IUC26529-89 MERIT AWARD: Sex Differences in Enfortumab Vedotin Efficacy and NECTIN-4 Levels in Metastatic Urothelial Cancer

Abstract Background Antibody-drug conjugates (ADCs) represent an emerging class of anti-cancer therapies. Enfortumab vedotin (EV), a NECTIN-4–targeting ADC, has recently been integrated into the treatment landscape for urothelial cancer (UC). Prior subgroup analyses suggest sex may influence treatment efficacy – a factor often underexplored in research. To investigate this, we conducted a multi-center real-world data analysis, complemented by translational research, to gain deeper insight into this disparity. Methods Clinical outcomes were collected from the ARON2-EV retrospective study. Kaplan–Meier and log-rank tests were used for analysis. TCGA data for patients diagnosed with T2-T4a UC were analyzed for NECTIN-4 expression, sex differences, smoking status, molecular subtypes and regulating pathways. Results 454 patients with metastatic UC treated with EV across 51 centers in 18 countries were included. Overall survival was 13.6 months in males vs 7.7 months in females (p<.001), consistent after stratification by ECOG status, tumor histology, smoking status and prior therapy. Males also had longer time on-treatment (13.3 vs 7.4 months, p<.001). Objective response rate was similar (45% in males vs 36% in females), but primary refractory rates differed significantly (26% vs 44%, respectively, p = .008). NECTIN-4 expression was higher in men compared to women (p<.001), an effect that was augmented in smokers. Women were more often diagnosed with basal histology, which exhibits lower NECTIN-4 expression; However, differences persisted even after stratification by molecular subtype (p = .002). NECTIN-4 expression was most strongly associated with estrogen response gene set (p<.001), and smoking was found to reduce estrogen levels specifically in women. Conclusions Females appear to benefit less from EV treatment, potentially due to lower Nectin-4 expression driven by molecular subtype, mutational signatures, and the differential impact of smoking on estrogen levels. As ADCs continue to emerge as a novel class of therapy, these findings of an ADC with sex differences underscore the importance of evaluating the influence of sex on ADC efficacy and toxicity in clinical trials. Acknowledgements ARON Research Foundation ETS for its support and encouragement. All other co-authors: Jalal Baranseh, Enrique Grande, Sebastiano Buti, Francesco Massari, Fernando Sabino Marques Monteiro, Giandomenico Roviello, Cristian Lolli, Hideki Takeshita, Avivit Peer, Aristotelis Bamias.