Pharmacokinetic (PK) analysis of concurrent administration of enzalutamide (enza) and crizotinib (crizo) in patients with metastatic castration resistant prostate cancer (CRPC)

Abstract

Background: Androgen receptor (AR) inhibition can upregulate c-MET expression which can drive CRPC progression. We have previously described the safety and toxicity profile of concurrent treatment with enza and crizo, a potent c-MET inhibitor in a phase 1 study. Since crizo is a substrate for CYP3A4, which is strongly induced by enza, we performed a PK analysis to evaluate its impact on steady state crizo levels. Methods:A3+3 dose escalation design was employed to test increasing doses of crizo at 250mg daily (dose level 1; n=3), 200 mg BID(dose level 2; n=6) and 250mg BID(dose level 3; n=15) in combination with a fixed dose of enza 160mg daily in 28 day cycles. PK samples drawn during cycle 2 were used to estimate steady state PK parameters including peak (Cmaxss) and trough (Cminss) plasma concentration and area under the curve over a dosing interval (AUCsss), reported as the geometric mean±SD. Results: The crizo Cminss increased progressively across dose levels from 20.7±1.8 ng/mL (250 mg QD) to 70.2±36.4 ng/mL (250 mg BID). Among the 12 patients enrolled on dose level 3 with available PK data, the crizo Cmaxss and AUCsss were 104 ±45 ng/mL and 1,000±476 ng-h/mL respectively. This represents a 73.8% decrease in crizo steady state exposure compared to a historical data for NSCLC patients with normal renal function treated with crizo monotherapy at 250 mg BID (Cminss: 285.0 ng/ mL; Cmaxss: 315 ng/mL and AUCsss: 3,817 ng-h/mL; Tan et al Inv. New Drugs 2016). Enza Cminss was similar across the crizo dose levels (250mg QD: 10.6±4.6 μg/mL; 250mg BID: 12.5±3.2 μg/mL) and was in excellent agreement with previously reported steady state levels in the phase 3 AFFIRM trial (11.7±2.9μg/mL; Gibbons et al Clin Pharmacokinetics 2015). Conclusions: Concurrent administration of enza resulted in a clinically significant∼74% increase in the apparent oral clearance of crizo suggestive of a clinically significant PK drug interaction. Further investigation into the optimal combination of c-MET inhibitors with novel AR inhibitors is required. Our results highlight the importance of considering PK interactions when evaluating novel combination strategies in CRPC.