Denosumab Continues to Dampen Skeletal-Related Side Effects in Breast Cancer Bone Metastases

SAN ANTONIO-Denosumab (Xgeva) may be superior to zoledronic acid (Zometa) in delaying or preventing skeletal-related events (SREs) in patients with breast cancer and bone metastases. Specifically, denosumab delayed SREs five months longer than zoledronic acid.

“The average life expectancy of patients with metastatic breast cancer is approximately 2.5 years, so if you can prolong the time without a skeletal-related event by five months, you are substantially benefiting the patient,” said lead investigator Alison Stopeck, MD, an associate professor of medicine and director of the clinical breast cancer program at the Arizona Cancer Center, University of Arizona in Tucson.

Previous results from this phase III trial indicated that denosumab was superior to zoledronic acid in delaying the time to first on-study SREs, such as fracture, radiation to bone, surgery to bone, or spinal cord compression in patients with breast cancer metastatic to the bone. In the current study, Dr. Stopeck updated the results after an additional four months of blinded treatment (SABCS 2009 abstract 22 and SABCS 2010 abstracts 615 and P6-14-01).

Denosumab is a fully human monoclonal antibody that inhibits RANKL, a key mediator of osteoclast activity. Dr. Stopeck and her colleagues randomized 2,046 patients with advanced breast cancer and bone metastases to receive either 120 mg of subcutaneous denosumab or 4 mg of intravenous zoledronic acid every four weeks. All the subjects took calcium (500 mg or greater daily) and vitamin D (400 IU or greater daily).

The researchers found that denosumab was better at delaying the time to first on-study SRE by 18% and the time to first and subsequent on-study events by 22%. The researchers also found that overall survival and disease progression were similar for both treatment groups. The side effects rate was 96.2% in the denosumab arm and 97.4% in the zoledronic acid arm. Serious adverse events occurred in 47.9% of the denosumab patients and 50.2% of the zoledronic acid patients.

“We now have an alternative to zoledronic acid that is more convenient, less toxic, and more effective for patients with bone metastases,” Dr. Stopeck said. She noted that denosumab is easy to administer via subcutaneous injection compared to IV zoledronic acid. In addition, dose adjustments are not required, and there is no need for renal monitoring. The FDA approved denosumab in November 2010 for the prevention of SREs in patients with bone metastases from solid tumors.

Osteonecrosis of the jaw (ONJ) is a serious concern with bisphosphonates, and, in the current study, ONJ occurred in 2.5% of patients taking denosumab compared to 1.8% of those taking zoledronic acid (P = .29). Dr. Stopeck said it is up to oncologists to perform an oral exam of patients with bone metastases before placing them on denosumab, pointing out that the problem tends to occur in patients with dentures and/or poor dental hygiene.

“Oncologists need to look into the patient’s mouth and see if there are any cracked and decaying teeth and determine if this is a patient who will have a problem with jaw osteonecrosis. In this study, nobody was required to see a dentist at any point. Many of the patients had no dental care,” said Dr. Stopeck in an interview with Oncology NEWS International. “The risk factors of osteonecrosis of the jaw are not a problem if a patient maintains good dental hygiene. I tell the patients they have to floss and they have to go to the dentist twice a year.”

Mothaffar Rimawi, MD, a professor of medicine and medical director of the breast center at Baylor College of Medicine in Houston, said these findings provide clinicians with a potentially better agent for preventing SREs in this patient population.

“I think this is another tool and another option that seems to be even more effective,” Dr. Rimawi told Oncology NEWS International. “So, you may want to consider using it upfront because it has now been shown to be more effective. However, the cost may be an issue because new agents tend to cost more and you have balance the cost with the benefits.”