In men with bone metastasis from castration-resistant prostate cancer (CRPC), a monthly subcutaneous injection with denosumab, 120 mg, is superior to Zometa, a multinational group of researchers reported at the American Society of Clinical Oncology annual meeting.

The current standard of care is for men with bone metastasis from castration-resistant prostate cancer (CRPC) is to receive a monthly intravenous zoledronic acid (Zometa), 4 mg, for preventing and delaying multiple skeletal-related events (SREs). A phase III study, which enrolled 1,901 men, studied the difference in the prevention of SREs between Zometa and denosumab, recently approved by the FDA for treating postmenopausal osteoporosis, but nor approved for men who are suffering with CRPC . The trial randomized (1:1), was double blind, and of double-dummy design.

Prior to randomization, the men were stratified by serum PSA, previous or ongoing chemotherapy, and previous history of SRE. All of the subject men also received calcium and vitamin D supplementation.

During the study, more than 20% of zoledronic acid men required dose adjustment at baseline because of reduced creatinine clearance, and another 15% required dose(s) withheld during the study because of an increase in serum creatinine.

Denosumab achieved the primary endpoint of the study (p=.0002), which sought to establish its non-inferiority compared with zoledronic acid in the time to first on-study SRE. Therefore, secondary efficacy endpoints were analyzed that investigated the potential superiority of denosumab in extending the time to first and multiple SREs.

1- Compared with zoledronic acid, denosumab significantly increased the median time to first SRE (20.7 months vs. 17.1 months; 18% risk reduction, p=.008) and had a similar benefit in the multiple event analysis.

2- There were no significant differences between the treatment arms in median PSA over time, overall disease progression, or overall survival.

3 -The researchers found that both treatments were generally well tolerated, and rates of
adverse event-related withdrawals were similar in the two groups (~16%). However, some differences in safety profiles emerged. Acute phase reactions were more common with zoledronic acid than with denosumab (18.8% vs. 8.4%), while denosumab-treated men had higher rates of hypocalcemic events (the presence of low serum calcium levels in the blood) (12.8% vs. 5.8%) and osteonecrosis of the jaw (

[ONJ] 2.3% vs. 1.3%).

According to the first author Karim Fizazi, MD, PhD, head of the department of cancer medicine, Institut Gustave Roussy, Villejuif, France, “To our knowledge, this is one of the largest phase III trials ever reported of patients with bone metastasis from CRPC…. In addition to the superiority denosumab demonstrated against zoledronic acid in preventing/delaying SREs, this novel agent has other advantages, including its easier route of administration, lack of nephrotoxicity that eliminates any need for renal monitoring and renal function-based dose adjustment, and reduced risk of acute phase reactions.

“Hypocalcemia and ONJ are ob-served with both zoledronic acid and denosumab, and these events should be systematically prevented or readily detected with appropriate follow-up,” Dr. Fizazi said.

Robert E. Coleman, MD, professor of medical oncology at the University of Sheffield, UK, discussed the paper at the ASCO meeting. Highlighting the frequency and impact of skeletal morbidity in CRPC, he pointed out that while zoledronic acid has been the only bisphosphonate approved for use in CRPC, considering its benefits, there is room for improvement. “Based on the results from the phase III trial reported here, monthly SC denosumab may be considered the resorption inhibitor of choice for men with bone metastases related to CRPC,” said Dr. Coleman said.

However, Dr. Coleman did express concern about and the need for further investigation of denosumab’s association with hypocalcemic events and ONJ.

presented at the ASCO Meeting – 2010 in Chicago

Joel T Nowak, M.A., M.S.W.