Denosumab In Prostate Cancer Research Articles

Role of denosumab in prostate cancer

Prostate cancer is known to have a tissue tropism for bone. This tissue tropism coupled with the experience with androgen deprivation therapy (ADT) over the past decade has led to heightened awareness of bone complications. Osteopenia and subsequent skeletal-related events (SREs) are one of the more concerning repercussions of ADT along with cardiovascular sequelae. To combat this decrease in bone mineral density, several agents have been developed for bone protection. The largest experience is with bisphosphonates (BPs), but recently (2011) head to head trials have established the role of monoclonal antibodies, particularly in patients with prostate cancer bone metastasis. For patients initiating ADT, monthly denosumab increased bone mineral density, the time for occurrence of any bone metastasis and time for symptomatic bone metastasis. Denosumab is a fully human monoclonal antibody of the IgG(2) subtype that selectively binds and neutralizes receptor activator NF kappa B ligand (RANKL), inhibiting osteoclastogenesis and bone turnover. In vitro binding assays have shown high-affinity binding of denosumab and osteoprotegerin to both soluble and membrane-bound forms of human RANKL. As clinicians may be less familiar with this newer agent, we compiled this review to summarize denosumab's current clinical indications for bone stabilization and mechanism of reduction in tumor burden.

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

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.

Unravelling the role of denosumab in prostate cancer

Advances in cancer therapies have brought about changes in the treatment of metastatic prostate cancer. Because prostate cancer usually metastasises to the bone, 1 Carlin BI Andriole GL The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma. Cancer. 2000; 88: 2989-2994 Crossref PubMed Google Scholar strategies to target the bone are being actively developed (panel). Zoledronic acid was the first approved agent for retarding skeletal events in men with metastatic prostate cancer, on the basis of the phase 3 trial 2 Saad F Gleason DM Murray R et al. for the Zoledronic Acid Prostate Cancer Study GroupA randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002; 94: 1458-1468 Crossref PubMed Scopus (1449) Google Scholar showing that it was superior to placebo. Since then, this drug has become a standard adjunctive treatment for men with prostate cancer with bone metastases. PanelTherapeutic strategies targeting bone signalling and metastases in prostate cancerTargeting bone-forming osteoblasts •Bone-seeking radiopharmaceuticals (samarium-153, strontium-89) •Inhibition of endothelin axis (ZD4054) •Targeting insulin-like growth factor (IGF) axis •Targeting transforming growth factor (TGF) axis, Wnt signalling, and bone morphogenic proteins (BMP) pathways Targeting bone-resorptive osteoclasts •Bisphosphonates (zoledronic acid) •Inhibition of receptor activator of nuclear factor κ-B ligand (RANKL; denosumab) •Inhibition of osteoclast function (cathepsins, Src homology 2 inhibitors, interleukin-6 inhibitors) Targeting bone-forming osteoblasts •Bone-seeking radiopharmaceuticals (samarium-153, strontium-89) •Inhibition of endothelin axis (ZD4054) •Targeting insulin-like growth factor (IGF) axis •Targeting transforming growth factor (TGF) axis, Wnt signalling, and bone morphogenic proteins (BMP) pathways Targeting bone-resorptive osteoclasts •Bisphosphonates (zoledronic acid) •Inhibition of receptor activator of nuclear factor κ-B ligand (RANKL; denosumab) •Inhibition of osteoclast function (cathepsins, Src homology 2 inhibitors, interleukin-6 inhibitors) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind studyDenosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer. Full-Text PDF