By: Walter Alexander

SAN ANTONIO, TX – Researchers suggested that women with breast cancer experienced fewer skeletal adverse events if they are treated with the monoclonal antibody denosumab instead of zoledronic acid.

Up to 75% of patients with advanced breast cancer develop bone metastases, which in turn lead to osteoclast-related bone destruction, said Alison Stopeck, MD, associate professor of medicine at the University of Arizona, Tucson.

That can lead to fractures, need for radiation therapy and/or surgery, spinal compression, and pain. Intravenous bisphosphonates, predominantly zoledronic acid, are frequently used to delay or prevent these events. Denosumab inhibits Receptor Activator for Nuclear Factor κ B Ligand, the primary mediator of osteoclast formation, function and survival.

She reported the results at the 32nd San Antonio Breast Cancer Symposium.

Based on Phase 2 trials that demonstrated lowered bone turnover markers and reduced skeletal-related events with denosumab, an international, randomized, double-blind phase 3 trial was conducted among 2046 adults with advanced breast cancer and confirmed bone metastases.

Every 4 weeks, the patients received either denosumab 120 mg in a subcutaneous injection and placebo intravenously or subcutaneous placebo and intravenous zoledronic acid 4mg. Patients were encouraged to take supplemental calcium and vitamin D.

At the primary analysis cutoff date after 34 months, 45% of patients remained on study. About 17% of the patients died; another 17% exhibited disease progression; about 12% withdrew consent.

Time to first on-study skeletal-related event was reduced a significant 18% (P=0.01), at a median of 26.5 months for zoledronic acid and with median not reached for denosumab.

Curves began to separate as early as 6 months, Dr. Stopeck noted. After a median time on study of 17 months, events were experienced in 36.5% of zoledronic acid patients and in 30.7% of the denosumab patients.

Time to first on-study skeletal-related event or hypercalcemia of malignancy also favored denosumab (P=0.007) at a median of 25.2 months for zoledronic acid and median not reached for denosumab.
Dr. Stopeck explained that hypercalcemia of malignancy is typically a direct consequence of bone metastases and often has particularly dire clinical consequences.

Also, time to first-and-subsequent on-study skeletal-related events favored denosumab as did time to first radiation to bone and time to experiencing moderate or severe pain.

Overall disease progression was similar for both treatments.
While adverse events were experienced at similar rates between groups, acute phase reactions of pyrexia, bone pain, chills, arthralgia, influenza-like illness, myalgia, and flushing occurred in about 27.3% of patients on zoledronic acid compared with 10.4% of patients on denosumab.

“Denosumab was more efficacious than zoledronic acid,” Dr. Stopeck said. “Denosumab administered as a monthly subcutaneous injection represents a novel treatment option for the management of bone metastases without the need for renal monitoring.”

When asked in the question and answer period if she would use the agent if it is approved, she replied, “I would incorporate it rather quickly because it shows better efficacy, the subcutaneous injection is easier to give, I don’t have to monitor the creatinine and it has less toxicity—assuming the price isn’t exorbitant.”

- MFP Wire Services
- 02-05-2010