Abstract
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.