A critical week for denosumab

Tomorrow (Thursday) an advisory committee to the US Food and Drug Administration (FDA) meets to decide whether to recommend approval of Amgen’s new RANK-L inhibitor, denosumab, which offers an entirely new mechanism for the reduction of the risk of fractures and other skeletal related events (SREs) caused by long term hormone therapy (both in patients with breast cancer and those with prostate cancer).

New data published yesterday in the New England Journal of Medicine clearly suggests that denosumab has a significant effect compared to placebo in men with prostate cancer. In this double-blind, randomized, multicenter study reported by Smith et al.:

  • Patients were randomized to receive either denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (734 patients in each group).
  • The primary end point was percent change in bone mineral density at the lumbar spine at 24 months.
  • Secondary end points included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at all three sites at 36 months, as well as incidence of new vertebral fractures.
  • At 24 months, bone mineral density of the lumbar spine had increased by 5.6 percent in the patients receiving denosumab as compared with a loss of 1.0 percent in the patients receiving placebo (P<0.001).
  • Denosumab therapy was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third of the radius at all time points.
  • Patients who received denosumab had an incidence of new vertebral fractures of 1.5 percent at 36 months compared to an incidence of 3.9 percent in patients treated with the placebo.
  • Rates of adverse events were similar between the two groups.

However, the FDA has expressed concern about the potential effects of denosumab on patients’ immune systems. And it seems likely to The “New” Prostate Cancer InfoLink that approval of denosumab may come with some fairly strong warnings. Specifically, the FDA is most concerned that over-use of denosumab has the potential to induce serious infections and certain types of secondary cancers.

The “New” Prostate Cancer InfoLink believes that the FDA will approve denosumab. What is less clear at this point in time is whether denosumab offers significant benefits compared to bisphosphonate therapy in patients receiving hormone therapy for advanced prostate cancer — particularly in light of the other report yesterday suggesting that bisphosphonate therapy may be associated with an overall survival benefit in men with metastatic prostate cancer.

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