title: Long-term Safety and Antitumor Activity in the Phase 1-2 Study of Enzalutamide in Pre- and Post-docetaxel Castration-Resistant Prostate Cancer.
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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  RESULTS
  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.
authors.affiliation: University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Electronic address: thigano@u.washington.edu.
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.affiliation: Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA.
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.affiliation: Medivation Inc., San Francisco, CA, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hirmand
authors.affiliation: Medivation Inc., San Francisco, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Forer
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059002:Androgen Receptor Antagonists / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001549:Benzamides; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D018572:Disease-Free Survival; D000077143:Docetaxel; D006801:Humans; D007610:Kallikreins / Q000097:blood; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood*; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000627:therapeutic use*
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; D009570:Nitriles; D043823:Taxoids; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C540278:enzalutamide; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Androgen receptor inhibitor; Castration-resistant prostate cancer; Enzalutamide; Long-term follow-up; MDV3100; Tolerability