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

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

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

Study Overview

• Status: Terminated
• Conditions: Ovarian Neoplasms; BRCA1 Gene Mutation; BRCA2 Gene Mutation; Neoplasms, Breast; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Carcinoma of Breast
• Intervention / Treatment: Drug: Physician's choice; Drug: niraparib

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 Type: Interventional
• Enrollment (Actual): 216
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Aalst, Belgium, 9300
    • GSK Investigational Site
  • Brussels, Belgium, 1200
    • GSK Investigational Site
  • Bruxelles, Belgium, 1000
    • GSK Investigational Site
  • Edegem, Belgium, 2650
    • GSK Investigational Site
  • Liège, Belgium, 4000
    • GSK Investigational Site
  • Namur, Belgium, 5000
    • GSK Investigational Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • GSK Investigational Site
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 5L3
      • GSK Investigational Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • GSK Investigational Site
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • GSK Investigational Site
• France
  • Bordeaux, France, 33076
    • GSK Investigational Site
  • Dijon Cedex, France, 21079
    • GSK Investigational Site
  • Lille Cedex, France, 59020
    • GSK Investigational Site
  • Lyon Cedex 08, France, 69373
    • GSK Investigational Site
  • Montpellier, France, 34298
    • GSK Investigational Site
  • Nantes cedex, France, 44202
    • GSK Investigational Site
  • Paris Cedex 5, France, 75248
    • GSK Investigational Site
  • Saint-Cloud, France, 92210
    • GSK Investigational Site
• Greece
  • Heraklion,Crete, Greece, 71110
    • GSK Investigational Site
  • Maroussi, Greece, 15123
    • GSK Investigational Site
  • Nea Kifissia, Greece, 14564
    • GSK Investigational Site
  • Neo Faliro, Greece, 18547
    • GSK Investigational Site
  • Thessaloniki, Greece, 57001
    • GSK Investigational Site
• Hungary
  • Budapest, Hungary, 1122
    • GSK Investigational Site
  • Debrecen, Hungary, 4032
    • GSK Investigational Site
  • Miskolc, Hungary, 3501
    • GSK Investigational Site
  • Nyiregyhaza, Hungary, 4400
    • GSK Investigational Site
  • Pécs, Hungary, 7624
    • GSK Investigational Site
  • Szeged, Hungary, 6720
    • GSK Investigational Site
• Iceland
  • Reykjavik, Iceland, IS-101
    • GSK Investigational Site
• Israel
  • Haifa, Israel, 3109601
    • GSK Investigational Site
  • Holon, Israel, 58100
    • GSK Investigational Site
  • Kfar-Saba, Israel, 44281
    • GSK Investigational Site
  • Rehovot, Israel, 76100
    • GSK Investigational Site
  • Tel Aviv, Israel, 6423906
    • GSK Investigational Site
  • Tel Hashomer, Israel, 52621
    • GSK Investigational Site
• Italy
  • Emilia-Romagna
    • Meldola (FC), Emilia-Romagna, Italy, 47014
      • GSK Investigational Site
    • Parma, Emilia-Romagna, Italy, 43100
      • GSK Investigational Site
    • Rimini, Emilia-Romagna, Italy, 47900
      • GSK Investigational Site
  • Lazio
    • Viterbo, Lazio, Italy, 01100
      • GSK Investigational Site
  • Liguria
    • Genova, Liguria, Italy, 16132
      • GSK Investigational Site
  • Lombardia
    • Cremona, Lombardia, Italy, 26100
      • GSK Investigational Site
    • Milano, Lombardia, Italy, 20141
      • GSK Investigational Site
  • Marche
    • Ancona, Marche, Italy, 60020
      • GSK Investigational Site
  • Puglia
    • Lecce, Puglia, Italy, 73100
      • GSK Investigational Site
  • Toscana
    • Prato, Toscana, Italy, 59100
      • GSK Investigational Site
  • Veneto
    • Legnago (VR), Veneto, Italy, 37045
      • GSK Investigational Site
• Netherlands
  • Leiden, RC, Netherlands, 2333 ZA
    • GSK Investigational Site
  • Limburg, Netherlands, 6229HX
    • GSK Investigational Site
  • Zwolle, Netherlands, 8025 AB
    • GSK Investigational Site
• Poland
  • Lodz, Poland, 93-513
    • GSK Investigational Site
