BRAVO: A Phase III Trial of Niraparib Versus Physician's Choice in HER2 Negative, Germline BRCA Mutation-positive Breast Cancer Patients

• Sponsor: Tesaro, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01905592
• Collaborator: European Organisation for Research and Treatment of Cancer - EORTC (Other), Breast International Group (Other), Myriad Genetic Laboratories, Inc. (Industry), US Oncology Research (Industry), Sarah Cannon (Industry), Facing Our Risk of Cancer Empowered (Other)
• Enrollment: 215
• Locations: 104
• Arms: 2
• Actual Duration (Months): 92
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Neoplasms, Breast; Carcinoma of Breast; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; BRCA1 Gene Mutation; BRCA2 Gene Mutation; Ovarian Neoplasms	Drug: niraparib; Drug: Physician's choice	Phase 3

Detailed Description

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 215 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomization will be 2:1 (treatment:control) in at least 215 patients with germline BRCA mutations.Randomization will be 2:1 (treatment:control) in at least 215 patients with germline BRCA mutations.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Open Label, Multicenter, Controlled Trial of Niraparib Versus Physician's Choice in Previously-treated, HER2 Negative, Germline BRCA Mutation-positive Breast Cancer Patients
• Actual Study Start Date: Feb 25, 2014
• Actual Primary Completion Date: May 23, 2018
• Actual Study Completion Date: Oct 26, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Physician's choice Physician may select from 4 active comparators	Drug: Physician's choice; Choice of 4 standard of care metastatic breast cancer chemotherapies, until progression or unacceptable toxicity develops
Experimental: niraparib Patients will be randomized 2:1 to receive niraparib 300 mg (3x100 mg capsules) once daily for 21 continuous days	Drug: niraparib; 300 mg (3x100 mg capsules) once daily until progression or unacceptable toxicity develops; Other Names: formerly MK-4827

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) - Central Review Assessment [From the date of randomization to the date of disease progression or death due to any cause, whichever occurs earlier, up to 4 years]

   The primary objective of this study is to compare progression-free survival (PFS), as assessed by blinded central review, of patients with advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gBRCAmut breast cancer when treated with niraparib as compared to those treated with physician's choice single agent chemotherapy standards (eribulin, vinorelbine, gemcitabine or capecitabine). PFS is defined as the date of randomization to the date of disease progression or death due to any cause, whichever occurs earlier as per Response evaluation criteria in solid tumors (RECIST) version 1.1 as determined by central review assessment.

Secondary Outcome Measures

1. Overall Survival [From treatment randomization to date of death of any cause, up to 4 years]

   To compare overall survival of patients with advanced/metastatic HER2-negative gBRCAmut breast cancer who have a gBRCAmut when treated with niraparib as compared to those treated with physician's choice. Overall Survival (OS) is defined as the time from randomization to the date of death of any causes.

2. Determine Concordance Between gBRCAmut Tests for the Purpose of Developing a Commercial Companion Diagnostic Test [End of study]

   To establish germline BRCA (gBRCA) mutation status of screened patients using a centrally provided, validated test as well as future tests, and determine concordance between tests for the purpose of developing a commercial companion diagnostic test. The concordance of the candidate companion diagnostic test with the centralized gBRCA mutation test with respect to identifying gBRCA mutated patients will be evaluated using a separate blood sample. The sensitivity and specificity of the companion diagnostic test to the centralized validated test with respect to gBRCA status will be determined along with the corresponding 95% confidence intervals.

3. Safety and Tolerability [End of Study]

   To evaluate safety and tolerability as measured by all adverse events (AEs). Safety and tolerability will be described using frequency of AEs and AEs of Common Terminology Criteria for Adverse Events (CTCAE) grade >=3. Safety analyses will include all patients who have received at least one dose of study drug and will be evaluated descriptively.

4. Progression Free Survival (PFS) - Investigator Assessment [Assessed up to 4 years]

   PFS is defined as the date of randomization to the date of disease progression or death due to any cause, whichever occurs earlier as per RECIST version 1.1 as determined by Investigator assessment.

5. Time to Treatment Failure [Date of randomization to discontinuation of treatment for any reason, up to 4 years]

   To evaluate time to treatment failure (discontinuation of treatment for any reason). Time to treatment failure is defined from the date of randomization to progression or discontinuation of treatment for any reason, including but not restricted to disease progression, treatment toxicity, and death. If progressive disease occurred earlier than treatment discontinuation, the date of progressive disease was considered the date of treatment failure. At the time of analysis, patients who were continuing to receive treatment were censored on the date of last contact.

