Denosumab (Xgeva) was superior to zolendronate (zoledronic acid; Zometa) in patients with advanced cancer and bone metastases in preventing or delaying time to first skeletal-related events, as well as reducing the incidence of these events, in a pooled analysis of three pivotal trials presented at the 35th ESMO Congress.¹ This effect was consistent regardless of the type of skeletal-related event. Overall survival and progression-free survival were similar between the two treatment arms. The overall rates of adverse events, including osteonecrosis of the jaw, were similar as well, with the exception of an increased incidence of hypocalcemia with denosumab.

"The take-home message of this analysis is that the newer drug, denosumab, is statistically better than zoledronicacid in delaying [skeletal-related events] in cancer patients with bone metastases," said lead author Allan Lipton, MD, of Hershey Medical Center, Hershey, Pennsylvania. "Denosumab is easier to administer [it is given subcutaneously, whereas zoledronic acid is given intravenously] and does not require renal monitoring. The incidence of severe adverse events was similar between both groups."

Key Data

Taken together, the three studies (all sponsored by Amgen) included 2,862 patients randomly assigned to denosumab and 2,861 patients randomly assigned to zolendronate. Mean age was 63 years, and about 40% had had a previous skeletal-related event at baseline.

The main findings favoring denosumab were as follows:

• • A 17% delay in time to first on-study skeletal-related events (P < .001), with a median time to first event of 27.7 months for denosumab and 19.5 months for zolendronate
• • An 18% delay in time to first and subsequent on-study skeletal-related events (multiple-event analysis, P < .001)
• • Longer time to first on-study skeletal-related events in those with previous skeletal complications (P < .01) and in those who had not experienced such effects previously (P = .0006)

The curves for both treatment arms were superimposable for progression-free and overall survival. Osteonecrosis of the jaw after 2 years of treatment was reported in 1.8% of the denosumab group and 1.3% of zolendronate recipients (P = .13). Hypocalcemia occurred in 9.6% and 5%, respectively.

Denosumab is approved for treatment of osteoporosis and to help skeletal-related events in patients with metastatic cancer (see here). Both denosumab and zolendronate are being studied for the potential treatment of bone metastases and prevention of new bone metastases, and results of large randomized trials in breast and prostate cancer should be available soon.

"We are waiting for results of these studies. If positive, they may move up bone-targeting therapy to the adjuvant setting," Dr. Lipton said. "In metastatic disease, denosumab looks more effective than zoledronic acid."

High Health Resource Utilization

An international observational study in patients with bone metastases, also sponsored by Amgen, showed that skeletal-related events entailed high consumption of health resource utilization in a cohort of 206 U.S. patients.2 In this cohort, each of the four types of skeletal-related event-pathologic fracture, radiation to the bone, spinal cord compression, and surgery to the bone-consumed a significant amount of health resource utilization in terms of outpatient visits, emergency room visits, inpatient stays, mean length of inpatient stay, and procedures.

The patterns of health resource utilization reflected the underlying type of skeletal-related event, according to lead author James Lee, MD, Hematology Oncology Associates of South Jersey, Mt. Holly, New Jersey, and colleagues.
Radiation to the bone occurred in 70% of skeletal-related events, making it the most common such effect.  Surgery to the bone and spinal cord compression required inpatient stays most frequently of the four event types, with more than 50% of patients in these groups hospitalized. However, all four types of skeletal-related events required related inpatient stays, and the average duration of inpatient stay was 11 days. Each type of skeletal-related event was associated with an average of 10 procedures. All four types were associated with outpatient visits as well. Emergency room visits were more common with spinal cord compression.

These preliminary results require confirmation, the authors noted. The final analysis will show results according to tumor type. ■

References

1. Lipton A, Siena S, Rader M, et al: Comparison of denosumab versus zoledronic acid for treatment of bone metastases in advanced cancer patients: An integrated analysis of 3 pivotal trials. 35th ESMO Congress. Abstract 1249P. Presented October 10, 2010.

2. Lee J, Suenaert P, Atchison C, et al: Health resource utilization associated with skeletal-related events in patients with bone metastases-US interim analysis results from a multinational observational study. 35th ESMO Congress. Abstract 1101P. Presented October 9, 2010.