Exposure-Response Model With Time-Varying Predictors to Estimate the Effects of Veliparib in Combination With Carboplatin/Paclitaxel and as Monotherapy: Veliparib Phase 3 Study in BRCA-Mutated Advanced Breast Cancer (BROCADE3) Trial.

BRCA-Mutated Advanced Breast Cancer (BROCADE3) is a phase 3 study, evaluating veliparib in combination with carboplatin/paclitaxel with continuation as monotherapy if carboplatin/paclitaxel is discontinued in patients with germline BRCA1/2 mutation-associated, advanced human epidermal growth factor receptor 2-negative breast cancer. The objective of the current analysis was to characterize the veliparib exposure-response relationships for efficacy (progression-free survival [PFS]) and safety in this study. Exposure-efficacy analyses of PFS were conducted using Kaplan-Meier plots and cox proportional hazards (CPH) models using treatment alone or both treatment and exposure as time-dependent predictors to estimate the effect of veliparib in combination with carboplatin/paclitaxel and as monotherapy. The cox proportional hazards model with only treatment as the time-varying predictor estimated a statistically significant benefit of veliparib monotherapy compared to placebo monotherapy (hazard ratio, 0.49; 95%CI, 0.33-0.73) and a modest, non-statistically significant benefit (hazard ratio, 0.81; 95%CI, 0.62-1.05) of adding veliparib to carboplatin/paclitaxel. Inclusion of exposure as an additional time-varying predictor in the cox proportional hazards model indicated a flat exposure-response relationship between the veliparib exposure and PFS when veliparib was administered in combination with carboplatin/paclitaxel or as monotherapy. The exposure-safety analysis did not reveal any meaningful exposure-dependent trend in the incidence of adverse events of interest. These analyses support the dose regimen of veliparib (120 mg twice daily) in combination with carboplatin/paclitaxel and continuation of veliparib (300-400 mg twice daily) as monotherapy if carboplatin/paclitaxel were discontinued before disease progression in this patient population. This study is registered with ClinicalTrials.gov with a registration ID: NCT02163694.