6. Response Rate and Duration of Response [End of Study]

   To compare response rate and duration of response. The best response (complete response [CR], partial response [PR], stable disease [SD] or disease progression [PD]) for each patient will be summarized by treatment arm. The overall response rate (ORR) (ORR = CR+PR) will be summarized by treatment arm along with the corresponding exact 2-sided 95% confidence interval. A chi-square test will be used to compare ORR between the treatment arms. Duration of response will be summarized for the subgroup of patients that obtained objective response (CR or PR) using the Kaplan-Meier method and be displayed graphically where appropriate. The median duration and 2-sided 95% confidence interval for the median will be provided for each treatment arm.

7. To Compare Time to Deterioration of Health-related Quality of Life: QLQ-C30 and EQ-5D-5L [13 months]

   To compare time to deterioration of health-related quality of life (HRQoL): European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and EuroQol 5 Dimension 5 Level (EQ-5D-5L). Patient reported outcomes were collected via questionnaires (EORTC QLQ-C30 and EQ-5D-5L). These had to be completed within 4 weeks prior to randomization and subsequent questionnaires were filled in every 2 cycles (ie. 6 weeks) while on-treatment and every 3 months while in follow- up. Collection of HRQoL data was limited to the first 12 months after randomization. The primary HRQoL endpoint considered relevant for this study is time to HRQoL deterioration (TTQ). TTQ is defined as the time from randomization to death, progression or clinical relevant deterioration in pre-specified QLQ-C30 scales. Patients who had not experienced an event at the time of analysis were censored at the time of the last completed HRQoL assessment.

8. Subsequent Therapies and Potential Relationships With Outcomes [End of Study]

   To describe subsequent therapies and potential relationships with outcomes

9. Assess Genetic and Non-genetic Biomarkers [End of Study]

   To assess genetic and non-genetic biomarkers relating to treatment efficacy. Germline and tumor mutations may be explored including somatic BRCA1 and 2 mutations, reversion mutations, loss of heterozygosity as well as genome landscape and transcriptional or functional measures of homologous recombination (HR) deficiency.

10. Assess Outcomes by Germline Mutation BRCA1 vs BRCA2 [End of Study]

    To assess outcomes by germline mutation BRCA1 vs BRCA2

11. Post-treatment Data [End of Study]

    Descriptive summary statistics will be used to summarize post- treatment data (.i.e subsequent anticancer therapies and any new malignancy)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Germline BRCA1 or BRCA2 mutation; patients with unknown BRCA status who meet NCCN BRCA screening criteria will be screened for BRCA mutation.

2. Histologically or cytologically confirmed HER2-negative metastatic or locally advanced disease that is not amenable to resection or radiation with curative intent.

3. Up to 2 prior cytotoxic regimens for advanced or metastatic breast cancer; patients with no prior cytotoxic regimens for advanced or metastatic disease will only be allowed if they relapsed during or within 12 months of (neo-) adjuvant cytotoxic therapy.

4. Prior therapy should have included a taxane and/or anthracycline (unless contraindication to those) in the neoadjuvant, adjuvant, or advanced/metastatic setting.

1. Hormone receptor positive patients must also have hormone resistant disease; either relapsed while on adjuvant endocrine treatment, or within one year of completing adjuvant endocrine treatment, or progression on at least one line of endocrine treatment for advanced cancer.

1. ECOG performance status 0-2

2. Adequate bone marrow, kidney and liver function

Exclusion Criteria:

1. Patients with platinum resistant cancer

2. Symptomatic uncontrolled brain metastases

3. Prior diagnosis of Stage IV ovarian cancer; Stage III ovarian cancer must have a 5-year disease-free interval; Stage II ovarian cancer must have a 2-year disease-free interval

4. Known hypersensitivity to the components of niraparib

5. Invasive cancer other than breast cancer within 2 years (except basal or squamous cell carcinoma of the skin that has been definitely treated)

