A drug-drug interaction study on the combination of cabazitaxel with enzalutamide in patients with metastatic castration-resistant prostate cancer.

Abstract

188 Background: Cabazitaxel and enzalutamide are effective single agent treatment options for metastatic castration resistant prostate cancer (mCRPC). Preclinical studies suggest enhanced efficacy of the combination of a taxane with enzalutamide. Recently, Morris et al. (CCR 2016) reported on an interaction study between docetaxel and enzalutamide: docetaxel mean exposure decreased by 12% during a short period of co-treatment with enzalutamide, probably due to enzyme (CYP3A4) induction. Since cabazitaxel is a CYP3A4 substrate, we investigated the influence of enzalutamide on cabazitaxel pharmacokinetics (PK) and toxicity during 3 chemotherapy cycles. Methods: We performed a cross-over study in 14 evaluable mCRPC patients who were treated with i.v. cabazitaxel Q3W (25 mg/m2). PK-sampling (over 24h) was conducted on day 1 of each cycle during 3 consecutive cabazitaxel cycles. From day 8 (±1) of the first cycle until day 8 (±1) of the third cycle, enzalutamide (160 mg/day) was administered concomitantly. Primary endpoint was the difference in geometric mean area under the curve (AUC0-24h) between the first and third cycle. Secondary endpoints included safety parameters and PSA response. Results: The AUC was 22% (95%CI 9-34%) lower during the third cycle (181 ng*h/mL, 95%CI 150-219 ng*h/mL) than during the first cycle (234 ng*h/mL, 95%CI 209-261 ng*h/mL; p = 0.005). No relevant adverse events occurred due to the drug combination. Nine patients (64%) received the full dose of cabazitaxel during the 3 study cycles. No enzalutamide dose reductions took place, and the combination was well tolerated. PSA response ( ≥ 50% decrease of baseline PSA ) was observed in 10 patients (71%). Conclusions: Cabazitaxel exposure is both statistically and clinically significantly reduced by concomitant enzalutamide use. Since the PROSELICA study (De Bono et al, ASCO 2016) may lead to an adapted standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be extensive, since it is likely to result in suboptimal exposures. We stimulate clinical studies with this combination, but these should include monitoring of the PK of cabazitaxel, and appropriate dose adaptations. Clinical trial information: NTR5164.