<p><b>Objective</b> It is unclear how well different outcome measures in randomized controlled trials (RCTs) perform in predicting real-world cancer survival. We assess the ability of RCT overall survival (OS) and surrogate endpoints – progression-free survival (PFS) and time to progression (TTP) – to predict real-world OS across five cancers.</p> <p><b>Methods</b> We identified 20 treatments and 31 indications for breast, colorectal, lung, ovarian, and pancreatic cancer that had a phase III RCT reporting median OS and median PFS or TTP. Median real-world OS was determined using a Kaplan–Meier estimator applied to patients in the Surveillance and Epidemiology End Results (SEER)-Medicare database (1991–2010). Performance of RCT OS and PFS/TTP in predicting real-world OS was measured using <i>t</i>-tests, median absolute prediction error, and <i>R</i><sup>2</sup> from linear regressions.</p> <p><b>Results</b> Among 72,600 SEER-Medicare patients similar to RCT participants, median survival was 5.9 months for trial surrogates, 14.1 months for trial OS, and 13.4 months for real-world OS. For this sample, regression models using clinical trial OS and trial surrogates as independent variables predicted real-world OS significantly better than models using surrogates alone (<i>P</i> = 0.026). Among all real-world patients using sample treatments (<i>N</i> = 309,182), however, adding trial OS did not improve predictive power over predictions based on surrogates alone (<i>P</i> = 0.194). Results were qualitatively similar using median absolute prediction error and <i>R</i><sup>2</sup> metrics.</p> <p><b>Conclusions</b> Among the five tumor types investigated, trial OS and surrogates were each independently valuable in predicting real-world OS outcomes for patients similar to trial participants. In broader real-world populations, however, trial OS added little incremental value over surrogates alone.</p