6. Pregnant or breast feeding patients

7. Immunocompromised patients

8. Known active Hepatitis B or C

9. Prior treatment with a PARP inhibitor

10. Known history of myelodysplastic syndrome (MDS).

11. known and persistent (>4 weeks) >/= grade 3 toxicity or fatigue from prior cancer treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Tucson	Arizona	United States	85710
2	GSK Investigational Site	Los Angeles	California	United States	90033
3	GSK Investigational Site	Los Angeles	California	United States	90048
4	GSK Investigational Site	Fort Myers	Florida	United States	33901
5	GSK Investigational Site	Miami	Florida	United States	33176
6	GSK Investigational Site	Boston	Massachusetts	United States	02111
7	GSK Investigational Site	Omaha	Nebraska	United States	68114
8	GSK Investigational Site	Henderson	Nevada	United States	89074
9	GSK Investigational Site	Clifton Park	New York	United States	12065
10	GSK Investigational Site	Lake Success	New York	United States	11042
11	GSK Investigational Site	Cleveland	Ohio	United States	44195
12	GSK Investigational Site	Eugene	Oregon	United States	97401
13	GSK Investigational Site	Portland	Oregon	United States	97225
14	GSK Investigational Site	Philadelphia	Pennsylvania	United States	19111
15	GSK Investigational Site	Nashville	Tennessee	United States	37203-1625
16	GSK Investigational Site	Nashville	Tennessee	United States	37232
17	GSK Investigational Site	Dallas	Texas	United States	75237
18	GSK Investigational Site	Fort Worth	Texas	United States	76104
19	GSK Investigational Site	San Antonio	Texas	United States	78217
20	GSK Investigational Site	Webster	Texas	United States	77598
21	GSK Investigational Site	Weslaco	Texas	United States	78596
22	GSK Investigational Site	Low Moor	Virginia	United States	24457
23	GSK Investigational Site	Everett	Washington	United States	98201
24	GSK Investigational Site	Seattle	Washington	United States	98111
25	GSK Investigational Site	Green Bay	Wisconsin	United States	54311
26	GSK Investigational Site	Aalst		Belgium	9300
27	GSK Investigational Site	Brussels		Belgium	1200
28	GSK Investigational Site	Bruxelles		Belgium	1000
29	GSK Investigational Site	Edegem		Belgium	2650
30	GSK Investigational Site	Liège		Belgium	4000
31	GSK Investigational Site	Namur		Belgium	5000
32	GSK Investigational Site	Calgary	Alberta	Canada	T2N 4N2
33	GSK Investigational Site	Kelowna	British Columbia	Canada	V1Y 5L3
34	GSK Investigational Site	Toronto	Ontario	Canada	M5G 2M9
35	GSK Investigational Site	Montreal	Quebec	Canada	H2L 4M1
36	GSK Investigational Site	Bordeaux		France	33076
37	GSK Investigational Site	Dijon Cedex		France	21079
38	GSK Investigational Site	Lille Cedex		France	59020
39	GSK Investigational Site	Lyon Cedex 08		France	69373
40	GSK Investigational Site	Montpellier		France	34298
41	GSK Investigational Site	Nantes cedex		France	44202
42	GSK Investigational Site	Paris Cedex 5		France	75248
43	GSK Investigational Site	Saint-Cloud		France	92210
44	GSK Investigational Site	Heraklion,Crete		Greece	71110
45	GSK Investigational Site	Maroussi		Greece	15123
46	GSK Investigational Site	Nea Kifissia		Greece	14564
47	GSK Investigational Site	Neo Faliro		Greece	18547
48	GSK Investigational Site	Thessaloniki		Greece	57001
49	GSK Investigational Site	Budapest		Hungary	1122
50	GSK Investigational Site	Debrecen		Hungary	4032
51	GSK Investigational Site	Miskolc		Hungary	3501
52	GSK Investigational Site	Nyiregyhaza		Hungary	4400
53	GSK Investigational Site	Pécs		Hungary	7624
54	GSK Investigational Site	Szeged		Hungary	6720
55	GSK Investigational Site	Reykjavik		Iceland	IS-101
56	GSK Investigational Site	Haifa		Israel	3109601
57	GSK Investigational Site	Holon		Israel	58100
58	GSK Investigational Site	Kfar-Saba		Israel	44281
59	GSK Investigational Site	Rehovot		Israel	76100
60	GSK Investigational Site	Tel Aviv		Israel	6423906
61	GSK Investigational Site	Tel Hashomer		Israel	52621
62	GSK Investigational Site	Meldola (FC)	Emilia-Romagna	Italy	47014
63	GSK Investigational Site	Parma	Emilia-Romagna	Italy	43100
64	GSK Investigational Site	Rimini	Emilia-Romagna	Italy	47900
65	GSK Investigational Site	Viterbo	Lazio	Italy	01100
66	GSK Investigational Site	Genova	Liguria	Italy	16132
67	GSK Investigational Site	Cremona	Lombardia	Italy	26100
68	GSK Investigational Site	Milano	Lombardia	Italy	20141
69	GSK Investigational Site	Ancona	Marche	Italy	60020
70	GSK Investigational Site	Lecce	Puglia	Italy	73100
71	GSK Investigational Site	Prato	Toscana	Italy	59100
72	GSK Investigational Site	Legnago (VR)	Veneto	Italy	37045
73	GSK Investigational Site	Leiden, RC		Netherlands	2333 ZA
74	GSK Investigational Site	Limburg		Netherlands	6229HX
75	GSK Investigational Site	Zwolle		Netherlands	8025 AB
76	GSK Investigational Site	Lodz		Poland	93-513
77	GSK Investigational Site	Raciborz		Poland	47-400
78	GSK Investigational Site	Coimbra		Portugal	3000-075
79	GSK Investigational Site	Lisbon		Portugal	1400-038
80	GSK Investigational Site	Porto		Portugal	4200-072
81	GSK Investigational Site	Barcelona		Spain	8035
82	GSK Investigational Site	Burgos		Spain	09005
83	GSK Investigational Site	Cáceres		Spain	10003
84	GSK Investigational Site	L'Hospitalet de Llobregat		Spain	8907
85	GSK Investigational Site	Lerida		Spain	25198
86	GSK Investigational Site	Lugo		Spain	27003
87	GSK Investigational Site	Madrid		Spain	28041
88	GSK Investigational Site	Pamplona		Spain	31008
89	GSK Investigational Site	Valencia		Spain	46009
90	GSK Investigational Site	Valencia		Spain	46015
91	GSK Investigational Site	Vigo		Spain	36312
92	GSK Investigational Site	Southampton	Hampshire	United Kingdom	SO16 6YD
93	GSK Investigational Site	Northwood	Middlesex	United Kingdom	HA6 2RN
94	GSK Investigational Site	Headington, Oxford	Oxfordshire	United Kingdom	OX3 7LJ
95	GSK Investigational Site	Sutton	Surrey	United Kingdom	SM2 5PT
96	GSK Investigational Site	Bebington, Wirral		United Kingdom	CH63 4JY
97	GSK Investigational Site	Belfast		United Kingdom	BT9 7AB
98	GSK Investigational Site	Edinburgh		United Kingdom	EH4 2XU
99	GSK Investigational Site	Glasgow		United Kingdom	G11 6NT
100	GSK Investigational Site	London		United Kingdom	NW1 2PG
101	GSK Investigational Site	London		United Kingdom	SE1 9RT
102	GSK Investigational Site	London		United Kingdom	SW3 6JJ
103	GSK Investigational Site	Nottingham		United Kingdom	NG5 1PB
104	GSK Investigational Site	Whitchurch, Cardiff		United Kingdom	CF14 2TL

