The injectable osteoclast-inhibiting drug denosumab delayed the time to a first skeletal-related adverse event by a median of five months longer than did zoledronic acid, according to updated results from the landmark Phase III trial comparing the two agents.
Additionally, the time to a composite secondary endpoint of a first skeletal-related event or hypercalcemia was delayed by a median of 7.3 months in patients given denosumab, compared with those given zoledronic acid. Alison T. Stopeck, MD, Director of the Clinical Breast Cancer Program at the Arizona Cancer Center at the University of Arizona, reported the updated results at the CTRC-AACR San Antonio Breast Cancer Symposium.
"Hypercalcemia is a life-threatening complication of metastatic bone disease that is feared by oncologists," she said. "Since the average life expectancy of these patients is generally two-and-a-half to three years, an additional seven months of freedom from these complications is a substantial amount."
1% of Participants Male
In November, denosumab, a fully human monoclonal antibody that acts as a RANK ligand inhibitor, was approved by the FDA for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
The updated analysis provided four more months of extended blinded data than previously reported from the randomized, double-blind, double-dummy, active-controlled study pitting denosumab against zoledronic acid as reported at the 2009 SABCS and the joint ECCO-ESMO Congress earlier in 2009 and published at the end of last year in the Journal of Clinical Oncology (2010;28:5132-5139).
In the study, which was funded by Amgen, a total of 2,046 patients with advanced breast cancer and bone metastases were randomized to receive 120 mg of subcutaneous denosumab or 4 mg of intravenous zoledronic acid, every four weeks. Only 4% of patients had prior bisphosphonate therapy.
Dr. Stopeck noted that one unusual aspect of the study population was that 1% of the participants were men-which is approximately the same percentage of cases of breast cancer that occur in males.
At the time of the extended analysis out to three years, the median time to a first skeletal-related event was 32.4 months in the denosumab arm vs 27.4 months in the zoledronic acid group.
"This corresponds to a highly significant 18% reduction in the risk of an event such as fracture, spinal-cord compression, or bone radiation or surgery with denosumab treatment," she said.
The time to the first skeletal-related event or hypercalcemia, a secondary endpoint, was a median of 32.4 months in the denosumab group, compared with 25.1 months in the zoledronic acid. This also corresponded to a significant 18% reduction in risk, Dr. Stopeck said.
The proportion of patients experiencing one or more skeletal-related events was 32.9% in the denosumab arm vs 38.9% in the zoledronic acid group, corresponding to a 15.4% relative reduction with denosumab.
One hundred more skeletal-related events occurred during the additional four months of blinded treatment, bringing the total number of such events to 526 in the denosumab arm and 669 in the zoledronic acid arm.
This represents a 22% reduced risk of both first and subsequent skeletal-related events with denosumab, compared with zoledronic acid, and the event curves are continuing to separate over time, Dr. Stopeck said.
Adverse Effects
"There were no new safety signals with the continued follow-up," she said.
Serious adverse events occurred in about half of patients in both groups. Importantly, denosumab was associated with a lower rate of renal toxicity-related events than zoledronic acid was: 5.4% vs 9.4%.
A total of 2.5% of patients on denosumab developed osteonecrosis of the jaw, compared with 1.8% on zoledronic acid, but the difference did not reach statistical significance.
Acute phase reactions involving bone pain and/or flulike symptoms were more common in the zoledronic acid group: 28.2% vs 10.7% for denosumab.
Hypocalcemia occurred in 6.1% of the denosumab group, compared with 3.7% on zoledronic acid.
Ease of Use
Denosumab offers a number of advantages in terms of ease of use, Dr. Stopeck said. It's given via a once-monthly subcutaneous injection, while zoledronic acid requires an intravenous infusion. And renal monitoring and dose adjustments are not required with denosumab, she said.
In the study, none of the patients treated with denosumab missed doses or had a dose reduced dzzue to toxicity, compared with about 15% of patients on zoledronic acid.
Phase III Study Starting
The next step: A Phase III study of denosumab as adjuvant treatment for women with early-stage breast cancer at high risk of recurrence. The trial, also funded by Amgen, has begun enrolling a planned 4,500 patients and is comparing the effect of denosumab compared with placebo on prolonging bone metastasis-free survival rates, with overall and disease-free survival rates as secondary endpoints.
"The idea is to see if we can actually prevent cancer from spreading at an earlier stage by manipulating the bone microenvironment. Preventing skeletal-related events is good, but we'd like to move earlier," Dr. Stopeck said.
The bone milieu may be a holding cell for circulating tumor cells, noted Minetta C. Liu, MD, Director of Translational Breast Cancer Research at Georgetown Lombardi Comprehensive Cancer Center.
One current theory holds that circulating tumor cells may hide or lie dormant in the bone marrow, until they at some point escape into the bloodstream, spread to other parts of the body, and cause metastases, she explained.