by ecancer reporter Janet Fricker

Denosumab has been found to be superior to zoledronic acid, in delaying or preventing skeletal related events (SRE) in breast cancer patients with bone metastases, reports a study in the Journal of Clinical Oncology.

Up to 80% of patients with metastatic breast cancer develop bone metastases that induce increased osteoclast activity resulting in local bone destruction and skeletal complications, including pain, hypercalcemia and skeletal related events (SREs) . Intravenous bisphosphonates, such as zoledronic acid, are effective in preventing SREs. SREs, however, still occur in a large proportion of patients, and furthermore creatinine screening is required to protect against nephrotoxicity, with the possibility that management may be further complicated by the development of flu-like symptoms.  It has therefore been recognised that new treatments are needed to further reduce SREs and limit toxicity.

Denosumab is the first fully human monoclonal antibody developed to specifically target the RANK Ligand,  which is a key mediator of osteoclast formation, function and survival.  Denosumab has been demonstrated to reduce bone resorption, tumour-induced bone destruction and SREs.

In the current double blind phase 3 study, Alison Stopeck and colleagues from the University of Arizona (Tucson, Arizona), randomised breast cancer patients with evidence of at least one bone metastasis to receive either subcutaneous denosumab 120 mg and intravenous placebo (N=1,026) or intravenous zoledronic acid 4mg (adjusted for creatinine clearance) and subcutaneous placebo (N=1,020) every four weeks.  The primary endpoint was time to first on study SRE (defined as a pathologic fracture, radiation or surgery to bone, or spinal cord compression).

Results showed that denosumab significantly delayed time to first on-study SRE by 18% compared with zoledronic acid (HR, 0.82; 95% CI, 0.71 to 0.95; P<.01).  Furthermore, denosumab reduced the risk of developing multiple SREs (time to first and subsequent SREs) by 23% compared with zoledronic acid (rate ratio, 0.77, 95%CI, 0.66 to 0.89; p= .001). Overall survival, disease progression and rates of adverse events (AEs) and serious AEs were similar between the groups, with renal AEs and acute phase reactions occurring more frequently with zoledronic acid, and  hypocalcemia occurring more frequently with denosumab.

 “Denosumab was superior to zoledronic acid for delaying or preventing SREs and has several potentially beneficial characteristics for patients, including the avoidance of renal toxicity and acute phase reactions and the convenience of a subcutaneous injection,” concluded the authors.

Use of  denosumab, they added,  is likely to represent a  particularly helpful therapeutic option for patients with chronic renal failure, renal insufficiency and those receiving nephrotoxic platinum-based chemotherapy regiments.

Reference

A T Stopeck, A Lipton, JJ Body et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomised, double-blind study. JCO.

DOI: 10.1200/JCO.2010.29.7101