Surrogacy of Intermediate Clinical Endpoints for Overall Survival in Patients With Localized Muscle-Invasive Bladder Cancer.
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Scilipoti Pietro, de Angelis Mario, Thibault Constance, Ślusarczyk Aleksander, Del Giudice Francesco, Contieri Roberto, Hurle Rodolfo, Subiela José Daniel, Simone Giuseppe, Proietti Flavia, Mori Keiichiro, Shariat Shahrokh, D'Andrea David, Zamboni Stefania, Suardi Nazareno, Tanaka Hajime, Matsumoto Shunya, Fujii Yasuhisa, Bertolo Riccardo, Antonelli Alessandro, Diamant Elliott, Vordos Dimitri, Gabriel Pierre-Etienne, Harber Théo, Colombel Marc, Hanquiez Paul, Chatain Vera, Duquesne Igor, Borz Mihnea Bogdan, Verhoest Gregory, Mauger De Varennes Anne, Surlemont Louis, Ghenassia Marion, Masson-Lecomte Alexandra, Peyrottes Arthur, Lebacle Cédric, Beniac Peter, Léon Priscilla, Larré Stéphane, Taha Fayek, Marcq Gautier, Szostek Aleksandra, Pradere Benjamin, Calleris Giorgio, Audenet François, Xylinas Evanguelos, Allory Yves, Bajeot Anne-Sophie, Prost Doriane, Grobet-Jeandin Elisabeth, Montorsi Francesco, Necchi Andrea, Briganti Alberto, Moschini Marco, Roumiguié Mathieu, Rouprêt Morgan, Seisen Thomas
Аннотация
PATIENTS AND METHODS: We analyzed 4,828 patients with MIBC (cT2-T4N0M0) who underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) across 29 European centers (2001-2024). The inverse probability of treatment weighting (IPTW) approach was used to adjust for confounding between NAC and RC-only groups. Surrogacy was evaluated using: (1) adapted Prentice criteria to test whether each ICE remained a significant predictor of OS while the treatment effect disappeared in IPTW-adjusted multivariable Cox models; (2) the proportion of treatment effect explained (PTE); and (3) an emulated 2-stage meta-analytic framework to estimate the pseudo-trial-level R2 between treatment effects on each ICE and OS across 1,000 replicates of 5 random clusters. The surrogate threshold effect (STE) was calculated for ICEs demonstrating strong surrogacy (R2≥0.7).
RESULTS: Overall, 1,288 (26.7%) patients received NAC followed by RC and 3,540 (73.3%) underwent RC alone. In IPTW-adjusted Cox regression analyses including NAC and each ICE separately, pCR (hazard ratio [HR], 0.32; 95% CI, 0.24-0.41; P<.001), pOR (HR, 0.26; 95% CI, 0.21-0.31; P<.001), and DFS (HR, 5.17; 95% CI, 4.56-5.86; P<.001) were independent predictors of OS. The PTE was 0.42 (95% CI, 0.22-0.54), 0.48 (95% CI, 0.24-0.58), and 0.84 (95% CI, 0.66-0.96) for pCR, pOR, and DFS, respectively. At the pseudo-trial level, the R2 was 0.22 (95% CI, 0.20-0.25), 0.33 (95% CI, 0.31-0.36), and 0.83 (95% CI, 0.81-0.84) for the correlation between treatment effects on pCR, pOR, and DFS and OS, respectively. The STE was 0.82 (95% CI, 0.81-0.84) for DFS.
CONCLUSIONS: We observed uncertainty regarding the surrogacy of pCR and pOR in patients undergoing RC with or without NAC for localized MIBC. Only DFS consistently mediated the treatment effect on OS, supporting its use as a surrogate for RCT dimensioning when a recurrence or death risk reduction of ≥18% is expected.