FDA approves denosumab for prevention of SREs in patients with bone metastases from solid tumors

FDA has approved denosumab (Xgeva, Amgen), the first and only RANK Ligand inhibitor for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. Xgeva was approved following a 6-month priority review by FDA. Xgeva is not indicated for the prevention of SREs in patients with multiple myeloma.

“Given the relative frequency of skeletal-related events in patients suffering from bone metastasis secondary to solid tumors, as well as the enhanced morbidity and complexity of care management in these patients, Xgeva provides a unique and promising alternative to bisphosphonate therapy in advancing the care of this patient population,” said David Calabrese, RPh, MPH, chief clinical officer, Med Metrics Health Partners, Worcester, Mass. and clinical editor of Formulary, Drug Topics’ sister publication.

In the United States alone, the total economic burden of patients with bone metastases is estimated to be $12.6 billion annually. Patients who experience an SRE as a result of bone metastases incur significantly higher medical costs compared with those who do not experience such events. In addition, once patients experience an SRE, the risk of a subsequent SRE is increased. The costs of SREs vary by type and severity, ranging from relatively low costs for minor fractures to high-cost events such as spinal-cord compression associated with hospitalization. Studies have shown that treatment of SREs constitutes a significant cost burden. Based on wholesale acquisition cost, the cost of Xgeva will be $1,650 monthly.

Xgeva is a fully human monoclonal antibody that binds to RANK Ligand, a protein essential for the formation, function, and survival of osteoclasts. Xgeva prevents RANK Ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction.

FDA approval of Xgeva is based on the results of 3 pivotal, phase 3 head-to-head trials that evaluated Xgeva delivered every 4 weeks as a 120-mg subcutaneous injection versus zoledronic acid (Zometa) delivered every 4 weeks via a 15-minute intravenous infusion, adjusted for kidney function per the labeled instructions. The clinical program for Xgeva spanned more than 50 tumor types in more than 5,700 patients. In the phase 3 trials, Xgeva demonstrated a clinically meaningful improvement in preventing SREs compared to Zometa. Specifically, in patients with breast or prostate cancer and bone metastases, Xgeva was superior to Zometa in reducing the risk of SREs. In patients with bone metastasis due to other solid tumors, or bone lesions due to multiple myeloma, XGEVA was noninferior (trending toward superiority) to Zometa in reducing the risk of SREs. Superiority was also seen in the integrated analysis of the phase 3 studies.

Overall rates of adverse events and serious adverse events were generally similar between XGEVA and Zometa. Osteonecrosis of the jaw (ONJ) was infrequent, with no statistically significant difference between treatment arms. Hypocalcemia was more frequent in the Xgeva arm. Overall survival and progression-free survival were similar between arms in all 3 trials.