Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial.

BACKGROUND: Zoledronic acid reduces skeletal-related events in patients with breast cancer, but concerns have been raised about prolonged monthly administration. We assessed the efficacy and safety of a reduced dosing frequency of zoledronic acid in women treated previously with monthly zoledronic acid. METHODS: We did this non-inferiority, phase 3 trial in 62 centres in Italy. We enrolled patients with breast cancer who had one or more bone metastases and had completed 12-15 months of monthly treatment with zoledronic acid. Patients were randomly assigned with a permutated block (size four to eight) random list stratified by centre in a 1:1 ratio to zoledronic acid 4 mg once every 12 weeks or once every 4 weeks, and followed up for at least 1 year. Neither patients nor investigators were masked to treatment allocation. The primary outcome was skeletal morbidity rate (skeletal-related events per patient per year) in the intention-to-treat population. We used a non-inferiority margin of 0·19. The trial is registered with EudraCT, number 2005-004942-15. FINDINGS: We screened 430 patients and enrolled 425, of whom 209 were assigned to the 12-week group and 216 to the 4-week group. The skeletal morbidity rate was 0·26 (95% CI 0·15-0·37) in the 12-week group versus 0·22 (0·14-0·29) in the 4-week group. The between-group difference was 0·04 and the upper limit of one-tailed 97·5% CI was 0·17, which is lower than the non-inferiority margin. The most common grade 3-4 adverse events were bone pain (56 [27%] patients in the 12-week group vs 65 [30%] in the 4-week group), nausea (24 [11%] vs 33 [15%]), and asthenia (18 [9%] vs 33 [15%]). Renal adverse events occurred in one patient (<1%) in the 12-week group versus two (1%) in the 4-week group. One patient (<1%) in the 4-week group had grade 1 acute renal failure. Osteonecrosis of the jaw occurred in four patients in the 12-week group versus three in the 4-week group. No treatment-related deaths were reported. Median N-terminal telopeptide concentration changed from baseline more in the 12-week group than in the 4-week group after 12 months (12·2%vs 0·0%; p=0·011). INTERPRETATION: Our results raise the possibility of decreasing administration of zoledronic acid to a 12-weekly regimen to reduce exposure during the second year, while maintaining its therapeutic effects. However, the effects on N-terminal telopeptide should be investigated further before changing current practice. FUNDING: Novartis Farma.