[S4-5] Adjuvant Treatment with Zoledronic Acid in Stage II/III Breast Cancer. The AZURE Trial (BIG 01/04).

Coleman RE, Thorpe HC, Cameron D, Dodwell D, Burkinshaw R, Keane M, Gil M, Houston SJ, Grieve RJ, Barrett-Lee PJ, Ritchie D, Davies C, Bell R. Weston Park Hospital, Sheffield, United Kingdom; University of Leeds, United Kingdom; AZURE (BIG 01/01) Investigators

Background: The ABCSG XII trial demonstrated a 32% risk reduction in disease-free survival (DFS) events with Zoledronic acid (ZOL) use in a cohort of premenopausal women treated with endocrine therapy at 62 months median follow-up.1,2 This stategy is increasingly being adopted in the wider breast cancer population. The AZURE trial is an academic study designed to determine whether treatment with ZOL added to standard adjuvant therapy improves DFS and bone metastasis-free survival (BMFS) in a broader range of patients with stage II/III breast cancer.
Materials and methods: 3360 patients from 174 centres were randomized to receive (neo) adjuvant chemotherapy (CT) and/or endocrine therapy (ET) +/- ZOL 4mg iv every 3-4 weeks for 6 doses, then 3 monthly x 8 and 6 monthly x 5 to complete 5 years treatment. The primary DFS endpoint was to be determined after 940 DFS events, providing 80% power to detect a 17% reduction in hazard rates (HR) for DFS events. The rate of events on study has been slower than expected, resulting in an estimated final analysis in 2012. In light of the clinical interest in the results of AZURE, the DMEC agreed to a second interim analysis with boundaries set by an independent statistician, unaware of results at the first interim analysis, for both 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).
Results: Patient characteristics including stage, number of positive axillary nodes, CT type, ER status, menopausal status and statin use were well balanced. 3208 patients (96%) received (neo) adjuvant CT (93% anthracyclines, 23% taxanes). 152 patients received ET alone. The safety population comprised 3340 patients (ZOL 1665; control 1675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. Serious adverse events (SAE) were similar in both treatment arms. To date 13 confirmed (0.83%; 95% CI 0.38%, 1.28%) cases of osteonecrosis of the jaw (ONJ) in the ZOL arm have occurred. As of October 18th 2010, with a median follow up of 59 (IQR 53-61) months, there have been 752 DFS events (ZOL 377; control 375 – H.R. 0.98, 95% CI 0.85-1.13; p=0.79). Subgroup analysis of premenopausal, ER+ patients (n=1185), approximating to the ABCSG XII population, also gave no indication of benefit from ZOL.
Discussion: AZURE is one of the largest phase III studies of adjuvant bisphosphonates, and with more DFS events than all previously reported studies combined. The results do not support the routine use of adjuvant ZOL in the management of early breast cancer.
1Gnant M et al. NEJM 2009; 360(7):679-691
2Gnant M et al. ASCO 2010 Proceedings; abs #533.

Friday, December 10, 2010 4:15 PM

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