Zoledronic acid add-on therapy for standard-risk Ewing sarcoma patients in the Ewing 2008R1 trial.

The phase III, open-label, prospective, multicenter, randomized Ewing 2008R1 trial (EudraCT2008-003658-13) was conducted in 12 countries to evaluate the effect of Zoledronic acid (ZOL) maintenance therapy compared to no add-on regarding event-free (EFS, primary endpoint) and overall survival (OS) in standard-risk Ewing Sarcoma (EWS). Eligible patients had localized EWS with either good histological response to induction chemotherapy and/or small tumors (<200ml). Patients received 6 cycles VIDE induction and 8 cycles VAI (male) or 8 cycles VAC (female) consolidation. ZOL treatment started parallel to the 6th consolidation cycle. Randomization was stratified by tumor site (pelvis/other). The two-sided adaptive inverse-normal 4-stage design (planned sample size 448 patients, significance level 5%, power 80%) was changed after the 1st interim analysis using Müller-Schäfer method. Between 04/2010 and 11/2018 284 patients were randomized (142 ZOL/142 no add-on). With a median follow-up of 3.9 years, EFS was not significantly different between ZOL and no add-on group in the adaptive design (HR 0.74, 95% CI 0.43-1.28, p=0.27, intention-to-treat). 3-y-EFS rates were 84.0% (95%CI 77.7-90.8%) for ZOL vs 81.7% (95%CI 75.2-88.8%) for no add-on. Results were similar in the per-protocol collective. OS was not different between groups. The 3y-OS was 92.8% (95%CI 88.4-97.5%) for ZOL and 94.6% (95%CI 90.9-98.6%) for no add-on. Noticeable more renal, neurological and gastrointestinal toxicities were observed for ZOL (p<0.05). Severe renal toxicities occurred more often in the ZOL arm (p=0.003). In patients with standard-risk localized EWS, there is no additional benefit from maintenance treatment with ZOL.