Sponsors and Collaborators

• Tesaro, Inc.
• European Organisation for Research and Treatment of Cancer - EORTC
• Breast International Group
• Myriad Genetic Laboratories, Inc.
• US Oncology Research
• Sarah Cannon
• Facing Our Risk of Cancer Empowered

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Jan 13, 2017
• Statistical Analysis Plan - Jan 24, 2017

More Information

Additional Information:

• Facing our risk of cancer empowered website

Publications

None provided.

• Responsible Party: Tesaro, Inc.
• ClinicalTrials.gov Identifier: NCT01905592
• Other Study ID Numbers: 213551; 1307-BCG, BIG5-13; PR-30-5010-C
• First Posted: Jul 23, 2013
• Last Update Posted: Nov 5, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Keywords provided by Tesaro, Inc.: Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; BRCA1 Gene Mutation; BRCA2 Gene Mutation; PARP Inhibitor; BRCA
• Additional relevant MeSH terms: Carcinoma; Neoplasms; Ovarian Neoplasms; Breast Neoplasms; Niraparib

Study Results

Participant Flow

Recruitment Details	Previously treated, HER2 negative, germline BRCA mutation positive breast cancer patients were enrolled. The study was designed to randomize 306 patients, however enrollment was ended prematurely due to futility. Results are presented based on the primary analysis (data assessed from enrollment to end of follow-up, up to a maximum of 4 years).
Pre-assignment Detail	Of the 215 patients enrolled, 9 patients enrolled based on a local Breast Cancer gene (BRCA) test results were later determined to be BRCA wild type by central testing. Therefore, only 206 of the 215 patients enrolled were included in the analysis, and were considered in centrally confirmed intent-to-treat (ITT) population.

