CONTEXT: Several phase III randomized controlled trials (RCTs) have shown the importance of perioperative systemic therapy, especially for the efficacy of immune checkpoint inhibitors (ICIs) in both neoadjuvant and adjuvant settings for muscle-invasive bladder cancer (MIBC). OBJECTIVE: To synthesize the growing evidence on the efficacy and safety of systemic therapies for MIBC utilizing the data from RCTs. EVIDENCE ACQUISITION: Three databases and ClinicalTrials.gov were searched in October 2024 for eligible RCTs evaluating oncologic outcomes in MIBC patients treated with systemic therapy. We evaluated pathological complete response (pCR), disease-free survival (DFS), progression-free survival (PFS), event-free survival (EFS), overall survival (OS), and adverse events (AEs). EVIDENCE SYNTHESIS: Thirty-three RCTs (including 14 ongoing trials) were included in this systematic review. Neoadjuvant chemotherapy improved OS compared to radical cystectomy alone. Particularly, the VESPER trial demonstrated that dd-MVAC provided oncological benefits over GC alone in terms of pCR rates, OS (HR: 0.71), and PFS (HR: 0.70). Recently, the NIAGARA trial showed that perioperative durvalumab plus GC outperformed GC alone in terms of pCR rates, OS (HR: 0.75), and EFS (HR: 0.68). Despite the lack of data on overall AE rates in the VESPER trial, differential safety profiles in hematologic toxicity were reported between dd-MVAC and durvalumab plus GC regimens. In the adjuvant setting, no study provided the OS benefit from adjuvant chemotherapy. However, only adjuvant nivolumab had significant DFS and OS benefits compared to placebo. CONCLUSIONS: Neoadjuvant chemotherapy remains the current standard of care for MIBC. Durvalumab shed light on the promising impact of ICIs added to neoadjuvant chemotherapy. Nivolumab is the only ICI recommended as adjuvant therapy in patients who harbored adverse pathologic outcomes. Ongoing trials will provide further information on the impact of combination therapy, including chemotherapy, ICIs, and enfortumab vedotin, in both neoadjuvant and adjuvant settings.

2nd Department of Urology Centre of Postgraduate Medical Education Warsaw Poland

Department of Surgery S H Ho Urology Centre The Chinese University of Hong Kong Hong Kong China

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

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

Department of Urology King Fahad Specialist Hospital Dammam Saudi Arabia

Department of Urology Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan

Department of Urology San Raffaele Hospital and Scientific Institute Milan Italy

Department of Urology Semmelweis University Budapest Hungary

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University of Texas Southwestern Medical Center Dallas TX USA

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

Department of Urology Weill Cornell Medical College New York NY USA

Division of Urology Department of Special Surgery The University of Jordan Amman Jordan

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

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