Abstract

In non-muscle-invasive bladder cancer (NMIBC), the occurrence of a high-grade (HG) recurrence following Bacillus Calmette-Guérin (BCG) treatment identifies a disease category that is associated with a particularly poor prognosis and for which radical cystectomy (RC) is the gold standard. The latest definition of European Association of Urology (EAU) BCG-unresponsive disease has been endorsed by the United States Food and Drug Administration for clinical trials and adopted by EAU guidelines, despite limited clinical data supporting it. To provide a clinical validation of the current EAU definitions of BCG failure. This is an international retrospective multicenter study. Patients with NMIBC treated with at least five out of six BCG induction instillations after January 2000 and presenting with disease recurrence were included. The minimum allowed follow-up was 6 mo. Patients presenting with disease progression at 3 mo and those receiving RC prior to the first follow-up cystoscopy were excluded. The main objective of the study was to validate the prognostic value of the different categories of BCG failure, focusing on the EAU definitions of BCG-refractory, BCG-relapsing and BCG-unresponsive disease. The primary endpoint was the time to progression to muscle-invasive disease, the development of nodal disease or distant metastases. Patients were classified according to the EAU definitions of BCG failure, which were applied a priori and subsequently evaluated for their association with disease progression. Overall, 776 patients with recurrence after BCG were included. Of these, 448 (58%) experienced a HG recurrence. The BCG-refractory subgroups displayed the highest progression rates, the worst being represented by HG recurrence at 6 mo during BCG maintenance (46% progression at 5 yr), followed by T1HG recurrence at 3 mo (30% at 5 yr). BCG-relapsing disease showed a marginally more favorable outcome. Notably, early BCG recurrences included in the definition of BCG-unresponsive disease conveyed progression-free survival similar to BCG-refractory (35% at 5 yr), thus supporting their inclusion in this disease category. We have provided the first clinical validation of the EAU definitions of BCG failure/unresponsive disease. They are prognostically informative and can be used to support clinical decision-making. [Abstract copyright: Copyright © 2026 European Association of Urology. All rights reserved.]