Arm/Group Title	Physician's Choice	Niraparib
Arm/Group Description	Physician selection from 4 standard of care metastatic breast cancer chemotherapies (eribulin or vinorelbine or gemcitabine or capecitabine), until progression or unacceptable toxicity develops.	Niraparib 300 milligram (mg) (3x100 mg capsules) once daily until progression or unacceptable toxicity develops
Period Title: Overall Study
STARTED	71	135
COMPLETED	0	0
NOT COMPLETED	71	135

Baseline Characteristics

Arm/Group Title	Physician's Choice	Niraparib	Total
Arm/Group Description	Physician selection from 4 standard of care metastatic breast cancer chemotherapies (eribulin or vinorelbine or gemcitabine or capecitabine), until progression or unacceptable toxicity develops.	Niraparib 300 mg (3x100 mg capsules) once daily until progression or unacceptable toxicity develops	Total of all reporting groups
Overall Participants	71	135	206
Age, Customized (Count of Participants)
18-64	67 94.4%	127 94.1%	194 94.2%
65-74	3 4.2%	5 3.7%	8 3.9%
>=75	1 1.4%	3 2.2%	4 1.9%
Sex: Female, Male (Count of Participants)
Female	68 95.8%	135 100%	203 98.5%
Male	3 4.2%	0 0%	3 1.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 8.5%	6 4.4%	12 5.8%
Not Hispanic or Latino	50 70.4%	110 81.5%	160 77.7%
Unknown or Not Reported	15 21.1%	19 14.1%	34 16.5%
Race/Ethnicity, Customized (Count of Participants)
Ashkenazi Jewish descendant	6 8.5%	5 3.7%	11 5.3%
White or Caucasian	59 83.1%	108 80%	167 81.1%
Black	3 4.2%	6 4.4%	9 4.4%
Asian	0 0%	2 1.5%	2 1%
Other	0 0%	4 3%	4 1.9%
Unknown	1 1.4%	3 2.2%	4 1.9%
Missing	2 2.8%	7 5.2%	9 4.4%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) - Central Review Assessment
Description	The primary objective of this study is to compare progression-free survival (PFS), as assessed by blinded central review, of patients with advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gBRCAmut breast cancer when treated with niraparib as compared to those treated with physician's choice single agent chemotherapy standards (eribulin, vinorelbine, gemcitabine or capecitabine). PFS is defined as the date of randomization to the date of disease progression or death due to any cause, whichever occurs earlier as per Response evaluation criteria in solid tumors (RECIST) version 1.1 as determined by central review assessment.
Time Frame	From the date of randomization to the date of disease progression or death due to any cause, whichever occurs earlier, up to 4 years

Outcome Measure Data

Analysis Population Description

The intent-to-treat population is defined as all randomized patients with a central confirmation of germline BRCA mutation.

Arm/Group Title	Physician's Choice	Niraparib
Arm/Group Description	Physician selection from 4 standard of care metastatic breast cancer chemotherapies (eribulin or vinorelbine or gemcitabine or capecitabine), until progression or unacceptable toxicity develops.	Niraparib 300 mg (3x100 mg capsules) once daily until progression or unacceptable toxicity develops
Measure Participants	71	135
Median (95% Confidence Interval) [months]	3.1	4.1

2. Secondary Outcome

Title	Overall Survival
Description	To compare overall survival of patients with advanced/metastatic HER2-negative gBRCAmut breast cancer who have a gBRCAmut when treated with niraparib as compared to those treated with physician's choice. Overall Survival (OS) is defined as the time from randomization to the date of death of any causes.
Time Frame	From treatment randomization to date of death of any cause, up to 4 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat Population.

Arm/Group Title	Physician's Choice	Niraparib
Arm/Group Description	Physician selection from 4 standard of care metastatic breast cancer chemotherapies (eribulin or vinorelbine or gemcitabine or capecitabine), until progression or unacceptable toxicity develops.	Niraparib 300 mg (3x100 mg capsules) once daily until progression or unacceptable toxicity develops
Measure Participants	71	135
Median (95% Confidence Interval) [months]	15.8	14.5

3. Secondary Outcome

Title	Determine Concordance Between gBRCAmut Tests for the Purpose of Developing a Commercial Companion Diagnostic Test
Description	To establish germline BRCA (gBRCA) mutation status of screened patients using a centrally provided, validated test as well as future tests, and determine concordance between tests for the purpose of developing a commercial companion diagnostic test. The concordance of the candidate companion diagnostic test with the centralized gBRCA mutation test with respect to identifying gBRCA mutated patients will be evaluated using a separate blood sample. The sensitivity and specificity of the companion diagnostic test to the centralized validated test with respect to gBRCA status will be determined along with the corresponding 95% confidence intervals.
Time Frame	End of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Safety and Tolerability
Description	To evaluate safety and tolerability as measured by all adverse events (AEs). Safety and tolerability will be described using frequency of AEs and AEs of Common Terminology Criteria for Adverse Events (CTCAE) grade >=3. Safety analyses will include all patients who have received at least one dose of study drug and will be evaluated descriptively.
Time Frame	End of Study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Progression Free Survival (PFS) - Investigator Assessment
Description	PFS is defined as the date of randomization to the date of disease progression or death due to any cause, whichever occurs earlier as per RECIST version 1.1 as determined by Investigator assessment.
Time Frame	Assessed up to 4 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat Population.

