title: Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer.
abstract: PURPOSE As part of the ENTHUSE (Endothelin A Use) program, the efficacy and safety of zibotentan (ZD4054), an oral specific endothelin A receptor antagonist, has been investigated in combination with docetaxel in patients with metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS In this randomized, double-blind, placebo-controlled, phase III study, patients received intravenous docetaxel 75 mg/m(2) on day 1 of 21-day cycles plus oral zibotentan 10 mg or placebo once daily. The primary end point was overall survival (OS). Secondary end points included time to pain and prostate-specific antigen (PSA) progression, pain and PSA response, progression-free survival, health-related quality of life, and safety. Results A total of 1,052 patients received study treatment (docetaxel-zibotentan, n = 524; docetaxel-placebo, n = 528). At the time of data cutoff, there had been 277 and 280 deaths, respectively. There was no difference in OS for patients receiving docetaxel-zibotentan compared with those receiving docetaxel-placebo (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P = .963). No significant differences were observed on secondary end points, including time to pain progression (median 9.3 v 10.0 months, respectively) or pain response (odds ratio, 0.84; 95% CI, 0.61 to 1.16; P = .283). The median time to death was 20.0 and 19.2 months for the zibotentan and placebo groups, respectively. The most commonly reported adverse events in zibotentan-treated patients were peripheral edema (52.7%), diarrhea (35.4%), alopecia (33.9%), and nausea (33.3%). CONCLUSION Docetaxel plus zibotentan 10 mg/d did not result in a significant improvement in OS compared with docetaxel plus placebo in patients with metastatic CRPC.
authors.affiliation: Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, 39 rue Camille Desmoulins, Villejuif, France. fizazi@igr.fr
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, 39 rue Camille Desmoulins, Villejuif, France. fizazi@igr.fr
authors.forename: Karim S
authors.initials: KS
authors.lastname: Fizazi
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.forename: Joel B
authors.initials: JB
authors.lastname: Nelson
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.forename: Thomas
authors.initials: T
authors.lastname: Morris
authors.forename: Faith E
authors.initials: FE
authors.lastname: Nathan
authors.forename: Stuart
authors.initials: S
authors.lastname: McIntosh
authors.forename: Kristine
authors.initials: K
authors.lastname: Pemberton
authors.forename: Judd W
authors.initials: JW
authors.lastname: Moul
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000601:surgery; D011759:Pyrrolidines / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage; D017211:Treatment Failure
chemical_list: D011759:Pyrrolidines; D043823:Taxoids; C511404:ZD4054; D000077143:Docetaxel; D017430:Prostate-Specific Antigen