Emerging therapies to prevent skeletal morbidity in men with prostate cancer

Abstract

Skeletal morbidity is a prominent burden to men with advanced prostate cancer throughout the natural history of the disease. Bone metastases can cause pain and greatly elevate the risk for fractures and other structural complications. Distinct from the problem of metastases, treatment-related osteoporosis and associated fragility fractures are potential complications of androgen-deprivation therapy. Bone-targeted therapies for prostate cancer have therefore been the focus of considerable research and drug development efforts. The osteoclast is a validated therapeutic target in the management of prostate cancer. Osteoclast inhibition with zoledronic acid (a bisphosphonate) or with denosumab (a monoclonal antibody to RANK ligand) reduces risk for skeletal events in men with castration-resistant prostate cancer metastatic to bone. Osteoclast inhibition with any of several bisphosphonates improves bone mineral density, a surrogate for osteoporotic fracture risk. Denosumab and toremifene (a selective estrogen receptor modulator) have each been shown to reduce osteoporotic fracture risk among men receiving androgen-deprivation therapy. Beta-emitting radiopharmaceuticals reduce pain due to metastatic disease. Investigations involving alpha-emitting radium-223, endothelin-A receptor antagonists atrasentan and zibotentan, proto-oncogene tyrosine-protein kinase (SRC) inhibitor dasatinib, and tyrosine kinase inhibitor cabozantinib (XL184) are ongoing in clinical trials and are also discussed.

Fig 1.

Spectrum of bone disease in prostate cancer. Men with prostate cancer are vulnerable to skeletal morbidity throughout the natural history of the disease and its treatment. Treatment-related osteoporosis and fractures are an early danger. The development and progression of micrometastases is later followed by risk for skeletal-related events.

Fig 2.

The role of the receptor activator of nuclear factor kappa B (RANK) and RANK ligand (RANKL) in normal bone physiology. RANK signaling is a central regulator of osteoclast differentiation, activity, and survival. Osteoblasts promote this by secreting RANKL. Osteoprotegerin (OPG) is a soluble decoy receptor for RANKL and serves as a negative regulator. GM-CFU, granulocyte-macrophage colony-forming unit. Adapted.

Fig 3.

Primary analysis of the Denosumab 103 trial. Denosumab (120 mg subcutaneously every 4 weeks) was compared with zoledronic acid (4 mg intravenously every 4 weeks) in men with castration-resistant prostate cancer metastatic to bone. Median time to first skeletal-related event (SRE) was significantly longer in the denosumab arm (20.7 v 17.1 months). Analyses for noninferiority and for superiority were both significant. HR, hazard ratio; KM, Kaplan-Meier.