Arm/Group Title	Physician's Choice	Niraparib
Arm/Group Description	Physician selection from 4 standard of care metastatic breast cancer chemotherapies (eribulin or vinorelbine or gemcitabine or capecitabine), until progression or unacceptable toxicity develops.	Niraparib 300 mg (3x100 mg capsules) once daily until progression or unacceptable toxicity develops
Measure Participants	71	135
Median (95% Confidence Interval) [months]	3.1	5.0

6. Secondary Outcome

Title	Time to Treatment Failure
Description	To evaluate time to treatment failure (discontinuation of treatment for any reason). Time to treatment failure is defined from the date of randomization to progression or discontinuation of treatment for any reason, including but not restricted to disease progression, treatment toxicity, and death. If progressive disease occurred earlier than treatment discontinuation, the date of progressive disease was considered the date of treatment failure. At the time of analysis, patients who were continuing to receive treatment were censored on the date of last contact.
Time Frame	Date of randomization to discontinuation of treatment for any reason, up to 4 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat Population.

Arm/Group Title	Physician's Choice	Niraparib
Arm/Group Description	Physician selection from 4 standard of care metastatic breast cancer chemotherapies (eribulin or vinorelbine or gemcitabine or capecitabine), until progression or unacceptable toxicity develops.	Niraparib 300 mg (3x100 mg capsules) once daily until progression or unacceptable toxicity develops
Measure Participants	71	135
Median (95% Confidence Interval) [months]	2.6	4.3

