title: Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial.
abstract: BACKGROUND
  The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases.
  
  
  METHODS
  In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m(2) every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00134056.
  
  
  RESULTS
  498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5-9·9) in the atrasentan group and 9·1 months (8·4-10·2) in the placebo group (hazard ratio 1·02, 0·89-1·16; p=0·81). Median overall survival was 17·8 months (16·4-19·8) in the atrasentan group versus 17·6 months (16·4-20·1) in the placebo group (1·04, 0·90-1·19; p=0·64). 278 (57%) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment.
  
  
  CONCLUSIONS
  Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments.
  National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA. diquinn@med.usc.edu
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Tangen
authors.forename: Maha
authors.initials: M
authors.lastname: Hussain
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.forename: Amir
authors.initials: A
authors.lastname: Goldkorn
authors.forename: Carol M
authors.initials: CM
authors.lastname: Moinpour
authors.forename: Mark G
authors.initials: MG
authors.lastname: Garzotto
authors.forename: Philip C
authors.initials: PC
authors.lastname: Mack
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: J Paul
authors.initials: JP
authors.lastname: Monk
authors.forename: Przemyslaw W
authors.initials: PW
authors.lastname: Twardowski
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Van Veldhuizen
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: Ian M
authors.initials: IM
authors.lastname: Thompson
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077868:Atrasentan; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D002369:Castration; D000077143:Docetaxel; D004311:Double-Blind Method; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011759:Pyrrolidines / Q000008:administration & dosage; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D011759:Pyrrolidines; D043823:Taxoids; D000077143:Docetaxel; D000077868:Atrasentan