Long-awaited results from the Phase III AZURE (Adjuvant Zoledronic acid to redUce REcurrence) in breast cancer patients show no effect from bisphosphonate zolendronic acid on the recurrence of breast cancer or on overall survival according to researchers at the 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium. However, a subset analysis showed a significant effect on both recurrence and survival in postmenopausal women (more than 5 years after menopause), but no effect on premenopausal women.

"Adjuvant use of bisphosphonates like zoledronic acid is widespread among women with breast cancer, and the results of this trial will help answer many questions as well invite new ones," said Robert Coleman, M.D., professor of medical oncology at the University of Sheffield in England.

The AZURE trial included 3,360 patients from 174 centers. Coleman and colleagues randomized patients to standard therapy or standard therapy plus zoledronic acid for five years. All patients had stage II/III breast cancer.

Results from the second interim analysis of the Phase III AZURE (Adjuvant Zoledronic acid to redUce REcurrence) trial show that Zometa® (zoledronic acid) did not demonstrate a disease-free survival (DFS) advantage when added to standard adjuvant (post-surgery) chemotherapy and/or hormonal therapy in pre- and postmenopausal women with early breast cancer. In a preplanned analysis based on menopausal status, a benefit in disease free survival and overall survival was seen in women with well-established menopause in the Zometa arm.

The AZURE trial was conducted to determine if Zometa as adjuvant therapy had a benefit in preventing recurrences in premenopausal and postmenopausal women with early breast cancer. The results were presented at the 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium in San Antonio, Texas, US.

Zometa is currently approved for the reduction or delay of bone complications (skeletal-related events, or SREs) across a broad range of metastatic cancers (breast, prostate, lung and other solid tumors) involving bone and multiple myeloma, as well as for the treatment of hypercalcemia of malignancy (HCM) and is the most widely used bisphosphonate in the oncology setting.

The potential anticancer benefit of Zometa was previously observed in a large, randomized, Phase III study from the Austrian Breast & Colorectal Cancer Study Group (ABCSG-12 study), which included more than 1,800 premenopausal women with hormone receptor-positive (HR+) early-stage breast cancer who, following curative surgery and hormone therapy, including goserelin treatment to suppress ovarian function and induce menopause, were treated with or without Zometa for three years. The trial showed that the addition of three years of Zometa therapy to hormonal therapy following surgery improved disease-free survival by 32% (hazard ratio=0.68 [95% confidence interval 0.51-0.91], P=0.009).

AZURE is a randomized, open-label, multicenter, parallel group trial that enrolled 3,360 women from 174 centers in seven countries. The study is run by the National Cancer Research Network in the United Kingdom with input from an international collaborative group. Patients participate in a five-year treatment phase and a subsequent five-year follow-up phase. A small subset of patients also received neo-adjuvant (pre-surgery) therapy.

The primary endpoint of DFS was to be determined after 940 disease events. The data presented at SABCS are from a second interim analysis performed when at least 75% (752) of the final events had occurred. Secondary endpoints included invasive DFS, overall survival, bone metastasis free survival safety, and other translational endpoints. After a median follow up of 59 months (interquartile range 53-61), the hazard ratio (HR) for DFS in Zometa-treated (n=1681) compared to control patients (n=1678) was 0.98 (95% confidence interval [CI] [0.85-1.13], P=0.79), thus there was no clinically significant benefit between the treatment groups. The trend toward improved overall survival in patients on the Zometa arm was not statistically significant (HR=0.85 [95% CI 0.72-1.01], P=0.0726).

In a preplanned analysis of women based on menopausal status, a benefit of disease free survival and overall survival was seen in women with well-established menopause in the Zometa arm. An adjusted analysis for imbalances in prognostic factors (estrogen receptor, lymph node status and tumor stage) showed this benefit was statistically significant (29% improvement in overall survival (HR=0.71 [95% CI 0.54-0.94]; P=0.017). No benefit was seen in premenopausal women.

The tolerability profile of Zometa is well-established and results from this study were found to be consistent with the known profile. Generally, serious adverse events (SAE) were similar in both treatment arms. There were 17 cases of osteonecrosis of the jaw confirmed in the Zometa arm. This represents a rate of 1.16%, which is consistent with what has been seen in other well controlled trials.