Clinical trial NCT03329937
Conditions: Neoplasms, Breast
Keywords: Niraparib Human epidermal growth factor receptor Breast cancer Breast ultrasound Magnetic resonance imaging
Sponsor: Tesaro, Inc.
Start date: 2018-04-12; Completion date: 2020-03-31
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, single-arm pilot study evaluating the antitumor activity and safety of niraparib as neoadjuvant therapy in participants with Human epidermal growth factor receptor 2 (HER2)-negative and breast cancer susceptibility gene mutant (BRCAmut) localized breast cancer (primary tumor \>=1 centimeters \[cm\]). Breast magnetic resonance imaging (MRI), breast ultrasound, and tumor core biopsy will be performed at the screening (Days -28 to -1). Participants will receive niraparib (200 milligrams \[mg\] orally \[PO\]) treatment daily for 28 days (Cycle 1) and then will undergo breast ultrasound at the end of Cycle 1 on Day 28. Based on breast ultrasound reports, the participants will either discontinue the study (disease progression) or will continue niraparib treatment (complete response \[CR\], partial response \[PR\] or stable disease \[SD\]) for an additional cycle (Cycle 2). A breast MRI and breast ultrasound will be performed at the end of Cycle 2. Approximately 21 participants will be enrolled in this study and the study duration will be approximately 2 years.

Detailed description:

Arms: arm 1: Participants with HER2-negative and BRCAmut localized breast cancer (primary tumor \>=1 cm) will receive niraparib (200 mg PO).
Interventions: intervention 1: Niraparib
Intervention descriptions: intervention 1: Niraparib is a potent, orally active, highly selective poly adenosine diphosphate (\[ADP\]-ribose) polymerase 1 (PARP1) and PARP2 inhibitor. It will be supplied as 100 mg capsules and will be administered at starting dose of 200 mg PO daily throughout 28 days for 2 cycles (each cycle is 28 days), with the potential for an additional 4 cycles (maximum total of 6 cycles) at the assigned dose and schedule.

Protocol documents:
Prot_000.pdf: 
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1. 
TITLE PAGE 
 
NIRAPARIB 
3000-01-005 
AN OPEN-LABEL, SINGLE-ARM PILOT STUDY EVALUATING 
THE ANTITUMOR ACTIVITY AND SAFETY OF NIRAPARIB AS 
NEOADJUVANT TREATMENT IN LOCALIZED, HER2-NEGATIVE, 
BRCA-MUTANT BREAST CANCER PATIENTS 
 
Sponsor: 
TESARO, Inc. 
1000 Winter Street 
Waltham, MA 02451 
TESARO UK Limited 
55 Baker Street 
London W1U 7EU 
United Kingdom 
Medical Monitor: 
, MD 
Sr. Medical Director 
TESARO 
Sponsor Protocol No.: 
IND No: 
 
3000-01-005 
117580 
Study Drug Names: 
Niraparib capsules 
Development Phase: 
Date of Original Protocol: 
Pilot Study 
16 September 2017 
Date of Amendment 1: 
01 August 2018 
Version of Protocol: 
2.0 
The study will be conducted according to the protocol and in compliance with Good Clinical Practice 
(GCP), with the Declaration of Helsinki, and with other applicable regulatory requirements. 
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. 
 
PPD
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SPONSOR SIGNATURE PAGE 
Declaration of Sponsor or Responsible Medical Officer 
Title: An Open-Label, Single-arm Pilot Study Evaluating the Antitumor Activity and 
Safety of Niraparib as Neoadjuvant Treatment in Localized, HER2-negative, 
BRCA-mutant Breast Cancer Patients 
This study protocol was subjected to critical review and has been approved by the Sponsor. The 
information it contains is consistent with the current risk/benefit evaluation of the investigational 
products as well as with the moral, ethical, and scientific principles governing clinical research 
as set out in the Declaration of Helsinki and the guidelines on Good Clinical Practice. 
____
_______ _____________________ 
Date 
Bru
l Direcor 
PPD
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INVESTIGATOR’S AGREEMENT 
Declaration of the Principal Investigator 
 
Title: An Open-Label, Single-arm Pilot Study Evaluating the Antitumor Activity and 
Safety of Niraparib as Neoadjuvant Treatment in Localized, HER2-negative, 
BRCA-mutant Breast Cancer Patients 
 
 
I have read this study protocol, including all appendices. By signing this protocol, I agree to 
conduct the clinical study, following approval by an Independent Ethics Committee/Institutional 
Review Board, in accordance with the study protocol, the current International Council for 
Harmonisation Guideline for Good Clinical Practice, and applicable regulatory requirements. I 
will ensure that all personnel involved in the study under my direction will be informed about the 
contents of this study protocol and will receive all necessary instructions for performing the 
study according to the study protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Institution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 


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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone 
Number 
Clinical Study Leader 
, MD 
TESARO 
1000 Winter Street 
Waltham, MA 02451 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: TESARO 
Name of Investigational Product: Niraparib 
Name of Active Ingredient: Niraparib 
Title of Study: An Open-Label, Single-arm Pilot Study Evaluating the Antitumor Activity and 
Safety of Niraparib as Neoadjuvant Treatment in Localized, HER2-negative, BRCA-mutant 
Breast Cancer Patients  
Study center(s): North America (multicenter) 
Studied period (years):  
Estimated date first patient enrolled: April 2018 
Estimated date last patient completed: TBD 
Phase of development:  
Pilot Study 
Objectives:  
Primary: 
• 
To evaluate the preliminary antitumor activity of niraparib assessed as the tumor response 
rate based on the change in tumor volume as measured by breast MRI, observed after 
treatment with niraparib in the neoadjuvant treatment of localized, human epidermal 
growth factor receptor 2 (HER2)-negative, breast cancer susceptibility gene (BRCA) 
mutant (BRCAmut) breast cancer patients.  
Secondary: 
• 
To evaluate the preliminary antitumor activity of niraparib assessed by: 
− 
Presence of pathological complete response (pCR) defined as ypT0/Tis ypN0 by 
receipt of pre-operative chemotherapy (Yes versus No) 
− 
Percentage change in tumor volume from baseline after 2 months of niraparib 
treatment by MRI and ultrasound 
− 
Tumor response rate based on the change in tumor volume as measured by breast 
ultrasound 
• 
To evaluate safety and tolerability of niraparib per the current version of the National 
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 
criteria  
Exploratory: 
• 
To evaluate niraparib-induced changes in immune responses 
• 
To explore intra-tumoral niraparib concentration and correlation with blood  
• 
To estimate the preliminary antitumor activity of niraparib in BRCAmut triple-negative breast 
cancer (TNBC) patients and BRCAmut hormone-positive patients 
• 
To evaluate pharmacodynamic inhibition of PARP activity in the tumor 


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• 
To explore molecular biomarkers related to disease biology or response to treatment 
using tumor tissue or liquid biopsy approaches (e.g. ctDNA) 
Methodology:  
This is an open-label, single-arm pilot study evaluating the antitumor activity and safety of niraparib 
as neoadjuvant therapy in patients with HER2-negative and BRCAmut localized breast cancer 
(primary tumor ≥1 cm). The study design is summarized in the schema below. If antitumor activity in 
the BRCAmut cohort is demonstrated, the protocol may be amended to add a homologous 
recombination deficiency (HRD)-positive, BRCA-wild type cohort. 
Study Schema 
 
 
1Patients may receive up to 6 months of niraparib (see Section 7). 
2Breast ultrasounds are performed at the end of each month for those patients receiving additional 
cycles. 
3Core biopsy will be obtained preferably within 24 hours of the last dose of niraparib in cycle 2 and 
prior to any subsequent anticancer therapy or procedure. A surgical biopsy may be used in lieu of a 
core biopsy provided that surgery occurs within 24 hours of the last dose of niraparib in Cycle 2. 
4Tumor size cut-off for pre-surgery chemotherapy will be determined by investigator discretion.  
5Off-study visit is for the collection of pCR results for patients for whom the Safety Follow-up/EOT 
Visit occurred prior to surgery; for all other patients the Safety Follow-up/EOT Visit will act as the 
off-study visit. 
Breast magnetic resonance imaging (MRI), breast ultrasound, and tumor core biopsy will be 
performed at the Screening (-28 to -1 Day 1). 
Patients will receive niraparib (200 mg orally [PO]) treatment daily for 28 days (Cycle 1) and then 
will undergo breast ultrasound at the end of Cycle 1 on Day 28: 
• 
If breast ultrasound shows disease progression defined as an increase in tumor volume by 
greater than 20% by Investigator assessment, the patient will discontinue the study. If 
breast ultrasound shows complete response, partial response, or stable disease by 
Investigator assessment, the patient will continue niraparib treatment 200 mg PO for an 
additional cycle (Cycle 2). Patients may receive up to 6 months of niraparib treatment if, 
in the opinion of the Investigator and Sponsor, and agreed upon by the Sponsor, the 
patient would benefit from additional treatment. 


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A breast MRI and breast ultrasound will be performed at the end of Cycle 2. The investigational team 
will determine if the patient will proceed to surgery or to neoadjuvant chemotherapy.  
A core biopsy will be performed at the end of Cycle 2, which should occur within 24 hours of the last 
dose of niraparib. Niraparib treatment may be extended up to an additional 7 days after Cycle 2 Day 
28 to allow for scheduling of surgery or the core biopsy: 
• 
For those patients proceeding directly to surgery at the end of Cycle 2, a surgical biopsy may 
be obtained at the time of surgery provided that surgery occurs within 24 hours of the last 
dose of niraparib on Cycle 2 Day 28 (+7 days).  
• 
For all other patients, provided that their tumors are amenable to biopsy, a core biopsy should 
be obtained within 24 hours of the last dose of niraparib on Cycle 2 Day 28 (+7 days). The 
biopsy should be performed after the MRI and ultrasound and prior to any subsequent 
anticancer therapy.  
At the completion of all neoadjuvant therapy, patients will proceed to surgery and/or other local 
treatment as deemed appropriate by the investigator. For those patients who receive neoadjuvant 
therapy (niraparib alone or niraparib followed by chemotherapy), a pCR assessment will be made at 
the time of surgery. 
Patients shall discontinue treatment in case of unacceptable toxicity or withdrawal of consent. 
All adverse events (AEs) will be collected and recorded for each patient from the day of signing the 
informed consent form until 30 days after last study drug administration. 
Selected non-serious AEs and serious adverse events (SAEs) are also known as adverse events of 
special interest (AESI) and must be recorded as such on the electronic case report form (eCRF) and 
reported within 24 hours to the Sponsor as soon as the Investigator becomes aware of them. 
SAEs are required to be captured through 90 days after the last dose of study drug (or to a minimum 
of 30 days post treatment if the patient starts alternate anticancer therapy). All SAEs assessed by the 
Investigator as related to the study drug and AESIs will be collected and reported until study closeout. 
Any pregnancies that occur up to and including 180 days post-treatment will be reported. Pregnancies 
occurring more than 180 days after last dose, with an associated SAE (considered causally related to 
the study drug by the Investigator) will follow the SAE reporting requirements. 
All AEs and SAEs experienced by a patient, irrespective of the suspected causality, will be monitored 
until the AE or SAE has resolved, until abnormal laboratory values have returned to baseline or 
normalized, until there is a satisfactory explanation for the changes observed, until the patient is lost 
to follow-up, or until the patient has died. 
Number of patients (planned): Approximately 20 
Diagnosis and main criteria for inclusion:  
1. Patients age ≥18 years old 
2. Patients with a deleterious or suspected deleterious BRCA1 or BRCA2 mutation (germline or 
somatic) may be enrolled into the study based on either local or central laboratory testing of 
BRCA status 
3. Histologically-confirmed HER2-negative localized breast cancer by core biopsy.  


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4. Primary operable, non-metastatic invasive carcinoma of the breast, confirmed histologically 
by core biopsy. Fine-needle aspiration is not sufficient. Incisional biopsy is not allowed. In 
patients with multifocal and/or multicentric, the largest lesion should be measured. Both 
unilateral and bilateral breast cancer are allowed. 
5. Primary tumor size ≥1 cm  
6. Measurable disease by breast ultrasound and MRI 
7. Eastern Cooperative Oncology Group performance status of 0 or 1 
8. Adequate organ function, defined as follows: 
Note: Complete blood count should be obtained without transfusion or receipt of colony 
stimulating factors within 4 weeks prior to obtaining a sample. 
a. Absolute neutrophil count (ANC) ≥1,500/μL  
b. Platelets ≥100,000/μL  
c. Hemoglobin ≥9 g/dL  
d. Serum creatinine ≤1.5 x upper limit of normal (ULN) or calculated creatinine clearance 
≥ 50 mL/min using Cockcroft-Gault equation  
e. Total bilirubin ≤1.5× ULN except in patients with Gilbert’s syndrome. Patients with 
Gilbert’s syndrome may enroll if direct bilirubin ≤1.5 × ULN of the direct bilirubin 
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN  
9. Patient must have recovered to Grade 1 toxicity from prior cancer therapy (a patient with 
Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion and may qualify for 
this study). 
10. Able to take oral medications 
11. Patient meets the following criteria: 
a. Female patient (of childbearing potential) is not breastfeeding, has a negative serum 
pregnancy test within 72 hours prior to taking study drug, and agrees to abstain from 
activities that could result in pregnancy from the Screening through 180 days after the 
last dose of study drug, or is of nonchildbearing potential.  
Note: A urine pregnancy test may be performed if the serum pregnancy test is not available 
before dosing. 
b. Female patient is of nonchildbearing potential (other than medical reasons) as defined by 
the following: 
i. 
≥45 years of age and has not had menses for >1 year. 
ii. 
Amenorrheic for <2 years without a hysterectomy and oophorectomy and a 
follicle-stimulating hormone value in the postmenopausal range upon the 
Screening evaluation. 
iii. 
Has undergone post hysterectomy, bilateral oophorectomy, or tubal ligation. 
Documented hysterectomy, oophorectomy or tubal ligation must be confirmed in 
the medical records, otherwise the patient must be willing to use 2 adequate 
barrier methods throughout the study starting from the Screening visit through 
180 days after the last dose of study drug. Information must be captured 
appropriately within the site’s source documents. 


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c. Male patient agrees to use an effective method of contraception (please see Section 9.2.2 
for a list of acceptable birth control methods) starting with the first dose of study therapy 
through 120 days after the last dose of study therapy 
Note: Abstinence is acceptable if this is the established and preferred contraception method 
for the patient. 
12. Able to understand the study procedures and agree to participate in the study by providing 
written informed consent 
Exclusion Criteria: 
1. Prior anti-cancer therapies for current malignancy 
2. Known evidence of distant metastasis. Staging studies are not required.  
The decision to pursue staging studies is at the discretion of the treating clinician, based on 
the patient’s clinical and pathologic findings consistent with standard guidelines.  
3. Known hypersensitivity to the components of niraparib components or their formulation 
excipients 
4. Major surgery within 3 weeks of starting the study or patient has not recovered from any 
effects of any major surgery 
5. 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 90 days) myocardial infarction, 
uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava 
syndrome, uncontrolled hypertension, active uncontrolled coagulopathy, bleeding disorder, or 
any psychiatric disorder that prohibits obtaining informed consent 
6. History or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the patient’s participation for the full duration 
of the study drug, or is not in the best interest of the patient to participate 
7. Patient is pregnant or breastfeeding, or expecting to conceive children within the projected 
duration of the study drug or within the 180-day period after the last dose of study drug 
8. Immunocompromised patients (Note: patients with splenectomy are allowed) 
9. Known active hepatic disease (ie, Hepatitis B or C) 
10. Prior treatment with a known PARP inhibitor 
11. Other active malignancy that warrants systemic therapy 
12. Known history of myelodysplastic syndromes or acute myeloid leukemia 
Investigational product, dosage and mode of administration:  
Niraparib (100 mg niraparib capsules) will be supplied and starting dose will be 200 mg. Study drug 
will be administered PO daily throughout 28 days for 2 cycles, with the potential for an additional 
4 cycles (maximum total of 6 cycles), at the assigned dose and schedule. 


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Duration of treatment:  
Approximately 56 days. 
Reference therapy, dosage and mode of administration:  
Not applicable 
Criteria for evaluation: 
Efficacy: 
The primary efficacy endpoint is: 
• 
Tumor response rate based on the change in tumor volume as measured by breast MRI; a 
response is considered ≥30% reduction of tumor volume from baseline after 2 months of 
niraparib treatment. Tumor volume will be calculated as (length × width × height × π)/6. 
The secondary efficacy endpoints are: 
• 
pCR rate: pCR is defined as ypT0/Tis ypN0 by receipt of pre-operative chemotherapy (Yes vs. 
No). Pathological complete response (pCR) is defined as the absence of residual invasive 
cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all 
sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., 
ypT0/Tis ypN0 in the current AJCC staging system1). 
• 
Tumor response rate based on the change in tumor volume as measured by breast ultrasound; 
a response is considered ≥30% reduction of tumor volume from baseline after 2 months of 
niraparib treatment. Tumor volume will be calculated as (length × width × height × π)/6. 
• 
Percentage change in tumor volume from baseline after 2 months of niraparib treatment as 
measured by ultrasound. Tumor volume will be calculated as (length × width × height × π)/6. 
• 
Percentage change in tumor volume from baseline after 2 months of niraparib treatment as 
measured by MRI. Tumor volume will be calculated as (length × width × height × π)/6. 
The exploratory endpoints are: 
• 
Immune-related changes in gene expression profiles and cellular composition (eg, T-cells, 
myeloid cells, and natural killer cells) in pre vs. post niraparib treatment tumor samples 
• 
Niraparib concentration in post treatment tumor samples and correlation with PK in 
peripheral blood 
• 
Estimation of change in tumor volume in BRCAmut TNBC patients and in BRCAmut 
hormone-positive patients 
• 
Comparison of PARP enzymatic activity (eg, PARylation), DNA damage and repair (eg, 
phosphorylated histone H2AX, RAD51), proliferation (eg, Ki67) and survival (eg, Caspase 3) 
in pre vs. post niraparib treatment tumor samples 
• 
Potential biomarkers of sensitivity or resistance (e.g. BRCA reversion mutations, loss of 
heterozygosity [LOH]) in ctDNA or tumor tissue 
• 
Targeted (or whole exome) sequencing for other disease related molecular alterations with 
remaining blood or tumor samples 


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Safety: 
• 
Safety by toxicity grades as defined by the NCI-CTCAE v.4.03 criteria 
• 
Incidence of treatment-emergent AEs (TEAEs)  
• 
Changes in clinical laboratory parameters (hematology, chemistry)  
• 
Vital signs  
• 
Physical examinations 
• 
Usage of concomitant medications 
Statistical methods: 
No formal sample size calculation is done for this study. The sample size is determined based on the 
clinical considerations only.  
A total of approximately 20 evaluable patients will be enrolled. This sample size should be sufficient 
for signal finding prior to initiating a larger study. For example, it will provide approximately 80% 
power with 1-sided significance level of 0.15 to differentiate a response rate of 80% from a minimum 
response rate of 60%. Other examples are provided below. 
One-sided 
alpha 
SoC 
Response Rate 
Niraparib 
Response 
Rate 
Power 
0.15 
60% 
70% 
45% 
0.15 
60% 
75% 
65% 
0.15 
60% 
80% 
80% 
The safety population includes all patients who received any dose of study medication. The safety 
population will be the primary analysis population for the safety analyses. 
The efficacy evaluable population includes all patients who completed 2 cycles of treatment. The 
efficacy evaluable population will be the primary analysis population for the efficacy analyses. 
No formal statistical testing will be done for this study. Data will be summarized in a descriptive 
nature. Categorical variables will be summarized by frequency distributions (number and percentage 
of patients). Continuous variables will be summarized by the mean, standard deviation, median, 
minimum, maximum, first quartile and third quartile.  
Tumor response rate will be tabulated together with its 95% binomial exact confidence interval (CI). 
The change in tumor volume from baseline will be summarized using descriptive statistics. Data from 
patients who received neoadjuvant niraparib only will be analyzed separately from those who 
received neoadjuvant niraparib followed by neoadjuvant chemotherapy. 
Summary statistics will be provided for safety endpoints including TEAEs, clinical laboratory 
evaluations (hematology, chemistry, and urinalysis), vital signs, electrocardiograms, physical 
examinations, and use of concomitant medications. 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................18 
5. 
INTRODUCTION ......................................................................................................20 
5.1. 
Background .................................................................................................................20 
5.1.1. 
Breast Cancer ..............................................................................................................20 
5.1.1.1. 
Niraparib: Pre-Clinical Summary ...............................................................................22 
5.1.1.2. 
Niraparib: Clinical Summary ......................................................................................23 
5.1.1.3. 
Study Rationale ...........................................................................................................25 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................26 
6.1. 
Primary Objective .......................................................................................................26 
6.2. 
Secondary Objectives .................................................................................................26 
6.3. 
Exploratory Objectives ...............................................................................................26 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.1.1. 
General Study Conduct ...............................................................................................28 
7.2. 
Number of Patients .....................................................................................................30 
7.3. 
Treatment Assignment ................................................................................................30 
7.4. 
Dose Adjustment Criteria ...........................................................................................30 
7.5. 
Criteria for Study Termination ...................................................................................33 
7.6. 
Schedule of Events .....................................................................................................33 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................38 
8.1. 
Patient Inclusion Criteria ............................................................................................38 
8.2. 
Patient Exclusion Criteria ...........................................................................................39 
8.3. 
Restrictions During Study ...........................................................................................40 
8.4. 
Patient Withdrawal Criteria ........................................................................................41 
8.4.1. 
Discontinuation from Treatment .................................................................................41 


