Management of bone metastases in refractory prostate cancer – role of denosumab

Abstract

This article reviews the problem of bone disease in prostate cancer and the evolving role of the novel agent denosumab, a fully human monoclonal antibody that inhibits the receptor activator of nuclear factor-ΚB ligand, in suppressing bone resorption and offering bone protection in this disease. Prostate cancer frequently metastasizes to bone, and additionally its treatment with androgen deprivation leads to accelerated bone loss resulting in clinically relevant skeletal complications associated with disabling symptoms. Among the bone-targeting therapeutic strategies investigated for the prevention of bone complications, the potent bisphosphonate zoledronic acid has been the most widely used agent for bone protection in the past decade. Denosumab is the first among a new class of osteoclast-targeting agents to show superior efficacy in several clinical scenarios in both prostate and breast cancer, as well as in osteoporosis, but the focus of this review will be on its role in prostate cancer. The safety and efficacy of denosumab versus zoledronic acid was established in a randomized trial, demonstrating a delay in skeletal-related events in metastatic castration-resistant prostate cancer patients. This study led to the approval of denosumab in the US. The chief risks of denosumab were hypocalcemia and osteonecrosis of the jaw. Denosumab was also approved for fracture risk reduction in patients on androgen-deprivation therapy for nonmetastatic prostate cancer. Although denosumab extended bone metastasis-free survival in a Phase III trial in men with castration-resistant nonmetastatic prostate cancer to a statistically significant degree, a Food and Drug Administration committee found that the effect was not sufficiently clinically meaningful for regulatory approval, and the Food and Drug Administration issued a letter concurring with the committee's recommendation. The role of denosumab in prostate cancer will continue to evolve either as monotherapy or in combination with other bone-targeting strategies.