title: Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302).
abstract: BACKGROUND
  Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy.
  
  
  OBJECTIVE
  Report the prespecified third interim analysis (IA) of efficacy and safety outcomes in study COU-AA-302.
  
  
  METHODS
  Study COU-AA-302, a double-blind placebo-controlled study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1).
  
  
  METHODS
  Patients were randomised 1:1 to abiraterone 1000mg plus prednisone 5mg twice daily by mouth versus prednisone.
  
  
  METHODS
  Co-primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming Lan-DeMets α-spending function was used for OS. Adverse events were summarised descriptively.
  
  
  CONCLUSIONS
  With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45-0.61]; p<0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66-0.95]; p=0.0151) but did not reach the prespecified statistical efficacy boundary (α-level: 0.0035). A post hoc multivariate analysis for OS using known prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61-0.89]; p=0.0017), and all clinically relevant secondary end points and patient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports.
  
  
  CONCLUSIONS
  The updated IA of study COU-AA-302 in patients with mCRPC without prior chemotherapy confirms that abiraterone delays disease progression, pain, and functional deterioration and has clinical benefit with a favourable safety profile, including in patients treated for ≥24 mo.
  
  
  BACKGROUND
  Study COU-AA-302, ClinicalTrials.gov number, NCT00887198.
  
  
  RESULTS
  The updated results of this ongoing study showed that disease progression was delayed in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone, and there was a continued trend in prolongation of life compared with patients treated with prednisone alone. Treatment with abiraterone acetate and prednisone was well tolerated by patients who were treated for >2 yr.
authors.affiliation: Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. Electronic address: rathkopd@mskcc.org.
authors.forename: Dana E
authors.initials: DE
authors.lastname: Rathkopf
authors.affiliation: Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
authors.affiliation: The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK.
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
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: University of Western Sydney School of Medicine, Penrith, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: de Souza
authors.affiliation: Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Peter F A
authors.initials: PF
authors.lastname: Mulders
authors.affiliation: Hematology & Oncology Clinics of Australia, Brisbane, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Mainwaring
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Hainsworth
authors.affiliation: Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA.
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
authors.affiliation: Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: North
authors.affiliation: Laval University, Québec City, Québec, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Fradet
authors.affiliation: University Hospital Leuven, Leuven, Belgium.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Van Poppel
authors.affiliation: Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, 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: MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.affiliation: University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Yu
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: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
authors.affiliation: Janssen Research & Development, Los Angeles, CA, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Griffin
authors.affiliation: Janssen Research & Development, Raritan, NJ, USA.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Todd
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, Los Angeles, CA, USA.
authors.forename: Thian
authors.initials: T
authors.lastname: Kheoh
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
authors.affiliation: Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.affiliation: Janssen Research & Development, Menlo Park, CA, USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Molina
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Ryan
authors.affiliation: CRCHUM, University of Montréal, Montréal, Québec, Canada.
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
mesh_terms: D000069501:Abiraterone Acetate; D000368:Aged; D000736:Androstenes / Q000008:administration & dosage* / Q000009:adverse effects; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D011241:Prednisone / Q000008:administration & dosage; D016016:Proportional Hazards Models; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D012307:Risk Factors; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000736:Androstenes; D018931:Antineoplastic Agents, Hormonal; D065607:Cytochrome P-450 Enzyme Inhibitors; D013254:Steroid 17-alpha-Hydroxylase; D000069501:Abiraterone Acetate; D011241:Prednisone
keywords: Abiraterone acetate; Chemotherapy-naive; Efficacy; Metastatic castration-resistant prostate cancer; Safety