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8.4.2. 
Discontinuation from the Study ..................................................................................41 
9. 
TREATMENT OF PATIENTS ..................................................................................43 
9.1. 
Description of Study Drug ..........................................................................................43 
9.2. 
Concomitant Medications ...........................................................................................43 
9.2.1. 
Prohibited Medications ...............................................................................................43 
9.2.2. 
Contraception ..............................................................................................................44 
9.2.3. 
Other Study Restrictions .............................................................................................44 
9.3. 
Treatment Compliance ................................................................................................44 
9.4. 
Randomization and Blinding ......................................................................................45 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................46 
10.1. 
Study Drug ..................................................................................................................46 
10.2. 
Study Drug Packaging and Labeling ..........................................................................46 
10.3. 
Study Drug Storage .....................................................................................................46 
10.4. 
Study Drug Preparation ..............................................................................................46 
10.5. 
Administration ............................................................................................................46 
10.6. 
Presurgery Chemotherapy ..........................................................................................47 
10.7. 
Study Drug Accountability .........................................................................................47 
10.8. 
Study Drug Handling and Disposal ............................................................................47 
11. 
ASSESSMENT OF EFFICACY ................................................................................48 
11.1. 
Efficacy Endpoints ......................................................................................................48 
11.1.1. 
Primary Endpoint ........................................................................................................48 
11.1.2. 
Secondary Endpoints ..................................................................................................48 
11.2. 
Exploratory Endpoints ................................................................................................48 
12. 
TRANSLATIONAL RESEARCH .............................................................................50 
12.1. 
Effect of Niraparib Treatment on the Tumor Immune Contexture and 
Pharmacodynamic Changes in Tumor Cells ...............................................................50 
12.1.1. 
Tumor Immune Contexture ........................................................................................50 
12.1.2. 
Intra-tumoral Niraparib Concentration .......................................................................50 
12.1.3. 
Pharmacodynamic Changes ........................................................................................50 
12.1.4. 
Molecular Mechanisms Mediating Resistance to Niraparib in BRCAmut 
Population ...................................................................................................................51 
12.2. 
Assessment of Blood-based Predictive Biomarkers for Niraparib Efficacy 
and Resistance ............................................................................................................51 


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12.2.1. 
BRCA Status and Other Biomarker Analysis of Circulating Tumor DNA .................51 
12.3. 
Summary of Sample Collection ..................................................................................51 
12.4. 
Safety Endpoints .........................................................................................................52 
13. 
ASSESSMENT OF SAFETY .....................................................................................53 
13.1. 
Safety Parameters .......................................................................................................53 
13.1.1. 
Demographic/Medical History ...................................................................................53 
13.1.2. 
Disease History ...........................................................................................................53 
13.1.3. 
Medical and Surgical History .....................................................................................53 
13.1.4. 
Vital Signs ..................................................................................................................53 
13.1.5. 
Weight and Height ......................................................................................................53 
13.1.6. 
Physical Examination .................................................................................................53 
13.1.7. 
Electrocardiogram .......................................................................................................54 
13.1.8. 
Clinical Laboratory Assessments ...............................................................................54 
13.1.8.1. 
Hematology .................................................................................................................54 
13.1.8.2. 
Blood Chemistry .........................................................................................................54 
13.1.8.3. 
Urinalysis ....................................................................................................................55 
13.1.8.4. 
Virus Serology ............................................................................................................55 
13.1.8.5. 
Drug Screen ................................................................................................................55 
13.1.8.6. 
Pregnancy Screen ........................................................................................................55 
13.1.9. 
ECOG Performance Status .........................................................................................55 
13.2. 
Adverse Events and Special Situations .......................................................................55 
13.2.1. 
Definition ....................................................................................................................55 
13.2.1.1. 
Adverse Event (AE) ....................................................................................................55 
13.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................56 
13.2.1.3. 
Treatment-Emergent Adverse Event (TEAE) ............................................................56 
13.2.1.4. 
Adverse Event of Special Interest (AESI) ..................................................................56 
13.2.1.5. 
Special Situations: Abuse, Misuse, Medication Errors, Overdose, and 
Accidental or Occupational Exposure ........................................................................56 
13.2.2. 
Assessment of Adverse Events ...................................................................................57 
13.2.2.1. 
Severity Assessment ...................................................................................................57 
13.2.2.2. 
Relationship to Study Intervention .............................................................................58 
13.2.2.3. 
Expectedness ...............................................................................................................58 
13.2.3. 
Collection and Recording Adverse Events .................................................................58 


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13.2.4. 
Follow-Up of Adverse Events ....................................................................................59 
13.2.5. 
Reporting ....................................................................................................................59 
13.2.6. 
Submission and Distribution of Serious Adverse Event Reports ...............................59 
13.2.7. 
Adverse Events of Special Interest .............................................................................60 
13.2.8. 
Pregnancy ...................................................................................................................60 
13.2.9. 
Special Situations ........................................................................................................61 
14. 
STATISTICS ..............................................................................................................62 
14.1. 
Sample size determination ..........................................................................................62 
14.2. 
Populations for Analysis .............................................................................................62 
14.3. 
Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications .................................................................................................................62 
14.4. 
Efficacy Analyses .......................................................................................................63 
14.5. 
Safety Analyses ..........................................................................................................63 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................63 
15.1. 
Study Monitoring ........................................................................................................63 
15.2. 
Audits and Inspections ................................................................................................64 
15.3. 
Institutional Review Board .........................................................................................64 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................65 
17. 
ETHICS ......................................................................................................................66 
17.1. 
Ethics Review .............................................................................................................66 
17.2. 
Ethical Conduct of the Study ......................................................................................66 
17.3. 
Written Informed Consent ..........................................................................................66 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................67 
18.1. 
Inspection of Records .................................................................................................67 
18.2. 
Retention of Records ..................................................................................................67 
19. 
PUBLICATION POLICY ..........................................................................................68 
20. 
LIST OF REFERENCES ............................................................................................69 
21. 
APPENDICES ............................................................................................................72 
APPENDIX 1. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS .....................................................................................................................73 
APPENDIX 2. DISEASE ASSESSMENT CRITERIA ..............................................................74 
APPENDIX 3. TNM  DEFINITIONS ........................................................................................75 
APPENDIX 4. AJCC STAGE GROUPINGS ............................................................................76 


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APPENDIX 5. NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS .....................................................................77 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 3: 
Progression-Free Survival in Ovarian Cancer Patients in NOVA ..............................24 
Table 4: 
Niraparib Dose Reductions for Non-Hematologic Toxicities .....................................31 
Table 5: 
Management of Hematologic Toxicities ....................................................................31 
Table 6: 
Schedule of Events .....................................................................................................34 
Table 7: 
Investigational Product ...............................................................................................43 
Table 8: 
Summary of Sample Collection ..................................................................................52 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................27 
 
  


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BCSS 
breast cancer-specific survival 
BRCA 
breast cancer susceptibility gene 
BRCAmut 
breast cancer susceptibility gene mutant 
C1 
cohort 1 
C2 
cohort 2 
CBC 
complete blood count 
CI 
confidence interval 
CR 
complete response 
ctDNA 
circulating tumor DNA 
CYP 
cytochrome P450 
DFS 
disease free survival 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EFS 
event-free survival 
EOT 
end of treatment 
FFPE 
formalin-fixed paraffin embedded 
gBRCA 
germline breast cancer susceptibility gene 
GCP 
Good Clinical Practice 
HER2 
Human epidermal growth factor receptor 2 
HR 
hazard ratio 
HRD 
homologous recombination deficiency 


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Abbreviation or Specialist Term 
Explanation 
IC50 
half maximal inhibitory concentration of control 
IC90 
90% inhibitory concentration of control 
IEC 
Independent Ethics Committee 
IRB 
 
Institutional Review Board 
LOH 
loss of heterozygosity 
MDS 
myelodysplastic syndrome  
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NBF 
neutral buffered formalin 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria 
for Adverse Events 
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly(ADP-ribose) polymerase 
pCR 
pathological complete response 
PD 
pharmacodynamic 
PDX 
patient-derived tumor graft 
PFS 
progression free survival 
PI 
Principal Investigator 
The Investigator who leads the study conduct at an 
individual study center. Every study center has a principal 
Investigator. 
PK 
pharmacokinetics 
PO 
oral(ly) 
PR 
partial response 
QD 
once daily 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SD 
stable disease 
TEAE 
treatment-emergent adverse event 
TNBC 
triple-negative breast cancer 
US 
United States of America 
ULN 
upper limit of normal 


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5. 
INTRODUCTION 
5.1. 
Background 
5.1.1. 
Breast Cancer 
Breast cancer is the most common cancer in women worldwide, with nearly 1.7 million new 
cases diagnosed in 2012 (second most common cancer overall). This represents about 12% of all 
new cancer cases and 25% of all cancers in women.2 In the United States of America (U.S.), 
approximately 1 in 8 women (about 12%) will develop invasive breast cancer over the course of 
her lifetime. In the U.S. alone, it is estimated that there will be 252,710 new cases of female 
breast cancer and an estimated 40,610 people will die of this disease in 2017.3 In Europe, more 
than 464,000 new cases of breast cancer were estimated to have been diagnosed in 2012.4 
Approximately 20 to 25 % of hereditary breast cancers and 5 to 10% of all breast cancers are 
associated with pathogenic germline alterations in breast cancer susceptibility gene (BRCA)1 and 
BRCA2.5,6 Women with BRCA mutations have a lifetime risk of developing breast cancer of 45 
to 75%.7-9 BRCAmut breast cancer is characterized by more aggressive phenotype than sporadic 
breast cancer, with BRCA1-mutated breast cancer being more frequently high grade and triple 
negative, and BRCA2-mutated breast cancer being on average of higher histological grade than 
sporadic cases.7,10,11 BRCA1 mutation carriers have worse overall survival (OS) than 
BRCA-wildtype cases (hazard ratio [HR]: 1.30, 95% CI: 1.11–1.52) and worse breast 
cancer-specific survival (BCSS) than sporadic/BRCA-wildtype cases among patients with stage 
I–III breast cancer (HR 1.45, 95% CI: 1.01–2.07). BRCA2 mutation carriers have worse BCSS 
than sporadic/BRCA-wildtype cases (HR 1.29, 95% CI: 1.03–1.62), although they have similar 
OS. Among Ashkenazi Jewish women, BRCA1/2 mutation carriers presented higher risk of death 
from breast cancer (HR 1.44, 95% CI: 1.05–1.97) and of distant metastases (HR 1.82, 95% CI: 
1.05–3.16) than sporadic/BRCA-wildtype patients.12 
BRCA1/2-mutant cells are hypersensitive to inactivation of poly (ADP-ribose) polymerase 1 
(PARP-1), garnering great interest in the treatment of breast cancer patients with 
BRCA1/2-mutant disease via PARP inhibition. The PARP inhibitor olaparib was assessed for 
efficacy and safety in women with BRCA1 or BRCA2-mutant advanced breast cancer.13 In this 
proof-of concept phase 2 study, women were assigned to two sequential cohorts, the first cohort 
(n = 27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), 
and the second (n = 27) was given a lower dose (100 mg twice daily). The primary objective was 
objective response rate (ORR); ORR was 11 (41%) of 27 patients (95% CI 25–59) in the cohort 
assigned to 400 mg twice daily, and 6 (22%) of 273,12,14,15 in the cohort assigned to 100 mg twice 
daily. The results of this study provided proof of concept for PARP inhibition in BRCAmut 
breast cancers and shows a favorable therapeutic index for a novel targeted treatment strategy in 
patients with tumors that have genetic loss of function of BRCA1-associated or 
BRCA2-associated deoxyribonucleic acid (DNA) repair. 
More recently, the ABRAZO study was initiated to investigate the use of PARP inhibitor 
talazoparib in patients with gBRCA1/2 mutation previously exposed to platinum or multiple prior 
cytotoxic regimens (Turner et al 2017).16 This study is a 2-cohort, 2-stage phase 2 study of 
talazoparib following platinum-based therapy (Cohort 1 [C1]) or ≥ 3 platinum-free 
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cancer and gBRCA1/2 mutation. Five responses per cohort were required in ≤ 35 patients to 
progress to stage 2. The primary endpoint was confirmed ORR by independent radiology facility. 
As of Sep 2016, 84 patients had enrolled (C1, n = 49; C2, n = 35). Both cohorts proceeded to 
stage 2 before enrollment closed. Triple negative breast cancer (TNBC)/human epidermal growth 
factor receptor 2 (HER2)-positive (TNBC/HER2-positive) breast cancer incidence in C1 and C2 
was 59%/41% and 17%/83%, respectively. ORR for BRCA1/BRCA2 was 24%/34%, and ORR by 
for TNBC/HER2-positive was 26%/29%. Based on these data, the phase 3 EMBRACA trial was 
initiated to test the use of talazoparib versus physician’s choice of treatment in 
gBRCA1/2-mutated metastatic breast cancer. 
The efficacy and tolerability of the PARP inhibitor veliparib was tested in combination with 
carboplatin and paclitaxel versus placebo given with carboplatin and paclitaxel in patients with 
BRCA1 or BRCA2 mutations and metastatic breast cancer in the BROCADE study.17 In this 
randomized, phase 2 study, 290 patients with BRCA1 or BRCA2 mutation were randomized to 
three arms: 97 were randomized to veliparib plus carboplatin and paclitaxel, 99 to placebo plus 
carboplatin and paclitaxel, and 94 to veliparib plus temozolomide. The overall response rate for 
the veliparib arm was 77.8%, compared with 61.3% for the placebo arm. The improvement in 
progression-free survival in the veliparib arm (14.1 vs 12.3 months) was not statistically 
significant. The trend to improved overall survival was also not statistically significant (28.3 vs 
25.9 months). These results indicate that not all PARP inhibitors can be expected to be effective 
in the treatment of BRCA1/2-mutant breast cancer, thus requiring careful investigation for the 
optimal treatment of these patients in each setting. 
Most recently and importantly, the benefit of treatment with olaparib was confirmed in the 
phase 3 OlympiAD study, which included 302 patients with HER2-negative metastatic breast 
cancer who harbored germline BRCA1 or BRCA2 mutations. Patients were randomized to 
olaparib (300 mg twice daily) or physician’s choice of standard chemotherapy (capecitabine, 
vinorelbine, or eribulin). The primary endpoint of the trial was progression free survival (PFS) 
per a blinded independent review. Results showed a statistically-significant and 
clinically-meaningful improvement in PFS for patients treated with olaparib tablets compared to 
treatment with physician’s choice of a standard of care chemotherapy. In addition to meeting its 
primary endpoint, the trial showed that patients treated with olaparib had a 42% reduction in risk 
of their disease worsening or death (HR 0.58; 95% CI 0.43-0.80; p=0.0009; median 7.0 vs 
4.2 months) compared to those who received chemotherapy (capecitabine, vinorelbine, 
eribulin).18 Secondary endpoints showed an improvement in time until second progression or 
death (PFS2) in the olaparib arm of the trial versus those treated with chemotherapy (HR 0.57; 
95% CI: 0.40-0.83). In addition, the ORR was more than doubled, with 59.9% of patients in the 
olaparib arm showing response to treatment, compared to 28.8% of patients treated with 
chemotherapy. Notably, there was a lower incidence of grade ≥3 adverse events (AEs) in the 
olaparib arm compared to the chemotherapy arm (36.6% vs 50.5% respectively). This study 
establishes PARP inhibition with olaparib as effective in the treatment of BRCA1/2-mutant breast 
cancer. 
Originally developed for patients with locally advanced breast cancer, neoadjuvant 
chemotherapy is now frequently administered to patients with operable breast cancers. The 
outcomes of neoadjuvant chemotherapy were demonstrated in a 2007 meta-analysis that included 
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Compared with adjuvant chemotherapy, neoadjuvant chemotherapy resulted in a reduction in the 
risk of having a modified radical mastectomy performed (hazard ratio [HR] 0.71, 95% CI 
0.67-0.75), but equivalent OS (HR 0.98, 95% CI 0.87-1.09) and disease free survival (DFS) (HR 
0.97, 95% CI 0.89-1.07). Among patients treated with neoadjuvant chemotherapy, a documented 
pathologic complete response (pCR) at surgery was prognostically significant in that these 
patients had significant improvements in both OS (HR 0.48, 95% CI 0.33-0.69) and DFS (HR 
0.48, 95% CI 0.37-0.63) compared with patients with residual invasive disease.14,15,19 These 
differences are more pronounced in patients with more proliferative breast cancer subtypes, 
including triple-negative breast cancer (TNBC; event-free survival [EFS] HR 0.24 for pCR 
versus not) and HER2-positive breast cancer (EFS HR 0.39 for pCR versus not).15 Commonly 
used regimens for patients with HER2-negative disease include anthracycline-based regimens 
such as doxorubicin and cyclophosphamide followed or preceded by a taxane (docetaxel or 
paclitaxel) and nonanthracycline-containing regimens such as docetaxel and cyclophosphamide, 
amongst others.  
In an effort to improve outcomes, additions to these agents, including antiangiogenesis agents 
have been investigated. The GeparQuinto phase 3 study was initiated in part to investigate 
subtype-specific treatment approaches for patients with HER2-negative primary breast cancer 
(group 1).20 In this group, the rates of pCR after neoadjuvant chemotherapy with or without 
bevacizumab was evaluated. Results from this prespecified subgroup analyses suggested that the 
effect of bevacizumab derived mainly from patients with triple-negative breast cancer (odds 
ratio, 1.67). However, the test for interaction was not significant (P = 0.07) in this study, which 
was not powered to show these differential effects. In the National Surgical Adjuvant Breast and 
Bowel Project B-40 study a numerical but statistically nonsignificant increase in the rate of pCR 
was reported with the use of bevacizumab in the subgroup of 490 patients with triple-negative 
breast cancer.21 In both studies, higher rates of bleeding, thromboembolic events, and 
postsurgical complications (early and late) were seen with the addition of bevacizumab therapy. 
The use of PARP inhibitors has also been investigated in combination with chemotherapy in the 
neoadjuvant setting. Most recently, a pilot study of talazoparib for early-stage breast cancer 
patients with a BRCA mutation was initiated22. Thirteen patients were enrolled in initial stage of 
the study, BRCA1-mutant=10; BRCA2-mutant=3. Eight had hormone receptor negative and 4 had 
hormone receptor positive breast cancer, and 1 metaplastic. Two had clinical stage III, 9 had 
clinical stage II, and 2 had clinical stage I cancers. Decreases in tumor volume occurred in all 
13 patients following 2 months of talazoparib monotherapy, with an average volume loss of 78% 
(range 30-98%). Talazoparib was well tolerated with no grade 4 toxicities and only one patient 
requiring dose reduction due to grade 3 neutropenia. Given the profound clinical response with 
only 2 months of therapy and favorable toxicity profile, the pilot study was discontinued early 
and an expansion cohort to estimate pathologic response to talazoparib alone with 4 to 6 months 
is underway. This small study provides early evidence of proof-of-concept in the treatment of 
BRCA1/2-mutant breast cancer with PARP inhibition. 
5.1.1.1. 
Niraparib: Pre-Clinical Summary 
Niraparib 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 


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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.23 
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, ataxia telangiectasia-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.24  
Nonclinical testing of niraparib did not indicate any untoward effects that would prevent clinical 
investigation in the human setting. Nonclinical pharmacology studies with niraparib have 
generated sufficient data to support its clinical evaluation as a monotherapy for patients with 
advanced/metastatic breast cancer with BRCA mutation. 
Details of the nonclinical studies conducted with niraparib can be found in the current 
Investigator’s Brochure. 
5.1.1.2. 
Niraparib: Clinical Summary 
Clinical studies have shown that PARP inhibitors are active in recurrent ovarian cancer.25-31  
PARP inhibition appears to be most active in patients with germline breast cancer susceptibility 
gene (gBRCA) mutation and in patients who are sensitive to platinum-containing therapy. 
However, clinical benefit has also been observed in gBRCA wild-type.27-30 Maintenance 
treatment of high-grade serous ovarian cancer patients with recurrent platinum sensitivity 
showed that the PARP1/2 inhibitor niraparib significantly improved PFS in gBRCAmut patients 
(21 months for niraparib vs. 5.5 months for control). Furthermore, in the gBRCA wild-type 
population, significant improvement in PFS also was observed (9.3 months for niraparib versus 
3.9 months for placebo, HR = 0.45, p<0.0001).31,32 Zejula™ (niraparib) has been recently 
approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, 
fallopian tube, or primary peritoneal cancer. For more details, refer to Zejula label.33 
There are 3 ongoing Phase 3 niraparib studies, Study PR-30-5010-C (BRAVO), Study 
PR-30-5017-C (PRIMA), and Study PR-30-5011-C (NOVA). There is also 1 ongoing Phase 1/2 
study, Study 3000-PN162-01-001 (TOPACIO) and 1 ongoing Phase 2 study, Study 
PR-30-5020-C (QUADRA). 
NOVA is a double-blind, placebo-controlled study in patients with platinum-sensitive ovarian 
cancer who have received at least 2 platinum-based regimens.32  A total of 553 patients were 
categorized according to the presence or absence of a gBRCAmut (gBRCA cohort and 
non-gBRCA cohort) and the type of non-gBRCAmut, and were randomly assigned in a 2:1 ratio 
to receive niraparib (300 mg) or placebo once daily (QD). The primary endpoint was PFS. The 
study enrolled 203 patients in the gBRCAmut cohort and 350 patients in the non-gBRCAmut 
cohort. Among the 350 patients in the non-gBRCAmut cohort, 162 had tumors that were defined 
as HRD positive and 134 had tumors that were HRD negative. HRD status was not determined 
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Demographic and baseline characteristics were well balanced. Table 3 shows the results for the 
PFS primary endpoint for each of the 3 primary efficacy populations (ie, gBRCA-mutant cohort, 
HRD positive cohort, and overall non-gBRCAmut cohort). In addition, median PFS in patients 
with HRD negative tumors was 6.9 months (95% CI: 5.6, 9.6) in the niraparib arm vs. 
3.8 months (95% CI: 3.7, 5.6) in the placebo arm, with an HR of 0.58 (95% CI: 0.361, 0.922) 
(p=0.0226). 
Table 3: 
Progression-Free Survival in Ovarian Cancer Patients in NOVA 
 
gBRCA-mutant cohort 
Non-gBRCA-mutant cohort 
(regardless of HRD status) 
HRDpos 
(within non-gBRCA-mutant 
cohort) 
 
