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

Abstract 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.