Simple SummaryLocally advanced rectal cancer (LARC) is a heterogeneous disease showing a limited response to neoadjuvant therapies that may be associated with a worse prognosis; therefore, the prediction of long-term outcomes by surrogate endpoints could help with patient stratification from the diagnosis. While the pathologic complete response (pCR) is widely adopted as the primary endpoint in trials, there is little use of 2-year disease-free survival (2yDFS) in this context, although there is some evidence that it can be a strong predictor for overall survival (OS). We conducted a pooled analysis on a large cohort of LARC patients coming from 11 trials, aiming to assess the strength of the combination of pCR and 2yDFS as surrogate endpoints for OS. The results could contribute to understanding the prognostic role of the two single and combined endpoints to identify early on the high-risk patients and consequently tailor therapies.AbstractLARC is managed by multimodal treatments whose intensity can be highly modulated. In this context, we need surrogate endpoints to help predict long-term outcomes and better personalize treatments. A previous study identified 2yDFS as a stronger predictor of OS than pCR in LARC patients undergoing neoadjuvant RT. The aim of this pooled analysis was to assess the role of pCR and 2yDFS as surrogate endpoints for OS in a larger cohort. The pooled and subgroup analyses were performed on large rectal cancer randomized trial cohorts who received long-course RT. Our analysis focused on the evaluation of OS in relation to the pCR and 2-year disease status. A total of 4600 patients were analyzed. Four groups were identified according to intermediate outcomes: 12% had both pCR and 2yDFS (the better); 67% achieved 2yDFS but not pCR (the good); 1% had pCR but not 2yDFS; and 20% had neither pCR nor 2yDFS (the bad). The pCR and 2yDFS were favorably associated with OS in the univariate analysis, and 2yDFS maintained a statistically significant association in the multivariate analysis independently of the pCR status. The combination of the pCR and 2yDFS results in a strong predictor of OS, whereas failure to achieve 2yDFS carries a poor prognosis regardless of the pCR status. This new stratification of LARC patients could help design predictive models where the combination of 2yDFS and pCR should be employed as the primary outcome.