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