BACKGROUND AND OBJECTIVE: Bacillus Calmette-Guérin (BCG) is the standard treatment in patients harboring high-risk (HR) non-muscle-invasive bladder cancer (NMIBC). However, BCG therapy faces frequent adverse events (AEs), limited efficacy, and ongoing shortages, leading to a low completion rate, access challenges, and high recurrence. In consequence, there is a growing interest in exploring alternative treatments, including immune checkpoint inhibitors, chemotherapy combinations, and novel intravesical therapies. This systematic review summarizes current prospective evidence on BCG and alternative treatment options for BCG-naïve HR-NMIBC patients (PROSPERO: CRD42024564900). METHODS: A systematic search in MEDLINE, EMBASE, Scopus, Web of Science, and Cochrane Library retrieved 1042 studies, of which 17 met the inclusion criteria (following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines). KEY FINDINGS AND LIMITATIONS: In 12 studies on BCG-treated patients (n = 1418), recurrence-free survival (RFS) rates were 66-96% at 1-yr, 63-96% at 2-yr, and 39-66% at 5-yr follow-up. Progression-free survival (PFS) rates were 81-98% at 1-yr, 70-96% at 2-yr, and 70-84% at 5-yr follow-up. In nine studies focusing on patients treated with alternative strategies (n = 657), RFS rates were 51-99% at 1-yr, 48-88% at 2-yr, and 47-55% at 5-yr follow-up. PFS was 90-100% at 1-yr, 88-96% at 2-yr, and 84-93% at 5-yr follow-up. AE rates varied widely across studies, for both BCG and alternative treatments. Unfortunately, studies heterogeneity and a small sample sizes limit statistically meaningful conclusions. Twelve clinical trials are currently investigating new strategies for BCG-naïve HR NMIBC patients. CONCLUSIONS AND CLINICAL IMPLICATIONS: Alternative therapies for BCG-naïve HR NMIBC patients are emerging but need further validation. As challenges such as toxicity, cost, and long-term efficacy persist, ongoing trial results will be crucial in determining their role in future clinical practice.

Department of General Oncological and Functional Urology Medical University of Warsaw Warsaw Poland

Department of Maternal Infant and Urologic Sciences Sapienza University of Rome Policlinico Umberto 1 Hospital Rome Italy

Department of Urology and Oncologic Urology Wroclaw Medical University Wroclaw Poland

Department of Urology Bichat Claude Bernard Hospital AP HP Université de Paris Paris France

Department of Urology Careggi Hospital University of Florence Florence Italy

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

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Department of Urology University of Texas Southwestern Dallas TX USA; Karl Landsteiner Institute of Urology and Andrology Vienna Austria; Department of Urology Weill Cornell Medical College New York NY USA; Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Instituto Ramón y Cajal de Investigación Sanitaria Hospital Universitario Ramón y Cajal Universidad de Alcalá Madrid Spain

Department of Urology Luzerner Kantonsspital Lucerne Switzerland

Department of Urology Medical University of Innsbruck Innsbruck Austria

Department of Urology Netherlands Cancer Institute Amsterdam The Netherlands

Department of Urology Puigvert Foundation Autonomous University of Barcelona Barcelona Spain

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University of Tor Vergata Rome Italy

Department of Urology UROSUD La Croix Du Sud Hospital Quint Fonsegrives France

Division of Urology Department of Surgical Sciences San Giovanni Battista Hospital University of Studies of Torino Turin Italy

Unit of Urology Division of Oncology Gianfranco Soldera Prostate Cancer Lab IRCCS San Raffaele Scientific Institute Milan Italy; Vita Salute San Raffaele University Milan Italy

Urology GRC no 5 Predictive Onco Urology Hôpital Pitié Salpêtrière AP HP Sorbonne Université Paris France

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