1. Relevance of Platinum-free Interval and BRCA Reversion Mutations for Veliparib Monotherapy after Progression on Carboplatin/Paclitaxel for g BRCA Advanced Breast Cancer (BROCADE3 Crossover).
- Author
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Puhalla SL, Diéras V, Arun BK, Kaufman B, Wildiers H, Han HS, Ayoub JP, Stearns V, Yuan Y, Helsten T, Riley-Gillis B, Murphy E, Kundu MG, Wu M, Maag D, Ratajczak CK, Ramathal CY, and Friedlander M
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Benzimidazoles, Carboplatin adverse effects, Female, Humans, Mutation, Paclitaxel adverse effects, Platinum therapeutic use, Retrospective Studies, Breast Neoplasms drug therapy, Breast Neoplasms genetics
- Abstract
Purpose: Safety, efficacy, and exploratory biomarker analyses were evaluated in patients with advanced HER2-negative germline breast cancer susceptibility gene (g BRCA )-associated breast cancer enrolled in the BROCADE3 trial who received crossover veliparib monotherapy after disease progression on placebo plus carboplatin/paclitaxel., Patients and Methods: Eligible patients ( N = 513) were randomized 2:1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel; patients had variable platinum-free intervals (PFI) at progression. In the placebo arm, patients were eligible to receive crossover veliparib monotherapy (300-400 mg twice daily continuous). Antitumor activity and adverse events were assessed during crossover veliparib treatment. BRCA reversion mutations at crossover were analyzed retrospectively using next-generation sequencing on plasma circulating tumor DNA (ctDNA)., Results: Seventy-five patients in the placebo plus carboplatin/paclitaxel arm received ≥1 dose of crossover veliparib postprogression (mean treatment duration: 154 days). Eight of 50 (16%) patients with measurable disease had a RECIST v1.1 response. Activity was greater in patients with PFI ≥180 days compared with <180 days [responses in 23.1% (3/13) vs. 13.5% (5/37) of patients]. BRCA reversion mutations that restored protein function were detected in ctDNA from 4 of 28 patients tested, and the mean duration of crossover veliparib monotherapy was <1 month in these 4 patients versus 7.49 months in patients lacking reversion mutations. The most frequent adverse events were nausea (61%), vomiting (29%), and fatigue (24%)., Conclusions: Crossover veliparib monotherapy demonstrated limited antitumor activity in patients who experienced disease progression on placebo plus carboplatin/paclitaxel. PFI appeared to affect veliparib activity. BRCA reversion mutations may promote cross-resistance and limit veliparib activity following progression on platinum., (©2021 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2021
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