Top-line results from the pivotal phase III ‘147 study evaluating denosumab (Xgeva?, Amgen) versus placebo in 1,432 men with castrate-resistant prostate cancer demonstrated that the new drug significantly improved median bone metastasis-free survival by 4.2 months (HR=0.85, 95 percent CI 0.73-0.98, p=0.03) compared to placebo (primary endpoint), and significantly improved time to first occurrence of bone metastases (secondary endpoint). Overall survival was similar between the denosumab and placebo groups (secondary endpoint).

Overall rates of adverse events and serious adverse events were generally similar between denosumab and placebo, with hypocalcemia and osteonecrosis of the jaw (ONJ) observed at increased frequencies in the denosumab arm. The yearly rate of ONJ in the denosumab-treated group was similar to what has been observed in prior denosumab trials.

Bone metastases occur in more than 1.5 million patients with cancer worldwide and are most commonly associated with cancers of the prostate, lung, and breast, with incidence rates as high as 75 percent of patients with metastatic disease. [1] The total economic burden of patients with bone metastases in the U.S. alone estimated to be $12.6 billion annually.

“Our data demonstrate that Xgeva, which antagonizes the RANK Ligand axis, limits the ability of tumors to colonize bone, an important finding for men at risk for bone metastases and their healthcare providers,” said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. “We look forward to presenting these landmark data at an upcoming medical conference.”

The RANK Ligand pathway, first discovered by Amgen scientists in the mid-1990s, is believed to play a central role in cancer-induced bone destruction, regardless of cancer type. Data suggest that in bone metastasis, the invasion of cancer is facilitated by bone destruction. Hence, increased bone resorption due to increased RANK Ligand expression appears to augment bone metastasis.

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Denosumab is a fully human monoclonal antibody that binds to RANK Ligand, a protein essential for the formation, function and survival of osteoclasts (the cells that break down bone). Denosumab prevents RANK Ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and halting release of growth factors, making the environment less conducive to tumor growth. Study ‘147 was a randomized, placebo-controlled, multi-center Phase III study comparing the treatment effect of denosumab with placebo on prolonging bone metastasis-free survival in men with hormone-refractory (castrate-resistant) prostate cancer with rapidly-rising PSA levels who had no bone metastases at baseline. The primary endpoint of the trial was time to first occurrence of bone metastasis or death from any cause, with secondary endpoints including time to first occurrence of bone metastasis (excluding death) and overall survival.

Regulatory Status
Denosumab was approved by the U.S. Food and Drug Administration (FDA) for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors on November 18, 2010. The drug is not indicated to prevent SREs in patients with multiple myeloma. Administered as a single 120 mg subcutaneous injection every four weeks, denosumab provides a new option for urologists and oncologists to prevent serious bone complications in men with prostate cancer.

Studies show that the most common adverse reactions in patients receiving denosumab were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction in patients receiving denosumab was dyspnea. The most common adverse reactions resulting in discontinuation of denosumab were osteonecrosis and hypocalcemia.

Denosumab is also marketed as Prolia? in other indications.

[1] Coleman RE. Skeletal complications of malignancy. Cancer. 1997; 80(suppl): 1588-1594.

For more information:
Denosumab Approved To Help Prevent Cancer-Related Bone Injury

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