Targeting the tumour microenvironment: denosumab, a new RANKL inhibitor

Bone is the most common site for metastasis and is of particular clinical importance in breast cancer, which is common and associated with a relatively long clinical course. Metastatic bone disease results from the interactions between cancer cells in the bone marrow microenvironment and normal bone cells rather than direct destruction by cancer cells. These growth factor and cytokine-mediated interactions typically lead to stimulation of both osteoclast and osteoblast function with uncoupling and imbalance in bone remodelling. This provides the rationale for bone-targeted therapies to reduce the risk of skeletal complications such as fracture, and to relieve bone pain. Additionally, bone-derived growth factors released from bone promote a fertile environment for the survival and proliferation of cancer cells, creating a vicious cycle of bone destruction. Receptor activator of NF-κB ligand (RANKL) is a key mediator in this process. Within the bone microenvironment, factors secreted by tumour cells stimulate stromal cells and osteoblasts to secrete RANKL, which binds to its cognate receptor RANK on the surface of precursor and mature osteoclasts. RANKL is a critical mediator of osteoclast differentiation, function, and survival.

Denosumab is a fully humanised monoclonal antibody that inhibits RANKL. A dose of 120 mg, 4-weekly, administered by subcutaneous injection has been defined in a large dose-finding randomised phase II study for the treatment of advanced malignancy [1]. To prevent treatment-induced bone loss, an osteoporosis dose and schedule of 60 mg every 6 months has been evaluated, and was shown to prevent aromatase inhibitor-induced bone loss [2]. The large phase III trials in metastatic bone disease comparing denosumab with zoledronic acid have completed accrual and will report in the next year.

Preclinical data suggest that denosumab is a more complete inhibitor of osteoclast function than the bisphosphonates (BPs). Additionally, a randomised phase II study in patients with increased bone resorption despite ongoing BPs has compared changing to denosumab, an antibody to RANK ligand, with continuation of the BP. This showed rapid and sustained biochemical response in >80% of patients with denosumab compared with <30% for those on standard BP treatment. Additionally, the number of skeletal events appeared to be less in the denosumab-treated patients [3]. The Austrian Breast Cancer Study Group are conducting a large randomised trial in postmenopausal women receiving endocrine treatment with the 60 mg every 6 months schedule. This is primarily to evaluate effects on bone mineral density and fractures, but with disease-free survival as a secondary endpoint. Other metastasis prevention trials are planned.