In men with bone metastasis from castration-resistant prostate cancer, a monthly subcutaneous injection with denosumab, 120 mg, is superior to monthly intravenous zoledronic acid (Zometa), 4 mg, for preventing and delaying first on-study and multiple skeletal-related events.
The phase III study, which enrolled 1,901 men, had a randomized (1:1), double blind, double-dummy design and excluded patients with a history of bisphosphonate use. Prior to randomization, patients were stratified by serum PSA, previous or ongoing chemotherapy, and previous history of SRE. All patients received calcium and vitamin D supplementation. During the study, more than 20% of zoledronic acid patients 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.
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. There were no significant differences between the treatment arms in median PSA over time, overall disease progression, or overall survival.
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 patients had higher rates of hypocalcemic events (12.8% vs. 5.8%) and osteonecrosis of the jaw ([ONJ] 2.3% vs. 1.3%).
"To our knowledge, this is one of the largest phase III trials ever reported of patients with bone metastasis from CRPC," said first author Karim Fizazi, MD, PhD, head of the department of cancer medicine, Institut Gustave Roussy, Villejuif, France. "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 denosu-mab, 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," Dr. Coleman said.
However, he expressed a need for further investigation of denosumab's association with hypocalcemic events and ONJ.
Denosumab was recently approved by the FDA for treating postmenopausal osteoporosis. It is a fully human monoclonal antibody with high affinity and specificity for receptor activator of nuclear factor-kB ligand (RANKL), which has been identified as a central mediator of a vicious cycle of bone destruction occurring in metastatic cancer. By binding to RANKL, denosumab turns off osteoclastic activity and acts as a potent inhibitor of bone resorption.
Potential role for agent's earlier use
Reviewing the role of RANKL/RANK in the spectrum of bone disease in prostate cancer, Dr. Coleman noted there is potential for earlier use of denosumab. Results of a published study indicate denosumab holds promise for preventing bone complications in men treated with androgen deprivation therapy for nonmetastatic prostate cancer (N Engl J Med 2009; 361:745-55). Additionally, a large placebo-controlled trial of denosumab for prevention of bone metastasis in men with CRPC and rising PSA has completed accrual.
Dr. Fizazi and Dr. Coleman disclosed financial or other interests in both Amgen and Novartis.