Denosumab significantly increased the time to sustaining a skeletal-related event (SRE) compared to zoledronic acid in men with castration-resistant (hormone-refractory) prostate cancer, in one of the largest trials conducted in this setting.¹

The study's primary endpoint was to show noninferiority of denosumab vs zoledronic acid, and the secondary endpoint was to demonstrate superiority, explained Karim Fizazi, MD, PhD, Head of the Department of Medical Oncology at Institut Gustave Roussy, Villejuif, France. "The study met both endpoints. Denosumab was superior to zoledronic acid in preventing or delaying the first SRE and in preventing or delaying multiple skeletal events," he stated.

The FDA approved denosumab in June for the treatment of postmenopausal women with osteoporosis at high risk of fracture, but this monoclonal antibody remains investigational in men receiving hormone-deprivation therapy for prostate cancer. (On July 16, the FDA granted priority review designation to denosumab for the treatment of bone metastasese to reduce SREs in patients with cancer.)

The drug has substantial affinity and specificity for RANK ligand and is designed to interrupt the cascade of molecular events leading to bone metastasis. Unlike the bisphosphonate zoledronic acid, denosumab has no requirement for monitoring renal toxicity or dose adjustment and is associated with little risk of acute-phase reactions.

Study Background

The phase III trial randomly assigned 950 patients to subcutaneous denosumab at 120 mg and 951 patients to intravenous zoledronic acid at 4 mg. All patients received oral calcium and vitamin D supplementation. The study period was 2006 to 2008.  The mean age of patients was 71 years. All patients had bone metastases, and 93% had good performance status.

Patients in both arms were treated for about 1 year. More than 20% of patients on the zoledronic acid arm required dose adjustment for creatinine clearance at baseline and 15%, during the study. An additional 15% of those treated with the bisphosphonate required doses withheld for serum creatinine increases on study. This did not occur on the denosumab arm.

Denosumab was superior to zoledronic acid for time to first SRE. An SRE was sustained by 36% in the denosumab arm vs 41% in the zoledronic acid arm (P = .0002). Denosumab achieved an 18% risk reduction vs zoledronic acid for time to first and subsequent on-study SREs. The median time to experiencing an SRE with denosumab was 20.7 months, compared with 17.1 months for men treated with zoledronic acid, and this difference was statistically significant (P = .008).

Types of first on-study SRE in all patients included radiation to the bone (20%), fracture (14.7%), spinal cord compression (3.3%), and surgery to the bone (0.3%).

However, no difference was seen between the two treatment arms for prostate-specific antigen (PSA) time course, cancer progression, or overall survival.

Adverse Events

Approximately 20% of all patients required radiation to the bone for SRE. About 14.7% experienced pathologic bone fractures, 3.3% had spinal cord compression, and 0.3% required bone surgery.

The rates of overall adverse events were similar between the two arms: About 97% in each arm experienced adverse events, mainly caused by underlying cancer. These events included anemia, back pain, nausea, fatigue, and decreased appetite. The rates of infection were also similar. Acute-phase reactions (during the first 3 days of treatment) occurred in 8.4% of the denosumab group vs 17.8% of the zoledronic acid group. Hypocalcemia occurred in 12.8% and 5.8%, respectively.

Osteonecrosis of the jaw, a side effect of major concern with these drugs, occurred in 1.3% of the zoledronic acid group vs 2.3% in the denosumab group.

"The large majority of patients who experienced osteonecrosis of the jaw had risk factors. Less than 10% required bone resection," Dr. Fizazi said.

Is Cost Justified?

Ian Tannock, MD, of Princess Margaret Hospital, Toronto, Canada, raised some important issues, commenting from the audience. "The study shows a difference in time to SRE [including radiation to the bone]. Denosumab costs a lot of money, yet there is no difference in overall survival, the endpoint we really care about.  If fractures are not clinically evident, is a delay in time to SRE an important endpoint for improving these men's lives?"

Similarly, formal discussant of the trial, Robert E. Coleman, MD, Professor of Medical Oncology at the University of Sheffield, UK, noted, "This study showed an improvement from 17.1 to 20.7 months (or a risk reduction of 18%) in time to first SRE in patients not on the bisphosphonate, but disease-free survival and progression were unaffected."
Issues that remain to be addressed with denosumab include benefits in specific subgroups, impact on quality of life, optimum duration of therapy, and whether denosumab can prevent or delay bone metastasis, he continued.

"The cluster of events including hypocalcemia and oral health with denosumab need further study," Dr. Coleman added. "Denosumab could be considered for preventing bone loss, it should be considered for preventing skeletal morbidity, and we await data on whether it will prevent bone metastasis."

The study was supported by Amgen. ■

Reference

1. Fizazi K, Carducci MA, Smith MR, et al: A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer. 2010 ASCO Annual Meeting. Abstract LBA4507. Presented June 6, 2010.