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

• ClinicalTrials.gov Identifier: NCT01905592
• Recruitment Status: Completed
• First Posted: July 23, 2013
• Results First Posted: August 27, 2020
• Last Update Posted: November 5, 2021
• Sponsor: Tesaro, Inc.
• Collaborators: 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
• Information provided by (Responsible Party): Tesaro, Inc.

Tracking Information

• First Submitted Date: July 18, 2013
• First Posted Date: July 23, 2013
• Results First Submitted Date: January 29, 2020
• Results First Posted Date: August 27, 2020
• Last Update Posted Date: November 5, 2021
• Actual Study Start Date: February 25, 2014
• Actual Primary Completion Date: May 23, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 10, 2020)

Progression Free Survival (PFS) - 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 ]

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.

Original Primary Outcome Measures (submitted: July 18, 2013)

Progression Free Survival (PFS) [ Time Frame: After 96 PFS events (40%) have been documented. Anticipated in about 16 months from first patient enrolled ]

The primary objective of this study is to compare progression-free survival as determined by central, blinded review, of patients with advanced/metastatic HER2-negative breast cancer who have a gBRCAmut when treated with niraparib as compared to those treated with physician's choice

Current Secondary Outcome Measures (submitted: August 10, 2020)

• Overall Survival [ Time Frame: 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.
• Determine Concordance Between gBRCAmut Tests for the Purpose of Developing a Commercial Companion Diagnostic Test [ Time Frame: 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.
• Safety and Tolerability [ Time Frame: 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.
• Progression Free Survival (PFS) - Investigator Assessment [ Time Frame: 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.
• Time to Treatment Failure [ Time Frame: 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.
• Response Rate and Duration of Response [ Time Frame: 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.
• To Compare Time to Deterioration of Health-related Quality of Life: QLQ-C30 and EQ-5D-5L [ Time Frame: 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.
• Subsequent Therapies and Potential Relationships With Outcomes [ Time Frame: End of Study ]
  To describe subsequent therapies and potential relationships with outcomes
• Assess Genetic and Non-genetic Biomarkers [ Time Frame: 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.
• Assess Outcomes by Germline Mutation BRCA1 vs BRCA2 [ Time Frame: End of Study ]
  To assess outcomes by germline mutation BRCA1 vs BRCA2
• Post-treatment Data [ Time Frame: End of Study ]
  Descriptive summary statistics will be used to summarize post- treatment data (.i.e subsequent anticancer therapies and any new malignancy)

Original Secondary Outcome Measures (submitted: July 18, 2013)

Overall survival [ Time Frame: 54 months after the first patient is enrolled ]

To compare overall survival of patients with advanced/metastatic HER2-negative breast cancer who have a gBRCAmut when treated with niraparib as compared to those treated with physician's choice

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: July 18, 2013)

Health related quality of life [ Time Frame: End of study Oct 2015 ]

2 validated questionnaires to assess general quality of life and deterioration due to breast cancer

Descriptive Information

• Brief Title: A Phase III Trial of Niraparib Versus Physician's Choice in HER2 Negative, Germline BRCA Mutation-positive Breast Cancer Patients
• 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
• Brief Summary: The purpose of this study is to compare progression-free survival (PFS) in patients with advanced/metastatic breast cancer who have a BRCA mutation when treated with niraparib as compared to those treated with physician's choice
• Detailed Description: This is a phase III, randomized, open label, multicenter, controlled trial of niraparib versus physician's choice in previously-treated, HER2 negative, germline BRCA mutation-positive breast cancer patients. Niraparib is an orally active PARP inhibitor. Niraparib (in a 2:1 ratio) will be administered once daily continuously during a 21-day cycle. Physician's choice will be administered on a 21-day cycle. Health-related quality of life will be measured. The safety and tolerability will be assessed by clinical review of adverse events (AEs), physical examinations, electrocardiograms (ECGs), and safety laboratory values.
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

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.

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Neoplasms, Breast
• Carcinoma of Breast
• Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
• BRCA1 Gene Mutation
• BRCA2 Gene Mutation
• Ovarian Neoplasms

Intervention

• Drug: niraparib
  300 mg (3x100 mg capsules) once daily until progression or unacceptable toxicity develops
  Other Name: formerly MK-4827
• Drug: Physician's choice
  Choice of 4 standard of care metastatic breast cancer chemotherapies, until progression or unacceptable toxicity develops

Study Arms

• Active Comparator: Physician's choice
  Physician may select from 4 active comparators
  Intervention: Drug: Physician's choice
• Experimental: niraparib
  Patients will be randomized 2:1 to receive niraparib 300 mg (3x100 mg capsules) once daily for 21 continuous days
  Intervention: Drug: niraparib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 25, 2019): 215
• Original Estimated Enrollment (submitted: July 18, 2013): 306
• Actual Study Completion Date: October 26, 2021
• Actual Primary Completion Date: May 23, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, France, Greece, Hungary, Iceland, Israel, Italy, Netherlands, Poland, Portugal, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT01905592
• Other Study ID Numbers: 213551; 1307-BCG, BIG5-13 ( Other Identifier: EORTC, BIG ); PR-30-5010-C ( Other Identifier: Tesaro )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Tesaro, Inc.
• Study Sponsor: Tesaro, Inc.

Collaborators

• 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

• PRS Account: Tesaro, Inc.
• Verification Date: October 2021