Background: Radiation with sensitizing fluoropyrimidine (5FUCRT) is a standard curative intent treatment for LARC. It improves disease-free survival (DFS) by decreasing pelvic recurrence but has short- and long-term toxicity. The PROSPECT trial compares FOLFOX chemotherapy with selective use of 5FUCRT (intervention) to 5FUCRT (control) for neoadjuvant treatment prior to TME for LARC. Methods: Eligible patients (pts) had cT2N+, cT3N-, cT3N+ rectal cancers deemed appropriate for neoadjuvant therapy prior to low anterior resection with TME. Pts with distal, T4 tumors, threatened radial margins or > 4 enlarged lymph nodes were ineligible. Pts were randomized 1:1 without blinding. Pts in the control group received 5FUCRT with 5040 cGy over 5.5 weeks with either capecitabine or 5FU. Pts in the intervention group had 6 cycles of mFOLFOX6 followed by restaging. If tumor regression was > 20%, then TME was performed without radiation; if < 20%, 5FUCRT was given before TME. DFS was the 1°outcome, defined as time from randomization to any recurrence or death, analyzed in the per-protocol population. One interim analysis was conducted with α spending = 0.001. Noninferiority (NI) of the intervention could be claimed if the upper limit of the 2-sided 90.2% confidence interval (CI) of the DFS hazard ratio did not exceed 1.29 (NI margin). Secondary endpoints included overall survival (OS), local recurrence free survival, R0 resection, pathologic complete response (CR), and toxicity. Results: From June 2012 to December 2018, 1194, pts were randomized and 1128 initiated protocol-assigned treatment. Median age was 57, 34.5% were women and 61.9% had clinically positive nodes. 53 of 585 pts in the intervention group (9%) received preop 5FUCRT. DFS was analyzed after 227 events and median follow-up of 58 months. Conclusions: FOLFOX chemotherapy with selective use of 5FUCRT is non-inferior to 5FUCRT for neoadjuvant treatment of LARC prior to low anterior resection with TME. Patients and physicians have alternative strategies for management of LARC. Clinical trial information: NCT01515787.

^*Two-sided 90.2% CI for DFS and two-sided 95% CI for 2° endpoints. ^&One-sided NI testing for DFS and two-sided superiority testing for 2° endpoints. ^#Among patients who had TME.