Metastatic breast cancer that has spread to one or more bones can be painful and can cause broken bones and spinal compression if bone is destroyed by the cancer. Zometa (chemical name: zoledronic acid) is used to strengthen bones in women diagnosed with breast cancer that has spread to the bone. Zometa is given intravenously and can reduce bone pain and the risk of fractures and other bone complications.
The study reviewed here found that denosumab, an experimental targeted therapy medicine, was a little better than Zometa at preventing bone pain and slowing bone complications, including broken bones, from breast cancer that had spread to the bones. These results were reported at the 2009 San Antonio Breast Cancer Symposium.
Targeted therapy medicines target specific cell characteristics that affect how the cells behave. Some targeted therapies, including denosumab, are antibodies that work like the antibodies made naturally by the body's immune system. Denosumab targets a protein called RANK ligand (RANKL), which affects the activity of certain bone cells (osteoclasts). Osteoclasts cause a normal amount of bone breakdown to help regulate the body's calcium level. Osteoclasts tend to be overactive when breast cancer spreads to the bones. Overactive osteoclasts can cause bone pain and bone destruction. By blocking or inhibiting the RANKL protein, denosumab lowers the activity level of the osteoclasts, which reduces the risk of pain and other bone complications.
In the study reviewed here, 2,046 women diagnosed with advanced-stage breast cancer that had spread to bone were split into two groups:
To make sure that neither the doctors nor the women knew who was getting which medicine, all the women got both an injection and an intravenous infusion, one of which had no medicine in it, every 4 weeks.
All the women were monitored for bone pain, bone fractures, and spinal cord compression. The researchers also watched to see if any of the women needed radiation treatments or surgery to treat bone complications due to the cancer.
Denosumab seemed to cause the same side effects as Zometa. A rare but serious side effect of both medicines is osteonecrosis of the jaw, a condition in which the cells in the jawbone start to die. Osteonecrosis of the jaw developed in 1.4% of women who got Zometa and 2% of women who got denosumab.
While these results are promising, denosumab is still considered an experimental treatment. The U.S. Food and Drug Administration (FDA) is considering approving denosumab to treat women diagnosed with breast cancer that has spread to bone. One advantage of denosumab is that it's given by a simple injection under the skin, instead of an intravenous infusion like Zometa. Still, denosumab is expected to be more expensive than Zometa.
If you've been diagnosed with advanced-stage breast cancer that has spread to one or more of your bones, you and your doctor will work together to develop a treatment plan that minimizes any pain you might have and reduces your risk of bone complications. Zometa may be part of your plan, but if denosumab is approved by the FDA, it could be an option.
SAN ANTONIO (MedPage Today) -- The investigational monoclonal antibody denosumab relieves painful bone metastases and prevents their serious complications in breast cancer patients better than standard zoledronic acid (Zometa).
The skeletal morbidity rate dropped a relative 22% with denosumab compared with the bisphosphonate (0.45 versus 0.58 per person-year, P=0.004) in a randomized controlled trial of more than 2,000 breast cancer patients with bone metastases, Alison Stopeck, MD, of the Arizona Cancer Center at the University of Arizona in Tuscon, and colleagues found.
Time to first radiation treatment for bone metastases as an objective measure of pain improved by a relative 26% as well with the novel injectable drug compared with zoledronic acid (P=0.01), they reported here at the San Antonio Breast Cancer Symposium.
And the boost in efficacy did not come at the price of more overall or serious adverse events, Stopek said.
Denosumab -- a biologic agent targeted at the RANK ligand, the primary mediator of bone-resorbing osteoclast formation -- is currently in regulatory limbo.
When drug developer Amgen went before the FDA in the fall seeking approval for indications in osteoporosis and osteopenia, the agency didn't heed its advisory panel's recommendation and instead delayed a decision.
Whether the skeletal event data will be enough to convince the agency to grant an indication in bone metastases secondary to breast cancer is anyone's guess, said Gary H. Lyman, MD, MPH, of Duke University.
But the new positive findings presented at SABCS came as no surprise, said Lyman, who sits on the FDA's Oncologic Drugs Advisory Panel. (He recused himself for the denosumab decision.)
As Stopeck reported at the ECCO-ESMO meeting earlier this year, denosumab extended the time to first skeletal-related event by a relative 18% compared with zoledronic acid.
Thus the trial met both noninferiority and superiority criteria for this primary endpoint (P<0.0001 and P=0.01, respectively).
It included 2,046 advanced breast cancer patients with confirmed bone metastases randomized to double-blind, double-dummy treatment with denosumab (120 mg subcutaneously) or zoledronic acid (4 mg intravenously) every four weeks.
The researchers again reported that denosumab-treated patients went 13% longer before experiencing moderate or severe pain than those on the current standard of care (median 88 versus 64 days, P=0.009).
A new secondary result presented here showed fewer patients had skeletal-related events -- defined by fracture, radiation, surgery, or spinal cord compression on denosumab.
The crude proportion of patients who had at least one of these events was 5.6% lower with denosumab at month 12 (25.1% versus 26.6%), 11.5% lower at month 18 (28.6% versus 32.3%), and 15.9% lower at month 34 (30.7% versus 36.5%). Although the curves appeared to be separating, the difference didn't reach statistical significance at any of these time points.
Because there is no single universally accepted measure for skeletal health in this population, the additional secondary endpoints "strengthen the interest and confidence that there is greater efficacy with the RANK ligand inhibitor denosumab," Lyman told MedPage Today.
Stopeck said that if the drug were approved, she would rapidly incorporate it into her practice for its efficacy and convenience as a subcutaneous injection that doesn't require renal monitoring, "assuming the price isn't exorbitant."
Although the drug's developer has not released pricing information, cost is likely to be an issue, Lyman noted.
There have also been concerns over osteonecrosis of the jaw, which was numerically more frequent with denosumab than with zoledronic acid in the trial (2.0% versus 1.4%), but the difference was not statistically significant.
Stopeck said that the majority of these patients had risk factors, such as poor oral health or a tooth extraction, and chalked it up as a chance event. Lyman agreed that this difference would not be clinically significant.
In fact, Theresa Guise, MD, of Indiana University in Indianapolis, who moderated a press conference at which the results were presented, said she took the data as evidence against osteonecrosis of the jaw as a class effect for potent bisphosphonates.
Whether there is any difference in the reversibility of this adverse event is a question Stopeck said her group plans to analyze.
The study was supported by Amgen, which is developing denosumab. Stopeck reported conflicts of interest for Amgen as well as Novartis, maker of zoledronic acid.
Co-authors reported conflicts of interest with Novartis, GlaxoSmithKline, Daiichi-Sankyo, Eisai, Taiho, Pfizer, Amgen, Abraxis, Monogram Biosciences, and Eli Lilly. Several reported being employed by and major stockholders in Amgen.
Guise reported being on the advisory board for Amgen, Novartis, Lilly, and Roche.
Lyman reported having recieved neutropenia-related research funding from Amgen and sitting on the FDA's Oncologic Drugs Advisory Panel.
Primary source: San Antonio Breast Cancer Symposium Source reference: Stopeck A, et al "A comparison of denosumab versus zoledronic acid on the incidence of skeletal-related events in breast cancer patients with bone metastases" SABCS 2009; Abstract 22.
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