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

Eur Urol. 2015 Nov;68(5):795-801. doi: 10.1016/j.eururo.2015.01.026. Epub 2015 Feb 16.


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 30-600mg/d oral enzalutamide. During long-term dosing, all patients were switched first to the maximum tolerated dose of 240mg/d and then to the phase 3 dose of 160mg/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.

Keywords: Androgen receptor inhibitor; Castration-resistant prostate cancer; Enzalutamide; Long-term follow-up; MDV3100; Tolerability.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Androgen Receptor Antagonists / therapeutic use*
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / secondary
  • Disease-Free Survival
  • Docetaxel
  • Humans
  • Kallikreins / blood
  • Lymph Nodes / pathology
  • Male
  • Maximum Tolerated Dose
  • 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*


  • Androgen Receptor Antagonists
  • Antineoplastic Agents
  • Antineoplastic Agents, Hormonal
  • MDV 3100
  • Taxoids
  • Docetaxel
  • Phenylthiohydantoin
  • Kallikreins
  • kallikrein-related peptidase 3, human
  • Prostate-Specific Antigen