Indirect Comparison of Neoadjuvant Treatment Strategies for Muscle‐Invasive Bladder Cancer: ddMVAC and Perioperative Durvalumab‐Gemcitabine‐Cisplatin Versus Gemcitabine‐Cisplatin: A Systematic Review and Network Meta‐Analysis of Randomised Controlled Trials

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For cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC), neoadjuvant cisplatin-based chemotherapy (NAC) is standard of care. More intensive regimens such as dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (ddMVAC) and chemoimmunotherapy with durvalumab plus gemcitabine-cisplatin (D-GC) have shown superior outcomes. This network meta-analysis (NMA) compares the efficacy of ddMVAC, D-GC and GC and explores the efficacy thresholds for emerging therapy options, such as enfortumab vedotin plus pembrolizumab (EV-P), to surpass current standards. Following PROSPERO registration (CRD420251077606), systematic searches of PubMed, CENTRAL and Web of Science were conducted to March 2025. Randomised controlled trials (RCTs) comparing neoadjuvant regimens in cisplatin-eligible MIBC were included. A random-effects NMA was performed. Simulations explored hypothetical hazard ratios (HRs) for EV-P. Three RCTs were included. ddMVAC (HR 0.75, 95% CI 0.58-0.98; p = 0.034) and D-GC (HR 0.75, 95% CI 0.66-0.85; p < 0.001) improved overall survival (OS) versus GC, without differences between ddMVAC and D-GC (HR 0.99, 95% CI 0.75-1.33; p = 0.97). Both regimens improved progression-free survival. D-GC achieved higher pathological complete response (pCR) versus GC (OR 1.57, 95% CI 1.21-2.03; p < 0.001), whereas ddMVAC did not. No significant difference in pCR was found between ddMVAC and D-GC. Simulation-NMA suggested EV-P would need to achieve HR ≤ 0.45 versus GC to outperform ddMVAC and D-GC. Limitations include few trials and indirect comparisons. DdMVAC and D-GC improve survival compared with GC in neoadjuvant MIBC. Alternative therapeutic strategies must demonstrate substantial survival benefits to warrant replacing established neoadjuvant regimens.

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