A monoclonal antibody that disrupts the activation of osteoclasts increased bone-metastasis-free (BMF) survival in men with prostate cancer in a recent large trial.

Denosumab, which is FDA-approved for the treatment of osteoporosis and the prevention of fractures in patients with bone metastases from solid tumors, works against a signaling protein known as RANKL, which activates osteoclasts to cause bone resorption. Animal studies have indicated that inhibiting osteoclasts can prevent metastasis, and that the expression of RANKL on cancer cells may prepare the bone microenvironment for tumor spread. Bone metastases are a major cause of morbidity and mortality in men with prostate cancer.

A team led by Professor Matthew R. Smith, MD, of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts, conducted a phase 3, double-blind, randomized, placebo-controlled study of 1,432 men across 30 countries who had non-metastatic castration-resistant prostate cancer. The men, who were deemed to be at high risk of bone metastasis based on having prostate-specific antigen (PSA) readings on 8.0 μg/L or higher or PSA doubling time of no more than 10 months, or both, were assigned to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks.

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Although overall survival did not differ between groups (43.9 months with denosumab vs 44.8 months with placebo), denosumab significantly increased bone-metastasis-free survival by a median of 4.2 months compared with placebo (median BMF survival 29.5 months vs 25.2 months). The agent also significantly delayed time to first bone metastasis: 33.2 months for the denosumab patients compared with 29.5 months among the placebo users.

Osteonecrosis of the jaw developed in 33 (5%) of the 716 men receiving denosumab and in none of the 716 placebo users. Hypocalcemia was also more prevalent in the denosumab group, occurring in 12 (2%) patients compared with two (less than 1%) in the placebo group. Rates of other adverse and serious adverse events were similar in the two groups.

Smith and colleagues concluded in The Lancet that targeting the bone microenvironment can delay bone metastasis in men with prostate cancer.