Sex-based differences in clinical outcomes of enfortumab vedotin and NECTIN-4 expression in urothelial cancer

Sex-based differences in outcomes are well documented across tumor types and treatment modalities; however, it remains unclear whether these disparities extend to antibody-drug conjugates (ADCs). We report a retrospective, international real-world analysis of metastatic urothelial carcinoma (mUC) patients treated with Enfortumab Vedotin (EV), a NECTIN-4 ADC. Male patients demonstrate significantly longer median overall survival and time on treatment compared to female patients. Analysis of NECTIN-4 expression in urothelial cancer samples from the TCGA database reveals significantly higher expression in male patients’ tumors. This difference remains significant after adjusting for molecular subtype and is further modulated by smoking status and associates with estrogen pathway activity. These findings suggest that sex-related differences in target expression and hormonal signaling correlate with clinical outcomes of EV in mUC. Prospective studies should incorporate sex as a biological variable in ADC research to optimize treatment strategies for both male and female patients.