To explore whether sex differences in the drug’s target might contribute to the outcome gap, the researchers analyzed NECTIN-4 expression in urothelial cancer samples from the TCGA database. They found significantly higher NECTIN-4 expression in tumors from male patients than in those from female patients.

The difference in NECTIN-4 expression remained significant after the researchers adjusted for molecular subtype of the tumor. The analysis further showed that the expression difference was modulated by smoking status and was associated with estrogen pathway activity, suggesting that sex-related hormonal signaling may influence how much of the drug target is present on tumor cells.

The authors caution that these findings are correlational. The clinical results come from a retrospective analysis of real-world patients rather than a randomized trial designed to test sex differences, and the expression findings come from database samples rather than from measurements in the treated patients themselves. The study therefore suggests, but does not prove, that differences in target expression and hormonal signaling contribute to the survival gap.

The researchers conclude that prospective studies should incorporate sex as a biological variable in antibody-drug conjugate research, so that treatment strategies can be optimized for both male and female patients. Because the article is being shared early as a peer-reviewed accepted manuscript, it remains subject to further edits before the final version of record is published.

Subject of Research: Sex-based differences in survival on enfortumab vedotin and NECTIN-4 expression in metastatic urothelial carcinoma

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

Article References: Taha, T., Alpert, A., Baranseh, J., Rizzo, A., Ciccimarra, F., Grande, E., Bellmunt, J., Buti, S., Massari, F., Gupta, S., Monteiro, F. S. M., Kanesvaran, R., Roviello, G., Lolli, C., Ürün, Y., Takeshita, H., Peer, A., Bamias, A., Santoni, M., & Waldhorn, I. (2026). Sex-based differences in clinical outcomes of enfortumab vedotin and NECTIN-4 expression in urothelial cancer. Nature Communications. https://doi.org/10.1038/s41467-026-78988-7

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78988-7

Keywords: enfortumab vedotin, NECTIN-4, urothelial carcinoma, antibody-drug conjugate, sex differences, overall survival, TCGA, estrogen pathway, smoking status, molecular subtype, real-world analysis, metastatic cancer