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Comparative efficacy of perioperative systemic therapies for muscle-invasive bladder cancer: a network meta-analysis
B A Maiorano1, M Maruzzo2, A Ślusarczyk3
1Department of Medical Oncology, Comprehensive Cancer Center, IRCCS San Raffaele, Milan, Italy.
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.
Insights
Perioperative immune checkpoint inhibitors and antibody-drug conjugates show improved survival and response in muscle-invasive bladder cancer. Enfortumab vedotin-pembrolizumab ranked highest, offering a promising new treatment option.
Area of Science:
- Urology
- Medical Oncology
- Clinical Trials
Background:
- Muscle-invasive bladder cancer (MIBC) treatment is evolving with immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs).
- Lack of direct comparative trials hinders optimal treatment selection for perioperative MIBC management.
- Network meta-analysis (NMA) is employed to indirectly compare contemporary perioperative regimens.
Purpose of the Study:
- To compare the efficacy of perioperative systemic treatment strategies for MIBC.
- To evaluate overall survival (OS), event-free survival (EFS), and pathological complete response (pCR) across different regimens.
- To rank treatments based on their comparative effectiveness using network meta-analysis.
Main Methods:
- Systematic literature search of PubMed, Embase, Web of Science, and congress abstracts up to February 28, 2026.
- Inclusion of Phase II-III randomized controlled trials (RCTs) of perioperative systemic therapy for MIBC prior to radical cystectomy.
- Frequentist graph-theoretical network meta-analysis comparing three contemporary RCTs, with gemcitabine-cisplatin (GC) as the common comparator.
Main Results:
- Enfortumab vedotin-pembrolizumab (EVP) and gemcitabine-cisplatin plus durvalumab showed improved OS, EFS, and pCR compared to GC alone.
- EVP demonstrated the most favorable ranking across all evaluated endpoints based on P-scores.
- Subgroup and sensitivity analyses confirmed consistent treatment effects.
Conclusions:
- Perioperative regimens including ICIs and ADCs offer improved survival and pathologic response in MIBC compared to GC.
- EVP emerged as a highly ranked treatment option in this network meta-analysis.
- Findings provide a clinical framework for perioperative MIBC treatment, acknowledging the indirect nature of comparative estimates.