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

Purpose: 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, i.e. enzalutamide and abiraterone, is currently being explored. Since enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug-drug interaction needs to be investigated. Design: 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 QD) 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. Results: A potential clinically relevant 22% (95%CI: 9-34%, p=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, while PSA response was promising. Conclusions: 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. Since 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, since the addition of enzalutamide may result in sub-therapeutic cabazitaxel exposure.

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