Niraparib 
(N=138) 
Placebo 
(N=65) 
Niraparib 
(N=234) 
Placebo 
(N=116) 
Niraparib 
(N=106) 
Placebo 
(N=56) 
PFS median 
(95% CI) 
21.0 
(12.9, NR) 
5.5 
(3.8, 7.2) 
9.3 
(7.2, 11.2) 
3.9 
(3.7, 5.5) 
12.9 
(8.1, 15.9) 
3.8 
(3.5, 5.7) 
p-value 
<0.0001 
<0.0001 
<0.0001 
Hazard ratio 
(Nir:Plac) 
(95% CI) 
0.27 
(0.173, 0.410) 
0.45 
(0.338, 0.607) 
0.38 
(0.243, 0.586) 
Abbreviations: CI = confidence interval; gBRCA mutant = patients with germline breast cancer gene mutation; 
HRD = homologous recombination deficiency; HRDpos = homologous recombination deficiency-positive; 
Nir = niraparib; NR = not reported; PFS = progression-free survival; Plac = placebo. 
 PFS is defined as the time in months from the date of first dose to progression or death  
 Source:33 
The primary data to support the safety of treatment with niraparib are derived from the NOVA 
main study in which a total of 546 patients received study drug. All 367 patients who received 
niraparib and 171 (96%) of 179 patients who received placebo experienced at least 
1 treatment-emergent adverse event (TEAE). The high rate of TEAEs in the placebo group 
indicates the burden of prior chemotherapy and the patient’s underlying ovarian cancer. Review 
of the data across study cohorts for TEAE incidence showed that, in general, the results were 
similar in the gBRCAmut and non-gBRCAmut cohorts. In the overall safety population, for the 
niraparib vs. placebo treatment arms, the incidences of Grade 3 to 4 TEAEs (74% vs. 23%), 
serious adverse events (SAEs) (30% vs. 15%), TEAEs leading to treatment interruption (69% vs. 
5%), TEAEs leading to dose reduction (67% vs. 15%), and TEAEs leading to treatment 
discontinuation (15% vs 2%) were higher for niraparib. There were no on-treatment deaths 
reported. 
The most commonly observed nonhematologic TEAEs (all grades) observed in niraparib 
compared to placebo-treated patients were nausea (74% vs. 35%), fatigue (46% vs. 32%), 
constipation (40% vs. 20%), and vomiting (34% vs. 16%). The majority of the nonhematological 
TEAEs were mild to moderate in severity. The most commonly observed hematologic TEAEs 
(all grades) of niraparib were anemia (49%), thrombocytopenia (46%), and neutropenia (18%). 
Although Grade 3 to 4 hematologic laboratory events were common at the initiation of treatment, 
no severe clinical sequelae were observed, and relatively few patients discontinued due to these 
AEs. Dose adjustment based on individual tolerability during the first 3 cycles substantially 


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reduced the incidence of these events beyond Cycle 3, indicating the overall effectiveness of the 
approach to dose modification. These TEAEs can be monitored routinely using standard 
assessments of hematological laboratory parameters, as is routine for patients with ovarian 
cancer receiving anticancer therapies. In the NOVA study, niraparib dose adjustment tended to 
occur early with most patients reaching their individual adjusted dose level at the end of Month 3 
(ie, Cycle 3) of treatment. Approximately 36% patients were kept on 300 mg and approximately 
64% patients had dose adjustments after 3 cycles in NOVA. However, in the Phase 1 portion of 
the TOPACIO study (combination of niraparib and pembrolizumab), no patients were able to 
tolerate the 300 mg dose of niraparib. 
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are potential adverse 
class effects associated with PARP inhibitors.34 MDS and AML therefore represent a potential 
risk to patients receiving niraparib. In the Phase 3 NOVA study, the incidence of MDS/AML in 
patients who received niraparib (5 of 367; 1.4%) was similar to its incidence in patients who 
received placebo (2 of 179; 1.1%). Guidance on monitoring patients for new events of 
MDS/AML and the follow-up of patients with suspected MDS/AML is provided in 
Section 13.1.8.  
Study PR-30-5011-C1 (NOVA corrected QT interval [QTc] substudy n = 26) was an open-label 
evaluation of the effects of niraparib on QTc measurements in patients with histologically 
diagnosed ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. There were no 
reports of clinically significant abnormal electrocardiogram (ECG) changes, including QTc 
interval prolongation, attributed to niraparib. Administration of niraparib at the therapeutic dose 
did not prolong the QT interval. There was no correlation between the exposure level (ie, plasma 
concentration) of niraparib and QTc changes (ie, changes in QTc using Fridericia’s formula). 
MDS and 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.  
Details of the clinical studies conducted with niraparib can be found in the current Investigator's 
Brochure. 
5.1.1.3. 
Study Rationale 
This study aims to investigate the preliminary antitumor activity of niraparib assessed as the 
change in tumor volume observed after treatment with niraparib in the neoadjuvant treatment of 
localized, HER2-negative, BRCAmut breast cancer patients. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
• To evaluate the preliminary antitumor activity of niraparib assessed as the tumor response 
rate based on the change in tumor volume as measured by breast MRI, observed after 
treatment with niraparib in the neoadjuvant treatment of localized, human epidermal 
growth factor receptor 2 (HER2) negative, breast cancer susceptibility gene (BRCA) 
mutant breast cancer patients. 
6.2. 
Secondary Objectives 
• To evaluate the preliminary antitumor activity of niraparib assessed by:  
− Presence of pCR defined as ypT0/Tis ypN0 by receipt of pre-operative 
chemotherapy (Yes versus No) 
− Percentage change in tumor volume from baseline after 2 months of niraparib 
treatment 
− Tumor response rate based on the change in tumor volume as measured by breast 
ultrasound 
• To evaluate safety and tolerability of niraparib per National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 criteria 
6.3. 
Exploratory Objectives 
• To evaluate niraparib-induced changes in immune responses 
• To explore intra-tumoral niraparib concentration and correlation with blood  
• To estimate the preliminary antitumor activity of niraparib in BRCAmut TNBC 
patients and BRCAmut hormone-positive patients 
• To evaluate pharmacodynamic inhibition of PARP activity in the tumor 
• To explore molecular biomarkers related to disease biology or response to treatment 
using tumor tissue or liquid biopsy approaches (e.g. ctDNA) 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is an open-label, single-arm pilot study evaluating the antitumor activity and safety of 
niraparib as neoadjuvant therapy in patients with HER2-negative and BRCAmut localized breast 
cancer (primary tumor ≥1 cm). The study design is summarized in Figure 1. If antitumor activity 
in the BRCAmut cohort is demonstrated, the protocol may be amended to add an HRD-positive, 
BRCA-wild type cohort. 
Figure 1: 
Study Schema 
 
 
1Patients may receive up to 6 months of niraparib (see Section 7). 
2Breast ultrasounds are performed at the end of each month for those patients receiving additional cycles. 
3Core biopsy will be obtained preferably within 24 hours of the last dose of niraparib in cycle 2 and prior to any subsequent 
anticancer therapy or procedure. A surgical biopsy may be used in lieu of a core biopsy provided that surgery occurs within 24 
hours of the last dose of niraparib in Cycle 2. 
4Tumor size cut-off for pre-surgery chemotherapy will be determined by investigator discretion.  
5Off-study visit is for the collection of pCR results for patients for whom the Safety Follow-up/EOT Visit occurred prior to 
surgery; for all other patients the Safety Follow-up/EOT Visit will act as the off-study visit. 
Breast magnetic resonance imaging (MRI), breast ultrasound, and tumor core biopsy will be 
performed at the Screening (Day -28 to Day -1). 
Patients will receive niraparib (200 mg orally [PO]) treatment daily for 28 days (Cycle 1) and 
then will undergo breast ultrasound at the end of Cycle 1 on Day 28: 
• If breast ultrasound shows disease progression defined as an increase in tumor 
volume by greater than 20% by Investigator assessment, the patient will discontinue 
study. If breast ultrasound shows CR, PR or stable disease (SD) by Investigator 
assessment (please see Appendix 2), the patient will continue niraparib treatment 
200 mg PO for an additional cycle (Cycle 2). Patients may receive up to 6 months of 
niraparib treatment if, in the opinion of the Investigator and Sponsor, and agreed upon 
by the Sponsor, the patient would benefit from additional treatment. 
A breast MRI and breast ultrasound will be performed at the end of Cycle 2. The investigational 
team will determine if the patient will proceed to surgery or to standard of care neoadjuvant 
chemotherapy.  


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A core biopsy will be performed at the end of Cycle 2, which should occur within 24 hours of the 
last dose of niraparib. Niraparib treatment may be extended up to an additional 7 days after 
Cycle 2 Day 28 to allow for scheduling of surgery or the core biopsy: 
• For those patients proceeding directly to surgery at the end of Cycle 2, a surgical biopsy 
may be obtained at the time of surgery provided that surgery occurs within 24 hours of 
the last dose of niraparib on Cycle 2 Day 28 (+7 days).  
• For all other patients, provided that their tumors are amenable to biopsy, a core biopsy 
should be obtained within 24 hours of the last dose of niraparib on Cycle 2 Day 28 
(+7 days). The biopsy should be performed after the MRI and ultrasound and prior to any 
subsequent anticancer therapy.  
At the completion of all neoadjuvant therapy, patients will proceed to surgery and/or other local 
treatment as deemed appropriate by the investigator. For those patients who receive neoadjuvant 
therapy (niraparib alone or niraparib followed by chemotherapy), a pCR assessment will be made 
at the time of surgery. 
Patients shall discontinue treatment in case of unacceptable toxicity or withdrawal of consent. 
AEs, regardless of the source of identification (eg, physical examination, laboratory assessment, 
ECG, or reported by patient), will be collected and recorded in the electronic case report form 
(eCRF) for each patient from the day of signed informed consent form until 30 days after last 
dose of study treatment. 
SAEs and adverse events of special interest (AESIs) concerning hypertension and hematologic 
toxicities will be collected and recorded in the eCRF and on an SAE report form for each patient 
from the date of signed informed consent until 90 days after the last dose of study drug (or until 
the start of alternate anticancer therapy, whichever occurs first). 
Related SAEs (assessed as related to study drug by the Investigator) will be collected for each 
patient from the date of signed informed consent until study closeout. 
AESIs concerning MDS/AML, secondary cancers, pneumonitis, and embryo-fetal toxicity must 
be collected and reported to the Sponsor for each patient from the date of signed informed 
consent until study closeout. 
Any pregnancies that occur up to and including 180 days post treatment will be reported. 
Pregnancies occurring more than 180 days after last dose, with an associated SAE (considered 
causally related to the study drug by the Investigator) will follow the SAE reporting 
requirements. 
7.1.1. 
General Study Conduct 
This study will consist of a Screening Period (Day -28 to Day -1), a Treatment Period, 
Presurgery chemotherapy (if appropriate), Surgery, a Safety Follow-up/EOT visit occurring 
30 days (+7 days) after the last dose of study medication, and an Off-Study Visit for the purposes 
of collecting the pCR results for patients for whom the Safety Follow-up/EOT Visit occurred 
prior to surgery; for all other patients the Safety Follow-up/EOT Visit will act as the off-study 
visit. 


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Following informed consent, all patients will undergo screening procedures within 28 days prior 
to the first dose of study drug to determine eligibility for study entry. Screening procedures 
include medical, surgical, cancer, and medication history; complete physical examination, 
including vital signs, height, and weight; Eastern Cooperative Oncology Group (ECOG) 
performance status; clinical laboratory assessments (complete blood count [CBC], serum 
chemistry, and urinalysis); pregnancy test for women of childbearing potential; and ECG. 
Patients must have a baseline tumor assessment by ultrasound and MRI to determine extent of 
disease and confirm presence of measurable disease. Tumor volume will be calculated at 
baseline and after Cycle 2 via MRI and ultrasound as follows: (length × width × height × π)/6.35 
Patients will also undergo core biopsy at baseline and at the end of Cycle 2 obtained preferably 
within 24 hours of the last dose of niraparib, after the MRI and ultrasound, and prior to any 
subsequent anticancer therapy. A surgical biopsy may be used in lieu of a core biopsy provided 
that surgery occurs within 24 hours of the last dose of niraparib in Cycle 2. Niraparib treatment 
may be extended up to an additional 7 days after Cycle 2 Day 28 to allow for scheduling of 
surgery or the core biopsy. During treatment, patients will undergo a breast ultrasound at the end 
of each 28-day cycle. If the breast ultrasound shows disease progression defined as an increase in 
tumor volume by greater than 20% by Investigator assessment, the patient will discontinue the 
study. If the breast ultrasound shows CR, PR, or SD by Investigator assessment (please see 
Appendix 2) at the end of Cycle 1, the patient will continue niraparib treatment 200 mg PO for 
an additional cycle (Cycle 2). Patients may receive up to 6 months of niraparib treatment if, in 
the opinion of the Investigator and Sponsor, and agreed upon by the Sponsor, the patient would 
benefit from additional treatment. 
At the completion of neoadjuvant treatment with niraparib, patients will be assessed for 
presurgery neoadjuvant chemotherapy, the appropriateness of which is up to the Investigator’s 
clinical judgment. For those patients who receive neoadjuvant therapy (niraparib alone or 
niraparib followed by chemotherapy), a pCR assessment will be made at the time of surgery. 
Pathological complete response (pCR) is defined as the absence of residual invasive cancer on 
hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional 
lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0/Tis ypN0 in the 
current AJCC staging system). 
Safety assessments conducted throughout the study include symptom-directed physical 
examination, vital signs, ECOG performance status, clinical laboratory assessments (CBC, serum 
chemistry, and urinalysis) (Table 6). 
Blood samples will be collected predose on Day 1 of Cycles 1 and 2, and at 2 and 4 hours post 
dose, and in conjunction with the post-treatment core biopsy to evaluate PK of niraparib. 
Blood samples for the analysis of circulating tumor DNA (ctDNA) will be collected at 
Screening, on Cycle 1/Day 28 predose, on Cycle 2/Day 28 predose, and at presurgery 
assessment. BRCA, HER2,estrogen receptor (ER), progesterone (PR) status must be available for 
all patients. All patients will undergo a Safety Follow-up/EOT Visit occurring 30 days (+7 days) 
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7.2. 
Number of Patients 
A total of approximately 20 evaluable patients will be enrolled. This sample size should be 
sufficient for signal finding prior to initiating a larger study. For example, it will provide 
approximately 80% power with 1-sided significance level of 0.15 to differentiate a response rate 
of 80% from a minimum response rate of 60%. 
7.3. 
Treatment Assignment 
All patients in this single-arm study will receive neoadjuvant treatment with niraparib for 
2 cycles and up to 6 cycles if, in the opinion of the Investigator and Sponsor, and agreed upon by 
the Sponsor, the patient would benefit from additional treatment. 
7.4. 
Dose Adjustment Criteria 
Dose interruption and/or reduction may be implemented at any time for any grade toxicity 
considered intolerable by the patient. In addition, protocol-defined criteria for dose modification 
are discussed below. 
Treatment must be interrupted for any treatment- related non-hematologic Common 
Terminology Criteria for Adverse Events v 4.03 (CTCAE), Grade 3 or 4 AE or SAE that the 
Investigator considers to be related to the administration of niraparib. If the toxicity is resolved to 
baseline or  Grade ≤1 within 28 days, the patient may restart treatment with niraparib but with a 
dose level reduction unless prophylaxis is considered feasible (Table 4). If the event recurs at a 
similar or worse grade, treatment should be interrupted again, and upon resolution, a further dose 
reduction must be made. If upon rechallenging with niraparib at the lowest allowable dose, any 
CTCAE Grade 3 or 4 AEs recur, the patient must be discontinued. At the Investigator’s 
discretion, following dose interruption (no longer than 28 days), patients may be considered for a 
dose reduction (no more than 1 dose reduction will be permitted). For major surgery, up to 
28 days of drug interruption is allowed. 
In the case of dose interruptions, the next cycle will follow the 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 drug is interrupted. 
Additional laboratory work-up prior to next treatment initiation should also be performed at the 
physician's discretion. Missed doses of niraparib (ie, any dose that is not administered within the 
protocol-defined administration window) will not be taken at a later date. 
If the toxicity requiring dose interruption has not resolved completely or has not been reduced to 
NCI-CTCAE v.4.03 criteria Grade ≤1 during a maximum of 4 weeks (28 days) of dose 
interruption period, and/or the patient has already undergone a maximum of one dose reduction 
(to a minimum dose of 100 mg QD), the patient must permanently discontinue treatment with 
niraparib. 


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Table 4: 
Niraparib Dose Reductions for Non-Hematologic Toxicities 
Event 
Dose1 
Initial dose 
 
200 mg QD 
First 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 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events SAE = serious 
adverse event; QD = once daily 
Dose not to be decreased below 100 mg daily 
Management of hematologic toxicities is described in Table 5. For Grade 3 or 4 neutropenia, 
thrombocytopenia, or anemia, treatment with niraparib must be interrupted with weekly blood 
counts monitored until recovery (neutrophils ≥1,500/μL, platelets ≥100,000/μL, or hemoglobin 
≥9.0 g/dL, respectively). Niraparib should be resumed with a dose level reduction at that time. 
Cytokines (granulocyte colony stimulating factor) may be administered as clinically indicated 
according to local standard of care.  
For major surgery not related to the breast tumor, up to 28 days of drug interruption is allowed. 
Thrombocytopenia is an expected event associated with the use of niraparib and is described in 
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 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 AE 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 drug is resumed. 
It is strongly recommended to refer the patient to the hematologist for further evaluation if (1) 
transfusions are required on more than 2 occasions in the absence of non-treatment related causes 
or (2) 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 drug. 
Table 5: 
Management of Hematologic Toxicities  
Platelet count <100,000/μL 
First occurrence: 
• 
Withhold study medication for a 
maximum of 28 days and monitor blood 


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counts weekly until platelet counts return 
to ≥100,000/μL. 
• 
Resume study medication at same or 
reduced dose per Table 4.  
• 
If platelet count is <75,000/μL, resume at 
a reduced dose. 
Second occurrence: 
• 
Withhold study medication for a 
maximum of 28 days and monitor blood 
counts weekly until platelet counts return 
to ≥100,000/μL. 
• 
Resume study medication at a reduced 
dose per Table 4.  
• 
Discontinue study medication if platelet 
count has not returned to acceptable 
levels within 28 days of the dose 
interruption period, or if the patient has 
already undergone dose reduction to 
100 mg once daily.1 
Neutrophil <1,000/µL or Hb <8 g/dL 
• 
Withhold study medication for a 
maximum of 28 days and monitor blood 
counts weekly until neutrophil counts 
return to ≥1,500/μL or Hb returns to ≥9 
g/dL. 
• 
Resume study medication at a reduced 
dose per Table 4. 
• 
Discontinue study medication if 
neutrophils and/or Hb has not returned to 
acceptable levels within 28 days of the 
dose interruption period, or if the patient 
has already undergone dose reduction to 
100 mg once daily.1 
Hematologic adverse reaction requiring 
transfusion 
• 
For patients with platelet count 
≤10,000/μL, platelet transfusion should be 
considered. If there are other risk factors 
such as co-administration of 
anticoagulation or antiplatelet drugs, 
consider interrupting these drugs and/or 
transfusion at a higher platelet count. 
• 
Resume study medication at a reduced 
dose. 
Confirmed myeloplastic syndrome or acute 
myeloid leukemia 
• 
Permanently discontinue treatment 
Abbreviations:  Hb = hemoglobin.  


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7.5. 
Criteria for Study Termination 
The Sponsor may terminate this study at any time. The Sponsor will notify the Investigators 
when the study is to be placed on hold, completed, or terminated. 
7.6. 
Schedule of Events 
The schedule of events for this study is provided in Table 6.  


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Table 6: 
Schedule of Events  
Cycle/Visit: 
Screening 
Cycle 1 
± 7 days 
Cycle 2 
± 7 days 
Cycles 3-6 
± 7 days 
(if applicable) 
 
Pre-
surgery 
Surgery 
 
Safety Follow- 
Up/EOT Visit  
Day of Procedure 
-28 to -1 
1 
8 
15 
21 
28 
1 
28 
1 
28 
 
 
30 + 7 days post 
last dose of 
niraparib  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, surgical, 
cancer, and medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Local Confirmation 
HER2 negative and ER, 
PR status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
exploratory biomarkers 
(ctDNA) 
X 
 
 
 
 
X2 
 
X2 
 
 
X3 
 
 
BRCA1/2 mutation 
testing1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Completion of neo-
adjuvant chemotherapy 
eCRFs, if applicable 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Breast ultrasound tumor 
assessment 
X  
 
 
 
 
X4 
 
X4 
 
X4 
 
 
 
Breast MRI tumor 
assessment 
X 
 
 
 
 
 
 
X4 
 
 
 
 
 


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Table 6: 
Schedule of Events (Continued) 
Cycle/Visit: 
Screening 
Cycle 1 
± 7 days 
Cycle 2 
± 7 days 
Cycles 3-6 
± 7 days 
(if applicable) 
 
Pre-
surgery 
Surgery 
 
Safety Follow- 
Up/EOT Visit  
Day of Procedure 
-28 to -1 
1 
8 
15 
21 
28 
1 
28 
1 
28 
 
 
30 + 7 days post 
last dose of 
niraparib  
Core biopsy 
X 
 
 
 
 
 
 
X5 
 
 
 
X5 
 
pCR assessment 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Laboratory assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
X6 
X 
X 
X 
 
X6 
  
X6 
 
 
 
X 
Serum chemistry 
X 
X6 
 
X 
 
 
X6 
 
X6 
 
 
 
X 
Pregnancy test 
X7 
X7 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Symptom-directed 
physical examination 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Physical breast 
examination 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
Vital signs and weight 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 6: 
Schedule of Events (Continued) 
Cycle/Visit: 
Screening 
Cycle 1 
± 7 days 
Cycle 2 
± 7 days 
Cycles 3-6 
± 7 days 
(if applicable) 
 
Pre-
surgery 
Surgery 
 
Safety Follow- 
Up/EOT Visit  
Day of Procedure 
-28 to -1 
1 
8 
15 
21 
28 
1 
28 
1 
28 
 
 
30 + 7 days post 
last dose of 
niraparib  
ECOG performance 
status 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant 
medications and 
procedures 
X 
Recorded from informed consent through Safety Follow-up/EOT 
Adverse event 
monitoring8 
X 
Recorded from informed consent through 30 days post-treatment 
Niraparib study drug 
dispensed/collected 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
PK Sample Collection 
 
X9 
 
 
 
 
X9 
 
 
 
 
 
 
Abbreviations: AESI = adverse events of special interest; AML = acute myeloid leukemia; BRCA = breast cancer susceptibility gene; CBC = complete blood 
count; ctDNA = circulating tumor deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case 
report form; EOT = end of treatment; ER = estrogen receptor; IEC = Independent Ethics Committee; IRB = Institutional Review Board; MDS = myelodysplastic 
syndrome; pCR = pathological complete response; PK = pharmacokinetic; PR = progesterone receptor; SAE = serious adverse event. 
1 If BRCA status is known, it need not be repeated. Results may have been obtained by either local or central laboratory testing. 
2 Can be collected pre-dose Day 1 of the next cycle. 
3Pre-surgery blood sample is not required for patients proceeding directly to surgery at the end of Cycle 2. 
4 Can be performed +/- 3 days from Day 28, but results must be available prior to the start of the next cycle. 
5Core biopsy should be obtained on Cycle 2 Day 28 (+7 days) within 24 hours of last dose of niraparib and prior to ultrasound, MRI, and any subsequent 
anticancer therapy or procedure. A surgical biopsy may be used in lieu of a core biopsy provided that surgery occurs within 24 hours of the last dose of 
niraparib in Cycle 2. 
6Cycle 1 Day 1 testing not required if screening assessments were performed within 72 hours of Day 1.  
7 A serum pregnancy test will be performed locally for all women of childbearing potential at Screening (within 72 hours prior to the first dose of study drug). 
The result must be negative before the first dose of study drug is administered. If the serum pregnancy result is not available before dosing, a urine pregnancy 
test may be performed. Pregnancy tests may also be repeated during the study if requested by an IEC/IRB or if required by local regulations. 


