Bone-Targeted Agent Delays Skeletal Metastases in CRPC

Denosumab can delay bone metastases in men with castration-resistant prostate cancer (CRPC), a study found.

In a phase 3 study of 1,432 men with non-metastatic CRPC randomly assigned to receive denosumab or placebo (716 patients in each group), denosumab significantly increased bone-metastasis-free survival by a median 4.2 months compared with placebo, according to a report in The Lancet (published online ahead of print). The median survival times were 29.5 and 25.2 months, respectively. Denosumab was associated with a 15% decrease risk of bone metastasis. In addition, the drug significantly delayed the time to first bone metastasis (33.2 vs. 29.5 months). Overall survival did not differ between the denosumab and placebo arms (43.9 and 44.8 months, respectively).

The treatment arms had similar rates of adverse events (AEs) and serious AEs, except for osteonecrosis of the jaw—which developed in 33 denosumab-treated patients and in none of the placebo recipients—and hypocalcemia, which developed in 12 patients who received denosumab compared with only two who received placebo.

Denosumab is a fully human monoclonal antibody that specifically binds and inactivates RANKL, an essential mediator of osteoclast formation, function, and survival, according to researchers Matthew R. Smith, MD, of Massachusetts General Hospital Medical Center in Boston, and colleagues. In the bone microenvironment, they explained, growth factors secreted by tumor cells induce stromal cells and osteoblasts to express RANKL. "Activation of osteoclasts by RANKL results in increased bone turnover and release of growth factors from bone matrix that might promote establishment of prostate cancer in the skeleton," they noted.

"Improvement in bone-metastasis-free survival and time to first bone metastasis with denosumab treatment in our study shows that a bone-targeted agent can delay time to bone metastasis in men with prostate cancer," the investigators wrote. "Our findings also provide the first direct clinical evidence for the important role of the bone microenvironment and RANKL signaling in the development of bone metastases in men with prostate cancer."