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Phase 3, randomized, placebo‐controlled study of zibotentan (ZD4054) in patients with castration‐resistant prostate cancer metastatic to bone
Author(s) -
Nelson Joel B.,
Fizazi Karim,
Miller Kurt,
Higano Celestia,
Moul Judd W.,
Akaza Hideyuki,
Morris Thomas,
McIntosh Stuart,
Pemberton Kristine,
Gleave Martin
Publication year - 2012
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.27674
Subject(s) - medicine , prostate cancer , placebo , clinical endpoint , hazard ratio , peripheral edema , adverse effect , bone pain , randomized controlled trial , common terminology criteria for adverse events , population , cancer , surgery , confidence interval , pathology , alternative medicine , environmental health
BACKGROUND: Endothelin‐1 and the endothelin A (ET A ) receptor have been implicated in prostate cancer progression in bone. This study aimed to determine whether the specific ET A receptor antagonist, zibotentan, prolonged overall survival (OS) in patients with castration‐resistant prostate cancer and bone metastases who were pain‐free or mildly symptomatic for pain. METHODS: Patients were randomized 1:1 to zibotentan 10 mg/day or placebo, plus standard prostate cancer treatment. The primary endpoint was OS. Secondary endpoints included times to pain progression, chemotherapy use, new bone metastases, and safety. Efficacy endpoints were analyzed using a log‐rank test. RESULTS: A total of 594 patients were randomized (zibotentan, n = 299; placebo, n = 295). Median OS was 24.5 months in zibotentan‐treated patients versus 22.5 months for placebo, but the difference did not reach statistical significance (hazard ratio, 0.87; 95.2% confidence interval, 0.69‐1.10; P = .240). No statistically significant differences were observed for any secondary efficacy endpoints. Peripheral edema (44%) and headache (31%) were the most commonly reported adverse events in the zibotentan group. Cardiac failure events were higher in the zibotentan group than placebo (any grade, 5.7% and 1.7%; Common Terminology Criteria for Adverse Events grade ≥3, 3.0% and 1.0%, respectively); these were manageable and reversible. CONCLUSIONS: In this large, randomized, placebo‐controlled phase 3 trial, treatment with zibotentan 10 mg/day did not lead to a statistically significant improvement in OS in this patient population. Zibotentan had an acceptable safety profile. Cancer 2012. © 2012 American Cancer Society.