  • Raciborz, Poland, 47-400
    • GSK Investigational Site
• Portugal
  • Coimbra, Portugal, 3000-075
    • GSK Investigational Site
  • Lisbon, Portugal, 1400-038
    • GSK Investigational Site
  • Porto, Portugal, 4200-072
    • GSK Investigational Site
• Spain
  • Barcelona, Spain, 8035
    • GSK Investigational Site
  • Burgos, Spain, 09005
    • GSK Investigational Site
  • Cáceres, Spain, 10003
    • GSK Investigational Site
  • L'Hospitalet de Llobregat, Spain, 8907
    • GSK Investigational Site
  • Lerida, Spain, 25198
    • GSK Investigational Site
  • Lugo, Spain, 27003
    • GSK Investigational Site
  • Madrid, Spain, 28041
    • GSK Investigational Site
  • Pamplona, Spain, 31008
    • GSK Investigational Site
  • Valencia, Spain, 46015
    • GSK Investigational Site
  • Valencia, Spain, 46009
    • GSK Investigational Site
  • Vigo, Spain, 36312
    • GSK Investigational Site
• United Kingdom
  • Bebington, Wirral, United Kingdom, CH63 4JY
    • GSK Investigational Site
  • Belfast, United Kingdom, BT9 7AB
    • GSK Investigational Site
  • Edinburgh, United Kingdom, EH4 2XU
    • GSK Investigational Site
  • Glasgow, United Kingdom, G11 6NT
    • GSK Investigational Site
  • London, United Kingdom, SE1 9RT
    • GSK Investigational Site
  • London, United Kingdom, NW1 2PG
    • GSK Investigational Site
  • London, United Kingdom, SW3 6JJ
    • GSK Investigational Site
  • Nottingham, United Kingdom, NG5 1PB
    • GSK Investigational Site
  • Whitchurch, Cardiff, United Kingdom, CF14 2TL
    • GSK Investigational Site
  • Hampshire
    • Southampton, Hampshire, United Kingdom, SO16 6YD
      • GSK Investigational Site
  • Middlesex
    • Northwood, Middlesex, United Kingdom, HA6 2RN
      • GSK Investigational Site
  • Oxfordshire
    • Headington, Oxford, Oxfordshire, United Kingdom, OX3 7LJ
      • GSK Investigational Site
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • GSK Investigational Site
• United States
  • Arizona
    • Tucson, Arizona, United States, 85710
      • GSK Investigational Site
  • California
    • Los Angeles, California, United States, 90048
      • GSK Investigational Site
    • Los Angeles, California, United States, 90033
      • GSK Investigational Site
  • Florida
    • Fort Myers, Florida, United States, 33901
      • GSK Investigational Site
    • Miami, Florida, United States, 33176
      • GSK Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • GSK Investigational Site
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • GSK Investigational Site
  • Nevada
    • Henderson, Nevada, United States, 89074
      • GSK Investigational Site
  • New York
    • Clifton Park, New York, United States, 12065
      • GSK Investigational Site
    • Lake Success, New York, United States, 11042
      • GSK Investigational Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • GSK Investigational Site
  • Oregon
    • Eugene, Oregon, United States, 97401
      • GSK Investigational Site
    • Portland, Oregon, United States, 97225
      • GSK Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • GSK Investigational Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • GSK Investigational Site
    • Nashville, Tennessee, United States, 37232
      • GSK Investigational Site
  • Texas
    • Dallas, Texas, United States, 75237
      • GSK Investigational Site
    • Fort Worth, Texas, United States, 76104
      • GSK Investigational Site
    • San Antonio, Texas, United States, 78217
      • GSK Investigational Site
    • Webster, Texas, United States, 77598
      • GSK Investigational Site
    • Weslaco, Texas, United States, 78596
      • GSK Investigational Site
  • Virginia
    • Low Moor, Virginia, United States, 24457
      • GSK Investigational Site
  • Washington
    • Everett, Washington, United States, 98201
      • GSK Investigational Site
    • Seattle, Washington, United States, 98111
      • GSK Investigational Site
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54311
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

