Surrogacy of intermediate clinical endpoints for overall survival in BCG-naïve high-risk non-muscle-invasive bladder cancer.

Authors

Pietro Scilipoti, Aleksander Ślusarczyk, José Daniel Subiela, Mattia Longoni, Angelo Occhi, Paolo Zaurito, Giovanni Tremolada, Brigida Maiorano, Francesco Soria, Wojciech Krajewski, David D'Andrea, Francesco Claps, Francesco Del Giudice, Renate Pichler, Elisabeth Grobet-Jeandin, Andrea Gallioli, Luca Afferi, Riccardo Mastroianni, Giuseppe Simone, Laura S Mertens, Ekaterina Laukhtina, José Luis Rodriguez Elena, Javier Aranda, Alfonso Lafuente Puentedura, Jorge Caño Velasco, Roberto Contieri, Federico Zorzi, Giovanni Liguori, Rodolfo Hurle, Giuseppe Ottone Cirulli, Richard Naspro, Keiichiro Mori, Gautier Marcq, Piotr Radziszewski, Shahrokh F Shariat, Paolo Gontero, Morgan Rouprêt, Thomas Seisen, Francesco Montorsi, Alberto Briganti, Benjamin Pradere, Marco Moschini, European Association of Urology -Young Academic Urologists (EAU-YAU), Urothelial carcinoma working group

Published in

World journal of urology. Volume 44. Issue 1. Oct 01, 2026. Epub Oct 01, 2026.

Abstract

Recent trials in BCG-naïve high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have added immunotherapy to BCG, often using event-free survival (EFS) as the primary endpoint. However, neither EFS nor progression-free survival (PFS) has been validated as a surrogate for overall survival (OS) in this setting.
We retrospectively analyzed data from 18 international centers, including patients with BCG-naïve HR-NMIBC treated between 2001 and 2025. Adequate BCG exposure (International Bladder Cancer Group criteria) was the treatment contrast for its effects on intermediate clinical endpoints (ICEs) and OS, using a 12-month landmark approach and inverse probability of treatment weighting (IPTW). Surrogacy was assessed with: (1) adapted Prentice criteria, with time-varying ICEs in IPTW-adjusted Cox models for OS; and (2) an emulated two-stage meta-analytic framework estimating individual-level association (Kendall's τ) and pseudo-trial-level surrogacy (R²) across 500 random pseudo-trial replications.
Of 3384 patients, 3153 entered the landmark analysis; 2697 (85.5%) received adequate BCG. Median follow-up was 50 months (IQR 17-77). Adequate BCG was associated with improved OS (HR 0.63, 95% CI 0.47-0.83) and lower risks of PFS events (HR 0.46, 95% CI 0.37-0.58) and EFS events (HR 0.48, 95% CI 0.40-0.58). Both ICEs were independently associated with OS, but adjusting for each did not fully attenuate the BCG effect. Individual-level association with OS was strong for PFS (τ = 0.79, 95% CI 0.75-0.83) and EFS (τ = 0.71, 95% CI 0.66-0.75). Pseudo-trial-level surrogacy was moderate, with median R² of 0.60 (PFS) and 0.51 (EFS) and wide dispersion across replications, both below the prespecified threshold for adequate surrogacy (≥ 0.70).
In this exploratory, hypothesis-generating analysis, PFS and EFS were strongly associated with OS at the individual level but failed to demonstrate robust pseudo-trial-level surrogacy. These endpoints may not fully capture treatment effects on OS, warranting caution when interpreting ICE-driven trial results in BCG-naïve HR-NMIBC.

PMID:
42823574
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.

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