title: Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study.
abstract: BACKGROUND
  Abiraterone acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of abiraterone acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies.
  
  
  METHODS
  In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily; abiraterone acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00887198.
  
  
  RESULTS
  At a median follow-up of 49.2 months (IQR 47.0-51.8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the abiraterone acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received abiraterone acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group (34.7 months [95% CI 32.7-36.8] vs 30.3 months [28.7-33.3]; hazard ratio 0.81 [95% CI 0.70-0.93]; p=0.0033). The most common grade 3-4 adverse events of special interest were cardiac disorders (41 [8%] of 542 patients in the abiraterone acetate group vs 20 [4%] of 540 patients in the placebo group), increased alanine aminotransferase (32 [6%] vs four [<1%]), and hypertension (25 [5%] vs 17 [3%]).
  
  
  CONCLUSIONS
  In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer.
  
  
  BACKGROUND
  Janssen Research & Development.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. Electronic address: ryanc@medicine.ucsf.edu.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Ryan
authors.affiliation: Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
authors.affiliation: Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: University of Montréal, Montréal, Québec, Canada.
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.affiliation: Radboud University Medical Centre, Nijmegen, Netherlands.
authors.forename: Peter F A
authors.initials: PF
authors.lastname: Mulders
authors.affiliation: San Camillo and Forlanini Hospitals, Rome, Italy.
authors.forename: Cora N
authors.initials: CN
authors.lastname: Sternberg
authors.affiliation: Charité Berlin, Berlin, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.affiliation: MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.affiliation: Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, SC, USA.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Shore
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
authors.affiliation: Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Carles
authors.affiliation: University of Colorado Cancer Center and University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Flaig
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
authors.affiliation: University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.affiliation: University of Western Sydney School of Medicine and Ingham Institute, Liverpool, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: de Souza
authors.affiliation: The Institute of Cancer Research and the Royal Marsden Hospital, Sutton, United Kingdom.
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.affiliation: Janssen Research & Development, Los Angeles, CA, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Griffin
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Porre
authors.affiliation: Janssen Research & Development, Los Angeles, CA, USA.
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Yu
authors.affiliation: Janssen Research & Development, Raritan, NJ, USA.
authors.forename: Youn C
authors.initials: YC
authors.lastname: Park
authors.affiliation: Janssen Research & Development, Raritan, NJ, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Li
authors.affiliation: Janssen Research & Development, Los Angeles, CA, USA.
authors.forename: Thian
authors.initials: T
authors.lastname: Kheoh
authors.affiliation: Janssen Research & Development, Los Angeles, CA, USA.
authors.forename: Vahid
authors.initials: V
authors.lastname: Naini
authors.affiliation: Janssen Research & Development, Menlo Park, CA, USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Molina
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Dana E
authors.initials: DE
authors.lastname: Rathkopf
mesh_terms: D000368:Aged; D000736:Androstenes / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000556:secondary; D018450:Disease Progression; D004311:Double-Blind Method; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D011241:Prednisone / Q000627:therapeutic use*; D011379:Prognosis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D015996:Survival Rate
chemical_list: D000736:Androstenes; D018931:Antineoplastic Agents, Hormonal; C089740:abiraterone; D011241:Prednisone