The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended a positive opinion for the marketing authorization of denosumab (XGEVA?, Amgen)for the prevention of skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumors.

If approved by the European Commission, Amgen, the manufacturer of the drug, will receive marketing authorization for denosumab in all European Union (EU) Member States. The CHMP also recommended to grant denosumab an additional year of data and market exclusivity in the EU since the indication was considered significantly new for denosumab, and based on the significant clinical benefit of the product in comparison with existing therapies.

Bone metastases, the spread of cancer to the bones, are a common and serious concern for patients with advanced cancer and present a burden to the healthcare system. Weakened bones due to metastases can lead to fractures and compression of the spinal cord and necessitate procedures like major surgery and radiation, collectively called skeletal-related events (SREs). The primary goal of treatment for bone metastases is to prevent the occurrence of these debilitating and costly SREs.

“A diagnosis of skeletal-related events associated with bone metastases is devastating for patients living with cancer, and our goal is to prevent the occurrence of these debilitating bone complications, which can disrupt a patient’s life and cause disability, pain, and hospitalization,” said Willard Dere, M.D., senior vice president and international chief medical officer, Amgen. “XGEVA provides patients with superior efficacy over Zometa in preventing skeletal-related events in patients with solid tumors and prolonging the time until pain worsens. XGEVA also offers the ease of every four weeks subcutaneous injection and no requirement for dose adjustment for changes in renal function. XGEVA has the potential to make a meaningful difference for patients with advanced cancer and their healthcare providers.”

The CHMP positive opinion is based on three pivotal, Phase III head-to-head trials that evaluated the effectiveness of denosumab versus zoledronic acid (Zometa?, Novartis)at delaying SREs. The clinical program for denosumab spanned more than 50 tumor types in over 5,700 patients. In the SRE trials, denosumab demonstrated a clinically meaningful improvement in preventing SREs compared to zoledronic acid.

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Specifically, in patients with breast or prostate cancer and bone metastases, denosumab was superior to zoledronic acid in reducing the risk of SREs. In patients with bone metastases due to other solid tumors or multiple myeloma, denosumab was non-inferior to zoledronic acid in reducing the risk of SREs. In an integrated analysis of all three studies denosumab was superior to zoledronic acid in delaying time to first on-study SRE by 17% or 8.2 months (median time to first skeletal related event of 27.6 months for denosumab and 19.4 months for zoledronic acid, p <0.0001). In this analysis, denosumab was also superior to zoledronic acid in delaying time to first-and-subsequent on-study SRE by 18% (p<0.0001).

In patients with mild or no pain at baseline, time to worsening pain was delayed for denosumab compared to zoledronic acid(198 versus 143 days) (p=0.0002). The time to pain improvement was similar for denosumab and zoledronic acid.

In these double-blind trials, denosumab was administered every four weeks as a 120 mg subcutaneous injection, versus zoledronic acid delivered every four weeks via a 15-minute intravenous infusion, with adjustments for kidney function per the requirements of the zoledronic acid prescribing information. Denosumab was not associated with renal toxicity or acute phase reactions, both well known side effects of zoledronic acid treatment.

Overall rates of adverse events and serious adverse events were generally similar between denosumab and zoledronic acid. Osteonecrosis of the jaw (ONJ) was infrequent, with no statistically significant difference between treatment arms. Hypocalcemia was more frequent in the denosumab treatment group. Overall survival and progression-free survival were similar between arms in all three trials.

Regulatory Status
Denosumab is currently approved in the United States (U.S.) for the prevention of SREs in patients with bone metastases from solid tumors. Denosumab was approved following a six month priority review by the U.S. Food and Drug Administration (FDA). In the U.S., denosumab is not indicated for the prevention of SREs in patients with multiple myeloma.[1] Denosumab is also approved in Canada for reducing the risk of developing SREs in patients with bone metastases from breast cancer, prostate cancer, non-small cell lung cancer, and other solid tumors. In Canada, denosumab is not indicated for reducing the risk of developing SREs in patients with multiple myeloma.

Bone Metastases and SREs: Prevalence and Impact
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 90% of patients with metastatic disease.[2, 3, 4, 5]

Approximately 50-70% of cancer patients with bone metastases will experience debilitating SREs [6, 7, 8,]. Events considered to be SREs include fractures, spinal cord compression, and severe bone pain that may require surgery or radiation.[9] Such events can profoundly disrupt a patient’s life and can cause disability and pain. [10, 11, 12]

For more information:
[1] XGEVA? (denosumab) [prescribing information]. Thousand Oaks, Calif: Amgen; 2010.
[2] Tannock IF, Wit R, Berry WR, Horti J, Pluzanska A, Chi K, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-12.
[3] Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513-1520.
[4] Prostate cancer clinical trial end points: ”RECIST”ing a step backwards. American Association for Cancer Research website. Accessed on February 16, 2011.
[5] Coleman RE. Skeletal complications of malignancy. Cancer. 1997; 80(suppl): 1588-1594.
[6] 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.
[7] 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.
[8] Rosen LS, Gordon D, Tchekmedyian NS, et al. Nonsmall cell lung carcinoma and other solid tumors. Cancer. 2004;100:2613-2621.
[9] 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.
[10] 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.
[11] Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos In.t 2006;17:1726?1733.
[12] 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:

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