Denosumab (XGEVA?, Amgen) is better than zoledronic acid (Zometa?, Novartis Oncology) for prevention of skeletal-related events (SREs) and may represents a novel treatment option im men with bone metastases from castration-resistant prostate cancer. This is the conclusion from a study published this week in The Lancet.[1]

The article reports the findings from a phase III head-to-head trial comparing denosumab to zoledronic acid to in preventing skeletal-related events (SREs) in 1,901 men with prostate cancer and bone metastases. The study met its primary and secondary endpoints, adequately demonstrating superiority of denosumabcompared to zoledronic acid in preventing SREs.

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% of patients with metastatic disease.[2] Approximately 50-70 percent of cancer patients with bone metastases will experience debilitating SREs.[3, 4, 5] Skeletal-related events include fractures, spinal cord compression, and severe bone pain that may require surgery or radiation.[6] Such events can profoundly disrupt a patient’s life and can cause disability and pain.[7,8, 9]

Study Design
Study “103” is an international, phase III, randomized, double-blind study comparing denosumab with zoledronic acid in the treatment of bone metastases in patients with advanced prostate cancer to prevent SREs. Patients enrolled in the study were randomized in a one-to-one ratio to receive either 120 mg of denosuma subcutaneously every four weeks (Q4W) or zoledronic acid administered intravenously at a dose of 4 mg in a 15 minute infusion every four weeks adjusted for renal function as per the zoledronic acid label instructions. The study consisted of 1,901 patients with a median age of 71, who had bone metastases from castration resistant prostate cancer. The primary endpoint was time to first on-study SRE.

Study Results
An SRE consists of any of the following: fracture, radiation to bone, surgery to bone or spinal cord compression. All can be serious complications for advanced cancer patients. In this study, denosuma was superior to zoledronic acid in significantly delaying the time to first on-study SRE (hazard ratio 0.82, 95% CI: 0.71, 0.95; P = 0.008) with a median time to first on-study SRE of 20.7 months versus 17.1 months for zoledronic acid. denosuma was also superior to zoledronic acid in significantly delaying the development of multiple SREs (time to first and subsequent on-study SRE) (hazard ratio 0.82, 95% CI: 0.71, 0.94; P = 0.008).

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Overall rates of adverse events (AEs) and serious adverse events were generally similar between the two arms. Osteonecrosis of the jaw (ONJ) was infrequent, 22 patients receiving denosuma (2%), as compared with 12 patients receiving zoledronic acid (1%); the incidence of ONJ was not significantly different between treatment arms (P = 0.09). As with previous studies in advanced cancer patients, hypocalcemia was more frequent in the denosuma arm. Overall survival and progression-free survival were similar between treatment arms. The most common AEs for denosuma were anemia, back pain, and nausea, and the most common AEs for zoledronic acid were anemia, back pain, and decreased appetite.

Regulatory Status
Denosumab was approved by the U.S. Food and Drug Administration (FDA) on Nov. 18, 2010 for the prevention of SREs in patients with bone metastases from solid tumors, including prostate cancer denosumab is not indicated for the prevention of SREs in patients with multiple myeloma denosumab, the first and only FDA-approved RANK Ligand inhibitor, is the first new treatment for advanced cancer patients with bone metastases in nearly a decade.

“Bone metastases represent a significant risk for advanced prostate cancer patients due to the potential for serious bone complications such as fracture and spinal cord compression,” said Karim Fizazi, M.D., Ph.D., head of the department of Medical Oncology, Institut Gustave-Roussy, Villejuif, France. “The results of this study show that denosumab prevents these serious bone complications more effectively than Zometa without the requirement of intravenous infusion and without the need for dose adjustment for renal function. Denosuma represents an important new treatment option for advanced prostate cancer patients with bone metastases.”

Bone metastases, the spread of cancer to the bones, are a serious concern for patients with advanced cancer and present a considerable burden to the healthcare system. Weakened bones due to metastases can lead to fractures and compression of the spinal cord and necessitate procedures including major surgery and radiation, designed to prevent or manage these bone complications. The primary goal of treatment for bone metastases is to prevent the occurrence of debilitating and costly bone complications, which can disrupt a patient’s life and cause disability, pain and hospitalization.

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.

Regulatory Status and Ongoing Development
This study is one of three pivotal Phase III head-to-head trials comparing denosuma to Zometa. In total, these studies, which formed the basis of the FDA’s approval, enrolled over 5,700 patients with advanced cancer. 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. Amgen is studying denosumab in numerous tumor types across the spectrum of cancer-related bone diseases. Over 11,000 patients have been enrolled in the denosumab oncology clinical trials. In addition to this newly approved indication, Denosumab is also being investigated for its potential to delay bone metastases in prostate and breast cancer.

For more information:
Double-blind Study of Denosumab Compared With Zoledronic Acid in the Treatment of Bone Metastases in Men With Hormone-refractory Prostate Cancer (NCT00321620)

[1] Fizazi K, Carducci M, Smith M, Dami?o R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. The Lancet, Early Online Publication, 25 February 2011 doi:10.1016/S0140-6736(10)62344-6.
[2] Coleman RE. Skeletal complications of malignancy. Cancer. 1997; 80(suppl): 1588-1594.
[3] Lipton A, Theriault RL, Hortobagyi GN. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases. Cancer 2000;88:1082-1090.
[4] Saad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R. Pathologic fractures correlated with reduced survival in patients with malignant bone disease. Cancer. 2007;110:1860-1867.
[5] Rosen LS, Gordon D, Tchekmedyian NS, et al. Nonsmall cell lung carcinoma and other solid tumors
. Cancer. 2004;100:2613-2621.
[6] Costa L, Badia X, Chow E, Lipton A, Wardley A. Impact of skeletal complications on patients’ quality of life, mobility, and functional independence. Support Care Cancer. 2008; 16: 879-889.
[7] Norgaard M, Jensen AO, Jacobsen JB, Cetin K, Fryzek JP, Sorensen HT. Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007).J Urol 2010; 184:162-167.
[8] Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006;17:1726?1733.
[9] Saad F, Gleason DM, Murray R, et al. A Randomized, Placebo-Controlled Trial of Zoledronic Acid in Patients With Hormone-Refractory MetastaticProstate Carcinoma. Journal Ntl Cancer Inst 2002;19:1458-1468.

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