Population Pharmacokinetics Analysis of Talazoparib and Enzalutamide Combination Therapy for Patients With Metastatic...

The poly(ADP-ribose) polymerase inhibitor talazoparib, combined with the androgen receptor inhibitor enzalutamide is approved for patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) in the US and with mCRPC in whom chemotherapy is not clinically indicated in Europe. We provide a population pharmacokinetic model for this combination in patients with mCRPC unselected for HRR deficiencies from TALAPRO-2 (NCT03395197). The pooled dataset included 811 patients treated with enzalutamide plus either talazoparib or placebo. The final enzalutamide model was a two-compartment model with first-order absorption and inter-individual variability (IIV) on apparent clearance (CL_e/F_e) and apparent central volume of distribution (Vc_e/F_e) and included effects of baseline body weight and age on CL_e/F_e and Vc_e/F_e. For the active metabolite N-desmethyl enzalutamide, a two-compartment model with IIV on CL_n and Vc_n adequately described the observed data and included the effect of body weight on CL_n and Vc_n. The final talazoparib model was well characterized by a two-compartment model with first-order absorption and IIV on talazoparib apparent base clearance (CL_t0/F_t) and Vc_t/F_t. The effect of enzalutamide and N-desmethyl enzalutamide on CL_t/F_t of talazoparib was modeled through a linear relationship. The single covariate effect of baseline creatinine clearance on CL_t0/F_t showed that relative to the reference value for normal renal function, CL_t0/F_t decreased by 8% for mild, 27% for moderate, and 46.7% for severe renal impairment. Simulations showed that a dose reduction of enzalutamide does not require talazoparib dose modification since the magnitude of exposure reduction for talazoparib was not considered clinically significant.