Comparative efficacy of perioperative systemic therapies for muscle-invasive bladder cancer: a network meta-analysis of randomized trials

BACKGROUND: 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). PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.