Mixed Results for Zometa as a Breast Cancer Treatment

Findings from the long-awaited AZURE trial show Zometa may prevent recurrence, but not for everyone.

Two years ago, a study out of Austria found that the bone-building drug Zometa (zoledronic acid) reduced the risk of cancer recurrence by one-third in premenopausal, early-stage breast cancer patients. Now, long-awaited findings from a study of both pre- and postmenopausal patients show Zometa may indeed prevent recurrence, but not for everyone.

Findings from the AZURE trial suggest Zometa only works in women who are well into menopause. Not only do these select women have a lower risk of recurrence with Zometa, they also appear to live longer than women receiving standard treatment alone.

When looking at the study’s 3,360 patients as a whole, there was no difference in disease-free survival after almost five years of follow-up, said Robert Coleman, MD, a professor of medical oncology at the University of Sheffield in England, who presented the findings at the San Antonio Breast Cancer Symposium. “That tells us that for patients, in general, with breast cancer, the use of [post-surgery] zoledronic acid can’t be supported.”

But among the 1,101 women who were at least five years past menopause or over age 60, adding Zometa to standard treatment led to a 29 percent reduction in the risk of death, with 120 deaths in the standard treatment-alone group and 86 deaths in the Zometa group. “Our conclusion would be that this is not an approach for all patients. But for those patients with established menopause or low estrogen levels, this does appear to be a treatment approach that should be considered,” Coleman said.

Seventeen women—representing about 1 percent of patients—on Zometa experienced jaw bone decay, a side effect associated with bisphosphonate drugs.

Given the overall negative results of AZURE, drugmaker Novartis has pulled its application for approval of Zometa to prevent recurrence in premenopausal women with early-stage, hormone receptor-positive breast cancer.

The differing results between AZURE and the Austrian study, known as ABCSG-12, may be explained by the minimal overlap in the type of patients enrolled and the treatment they received. Patients in AZURE had stage 2 or 3 breast cancer and received 19 total doses of Zometa over five years, whereas ABCSG-12 patients had stage 1 or 2 disease and received only seven doses over three years. But most notably, nearly all the pre- and postmenopausal women in AZURE received chemotherapy, while the treatment regimen for premenopausal women in ABCSG-12 included goserelin, a drug that switches off ovarian function and thus induces menopause.

Coleman believes estrogen may be the common thread between the two studies. “In both of those settings, women would have had very low estrogen levels. In our study, just by virtue of age, and in ABCSG-12, because they were given goserelin. The effect we’re seeing is on the host, not on the tumor,” he said.

Even if the hormonal age of the patient is driving the difference in outcome, experts caution the concept is intriguing but not definitive. A number of other studies testing Zometa and related bone drugs will report findings over the next year, Coleman said. “I think they will greatly help us tease out this benefit or not.”

Zometa, part of a class of bone-protecting drugs called bisphosphonates, is currently approved for reducing or delaying fractures and other bone complications in patients with multiple myeloma or cancer that has spread to the bone. Doctors also use the drug to build up bone in patients receiving certain cancer treatments—aromatase inhibitors, for instance—that can cause bone loss. Zometa works by slowing down the activity of osteoclasts, the cells that break down bone tissue.

Surprised and disappointed after hearing the results, Julie Gralow, MD, director of breast medical oncology at Seattle Cancer Care Alliance and a professor of medical oncology at the University of Washington School of Medicine, said the findings mean she won’t change how she treats patients.

“For preservation of bone mineral density and prevention of fractures, I think it’s proven,” said Gralow, who was not involved in the studies. “If I have a patient with bone loss—someone on an aromatase inhibitor or who has been put through [treatment-induced] early menopause—I wouldn’t hesitate to give it.” And if there happens to be disease benefit along the way, she’ll take it. “We try to do evidence-based medicine, but we also try to do the best for our patients,” she said.

Gralow’s preferred dosing of Zometa would be in line with the ABCSG-12 study: every six months for three years, possibly up to five years depending on the patient’s bone density.

In an updated analysis of the ABCSG-12 study reported in San Antonio, Zometa continues to protect patients from recurrence after more than five years of follow-up, with a 32 percent risk reduction.

Michael Gnant, MD, lead investigator of the ABCSG-12 study and a professor of surgery at the Medical University of Vienna, said he would give Zometa to a premenopausal woman with endocrine-responsive breast cancer based on his study’s results. And now knowing the AZURE findings in postmenopausal women, he would give the drug to those women as well.

Clinical trials with a new bone-targeting drug called Xgeva (denosumab) are now starting for early-stage breast cancer to evaluate whether the drug reduces the risk of recurrence. The Food and Drug Administration approved Xgeva last month for the prevention of bone-related complications in patients with cancer that has spread to the bone. With a different mode of action than Zometa, the monoclonal antibody Xgeva targets a protein that tells the body to destroy bone.

For now, the AZURE study has raised more questions than it was hoping to answer. “I think our results will put a brake on the enthusiasm for adjuvant bisphosphonates that was engendered by the ABCSG-12 results,” Coleman said. “Inevitably it’s going to be a mixed message, and people are going to disagree or debate what the role is for some time to come.”