The perioperative treatment landscape of muscle-invasive bladder cancer (MIBC) is rapidly evolving with the introduction of immune checkpoint inhibitor (ICI)- and antibody-drug conjugate (ADC)-based strategies. However, direct randomized comparisons among contemporary regimens are lacking, limiting the interpretation and positioning of treatments. We aimed to compare the efficacy of perioperative systemic treatment strategies for MIBC with a network meta-analysis (NMA) of randomized controlled trials (RCTs).
PubMed, Embase, Web of Science, and congress abstracts were systematically searched up to 28 February 2026. Phase II-III RCTs enrolling patients with MIBC treated with perioperative systemic therapy initiated before radical cystectomy and reporting overall survival (OS), event-free survival (EFS), and/or pathological complete response (pCR) were included. A frequentist graph-theoretical NMA was carried out to compare three contemporary RCTs using a star-shaped network anchored to gemcitabine-cisplatin (GC) as the common comparator. Treatment ranking was estimated using P-scores. The primary outcome was OS. Secondary outcomes included EFS and pCR.
In total, 2293 patients from three RCTs contributed to the primary network. Compared with GC, enfortumab vedotin-pembrolizumab (EVP) was associated with improved OS [hazard ratio (HR) 0.65], as was GC plus durvalumab (HR 0.75). EVP and GC plus durvalumab were also associated with improved EFS (EVP HR 0.53, GC plus durvalumab HR 0.68) and higher pCR rates [EVP odds ratio (OR) 2.62, GC plus durvalumab OR 1.57] compared with GC. Across evaluated endpoints, EVP consistently achieved the most relevant P-score-based ranking. Subgroup-specific and sensitivity analyses demonstrated a consistent treatment direction.
In this NMA of RCTs, perioperative regimens incorporating ICIs and ADCs were associated with improved survival and pathologic response outcomes compared with GC alone. Given the sparse star-shaped network and the absence of closed loops, these findings should be interpreted as indirect comparative estimates rather than definitive evidence of treatment superiority, while still providing a clinically relevant framework for contextualizing contemporary perioperative regimens.
ESMO open. 2026 Jul 22 [Epub ahead of print]
B A Maiorano, M Maruzzo, A Ślusarczyk, J D Subiela, F Soria, S Albisinni, A Mari, F Claps, R Contieri, A Gallioli, J Caño-Velasco, D D'Andrea, E Laukhtina, G Marcq, W Krajewski, E Grobet-Jeandin, L Afferi, F Del Giudice, A Rizzo, M Moschini, L S Mertens, A Cigliola, C Mercinelli, M Piacentini, M Santoni, B Pradère, A Necchi, Young Academic Urologist (YAU) Urothelial Carcinoma Working Group
Department of Medical Oncology, Comprehensive Cancer Center, IRCCS San Raffaele, Milan, Italy. Electronic address: ., Oncology Unit 3, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy., Department of General, Oncological and Functional Urology, Medical University of Warsaw, Warsaw, Poland., Department of Urology, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcalá, Madrid, Spain., Division of Urology, Department of Surgical Sciences, AOU Città della Salute e della Scienza di Torino, Torino School of Medicine, Torino, Italy., Urology Unit, Department of Surgical Sciences, Università Tor Vergata, Rome, Italy., Unit of Oncologic Minimally-Invasive Urology and Andrology, Department of Experimental and Clinical Medicine, Careggi Hospital, University of Florence, Florence, Italy., Oncological Urology, Veneto Institute of Oncology IRCCS, Padua, Italy., Department of Urology, National Cancer Institute, IRCCS Fondazione G. Pascale, Naples, Italy., Department of Urology, Fundació Puigvert, Barcelona, Spain; Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain., Department of Urology, Clinica Universidad de Navarra, Cancer Center, Pamplona, Spain., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Urology Department, Claude Huriez Hospital, CHU Lille, Lille, France., Department of Minimally Invasive Robotic Urology, Center of Excellence in Urology, Wroclaw Medical University, Wrocław, Poland., Department of Urology, Geneva University Hospitals (HUG), University of Geneva, Geneva, Switzerland., Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland., Department of Maternal Infant and Urologic Sciences, "Sapienza" University of Rome, Policlinico Umberto I Hospital, Rome, Italy., SSD COrO Bed Management Presa in Carico, TDM, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy., Division of Experimental Oncology, Department of Urology, Urological Research Institute, Vita-Salute San Raffaele University, Milan, Italy., Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands., Department of Medical Oncology, Comprehensive Cancer Center, IRCCS San Raffaele, Milan, Italy., Medical Oncology Unit, Macerata Hospital, Macerata, Italy., Department of Urology UROSUD, La Croix du Sud Hospital, Quint-Fonsegrives, France., Department of Medical Oncology, Comprehensive Cancer Center, IRCCS San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.