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.
RCT Entities:
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.
Authors: Maha Hussain; Karim Fizazi; Fred Saad; Per Rathenborg; Neal Shore; Ubirajara Ferreira; Petro Ivashchenko; Eren Demirhan; Katharina Modelska; Andrew Krivoshik; Cora N Sternberg Journal: N Engl J Med Date: 2018-06-28 Impact factor: 91.245
Authors: Yu Pan; Chun Hu; Pei Hua Chen; Yan Hong Gu; Qing Yan Qiao; Li Hua Pan; Dong Chi Zhou; Hui Fang Gu; Shun Kun Fu; Hui Min Jin Journal: Eur J Clin Pharmacol Date: 2016-12-13 Impact factor: 2.953
Authors: Inés Pulido; Stephen Ollosi; Salvador Aparisi; Jeffrey H Becker; Alicia Aliena-Valero; Marta Benet; María L Rodríguez; Adrián López; Eva Tamayo-Torres; Lourdes Chuliá-Peris; Juan Carlos García-Cañaveras; Margaret Soucheray; Annika V Dalheim; Juan B Salom; Wei Qiu; Simon Kaja; Javier Alcácer Fernández-Coronado; Sandra Alandes; Javier Alcácer; Fátima Al-Shahrour; Jeffrey A Borgia; Oscar Juan; Michael I Nishimura; Agustín Lahoz; Julián Carretero; Takeshi Shimamura Journal: Cancer Res Date: 2020-08-03 Impact factor: 12.701