By ecancer reporter Jo Armstrong

Presentation: Bone targeting in prostate cancer - K. Fizazi

The skeleton is the primary site of metastases in patients with advanced prostate cancer, and virtually all patients who die from prostate cancer have bone metastases. Under normal conditions, bone undergoes continuous remodelling in a tightly coordinated and balanced process of bone resorption (mediated by osteoclasts) and bone formation (mediated by osteoblasts). In bone metastases, a perturbation between osteoblast and osteoclast is induced by tumour cell and consisting in a "vicious cycle. Bisphosphonates are potent inhibitors of osteoclastic bone resorption and until recently, zoledronic acid was the only bisphosphonate to demonstrate in a randomized trial a reduction in the incidence of skeletal-related events (SRE). Besides bisphosphonates, the main and currently most advanced attempts to target osteoclast activation by cancer cells include denosumab, a fully human monoclonal antibody directed to RANK-L, which was shown to reduce urinary N-telopeptide (uNTx) levels significantly better than zoledronic acid does in patients with bone metastases and elevated levels while on IV bisphosphonate. Denosumab was recently demonstrated to be superior to zoledronic acid in preventing or delaying SRE in patients with bone metastases from castration-resistant prostate cancer (CRPC) in a large phase III trial. Activation of the endothelin A (ETA) receptor by endothelin-1 mediates a signalling cascade, which promotes tumour cell growth and survival, angiogenesis, invasion and metastasis, and inhibition of apoptosis. Zibotentan (ZD4054) is an oral, specific ETA receptor antagonist with promising results in a randomised phase II trial. A large phase III programme is ongoing (ENTHUSE) to evaluate zibotentan in CRPC in various settings: in prevention of bone metastases, before chemotherapy, and in combination with docetaxel. Dasatinib, a src inhibitor was also demonstrated to result in decreased uNTx levels in patients with bone metastases and is currently assessed in a phase III study. Finally, phase II data support the use of a bone-targeting strategy combining chemotherapy and radiopharmaceuticals like samarium-153ⁱⁱⁱ or strontium-89.