Surrogacy of intermediate clinical endpoints for overall survival in BCG-naïve high-risk non-muscle-invasive bladder cancer.
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.
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.
Authors
Scilipoti Scilipoti, Ślusarczyk Ślusarczyk, Subiela Subiela, Longoni Longoni, Occhi Occhi, Zaurito Zaurito, Tremolada Tremolada, Maiorano Maiorano, Soria Soria, Krajewski Krajewski, D'Andrea D'Andrea, Claps Claps, Del Giudice Del Giudice, Pichler Pichler, Grobet-Jeandin Grobet-Jeandin, Gallioli Gallioli, Afferi Afferi, Mastroianni Mastroianni, Simone Simone, Mertens Mertens, Laukhtina Laukhtina, Rodriguez Elena Rodriguez Elena, Aranda Aranda, Lafuente Puentedura Lafuente Puentedura, Caño Velasco Caño Velasco, Contieri Contieri, Zorzi Zorzi, Liguori Liguori, Hurle Hurle, Cirulli Cirulli, Naspro Naspro, Mori Mori, Marcq Marcq, Radziszewski Radziszewski, Shariat Shariat, Gontero Gontero, Rouprêt Rouprêt, Seisen Seisen, Montorsi Montorsi, Briganti Briganti, Pradere Pradere, Moschini Moschini,
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