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

Abstract

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 ¼ 299; placebo, n ¼ 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 ¼ .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

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

“…10 Results from this interim analysis revealed that the criteria for continuation of this study were not met; consequently, the study was terminated early. It should be noted that the early cessation of the trial (leading to reduced post-randomization power) and low numbers of observed mortality and PFS events (as evidenced by the large confidence intervals associated with end point estimates) represent a major study limitation and preclude definitive conclusions regarding the efficacy of the study treatment.…”

“…Results from the two monotherapy studies documented a failure of zibotentan to demonstrate a significant benefit over placebo, irrespective of metastasis. 10 Encouraging preclinical data and initial clinical evidence supported investigation of zibotentan in combination with docetaxel in the phase III setting; [11][12][13][14] however, ENTHUSE M1C failed to confirm superiority for the zibotentan and docetaxel combination in mCRPC. 15 Collectively, results from the ENTHUSE programme, while disappointing, are consistent with those of the selective ET A receptor antagonist atrasentan, which produced positive phase II data, 11,16,17 but which also failed to significantly impact disease progression in the phase III setting.…”

“…The absence of a significant survival benefit in the phase III ENTHUSE M1 study (NCT00554229), 10 prompted an interim analysis of data in this study to assess the feasibility of achieving the co-primary objectives of the study, the findings of which precipitated early termination of the study (data cutoff (DCO): 1 October 2010). As a consequence, all patients were discontinued from study treatment, with collection of data limited thereafter to safety end points until final DCO (27 June 2011).…”

Predictors of Congestive Heart Failure after Treatment with an Endothelin Receptor Antagonist

“…Although ASCEND was the first study that showed an increased CHF risk after ERA treatment, earlier studies with both nonselective ERAs (9,10) as well as with endothelin-A selective antagonists (11,(16)(17)(18) showed clinical signs suggestive of fluid retention. The exact mechanisms responsible for these fluid-retaining effects are not yet fully understood.…”

Cancer-targeted therapies and radiopharmaceuticals

“…23 Another trial using the ET-1 receptor antagonist named zibotentan (ZD4054) failed to provide a significant clinical benefit in patients with prostate cancer when applied singularly and in combination with docetaxel. 24,25 In summary, although there is evidence of bone regulating potential by ET-1 modulation, up to date studies of ET-1 inhibition have failed to provide clinical benefit in patients with advanced prostate cancer.…”