Over the past decade, the treatment landscape for metastatic urothelial carcinoma (mUC) has improved significantly with the introduction of immunotherapy, targeted agents, and antibody-drug conjugates. The median overall survival (mOS) reached 36.7 months in cisplatin-eligible and 25.6 months in cisplatin-ineligible patients in the first-line setting and over 10 months post-platinum failure. However, liver metastases remain a known poor prognostic factor.
We conducted a retrospective analysis of mUC patients treated at 79 global institutions. Two cohorts were defined: cohort 1 included patients who progressed after platinum-based therapy and received pembrolizumab, and cohort 2 included patients who received avelumab as maintenance therapy. Treatments were administered between 1 January 2016 and 31 October 2024.
Cohort 1 (n = 1,341) had an mOS of 17.5 months. Patients without liver metastases had significantly longer OS than those with liver involvement (20.1 vs. 9.4 months, p <0.001). Among patients with liver metastases, OS was 11.8 months in males vs. 5.8 months in females (p = 0.066). OS was longer in those with BMI ≥25 kg/m² (14.1 vs. 8.1 months, p = 0.028) and better ECOG-PS (ECOG 0: 17.0 months; ECOG 1: 9.8; ECOG ≥2: 3.1; p <0.001). Cohort 2 (n = 291) had an mOS of 25.8 months. Again, OS was longer in patients without liver metastases (27.0 vs. 16.4 months, p <0.001). Among those with liver involvement, OS was 14.7 months in males and 20.0 months in females (p = 0.310). Patients with BMI ≥25 had non-reached OS versus 17.1 months in those with lower BMI (p <0.001). ECOG-PS remained a strong prognostic factor (NR for ECOG 0; 14.7 months for ECOG 1; 4.6 months for ECOG ≥2, p <0.001).
Liver metastases are associated with significantly reduced survival in patients with mUC receiving immunotherapy. However, both pembrolizumab and avelumab demonstrated improved outcomes compared with historical chemotherapy data. These findings underscore the need for personalized treatment strategies in high-risk subgroups.
Frontiers in immunology. 2026 Feb 24*** epublish ***
Linda Cerbone, Giandomenico Roviello, Fabio Calabrò, Tarek Taha, Enrique Grande, Kirstin Binz, Ravindran Kanesvaran, Alina Pirstuk, Ondřej Fiala, Javier Molina-Cerrillo, Teresa Alonso-Gordoa, Alessandro Rizzo, Renate Pichler, Zin W Myint, Alexandr Poprach, Gaetano Facchini, Melichar Bohuslav, Hana Studentova, Franco Morelli, Tomas Buchler, Alessia Mennitto, Deniz Tural, Luigi Formisano, Inmaculada Orejana, Martina Catalano, Sebastiano Buti, Fernando Sabino Marques Monteiro, Andrey Soares, Shilpa Gupta, Francesco Massari, Matteo Santoni
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), National Cancer Institute Regina Elena, Rome, Italy., Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy., The Royal Marsden National Health Service (NHS) Foundation Trust, The Institute of Cancer Research, London, United Kingdom., Department of Medical Oncology, MD Anderson Cancer Center Madrid, Madrid, Spain., Division of Medical Oncology, Department of Internal Medicine, University of Kansas Cancer Center, Kansas City, KS, United States., Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore., Department of Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia., Department of Oncology and Radiotherapeutics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czechia., Department of Medical Oncology, Hospital Ramón y Cajal, Madrid, Spain., S.S.D. C.O.r.O. Bed Management Presa in Carico, TDM, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo II,", Bari, Italy., Department of Urology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria., Division of Medical Oncology, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY, United States., Masaryk Memorial Cancer Institute, Masaryk University, Brno, Czechia., Oncology Operative Unit, Santa Maria delle Grazie Hospital, Azienda Sanitaria Locale (ASL) NA2 NORD, P, ozzuoli, Napoli, Italy., Department of Oncology, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czechia., Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, Foggia, Italy., Department of Oncology, Charles University and University Hospital Motol, Prague, Czechia., Department of Medical Oncology, Azienda Ospedaliera Universitaria "Maggiore Della Carità,", Novara, Italy., Department of Medical Oncology, Koc University Medical Faculty, Istanbul, Türkiye., Department of Medicine and Surgery, Federico II University, Naples, Italy., Medical Oncology Unit, University Hospital of Parma, Parma, Italy., Oncology and Hematology Department, Hospital Sírio Libanês, Brasília, Brazil., Latin American Cooperative Oncology Group (LACOG), Porto Alegre, Brazil., Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States., Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Medical Oncology Unit, Macerata Hospital, Macerata, Italy.