7. Secondary Outcome

Title	Response Rate and Duration of Response
Description	To compare response rate and duration of response. The best response (complete response [CR], partial response [PR], stable disease [SD] or disease progression [PD]) for each patient will be summarized by treatment arm. The overall response rate (ORR) (ORR = CR+PR) will be summarized by treatment arm along with the corresponding exact 2-sided 95% confidence interval. A chi-square test will be used to compare ORR between the treatment arms. Duration of response will be summarized for the subgroup of patients that obtained objective response (CR or PR) using the Kaplan-Meier method and be displayed graphically where appropriate. The median duration and 2-sided 95% confidence interval for the median will be provided for each treatment arm.
Time Frame	End of Study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	To Compare Time to Deterioration of Health-related Quality of Life: QLQ-C30 and EQ-5D-5L
Description	To compare time to deterioration of health-related quality of life (HRQoL): European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and EuroQol 5 Dimension 5 Level (EQ-5D-5L). Patient reported outcomes were collected via questionnaires (EORTC QLQ-C30 and EQ-5D-5L). These had to be completed within 4 weeks prior to randomization and subsequent questionnaires were filled in every 2 cycles (ie. 6 weeks) while on-treatment and every 3 months while in follow- up. Collection of HRQoL data was limited to the first 12 months after randomization. The primary HRQoL endpoint considered relevant for this study is time to HRQoL deterioration (TTQ). TTQ is defined as the time from randomization to death, progression or clinical relevant deterioration in pre-specified QLQ-C30 scales. Patients who had not experienced an event at the time of analysis were censored at the time of the last completed HRQoL assessment.
Time Frame	13 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Subsequent Therapies and Potential Relationships With Outcomes
Description	To describe subsequent therapies and potential relationships with outcomes
Time Frame	End of Study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Assess Genetic and Non-genetic Biomarkers
Description	To assess genetic and non-genetic biomarkers relating to treatment efficacy. Germline and tumor mutations may be explored including somatic BRCA1 and 2 mutations, reversion mutations, loss of heterozygosity as well as genome landscape and transcriptional or functional measures of homologous recombination (HR) deficiency.
Time Frame	End of Study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Assess Outcomes by Germline Mutation BRCA1 vs BRCA2
Description	To assess outcomes by germline mutation BRCA1 vs BRCA2
Time Frame	End of Study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Post-treatment Data
Description	Descriptive summary statistics will be used to summarize post- treatment data (.i.e subsequent anticancer therapies and any new malignancy)
Time Frame	End of Study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 4 years
Adverse Event Reporting Description	Safety analyses included all patients who have received at least one dose of study drug.
Arm/Group Title	Physician's Choice		Niraparib
Arm/Group Description	Physician selection from 4 standard of care metastatic breast cancer chemotherapies (eribulin or vinorelbine or gemcitabine or capecitabine), until progression or unacceptable toxicity develops.		Niraparib 300 mg (3x100 mg capsules) once daily until progression or unacceptable toxicity develops
All Cause Mortality
	Physician's Choice		Niraparib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/65 (60%)		79/134 (59%)
Serious Adverse Events
	Physician's Choice		Niraparib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/65 (6.2%)		33/134 (24.6%)
Blood and lymphatic system disorders
Thrombocytopenia	0/65 (0%)		10/134 (7.5%)
Anaemia	0/65 (0%)		9/134 (6.7%)
Febrile neutropenia	0/65 (0%)		1/134 (0.7%)
Leukopenia	0/65 (0%)		1/134 (0.7%)
Neutropenia	0/65 (0%)		1/134 (0.7%)
Cardiac disorders
Pericardial effusion	0/65 (0%)		1/134 (0.7%)
Tachycardia	0/65 (0%)		1/134 (0.7%)
Gastrointestinal disorders
Nausea	0/65 (0%)		5/134 (3.7%)
Vomiting	1/65 (1.5%)		3/134 (2.2%)
Constipation	0/65 (0%)		2/134 (1.5%)
Abdominal pain	0/65 (0%)		1/134 (0.7%)
Diarrhoea	0/65 (0%)		1/134 (0.7%)
Proctalgia	0/65 (0%)		1/134 (0.7%)
General disorders
Pain	1/65 (1.5%)		1/134 (0.7%)
Pyrexia	1/65 (1.5%)		1/134 (0.7%)
Asthenia	0/65 (0%)		1/134 (0.7%)
Fatique	0/65 (0%)		1/134 (0.7%)
Malaise	0/65 (0%)		1/134 (0.7%)
Infections and infestations
Pneumonia	0/65 (0%)		2/134 (1.5%)
Sepsis	0/65 (0%)		2/134 (1.5%)
Cellulitis	0/65 (0%)		1/134 (0.7%)
Lower respiratory tract infection	0/65 (0%)		1/134 (0.7%)
Lung infection	0/65 (0%)		1/134 (0.7%)
