biostudies-literatureSherry ADNational Institutes of HealthNIH HHSAndrew Sabin Family Foundation256https://www.ebi.ac.uk/biostudies/studies/S-EPMC12289950biostudies-literatureUnknown9(1)In phase III oncology trials, superiority is defined by statistical significance using P thresholds. However, this approach has been criticized because P is continuous. Here, we reconstruct patient-level data for 230 phase III oncology trials to model the robustness of statistical significance by estimating the survival-inferred fragility index (SIFI), defined as the smallest number of patients changing arms that alters the statistical significance interpretation. The median SIFI was 8 patients (IQR 4-19), representing 1.4% of enrollments (IQR 0.7%-3%). As a continuous statistic, P-but not the significance interpretation-was correlated with SIFI. Moreover, overall survival endpoints were more fragile than surrogate endpoints. Taken together, while phase III oncology trials are intended to NPJ precision oncologySurvival-inferred fragility of statistical significance in phase III oncology trials.PMC12289950P30CA016672Miller AMKouzy RLudmir EBKoong AMeirson TEl-Alam MBMcCaw ZRLiu YAbi Jaoude JBomze DLin COfer JLin TAMsaouel PPatel RRSherry ADOwiwi MfalseSurvival-inferred fragility of statistical significance in phase III oncology trials.In phase III oncology trials, superiority is defined by statistical significance using P thresholds. However, this approach has been criticized because P is continuous. Here, we reconstruct patient-level data for 230 phase III oncology trials to model the robustness of statistical significance by estimating the survival-inferred fragility index (SIFI), defined as the smallest number of patients changing arms that alters the statistical significance interpretation. The median SIFI was 8 patients (IQR 4-19), representing 1.4% of enrollments (IQR 0.7%-3%). As a continuous statistic, P-but not the significance interpretation-was correlated with SIFI. Moreover, overall survival endpoints were more fragile than surrogate endpoints. Taken together, while phase III oncology trials are intended to 2025-01-01T00:00:00Z2025 Jul2026-03-17T13:41:10.189Z2025-08-16T03:05:31.188ZS-EPMC122899504070772410.1038/s41698-025-01024-2