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8 SAEs and AESIs concerning hypertension and hematologic toxicities will be collected and recorded in the eCRF and on an SAE report form for each patient 
from the date of signed informed consent until 90 days after the last dose of study drug (or until the start of alternate anticancer therapy, whichever occurs first). 
AESIs concerning MDS/AML, secondary cancers, pneumonitis, and embryo-fetal toxicity must be collected and reported to the Sponsor for each patient from 
the date of signed informed consent until study closeout. 
9 Samples for PK assessment with be collected on Day 1 of Cycles 1 and 2 predose, 2 (± 30 minutes) and 4 (± 30 minutes) hours post dose, and in conjunction 
with the post-treatment core biopsy. 


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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
To be eligible for participation in this study, patients must meet all of the following criteria: 
1. Patients age ≥18 years old 
2. Patients with a deleterious or suspected deleterious BRCA1 or BRCA2 mutation (germline 
or somatic) may be enrolled into the study based on either local or central laboratory 
testing of BRCA status  
3. Histologically-confirmed HER2-negative localized breast cancer by core biopsy.  
4. Primary operable, non-metastatic invasive carcinoma of the breast, confirmed 
histologically by core biopsy. Fine-needle aspiration is not sufficient. Incisional biopsy is 
not allowed. In patients with multifocal and/or multicentric, the largest lesion should be 
measured. Both unilateral and bilateral breast cancer are allowed. 
5. Primary tumor size ≥1 cm  
6. Measurable disease by breast ultrasound and MRI  
7. ECOG performance status of 0 or 1 
8. Adequate organ function, defined as follows:  
Note: CBC should be obtained without transfusion or receipt of colony stimulating factors 
within 4 weeks prior to obtaining a sample. 
a. ANC ≥ 1,500/μL  
b. Platelets ≥ 100,000/μL  
c. Hemoglobin ≥ 9 g/dL  
d. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine 
clearance ≥ 50 mL/min using Cockcroft-Gault equation  
e. Total bilirubin ≤ 1.5× ULN except in patients with Gilbert’s syndrome. Patients with 
Gilbert’s syndrome may enroll if direct bilirubin ≤ 1.5 × ULN of the direct bilirubin 
f. AST and ALT ≤ 2.5 x ULN  
9. Patient must have recovered to Grade 1 toxicity from prior cancer therapy (a patient with 
Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion and may qualify 
for this study). 
10. Able to take oral medications 
11. Patient meets the following criteria: 
a. Female patient (of childbearing potential) is not breastfeeding, has a negative serum 
pregnancy test within 72 hours prior to taking study drug, and agrees to abstain from 
activities that could result in pregnancy from Screening through 180 days after the 
last dose of study drug, or is of nonchildbearing potential.  


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Note: A urine pregnancy test may be performed if the serum pregnancy test is not 
available before dosing. 
b. Female patient is of non-childbearing potential (other than medical reasons) as 
defined by the following: 
i. 
≥45 years of age and has not had menses for >1 year. 
ii. 
Amenorrheic for <2 years without a hysterectomy and oophorectomy and a 
follicle-stimulating hormone value in the postmenopausal range upon 
Screening evaluation. 
iii. 
Had undergone a hysterectomy, bilateral oophorectomy, or tubal ligation. 
Documented hysterectomy, oophorectomy, or tubal ligation must be 
confirmed in the medical records; otherwise the patient must be willing to use 
2 adequate barrier methods throughout the study starting from the Screening 
visit through 180 days after the last dose of study drug. Please see 
Section 9.2.2 for a list of acceptable birth control methods. Information must 
be captured appropriately within the site’s source documents. 
 
c. Male patient agrees to use an effective method of contraception (please see Section 
9.2.2 for a list of acceptable birth control methods) starting with the first dose of 
study therapy through 120 days after the last dose of study therapy. 
 
Note: Abstinence is acceptable if this is the established and preferred contraception 
for the patient. 
12. Able to understand the study procedures and agree to participate in the study by 
providing written informed consent 
8.2. 
Patient Exclusion Criteria 
To be eligible for participation in this study, patients may not meet any of the following criteria: 
1. Prior anti-cancer therapies for current malignancy 
2. Known evidence of distant metastasis. Staging studies are not required.  
The decision to pursue staging studies is at the discretion of the treating clinician, based 
on the patient’s clinical and pathologic findings consistent with standard guidelines.  
3. Known hypersensitivity to the components of niraparib components or their formulation 
excipients 
4. Major surgery within 3 weeks of starting the study or patient has not recovered from any 
effects of any major surgery 
5. 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 90 days) myocardial infarction, 
uncontrolled major seizure disorder, unstable spinal cord compression, superior vena 
cava syndrome, uncontrolled hypertension, active uncontrolled coagulopathy, bleeding 
disorder, or any psychiatric disorder that prohibits obtaining informed consent 


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6. History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the patient’s participation for the 
full duration of the study drug, or is not in the best interest of the patient to participate 
7. Patient is pregnant or breastfeeding, or expecting to conceive children within the 
projected duration of the study drug or within the 180-day period after the last dose of 
study drug. 
8. Immunocompromised patients (Note: patients with splenectomy are allowed). 
9. Known active hepatic disease (ie, Hepatitis B or C) 
10. Prior treatment with a known PARP inhibitor 
11. Other active malignancy that warrants systemic therapy 
12. Known history of MDS or AML 
8.3. 
Restrictions During Study 
1. Patients of child bearing potential and their partners who are sexually active (exception: 
abstinence for the total duration of the trial), must agree to the use of two highly effective 
forms of contraception throughout their participation during the study treatment and for 
180 days after last dose of study treatment(s): 
a. Condom with spermicide and one of the following: 
− Oral contraceptive or hormonal therapy (eg, hormone implants) 
− Placement of an intrauterine device (IUD) 
Acceptable non-hormonal birth control methods include: 
b. Total sexual abstinence for the total duration of the trial, defined as the time from the 
patient’s signing of the main ICF through the drug washout period. The washout period 
for niraparib is at least 90 days 
c. Vasectomized sexual partner plus male condom with spermicide and participant 
assurance that partner received post-vasectomy confirmation of azoospermia 
d. Tubal occlusion plus male condom with spermicide 
e. IUD plus male condom with spermicide 
Acceptable hormonal methods include: 
f. Etonogestrel implants (eg, Implanon, Norplan) plus male condom with spermicide 
g. Normal and low dose combined oral pills plus male condom with spermicide 
h. Norelgestromin/ethinyl estradiol transdermal system plus male condom with 
spermicide 
i. Intravaginal device plus male condom with spermicide (eg, ethinyl estradiol and 
etonogestrel) 
j. Cerazette® (desogestrel) plus male condom with spermicide. Cerazette is currently the 
only highly efficacious progesterone-based pill 


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8.4. 
Patient Withdrawal Criteria 
8.4.1. 
Discontinuation from Treatment 
Patients may be discontinued from study drug at any time. Specific reasons for discontinuing all 
study drugs include the following: 
• Unacceptable toxicity that cannot be managed by dose modification 
• Disease progression as outlined per Response Evaluation Criteria in Solid Tumors 
v1.136 
• In the best interest of the patient as judged by the Investigator and/or Sponsor 
• Severe noncompliance with the protocol as judged by the Investigator and/or Sponsor 
• Withdrawal of consent  
− Note: All reasonable efforts should be made to encourage patients to remain on 
study even if they withdraw from treatment.  
• Patient becomes pregnant 
• Sponsor decision to terminate study 
• Death 
Details of required niraparib dose modifications, including interruptions, dose reductions, and 
permanent discontinuations, related to toxicity, are provided in Section 7.4 . 
Patients who discontinue from study drug will continue to receive follow-up assessments 
(Table 6) as part of the study unless they are discontinued from the study. 
8.4.2. 
Discontinuation from the Study 
Patients may be discontinued from the study for any of the following reasons: 
• Withdrawal of consent by the patient, who is at any time free to discontinue their 
participation in the study 
• Death from any cause 
• Lost to follow-up 
• Sponsor decision to terminate study 
Patients who withdraw from study drug will be asked to continue the study visits and 
assessments as outlined in the Schedule of Events (Section 7.1.1, Table 6). If a patient is lost to 
follow-up, attempts should be made to contact the patient to determine the reason for 
discontinuation. For patients who are lost to follow-up, at least three documented attempts, 
including one via certified mail, should be made to contact the patient before considering the 
patient lost to follow-up. 
If a patient discontinues study drug prior to the second MRI assessment of disease (scheduled 
radiological assessment at the end of Cycle 2), the patient may be replaced for the purposes of 


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efficacy analysis after consultation between the Sponsor and Investigator. The efficacy analysis 
population includes all patients who completed 2 cycles of treatment. 


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9. 
TREATMENT OF PATIENTS 
9.1. 
Description of Study Drug 
Table 7: 
Investigational Product 
 
Investigational Product 
Product Name: 
Niraparib 
Dosage Form: 
100 mg capsule 
Unit Dose 
2 capsules of 100 mg each (200 mg/day) 
Administered once daily 
Route of Administration 
PO 
Physical Description 
Capsules  
Abbreviation: PO = oral 
9.2. 
Concomitant Medications 
Any medication the patient takes during the study other than the study drugs, including herbal 
and other nontraditional remedies, is considered a concomitant medication. All concomitant 
medications must be recorded in the eCRF. The following information must be recorded in the 
eCRF for each concomitant medication: 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 eCRF. 
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 or have taken since the previous visit. 
Niraparib weakly induces cytochrome P450 (CYP)1A2 in vitro and is an insensitive substrate for 
P-glycoprotein (P-gp); therefore, investigators should be advised to use caution with drugs that 
are the sensitive substrates for CYP1A2 with a narrow therapeutic range, i.e. theophylline and 
tizanidine. 
9.2.1. 
Prohibited Medications 
Patients are prohibited from receiving the following therapies during the screening and treatment 
phase of this study: 
• Antineoplastic systemic chemotherapy or biological therapy 
• Radiation therapy or immunotherapy  
• Chemotherapy during niraparib treatment 
• Investigational agents other than niraparib  
• Live vaccines within 30 days prior to the first dose of study drug and while 
participating in the study. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacille 


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Calmette-Guerin, and typhoid (PO) vaccine. Seasonal influenza vaccines for injection 
are generally killed virus vaccines and are allowed. However, intranasal influenza 
vaccines (eg, Flu-Mist®) are live attenuated vaccines and, therefore, are not allowed. 
• Prophylactic cytokines (granulocyte colony-stimulating factor) should not be 
administered in the first cycle of the study but may be administered in subsequent 
cycles according to current American Society of Clinical Oncology guidelines.37 
If there is a clinical indication for any medication or vaccination specifically prohibited during 
the study, discontinuation from study drug may be required. The Investigator should discuss any 
questions regarding this with the Sponsor. The final decision on any supportive therapy or 
vaccination rests with the Investigator and/or the patient’s primary physician. The decision to 
continue the patient on study drug, however, requires the mutual agreement of the Investigator, 
the Sponsor, and the patient. 
9.2.2. 
Contraception 
Niraparib is known to have properties that require the patient to use contraception. For details on 
niraparib, please refer to the Investigator’s Brochure. 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide per local regulations or guidelines. 
Appropriate hormonal contraceptives will include any registered and marketed contraceptive 
agent that contains an estrogen and/or a progestational agent (including PO, subcutaneous, 
intrauterine, or intramuscular agents). Abstinence is acceptable if this is the established and 
preferred contraception for the patient. 
Patients should be informed that taking the study medication may involve unknown risks to the 
fetus if pregnancy were to occur during the study. In order to participate in the study female 
patients must adhere to the contraception requirement (described above) for the duration of the 
study and through 180 days after the last study drug. Male patients should not donate sperm or 
father children from screening throughout the duration of the study up to 120 days after the last 
dose of study drug is received. If there is any question that a patient will not reliably comply with 
the requirements for contraception, that patient should not be entered into the study. 
9.2.3. 
Other Study Restrictions 
Patients who are blood donors should not donate blood during the study and for 90 days after the 
last dose of study drug. 
Patients should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea, or vomiting. 
9.3. 
Treatment Compliance 
Compliance with inclusion and exclusion criteria will be assessed as outlined in Section 8 and 
Section 8.2, respectively. 
Niraparib will be administered by site personnel at study sites as detailed in Section 10.5. 
Study drug accountability will be monitored as detailed in Section 10.7. 


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9.4. 
Randomization and Blinding 
Not applicable; this is a single-arm, open-label study. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Niraparib ([3S]-3-[4- phenyl] piperidine [tosylate monohydrate salt]) is a PO available, potent, 
highly selective PARP1 and PARP2 inhibitor. The excipients for niraparib are lactose 
monohydrate and magnesium stearate. Niraparib will be supplied as 100 mg capsules. 
10.2. 
Study Drug Packaging and Labeling 
Niraparib 100 mg capsules may be packed in high-density polyethylene bottles with 
child-resistant closures or in blister cards. The Sponsor is exploring a change in packaging 
configuration to blister cards, which may be implemented at some point during the study. 
The label text of the study drug will comply with Good Manufacturing Practice and national 
legislation to meet the requirements of the participating countries. The study drug will be 
open-label and nonpatient-specific. 
All study drug supplies must be stored in accordance with the Pharmacy Manual instructions and 
package labeling. Until dispensed or administered to the patients, the study drug will be stored in 
a securely locked area, accessible to authorized personnel only. 
10.3. 
Study Drug Storage 
All study drug supplies must be stored in accordance with the Pharmacy Manual instructions and 
package labeling. Until dispensed or administered to the patients, the study drug will be stored in 
a securely locked area, accessible to authorized personnel only. 
10.4. 
Study Drug Preparation 
The Pharmacy Manual contains descriptions of the packaging of study drug and instructions for 
administration of study drug.  
10.5. 
Administration 
Niraparib (100 mg niraparib capsules) will be supplied and starting dose will be 200 mg. Study 
drug will be administered PO daily throughout 28 days for 2 cycles, with the potential for an 
additional 4 cycles (maximum total of 6 cycles) at the assigned dose and schedule.  
Patients will be instructed to take study drug at approximately the same time each day. Bedtime 
administration may be a potential method for managing nausea. Patients must swallow capsules 
whole. Study drug may be taken with or without food. Study drug will be dispensed to patients 
on Day 1 of each cycle if breast ultrasound shows CR, PR, or SD after the previous cycle of 
niraparib treatment (please see Appendix 2).  
The Pharmacy Manual contains descriptions of the packaging of study drug and instructions for 
administration of study drug. 


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10.6. 
Presurgery Chemotherapy 
The decision to proceed to surgery or to pursue neoadjuvant chemotherapy following treatment 
with niraparib will be at the discretion of the treating investigator. Details regarding neoadjuvant 
chemotherapy, including agents, start and stop dates, will be recorded in the eCRF. 
10.7. 
Study Drug Accountability 
The Investigator or designee is responsible for maintaining accurate dispensing records of the 
study treatments throughout the clinical study. Study drug accountability should be maintained 
by each site based on the capsules dispensed versus returned to the clinic at each visit and the 
number of days since the last visit. 
Details of maintaining drug accountability, including information on the accountability log, will 
be provided in the Pharmacy Manual. 
All dispensation and accountability records will be available for the Sponsor review. The Study 
Monitor will assume the responsibility to reconcile the study treatment accountability log. The 
pharmacist will dispense study treatment for each patient according to the protocol and the 
Pharmacy Manual, if applicable. 
10.8. 
Study Drug Handling and Disposal 
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 in order to allow drug 
destruction or return procedure. 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 onsite destruction, the Sponsor will provide a return for destruction 
service to a third party. Both the unused and expired study drug must be destroyed, upon 
authorization of the Sponsor, according to local regulations and procedures, and a copy of the 
destruction form must be filed in the study binder. 
The medication provided for this study is to be used only as indicated in this protocol and only 
for the patients entered in this study. 


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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Efficacy Endpoints 
11.1.1. 
Primary Endpoint 
• Tumor response rate based on the change in tumor volume as measured by breast 
MRI.; a response is considered at least >30% reduction of tumor volume from 
baseline after 2 months of niraparib treatment. Tumor volume will be calculated as 
(length × width × height × π)/6.35 
11.1.2. 
Secondary Endpoints 
• pCR: pCR is defined as ypT0/Tis ypN0 by receipt of pre-operative chemotherapy 
(Yes vs. No). pCR is defined as the absence of residual invasive cancer on 
hematoxylin and eosin evaluation of the complete resected breast specimen and all 
sampled regional lymph nodes following completion of neoadjuvant systemic therapy 
(i.e., ypT0/Tis ypN0 in the current AJCC staging system1). 
• Tumor response rate based on the change in tumor volume as measured by breast 
ultrasound; a response is considered ≥30% reduction of tumor volume from baseline 
after 2 months of niraparib treatment. Tumor volume will be calculated as 
(length × width × height × π)/6.35 
• Percentage change in tumor volume from baseline after 2 months of niraparib 
treatment as measured by ultrasound. Tumor volume will be calculated as 
(length × width × height × π)/6.35 
• Percentage change in tumor volume from baseline after 2 months of niraparib 
treatment as measured by MRI. Tumor volume will be calculated as 
(length × width × height × π)/6.35 
11.2. 
Exploratory Endpoints 
• Immune-related changes in gene expression profiles and cellular composition (eg, 
T-cells, myeloid cells, and natural killer cells) in pre vs. post niraparib treatment tumor 
samples 
• Niraparib concentration in post treatment tumor samples and correlation with PK in 
peripheral blood 
• Estimation of change in tumor volume in BRCAmut TNBC patients and in BRCAmut 
hormone-positive patients 
• Comparison of PARP enzymatic activity (eg, PARylation), DNA damage and repair (eg, 
phosphorylated histone H2AX, RAD51), proliferation (eg, Ki67) and survival (eg, 
Caspase 3) in pre vs. post niraparib treatment tumor samples 
• Potential biomarkers of sensitivity or resistance (e.g. BRCA reversion mutations, LOH) in 
ctDNA or tumor tissue  


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• Targeted (or whole exome) sequencing for other disease related molecular alterations 
with remaining blood or tumor samples 


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12. 
TRANSLATIONAL RESEARCH 
The overall aims of translational research are the following: to evaluate the effect of niraparib 
treatment on the tumor immune contexture, as well as PD changes in the tumor; to explore molecular 
mechanisms mediating resistance to niraparib; and to assess the potential of blood-based predictive 
biomarkers, such as circulating tumor DNA. 
12.1. 
Effect of Niraparib Treatment on the Tumor Immune Contexture 
and Pharmacodynamic Changes in Tumor Cells 
12.1.1. 
Tumor Immune Contexture 
The immunologic underpinnings of a tumor play an important role in disease progression and 
response to anticancer therapies. However, the effect of PARP inhibitor treatment on the cancer 
immune response has not been well characterized. There is an emerging evidence suggesting that 
niraparib treatment may affect the tumor immune contexture, turning a cold (non-inflamed) 
tumor into a hot (inflamed) one. The effect may manifest as changes in immune-related gene 
expression profiles, cellular composition of tumor infiltrating immune cells (eg, T cells, myeloid 
cells, NK cells), as well as signaling pathways (eg, STING/IFN a/b), and chemokine/cytokine 
profiles. Better understanding of the immune modulatory effect of niraparib will help the 
development of more effective combination therapies. Tumor biopsies, collected in formalin-
fixed paraffin embedded (FFPE) before and after niraparib treatment, will be analyzed for 
biomarkers related to breast cancer biology, PARP inhibition, or immune oncology (eg, gene 
expression profiling), as well as immune phenotyping using multiplex immunofluorescence 
techniques. 
12.1.2. 
Intra-tumoral Niraparib Concentration 
Efficient tumor penetration is essential for achieving complete inhibition of PARP activity in all 
malignant cells within a tumor nodule. Preclinical data showed that niraparib has excellent tumor 
penetrance property. To evaluate concentration of niraparib in tumors, a post-treatment biopsy, 
collected within 24 hours after last dose of niraparib is needed. Niraparib concentration in tumor 
will be correlated with blood PK parameters, PD endpoints, and efficacy outcomes. 
12.1.3. 
Pharmacodynamic Changes 
Niraparib is a potent and selective inhibitor of PARP1 and PARP2. In tumors with deficiency in 
homologous recombination, the inhibition of PARP activity will lead to accumulation of 
unrepaired DNA damage and cell death. Fresh frozen tumor biopsies, collected before and after 
niraparib treatment, will be analyzed for PARP enzymatic activity (eg, PARylation assay). In 
addition, the FFPE biopsies will be analyzed for DNA damage and repair (eg, γH2AX, RAD51), 
proliferation (eg, Ki67), and cell death (eg, Cleaved Caspase 3)-related biomarkers. 
The studies detailed above will be conducted on frozen and FFPE core biopsies collected during 
the Screening and again at the end of Cycle 2. The biopsy at the end of Cycle 2 should be taken 
within 24 hours of the last dose of niraparib, whenever possible, to preserve the effects induced 
by niraparib treatment. A surgical biopsy may be used in lieu of a core biopsy provided that 
surgery occurs within 24 hours of the last dose of niraparib in Cycle 2. 


