1829P Exposure-safety analyses of talazoparib in combination of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) in TALAPRO-2 trial

The TALAPRO-2 trial (NCT03395197) showed that the addition of talazoparib (tala), a potent PARP inhibitor, to enzalutamide (enza) significantly improved radiographic progression-free survival in patients with mCRPC. Approximately 75% and 56% of patients (pts) in TALAPRO-2 experienced dose interruption and dose reduction of tala, respectively, due to an adverse event (AE). We investigated the relationship between tala exposure as well as other factors and Grade 3 or higher Anemia, Thrombocytopenia, and Neutropenia, the most common AEs leading to dose interruptions or reductions. Safety and PK data from 412 pts in the tala (starting dose of 0.5 mg QD) + enza (160 mg QD) arm were available. To account for the changes in tala exposure over time due to dose modifications and effect of enza and its n-desmethyl metabolite on tala exposure, time-varying average tala concentrations (Cavg,t) were used in the analysis. Cavg,t was calculated as posthoc estimated AUCt/t based on population PK model. The relationship between Cavg,t/potential predictive factors and the selected safety events was evaluated using Cox proportional hazard (PH) univariate and multivariate models with p value cutoff of 0.05. Visual examination suggested a higher Cavg,t in pts with Anemia, Thrombocytopenia, and Neutropenia events versus pts without events. Cox PH models indicated that a higher Cavg,t was associated with a higher risk of Grade 3 or higher Anemia, Thrombocytopenia, and Neutropenia. The HR (95% CI) for Cavg,t was 1.433 (1.32, 1.555) for Anemia, 1.609 (1.35, 1.917) for Thrombocytopenia, and 6.942 (3.337, 14.44) for Neutropenia. Higher risk of all tested safety endpoints was associated with lower baseline hemoglobin. Higher risk of Anemia was associated with lower baseline body weight (BWT) and higher baseline lactate dehydrogenase. Higher risk of Neutropenia was associated with lower absolute neutrophil count and lower BWT. A higher risk of Anemia, Thrombocytopenia, and Neutropenia was associated with higher tala exposure. These findings support the proposed dose modification algorithm as an effective approach for management of AEs.