BACKGROUND AND OBJECTIVE: The availability of immune checkpoint inhibitors (ICIs) has expanded perioperative treatment options for urothelial carcinoma. Our aim was to evaluate the effect of neoadjuvant ICI-based regimens on oncological outcomes for patients with muscle-invasive bladder cancer (MIBC). METHODS: We systematically searched MEDLINE, Embase, Web of Science, and ClinicalTrials.gov in September 2024 for studies on neoadjuvant therapies for MIBC. A proportion meta-analysis and network meta-analysis (NMA) using random-effect models were conducted to evaluate pooled pathological complete response (pCR) rates and to compare overall survival (OS) and adverse events. The review is registered on PROSPERO (CRD42024587964). KEY FINDINGS AND LIMITATIONS: We included 12 randomized controlled trials (RCTs; 5004 patients) and 35 non-RCTs (2964 patients). ICI-chemotherapy combination therapy was associated with a significantly higher pCR rate versus chemotherapy alone (40.6% vs 17.9%; p < 0.01). In the two phase 3 RCTs included (1556 patients) there was no significant difference in OS between dose-dense methotrexate + vinblastine + Adriamycin + cisplatin (ddMVAC) and durvalumab + gemcitabine + cisplatin (GC; hazard ratio 1.06, 95% confidence interval [CI] 0.72-1.55; p = 0.8). ddMVAC significantly increased the risk of grade ≥3 anemia (risk ratio [RR] 2.81, 95% CI 1.62-4.88) and asthenia (RR 3.46, 95% CI 1.68-7.14) in comparison to GC, while durvalumab + GC did not. Limitations include data heterogeneity across studies and the limited number of studies included in the NMA. CONCLUSIONS AND CLINICAL IMPLICATIONS: ICI addition to chemotherapy in the neoadjuvant MIBC setting significantly increased pCR rates in comparison to chemotherapy alone. However, there was no difference in OS between durvalumab + GC and ddMVAC. Further studies are needed to clarify the OS benefit of ICI-based combination therapy in comparison to the current standard chemotherapy regimen.

Department of Urology Azienda Ospedaliero Universitaria Ospedali Riuniti Di Ancona Università Politecnica Delle Marche Ancona 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; 2nd Department of Urology Centre of Postgraduate Medical Education Warsaw Poland; Division of Surgery and Interventional Science University College London London UK

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Department of Biomedical Sciences Humanitas University Pieve Emanuele Italy; Department of Urology IRCCS Humanitas Research Hospital Milan Italy

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Department of Urology Jikei University School of Medicine Tokyo Japan

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Department of Urology Jikei University School of Medicine Tokyo Japan; Division of Anatomy Medical University of Vienna Vienna Austria

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Department of Urology Semmelweis University Budapest Hungary

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Department of Urology Shariati Hospital Tehran University of Medical Science Tehran Iran; Department of Urology University of Texas Southwestern Medical Center Dallas TX USA; Department of Urology Weill Cornell Medical College New York NY USA; Department of Urology 2nd Faculty of Medicine Charles University Prague Czechia; Division of Urology Department of Special Surgery University of Jordan Amman Jordan; Karl Landsteiner Institute of Urology and Andrology Vienna Austria; Research Center for Evidence Medicine Urology Department Tabriz University of Medical Sciences Tabriz Iran

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Division of Anatomy Medical University of Vienna Vienna Austria; Collegium Medicum WSB University Dąbrowa Górnicza Poland

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Division of Anatomy Medical University of Vienna Vienna Austria; Department of Medical Oral and Biotechnological Sciences G d'Annunzio University of Chieti Chieti Italy

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Division of Anatomy Medical University of Vienna Vienna Austria; Department of Urology Azienda Ospedaliero Universitaria Ospedali Riuniti Di Ancona Università Politecnica Delle Marche Ancona Italy

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Division of Anatomy Medical University of Vienna Vienna Austria; Department of Urology Shariati Hospital Tehran University of Medical Science Tehran Iran

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Division of Anatomy Medical University of Vienna Vienna Austria; Department of Urology Shimane University Faculty of Medicine Shimane Japan

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Division of Anatomy Medical University of Vienna Vienna Austria; Department of Urology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Urology Jikei University School of Medicine Tokyo Japan

GRC 5 Predictive Onco Urology Department of Urology Pitié Salpêtrière Hôpital AP HP Sorbonne University Paris France

Pathology Unit Policlinico Foggia University of Foggia Foggia Italy

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