Gender- and sex-based disparities in response to immune-checkpoint inhibitors (ICI) has been reported in a variety of tumor types. Women have different anatomy with recurrent urinary tract infections, a different sex hormonal profile, and intrinsic differences in local and systemic immune systems and urobiome composition. Existing literature data in a pan-cancer context reveal contradictory results, and real-world evidence in urothelial carcinoma (UC) is lacking. This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic urothelial carcinoma (mUC) patients progressing or recurring after platinum-based therapy and treated with pembrolizumab as a part of routine clinical care. A total of 1039 patients, treated from January 1st, 2016 to December 31st, 2023 in 68 cancer centers were included. Our data showed that women with metastatic urothelial carcinoma treated with pembrolizumab had shorter OS than men, with a 13% advantage in the 5-year OS rate for male patients. A deeper understanding of these results may inform sex-stratification in future prospective clinical trials and help develop strategies to reduce the magnitude of the sex disparities observed in urothelial cancer outcomes.

2nd Propaedeutic Department of Internal Medicine ATTIKON University Hospital School of Medicine National and Kapodistrian University of Athens Athens Greece

Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Centro Oncologico Estatal ISSEMYM Toluca de Lerdo Mexico

Clínica AMO Salvador BA Brazil

Dana Farber Cancer Institute Harvard Medical School Boston MA USA

Department of Biomedical Sciences Humanitas University Pieve Emanuele Milan Italy

Department of Clinical Oncology and Radiotherapy University Hospital Hradec Kralove Hradec Kralove Czech Republic

Department of Medical Oncology Bakirköy Dr SadiKonuk Training and Research Hospital Tevfik Saglam St No 11 Zuhuratbaba District Bakirkoy Istanbul Turkey

Department of Medical Oncology Institut d'Investigació Biomèdica Sant Pau Hospital de la Santa Creu i Sant Pau Barcelona Spain

Department of Medicine and Surgery University of Parma Parma Italy

Department of Oncology and Radiotherapeutics Faculty of Medicine and University Hospital in Pilsen Charles University Pilsen Czech Republic

Department of Oncology IRCCS Humanitas Research Hospital Rozzano Milan Italy

Department of Precision Medicine in Medical Surgical and Critical Care Section of Medical Oncology University of Palermo 90127 Palermo Italy

Department of Urology Saitama Medical Center Saitama Medical University Saitama Japan

Dipartimento di Oncologia Medica Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Division of Medical Oncology A O U Consorziale Policlinico di Bari Piazza G Cesare 11 70124 Bari Italy

Hospital Ángel H Roffo CABA Buenos Aires Argentina

Hospital Sírio Libanês Brasilia DF Brazil

Instituto Alexander Fleming CABA Buenos Aires Argentina

Klinik Für Urologie Ratzeburger Allee 160 23538 Lübeck Germany

Latin American Cooperative Oncology Group LACOG Porto Alegre RS Brazil

Medical Oncology 1 IRCCS Regina Elena National Cancer Institute Rome Italy

Medical Oncology IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna Italy

Medical Oncology Tawam Hospital Al Ain United Arab Emirates

Medical Oncology Unit Medicine and Pharmacy Faculty National Institute of Oncology Mohamed 5 University Rabat Morocco

Medical Oncology Unit University Hospital of Parma Parma Italy

Michele and Pietro Ferrero Hospital ASL CN2 Verduno Italy

Oncology Institute of Vojvodina Faculty of Medicine University Novi Sad Novi Sad Serbia

Oncology Unit Macerata Hospital Via Santa Lucia 2 62100 Macerata Italy

University of Colorado Anschutz Medical Campus Aurora CO USA

UOC di Oncologia Azienda Ospedaliera di Rilievo Nazionale Cardarelli di Napoli Naples Italy

Urologic Oncology Champalimaud Clinical Center 1400 038 Lisbon Portugal

Urology Unit Azienda Ospedaliero Universitaria delle Marche Università Politecnica delle Marche Ancona Italy

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