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

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 ¼ 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 ¼ 0.589) or PFS (HR: 0.89; 95% CI: 0.71-1.12, P ¼ 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 415% 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.

Atrasentan in Patients With Advanced Renal Cell Carcinoma: A Phase 2 Trial of the ECOG-ACRIN Cancer Research Group (E6800)

“…Ultimately, all studies failed to achieve their primary endpoint and further development of atrasentan has stopped. Similar results were observed for zibotentan, another endothelin antagonist 27,28,29 . Our negative study in RCC confirms the lack of significant benefit in another tumor type.…”

Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015

“…Of note, the randomised trials conducted in this setting with bone-targeted therapies with the objective of delaying the onset of bone metastases were either negative or not convincingly positive [8,44,45]. In the placebo arm of the trial testing denosumab in this setting, time to first bone metastasis was 40.8 months in the overall population, and 26 and 18.5 months in the patients with a PSA doubling time (PSA-DT) 10 and 4 months, respectively [46].…”

Efficacy of Zibotentan in Colorectal Cancer—Letter

“…However, it remains elusive why encouraging preclinical data on zibotentan were not replicated at the clinical level about prostate cancer treatment. This was not only observed in the metastatic but also in the nonmetastatic setting (4).…”