Sex-based differences in clinical outcomes of enfortumab vedotin and NECTIN-4 expression in urothelial cancer
Abstract 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.
Authors
- Francesco Ciccimarra (ORCID: https://orcid.org/0009-0009-7321-0950)
- Tarek Taha (ORCID: https://orcid.org/0000-0001-7936-5245)
- Sebastiano Buti (ORCID: https://orcid.org/0000-0003-0876-0226)
- Shilpa Gupta (ORCID: https://orcid.org/0000-0002-8775-503X)
- Ayelet Alpert
- Matteo Santoni (ORCID: https://orcid.org/0000-0001-7340-6173)
- Cristian Lolli (ORCID: https://orcid.org/0000-0003-0347-9179)
- Ravindran Kanesvaran (ORCID: https://orcid.org/0000-0002-2351-881X)
- Giandomenico Roviello (ORCID: https://orcid.org/0000-0001-5504-8237)
- Enrique Grande (ORCID: https://orcid.org/0000-0002-0134-4732)
- Aristotelis Bamias (ORCID: https://orcid.org/0000-0002-5996-7262)
- Jalal Baranseh (ORCID: https://orcid.org/0000-0002-5748-1330)
- Ithai Waldhorn
- Francesco Massari (ORCID: https://orcid.org/0000-0001-6476-6871)
- Fernando Sabino Marques Monteiro (ORCID: https://orcid.org/0000-0002-6621-8251)
- Hideki Takeshita (ORCID: https://orcid.org/0000-0002-1512-6904)
- Avivit Peer
- Joaquim Bellmunt
- Alessandro Rizzo
- Yüksel Ürün
Institutions
- University of Parma (IT)
- Cleveland Clinic (US)
- Royal Marsden NHS Foundation Trust (GB)
- Harvard University (US)
- Bar-Ilan University (IL)
- Institute of Cancer Research (GB)
- Ankara University (TR)
- Technion – Israel Institute of Technology (IL)
- National and Kapodistrian University of Athens (GR)
- Universidad Francisco de Vitoria (ES)
- Rambam Health Care Campus (IL)
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT)
- Hospital Universitario Quirónsalud Madrid (ES)
- Dana-Farber Cancer Institute (US)
- Istituto Tumori Bari (IT)
- National Cancer Centre Singapore (SG)
- University General Hospital Attikon (GR)
- Hospital Sírio-Libanês (BR)
- Ospedale di Macerata (IT)
- Latin American Cooperative Oncology Group (LACOG) (BR)
- ARON Research Foundation ETS (IT)
- IDCQ Hospitales y Sanidad, S.L.U. (ES)
- Saitama Medical Center, Saitama Medical University (JP)
- University of Florence (IT)
- University of Bologna (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-10-27
- DOI
- https://doi.org/10.1038/s41467-026-78988-7
- Primary Topic
- Bladder and Urothelial Cancer Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00