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Clinical Research

Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer

Prostate Cancer and Prostatic Diseases volume 16, pages 187–192 (2013)Cite this article

Subjects

Abstract

Background:

Standard treatment options are limited for the management of non-metastatic castration-resistant prostate cancer (CRPC). This study, part of the ENTHUSE (EndoTHelin A USE) phase III programme, evaluated the efficacy and safety of the oral specific endothelin (ET)A receptor antagonist zibotentan vs placebo in patients with non-metastatic CRPC (non-mCRPC).

Methods:

This was a multicentre, randomized, double-blind, phase III study. Patients (n=1421) with non-mCRPC and biochemical progression (determined by rising serum PSA levels) were randomized to receive zibotentan 10 mg or placebo once daily. Based on the lack of efficacy signal in another ENTHUSE phase III study, an interim analysis was performed to determine whether the study was likely to achieve the co-primary objectives of improved overall survival (OS) and progression-free survival (PFS).

Results:

Criteria for continuation of this study were not met. A total of 79 deaths and 293 progression events were recorded at final data cutoff. Zibotentan-treated patients did not significantly differ from placebo-treated patients for OS (hazard ratio (HR): 1.13; 95% confidence interval (CI): 0.73–1.76, P=0.589) or PFS (HR: 0.89; 95% CI: 0.71–1.12, P=0.330). The most commonly reported adverse events in zibotentan-treated patients were peripheral oedema (37.7%), headache (26.2%) and nasal congestion (24.9%); each occurred with >15% higher incidence than in the placebo group.

Conclusions:

This trial was terminated early because of failure at interim analysis of the efficacy data to meet the defined criteria for continuation. Owing to the absence of demonstrable survival benefits in the ENTHUSE clinical studies, zibotentan is no longer under investigation as a potential treatment for prostate cancer.

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Acknowledgements

We thank Zoë van Helmond, PhD from Mudskipper Bioscience who provided writing assistance funded by AstraZeneca.

Author information

Authors and Affiliations

  1. Department of Urology, Charité–Universitätsmedizin Berlin, Berlin, Germany

    K Miller

  2. Division of Urology, Department of Surgery and Duke Prostate Center, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA

    J W Moul

  3. Vancouver Prostate Center, University of British Columbia, Vancouver, British Columbia, Canada

    M Gleave

  4. Institut Gustave Roussy, University of Paris Sud, Villejuif, France

    K Fizazi

  5. Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    J B Nelson

  6. AstraZeneca, Macclesfield, UK

    T Morris, S McIntosh & K Pemberton

  7. AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA

    F E Nathan

  8. Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA, USA

    C S Higano

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Correspondence to K Miller.

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Competing interests

KM is a consultant to AstraZeneca (AZ), Astellas and Janssen–Cilag; JWM is a paid consultant of AZ; MG, KF and CSH participated in an AZ advisory board; JBN is a paid consultant of AZ; TM, FEN, SM and KP are all employees of AZ and have stock ownership.

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Miller, K., Moul, J., Gleave, M. et al. Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 16, 187–192 (2013). https://doi.org/10.1038/pcan.2013.2

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