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12.1.4. 
Molecular Mechanisms Mediating Resistance to Niraparib in BRCAmut 
Population 
BRCAmut leads to malignancies deficient in homologous recombination and responsiveness to 
PARP inhibitors. However, many changes within the tumor (eg, BRCA reversion mutation, loss 
of 53BP1 expression) can partially restore homologous recombination function and cause 
resistance to PARP inhibitors. In addition, it has been shown that, in ovarian cancer patients with 
germline BRCA mutations, loss of heterozygosity (LOH) in the tumor is correlated with stronger 
clinical benefit from platinum based therapies. To study these sensitivity/resistance mechanisms, 
tumor sample from surgery may be deep sequenced to look for coexistent genomic alternations. 
If enough RNA can be extracted, gene expression of these tumors may be evaluated by 
sequencing technology or alternative methods.  
12.2. 
Assessment of Blood-based Predictive Biomarkers for Niraparib 
Efficacy and Resistance 
12.2.1. 
BRCA Status and Other Biomarker Analysis of Circulating Tumor DNA 
Plasma of most cancer patients contains ctDNA that carries information on tumor mutations and 
tumor burden. This information can be reliably retrieved with deep sequencing technology and 
may be useful as a minimally-invasive way of monitoring cancer genomic alterations (mutations, 
rearrangements). A next-generation sequencing (NGS)-based ctDNA panel, which includes both 
BRCA1 and BRCA2, has been developed and validated for investigational use only. This test can 
be used to identify patients with BRCA1/2 mutations for enrollment into this study. In addition, 
ctDNA analyses may allow tracking and monitoring of tumor dynamics during treatment, as well 
as the emergence of resistant subclones. ctDNA analysis will be conducted to evaluate genomic 
alternations, such as BRCA reversion mutations, LOH, and their correlation with response to 
treatment. 
12.3. 
Summary of Sample Collection 
The required samples for biomarker assessment are presented in Table 8.


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Table 8: 
Summary of Sample Collection 
Sample Type 
Collection 
Timepoints 
Sample Amount 
Local Storage 
Conditions 
Purpose 
Core biopsy1 
Screening, end of 
Cycle 2 
Core biopsies: 4 
to 5 cores (2 fresh 
frozen and 2 to 3 
fixed in NBF) 
Surgical biopsy (if 
applicable): 2 
pieces fresh 
frozen and 1 piece 
fixed in NBF 
 
-80°C (fresh 
frozen) and room 
temperature (NBF 
fixed) 
Immune 
contexture Tumor 
PK/PD 
Tumor from 
surgery 
Surgery 
1 FFPE block 
Room temperature Resistance 
biomarkers 
Blood 
Screening, end of 
Cycle 1, end of 
Cycle 2, and 
presurgery 
20 mL 
-80°C or -20°C 
ctDNA analysis 
Abbreviations: ctDNA = circulating tumor DNA; FFPE = formalin-fixed paraffin embedded; NBF = neutral 
buffered formalin; PD = pharmacodynamic; PK = pharmacokinetic. 
1A surgical biopsy may be used in lieu of a core biopsy provided that surgery occurs within 24 hours of the last dose 
of niraparib in Cycle 2. 
All samples will be collected and managed centrally when possible and will be distributed either 
directly or subsequently to designated translational research laboratories for biomarker testing. 
Details on blood and tissue sample collection, processing, storage, shipping, and handling 
instructions can be found in the Laboratory Manual. 
12.4. 
Safety Endpoints  
• Safety by toxicity grades as defined by the NCI-CTCAE v.4.03 criteria 
• Incidence of TEAEs  
• Changes in clinical laboratory parameters (hematology, chemistry)  
• Vital signs  
• Physical examinations 
• Usage of concomitant medications 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety Parameters 
Safety will be evaluated based on the incidence of TEAEs, SAEs, treatment discontinuations or 
dose reductions due to AEs, changes in clinical laboratory results (hematology and chemistry), 
vital sign measurements, observations during physical examination, and use of concomitant 
medications. All AEs will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA) coding system. 
13.1.1. 
Demographic/Medical History 
Demographic and baseline characteristics consist of those variables that are assessed at 
screening. Patient demography consists of age at screening, race, ethnicity, and sex. 
13.1.2. 
Disease History 
For disease history, the following will be documented: 
• Date of first diagnosis of breast cancer 
• Histology at diagnosis and most recent biopsy, if additional biopsy performed 
13.1.3. 
Medical and Surgical History 
Major medical and surgical history (including medication history), including history of 
thrombocytopenia, neutropenia, leukopenia, or anemia will be collected. Details of any prior 
invasive malignancy will be collected. Medical and surgical history will be obtained by 
interviewing the patient or by reviewing the patient’s medical records. 
13.1.4. 
Vital Signs 
Vital signs (blood pressure, pulse, and temperature) will be assessed according to the Schedule of 
Events (Table 6). 
Any vital signs assessed as clinically significant should be recorded as an AE or SAE. If SAE 
criteria are met or the abnormality is an AESI, the event should be recorded and reported 
according to the SAE reporting process (see Section 13.2.5). 
13.1.5. 
Weight and Height 
Body weight and height will be assessed according to the Schedule of Events (Table 6). 
13.1.6. 
Physical Examination 
Complete physical examination, symptom-directed physical examination, and physical breast 
examinations will be performed in accordance with the Schedule of Events (Table 6). 
Any physical examination or physical breast examination assessed as clinically significant 
should be recorded as an AE or SAE. If SAE criteria are met or the abnormality is an AESI, the 
event should be recorded and reported according to the SAE reporting process (see 
Section 13.2.5). 


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13.1.7. 
Electrocardiogram  
All patients will undergo ECGs in accordance with the Schedule of Events (Table 6). ECGs 
should be performed prior to blood draws. Patients will be supine and rested for approximately 
2 minutes before ECGs are recorded. 
Any ECG findings assessed as clinically significant should be recorded as an AE. If SAE criteria 
are met or the abnormality is an AESI, the event should be recorded and reported according to 
the SAE reporting process (see Section 13.2.5). 
13.1.8. 
Clinical Laboratory Assessments 
The hematology, blood chemistry, urinalysis, and pregnancy screening will occur in accordance 
with the Schedule of Events (Table 6). These tests will be performed by the local laboratory at 
the clinical site. For any patient diagnosed with MDS/AML while on study, a bone marrow 
aspirate and biopsy and sample collection (whole blood) for cytogenetic analysis will be 
obtained. 
13.1.8.1. Hematology 
Hematology will be measured in accordance with the Schedule of Events (Table 6). The 
following values will be obtained/analyzed: 
• CBC: 
− Hemoglobin 
− Platelet count 
− Mean corpuscular volume 
− White blood cell count 
− Differential white blood cell count 
13.1.8.2. Blood Chemistry 
Blood chemistry will be assessed in accordance with the Schedule of Events (Table 6). The 
following values will be obtained/analyzed: 
Sodium 
Total bilirubin 
Potassium 
Alkaline phosphatase 
Chloride 
Aspartate aminotransferase 
Creatinine 
Alanine aminotransferase 
Blood urea nitrogen 
Glucose  
Total protein  
Albumin 
Calcium  
Amylase 
Phosphate 
Magnesium 
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13.1.8.3. Urinalysis 
Urinalysis will be assessed in accordance with the Schedule of Events (Table 6). The following 
values will be obtained/analyzed: 
Specific gravity 
Protein 
Leukocyte esterase 
Glucose 
Nitrite 
Ketones 
Blood 
Bilirubin 
13.1.8.4. Virus Serology 
Not applicable. 
13.1.8.5. Drug Screen 
Not applicable. 
13.1.8.6. Pregnancy Screen 
A negative serum pregnancy test is required within 72 hours prior to Day 1 of Cycle 1 for 
females of childbearing potential. If the serum pregnancy result is not available before dosing, a 
urine pregnancy test may be performed. Additional urine pregnancy testing will be performed in 
accordance with the Schedule of Events (Table 6).  
13.1.9. 
ECOG Performance Status 
Performance status will be assessed using the ECOG scale (see Appendix 1) in accordance with 
the Schedule of Events (Table 6). The same observer should assess performance status each time. 
13.2. 
Adverse Events and Special Situations 
13.2.1. 
Definition  
13.2.1.1. Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
medicinal product and which does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of study treatment, whether or not considered related to the study 
treatment.  
AEs may include the onset of new illness and the exacerbation of pre-existing medical 
conditions. An AE can include an undesirable medical condition occurring at any time after the 
time of randomization and/or treatment assignment, including baseline or washout periods, even 
if no study treatment has been administered.  (See Section 13.2.3 for information about AE 
collecting and reporting.) 


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13.2.1.2. Serious Adverse Event (SAE) 
Any untoward medical occurrence that, at any dose; 
• Results in death;  
• Is life threatening (i.e., an event in which the patient was at risk of death at the time of 
the event; it does not refer to an event that hypothetically might have caused death if 
it were more severe);  
• Requires inpatient hospitalization* or prolongation of existing hospitalization;  
• Results in persistent or significant disability/incapacity;  
• Is a congenital anomaly/birth defect; or 
• Is an important medical event** 
*Exception: Preplanned (at time of informed consent) hospitalization for elective procedures, for 
protocol compliance or social reasons, or for observation will not be considered criteria for an 
SAE. The reason for the planned hospitalization should be captured in medical history section in 
the eCRF. Complications experienced during these hospitalizations must be reported as AEs (or 
SAEs, if hospitalization is prolonged due to the AE).  
**Medical and scientific judgment should be exercised in determining whether situations or 
events should be considered serious adverse events:  an important medical event may not be 
immediately life-threatening or result in death or require hospitalization but may jeopardize the 
patient or require intervention to prevent one of the above outcomes.  Examples of such events 
are allergic bronchospasm, blood dyscrasias, or convulsions that may require intensive treatment 
in an emergency room or at home but do not result in hospitalization, development of drug 
dependency or drug abuse, and transmission of disease associated with the administration of the 
study drug. (See Section 13.2.5 for information about SAE reporting.) 
13.2.1.3. Treatment-Emergent Adverse Event (TEAE) 
Any event that was not present prior to the initiation of study treatment or any event already 
present that worsens in either intensity or frequency following exposure to study treatment. 
13.2.1.4. Adverse Event of Special Interest (AESI) 
Any AE (serious or non-serious) that is of scientific and medical concern specific to the study 
treatment, for which ongoing monitoring and rapid communication by the Investigator to the 
Sponsor is appropriate. 
13.2.1.5. Special Situations: Abuse, Misuse, Medication Errors, Overdose, and Accidental 
or Occupational Exposure 
• Abuse:  is the persistent or sporadic, intentional excessive use of the study treatment 
which is accompanied by harmful physical or psychological effects.  
• Misuse: medicinal product is intentionally and inappropriately used not in accordance 
with the authorized/approved product information. 


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• Medication error:  is any preventable incident that may cause or lead to 
inappropriate study treatment use or patient harm while the study treatment is in the 
control of the health care professionals or patients. Such incident may be due to 
health care professional practice, product labeling, packaging and preparation, 
procedures for administration, and systems, including the following: prescribing, 
order communication, nomenclature, compounding, dispensing, distribution, 
administration, education, monitoring, and use. 
• Overdose:  is a deliberate or accidental administration of study treatment to a study 
patient, at a dose greater than that which was assigned to that patient per the study 
protocol and under the direction of the Investigator.  If an overdose occurs, the 
Investigator and the Sponsor should be notified immediately, and the patient should 
be observed closely for AEs. Associated AEs should be treated and monitored by the 
Investigator. The dosage of study drug administered, any associated AEs, and/or 
treatment provided to the patient because of the overdose, should be documented on 
the applicable sections within the eCRF. An overdose (including an AE or SAE 
resulting from the overdose, if any) will be reported as described in Section 13.2.5. 
• Accidental /Occupational exposure:  is the unintentional exposure to a study 
treatment as a result of one’s professional or non-professional occupation, or 
accidental exposure to a non-professional to whom exposure was not intended (i.e., 
study product given to wrong patient).  
Reporting Special Situations:  All occurrences of abuse, misuse, medication error, overdose, and 
accidental or occupational exposure with any study treatment must be reported on an SAE 
Report Form [or designated Special Form] to the Sponsor regardless of whether or not an AE or 
SAE has occurred. If the abuse, misuse, medication error, overdose, or accidental / occupational 
exposure is associated with an SAE, an SAE report form must be submitted to the Sponsor 
within 24 hours of awareness. If there is no AE or SAE, the occurrence must be submitted on the 
designated Special Form (indicate ‘no AE has occurred’) as soon as possible. 
13.2.2. 
Assessment of Adverse Events 
13.2.2.1. Severity Assessment 
All AEs will be assessed by the Investigator for severity* according to Common Terminology 
Criteria for Adverse Events (CTCAE) v4.03: 14 June 2010; National Institutes of Health (NIH), 
National Cancer Institute (NCI). The CTCAE severity grades 1 through 5 provide unique clinical 
descriptions of severity of each adverse event. The CTCAE v4.03 is available on the NCI/NIH 
website. 
Please note that there is a distinction between serious and severe AEs: Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 13.2.1.2.  For example, a mild 
degree of gastrointestinal bleeding requiring an overnight hospitalization for monitoring 
purposes may be considered an SAE but is not necessarily severe. 


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13.2.2.2. Relationship to Study Intervention 
The Investigator must provide a causality assessment regarding the relationship of the event with 
the study drug and/or study procedure for all AEs.  One of the following categories should be 
selected based on medical judgment, considering all contributing factors: 
• Related: A causal relationship between the medicinal product (and/or study 
procedures) and AE is a reasonable possibility. For example, the occurrence of the 
AE cannot be explained by other causative factors. The AE, however, can be 
explained by pharmacological effect of the medicinal product such as a similar event 
having been reported previously, alteration of the dose effect, or the timing or 
seriousness of the AE, etc. Positive rechallenge/dechallenge is supportive.  
• Not Related: A causal relationship between the medicinal product (and/or study 
procedures) and AE is not a reasonable possibility: there is no temporal relationship 
between the medicinal product and event, or an alternative etiology is more 
reasonable.  
13.2.2.3. Expectedness 
The Sponsor will be responsible for determining whether an adverse event is ‘expected’ or 
‘unexpected’.  An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information provided in the Reference Safety Information of 
the effective niraparib Investigator Brochure (IB). 
13.2.3. 
Collection and Recording Adverse Events 
AEs may be volunteered spontaneously by the study patient, or discovered by the study staff 
during physical examinations or by asking an open, nonleading question such as, “How have you 
been feeling since your last study visit?” The Investigator will document the nature of AE, date 
of onset of the AE (and time, if known), date of outcome of the AE (and time, if known), 
severity of the AE, action taken with study drug as a result of the AE, assessment of the 
seriousness of the AE, and assessment of the causal relationship of the AE to study drug and/or 
study procedure. 
AEs, including laboratory abnormalities that are assessed as clinically significant or require 
intervention, should be described using a diagnosis whenever possible, rather than individual 
underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or 
symptom should be recorded as a separate AE. 
All SAEs will be collected from the signing of the ICF for this study through 90 days after the 
last dose of study drug (or to a minimum of 30 days post treatment if the patient starts alternate 
anticancer therapy and recorded in the eCRF. SAEs will also be reported on an SAE form as 
described in Section 13.2.5 of this protocol. SAEs considered by the Investigator to be related to 
study medication are reported until study closeout. 
All AEs, regardless of the source of identification (e.g., physical examination, laboratory 
assessment, ECG, or reported by patient), will be collected and recorded in the eCRF for each 
patient from the signing of the ICF for this study until 30 days after last study drug 
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Concomitant illnesses that existed before entry into the study will not be considered AEs unless 
the illness worsens during the Treatment Period. Pre-existing conditions will be recorded as 
Medical History in the eCRF and on the SAE Report Form. 
Disease progression is an efficacy criterion and is therefore not considered an AE or SAE (even 
if fatal). Disease progression should be reported within the eCRF. If AEs/SAEs occur in relation 
to disease progression that are not consistent with the natural progression of the patient’s disease, 
these AEs/SAEs must be reported per AE/SAE reporting requirements described in 
Section 13.2.5.  
13.2.4. 
Follow-Up of Adverse Events 
All AEs experienced by a patient, regardless of the suspected causality, will be monitored until 
the AE or SAE has resolved, until any abnormal laboratory values have returned to baseline or 
normal levels, until stabilized with a satisfactory explanation for the changes observed, until the 
patient is lost to follow-up, or until the patient has died. 
If an Investigator becomes aware of an SAE after the specified follow-up period and considers 
the SAE related to the study drug, the Investigator should report the SAE to the Sponsor 
according to timelines for reporting SAEs described in Section 13.2.5.   
13.2.5. 
Reporting 
The Investigator must report all SAEs, and all follow up information to the Sponsor on an SAE 
Report Form within 24 hours of becoming aware of the initial event or follow-up information. 
The Investigator must provide a causality assessment and must sign and date all SAE Report 
Forms.   
It is the responsibility of the Investigator to review source documentation and describe pertinent 
information on the SAE Report Form.  If supporting documentation is requested (e.g., hospital 
reports, consultant reports, death certificates, autopsy reports, etc.), the Investigator should 
highlight all relevant and pertinent information within such documents, ensure that any patient’s 
personal identifiers (including Medical Record number) are removed, and submit the documents 
with the SAE Form to the Sponsor. The Sponsor (or designee) will return a confirmation of 
receipt for all email reports (if received from other than a “no reply” domain) within 1 business 
day.  
After receipt of the initial report, the Sponsor (or designee) will review the information and, if 
necessary, contact the Investigator to obtain further information. The Investigator must promptly 
respond to queries from the Sponsor. 
13.2.6. 
Submission and Distribution of Serious Adverse Event Reports 
Per regulatory requirements, if an event is assessed by the Sponsor as a Serious Unexpected 
Adverse Reaction (SUSAR), it is the responsibility of the Sponsor to submit the SUSAR 
Regulatory Authorities according to applicable regulations. 
In addition, the SUSAR will be distributed to the Investigators/sites, utilizing a Council for 
International Organizations of Medical Sciences (CIOMS) report form, or the MedWatch 3500A 
form). The Investigator/site will submit a copy of the report to their respective Institutional 


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Review Board (IRB) or Independent Ethics Committee (IEC) per the governing institutional 
requirements and in compliance with local laws and guidelines. 
13.2.7. 
Adverse Events of Special Interest 
Adverse Events of Special Interest (AESI) for niraparib are the following:  
• Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) 
• Secondary cancers (new malignancies [other than MDS or AML]) 
• Pneumonitis 
• Embyro-fetal toxicity 
AESI should be collected and reported as follows: 
• MDS and AML along with other secondary cancers should be reported to the Sponsor 
through 90 days after the last dose of study drug. 
• Pneumonitis should be reported to the Sponsor through 90 days after the last dose of 
study drug (or until the start of alternate anticancer therapy, whichever occurs first). 
• Embryo-fetal toxicity should be reported as outlined in Section 13.2.8  
13.2.8. 
Pregnancy  
Pregnancies occurring while female patients are enrolled in a study, or experienced by a female 
partner of a male patient enrolled in a study, must be reported to the Investigator and followed to 
outcome.  Furthermore, all pregnancies must be reported to the Sponsor. The Sponsor has the 
responsibility to monitor the outcome of all pregnancies reported during the clinical study. 
Each pregnancy must be reported by the Investigator to the Sponsor on an Initial Pregnancy 
Report Form within 24 hours of becoming aware of the pregnancy. Pregnancy is not an AE, and 
therefore does not need to be reported as an AE in the eCRF unless there is a suspicion that the 
study drug may have interfered with the effectiveness of a contraceptive medication. The 
Investigator must follow-up all pregnancies, document the course and the outcome, and report 
this information to the Sponsor on a Pregnancy Outcome Report Form within 24 hours of 
becoming aware - even if the patient was withdrawn from the study or the study has finished. 
An elective abortion without complications should not be regarded as an AE, however, it should 
be reported as the outcome to the pregnancy on the Pregnancy Outcome Report Form. 
Therapeutic abortions should be reported as a treatment procedure; the reason for the therapeutic 
abortion should be reported on the Pregnancy Outcome Report Form and as an AE in the eCRF. 
Hospitalization for normal delivery of a healthy newborn should not be considered an SAE. 
Any SAE that occurs during pregnancy must be recorded on the Pregnancy Outcome Report 
Form, reported as an SAE on the SAE Report Form (e.g., maternal serious complications, 
therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, birth 
defect) and reported to the Sponsor within 24 hours. Hospitalization for normal delivery of a 
healthy newborn should not be considered an SAE.  


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13.2.9. 
Special Situations 
All occurrences of abuse, misuse, medication error, overdose, and accidental or occupational 
exposure with any study treatment must be reported on a Special Situations Report Form to the 
Sponsor within 5 calendar days of becoming aware of the occurrence, regardless of whether it is 
categorized as an AE. If the occurrence is associated with an SAE, an SAE Report Form, along 
with the Special Situations Report Form, must be submitted to the Sponsor within 24 hours of 
awareness.   


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14. 
STATISTICS 
Details of the statistical analyses presented below will be provided in the Statistical Analysis 
Plan (SAP). 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. The SAP will be finalized 
prior to database lock. Any changes to the methods described in the plan will be described and 
justified in the final clinical study report. 
No formal statistical testing will be done for this study. Data will be summarized in a descriptive 
nature. Categorical variables will be summarized by frequency distributions (number and 
percentage of patients). Continuous variables will be summarized by the mean, standard 
deviation, median, minimum, maximum, first quartile and third quartile. Further details will be 
provided in the SAP. 
14.1. 
Sample size determination 
No formal sample size calculation has been done for this study. The sample size is determined 
based on the clinical considerations only.  
A total of approximately 20 evaluable patients will be enrolled. This sample size should be 
sufficient for signal finding prior to initiating a larger study. For example, it will provide 
approximately 80% power with 1-sided significance level of 0.15 to differentiate a response rate 
of 80% from a minimum response rate of 60%. Other examples are provided below. 
One-sided alpha 
SoC Response Rate 
Niraparib Response Rate 
Power 
0.15 
60% 
70% 
45% 
0.15 
60% 
75% 
65% 
0.15 
60% 
80% 
80% 
14.2. 
Populations for Analysis 
The Safety population includes all patients who received any dose of study medication. The 
safety population will be the primary analysis population for the safety analyses. 
The Efficacy Evaluable population includes all patients who completed 2 cycles of treatment. 
The efficacy evaluable population will be the primary analysis population for the efficacy 
analyses. 
14.3. 
Demographics, Medical History, Baseline Characteristics, and 
Concomitant Medications 
Demographics, baseline characteristics, and medical history information will be summarized for 
the Safety population using descriptive statistics. No formal statistical comparisons will be 
performed. 
Demographics, baseline characteristics, concomitant medications, and medical history data for 
each patient will be provided in data listings. 


