Influence of Enzalutamide on Cabazitaxel Pharmacokinetics: a Drug-Drug Interaction Study in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients.

Abstract

<b>Purpose:</b> In ongoing clinical research on metastatic castration-resistant prostate cancer (mCRPC) treatment, the potential enhanced efficacy of the combination of taxanes with AR-targeted agents, that is, enzalutamide and abiraterone, is currently being explored. Because enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug-drug interaction needs to be investigated.<b>Experimental Design:</b> Therefore, we performed a pharmacokinetic cross-over study in mCRPC patients who were scheduled for treatment with cabazitaxel Q3W (25 mg/m²). Patients were studied for three consecutive cabazitaxel cycles. Enzalutamide (160 mg once daily) was administered concomitantly after the first cabazitaxel cycle, during 6 weeks. Primary endpoint was the difference in mean area under the curve (AUC) between the first (cabazitaxel monotherapy) and third cabazitaxel cycle, when enzalutamide was added.<b>Results:</b> A potential clinically relevant 22% (95% CI, 9%-34%; <i>P</i> = 0.005) reduction in cabazitaxel exposure was found with concomitant enzalutamide use. The geometric mean AUC_0-24h of cabazitaxel was 181 ng*h/mL (95% CI, 150-219 ng*h/mL) in cycle 3 and 234 ng*h/mL (95% CI, 209-261 ng*h/mL) in cycle 1. This combination did not result in excessive toxicity, whereas PSA response was promising.<b>Conclusions:</b> We found a significant decrease in cabazitaxel exposure when combined with enzalutamide. In an era of clinical trials on combination strategies for mCRPC, it is important to be aware of clinically relevant drug-drug interactions. Because recent study results support the use of a lower standard cabazitaxel dose of 20 mg/m², the clinical relevance of this interaction may be substantial, because the addition of enzalutamide may result in subtherapeutic cabazitaxel exposure. <i>Clin Cancer Res; 24(3); 541-6. ©2017 AACR</i>.