Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial.

Background: The endothelin-A receptor (ETAR) has been implicated in the progression of prostate cancer.

Objectives: To investigate the safety and efficacy of the specific ETAR antagonist ZD4054 in patients with metastatic hormone-resistant prostate cancer (HRPC).

Design, Setting, And Participants: Double-blind, placebo-controlled, randomised, parallel-group, multicentre, phase 2 trial in patients attending cancer centres with HRPC and bone metastases who were pain free or mildly symptomatic for pain.

Intervention: Patients were randomised to receive once-daily oral tablets of ZD4054 10 mg, or ZD4054 15 mg, or placebo.

Measurements: The primary end point was time to progression, defined as clinical progression, requirement for opiate analgesia, objective progression of soft-tissue metastases, or death in the absence of progression. Secondary end points included overall survival, time to prostate-specific antigen (PSA) progression, and safety. Statistical significance was preset at 20%.

Results And Limitations: A total of 312 patients were randomised (ZD4054 10 mg, n=107; ZD4054 15 mg, n=98; placebo, n=107). At the primary analysis, median time to progression was 3.6 mo, 4.0 mo, and 3.8 mo in the placebo, ZD4054 10 mg, and ZD4054 15 mg groups, respectively, with no statistically significant difference between ZD4054 groups and placebo (hazard ratio [HR] vs placebo for the ZD4054 10mg group: 0.88 [80% CI: 0.71-1.09]; HR vs placebo for the ZD4054 15 mg group: 0.83 [80% CI: 0.66-1.03]). However, a signal for prolonged overall survival was observed in the ZD4054 treatment groups versus placebo, based on 40 deaths. At a subsequent analysis after 118 deaths, this survival benefit was confirmed (HR vs placebo for the ZD4054 10 mg group, 0.55 [80% CI: 0.41-0.73], p=0.008; HR vs placebo for the ZD4054 15 mg group, 0.65 [80% CI: 0.49-0.86], p=0.052) but the differences in time to progression remained nonsignificant. Median overall survival was 17.3 mo, 24.5 mo, and 23.5 mo in the placebo group, the ZD4054 10 mg group, and the ZD4054 15 mg group, respectively. Discordance between results for time to progression and overall survival may be due to the sensitivity of the definition of progression. Adverse events were in line with the expected pharmacologic effects of an ETAR antagonist.

Conclusions: The primary end point of time to progression was not achieved in this study, but an improvement was seen in overall survival in both active treatment arms. ZD4054 was well tolerated.

Trial Registration: Clinicaltrials.gov NCT00090363.