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14.4. 
Efficacy Analyses 
No formal statistical testing will be done for efficacy endpoints. Tumor response rate will be 
tabulated together with its 95% binomial exact CI. The change in tumor volume from baseline 
will be summarized using descriptive statistics. Data from patients who received neoadjuvant 
niraparib only will be analyzed separately from those who received neoadjuvant niraparib 
followed by neoadjuvant chemotherapy. 
14.5. 
Safety Analyses 
All analysis for safety endpoints is will be done in a descriptive manner. Summary statistics will 
be provided for safety endpoints including: TEAEs, other adverse events, AESIs, clinical 
laboratory evaluations (hematology, chemistry, urinalysis), vital signs, ECGs, physical 
examination, and use of concomitant medications. 
Medical history and AEs will be coded using the most up-to-date version of MedDRA. CTCAE 
v4.03 will be used to grade the severity of AEs and laboratory abnormalities. Prior/concomitant 
medication and anticancer treatment will be coded using the World Health Organization 
Anatomical Therapeutic Chemical classification system. 
AEs will include the following categories: 
• TEAEs 
− Drug-related TEAEs 
− Grade 3, 4, and 5 TEAEs (presented by grade and overall) 
− Grade 3,4, and 5 drug-related TEAES (presented by grade and overall) 
− TEAEs resulting in study drug discontinuation 
− Most commonly reported TEAEs (ie, those events reported by ≥10% of all 
patients) 
− Treatment-emergent SAEs 
• AESIs 
Details for the safety analysis will be specified in the Statistical Analysis Plan. 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of TESARO will 
visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of TESARO or its representatives. This will 
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During the study, a monitor from TESARO or representative will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the patient’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each patient 
(e.g., clinic charts). 
• Record and report any protocol deviations not previously sent to TESARO 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to TESARO and those SAEs that met criteria for reporting have 
been forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
15.2. 
Audits and Inspections 
Authorized representatives of TESARO, a regulatory authority, an Independent Ethics 
Committee or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification. The purpose of a TESARO audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP) guidelines of the 
International Conference on Harmonization, and any applicable regulatory requirements. The 
Investigator should contact TESARO immediately if contacted by a regulatory agency about an 
inspection. 
15.3. 
Institutional Review Board  
The PI must obtain IRB approval for the investigation. Initial IRB approval, and all materials 
approved by the IRB for this study including the patient consent form and recruitment materials 
must be maintained by the Investigator and made available for inspection. 


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, TESARO may 
conduct a quality assurance audit. Please see Section 15.2 for more details regarding the audit 
process. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate. The 
Investigator must submit written approval to TESARO before he or she can enroll any 
patient/patient into the study. 
The PI is responsible for informing the IRB or IEC of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB or IEC must approve all advertising 
used to recruit patients for the study. The protocol must be re-approved by the IRB or IEC upon 
receipt of amendments and annually, as local regulations require. 
The PI is also responsible for providing the IRB with reports of any reportable serious adverse 
drug reactions from any other study conducted with the investigational product. TESARO will 
provide this information to the PI. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
17.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonization/Good 
Clinical Practice, applicable regulatory requirements and the TESARO’s policy on Bioethics. 
17.3. 
Written Informed Consent 
The PI(s) at each center will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. Patients must also 
be notified that they are free to discontinue from the study at any time. The patient should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The patient’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The PI(s) must maintain the original, signed Informed Consent Form. A copy of the signed 
Informed Consent Form must be given to the patient. 


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18. 
DATA HANDLING AND RECORDKEEPING 
18.1. 
Inspection of Records 
TESARO will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
18.2. 
Retention of Records 
The PI must maintain all documentation relating to the study for a period of 2 years after the last 
marketing application approval, or if not approved 2 years following the discontinuance of the 
test article for investigation. If it becomes necessary for TESARO or the Regulatory Authority to 
review any documentation relating to the study, the Investigator must permit access to such 
records. 


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19. 
PUBLICATION POLICY 
Information regarding publication of study results is contained in the Clinical Trial Agreement 
for this study. 


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20. 
LIST OF REFERENCES 
1. 
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high-risk early-stage breast cancer: use as an endpoint to support accelerated approval. 
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2. 
Mills GB, Timms KM, Reid JE, et al. Homologous Recombination deficiency score 
shows superior association with outcome compared with its individual score components 
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Society of Gynecologic Oncology, 19-22 March 2016, San Diego. 
3. 
National Cancer Institute: Surveillance, Epidemiology, and End Results (SEER) 
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4. 
Morton LM, Dores GM, Tucker MA, et al. Evolving risk of therapy-related acute 
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5. 
Easton DF. How many more breast cancer predisposition genes are there? Breast Cancer 
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Campeau PM, Foulkes WD, Tischkowitz MD. Hereditary breast cancer: new genetic 
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Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer 
associated with BRCA1 or BRCA2 mutations detected in case series unselected for 
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8. 
Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 
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9. 
King MC, Marks JH, Mandell JB, New York Breast Cancer Study G. Breast and ovarian 
cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 
2003;302(5645):643-646. 
10. 
Armes JE, Egan AJ, Southey MC, et al. The histologic phenotypes of breast carcinoma 
occurring before age 40 years in women with and without BRCA1 or BRCA2 germline 
mutations: a population-based study. Cancer. 1998;83(11):2335-2345. 
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Southey MC, Ramus SJ, Dowty JG, et al. Morphological predictors of BRCA1 germline 
mutations in young women with breast cancer. Br J Cancer. 2011;104(6):903-909. 
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Baretta Z, Mocellin S, Goldin E, Olopade OI, Huo D. Effect of BRCA germline 
mutations on breast cancer prognosis: A systematic review and meta-analysis. Medicine 
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13. 
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. 2010;376(9737):235-244. 
14. 
Mieog JS, van der Hage JA, van de Velde CJ. Preoperative chemotherapy for women 
with operable breast cancer. Cochrane Database Syst Rev. 2007(2):CD005002. 
15. 
Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term 
clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 
2014;384(9938):164-172. 
16. 
Turner et al. J Clin Oncol 35, 2017 (suppl; abstr 1007). 


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17. 
Han HS, et al. Efficacy and tolerability of veliparib (V; ABT-888) in combination with 
carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or 
BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study. SABC 
2016, Abstract S2-05. . 
18. 
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing 
a common language for tumor response to immunotherapy: immune-related response 
criteria using unidimensional measurements. Clin Cancer Res. 2013;19(14):3936-3943. 
19. 
Symmans WF, Wei C, Gould R, et al. Long-term prognostic risk after neoadjuvant 
chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin 
Oncol. 2017;35(10):1049-1060. 
20. 
von Minckwitz G, Eidtmann H, Rezai M, et al. Neoadjuvant chemotherapy and 
bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012;366(4):299-309. 
21. 
Bear HD, Tang G, Rastogi P, et al. The effect on pCR of bevacizumab and/or 
antimetabolites added to standard neoadjuvant chemotherapy: NSABP protocol B-40. J 
Clin Oncol 2011;29:Suppl:1005-1005. 
22. 
Litton JK, Scoggins M, Ramirez DL, et al. A feasibility study of neoadjuvant talazoparib 
for operable breast cancer patients with a germline BRCA mutation demonstrates marked 
activity. NPJ Breast Cancer. 2017;3:49. 
23. 
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. 
2009;52(22):7170-7185. 
24. 
Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by Clinical PARP 
Inhibitors. Cancer Res. 2012;72(21):5588-5599. 
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Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors 
from BRCA mutation carriers. N Engl J Med. 2009;361(2):123-134. 
26. 
Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor 
olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a 
proof-of-concept trial. Lancet. 2010;376(9737):245-251. 
27. 
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. The Lancet. Oncology. 
2011;12(9):852-861. 
28. 
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. 2012;18(6):1726-1734. 
29. 
Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-
sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392. 
30. 
Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with 
platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of 
outcomes by BRCA status in a randomised phase 2 trial. The Lancet. Oncology. 
2014;15(8):852-861. 
31. 
Sandhu SK, Schelman WR, Wilding G, et al. The poly(ADP-ribose) polymerase inhibitor 
niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a 
phase 1 dose-escalation trial. The Lancet. Oncology. 2013;14(9):882-892. 


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32. 
Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib Maintenance Therapy in Platinum-
Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016;375(22):2154-2164. 
33. 
Guan J, Lim KS, Mekhail T, Chang CC. Programmed death ligand-1 (PD-L1) expression 
in the programmed death receptor-1 (PD-1)/PD-L1 blockade: a key player against various 
cancers. Arch Pathol Lab Med. 2017;141(6):851-861. 
34. 
Ricks TK, Chiu HJ, Ison G, et al. Successes and challenges of PARP inhibitors in cancer 
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35. 
Tomayko MM, Reynolds CP. Determination of subcutaneous tumor size in athymic 
(nude) mice. Cancer Chemother Pharmacol. 1989;24(3):148-154. 
36. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). European journal of cancer. 
2009;45(2):228-247. 
37. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the 
use of white blood cell growth factors: an evidence-based clinical practice guideline. J 
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38. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. American journal of clinical oncology. 1982;5(6):649-655. 
 


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21. 
APPENDICES 


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APPENDIX 1. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Description 
Grade 
Source:  38 
 
 
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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APPENDIX 2. DISEASE ASSESSMENT CRITERIA  
 
Definition of response  
Response will be assessed by imaging tests (ultrasound and MRI). Disease assessment is to be 
determined by changes in the tumor volume, calculated as length × width × height × π)/6. While 
all measurable lesions will be followed in cases multifocal or multicentric disease, only the 
largest or primary lesion will be used for assessing disease status as follows: 
• Clinical complete response (CR) 
Complete disappearance of all tumor signs in the breast as assessed by imaging test. The 
response of the axillary nodes is not to be considered. 
• Clinical partial response (PR) 
Reduction in the tumor volume of the primary tumor size by ≥30% assessed by palpation 
or imaging test. In patients with multifocal or multicentric disease, the lesion with the 
largest volume should be chosen for follow-up. The response of the axillary nodes is not 
to be considered. 
• Clinical stable disease (SD) 
No significant change in tumor volume during treatment. This category includes no 
change, an estimated reduction of the tumor volume of the primary lesion by less than 
30%, or an estimated increase in the size of the tumor volume of less than 20% measured 
imaging test. 
• Clinical progressive disease (cPD) 
Development of new, previously undetected lesions, or an estimated increase in the size 
of the primary lesion by greater than 20%. 
 


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APPENDIX 3. TNM  DEFINITIONS 
 
TNM Definitions  
Primary tumor (T):  
• TX: Primary tumor cannot be assessed. 
• T0: No evidence of primary tumor. 
• Tis: Carcinoma in situ (DCIS, LCIS, or Paget disease of the nipple with no associated 
tumor mass) 
• T1: Tumor ≤20 mm in greatest dimension. 
• T2: Tumor >20 mm but ≤50 mm in greatest dimension. 
• T3: Tumor >50 mm in greatest dimension. 
• T4: Tumor of any size with direct extension to the chest wall and/or to the skin 
(ulceration or skin nodules)  
 
Regional lymph nodes (N):  
• NX: Regional lymph nodes cannot be assessed (e.g., previously removed)  
• N0: No regional lymph node metastases  
• N1: Metastases to movable ipsilateral level I, II axillary lymph node(s). 
• N1mi: Micrometastases (>0.2 mm and/or >200 cells but none >2.0 mm). 
• N2: Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or 
matted OR Metastases in clinically detected ipsilateral internal mammary nodes in the 
absence of clinically evident axillary lymph node metastases. 
• N3: Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or 
without level I, II axillary lymph node involvement OR Metastases in clinically detected 
ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary 
lymph node metastases OR Metastases in ipsilateral supraclavicular lymph node(s) with 
or without axillary or internal mammary lymph node involvement.  
 
Distant metastasis (M):  
• MX: Presence of distant metastases cannot be assessed. 
• M0: No clinical or radiographic evidence of distant metastases. No distant metastasis  
• M1: Distant detectable metastases as determined by classic clinical and radiographic 
means and/or histologically proven >0.2 mm. 
 


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APPENDIX 4. AJCC STAGE GROUPINGS 
STAGE   TNM 
• Stage 0 
 
 
Tis, N0, M0 
• Stage I  
 
 
T1, N0, M0 / T0 or T1, N1mi, M0 
• Stage IIA  
 
T0 or T1, N1 (but not N1mi), M0 / T2, N0, M0 
• Stage IIB  
 
T2, N1, M0 / T3, N0, M0 
• Stage IIIA  
 
T0 to T2, N2, M0 / T3, N1 or N2, M0 
• Stage IIIB  
 
T4, N0 to N2, M0 
• Stage IIIC  
 
any T, N3, M0 
• Stage IV  
 
any T, any N, M1 
• UNKNOWN  
Unknown 
 


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APPENDIX 5. NATIONAL CANCER INSTITUTE COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
 
Refer to NCI CTCAE v.4.03 in the Study Reference Manual, or online at the following NCI 
website: http://ctep.cancer.gov/reporting/ctc.html 
 
1. Toxicity grade should reflect the most severe degree occurring during the evaluated 
period, not an average. 
2. When two criteria are available for similar toxicities, the one resulting in the more severe 
grade should be used. 
3. The evaluator must attempt to discriminate between disease/treatment and related 
signs/symptoms. 
 
An accurate baseline prior to therapy is essential. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Official Title of Study: AN OPEN-LABEL, SINGLE-ARM PILOT STUDY EVALUATING THE ANTITUMOR 
ACTIVITY AND SAFETY OF NIRAPARIB AS NEOADJUVANT TREATMENT IN LOCALIZED, HER2-NEGATIVE, 
BRCA-MUTANT BREAST CANCER PATIENTS 
 
NCT ID: NCT03329937 
Other Identifiers: 213355, 3000-01-005 
Date of Document: 05Sep2019 
 


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STATISTICAL ANALYSIS PLAN: Study  3000-01-005  
Study Title: 
An Open-Label, Single-Arm Pilot Study Evaluating the Antitumor Activity 
and Safety of Niraparib as Neoadjuvant Treatment in Localized, 
HER2-Negative, BRCA-Mutant Breast Cancer Patients 
Study Number: 
 3000-01-005  
Study Phase: 
2 
Product Name: 
Niraparib 
 
 
Sponsor: 
TESARO, Inc. 
Sponsor Contact: 
1000 Winter Street 
Waltham MA 02451 
 
 
Version 
Version Date 
Original Statistical Analysis Plan: 
V0.6 
02/11/2019 


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PPD
PPD
PPD
PPD
PPD
PPD


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SPONSOR SIGNATURES 
Study Title: 
An Open-Label, Single-Arm Pilot Study Evaluating the Antitumor 
Activity and Safety of Niraparib as Neoadjuvant Treatment in 
Localized, HER2-Negative, BRCA-Mutant Breast Cancer Patients 
Study Number: 
 3000-01-005  
Final Date: 
02/11/2019 
 
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. 
Author 
, PhD 
Director of Biostatistics 
LLX Solutions, LLC 
Signature: 
Date: 
  
Approver:  
 
 PhD 
Director of Biostatistics 
TESARO, Inc. 
Signature:  
Date: 
Senior Medical Director  
Clinical Research  
TESARO, Inc. 
Signature:  
Date: 
 
 
PPD
PPD
PPD


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TABLE OF CONTENTS 
SPONSOR SIGNATURES ......................................................................................................3 
TABLE OF CONTENTS ........................................................................................................4 
TABLES ....................................................................................................................................6 
LIST OF ABBREVIATIONS .................................................................................................7 
1 
INTRODUCTION ............................................................................................................9 
2 
STUDY DESIGN OVERVIEW ......................................................................................9 
2.1 
Overall Study Design .............................................................................................9 
2.2 
Sample Size ...........................................................................................................15 
2.3 
Randomization and Blinding ..............................................................................16 
3 
STUDY OBJECTIVES ..................................................................................................16 
3.1 
Primary Objective ................................................................................................16 
3.2 
Second Objectives ................................................................................................16 
3.3 
Exploratory Objectives ........................................................................................16 
4 
STUDY ENDPOINTS AND EVALUATIONS ............................................................17 
4.1 
Efficacy Endpoints ...............................................................................................17 
4.1.1 
Primary Efficacy Endpoint ..........................................................................17 
4.1.2 
Secondary Efficacy Endpoints .....................................................................17 
4.1.3 
Exploratory Efficacy Endpoints ...................................................................17 
4.2 
Safety Evaluations ................................................................................................18 
4.3 
Other Evaluations ................................................................................................18 
5 
PLANNED ANALYSES ................................................................................................19 
5.1 
Changes from planned Analyses in the Protocol ..............................................19 
5.2 
Interim Analyses ..................................................................................................19 
5.3 
Final Analyses and Reporting .............................................................................19 
6 
ANALYSIS POPULATIONS AND APPLICATIONS ...............................................19 
6.1 
Efficacy Evaluable Population ............................................................................19 
6.2 
Full Analysis Population .....................................................................................20 
6.3 
Pharmacokinetic Population ...............................................................................20 
6.4 
Safety Population .................................................................................................20 
6.5 
Application of Analysis Populations ..................................................................20 
7 
STATISTICAL CONSIDERATIONS .........................................................................20 
7.1 
General Statistical Procedures ............................................................................21 
7.2 
Patient Enrolment and Disposition ....................................................................21 
7.2.1 
Patient Enrollment .......................................................................................21 
7.2.2 
Patient Disposition .......................................................................................21 
7.2.3 
Protocol Deviations ......................................................................................21 


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7.3 
Demographic and Other Pre-treatment Variables ...........................................22 
7.3.1 
Demographics/Baseline Characteristics .......................................................22 
7.3.2 
Medical History ...........................................................................................23 
7.3.3 
Medication Use/Procedures .........................................................................24 
7.4 
Analysis of Efficacy Data.....................................................................................25 
7.4.1 
Primary Efficacy Data..................................................................................25 
7.4.2 
Secondary Efficacy Data..............................................................................25 
7.4.3 
Subgroup Analyses of Efficacy Data ...........................................................25 
7.5 
Analysis of Pharmacokinetic Data .....................................................................25 
7.6 
Analysis of Exploratory Efficacy Endpoints .....................................................26 
7.7 
Analysis of Safety Data ........................................................................................26 
7.7.1 
Adverse Events ............................................................................................26 
7.7.2 
Study Drug Exposure and Compliance ........................................................27 
7.7.3 
Clinical Laboratory Evaluations ..................................................................28 
7.7.4 
Vital Signs ....................................................................................................29 
7.7.5 
Electrocardiogram ........................................................................................29 
7.7.6 
Physical Examinations .................................................................................29 
7.7.7 
ECOG Performance Status ..........................................................................30 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ..........................30 
8.1 
Definition of Baseline ...........................................................................................30 
8.2 
Analysis Visit Window .........................................................................................30 
8.3 
Efficacy Data Handling .......................................................................................30 
8.4 
Safety Data Handling ...........................................................................................30 
8.4.1 
Handling of Repeated Clinical Laboratory Tests.........................................30 
8.4.2 
Handling of Partial Dates for AEs ...............................................................30 
8.4.3 
Handling of Partial Dates for Medications ..................................................31 
9 
REFERENCE .................................................................................................................32 
10 APPENDICE ..................................................................................................................33 
Appendix A. Disease Assessment Criteria ......................................................................33 
Appendix B. Common Terminology Criteria for Adverse Events v4.03 (CTCAE) ...34 
Appendix C. TNM Definitions ........................................................................................36 
Appendix D. AJCC Stage Groupings .............................................................................37 


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TABLES 
Table 1: Schedule of Events 
Table 2: Powers with Different Response Rates 
Table 3: Application of Analysis Populations for Tables and Graphs 
Table 4: Common Terminology Criteria for Adverse Events v4.03 (CTCAE) 
 


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LIST OF ABBREVIATIONS 
Abbreviatio
n  
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ALK 
anaplastic lymphoma kinase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BRCA  
breast cancer susceptibility gene  
BRCAmut  
breast cancer susceptibility gene mutant 
BMI 
body mass index 
BOR 
best overall response 
CI 
confidence interval 
CBC 
complete blood count 
CR 
complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG 
Easter Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
EOS 
end of study 
EOT 
end of treatment 
FDA 
US Food and Drug Administration 
ER- 
Estrogen receptor negative 
ER+ 
Estrogen receptor positive 
HER2- 
human epidermal growth factor receptor 2 negative 
HRD 
homologous recombination deficiency  
LLN 
lower limit of normal 
LOH 
loss of heterozygosity  
MedDRA 
Medical Dictionary for Regulatory Activities 
PARP  
poly(ADP-ribose) polymerase  
pCR  
pathological complete response  


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Abbreviatio
n  
Definition 
PD  
progressive disease  
PFS  
progression-free survival  
PK 
pharmacokinetics 
PO  
oral(ly)  
PR  
partial response  
PR-  
progesterone receptor negative 
PR+ 
progesterone receptor positive 
Q1 
first quartile 
Q3 
third quartile 
QD 
once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SD 
stable disease or standard deviation 
TEAE 
treatment-emergent adverse event 
TNBC 
triple-negative breast cancer 
ULN 
upper limit of normal 
WHO 
World Health Organization 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) provides the detailed statistical methods to be used for 
analyses and data presentation for reporting efficacy and safety of investigational drug niraparib 
for TESARO study protocol 3000-01-005.  
The pharmacokinetics and exposure-response analyses will be provided in a separate document. 
The exploration of blood and tumor-based biomarkers that predict sensitivity or resistance to 
niraparib will also be detailed in a separate document.  
This document has been prepared according to Study Protocol Version 2 dated 01 August 2018. 
2 
STUDY DESIGN OVERVIEW 
2.1 
Overall Study Design 
This is an open-label, single-arm pilot study evaluating the antitumor activity and safety of 
niraparib as neoadjuvant therapy in patients with human epidermal growth factor receptor 2 
(HER2) negative and breast cancer susceptibility gene mutant (BRCAmut) localized breast cancer 
(primary tumor ≥1 cm). The study design is summarized in the schema below. If antitumor 
activity in the BRCAmut cohort is demonstrated, the protocol may be amended to add a 
homologous recombination deficiency (HRD)-positive, BRCA-wild type cohort.  The study 
design is presented graphically as below. 
Study Schema: 
 
 


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This study will consist of a Screening Period (Day -28 to Day -1), a Treatment Period, Presurgery 
chemotherapy (if appropriate), Surgery, a Safety Follow-up/EOT visit occurring 30 days (+ 7 days) 
after the last dose of study medication, and an Off-Study Visit for the purposes of collecting the 
pathological complete response (pCR) results for patients for whom the Safety Follow-up/EOT Visit 
occurred prior to surgery; for all other patients the Safety Follow-up/EOT Visit will act as the off-study 
visit.  
 The schedules of assessments are presented in Table 1. 


