Long-term Safety and Antitumor Activity in the Phase 1–2 Study of Enzalutamide in Pre- and Post-docetaxel Castration-Resistant Prostate Cancer

• Published in: European urology 2015-11, Vol.68 (5), p.795-801
• Main Authors: Higano, Celestia S, Beer, Tomasz M, Taplin, Mary-Ellen, Efstathiou, Eleni, Hirmand, Mohammad, Forer, David, Scher, Howard I
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Androgen Receptor Antagonists - therapeutic use; Androgen receptor inhibitor; Antineoplastic Agents - therapeutic use; Antineoplastic Agents, Hormonal - therapeutic use; Bone Neoplasms - drug therapy; Bone Neoplasms - secondary; Castration-resistant prostate cancer; Disease-Free Survival; Docetaxel; Enzalutamide; Humans; Kallikreins - blood; Long-term follow-up; Lymph Nodes - pathology; Male; Maximum Tolerated Dose; MDV3100; Middle Aged; Neoplasm Recurrence, Local - blood; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - therapeutic use; Prostate-Specific Antigen - blood; Prostatic Neoplasms, Castration-Resistant - blood; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - pathology; Taxoids - therapeutic use; Tolerability; Urology
• ISSN: 0302-2838; 1873-7560
• DOI: 10.1016/j.eururo.2015.01.026

Abstract Background Given that some patients with castration-resistant prostate cancer (CRPC) have shown extended responses to the androgen receptor inhibitor enzalutamide, long-term safety of this drug is of interest. Objective To evaluate the long-term safety and antitumor activity of enzalutamide in CRPC patients. Design, setting, and participants This phase 1–2 study evaluated enzalutamide in 140 CRPC patients with and without prior chemotherapy. Initial findings were published in 2010. We report updated results from an additional 17-mo follow-up for antitumor activity and >4 yr for safety. Intervention Patients received 30–600 mg/d oral enzalutamide. During long-term dosing, all patients were switched first to the maximum tolerated dose of 240 mg/d and then to the phase 3 dose of 160 mg/d. Outcome measurements and statistical analysis Safety was assessed regularly. The Kaplan-Meier method was used to estimate the distributions of time to prostate-specific antigen (PSA) progression and time to radiographic progression. Results and limitations The safety profile of enzalutamide was consistent over time, with little change in the rates of commonly reported adverse events (AEs) or the incidence of grade 3/4 AEs. Fatigue of any grade was the most common dose-dependent AE, experienced by 70% of patients, with 14% of patients reporting grade 3/4 fatigue. The median time to PSA progression was not reached for chemotherapy-naive patients and was 45 wk for postchemotherapy patients; the corresponding median time to radiographic progression was 56 wk and 25 wk. Conclusions Enzalutamide showed durable antitumor activity in chemotherapy-naive and postchemotherapy patients, and was well tolerated, even in patients treated for 4 yr. Patient summary Enzalutamide was active against prostate cancer and was well tolerated, even for up to 4 yr of treatment, supporting its potential for long-term use in men with prostate cancer. Fatigue was the most common side effect, occurring at varying degrees of severity in most patients.