Eur Urol Oncol. 2026 Aug 31:S2588-9311(26)00190-2. doi: 10.1016/j.euo.2026.07.001. Online ahead of print.
ABSTRACT
BACKGROUND AND OBJECTIVE: The Food and Drug Administration and the European Medicine Agency approved erdafitinib for patients with FGFR3-altered metastatic urothelial carcinoma (mUC), highlighting the central role of tumor molecular profiling for patients with mUC. Although different studies described the molecular landscape of muscle-invasive bladder cancer (MIBC) using publicly-available data, a dedicated evaluation of real-world actionable alterations, with evidence-based therapeutic recommendations according to current Molecular Tumor Board (MTB) guidelines, is still lacking.
DESIGN, SETTING, AND PARTICIPANTS: We characterized actionable genetic alterations in a retrospective cohort of 233 patients with MIBC/mUC (Muscle-Invasive Erlangen [MIER] cohort) using targeted sequencing.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinically relevant variants were assessed through a custom bioinformatics workflow and expert medical review. To validate their clinical relevance in a real-world setting, we examined actionable alterations and associated therapy recommendations in a cohort of 40 patients with MIBC/mUC undergoing routine diagnostics (MTB cohort).
RESULTS AND LIMITATIONS: In the MIER cohort, 95% of patients (n = 226/233; 95% confidence interval [CI], 94-99) harbored at least one pathogenic/likely pathogenic variant. Therapeutically relevant FGFR3 alterations were identified in 11% of patients (n = 26/233; 95% CI, 7.4-16). Additionally, 40% of patients (95% CI, 34-47) showed alterations in 24 biomarkers for FDA-approved therapies. In the MTB cohort, 55% of patients received either on-label (5.0%) or off-label (50%) therapy recommendations. Notably, the recommendation was implemented in only one patient, who achieved stable disease for 4 mo with off-label alpelisib. Retrospectively, similar on-label and off-label indications could have applied to 10% and 70% of patients in the MIER cohort, respectively.
CONCLUSIONS: Overall, evidence-based indications for on-label and off-label therapies were observed for the majority of patients with MIBC/mUC. However, our results also revealed a significant gap between the high prevalence of actionable findings and the actual implementation of MTB-guided treatments in clinical practice, suggesting a need for enhanced therapy access and physician adherence to MTB recommendations.
PMID:42674932 | DOI:10.1016/j.euo.2026.07.001