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Table 1: Schedule of Events 
Cycle/Visit: 
Screening 
Cycle 1 
± 7 days 
Cycle 2 
± 7 days 
Cycles 3-6 
± 7 days 
(if applicable) 
Pre- 
surgery 
Surgery 
Safety Follow- 
Up/EOT Visit 
Day of Procedure 
-28 to -1 
1 
8 
15 
21 
28 
1 
28 
1 
28 
30 + 7 days post last 
dose of niraparib 
Informed consent 
X 
Inclusion/exclusion 
criteria review 
X 
Demographics 
X 
Medical, surgical, cancer, 
and medication history 
X 
Local Confirmation HER2 
negative and ER, PR status 
X 
Blood sample for 
exploratory biomarkers 
(ctDNA) 
X 
X2 
X2 
X3 
BRCA1/2 mutation 
testing1 
X 
Completion of neo- 
adjuvant chemotherapy 
eCRFs, if applicable 
X 


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Table 1: Schedule of Events 
Cycle/Visit: 
Screening 
Cycle 1 
± 7 days 
Cycle 2 
± 7 days 
Cycles 3-6 
± 7 days 
(if applicable) 
Pre- 
surgery 
Surgery 
Safety Follow- 
Up/EOT Visit 
Day of Procedure 
-28 to -1 
1 
8 
15 
21 
28 
1 
28 
1 
28 
30 + 7 days post last 
dose of niraparib 
Breast ultrasound tumor 
assessment 
X 
X4 
X4 
X4 
Breast MRI tumor 
assessment 
X 
X4 
Core biopsy 
X 
X5 
X5 
pCR assessment 
X 
Laboratory assessments: 
CBC 
X 
X6 
X 
X 
X 
X6 
X6 
X 
Serum chemistry 
X 
X6 
X 
X6 
X6 
X 
Pregnancy test 
X7 
X7 
X 
Urinalysis 
X 
ECG 
X 


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Table 1: Schedule of Events 
Cycle/Visit: 
Screening 
Cycle 1 
± 7 days 
Cycle 2 
± 7 days 
Cycles 3-6 
± 7 days 
(if applicable) 
Pre- 
surgery 
Surgery 
Safety Follow- 
Up/EOT Visit 
Day of Procedure 
-28 to -1 
1 
8 
15 
21 
28 
1 
28 
1 
28 
30 + 7 days post last 
dose of niraparib 
Complete physical 
examination 
X 
X 
Symptom-directed 
physical examination 
X 
X 
X 
Physical breast 
examination 
X 
X 
X 
X 
Vital signs and weight 
X 
X 
X 
X 
X 
Height 
X 
ECOG performance status 
X 
 
X 
Concomitant medications and 
procedures 
X 
Recorded from informed consent through Safety Follow-up/EOT 
Adverse event monitoring8 
X 
Recorded from informed consent through 30 days post-treatment 
Niraparib study drug 
dispensed/collected 
X 
X 
X 


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Table 1: Schedule of Events 
Cycle/Visit: 
Screening 
Cycle 1 
± 7 days 
Cycle 2 
± 7 days 
Cycles 3-6 
± 7 days 
(if applicable) 
Pre- 
surgery 
Surgery 
Safety Follow- 
Up/EOT Visit 
Day of Procedure 
-28 to -1 
1 
8 
15 
21 
28 
1 
28 
1 
28 
30 + 7 days post last 
dose of niraparib 
PK Sample Collection 
X9 
X9 
Abbreviations: AESI = adverse events of special interest; AML = acute myeloid leukemia; BRCA = breast cancer susceptibility gene; CBC = complete blood count; 
ctDNA = circulating tumor deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; 
EOT = end of treatment; ER = estrogen receptor; IEC = Independent Ethics Committee; IRB = Institutional Review Board; MDS = myelodysplastic syndrome; pCR = 
pathological complete response; PK = pharmacokinetic; PR = progesterone receptor; SAE = serious adverse event.  
1 If BRCA status is known, it need not be repeated. Results may have been obtained by either local or central laboratory testing.  
2 Can be collected pre-dose Day 1 of the next cycle.  
3 Pre-surgery blood sample is not required for patients proceeding directly to surgery at the end of Cycle 2.  
4 Can be performed +/- 3 days from Day 28, but results must be available prior to the start of the next cycle.  
5 Core biopsy should be obtained on Cycle 2 Day 28 (+7 days) within 24 hours of last dose of niraparib and prior to ultrasound, MRI, and any subsequent anticancer therapy 
or procedure. A surgical biopsy may be used in lieu of a core biopsy provided that surgery occurs within 24 hours of the last dose of niraparib in Cycle 2.  
6 Cycle 1 Day 1 testing not required if screening assessments were performed within 72 hours of Day 1.  
7 A serum pregnancy test will be performed locally for all women of childbearing potential at Screening (within 72 hours prior to the first dose of study drug). The result 
must be negative before the first dose of study drug is administered. If the serum pregnancy result is not available before dosing, a urine pregnancy test may be performed. 
Pregnancy tests may also be repeated during the study if requested by an IEC/IRB or if required by local regulations. 
8 SAEs and AESIs concerning hypertension and hematologic toxicities will be collected and recorded in the eCRF and on an SAE report form for each patient from the 
date of signed informed consent until 90 days after the last dose of study drug (or until the start of alternate anticancer therapy, whichever occurs first). AESIs 
concerning MDS/AML, secondary cancers, pneumonitis, and embryo-fetal toxicity must be collected and reported to the Sponsor for each patient from the date of 
signed informed consent until study closeout.  
9 Samples for PK assessment with be collected on Day 1 of Cycles 1 and 2 predose, 2 (± 30 minutes) and 4 (± 30 minutes) hours post dose, and in conjunction with the post-
treatment core biopsy. 


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2.2 
Sample Size 
No formal sample size calculation has been done for this study. The sample size is determined 
based on the clinical considerations only.  
A total of approximately 20 evaluable patients will be enrolled. This sample size should be 
sufficient for signal finding prior to initiating a larger study. For example, it will provide 
approximately 80% power with 1-sided significance level of 0.15 to differentiate a response 
rate of 80% from a minimum response rate of 60%. Other examples are provided below in 
Table 2.   
Table 2: Powers with Different Response Rates 
One-sided alpha Minimum Response Rate 
Niraparib Response Rate 
Power 
0.15 
60% 
70% 
45% 
0.15 
60% 
75% 
65% 
0.15 
60% 
80% 
80% 
 
 
 


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2.3 
Randomization and Blinding 
This is an open-label study and patients will not be randomized.   
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is:  
• To evaluate the preliminary antitumor activity of niraparib assessed as the tumor 
response rate based on the change in tumor volume as measured by breast MRI, 
observed after treatment with niraparib in the neoadjuvant treatment of localized, 
HER2 negative, breast cancer susceptibility gene mutant (BRCAmut) breast cancer 
patients.  
3.2 
Second Objectives 
The secondary objectives of the study are as follows:  
• To evaluate the preliminary antitumor activity of niraparib assessed by:  
- Presence of pCR defined as ypT0/Tis ypN0 by receipt of pre-operative 
chemotherapy (Yes versus No)  
- Percentage change in tumor volume from baseline after 2 months of niraparib 
treatment by MRI and ultrasound 
- Tumor response rate based on the change in tumor volume as measured by 
breast ultrasound  
• To evaluate safety and tolerability of niraparib per National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 criteria  
3.3 
Exploratory Objectives 
• To evaluate niraparib-induced changes in immune responses  
•  To explore intra-tumoral niraparib concentration and correlation with blood  
• To estimate the preliminary antitumor activity of niraparib in BRCAmut triple-
negative breast cancer (TNBC) patients and BRCAmut hormone-positive (HR+) 
patients  
• To evaluate pharmacodynamic inhibition of poly(ADP-ribose) polymerase (PARP) 
activity in the tumor  
• To explore molecular biomarkers related to disease biology or response to treatment 
using tumor tissue or liquid biopsy approaches (e.g. ctDNA) 


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4 
STUDY ENDPOINTS AND EVALUATIONS 
4.1 
Efficacy Endpoints 
4.1.1 Primary Efficacy Endpoint 
Tumor response rate based on the change in tumor volume as measured by breast MRI; a 
response is considered at least >30% reduction of tumor volume from baseline after 2 months 
of niraparib treatment without any new lesion development. Tumor volume will be calculated 
as (length × width × height × π)/6. The percentage reduction in tumor volume will be set as 
99% if the tumor becomes too small to measure at the post-baseline visit. 
4.1.2 Secondary Efficacy Endpoints 
• pCR is defined as ypT0/Tis ypN0 by receipt of pre-operative chemotherapy (Yes vs. 
No). pCR is defined as the absence of residual invasive cancer on hematoxylin and 
eosin evaluation of the complete resected breast specimen and all sampled regional 
lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0/Tis 
ypN0 in the current AJCC staging system [Appendix D]).  
• Tumor response rate based on the change in tumor volume as measured by breast 
ultrasound; a response is considered at least >30% reduction of tumor volume from 
baseline after 2 months of niraparib treatment without any new lesion development. 
Tumor volume will be calculated as (length × width × height × π)/6.  
• Percentage change in tumor volume from baseline after 2 months of niraparib 
treatment as measured by ultrasound. Tumor volume will be calculated as (length × 
width × height × π)/6. The percentage reduction in tumor volume will be set as 99% if 
the tumor becomes too small to measure at the post-baseline visit.  
• Percentage change in tumor volume from baseline after 2 months of niraparib 
treatment as measured by MRI. Tumor volume will be calculated as (length × width × 
height × π)/6. The percentage reduction in tumor volume will be set as 99% if the 
tumor becomes too small to measure at the post-baseline visit.  
4.1.3 Exploratory Efficacy Endpoints 
• Immune-related changes in gene expression profiles and cellular composition (eg, T-
cells, myeloid cells, and natural killer cells) in pre vs. post niraparib treatment tumor 
samples  
• Niraparib concentration in post treatment tumor samples and correlation with PK in 
peripheral blood  
• Estimation of change in tumor volume in BRCAmut TNBC patients and in BRCAmut 
hormone-positive patients  


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• Comparison of PARP enzymatic activity (eg, PARylation), DNA damage and repair 
(eg, phosphorylated histone H2AX, RAD51), proliferation (eg, Ki67) and survival (eg, 
Caspase 3) in pre vs. post niraparib treatment tumor samples  
• 
Potential biomarkers of sensitivity or resistance (e.g. BRCA reversion mutations, loss of 
heterozygosity [LOH]) in ctDNA or tumor tissue 
• 
Targeted (or whole exome) sequencing for other disease related molecular alterations 
with remaining blood or tumor samples 
Except for the third bullet point, analysis plan for other exploratory endpoints will be 
provided separately. 
4.2 
Safety Evaluations 
The safety evaluations include:  
• Treatment emergent adverse events (TEAEs) 
• Extent of exposure 
• Clinical laboratory assessments  
- Hematology 
- Chemistry  
• Serum or urine pregnancy testing 
• Vital signs 
• Physical examination findings 
• Physical breast examination  
• ECG 
 
4.3 
Other Evaluations 
Other evaluations include: 
 
• Demographics and baseline characteristics (including BRCA mutation test and 
hormone receptor test) 
• Medical history 
- Disease history (breast cancer history) 
- Other cancer history 
- Medical history 
- Surgical history  
- Prior blood disorders  
• Medication use/procedures 
- Prior and concomitant medication/therapy 
- Prior anticancer treatment for non-primary cancer 
- Growth factors 


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- Transfusions 
- Concomitant procedures/surgeries 
- Prior and concomitant radiotherapy 
- Concomitant chemotherapy 
- Neoadjuvant chemotherapy (post niraparib)  
• ECOG Performance status  
• Urinalysis 
• Drug accountability (Niraparib)  
• Surgery and tumor sample collection 
• MRI primary and non-primary lesion assessments 
• Ultrasound primary and non-primary lesion assessments 
• New lesion assessment 
• Niraparib dose modification 
• Evaluation of response on primary lesion based on MRI and ultrasound 
 
5 
PLANNED ANALYSES 
5.1 
Changes from planned Analyses in the Protocol 
There are no changes from planned Analyses in the Protocol. 
5.2 
Interim Analyses 
There are no planned interim analyses. 
5.3 
Final Analyses and Reporting 
All final planned analyses per protocol and this SAP will be performed only after database 
lock. 
6 
ANALYSIS POPULATIONS AND APPLICATIONS 
Statistical analysis and data tabulation will be performed using the following analysis 
populations unless specified otherwise: 
6.1 
Efficacy Evaluable Population  
Efficacy Evaluable (EE) population includes all patients who complete 2 cycles of treatment. 
The EE population will be the primary analysis population for the efficacy analyses. The 
patients need to have an observed outcome at the end of cycle 2 in order to be included in the 
analysis based on the EE population. 
 


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6.2 
Full Analysis Population  
Full Analysis Set (FAS) includes all patients who receive at least one dose of study 
medication and have at least one ultrasound scan at Month 1. 
6.3 
Pharmacokinetic Population  
Pharmacokinetic (PK) population includes all patients who receive at least one dose of study 
medication and have at least one post-dose niraparib concentration. 
6.4 
Safety Population 
Safety population includes patients who receive at least one dose of study medication.  The 
safety population will be the primary analysis population for the safety analyses. 
6.5 
Application of Analysis Populations 
The analysis population(s) that will be used for creating the summary table(s) of each type is 
provided in Table 3.  All data will be presented in listings for the enrolled patients. A patient 
will be considered enrolled when the patient has been consented in the electronic case report 
form (eCRF). 
Table 3: Application of Analysis Populations for Tables and Graphs 
Type 
Safety 
EE 
FAS 
PK* 
Disposition 
X 
 
 
 
Demographics and baseline 
characteristics 
X 
X 
X 
 
Protocol deviations 
X 
 
 
 
Medical and disease history 
X 
 
 
 
Prior and concomitant medications 
X 
 
 
 
Summary/analyses on efficacy endpoints 
 
X 
X 
 
Safety evaluations 
X 
 
 
 
Extent of Exposure 
X 
 
 
 
* The PK analyses will be provided in a separate document. 
7 
STATISTICAL CONSIDERATIONS 
All analyses described in this plan are considered a priori analyses in that they have been 
defined prior to locking the database.  All other analyses, if any, designed subsequently to 
locking the database, will be considered post hoc analyses and will be described as 
exploratory analyses in the Clinical Study Report.  


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All summaries and statistical analyses will be performed by SAS v9.3 or later.  
7.1 
General Statistical Procedures 
The descriptive statistics for continuous variables will be the mean, median, standard 
deviation (SD), quartiles (Q1, Q3), minimum, maximum, and number of patients.  
Frequency distributions for all categorical variables will be presented using counts and 
percentages. 
7.2 
Patient Enrolment and Disposition 
7.2.1 Patient Enrollment  
Number of patients will be provided for each analysis population.  For the Safety population, 
the denominators for percentages are based on number of screened patients. Screened 
population includes all patients who have been consented. 
For other populations, the denominators for percentages are based on number of patients in 
the Safety population. 
Enrollment information will be provided in a data listing. 
7.2.2 Patient Disposition 
Patient disposition will be summarized for the Safety population. The summary will present 
frequency distribution for patients completing the study and discontinuing from the study 
overall and by reason for discontinuation.   
Additionally, the frequency distribution will be provided for patients discontinuing treatment 
niraparib by reason for discontinuation.  
The denominators for calculating the percentages will be based on number of patients in the 
Safety population.  
Discontinued patients will be provided in a data listing. 
7.2.3 Protocol Deviations 
A protocol deviation (PD) is any failure to comply with the study protocol as approved by the 
relevant regulatory authority, ethics committee and/or institutional review board, whether 
planned or unplanned.  
 
PD will be assessed and classified as important or significant. A protocol deviation is 
classified as an important PD if there is the potential to:  
• Impact the completeness, accuracy, and/or reliability of the study data, or  


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• Affect a subject's rights, safety, or well-being.  
 
Important protocol deviations require review to confirm whether or not they are significant. 
The following are PDs that will always be considered important according to TESARO SOP 
1000-00021-CLN:  
• Failure to obtain informed consent for participation in the clinical trial  
• Enrollment of ineligible subject  
• Subject developed withdrawal criteria during the study but was not withdrawn  
• Subject received incorrect treatment  
• Incorrect or non-compliant dosing of a subject, i.e. dosing that is inconsistent with the 
protocol  
• Administration of an excluded concomitant treatment to a trial subject  
• Incorrect cohort assignment  
 
A protocol deviation is classified as a significant PD if it has been confirmed to:  
• Adversely impact the completeness, accuracy, and/or reliability of the study data  
• Affect a subject’s rights, safety, or well-being.  
 
The TESARO medical monitor in conjunction with other study team members as appropriate 
may determine any PD not listed above to be important or significant based on his/her 
assessment of (potential) impact. Additionally, a PD could be “downgraded.” In this case, the 
rationale for the change should be documented by the TESARO medical monitor.  
 
Criteria for important and/or significant PDs may be updated as needed throughout the 
course of the clinical trial. 
All PDs will be identified and finalized prior to database lock. 
Number and percentage of patients with important or significant protocol deviations will be 
summarized by type of deviation. The denominators for calculating the percentages will be 
based on number of patients in the Safety population.  
All protocol deviations will be listed. 
7.3 
Demographic and Other Pre-treatment Variables 
7.3.1 
Demographics/Baseline Characteristics 
Patient demographics and baseline characteristics include:  
• Age (years) calculated as date of screening minus date of birth / 365.25 if date of 
birth is reported, or age as reported on the eCRF will be used 


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• Age categories (18 to <65, >=65) 
• Race (American Indian/Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, and Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, and Unknown) 
• Baseline weight (in kilograms; if weight is reported in pounds, convert to kilograms 
by dividing by 2.2) 
• Baseline height (in centimeters; if height is reported in inches, convert to centimeters 
by multiplying by 2.54) 
• Baseline body mass index (BMI) (kg/m2), calculated using the patient’s height and 
weight [BMI (kg/m2) = weight (kg) / height (m)2] 
• ECOG performance status at baseline 
• If female, childbearing status (Childbearing potential, Non-childbearing potential)  
Continuous data will be summarized for each analysis population, using descriptive statistics.  
Categorical data will be summarized with frequency distributions using counts and 
percentages of patients in each category.  The denominators for calculating the percentages 
will be based on the number of patients for the Safety population. 
Demographics and baseline characteristics will be provided in a listing. 
7.3.2 
Medical History 
7.3.2.1 Breast Cancer History and Biomarkers 
Breast cancer history will be collected for date of initial diagnosis, laterality, cancer stage at 
time of initial diagnosis, breast cancer pathology, date of biopsy, histology type, and 
histology grade.  
Times from diagnosis to the date of first dose, laterality, stages of cancer, histopathologic 
type and histology grade will be summarized using descriptive statistics for continuous 
variables and frequency distribution for categorical variables.  
 
Additionally, BRCA mutation test data and hormone receptor test data will be summarized as 
well. 
 
 Data listings will be provided for breast cancer history,  BRCA mutation status and  
hormone receptor test results 
7.3.2.2 General Medical History 
The medical history will be coded using the current version of Medical Dictionary for 
Regulatory Activities (MedDRA). The frequency count and percentage of patients 


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experiencing any medical conditions will be tabulated by MedDRA SOC and PT for each 
analysis population.  The denominators for calculating the percentages will be based on 
number of patients in the Safety population.  
A data listing of medical history will be provided. 
7.3.2.3 Other Cancer History, Surgery History, and Prior Blood Disorders 
Other cancer history will be summarized using type of cancer collected on the CRF. 
Similarly, prior blood disorders will be summarized using events collected on the CRF as 
well.  
Data listings will be provided separately for prior blood disorders, other cancer history, and 
surgical history. 
7.3.3 
Medication Use/Procedures 
All medications/therapies will be coded using the current version of World Health 
Organization (WHO) Drug Dictionary. The count and percentage of patients who took 
prior/concomitant medications and anticancer treatment will be provided separately for each 
analysis population using therapeutic class and WHO Drug preferred name.  The 
denominators for calculating percentages will be based on the number of patients in each 
Analysis population. For the summary tables, if a patient has taken a prior or concomitant 
medication/subsequent treatment more than once, the patient will be counted only once for 
the medication/treatment. 
Prior medications are defined as medications received prior to the first dose of either study 
drugs. Concomitant medications are defined as medications that were received after the first 
dose of study medication.  
In addition, prior anticancer treatment for non-primary cancer will be summarized for any 
prior anticancer treatments received, reason for administration, numbers of prior anticancer 
treatments (treated as both continuous variable and categorical variable [i.e., 0, 1, 2, 3, 4, or 
>=5]), and time since the end of last prior anticancer treatment (months).   
All medications and prior anticancer treatment for non-primary cancer will be provided in 
data listings. In addition, separate listings will be provided for: 
• Growth factors 
• Transfusions 
• Concomitant Procedures/surgeries 
• Prior and concomitant radiotherapy 
• Concomitant chemotherapy 
• Neoadjuvant chemotherapy (post niraparib) 


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7.4 
Analysis of Efficacy Data 
No formal statistical testing will be done for efficacy endpoints. 
7.4.1 
Primary Efficacy Data 
Tumor response measured by breast MRI is defined as at least >30% reduction of tumor 
volume from baseline after 2 months of niraparib treatment without any new lesion 
development. 
Number of tumor responders measured by breast MRI, tumor response rate and its 95% 
binomial exact (Clopper-Pearson) confidence interval will be reported.  
7.4.2 
Secondary Efficacy Data 
pCR and tumor responder measured by breast ultrasound will be analyzed using the same 
methods for tumor response rate measured by breast MRI.  
Percent change in tumor volume from baseline after 2 months of niraparib treatment, 
measured in both MRI and ultrasound will be summarized using descriptive statistics.  
Clinical response (i.e., completed response, partial response, stable response, progressive 
disease, and not evaluable) based on MRI and ultrasound will be also summarized using 
frequency distribution. 
The above efficacy data, associated lesion assessments, new lesion assessment, and clinical 
response on primary lesion based on MRI and ultrasound will be provided in listings. 
7.4.3 
Subgroup Analyses of Efficacy Data 
In order to estimate of the preliminary antitumor activity of niraparib BRCAmut TNBC 
patients and BRCAmut HR+ patients, all the summaries and analyses for primary and 
secondary efficacy data will be repeated for the following subgroups: 
• TNBC patients -- TNBC is defined as estrogen receptor negative [ER-], progesterone 
receptor negative [PR-], and HER2- 
• HR+ patients -- HR+ is defined as HER2- with either estrogen receptor positive 
[ER+] or progesterone receptor positive [PR +]  
7.5 
Analysis of Pharmacokinetic Data 
 A separate PK analysis plan will detail the analyses of PK samples of niraparib. 


