Metastatic urothelial carcinoma (mUC) may present with metastases at the time of initial diagnosis (synchronous) or develop them during follow-up (metachronous). The impact of the timing of metastasis on the outcome of mUC remains unclear. We aimed to evaluate overall survival (OS) stratified by time to metastasis (TTM) in patients receiving systemic therapy in different lines. Retrospective real-world data from the ARON-2 study were analyzed to compare patient outcomes according to TTM. Cohort 1 included 735 patients receiving first-line platinum-based chemotherapy, Cohort 2 included 1164 patients receiving second-line pembrolizumab, Cohort 3 included 588 patients receiving third-line enfortumab vedotin. TTM (synchronous vs. < 6 months, and ≥ 6 months) significantly influenced overall survival (OS) in Cohort 1 (19.2 vs. 22.3 vs. 27.4 months, p = 0.004) and Cohort 2 (14.6 vs. 15.4 vs. 21.2 months, p = 0.015), but not in Cohort 3. In the multivariable Cox analysis, TTM remained an independent prognostic parameter of poor OS in Cohort 1 (hazard ratio [HR]: 1.14, 95% confidence interval [CI] 1.02-1.27; p = 0.016) and Cohort 2 (HR: 1.12, 95% CI 1.02-1.22; p = 0.014). Our findings suggest that the TTM in mUC significantly influences OS in patients receiving first-line platinum-based chemotherapy and second-line pembrolizumab. The prognostic role of TTM should be considered in the future clinical trial designs.

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

Clínica AMO Assistência Multidisciplinar em Oncologia Salvador Brazil

Clinical Oncology Genitourinary Oncology Unit Alexander Fleming Institute Buenos Aires Argentina

Department of Medical and Surgical Sciences University of Bologna Bologna Italy

Department of Medical Oncology Faculty of Medicine Ankara University 06620 Ankara Turkey

Department of Medical Oncology Hospital Ramón y Cajal Madrid Spain

Department of Medical Oncology Koc University Medical Faculty Istanbul Turkey

Department of Medical Oncology MD Anderson Cancer Center Madrid Madrid Spain

Department of Medicine and Surgery University of Parma Parma Italy

Department of Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol 5 Uvalu 84 150 06 Prague Czech Republic

Department of Oncology and Radiotherapeutics Faculty of Medicine and University Hospital Pilsen Charles University Prague Alej Svobody 80 304 60 Pilsen Czech Republic

Department of Uro Oncology Maria Sklodowska Curie National Research Institute of Oncology Warsaw Warsaw Poland

Department of Urology Comprehensive Cancer Center Innsbruck Medical University of Innsbruck Innsbruck Austria

Department of Urology Jikei University School of Medicine Tokyo Japan

Department of Urology Saitama Medical Center Saitama Medical University Kawagoe Saitama Japan

Division of Medical Oncology Department of Internal Medicine Markey Cancer Center University of Kentucky Lexington KY USA

Division of Medical Oncology Department of Internal Medicine University of Kansas Cancer Center Overland Park USA

Division of Medical Oncology National Cancer Centre Singapore Singapore Singapore

Hospital del Mar Barcelona Spain

Latin American Cooperative Oncology Group LACOG Porto Alegre Brazil

Masaryk Memorial Cancer Institute Brno Czech Republic Faculty of Medicine Masaryk University Brno Czech Republic

Medical Oncology Department CHU Insular Materno Infantil Las Palmas de Gran Canaria Spain

Medical Oncology IRCCS Azienda Ospedaliero Universitaria Di Bologna Bologna Italy

Medical Oncology Unit IRCCS Casa Sollievo Della Sofferenza Foggia Italy

Medical Oncology Unit Livorno Hospital Azienda Toscana Nord Ovest 57124 Leghorn Italy

Medical Oncology Unit Macerata Hospital Macerata Italy

Medical Oncology Unit University Hospital of Parma Parma Italy

Oncology and Hematology Department Hospital Sírio Libanês Brasília Brazil

Oncology Unit 2 University Hospital of Pisa 56126 Pisa Italy

Oncology Unit Hospital Israelita Albert Einstein São Paulo SP Brazil

Servicio de Oncología Hospital Universitario La Paz Madrid Spain

Taussig Cancer Institute Cleveland Clinic Cleveland OH USA

U O Oncologia Ospedale C Urbani Jesi Italy

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