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)

Abstract

Purpose: Safety, efficacy, and exploratory biomarker analyses were evaluated in patients with advanced HER2-negative germline breast cancer susceptibility gene (gBRCA)-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.

Trial registration: ClinicalTrials.gov NCT02163694.

©2021 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.

Swimmer plot of treatment overview and time of reversion in the biomarker subgroup (n = 28) for all patients (A) and patients with BRCA reversion (B). Each line represents an individual patient and each symbol indicates a key event (treatment, reversion). Left axis indicates patients who reverted versus those who did not. Colored line segments correspond to different periods in the treatment overview as indicated in the legend, with orange lines showing time on veliparib monotherapy after crossover. Timing of ctDNA assessments is indicated by pretreatment (star), cycle 3 (pentagon), and postprogression (square colored symbols). Green squares also denote completion of placebo plus carboplatin/paclitaxel treatment period. Time of detection of BRCA1/2 reversion mutations is denoted by a black cross.

Figure 2.

A heatmap representing co-occurring and deleterious non-BRCA1/2 alterations in all 28 patients in the ctDNA analysis cohort. Patients are organized in columns and grouped by reversion status, while genes are organized into rows and grouped by timepoint and mutation category (color coded). Response status to veliparib monotherapy in crossover period is indicated in orange or blue boxes per column and in legend. Each colored square in the heatmap corresponds to a potentially deleterious alteration in that gene for each patient per visit. The number in each colored square indicates the number of alterations detected in that gene per patient. Per gene row, total patients with alterations in that gene are enumerated in the rightmost column.