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7.6 
Analysis of Exploratory Efficacy Endpoints 
A separate analysis plan will detail the analyses of exploratory efficacy endpoints except for 
estimate of the preliminary antitumor activity of niraparib BRCAmut TNBC patients and 
BRCAmut HR+ patients.  
 
7.7 
Analysis of Safety Data 
7.7.1 
Adverse Events 
Adverse events will be classified into a standardized terminology MedDRA system organ 
classifications (SOC) and preferred terms (PT). Severity of AEs will be assessed by 
investigators according to CTCAE (v4.03).  
A treatment-emergent AE (TEAE) will be defined as any new AE that begins, or any 
preexisting condition that worsens in severity after the first dose of study treatment.   
The number and percentage of patients who experienced an AE will be summarized. The 
denominator for calculating the percentages will be based on the number of patients in the 
safety population.  
The following types of summaries will be provided: 
1. Overview of TEAEs 
2. TEAEs by SOC and PT 
3. TEAEs by SOC, PT, and Maximum CTCAE toxicity grade 
4. TEAEs by PT in descending frequency 
5. Related TEAEs by SOC and PT (Niraparib related and procedure related will be provided 
separately) 
6. Related TEAEs by SOC, PT and Maximum CTCAE grade (Niraparib related and 
procedure related will be provided separately) 
7. Related TEAEs by PT in descending frequency (Niraparib related and procedure related 
will be provided separately) 
8. Serious TEAEs by SOC and PT 
9. Related Serious TEAEs by SOC and PT (Niraparib related and procedure related will be 
provided separately)  
10. CTCAE Grade >=3 TEAEs by SOC, PT, and Maximum CTCAE grade 
11. Related CTCAE Grade >=3 TEAEs by SOC and PT (Niraparib related and procedure 
related will be provided separately) 
12. TEAEs leading to Niraparib interruption by SOC and PT 
13. TEAEs leading to Niraparib reduction by SOC and PT 
14. TEAEs leading to Niraparib discontinuation by SOC and PT 


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15. TEAEs leading to death by SOC and PT 
16. Treatment emergent AEs of special interest (AESI) by AESI category and PT: AESI 
categories are the following 
o Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)  
o Secondary cancers (new malignancies [other than MDS or AML])  
o Pneumonitis  
o Embryo-fetal toxicity 
17. Related Treatment emergent AESI by AESI category and PT ((Niraparib related and 
procedure related will be provided separately) 
18. Non-serious TEAEs ≥5% (required by Clinicaltrials.gov) 
If a preferred term or system organ class 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.  
In tabulation by severity (i.e., CTCAE toxicity grade),  
• For a given preferred term, only the most severe preferred term for each patient will be 
included.   
• For a given system organ class, only the most severe system organ class for each patient 
will be included.   
Similarly, in tabulation by relationship, 
• For a given preferred term, the most closely related preferred term to the study drug for 
each patient will be included.  
• For a given system organ class, the most closely related system organ class to the study 
drug for each patient will be included.  
All AEs will be provided in a data listing.  
7.7.2 
Study Drug Exposure and Compliance  
The following study drug exposure and compliance parameters will be summarized: 
• Duration of niraparib exposure in months defined as 
Date of last dose of niraparib − Date of first dose of niraparib +  1
30.4375
 
• Number of cycles initiated as continuous variable 
• Number of cycles initiated as a categorical variable (1 cycle, 2 cycles, etc.) 
• Number of patients with at least one dose interruption 
• Number of patients with at least one dose reduction 


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• Number of patients with at least one missed dose 
• Cumulative niraparib dosage (mg) received defined as sum of all niraparib dose 
received 
• Actual dose intensity (mg/day) for niraparib defined as sum of the doses actually 
received  divided by duration of niraparib exposure in days: 
Cumulative niraparib dosage (mg) received
Duration of niraparib exposure (Days)
 
• Intended dose intensity (mg/day) for niraparib defined as sum of planned doses 
divided by duration of niraparib exposure in days 
Sum of planned niraparib doses (mg)
Duration of niraparib exposure (Days) 
• Relative dose intensity (%) for niraparib defined as: 
Actual dose intensity
Intended dose intensity × 100% 
Study drug exposure and compliance parameters will be summarized using descriptive 
statistics. Details of study drug administration, dose modifications and duration of exposure 
will be listed. 
7.7.3 
Clinical Laboratory Evaluations 
Clinical laboratory assessments (CBC and serum chemistry) will be summarized by visit in 
descriptive nature. Descriptive statistics will be provided for continuous laboratory data and 
associated change from baseline. Frequency distribution will be provided for categorical 
laboratory.  
The worst toxicity grades for selected laboratory tests as listed in Appendix B (Table 4) will 
be determined for each patient based on worst abnormal high and abnormal low lab values.  
The shift table from baseline CTCAE grade to the worst NCI CTC grade will be provided. 
Laboratory measurements that are within their institutional limits of normal and are not 
graded as 1-4, per the CTCAE, will be summarized as “Grade 0,” which is defined as normal. 
Additionally, if a lab parameter is graded in both directions (e.g. glucose: hyperglycemia and 
hypoglycemia), then low direction toxicity grades at baseline and post baseline will be set to 
0 when the variables are derived for summarizing high direction toxicity, and vice 
versa.  Hyperglycemia will only be coded to grades ≥ 3 using non-fasting glucose and 
therefore will not be included in shift tables. 
For shift table from baseline to post-baseline visit, the denominators for calculating the 
percentages will be based on the number of patients with non-missing values at both baseline 
and post-baseline analysis visit in the Safety population.  


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Liver function tests post baseline will be summarized by the following categories: 
• ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN 
• AST ≥ 3×ULN, AST ≥ 5×ULN, AST ≥ 10×ULN, AST ≥ 20×ULN 
• (ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, 
(ALT or AST) ≥ 20×ULN 
• Total bilirubin ≥ 2×ULN 
• Concurrent ALT ≥ 3×ULN and total bilirubin ≥ 2×ULN 
• Concurrent AST ≥ 3×ULN and total bilirubin ≥ 2×ULN 
• Concurrent (ALT or AST) ≥ 3×ULN and total bilirubin ≥ 2×ULN 
• Concurrent (ALT or AST) ≥ 3×ULN and total bilirubin ≥ 2×ULN and ALP > 
2×ULN 
• Potential Hy’s law: Concurrent (ALT or AST) ≥ 3×ULN and total bilirubin ≥ 
2×ULN and ALP ≤ 2×ULN or missing 
Concurrent measurements are those occurring on the same date. 
Urinalysis is only collected at screening. The data will be provided in a listing. Pregnancy 
test data, if available, will also be provided in data listings. 
7.7.4 
 Vital Signs  
Vital signs (systolic and diastolic blood pressure, pulse, temperature, and weight) will be 
summarized by visit. Actual values and changes from baseline will be summarized at each 
visit.  
Furthermore, the maximum increase, maximum decrease, and maximum change/magnitude 
from baseline will be summarized.  
Baseline is defined as the last observation prior to start of the first dose of study drug(s). 
7.7.5 
Electrocardiogram 
Electrocardiogram is only collected at screening. Therefore, ECG results will be provided in 
a data listing only. 
7.7.6 
Physical Examinations 
Physical examinations and physical breast examinations will be provided in data listings 
only. 


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7.7.7 
ECOG Performance Status 
Shifts of ECOG performance status from baseline to the end of treatment will present 
frequency distribution for each category. The denominators for calculating the percentages 
will be based on the number of patients with non-missing baseline and post-baseline values. 
Details on ECOG status will be provided in a data listing. 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING  
As a general rule, missing data values are not imputed unless otherwise specified below and, 
in presentation of categorical variables, unknown and missing data may be presented as a 
separate category in some case and the denominator will include unknown or missing values 
as appropriate. 
8.1 
Definition of Baseline 
For all evaluations unless otherwise noted, baseline is defined as the most recent 
measurement prior to 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. 
8.2 
Analysis Visit Window 
For safety parameters excluding clinical laboratory data, measurements collected from 
unscheduled visits will not be included in the by-visit summary tables but will be included in 
the listings.  
8.3 
Efficacy Data Handling 
See Section 4.1.1 and 4.1.2 of the SAP. 
8.4 
Safety Data Handling 
For all safety data, only observed data will be used for analyses, and missing data will not be 
imputed. 
8.4.1 
Handling of Repeated Clinical Laboratory Tests 
The last repeat of laboratory results will be used in the summary tables for that visit. All the 
laboratory test results (original test results and repeated results) will be included in the data 
listings. 
8.4.2 
Handling of Partial Dates for AEs   
When determining the treatment emergent AE, partial dates will be handled as follows.  


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• 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 study treatment. In this case, the onset date will be 
assumed to be the date of treatment. 
• If the onset day and month are both missing, the month and day 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 set to the day of treatment to conservatively report the event as 
treatment-emergent.  
• A completely missing onset date will be set 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. 
8.4.3 
Handling of Partial Dates for Medications  
A medication with a completely missing start date will be considered a prior medication. A 
medication with a completely missing stop date will be considered a concomitant medication.   
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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9 
REFERENCE 


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10 APPENDICE 
Appendix A. Disease Assessment Criteria 
Response will be assessed by imaging tests (ultrasound and MRI). Disease assessment is to 
be determined by changes in the tumor volume, calculated as length × width × height × π)/6. 
While all measurable lesions will be followed in cases multifocal or multicentric disease, 
only the largest or primary lesion will be used for assessing disease status as follows: 
• Clinical complete response (CR) 
Complete disappearance of all tumor signs in the breast as assessed by imaging test. The 
response of the axillary nodes is not to be considered. 
• Clinical partial response (PR) 
Reduction in the tumor volume of the primary tumor size by 30% or more assessed by 
palpation or imaging test. In patients with multifocal or multicentric disease, the lesion 
with the largest volume should be chosen for follow-up. The response of the axillary 
nodes is not to be considered. 
• Clinical stable disease (SD) 
No significant change in tumor volume during treatment. This category includes no 
change, an estimated reduction of the tumor volume of the primary lesion by less than 
30%, or an estimated increase in the size of the tumor volume of less than 20% measured 
imaging test. 
• Clinical progressive disease (cPD) 
Development of new, previously undetected lesions, or an estimated increase in the size 
of the primary lesion by 20% or more. 
 


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Appendix B. Common Terminology Criteria for Adverse Events v4.03 
(CTCAE) 
Table 4: Common Terminology Criteria for Adverse Events v4.03 (CTCAE) 
 Lab Test 
Std. 
Unit 
CTCAE v4.0 
SOC 
CTCAE v4.0  
Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
g/L 
Blood and 
lymphatic 
system 
disorders 
Anemia 
<LLN - 100 
g/L 
<100 – 80 
g/L 
<80 g/L 
- 
aPTT 
sec 
Investigations 
Activated partial 
thromboplastin time 
prolonged 
>ULN - 1.5 
x ULN 
>1.5 - 2.5 x 
ULN 
>2.5 x 
ULN 
- 
ALT 
U/L 
Investigations 
Alanine 
aminotransferase 
increased 
>ULN - 3.0 
x ULN 
>3.0 - 5.0 x 
ULN 
>5.0 - 
20.0 x 
ULN 
>20.0 x 
ULN 
ALP 
U/L 
Investigations 
Alkaline phosphatase 
increased 
>ULN - 2.5 
x ULN 
>2.5 - 5.0 x 
ULN 
>5.0 - 
20.0 x 
ULN 
>20.0 x 
ULN 
AST 
U/L 
Investigations 
Aspartate 
aminotransferase 
increased 
>ULN - 3.0 
x ULN 
>3.0 - 5.0 x 
ULN 
>5.0 - 
20.0 x 
ULN 
>20.0 x 
ULN 
Bilirubin 
umol/L 
Investigations 
Blood bilirubin 
increased 
>ULN - 1.5 
x ULN 
>1.5 - 3.0 x 
ULN 
>3.0 - 
10.0 x 
ULN 
>10.0 x 
ULN 
CD4 
10e9/L 
Investigations 
CD4 lymphocytes 
decreased 
<LLN - 0.5 
x 10e9 /L 
<0.5 - 0.2 x 
10e9 /L 
<0.2 x 
0.05 - 
10e9 /L 
<0.05 x 
10e9 /L 
Cholesterol 
mmol/L 
Investigations 
Cholesterol high 
>ULN - 7.75 
mmol/L 
>7.75 - 
10.34 
mmol/L 
>10.34 - 
12.92 
mmol/L 
>12.92 
mmol/L 
CPK 
(creatinine 
phosphor-
kinase) 
- 
Investigations 
CPK increased 
>ULN - 2.5 
x ULN 
>2.5 - 5 x 
ULN 
>5 - 10 x 
ULN 
>10 x 
ULN 
Creatinine 
umol/L 
Investigations 
Creatinine increased 
>ULN - 1.5 
x ULN 
>1.5 - 3.0 x 
ULN 
>3.0 - 6.0 
x ULN 
>6.0 x 
ULN 
Fibrinogen 
- 
Investigations 
Fibrinogen decreased 
<1.0 - 0.75 x 
LLN 
<0.75 - 0.5 
x LLN 
<0.5 - 
0.25 x 
LLN 
<0.25 x 
LLN 
GGT 
(gamma-
glutamyl-
transferase) 
- 
Investigations 
GGT increased 
>ULN - 2.5 
x ULN 
>2.5 - 5.0 x 
ULN 
>5.0 - 
20.0 x 
ULN 
>20.0 x 
ULN 
INR 
- 
Investigations 
INR increased 
>1 - 1.5 x 
ULN 
>1.5 - 2.5 x 
ULN 
>2.5 x 
ULN 
- 
Lipase 
- 
Investigations 
Lipase increased 
>ULN - 1.5 
x ULN 
>1.5 - 2.0 x 
ULN 
>2.0 - 5.0 
x ULN 
>5.0 x 
ULN 
Lymphocytes 
10e9/L 
Investigations 
Lymphocyte count 
decreased 
<LLN - 0.8 
x 10e9/L 
<0.8 - 0.5 x 
10e9 /L 
<0.5 - 0.2 
x 10e9 /L 
<0.2 x 
10e9 /L 
Neutrophils 
10e9/L 
Investigations 
Neutrophil count 
decreased 
<LLN - 1.5 
x 10e9 /L 
<1.5 - 1.0 x 
10e9 /L 
<1.0 - 0.5 
x 10e9 /L 
<0.5 x 
10e9 /L 


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TESARO, Inc. 
Protocol No.  3000-01-005  
Statistical Analysis Plan 
02/11/2019 
 
 
Confidential 
Page 35 
 
 
Table 4: Common Terminology Criteria for Adverse Events v4.03 (CTCAE) 
 Lab Test 
Std. 
Unit 
CTCAE v4.0 
SOC 
CTCAE v4.0  
Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Platelets 
10e9/L 
Investigations 
Platelet count 
decreased 
<LLN - 75.0 
x 10e9 /L 
<75.0 - 
50.0 x 10e9 
/L 
<50.0 - 
25.0 x 
10e9 /L 
<25.0 x 
10e9 /L 
Amylase 
- 
Investigations 
Serum amylase 
increased 
>ULN - 1.5 
x ULN 
>1.5 - 2.0 x 
ULN 
>2.0 - 5.0 
x ULN 
>5.0 x 
ULN 
Leukocytes 
10e9/L 
Investigations 
White blood cell 
decreased 
<LLN - 3.0 
x 10e9 /L 
<3.0 - 2.0 x 
10e9 /L 
<2.0 - 1.0 
x 10e9 /L 
<1.0 x 
10e9 /L 
Calcium 
(corrected) 
mmol/L 
Metabolism 
and nutrition 
disorders 
Hypercalcemia 
>ULN - 2.9 
mmol/L 
>2.9 - 3.1 
mmol/L 
>3.1 - 3.4 
mmol/L 
>3.4 
mmol/L 
Glucose 
mmol/L 
Metabolism 
and nutrition 
disorders 
Hyperglycemia 
Fasting 
glucose 
>ULN - 8.9 
mmol/L 
Fasting 
glucose 
>8.9 - 13.9 
mmol/L 
>13.9 - 
27.8 
mmol/L 
>27.8 
mmol/L 
Potassium 
mmol/L 
Metabolism 
and nutrition 
disorders 
Hyperkalemia 
>ULN - 5.5 
mmol/L 
>5.5 - 6.0 
mmol/L 
>6.0 - 7.0 
mmol/L 
>7.0 
mmol/L 
Magnesium 
mmol/L 
Metabolism 
and nutrition 
disorders 
Hypermagnesemia 
>ULN - 1.23 
mmol/L 
- 
>1.23 - 
3.30 
mmol/L 
>3.30 
mmol/L 
Sodium 
mmol/L 
Metabolism 
and nutrition 
disorders 
Hypernatremia 
>ULN - 150 
mmol/L 
>150 - 155 
mmol/L 
>155 - 
160 
mmol/L 
>160 
mmol/L 
Triglyceride 
mmol/L 
Metabolism 
and nutrition 
disorders 
Hypertriglyceridemia 
1.71 - 3.42 
mmol/L 
>3.42 - 5.7 
mmol/L 
>5.7 - 
11.4 
mmol/L 
>11.4 
mmol/L 
Albumin 
g/L 
Metabolism 
and nutrition 
disorders 
Hypoalbuminemia 
<LLN - 30 
g/L 
<30 - 20 
g/L 
<20 g/L 
- 
Calcium 
(corrected) 
mmol/L 
Metabolism 
and nutrition 
disorders 
Hypocalcemia 
<LLN - 2.0 
mmol/L 
<2.0 - 1.75 
mmol/L 
<1.75 - 
1.5 
mmol/L 
<1.5 
mmol/L 
Glucose 
mmol/L 
Metabolism 
and nutrition 
disorders 
Hypoglycemia 
<LLN - 3.0 
mmol/L 
<3.0 - 2.2 
mmol/L 
<2.2 - 1.7 
mmol/L 
<1.7 
mmol/L 
Potassium 
mmol/L 
Metabolism 
and nutrition 
disorders 
Hypokalemia 
<LLN - 3.0 
mmol/L 
<LLN - 3.0 
mmol/L 
<3.0 - 2.5 
mmol/L 
<2.5 
mmol/L 
Magnesium 
mmol/L 
Metabolism 
and nutrition 
disorders 
Hypomagnesemia 
<LLN - 0.5 
mmol/L 
<0.5 - 0.4 
mmol/L 
<0.4 - 0.3 
mmol/L 
<0.3 
mmol/L 
Sodium 
mmol/L 
Metabolism 
and nutrition 
disorders 
Hyponatremia 
<LLN - 130 
mmol/L 
- 
<130 - 
120 
mmol/L 
<120 
mmol/L 
Phosphate 
mmol/L 
Metabolism 
and nutrition 
disorders 
Hypophosphatemia 
<LLN - 0.8 
mmol/L 
<0.8 - 0.6 
mmol/L 
<0.6 - 0.3 
mmol/L 
<0.3 
mmol/L 
 


Niraparib 
 
TESARO, Inc. 
Protocol No.  3000-01-005  
Statistical Analysis Plan 
02/11/2019 
 
 
Confidential 
Page 36 
 
 
Appendix C. TNM Definitions 
Primary tumor (T): 
• TX: Primary tumor cannot be assessed. 
• T0: No evidence of primary tumor. 
• Tis: Carcinoma in situ (DCIS, LCIS, or Paget disease of the nipple with no associated 
tumor mass) 
• T1: Tumor ≤20 mm in greatest dimension. 
• T2: Tumor >20 mm but ≤50 mm in greatest dimension. 
• T3: Tumor >50 mm in greatest dimension. 
• T4: Tumor of any size with direct extension to the chest wall and/or to the skin 
(ulceration or skin nodules) 
 
Regional lymph nodes (N): 
• NX: Regional lymph nodes cannot be assessed (e.g., previously removed) 
• N0: No regional lymph node metastases 
• N1: Metastases to movable ipsilateral level I, II axillary lymph node(s). 
• N1mi: Micrometastases (>0.2 mm and/or >200 cells but none >2.0 mm). 
• N2: Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or 
matted OR Metastases in clinically detected ipsilateral internal mammary nodes in the 
absence of clinically evident axillary lymph node metastases. 
• N3: Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or 
without level I, II axillary lymph node involvement OR Metastases in clinically 
detected ipsilateral internal mammary lymph node(s) with clinically evident level I, II 
axillary lymph node metastases OR Metastases in ipsilateral supraclavicular lymph 
node(s) with or without axillary or internal mammary lymph node involvement. 
Distant metastasis (M): 
• MX: Presence of distant metastases cannot be assessed. 
• M0: No clinical or radiographic evidence of distant metastases. No distant metastasis 
• M1: Distant detectable metastases as determined by classic clinical and radiographic 
means and/or histologically proven >0.2 mm. 


Niraparib 
 
TESARO, Inc. 
Protocol No.  3000-01-005  
Statistical Analysis Plan 
02/11/2019 
 
 
Confidential 
Page 37 
 
 
Appendix D. AJCC Stage Groupings 
Stage TNM 
• Stage 0    
Tis, N0, M0 
• Stage I   
 
T1, N0, M0 / T0 or T1, N1mi, M0 
• Stage IIA  
T0 or T1, N1 (but not N1mi), M0 / T2, N0, M0 
• Stage IIB  
T2, N1, M0 / T3, N0, M0 
• Stage IIIA  
T0 to T2, N2, M0 / T3, N1 or N2, M0 
• Stage IIIB  
T4, N0 to N2, M0 
• Stage IIIC  
any T, N3, M0 
• Stage IV  
any T, any N, M1 
• UNKNOWN Unknown