Taoufik Ouatas

Phase Ib Study of Enzalutamide in Combination with Docetaxel in Men with Metastatic Castration-Resistant Prostate Cancer

Purpose: Preclinical evidence suggests that both docetaxel and enzalutamide target androgen receptor translocation and signaling. This phase Ib study assessed the safety, tolerability, and pharmacokinetics of docetaxel when administered with enzalutamide as first-line systemic chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). Experimental Methods: Docetaxel-naïve patients received 21-day cycles of docetaxel (75 mg/m2). Enzalutamide (160 mg/day) was administered daily starting on day 2 of cycle 1. Patients were allowed to stop and restart docetaxel at any time following cycle 2. Treatment continued indefinitely until unacceptable toxicity or discontinuation due to investigator or patient preference. Results: A total of 22 patients received docetaxel, of whom 21 also received enzalutamide. Docetaxel was administered for a median of 5.0 cycles and enzalutamide for a median of 12.0 months. With concomitant treatment, geometric mean docetaxel exposure decreased by 11.8%, whereas peak concentrations decreased by 3.7% relative to docetaxel alone. The most common toxicities observed during the period of concomitant therapy were neutropenia (86.4%) and fatigue (77.3%). Common toxicities observed with post-docetaxel enzalutamide were constipation (23.8%), decreased appetite (19.0%), fatigue (19.0%), and musculoskeletal pain (19.0%). Treatment with enzalutamide and docetaxel resulted in prostate-specific antigen decreases in almost all patients based on exploratory analysis of available baseline and on-study prostate-specific antigen data. Conclusions: The combination of docetaxel and enzalutamide is feasible, although higher rates of neutropenia and neutropenic fever than anticipated were observed. Reductions in docetaxel exposure with enzalutamide coadministration were not considered clinically meaningful. This combination warrants further study in a larger mCRPC population. Clin Cancer Res; 22(15); 3774–81. ©2016 AACR.

A comparison of the pharmacokinetics and safety of enzalutamide in subjects with hepatic impairment and matched healthy subjects.

Enzalutamide is an androgen receptor inhibitor approved for treatment of metastatic castration‐resistant prostate cancer. Enzalutamide is highly protein bound and eliminated primarily by hepatic metabolism; therefore, it is important to understand whether enzalutamide pharmacokinetics is altered by hepatic impairment.

766PDLONG-TERM EFFICACY AND SAFETY OF ENZALUTAMIDE MONOTHERAPY IN HORMONE-NAIVE PROSTATE CANCER: 2-YEAR FOLLOW-UP

ABSTRACT Aim: Androgen-deprivation therapy (ADT) is the first-choice treatment for advanced prostate cancer (PC). Enzalutamide (ENZ) is approved for the treatment of post-docetaxel metastatic castration-resistant PC. In previous analyses of a Phase 2 study in pts with hormone-naive PC (HNPC) eligible for ADT, ENZ monotherapy after 6 mos and 1 yr (49 wks) was associated with a high prostate-specific antigen (PSA) response rate regardless of presence of metastatic disease at baseline, and with stable bone mineral density (BMD) and quality of life (QoL) on treatment. Here we report long-term efficacy and safety in pts treated up to 2 yrs (wk 97). Methods: 67 patients with HNPC and noncastrate testosterone (≥230 ng/dL) were enrolled in this open-label single-arm study (NCT01302041) and received ENZ 160 mg/d until disease progression or unacceptable toxicity. The primary variable of PSA response (≥80% decline from baseline) was assessed at 6 mos, 1 yr, and 2 yrs. Additional endpoints included best overall objective tumour response, BMD, body composition, QoL and safety. Results: 67 pts were treated. Median age was 73.0 yrs (range 48-86); 26 (38.8%) had metastatic disease at baseline, and 24 (35.8%) and 16 (23.9%) had prior prostatectomy and radiation, respectively. 4 pts discontinued during the second year of follow-up and 45 remained on ENZ at 2 yrs. PSA response rate in pts remaining on ENZ at 2 yrs was 100% (95% CI 92, 100). Of 26 pts with metastases at baseline, 13 (50%) had complete response and 4 (15.4%) partial response as best overall tumour response over 2 yrs. There were decreases in mean (SD) total body BMD of -0.39% (2.24) and lean body mass -5.27% (3.66) at 2 yrs. EORTC-QLQ C30 QoL data showed maintenance of global health status through 2 yrs, though there were clinically meaningful deteriorations (≥10 points) on the fatigue, and role functioning scales. Most common adverse events (AEs) were gynaecomastia, fatigue, nipple pain and hot flush. Conclusions: ENZ monotherapy was associated with significant long-term PSA reductions and good tumour response in men with HNPC. This was achieved without adversely affecting total body BMD or global health status. Disclosure: B. Tombal: has received consultancy fees from Astellas, Medivation, Amgen, and Sanofi Aventis; payment for speaker bureaus from Amgen, Sanofi Aventis, Ferring, and Bayer (for whom he is also a board member); and travel support from Astellas and Medivation; M. Borre: has received payment for speaker bureaus from Astellas and Janssen; is a member of a Medivation study Steering committee and has received consultancy fees from Astellas, Ferring and Sanofi Aventis; P. Rathenborg: has received research grant support paid to his institution from Astellas and Medivation; A. Heidenreich: has received consultancy fees and payment for speaker bureaus from Amgen, Jansen, Ipsen, Sanofi Aventis, and Takeda (for whom he is also a board member); research and travel support from Astellas, and a research grant from Sanofi Aventis; P. Iversen: Research grant support from Astellas and Medivation; travel support for meetings related to the study from Astellas and Medivation; honoraria from Astellas and Medivation; and consultancy fees from Janssen, Ferring and Sanofi-Aventis; J. Braeckman: has received payment for speaker bureaus from Amgen and Eli Lilly; E. Baskin-Bey, T. Ouatas, F.G. Perabo, D. Phung and B. Baron: Employee of Astellas; M. Hirmand: is an employee of Medivation and owns stock in Medivation; M.R. Smith: has received consultancy fees from Astellas, Medivation, Janssen, Aragon, and Millenium. All other authors have declared no conflicts of interest.