Osteoclast inhibitors to prevent bone metastases in men with high-risk, nonmetastatic prostate cancer: A systematic review and meta-Analysis

Background: In advanced prostate cancer, osteoclast inhibitors prevent and palliate skeletal related events associated with bone metastases. However, it is uncertain whether they play a disease-modifying role earlier in the course of the disease. Methods: Medline, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews and ASCO conference proceedings were searched for randomized controlled trials that compared osteoclast inhibitors with placebo and/or standard of care (SOC) in patients with high-risk, non-metastatic prostate cancer. The primary outcome measure was incidence of new bone metastases; secondary outcomes included overall survival (OS), prostate cancer specific survival, mortality unrelated to prostate cancer, toxicity and health related quality of life outcomes. Results are presented as relative risk (RR) with 95% confidence intervals (CI). Results: Six randomized controlled trials (5947 participants) were included, five evaluating bisphosphonates and one denosumab. Overall, there was no difference in incidence of bone metastases between participants treated with osteoclast inhibitors versus placebo/SOC (RR 1.09, 95%CI 0.84-1.41, p = 0.51) however significant heterogeneity was observed between studies. The denosumab trial was the largest and only positive trial amongst the included studies (RR 0.83, 95%CI 0.73-0.95, p = 0.007). No significant difference was observed in OS (RR 0.99 95% CI 0.89-1.10, p = 0.84) nor prostate cancer specific survival (RR 1.12 95%CI 0.93-1.36, p = 0.24). Most studies reported increased rates of osteonecrosis of the jaw (5% or less) and hypocalcemia (2% or less) with osteoclast inhibitors. Conclusions: While there is limited evidence that bisphosphonates alter the natural history of high-risk, non-metastatic prostate cancer, denosumab delays onset of bone metastases in this patient population. Neither class of osteoclast inhibitor demonstrated an impact on survival outcomes. Future trials with better defined patient selection and a robust definition for high risk disease is critical