed too low (< 50%), only an exploratory analysis will be 
performed in lieu of the main analysis. 


Study 1307 
 
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Overview table for the 4 analysis reports 
7
Section 
Section title 
IDMC-PFS 
FAR 
IDMC-OS* 
OS-AR 
6.2 
Patient availability 
X 
X 
 
X 
(only sections 6.2.2 and 6.2.4) 
6.5 
Baseline characteristics 
X 
X 
 
 
6.6 
Compliance to the protocol 
X 
X 
 
 
6.7 
Exposure to treatment 
X 
X 
 
X 
(limited to relative dose intensity and 
number of cycles received ) 
6.8 
Safety evaluations 
X 
X 
 
X 
6.9 
Reasons for stopping treatment 
X 
X 
 
X 
6.10 
Disease status 
X 
X 
(excluding deaths not pertaining 
to the primary endpoint) 
X 
(limited to 
deaths) 
X 
6.11.2 
Primary endpoint: PFS by independent 
central review 
 
X 
 
X 
6.11.3.1 
Overall survival 
X 
(excluding sensitivity 
analyses) 
 
 
X 
6.11.3.2 
PFS per investigator assessment 
 
X 
 
X 
6.11.3.3 
Response to treatment 
 
X 
 
X 
6.11.3.4 
Time to treatment failure 
 
X 
 
X 
6.12 
Interim analysis for futility for PFS 
X 
 
 
 
6.13 
Interim analysis for overall survival 
 
 
X 
 


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6.14 
Quality of Life 
 
X 
 
X 
* In addition, the IDMC is supplied with the FAR


Study 1307 
 
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Bibliography 
8
Brookmeyer, R., & Crowley, J. (1982). A confidence interval for the median survival time. Biometrics, 29-
41. 
Lin, D., Wei, L., & Ying, Z. (1993). D.Y. Lin, L.J. Wei et al (1993). Checking the Cox model with 
cumulative sums of martingale-based residuals. Biometrika, 557-572. 
Schemper, M., & Smith, T. (1996). A note on quantifying follow-up in studies of failure time. Controlled 
clinical trials, 343-346. 
 


Study 1307 
 
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Appendix 1: List of case report forms (CRFs) 
9
 
SAS Form code 
Form name 
form905 
health economics questionnaire 
form930 
QoL C-30 
formae 
adverse events form 
formcenbrca 
central BCRA mutation test form 
formdm01 
medical review form 
formdh 
disease history form 
formmh 
medical history form 
formeot 
end of treatment form 
formfu 
follow-up form 
formfum 
follow-up measurements form (RECIST 1.1) 
formim 
initial measurements form (RECIST 1.1) 
formlbbio 
biochemistry form 
formlbhem 
hematology form 
formmyh 
myelosuppresion history form 
formnllab 
normal ranges lab form 
formothbrca 
previous brca mutation test form 
formpe 
physical examination form 
formsf 
screening failure form 
formtrtc 
capecitabine treatment form 
formtrte 
eribulin treatment form 
formtrtg 
gemcitabine treatment form 
formtrtn 
niraparib treatment form 
formtrtviv 
IV vinorelbine treatment form 
formtrtvo 
oral vinorelbine treatment form 
formrg1  
screening-registration form (values provided at time of screening) 
formrg2  
eligibility checklist form (values provided at time of randomization) 
formcrg1 
screening-registration form (potentially corrected values) 
formcrg2 
eligibility checklist form (potentially corrected values) 
patient 
patient identifier form 
 
 


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Appendix 2: Tables and listing to be provided to IDMC for safety review 
10
Output Type 
(T/L/F) 
Number 
Title 
Analysis Set 
Accrual information 
T 
I.1 
Cumulative Proportion of Subjects Randomized by 
Calendar Time 
Full ITT population 
F 
F.1 
Subject Accrual over time  
Screening population  
T 
I.2 
Subject Accrual by site 
Screening population 
T 
I.3 
Number of patients registered per site 
Screening population 
F 
F.2 
Number of patients registered per site 
Screening population 
T 
I.4 
Accrual by country 
Screening population 
Study Conduct and Patient Disposition 
T 
C1 
Eligibility status 
Full ITT population 
L 
C.2 
Listing of ineligible patients 
Full ITT population 
T 
C.3 
Compliance to treatment allocation 
Full ITT population 
T 
C.4 
Patient disposition and reason for discontinuation 
Full ITT population 
L 
C.5 
Listing of patients who are not treated as 
randomized 
Full ITT population 
Kaplan-Meier 
C.6 
Time to protocol treatment discontinuation 
Full ITT population 
T 
C.7 
Distribution of stratification factors  
Full ITT population 
L 
C.8 
Listing of patients who are lost-to-follow-
up/withdrew from study 
Full ITT population 
Baseline data 
T 
B.1 
Demographic characteristics 
Full ITT population 
T 
B.2 
Primary Diagnoses and time since diagnosis 
Full ITT population 
T 
B.3 
Baseline Characteristics (incl. ECOG Performance 
Status) 
Full ITT population 
Study Treatment Exposure 
T 
T.1 
Number of cycles received 
Safety population 
T 
T.2 
Dose Interruptions, Reductions - overall 
Safety population 
T 
T.3 
Dose Interruptions, Reductions – by cycle 
Safety population 
T 
T.4 
Reason for first dose interruption/reduction 
Safety population 
T 
T.5 
Reason for stopping protocol treatment 
Safety population 
Adverse Events Data 
T 
A.1 
Discontinuations Due to toxicity 
Safety population 
T 
A.2 
Temporary Discontinuations or Dose Reductions 
Due to toxicity 
Safety population 


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T 
A.3 
Overall Summary of Adverse Events (worst grade 
during treatment) 
Safety population 
Kaplan-Meier 
F.3 
Kaplan-Meier Plots of Time to First Occurrence of 
Most Common Treatment Related grade 3-4 
Adverse Events   
Safety population 
T 
A.4 
Cause of Death 
Safety population 
L 
A.5 
Listing of Deaths and the cause 
Safety population 
L 
A.6 
Listing of serious Adverse Events 
Safety database 
L 
A.7 
Listing of (likely) treatment related adverse events 
that led to drug discontinuation 
Safety population 
L 
A.8 
Listing of  grade ≥ 3 Adverse events 
Safety population 
Laboratory Data 
T 
L.1 
Laboratory Results Summary by Maximum CTC 
Grade (Hematology, Cycle 1) 
Safety population 
T 
L.2 
Laboratory Results Summary by Maximum CTC 
Grade (Hematology, By Cycle, All cycles) 
Safety population 
T 
L.3 
Laboratory Results Summary by Maximum CTC 
Grade (Chemistries, All Cycles) 
Safety population 
T 
L.4 
Laboratory Results Summary by Maximum CTC 
Grade (Chemistries, Cycle 1) 
Safety population 
L 
L.5 
Listing of  CTC grade ≥ 3 (chemistries/hematology) 
Safety population