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New indication: Denosumab (Xgeva) has been approved for prevention of skeletal-related events from bone metastases from solid tumors.
As many as 3 out of 4 patients with advanced cancer, including that of the breast, lung, and prostate, will experience metastases to their bones resulting in substantial pain and suffering. Weakened bones due to metastases may lead to fractures and compression of the spinal cord and require procedures such as major surgery and radiation. On November 18, 2010, after a 6-month priority review, FDA approved denosumab, the first RANK ligand inhibitor indicated for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors (not indicated in patients with multiple myeloma).
Efficacy. Data on denosumab's efficacy for the prevention of SREs (defined as a pathologic fracture, radiation therapy or surgery to bone, or spinal cord compression) in patients with bone metastases from solid tumors are based on 3 randomized, double-blind clinical trials comparing denosumab (administered every 4 weeks as a 120-mg subcutaneous injection) to zoledronic acid (Zometa; administered every 4 weeks as a 15-minute intravenous infusion) with a total enrollment of 5,723 patients. One trial enrolled only patients with breast cancer; the second trial enrolled only patients with prostate cancer; and a third trial enrolled patients with a variety of other cancers. Denosumab was found to delay the time to first SRE compared to zoledronic acid in patients with breast cancer or castrate-resistant prostate cancer with osseous metastases. In patients with bone metastasis due to other solid tumors, denosumab was noninferior to zoledronic acid in delaying the time to first SRE. Overall survival and progression-free survival were similar between arms in all 3 trials. Of note, mortality was higher with denosumab in a subgroup analysis of patients (n=180) with multiple myeloma.
Safety. The most common adverse reactions in patients receiving denosumab were fatigue/asthenia (45%), hypophosphatemia (32%), and nausea (31%). Also of concern is severe hypocalcemia (3.1%) and osteonecrosis (1.8%). These later 2 adverse events were the most common causes of drug discontinuation in clinical trials.