title: Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy: final analysis of a multicentre, open-label, early-access protocol trial.
abstract: BACKGROUND
  In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy.
  
  
  METHODS
  We did a multicentre, open-label, early-access protocol trial in 23 countries. We enrolled patients who had metastatic castration-resistant prostate cancer progressing after taxane chemotherapy. Participants received oral doses of abiraterone acetate (1000 mg daily) and prednisone (5 mg twice a day) in 28-day cycles until disease progression, development of sustained side-effects, or abiraterone acetate becoming available in the respective country. The primary outcome was the number of adverse events arising during study treatment and within 30 days of discontinuation. Efficacy measures (time to prostate-specific antigen [PSA] progression and time to clinical progression) were gathered to guide treatment decisions. We included in our analysis all patients who received at least one dose of abiraterone acetate. This study is registered with ClinicalTrials.gov, number NCT01217697.
  
  
  RESULTS
  Between Nov 17, 2010, and Sept 30, 2013, 2314 patients were enrolled into the early-access protocol trial. Median follow-up was 5·7 months (IQR 3·5-10·6). 952 (41%) patients had a grade 3 or 4 treatment-related adverse event, and grade 3 or 4 serious adverse events were recorded in 585 (25%) people. The most common grade 3 and 4 adverse events were hepatotoxicity (188 [8%]), hypertension (99 [4%]), cardiac disorders (52 [2%]), osteoporosis (31 [1%]), hypokalaemia (28 [1%]), and fluid retention or oedema (23 [1%]). 172 (7%) patients discontinued the study because of adverse events (64 [3%] were drug-related), as assessed by the investigator, and 171 (7%) people died. The funder assessed causes of death, which were due to disease progression (85 [4%]), an unrelated adverse experience (72 [3%]), and unknown reasons (14 [1%]). Of the 86 deaths not attributable to disease progression, 18 (<1%) were caused by a drug-related adverse event, as assessed by the investigator. Median time to PSA progression was 8·5 months (95% CI 8·3-9·7) and median time to clinical progression was 12·7 months (11·8-13·8).
  
  
  CONCLUSIONS
  No new safety signals or unexpected adverse events were found in this early-access protocol trial to assess abiraterone acetate for patients with metastatic castration-resistant prostate cancer who progressed after chemotherapy. Future work is needed to ascertain the most effective regimen of abiraterone acetate to optimise patients' outcomes.
  
  
  BACKGROUND
  Janssen Research & Development.
authors.affiliation: Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy. Electronic address: cstern@mclink.it.
authors.forename: Cora N
authors.initials: CN
authors.lastname: Sternberg
authors.affiliation: Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Rigshospitalet, Copenhagen, Denmark.
authors.forename: Gedske
authors.initials: G
authors.lastname: Daugaard
authors.affiliation: National Institute of Oncology, Budapest, Hungary.
authors.forename: Lajos
authors.initials: L
authors.lastname: Géczi
authors.affiliation: McMaster University, Hamilton, ON, Canada.
authors.forename: Sebastien J
authors.initials: SJ
authors.lastname: Hotte
authors.affiliation: ICON Cancer Care, Brisbane, QLD, Australia.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Mainwaring
authors.affiliation: University of Montreal, Montreal, QC, Canada.
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.affiliation: Center for Oncology, Hospital Sírio-Libanês, São Paulo, Brazil.
authors.forename: Ciro
authors.initials: C
authors.lastname: Souza
authors.affiliation: OncoCare Cancer Centre, Singapore.
authors.forename: Miah H
authors.initials: MH
authors.lastname: Tay
authors.affiliation: Centro Oncologico Belenus, Cuernavaca, Mexico.
authors.forename: José M Tello
authors.initials: JM
authors.lastname: Garrido
authors.affiliation: University of Pisa, Pisa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Galli
authors.affiliation: Janssen Research & Development, Horsham, PA, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Londhe
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Porre
authors.affiliation: Janssen Research & Development, Horsham, PA, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Goon
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Emma
authors.initials: E
authors.lastname: Lee
authors.affiliation: Janssen Scientific Affairs, Horsham, PA, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: McGowan
authors.affiliation: Janssen Research & Development, Los Angeles, CA, USA.
authors.forename: Vahid
authors.initials: V
authors.lastname: Naini
authors.affiliation: Janssen Global Services, Raritan, NJ, USA.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Todd
authors.affiliation: Janssen Research & Development, Menlo Park, CA, USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Molina
authors.affiliation: Duke Cancer Institute, Durham, NC, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000008:administration & dosage; D000736:Androstenes; D000737:Androstenols / Q000008:administration & dosage*; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011239:Prednisolone / Q000008:administration & dosage*; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D000736:Androstenes; D000737:Androstenols; D011239:Prednisolone; D017430:Prostate-Specific Antigen; C089740:abiraterone