Biotechnology giant Amgen (AMGN) Monday said its drug candidate denosumab met its primary and secondary endpoints, compared to Novartis AG's (NVS) Zometa, in delaying bony complications in patients suffering from metastatic prostate cancer.
The pivotal, Phase 3, head-to-head trial evaluated denosumab in comparison with Zometa or zoledronic acid in the treatment of bone metastases in 1,901 men with advanced prostate cancer. Denosumab demonstrated superiority over Zometa in delaying the time to the first on-study skeletal related event, or SRE, such as fracture, radiation to bone, surgery to bone or spinal cord compression. It also showed superiority in reducing the rate of multiple SREs. Both results were statistically significant, Amgen said.
Denosumab is the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK ligand, the essential regulator of osteoclasts or the cells that break down bone. In bone metastases, those cancer cells that separate from tumors and migrate to bone tissue settle and grow there. This condition occurs in more than 1.5 million people worldwide. With bone metastases the growing cancer cells weaken and destroy the bone around the tumor, leading to the SREs. All are serious complications for advanced cancer patients.
The study was international, randomized and double-blind. Patients were randomized in a one-to-one ratio to receive either 120 mg of denosumab subcutaneously every four weeks or Zometa administered intravenously as at least a 15 minute infusion at a dose of 4 mg every four weeks. The mean age of the 1,901 patients enrolled in the study, who had bone metastases from hormone-refractory prostate cancer, was 71.
The primary and secondary endpoints of the denosumab bone metastases studies used a composite endpoint of four SREs - fracture, radiation to bone, surgery to bone, and spinal cord compression - to measure the effectiveness of denosumab compared to Zometa.
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 prostate 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 first-and-subsequent on-study SREs, and to assess the safety and tolerability of denosumab compared with Zometa.
According to Amgen, overall rates of adverse events and serious adverse events, including infections, were generally similar between the two arms. Osteonecrosis of the jaw was infrequent and there was no statistically significant difference between treatment arms, the company said. While the condition was found in 22 patients receiving denosumab, 12 patients receiving Zometa also showed osteonecrosis of the jaw. However, hypocalcemia was more frequent in the denosumab arm, as with previous studies in advanced cancer patients. Both overall survival and the time to cancer progression were balanced between treatment arms.
Commenting on the results, Roger Perlmutter, executive vice president of Research and Development at Amgen, said, "These Phase 3 results demonstrate the ability of denosumab to delay bony complications in patients suffering from metastatic prostate cancer. Denosumab has shown remarkable consistency in reducing the serious complications of bone metastases. Today's results greatly enhance our understanding of the efficacy of denosumab in multiple different tumor types."
This was the final study out of three pivotal trials investigating the potential of denosumab to treat bone metastases, conducted in over 5,700 advanced cancer patients. Results from the previous two trials were presented in September 2009. These three studies would form the basis of the clinical evidence package for denosumab in advanced cancer and would be submitted to regulatory authorities later this year, Amgen said.
The company will submit the full efficacy and safety data for the prostate cancer study to the American Society for Clinical Oncology, for possible presentation at their meeting in early June.
The company is expecting in the second half of the year results from a study investigating whether denosumab may prolong bone metastasis-free survival in prostate cancer patients.
Bone metastases are a significant problem for patients with certain types of advanced cancer, with incidence rates of nearly 100% in myeloma patients and up to 75% in breast and prostate cancer patients.
Amgen had said in September 2009 that a Phase 3, head-to-head trial evaluating denosumab in comparison with Zometa for the treatment of bone metastases in patients with advanced breast cancer met its primary and secondary endpoints and demonstrated superior efficacy.
In October, FDA had sought additional information for the Biologic License Applications for denosumab in the treatment and prevention of postmenopausal osteoporosis. In a Complete Response Letter, the FDA requested a new clinical program to support approval of the experimental drug for the prevention of postmenopausal osteoporosis indication.
AMGN closed Monday's regular trade at $57.46, down $0.22 or 0.38%, on 5.95 million shares. In the extended trade, the stock added $1.56 or 2.71% and was trading at $59.02.
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