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Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone.

Publication ,  Journal Article
Nelson, JB; Fizazi, K; Miller, K; Higano, C; Moul, JW; Akaza, H; Morris, T; McIntosh, S; Pemberton, K; Gleave, M
Published in: Cancer
November 15, 2012

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.

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Published In

Cancer

DOI

EISSN

1097-0142

Publication Date

November 15, 2012

Volume

118

Issue

22

Start / End Page

5709 / 5718

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Survival
  • Pyrrolidines
  • Prostatic Neoplasms
  • Placebos
  • Orchiectomy
  • Oncology & Carcinogenesis
  • Male
  • Humans
  • Endothelin-1
 

Citation

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Nelson, J. B., Fizazi, K., Miller, K., Higano, C., Moul, J. W., Akaza, H., … Gleave, M. (2012). Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone. Cancer, 118(22), 5709–5718. https://doi.org/10.1002/cncr.27674
Nelson, Joel B., Karim Fizazi, Kurt Miller, Celestia Higano, Judd W. Moul, Hideyuki Akaza, Thomas Morris, Stuart McIntosh, Kristine Pemberton, and Martin Gleave. “Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone.Cancer 118, no. 22 (November 15, 2012): 5709–18. https://doi.org/10.1002/cncr.27674.
Nelson JB, Fizazi K, Miller K, Higano C, Moul JW, Akaza H, et al. Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone. Cancer. 2012 Nov 15;118(22):5709–18.
Nelson, Joel B., et al. “Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone.Cancer, vol. 118, no. 22, Nov. 2012, pp. 5709–18. Pubmed, doi:10.1002/cncr.27674.
Nelson JB, Fizazi K, Miller K, Higano C, Moul JW, Akaza H, Morris T, McIntosh S, Pemberton K, Gleave M. Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone. Cancer. 2012 Nov 15;118(22):5709–5718.
Journal cover image

Published In

Cancer

DOI

EISSN

1097-0142

Publication Date

November 15, 2012

Volume

118

Issue

22

Start / End Page

5709 / 5718

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Survival
  • Pyrrolidines
  • Prostatic Neoplasms
  • Placebos
  • Orchiectomy
  • Oncology & Carcinogenesis
  • Male
  • Humans
  • Endothelin-1