Abstract PD07-09: Zoledronate versus ibandronate comparative evaluation (ZICE) trial - first results of a UK NCRI 1,405 patient phase III trial comparing oral ibandronate versus intravenous zoledronate in the treatment of breast cancer patients with bone metastases.

Introduction Bone metastases in patients with breast cancer have serious effects on health including pain, poor mobility, skeletal fractures, spinal cord compression and the need for radiotherapy/surgery. The introduction of intravenous (IV) bisphosphonates, such as zoledronic acid (Z) has significantly delayed the onset of skeletal-related events (SRE). However, prolonged IV bisphosphonates place burdens upon patient and hospital, and can also cause renal and acute phase toxicities. Ibandronic acid (I), a third generation amino-bisphosphonate in its oral form has previously been compared with placebo and was shown to be well tolerated and effective. Indirect comparisons with IV Z indicated similar efficacy in reducing bone events, but adverse events were overall comparable with placebo. One might therefore assume that oral ibandronate would be more acceptable to patients, and the ZICE Trial is the only large scale direct randomised comparison between IV Z and oral I to report. Methods Between January 2006 and October 2010, 1405 newly diagnosed metastatic breast cancer patients with proven bone metastases were randomised 1:1 to IV Z (4mg 15 min infusion every 3–4 weeks) or oral I (50mg per day) for up to 96 weeks. All patients were prescribed daily calcium & vitamin D supplementation, and patients with current active dental problems including infection were excluded. Patients also received chemotherapy, and or endocrine therapy as determined by their physician. The primary objective was to demonstrate non-inferiority of oral I in comparison with IV Z in terms of the SRE rate, defined as the number of SREs reported per year (using multiple event analysis). Secondary endpoints included time to 1st SRE, proportion of patients with SRE, Pain Scores, side effect profiles including ONJ and renal toxicities, quality of life and Health resources and overall survival. The trial was run under the auspices of the NCRI, sponsored by Velindre NHS Trust, coordinated by the Wales Cancer Trials Unit, funded by an educational grant from Roche and peer reviewed/endorsed by Cancer Research UK (CRUKE/04/022). Results At the time of this analysis the last randomised patient had completed 96 weeks of therapy, median follow up was 18.4 months and total number of SREs was 865 (468 in I and 397 in Z). For the primary objective, the SRE rate was 0.543 and 0.444 in I and Z groups respectively (Hazard ratio, 1.22; 95% CI, 1.04 to 1.45; P = .017). Ibandronate failed to meet the criteria for non-inferiority to Zoledronate, but was similar in delaying time to first SRE (hazard ratio, 1.11; 95% CI, 0.94 to 1.31; P = .233). Overall survival (disease progression), was very similar between groups but renal AEs occurred more frequently with Z than I; Compliance with oral therapy was 82%. ONJ rate was very low in both arms (0.71%, I; 1.29%, Z; P = 0.28). Conclusion Oral I is inferior to Z in terms of the SRE rate in metastatic breast cancer patients with bone metastases, but is similar to Z in delaying time to first SRE. Both drugs had acceptable safety profiles, with adverse events consistent with those reported previously. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-09.