A study published today in the Journal of Clinical Oncology, found that denosumab (XGEVA? , Amgen) was non-inferior to zoledronic acid (Zometa?, Novartis Oncology) in delaying or preventing skeletal-related events (SREs).

The conclusion is based on the results of a pivotal Phase III study (NCT00330759) of 1,776 advanced cancer patients. In this study, researchers compared denosumab, a fully human monoclonal anti-receptor activator of nuclear factor kappa-B ligand (RANKL) antibody, with zoledronic acid for delaying or preventing skeletal-related events in patients with advanced cancer and bone metastases (excluding breast and prostate) or myeloma. The researchers concluded that denosumab was noninferior- trending to superiority ? when compared to zoledronic acid in preventing or delaying first on-study skeletal-related events in patients with advanced cancer metastatic to bone or myeloma. They also noted that the drug represents a real ?potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.?

Debilitating skeletal-related events
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.[1]

Approximately 50-70% of cancer patients with bone metastases will experience debilitating skeletal-related events.[2,3, 4]. Events considered to be SREs include fractures, spinal cord compression, and severe bone pain that may require surgery or radiation.[5] Such events have important and significant effects on measures of health-related quality of life as they can profoundly disrupt a patient’s life and can cause disability and pain.[6, 7, 8]

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“Almost every type of cancer has the potential to spread to the bone, putting patients at risk for devastating bone complications, like fracture or compression of the spinal cord,” said David H. Henry, M.D., clinical professor of medicine, Pennsylvania Hospital, Philadelphia, PA. “Once a patient has bone metastases one of our major goals is to prevent events like fracture or spinal cord compression. XGEVA is an important new option to help prevent these debilitating complications.”

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RANKL is the primary mediator of osteoclast formation, function, and survival in both cortical and trabecular bone throughout the body. Osteoclasts are the cells responsible for resorbing bone. Many different factors, including PTH, TNF, IL-1, can lead to bone loss, but they all stimulate the expression of RANKL by stromal and bone lining cells. RANKL binds to RANK on the preosteoclast and mature osteoclast. In addition to being expressed on osteoclasts and osteoclast progenitors, RANK has been observed on dendritic cells, mammary gland epithelial cells, and many other cells.

The RANKL polypeptide is a type II transmembrane protein found on the surface of expressing cells as well as in a proteolytically released (cleaved) soluble form. Maturation of prefusion osteoclasts to multinucleated osteoclasts and finally to activated osteoclasts is initiated when RANKL binds to RANK.

Denosumab, the first and only RANKL inhibitor indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors was approved by the U.S. Food and Drug Administration (FDA) on Nov. 18, 2010. The approval was based in part on results described in this publication. Denosumab is not indicated for the prevention of SREs in patients with multiple myeloma.

Economic Burden: The healthcare costs of Skeletal-related Events
Because patients with Skeletal-related Events require continued medical care, the costs to individuals who experience SREs a sizable. Results from a one-year study published in 2008 in the American Journal of Managed Care reviewing the incidence of SREs, including radiation therapy, pathologic fracture, surgery, or spinal cord compression found that half of patients with prostate cancer and bony metastases experienced at least one SRE with a mean cost of $12,469 per patient/year. [9]

The same study showed that the average costs for patients who experienced more than one SRE within the study year (22% of the study population) was $26,384, significantly higher than those who experienced just one event ($8,484). The study also noted that 87% of patients who experienced an SRE did so within one year of their initial diagnosis of bony metastatic disease. These costs are comparable to those of SREs in the setting of advanced lung cancers.[10] Prevention strategies, timely diagnosis, and more cost-effective interventions have the potential to ultimately reduce both the clinical and economic burden of SREs.

Study results
For the primary endpoint of this study, the median time to first on-study SRE, defined as fracture, radiation to bone, surgery to bone, or spinal cord compression, was 20.6 months for patients receiving denosumab and 16.3 months for patients receiving zoledronic acid (hazard ratio 0.84, 95 percent CI: 0.71-0.98), which is statistically significant for non-inferiority (p=0.0007). Although numerically greater, the delay in the time to first SRE associated with denosumab was not statistically superior compared to zoledronic acid based upon the statistical testing strategy (adjusted p=0.06) (secondary endpoint). The time to first- and subsequent SRE was also numerically greater but not statistically superior compared to zoledronic acid (hazard ratio 0.90, 95% CI: 0.77-1.04, p=0.14) (secondary endpoint).

In a subgroup analysis of patients with multiple myeloma, mortality appeared to be higher for denosumab-treated patients compared to those in the control arm (hazard ratio [95% CI] of 2.26 [1.13, 4.50]; n = 180). The limited number of patients in this subgroup, however, precludes definitive conclusions regarding the effects of denosumab in multiple myeloma patients.

In the study, hypocalcemia occurred more frequently with denosumab, while osteonecrosis of the jaw (ONJ) occurred at similar rates in both groups. Acute phase reactions after the first dose occurred more frequently in the zoledronic acid arm, as did renal adverse events and elevation in serum creatinine. No dose adjustments or dose withholding for renal function are required for denosumab.

Study design
This study was an international, randomized, double-blind, double-dummy, active-controlled study, in which advanced cancer patients with solid tumors or multiple myeloma were randomized to receive either subcutaneous denosumab 120 mg and intravenous placebo (N=886), or zoledronic acid administered intravenously as at least a 15 minute infusion at a dose of 4 mg (or equivalent creatinine clearance-adjusted dose in patients with baseline creatinine clearance less than or equal to 60 mL/min) every four weeks as per the labeled instructions (N=890). All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary endpoint was time to first on-study SRE.

Ongoing trials
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.

References:

[1] Coleman RE. Skeletal complications of malignancy. Cancer. 1997; 80(suppl): 1588-1594.
[2] 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.
[3] 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.
[4] Rosen LS, Gordon D, Tchekmedyian NS, et al. Nonsmall cell lung carcinoma and other solid tumors. Cancer. 2004;100:2613-2621.
[5] 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.
[6] 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.
[7] Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006;17:1726?1733.
[8] 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.
[9] Lage MJ, Barber BL, Harrison DJ et al: The cost of treating skeletal-related events in patients with prostate cancer. Am J Manag Care 14:317?322, 2008/
[10] Delea T, Langer C, McKiernan J, et al. The cost of treatment of skeletal-related events in patients with bone metastases from lung cancer. Oncology 67: 390?396, 2004.

For more information:
Double-blind Study of Denosumab Compared With Zoledronic Acid in the Treatment of Bone Metastases in Subjects With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma (NCT00330759)
A Study Comparing Denosumab vs. Zoledronic Acid for the Treatment of Bone Metastases in Breast Cancer Subjects (NCT00321464)

Denosumab is also marketed as Prolia? in other indications.

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