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

5. ECOG performance status 0-2
6. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) - Central Review Assessment	The primary objective of this study is to compare progression-free survival (PFS), as assessed by blinded central review, of participants with advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gBRCA mutation 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 (v)1.1 as determined by central review assessment. Progressive Disease is defined as at least a 20 percent (%) increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including Baseline) and an absolute increase of >= 5 millimeter (mm).	From the date of randomization to the date of disease progression or death due to any cause, whichever occurs earlier, up to 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall Survival (OS) was defined as the time from randomization to the date of death of any causes.	From treatment randomization to date of death of any cause, up to 4 years
Number of Participants With Central BRCA Mutation Status	Blood samples were collected to evaluate central BRCA mutation status of participants. Baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug. Number of participants with central BRCA mutation status as BRCA1 positive only, BRCA2 positive only, Rearrangement only, BRCA1 and BRCA2 positive, BRCA1 positive and rearrangement, and BRCA2 positive and rearrangement were reported.	At Baseline (Cycle 1 Day1) (Cycle duration was 21 days)
Number of Participants With Serious Adverse Events (SAE) and Non-serious Adverse Events (Non-SAE)	An adverse event (AE) is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. An SAE is defined as any untoward medical occurrence or effect in a participant, whether or not considered related to the protocol treatment, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing participant hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an medically important event or reaction as per medical and scientific judgment. Adverse events which were not serious adverse events were considered as non serious adverse events.	Up to 7 years
Progression Free Survival (PFS) - Investigator Assessment	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. Progressive Disease is defined as at least a 20 % increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including Baseline) and an absolute increase of >= 5 mm.	Assessed up to 4 years
Time to Treatment Failure	Time to treatment failure was 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.	Date of randomization to discontinuation of treatment for any reason, up to 4 years
Overall Response Rate (ORR)	ORR was defined as the percentage of the participants who achieved a complete response (CR) or partial response (PR) to treatment evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete Response (CR)=disappearance of all target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures <10 mm. Partial Response (PR)= at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the Baseline sum of diameters. Percentage values are rounded off up to 1 decimal.	Up to 4 years
Duration of Response (DOR)	Duration of response was defined as the time from first documentation of response (confirmed CR or PR) until the time of first documentation of disease progression by RECIST v1.1 or death by any cause.	Up to 4 years
Number of Participants With Serious Adverse Events Related to New Malignancy	The number of participants with serious adverse events related to new malignancy were reported.	Up to 7 years
Number of Participants With Subsequent Anticancer Therapies	The number of participants with subsequent anticancer therapies were evaluated. Data has been reported as per following categories: any new anitumoral therapy, any chemotherapy, any radiotherapy, any surgery, any hormonal therapy, any targeted agents, and any other treatment. Participants may have received more than one subsequent therapies.	Up to 7 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Minimally Clinically Important Difference (MCID) Status in European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-C30 (EORTC-QLQ-C30)	The number of participants with MCID status in EORTC-QLQ-C30 was planned to be evaluated.The EORTC- QLQ-C30 includes 30-items with single and multi-item scales. These include five functional scales (physical functioning, role functioning cognitive functioning, emotional functioning and social functioning), three symptom scales (fatigue, pain and nausea/vomiting), a global health status (GHS)/ Quality-of-Life (QoL) scale, and six single items (constipation, diarrhea, insomnia, dyspnea, appetite loss and financial difficulties). Response options are 1 to 4. The average score can be transformed to 0 to 100, a high score for functional scales/ GHS/QoL represents better functioning ability or health-related quality-of-life (HRQoL), whereas a high score for symptom scales/ single items represents significant symptomatology.	Up to 7 years
Number of Participants With Euroqol 5 Dimension 5 Level (EQ-5D-5L) Dimension Scores by Visit	The number of participants with EQ-5D-5L scores by visit were planned to be evaluated. EQ-5D-5L is self-assessment questionnaire, consisting of 5 items covering 5 dimensions (mobility,self care, usual activities, pain/discomfort and anxiety/depression). Each dimension is measured by 5-point Likert scale(no problems, slight problems, moderate problems, severe problems and extreme problems). Responses for 5 dimensions together formed a 5-figure description of health state (e.g.11111 indicates no problems in all 5 dimensions). Each of these 5 figure health states were to be converted to a single index score. Range for EQ-5D-5L index score is 0 (worst health) to 100 (best health), higher the score better the health status.	Up to 7 years
Number of Participants With Any Subsequent Therapies Post Discontinuation of Study Treatment and Association With Potential Survival Related Outcomes	The number of participants with any subsequent therapies post-discontinuation of study treatment and association with potential survival related outcomes were planned to be evaluated.	Up to 7 years
Number of Participants With Presence of Genetic and Non-genetic Biomarkers	Biomarkers include germline and tumor mutations 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 were planned to be evaluated.	Up to 7 years
Number of Participants With Germline BRCA1 and BRCA2 Mutation Status in Association With Survival Related Outcomes	Participants with germline BRCA1 and BRCA2 mutation status in association with survival related outcomes were planned to be evaluated.	Up to 7 years

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Facing our risk of cancer empowered website

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2014
• Primary Completion (Actual): May 23, 2018
• Study Completion (Actual): October 26, 2021

Study Registration Dates

• First Submitted: July 18, 2013
• First Submitted That Met QC Criteria: July 18, 2013
• First Posted (Estimate): July 23, 2013

Study Record Updates

• Last Update Posted (Actual): November 15, 2022
• Last Update Submitted That Met QC Criteria: October 21, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: PARP Inhibitor; BRCA; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; BRCA1 Gene Mutation; BRCA2 Gene Mutation
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Breast Diseases; Neoplasms; Breast Neoplasms; Carcinoma; Ovarian Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Niraparib
• Other Study ID Numbers: 213551; 1307-BCG, BIG5-13 (Other Identifier: EORTC, BIG); PR-30-5010-C (Other Identifier: Tesaro)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes