Adjuvant treatment of stage II and III breast cancer with zoledronic acid (Zometa) failed to improve disease-free survival (DFS) in the large, randomized AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial, contrary to expectations of the investigators. AZURE was the largest study conducted of bisphosphonate use with adjuvant therapy for women with breast cancer, and it is highly unlikely that this conclusion will change with further follow-up, the authors said.
At the time the AZURE trial began, investigators were aware that momentum was growing to use zoledronic acid in the adjuvant setting. "We were surprised by the overall finding of AZURE," said lead author, Robert Coleman, MD, Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, United Kingdom, said at a press conference.
AZURE results contrast with those of the large randomized ABCSG (Austrian Breast and Colorectal Study Group)-12 trial, which did demonstrate a survival benefit with use of adjuvant zoledronic acid in patients who have earlier-stage breast cancer (stage I and II); those patients were younger and had been given goserelin to induce premature menopause. ABCSG-12 findings prompted some oncologists to consider giving zoledronic acid as a routine component of adjuvant therapy for women with breast cancer.
According to Coleman, "One intriguing finding of a prespecified subgroup analysis of AZURE was a significant DFS benefit for zoledronic acid confined to women who were more than 5 years' postmenopausal or older than age 60, so presumably in menopause for several years." He added that the P value of .001 for this observation was "rarely seen in a subgroup analysis" and called the finding "hypothesis-generating."
AZURE enrolled 3360 women with stage II and stage III breast cancer who did not have metastases and had not received bisphosphonates in the previous year. Treatment arms were well balanced in terms of disease characteristics. Patients were randomized to standard therapy (investigator's choice of chemotherapy, endocrine therapy, and/or surgery) with placebo or with 4 mg of zoledronic acid. Over 5 years, Zoledronic acid was given in 6 doses every 3 or 4 weeks and later in 8 doses every 3 months followed by 5 doses every 6 months. Both arms had similar percentages of patients Zoledronic Acid Improves Disease-Free Survival in Postmenopausal or Older Women Only who used systemic chemotherapy and endocrine therapy, and the types of therapy received were similar in both groups. More than 95% of patients in the study were treated with chemotherapy--97% with an anthracycline and 24% with a taxane. In addition, 74% of patients received a combination of chemotherapy and endocrine therapy.
At a median follow-up of ~59 months, the rate of serious adverse events was similar between the treatment arms, with the exception of osteonecrosis of the jaw (ONJ). Investigators reported 17 confirmed cases of ONJ in the zoledronic arm and 9 potential cases; no cases occurred in the control arm. "At 5 years, 1.5% of patients on zoledronic acid developed ONJ," Coleman noted.
Disease-free survival and invasive DFS were identical in the trial arms. The types of recurrences were similar and arose with similar frequency in both groups of patients. About two-thirds of recurrences were distant metastases, ~16% were loco-regional recurrences, ~6% were ipsilateral recurrences, and ~3% were contralateral recurrences. Approximately 6% of patients in each arm developed new primary cancers.
Patients treated with zoledronic acid were 15% less likely to die than patients in the control arm (hazard ratio, 0.85; P
= .07), but this was not significant. When overall survival was analyzed according to menopausal status, older postmenopausal women who received zoledronic acid were 29% less likely to die of breast cancer than premenopausal women (P
"This trial will not be the last word," said Sharon H. Giordano, MD, University of Texas M.D. Anderson Cancer Center, Houston, Texas. "Other studies are planned or are ongoing to look at the role of bisphosphonates in breast cancer. Routine use of zoledronic acid to prevent recurrence of breast cancer is not indicated, but bisphosphonates do have an important role in treating bone loss among women with breast cancer to prevent skeletal-related events," she said. Giordano called the differences in outcome by menopausal status in AZURE "intriguing but not definitive." Novartis, which manufactures zoledronic acid, said the company is withdrawing applications in the United States and Europe that sought approval for the drug as part of adjuvant therapy while it analyzes data from this study.
_______________________________________________Abstract P5-11-02. Gnant M, Mlineritsch B, Stoeger H, et al. The carryover effect of adjuvant zoledronic acid: comparison of 48- and 62-month analyses of ABCSG-12 suggests that the benefits of combining zoledronic acid with adjuvant endocrine therapy persist long after completion of therapy. Paper presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX.