Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline BRCA1/ 2 mutations and hormone receptor status from the phase-3 BROCADE3 trial

Jean-Pierre Ayoub, Hans Wildiers, Michael Friedlander, Banu K Arun, Hyo S Han, Shannon Puhalla, Yaroslav Shparyk, Erik H Jakobsen, Meijing Wu, Bruce A Bach, Dai Feng, Christine K Ratajczak, David Maag, Véronique Diéras, Jean-Pierre Ayoub, Hans Wildiers, Michael Friedlander, Banu K Arun, Hyo S Han, Shannon Puhalla, Yaroslav Shparyk, Erik H Jakobsen, Meijing Wu, Bruce A Bach, Dai Feng, Christine K Ratajczak, David Maag, Véronique Diéras

Abstract

Purpose: To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, germline BRCA (gBRCA)-associated breast cancer defined by hormone receptor (HR) and gBRCA1/2 mutation status.

Patients and methods: In this phase-3, double-blind, placebo-controlled trial, patients (N = 509) with advanced HER2-negative breast cancer and gBRCA1/2 mutations were randomized 2:1 to receive veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Patients who discontinued chemotherapy prior to disease progression continued receiving blinded veliparib/placebo monotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Subgroup analyses of PFS stratified by HR and gBRCA1/2 mutation status were prespecified.

Results: In the intention-to-treat population, there were similar proportions of patients with gBRCA1 versus gBRCA2 mutations (51% vs 49%) and HR+ disease versus triple-negative breast cancer (TNBC) (52% vs 48%). Median PFS was longer in the veliparib arm compared with the placebo arm for all subgroups (HR+: 13.0 vs 12.5 months, hazard ratio (95% confidence interval (CI)): 0.69 (0.52, 0.93), p = 0.013; TNBC: 16.6 vs 14.1 months, hazard ratio (95% CI): 0.72 (0.52, 1.00), p = 0.052; gBRCA1: 14.2 vs 12.6 months, hazard ratio (95% CI): 0.75 (0.55, 1.03), p = 0.073; gBRCA2: 14.6 vs 12.6 months, hazard ratio (95% CI): 0.69 (0.50, 0.95); p = 0.021). Benefit was durable, with improved PFS rates at 2 years (HR+, 27.5% vs 15.3%; TNBC, 40.4% vs 25.0%) and 3 years (HR+, 17.5% vs 8.6%; TNBC, 35.3% vs 13.0%) in all subgroups. gBRCA status (BRCA1 vs BRCA2) did not substantially affect the carboplatin/paclitaxel ± veliparib toxicity profile.

Conclusion: Veliparib plus carboplatin/paclitaxel resulted in durable benefit in subgroups defined by HR status or by gBRCA1 versus gBRCA2 mutation. Overall, addition of veliparib to carboplatin/paclitaxel was tolerable, and there were no clinically meaningful differences in adverse events between the gBRCA1 versus gBRCA2 and HR+ versus TNBC subgroups.

Trial registration: NCT02163694, https://ichgcp.net/clinical-trials-registry/NCT02163694.

Keywords: BRCA; PARP inhibitor; TNBC; breast cancer; phase 3.

Conflict of interest statement

Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JPA: Research funding (institution), AbbVie, Boston Biomedical; consultancy, AstraZeneca, Eisai, Eli Lilly, Novartis, Pfizer, Puma, Roche. HW: Consulting fees and honoraria (institution), Roche, AstraZeneca, Amgen, Lilly, Novartis, AbbVie, Vifor Pharma, Pfizer, Celldex Therapeutics, Janssen-Cilag, TRM Oncology, PUMA Biotechnology, Orion Corporation; unrestricted research grant, Roche; travel support, Roche, Pfizer. MF: Consulting/advisory role, AstraZeneca, MSD, AbbVie, Lilly, GSK, Takeda; speakers’ bureau, AstraZeneca; honoraria, AstraZeneca, MSD, GSK, Lilly, Takeda, Novartis, ACT Genomics; travel/accommodation expenses, AstraZeneca; research funding, BeiGene, AstraZeneca, Novartis. BKA: Research support (institution), AbbVie, PharmaMar, AstraZeneca, Invitae; steering committee (nonpaid), AbbVie. HSH: Research funding (institutions), Arvinas, AbbVie, BMS, Daiichi Pharma, GSK, G1 Therapeutics, Horizon, Karyopharm, Marker Therapeutics, Novartis, Pfizer, Prescient, Seattle Genetics, Zymeworks; speakers’ bureau, Lilly. SLP: Consultant, AbbVie, MedImmune, Celldex, Puma, Pfizer, AstraZeneca, Eisai, NanoString; research funding to institution, AbbVie, Pfizer, Lilly, Novartis, Incyte, Covance-Bayer, AstraZeneca, Genentech, Medivation. YS: Advisory board: Pfizer; speaker: Roche, AstraZeneca, Pfizer; research/clinical studies: AbbVie, Roche, MSD, Boehringer Ingelheim. EHJ: Consulting/advisory role: Pfizer, Roche, Novartis, Eli Lilly. BB: Former employee of AbbVie and may hold AbbVie stock. MW, DF, CKR, and DM: AbbVie employees and may own stock. VD: Consulting/advisory role, Roche/Genentech, Novartis, Lilly, Pfizer, AbbVie, MSD, Daiichi Sankyo, Seattle Genetics, AstraZeneca, Gilead.

© The Author(s), 2021.

Figures

Figure 1.
Figure 1.
Kaplan–Meier estimates of investigator-assessed progression-free survival in HR+ (a), TNBC (b), gBRCA1 (c), and gBRCA2 (d) subgroups. Distributions were estimated by means of the Kaplan–Meier method. BRCA, breast cancer susceptibility gene; CI, confidence interval; C/P, carboplatin plus paclitaxel; g, germline; HR+, hormone receptor positive (estrogen receptor and/or progesterone receptor); TNBC, triple-negative breast cancer.
Figure 2.
Figure 2.
Kaplan–Meier estimates of investigator-assessed overall survival in HR+ (a), TNBC (b), gBRCA1 (c), and gBRCA2 (d) subgroups. Distributions were estimated by means of the Kaplan-Meier method. BRCA, breast cancer susceptibility gene; CI, confidence interval; C/P, carboplatin plus paclitaxel; g, germline; HR+, hormone receptor positive (estrogen receptor and/or progesterone receptor); TNBC, triple-negative breast cancer.

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