Pyelonephritis	0/65 (0%)		1/134 (0.7%)
Upper respiratory tract infection	0/65 (0%)		1/134 (0.7%)
Urinary tract infection	0/65 (0%)		1/134 (0.7%)
Injury, poisoning and procedural complications
Accidental overdose	0/65 (0%)		1/134 (0.7%)
Investigations
Platelet count decreased	0/65 (0%)		2/134 (1.5%)
Electrocardiogram ST segment depression	0/65 (0%)		1/134 (0.7%)
Metabolism and nutrition disorders
Hypercalcaemia	0/65 (0%)		1/134 (0.7%)
Musculoskeletal and connective tissue disorders
Back pain	0/65 (0%)		1/134 (0.7%)
Joint range of motion decreased	1/65 (1.5%)		0/134 (0%)
Nervous system disorders
Headache	1/65 (1.5%)		3/134 (2.2%)
Dizziness	0/65 (0%)		1/134 (0.7%)
Hypoaesthesia	0/65 (0%)		1/134 (0.7%)
Language disorder	1/65 (1.5%)		0/134 (0%)
Syncope	0/65 (0%)		1/134 (0.7%)
Renal and urinary disorders
Acute kidney injury	1/65 (1.5%)		0/134 (0%)
Micturition disorder	1/65 (1.5%)		0/134 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/65 (0%)		1/134 (0.7%)
Pleurisy	0/65 (0%)		1/134 (0.7%)
Pleuritic pain	0/65 (0%)		1/134 (0.7%)
Respiratory failure	0/65 (0%)		1/134 (0.7%)
Vascular disorders
Deep vein thrombosis	0/65 (0%)		1/134 (0.7%)
Hypotension	0/65 (0%)		1/134 (0.7%)
Other (Not Including Serious) Adverse Events
	Physician's Choice		Niraparib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/65 (96.9%)		134/134 (100%)
Blood and lymphatic system disorders
Anaemia	23/65 (35.4%)		90/134 (67.2%)
Nausea	24/65 (36.9%)		81/134 (60.4%)
Thrombocytopenia	4/65 (6.2%)		48/134 (35.8%)
Neutropenia	19/65 (29.2%)		26/134 (19.4%)
Leukopenia	9/65 (13.8%)		11/134 (8.2%)
Cardiac disorders
Tachycardia	2/65 (3.1%)		11/134 (8.2%)
Gastrointestinal disorders
Vomiting	11/65 (16.9%)		49/134 (36.6%)
Constipation	11/65 (16.9%)		48/134 (35.8%)
Diarrhoea	22/65 (33.8%)		19/134 (14.2%)
Abdominal pain	10/65 (15.4%)		15/134 (11.2%)
Abdominal pain upper	3/65 (4.6%)		17/134 (12.7%)
Stomatitis	5/65 (7.7%)		15/134 (11.2%)
Dry mouth	5/65 (7.7%)		6/134 (4.5%)
Dyspepsia	1/65 (1.5%)		9/134 (6.7%)
General disorders
Fatigue	29/65 (44.6%)		66/134 (49.3%)
Asthenia	9/65 (13.8%)		23/134 (17.2%)
Dizziness	6/65 (9.2%)		27/134 (20.1%)
Insomnia	5/65 (7.7%)		24/134 (17.9%)
Pyrexia	4/65 (6.2%)		15/134 (11.2%)
Oedema peripheral	6/65 (9.2%)		9/134 (6.7%)
Palmar-plantar erythrodysaesthesia syndrome	12/65 (18.5%)		0/134 (0%)
Infections and infestations
Viral upper respiratory tract infection	3/65 (4.6%)		11/134 (8.2%)
Upper respiratory tract infection	4/65 (6.2%)		9/134 (6.7%)
Urinary tract infection	4/65 (6.2%)		7/134 (5.2%)
Influenza like illness	2/65 (3.1%)		8/134 (6%)
Investigations
Weight decreased	10/65 (15.4%)		53/134 (39.6%)
Platelet count decreased	3/65 (4.6%)		43/134 (32.1%)
Neutrophil count decreased	10/65 (15.4%)		26/134 (19.4%)
White blood cell count decreased	5/65 (7.7%)		31/134 (23.1%)
Alanine aminotransferase increased	7/65 (10.8%)		18/134 (13.4%)
Gamma-glutamyltransferase increased	7/65 (10.8%)		17/134 (12.7%)
Blood alkaline phosphatase increased	5/65 (7.7%)		15/134 (11.2%)
Aspartate aminotransferase increased	5/65 (7.7%)		13/134 (9.7%)
Lymphocyte count decreased	4/65 (6.2%)		9/134 (6.7%)
Weight increased	7/65 (10.8%)		4/134 (3%)
Metabolism and nutrition disorders
Decreased appetite	7/65 (10.8%)		41/134 (30.6%)
Musculoskeletal and connective tissue disorders
Back pain	7/65 (10.8%)		30/134 (22.4%)
Pain in extremity	4/65 (6.2%)		19/134 (14.2%)
Arthralgia	8/65 (12.3%)		9/134 (6.7%)
Bone pain	5/65 (7.7%)		9/134 (6.7%)
Musculoskeletal pain	4/65 (6.2%)		9/134 (6.7%)
Neck pain	3/65 (4.6%)		10/134 (7.5%)
Musculoskeletal chest pain	4/65 (6.2%)		7/134 (5.2%)
Myalgia	5/65 (7.7%)		6/134 (4.5%)
Nervous system disorders
Headache	10/65 (15.4%)		45/134 (33.6%)
Dysgeusia	5/65 (7.7%)		10/134 (7.5%)
Paraesthesia	6/65 (9.2%)		4/134 (3%)
Psychiatric disorders
Anxiety	8/65 (12.3%)		18/134 (13.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	8/65 (12.3%)		25/134 (18.7%)
Cough	5/65 (7.7%)		15/134 (11.2%)
Epistaxis	2/65 (3.1%)		10/134 (7.5%)
Skin and subcutaneous tissue disorders
Alopecia	7/65 (10.8%)		3/134 (2.2%)
Vascular disorders
Hypertension	1/65 (1.5%)		17/134 (12.7%)

Limitations/Caveats

IDMC interim analysis concluded that concerns with the quantity and quality of data in the control arm precluded meaningful comparative analyses and generation of a clinically useful endpoint, therefore enrollment was ended prematurely.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Neither Institution nor Investigator will submit for publication or public disclosure any publication or disclosure based on the results of the Study until after the first to occur of (a) publication of the Multi-Center Clinical Trial results; (b) notification by Sponsor that the Multi-Center Clinical Trial submission is no longer planned; or (c) the eighteen (18) month anniversary of the completion or early termination of the Multi-Center Clinical Trial.