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

Zobrazit více v PubMed

Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality world-wide for 36 cancers in 185 countries. PubMed DOI

Andreassen, B. K., Grimsrud, T. K. & Haug, E. S. Bladder cancer survival: Women better off in the long run. PubMed DOI

Waldhoer, T., Berger, I., Haidinger, G., Zielonke, N. & Madersbacher, S. Sex Differences of ≥ pT1 bladder cancer survival in Austria: A descriptive, long-term, nation-wide analysis based on 27,773 patients. PubMed DOI

Kamat, A. M. et al. Bladder cancer. PubMed DOI

Mungan, N. A. et al. Gender differences in stage-adjusted bladder cancer survival. PubMed DOI

Ristau, B. T. & Davies, B. J. Disparity in bladder cancer outcomes: What’s sex got to do with it?. PubMed DOI

Zaitsu, M. et al. Sex differences in bladder cancer pathology and survival: Analysis of a population‐based cancer registry. PubMed DOI PMC

Antoni, S. et al. Bladder cancer incidence and mortality: A global overview and recent trends. PubMed DOI

Marcos-Gragera, R. et al. EUROCARE-5 Working Group: Urinary tract cancer survival in Europe 1999–2007: Results of the population-based study EUROCARE-5. PubMed DOI

Doshi, B., Athans, S. R. & Woloszynska, A. Biological differences underlying sex and gender disparities in bladder cancer: Current synopsis and future directions. PubMed DOI PMC

Mazzaschi, G., Quaini, F. & Buti, S. Exploring genetic and immune underpinnings of the sexual dimorphism in tumor response to immune checkpoints inhibitors: A narrative review. PubMed DOI PMC

Koti, M. et al. Sex differences in bladder cancer immunobiology and outcomes: A collaborative review with implications for treatment. PubMed DOI

Dobruch, J. et al. Gender and bladder cancer: A collaborative review of etiology, biology, and outcomes. PubMed DOI

Powles, T. et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. PubMed DOI

Balar, A. V. et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEY- NOTE-052): A multicentre, single-arm, phase 2 study. PubMed DOI

Vuky, J. et al. Long-term outcomes in KEYNOTE-052: Phase II study investigating first-line pembroli- zumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. PubMed DOI

Bellmunt, J. et al. Pembrolizumab as sec- ond-line therapy for advanced urothelial carcinoma. PubMed DOI PMC

Balar, A. V. et al. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: Results from KEYNOTE-045 and keynote-052 after up to 5 years of follow- up. PubMed DOI

Wang, P. F., Song, H. F., Zhang, Q. & Yan, C. X. Pan-cancer immunogenomic analyses reveal sex disparity in the efficacy of cancer immunotherapy. PubMed DOI

Oertelt-Prigione, S. The influence of sex and gender on the immune response. PubMed DOI

Conforti, F. et al. Cancer immunotherapy efficacy and patients’ sex: A systematic review and meta-analysis. PubMed DOI

Wallis, C. J. D. et al. Association of patient sex with efficacy of immune checkpoint inhibitors and overall survival in advanced cancers: A systematic review and meta-analysis. PubMed DOI PMC

Santoni, M. et al. The impact of gender on The efficacy of immune checkpoint inhibitors in cancer patients: The MOUSEION-01 study. PubMed DOI

Hussein, A. A. et al. Does the urinary microbiome profile change after treatment of bladder cancer?. PubMed DOI

Massari, F. et al. Global real-world experiences with pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy: The ARON-2 study. PubMed DOI PMC

Santoni, M. et al. Real-world effectiveness of pembrolizumab as first-line therapy for cisplatin-ineligible patients with advanced urothelial carcinoma: The ARON-2 study. PubMed DOI PMC

Fiala, O. et al. Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: Data from the ARON-2 retrospective study. PubMed DOI PMC

Santoni, M. et al. Bone targeting agents, but not radiation therapy, improves survival in patients with bone metastases from advanced urothelial carcinoma receiving pembrolizumab: Results from the ARON-2 study. PubMed DOI

Fiala, O. et al. Enfortumab vedotin following platinum chemotherapy and avelumab maintenance in patients with metastatic urothelial carcinoma: A retrospective data from the ARON-2EV study. PubMed DOI PMC

Rizzo, M. et al. Real-life impact of enfortumab vedotin or chemotherapy in the sequential treatment of advanced urothelial carcinoma: The ARON-2 retrospective experience. PubMed DOI PMC

Cerrato, C. et al. Effect of sex on the oncological outcomes in response to immunotherapy and antibody-drug conjugates in patients with urothelial and kidney cancer: A systematic review and a network meta-analysis. PubMed DOI

Yanagisawa, T. et al. Impact of sex on the efficacy of immune checkpoint inhibitors in kidney and urothelial cancers: A systematic review and meta-analysis. PubMed DOI PMC

Schneidewind, L. et al. Gender-specific outcomes in immune checkpoint inhibitor therapy for advanced or metastatic urothelial cancer: A systematic review and meta-analysis. PubMed DOI PMC

Piasecka, B. et al. Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges. PubMed DOI PMC

Carè, A. et al. Sex disparity in cancer: Roles of microRNAs and related functional players. PubMed DOI PMC

Incorvaia, L. et al. Prognostic role of soluble PD-1 and BTN2A1 in overweight melanoma patients treated with nivolumab or pembrolizumab: Finding the missing links in the symbiotic immune-metabolic interplay. PubMed DOI PMC

Incorvaia, L. et al. A “lymphocyte MicroRNA signature” as predictive biomarker of immunotherapy response and plasma PD-1/PD-L1 expression levels in patients with metastatic renal cell carcinoma: Pointing towards epigenetic reprogramming. PubMed DOI PMC

Overdevest, J. B. et al. CD24 expression is important in male urothelial tumorigenesis and metastasis in mice and is androgen regulated. PubMed DOI PMC

Fouts, D. E. et al. Integrated next-generation sequencing of 16S rDNA and metaproteomics differentiate the healthy urine microbiome from asymptomatic bacteriuria in neuropathic bladder associated with spinal cord injury. PubMed DOI PMC

Taguchi, S. et al. Validation of a drug-based score in advanced urothelial carcinoma treated with pembrolizumab. PubMed DOI

Incorvaia, L. et al. Body mass index and baseline platelet count as predictive factors in Merkel cell carcinoma patients treated with avelumab. PubMed DOI PMC

Incorvaia, L. et al. Sex and survival outcomes in patients with renal cell carcinoma receiving first-line immune-based combinations. PubMed DOI PMC

Time to metastasis as a prognostic factor in metastatic urothelial carcinoma: results from the ARON-2 study