RANK ligand inhibitor delays development of PCa bone metastasis

Treatment with the RANK ligand inhibitor denosumab (XGEVA) is effective at delaying the development of bone metastases in men with nonmetastatic castration-resistant prostate cancer, according to a recent multicenter study.

"Prostate cancer patients who develop bone metastases usually have poor outcomes, so preventing the development of metastasis has been a major unmet clinical need," said first author Matthew Smith, MD, PhD, of Harvard Medical School, Boston. "This first demonstration of a treatment that can meet that goal is a significant accomplishment that should lead to better treatment strategies."

The study, which was published online in Lancet (Nov. 15, 2011), enrolled 1,432 prostate cancer patients whose tumors had stopped responding to androgen deprivation therapy and were metastasis-free, although rising PSA levels indicated they were at risk for metastasis. Study participants were from 319 centers in 30 countries.

Participants were randomly assigned to receive injections of either denosumab or a placebo every 4 weeks. During the 2-year study period, patients were examined every 4 months, and x-ray skeletal surveys were performed annually. If a bone scan indicated the presence of metastasis, it was confirmed with either x-ray, computed tomography, or magnetic resonance imaging, and study treatment was discontinued.

Results indicated that denosumab treatment increased bone metastasis-free survival by an average of more than 4 months, extended the time to first metastasis, and delayed symptoms of metastasis. Biochemical markers indicated that denosumab treatment reduced bone turnover. While there was no survival difference between the two study groups, the authors note that the fact that denosumab was discontinued when the first metastasis was diagnosed makes judging the drug’s effects on survival difficult.

Based on the results of this study, Amgen Inc., the maker of denosumab, filed a supplemental biologics license application to expand the indication for denosumab to treat men with castration-resistant prostate cancer to reduce the risk of developing bone metastases. The FDA has set April 26, 2012 as the targeted Prescription Drug User Fee Act action date for the application.

Dr. Smith is a consultant/adviser and investigator for Amgen.

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