Prevention of Bone Metastases in Patients with High-risk Nonmetastatic Prostate Cancer Treated with Zoledronic Acid: Efficacy and Safety Results of the Zometa European Study (ZEUS)

Background: Patients with high-risk localised prostate cancer (PCa) are at risk of developing bone metastases (BMs). Zoledronic acid (ZA) significantly reduces the incidence of skeletal complications in castration-resistant metastatic PCa versus placebo. Objective: To investigate ZA for the prevention of BMs in high-risk localised PCa. Design, setting, and participants: Randomised open-label multinational study with patients having at least one of the following: prostate-specific antigen ≥20 ng/ml, node-positive disease, or Gleason score 8-10. Intervention: Standard PCa therapy alone or combined with 4 mg ZA intravenously every 3 mo for ≤4 yr. Outcome measurements and statistical analysis: BMs were assessed using locally evaluated bone-imaging procedures (BIPs), with subsequent blinded central review. Patients with BMs, time to BMs, overall survival, and adverse events were compared between treatment groups. Results and limitations: A total of 1393 of 1433 randomised patients were used for intention-to-treat (ITT) efficacy analyses, with 1040 patients with BIP-BM outcome status at 4 ± 0.5 yr. The local urologist/radiologist diagnosed BIP-BMs in 88 of 515 patients (17.1%) in the ZA group and 89 of 525 patients (17.0%) in the control group (chi-square test: p = 0.95), with a difference between proportions of 0.1% (95% confidence interval [CI], -4.4 to 4.7) in favour of the control group. In the ITT population (n = 1393), the Kaplan-Meier estimated proportion of BMs after a median follow-up of 4.8 yr was 14.7% in the ZA group versus 13.2% in the control group (log-rank: p = 0.65). Low hot spot numbers on bone scans were confirmed as metastases with additional imaging. Central reviews of BIPs were possible only on a subset of patients. Conclusions: ZA administered every 3 mo was demonstrated to be ineffective for the prevention of BMs in high-risk localised PCa patients at 4 yr. Patient summary: Zoledronic acid administered every 3 mo was demonstrated to be ineffective for the prevention of bone metastases in high-risk nonmetastatic PCa patients at 4 yr. Trial registration: The ZEUS trial is registered in the Dutch trial register www.trialregister.nl and the ISRCTN register at http://www.controlled-trials.com/ISRCTN66626762. © 2014 European Association of Urology.