In a Phase 3, head-to-head trial of Denosumab versus Zoledronic acid ( Zometa ) in the treatment of bone metastases in 2,046 patients with advanced breast cancer, Denosumab met both primary and secondary endpoints and demonstrated superiority for both delaying the time to the first on-study skeletal related events ( SRE ) ( fracture, radiation to bone, surgery to bone, or spinal cord compression ) ( hazard ratio, HR=0.82 ), and delaying the time to the first-and subsequent SREs ( multiple SREs ) ( HR=0.77 ).
Both results were statistically significant.

Additional data from this study showed that Denosumab significantly reduced the mean annual skeletal morbidity rate ( SMR ) compared with Zometa ( 0.45 vs. 0.58, respectively; p=0.004 ).

Overall, the incidence of adverse events ( 96 percent Denosumab, 97 percent Zometa ) and serious adverse events ( 44 percent Denosumab, 46 percent Zometa ) was consistent with what has previously been reported for these two agents.
Adverse events potentially associated with acute phase reactions during the first three days of the study were reported in 10.4 percent of the Denosumab arm and 27.3 percent of the Zometa arm.
Adverse events potentially associated with renal toxicity occurred in 4.9 percent of patients treated with Denosumab compared to 8.5 percent in patients treated with Zometa.
Osteonecrosis of the jaw ( ONJ ) was seen infrequently in both treatment groups ( 20 patients receiving Denosumab [ 2.0 percent ] as compared with 14 patients [ 1.4 percent ] receiving Zometa ).
Rates of new primary malignancies were similar between treatment arms ( 5 patients receiving Denosumab [ 0.5 percent ] and 5 receiving Zometa [ 0.5 percent ] ).

This is an international, Phase 3, randomized, double-blind study comparing Denosumab with Zometa in the treatment of bone metastases in patients with advanced breast cancer. Patients enrolled in the study were randomized in a one-to-one ratio to receive either 120 mg of Denosumab subcutaneously every four weeks ( Q4W ) or Zometa administered intravenously at a dose of 4 mg in a 15 minute infusion every four weeks.

The primary endpoint was to evaluate if Denosumab is non-inferior to Zometa with respect to the first, on-study SRE in patients with advanced breast cancer and bone metastases. Secondary endpoints were to evaluate if Denosumab was superior to Zometa with respect to the first, on-study SRE, as well as the first-and-subsequent on-study SREs, and to assess the safety and tolerability of Denosumab compared with Zometa. Other endpoints included time to first radiation of bone; time to first on-study SRE or hypercalcemia of malignancy; skeletal morbidity rate; and the proportion of patients with at least 1 on-study SRE.

Denosumab is the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK Ligand, the essential regulator of osteoclasts.

Source: Amgen, 2009


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