BACKGROUND: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. METHODS: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. CONCLUSIONS: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.

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

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

Centro de Pesquisas Oncológicas CEPON Florianópolis SC Brazil

Centro Oncologico Estatal Dr José Luis Barrera Franco del ISSEMYM Toluca de Lerdo Mexico

Centro Paulista de Oncologia Oncoclinicas Sao Paulo Brazil

Clínica AMO Salvador BA Brazil

Clinica de Oncologia Clion Salvador BA Brazil

Clinica Medica Especializada en Oncologia Medica Guatemala City Guatemala

Clinical Oncology Sociedad de Oncología Y Hematología del Cesar Valledupar Colombia

Clinicas Medicas Especializadas NUCARE Guatemala City Guatemala

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 Genitourinary Medical Oncology and Clinical Pharmacology National Institute of Oncology Budapest Hungary

Department of Health Sciences Section of Clinical Pharmacology and Oncology University of Florence Viale Pieraccini 6 50139 Florence Italy

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

Department of Medical Oncology Centre Hospitalier de Jolimont Haine Saint Paul Belgium

Department of Medical Oncology Hospital Ramón Y Cajal Madrid Spain

Department of Medical Oncology Institutd' Investigació Biomèdica Sant Pau Hospital de La Santa Creu 1 Sant Pau Barcelona Spain

Department of Medical Oncology IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori Meldola Italy

Department of Medical Oncology Maggiore Della Carità University Hospital 28100 Novara Italy

Department of Medical Oncology MD Anderson Cancer Center Madrid Madrid Spain

Department of Medical Oncology Università Politecnica Delle Marche AOU Ospedali Riuniti Delle Marche Ancona Italy

Department of Medicine and Surgery University Hospital of Parma Parma Italy

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

Department of Oncology Candiolo Cancer Institute FPO IRCCS Candiolo Turin Italy

Department of Oncology Hospital Sírio Libanês São Paulo SP Brazil

Department of Oncology IRCCS Humanitas Research Hospital Rozzano Milan Italy

Department of Oncology Radiotherapy Prof Dr Alexandru Trestioreanu Institute of Oncology University of Medicine and Pharmacy Bucharest Romania

Department of Oncology San Camillo Forlanini Hospital Rome Italy

Department of Radiological Oncological and Anatomo Pathological Science Sapienza University of Rome Viale Regina Elena 324 00185 Rome Italy

Department of Radiological Oncological and Pathological Sciences Policlinico Umberto 1 Sapienza University of Rome Rome Italy

Department of Surgical Oncological and Oral Sciences Section of Medical Oncology University of Palermo Palermo Italy

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

Department of Urology Medical University of Innsbruck Anichstrasse 35 6020 Innsbruck Austria

Department of Urology Saitama Medical Center Saitama Medical University Saitama Japan

Department of Urology University Hospital Bonn 53127 Bonn Germany

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

Division of Oncology Institute for Cancer Research and Treatment Asl Cn2 Alba Brà 12051 Alba Brà Italy

Fundacion Centro Oncologico de Integracion Regional COIR Mendoza Argentina

Hospital AC Camargo São Paulo SP Brazil

Hospital Angel Roffo Buenos Aires CABA Argentina

Hospital Beneficencia Portuguesa de São Paulo São Paulo SP Brazil

Hospital do Câncer Porto Dias Rede Mater Dei de Saúde Belém PA Brazil

Hospital Erasto Gaertner Curitiba PR Brazil

Hospital Israelita Albert Einstein São Paulo SP Brazil

Hospital Santa Casa de Sao Paulo São Paulo SP Brazil

Hospital São Rafael Oncologia D'Or Salvador BA Brazil

Hospital Sao Rafael Salvador BA Brazil

Hospital Sirio Libanes Buenos Aires CABA Argentina

Instituto Alexander Fleming Buenos Aires CABA Argentina

Instituto D'Or de Ensino E Pesquisa Rio de Janeiro RJ Brazil

Interdisciplinary Department of Medicine University of Bari Aldo Moro Bari Italy

IRCCS Ospedale Policlinico San Martino Genoa Italy

Klinik Für Urologie Ratzeburger Allee 160 23538 Lübeck Germany

Latin American Cooperative Oncology Group LACOG Porto Alegre Brazil

Markey Cancer Center University of Kentucky Lexington KY 40536 0293 USA

Medical Oncology 1 IRCCS Regina Elena National Cancer Institute Rome Italy

Medical Oncology Department La Paz University Hospital Madrid Spain

Medical Oncology Division of Urogenital and Head and Neck Tumours IEO European Institute of Oncology IRCCS Milan Italy

Medical Oncology IRCCS Azienda Ospedaliero Universitaria Di Bologna Via Albertoni 15 Bologna Italy

Medical Oncology Tawam Hospital Al Ain United Arab Emirates

Medical Oncology Unit Gemelli Molise Hospital Università Cattolica del Sacro Cuore Campobasso Italy

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

Medical Oncology Unit Santa Chiara Hospital Trento Italy

Medical Oncology Unit University Hospital of Parma Parma Italy

National Cancer Centre Singapore Singapore Republic of Singapore

Niguarda Cancer Center Grande Ospedale Metropolitano Niguarda Milan Italy

Oncologia D'Or Fortaleza CE Brazil

Oncologia Medica Fondazione Policlinico Universitario Agostino Gemelli IRCCS Rome Italy

Oncologia Medica Ospedale Maggiore Di Cremona Cremona Italy

Oncology 1 Unit Department of Oncology Istituto Oncologico Veneto IOV IRCCS 35128 Padua Italy

Oncology and Hematology Department Hospital Santa Lucia SHLS 716 Cj C Brasília DF 70390 700 Brazil

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

Oncology Unit 2 University Hospital of Pisa 56126 Pisa Italy

Oncology Unit A R N A S Civico Palermo Italy

Oncology Unit Macerata Hospital Via Santa Lucia 2 62100 Macerata Italy

ONCOR Life Medical Center Saltillo Mexico

Pontificia Universidade Católica Do Rio Grande Do Sul PUCRS Porto Alegre RS Brazil

Section of Oncology Department of Medicine School of Medicine and Verona University Hospital Trust University of Verona Verona Italy

SOC Oncologia Medica Azienda Ospedaliera Pugliese Ciaccio Catanzaro Italy

Southampton Experimental Cancer Medicine Centre University of Southampton Southampton UK

Struttura Semplice Dipartimentale Di Oncologia Medica Per La Presa in Carico Globale del Paziente Oncologico Don Tonino Bello 1 R C C S Istituto Tumori Giovanni Paolo 2 Viale Orazio Flacco 65 70124 Bari Italy

Unità Di Oncologia Medica Azienda Ospedaliero Universitaria Di Cagliari Cagliari Italy

Universidade Federal de Minas Gerais UFMG Belo Horizonte MG Brazil

University of Colorado Cancer Center Anschutz Medical Campus Aurora CO USA

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

UOC Oncologia Azienda Ospedaliera Ospedali Riuniti Marche Nord Fano Italy

UOC Oncologia Medica Ospedale A Murri Fermo Italy

UOC Oncologia Medica Ospedale Dell'alta Val D'Elsa Usl sud est Toscana Area Senese Poggibonsi Italy

Urologic Oncology Champalimaud Clinical Center 1400 038 Lisbon Portugal

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