Abstract OT1-03-05: 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. An EORTC-BIG intergroup study (BRAVO study)
Authors: Balmana J , Tryfonidis K , Audeh W , Goulioti T , Slaets L , Agarwal S , Lema N , Cameron D , Turner N 
Published: May 2016

Abstract
Background
Germline BRCA mutations (gBRCAmut) amongst breast cancer (BC) patients ranges between 5% - 25% depending on family history of BC or ovarian cancer (OC). Cells treated with PARP inhibitors (PARPi) accumulate defects that lead to their death in the absence of homologous recombination (HR) repair (e.g. gBRCAmut). Niraparib is a PARPi in development. As the TNT study showed better results of 1st line carboplatin vs docetaxel in gBRCAmut patients, a rise of a platinum-exposed population is expected. Due to prior experience in OC where platinum sensitivity of HR deficient cells is linked with PARPi sensitivity, it seems that patients who progress on or soon after platinum should be excluded from PARPi therapy, without sparing from PARPi those who may retain sensitivity. The protocol was amended to include platinum-exposed patients.
Trial Design
Bravo is a multicenter (North America, Europe &Israel) EORTC & BIG phase III trial sponsored by TESARO. Patients with gBRCAmut will be randomized (2:1) to niraparib (per os) vs physician's choice (PC) (eribulin or capecitabine or gemcitabine or vinorelbine)-NCT01905592.
Eligibility Criteria
• Patients with deleterious/suspected deleterious gBRCAmut locally or centrally. Central confirmation will be done. If post inclusion, based on a previous test, mutation is not centrally confirmed, they can participate based on their physician/own preference.
• Up to 2 prior chemotherapy lines for metastatic disease (MD).
• Previously untreated for MD are allowed if they relapse during/within 12 months of (neo-) adjuvant chemotherapy.
• Prior therapy must include a taxane and/or anthracycline. Previously received platinum in the MD can be enrolled if they did not progress while on or within 8 weeks from the last day of the platinum administration. Those who received (neo-) adjuvant platinum are eligible, if relapsed 12 or &gt; months after the last platinum dose.
Specific aims
Primary endpoint is PFS assessed by blinded central review . Secondary are OS, safety, PFS on local investigator assessment, time to treatment failure, response & duration of response, health- related quality assessments & tests for companion diagnostic test development.
Statistical methods
The PFS analysis will be done after 232 PFS events in the population of centrally confirmed gBRCAmut randomized patients. Assuming that median PFS is 3 months for PC & 6 months for niraparib (hazard ratio=0.5), there is 99.6 % power (1- sided alpha=0.025) to detect a difference from 3 - 6 months. Sample size ensure power for an OS comparison. Assuming an increase in OS from 9 -13 months, with a hazard ratio of 0.69, there is 80% power at 1- sided alpha of 0.025 when 265 deaths are observed. Assuming 40% of patients will be randomized based on local test and 15% won't be mutated centrally, an over-enrollment of 18 patients is needed to obtain the 306 in the efficacy population. A futility interim analysis will happen at 40% of PFS events.
Present accrual and target accrual
1200 patients will be registered & 306 randomized. Accrual will finish in 2 years.
Citation Format: Balmana J, Tryfonidis K, Audeh W, Goulioti T, Slaets L, Agarwal S, Lema N, Cameron D, Turner N. 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. An EORTC-BIG intergroup study (BRAVO study). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-05.