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AZURE results may contradict ABCSG-12 results for zoledronic acid use
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33rd Annual San Antonio Breast Cancer Symposium
SAN ANTONIO — Results of the AZURE trial do not support the use of adjuvant zoledronic acid for the treatment of early breast cancer, according to findings presented at a press conference here.
Adjuvant zoledronic acid use was linked to a 32% reduction in DFS events among premenopausal women with breast cancer who had been treated with endocrine therapy in the Austrian Breast and Colorectal Cancer Study Group Trial 12 (ABCSG-12). However, no differences in DFS rates were observed between women who received adjuvant zoledronic acid and those who did not in the AZURE trial.
Results were presented by Robert E. Coleman, MD, of the academic unit of clinical oncology at Weston Park Hospital in Sheffield, UK, Sharon Giordano, MD, MPH, of The University of Texas MD Anderson Cancer Center, and Rowan Chlebowski, MD, PhD, of the medical oncology/hematology department at the University of California at Los Angeles, provided commentary. Michael Gnant, MD, professor of surgery at the Medical University of Vienna, delivered an overview of the updated ABCSG-12 trial results.
AZURE results
No significant effects on standard chemotherapy were observed in the zoledronic acid arm of the AZURE trial. The median follow-up reached 59 months (interquartile range, 53-61 months) as of Oct. 18. Up to that time, there were 752 DFS events, of which 377 occurred in the zoledronic acid group and 375 occurred in the control group (HR=0.98; 95% CI, 0.85-1.13).
“It is highly unlikely that this conclusion will change with further follow-up,” Coleman said.
Several subgroup analyses were conducted, including analyses based on age and menopausal status. Women more than 5 years past menopause or older than 60 years in the zoledronic acid arm had increased OS compared with women not receiving the treatment (HR=0.71; 95% CI, 0.54-0.94). This trend was not observed among women of premenopausal or perimenopausal status.
“There was an extraordinary heterogeneity of effect by menopausal status with improved DFS and OS in women more than 5 years from menopause,” Coleman said.
Chlebowski said this result was remarkable and could signal a new direction in research.
“I would consider this result hypothesis-generating and not clinical,” Giordano said. “The difference in menopausal outcome results is intriguing but not definitive. The AZURE trial will not be the final word on this topic.”
Differing conclusions
Coleman said the other key challenge will be to determine why the AZURE results were so different from the ABCSG-12 results.
“There was minimal overlap in patient selection and treatment between the two trials,” Gnant said, noting that there were differences in the proportion of patients receiving adjuvant chemotherapy in the two studies and also differences in the stage of cancer among patients.
“It is fair to say that the overall results of AZURE are a little disappointing,” he said. “But scientifically it makes sense.”
Gnant said he recommended using zoledronic acid with estrogen-reducing treatments.
AZURE protocols
There were 3,360 patients from 174 centers involved in the AZURE trial. Participants were randomly assigned to neo-adjuvant chemotherapy and/or endocrine therapy with or without IV zoledronic acid. The zoledronic acid regimen was as follows: 4 mg every 3 to 4 weeks for six doses; every 3 months for eight doses; and then every 6 months for five doses, resulting in a 5-year treatment plan.
The initial primary endpoint of DFS was to be determined after 940 DFS events, which the researchers said would have provided an 80% power to detect a 17% reduction in hazard rates for DFS.
“About 12 months ago, it became clear that our event rate was much lower than anticipated,” Coleman said. “If we stuck with the initial plan, it would not be until 2012 that we could present.”
A second interim analysis was conducted by independent statisticians who were unfamiliar with the results of the first analysis, according to Coleman. The evaluators conducted analyses for efficacy (HR=0.833; alpha spend 1%) and lack of clinical benefit (HR=0.936; with a 5% risk of declaring a false negative result).
Baseline patient characteristics were similar between the two groups. There were no significant differences in stage, number of positive axillary nodes, CT type, ER status, menopausal status and statin use.
Among 3,208 patients who received adjuvant CT, 93% received anthracyclines and 23% received taxanes. There were 152 patients who received endocrine therapy only.
For the safety population, there were 1,665 patients in the zoledronic acid arm and 1,675 patients in the control arm. Serious adverse event profiles were similar in both arms.
There have been 13 confirmed cases of osteonecrosis of the jaw in the zoledronic acid arm, resulting in an incidence rate of 0.83 (95% CI, 0.38-1.28). – by Rob Volansky
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