Adjuvant aspirin for stage III colorectal cancer after curative resection: Primary analysis of the randomized double-blind placebo-controlled phase III trial (EPISODE-III: JCOG1503C).

LBA3508 Background: Observational studies suggest aspirin benefits in colorectal cancer (CRC), but adjuvant evidence remains limited. In unselected populations, phase III trials have not shown a clear benefit, while biomarker-selected studies suggest a benefit in PI3K-altered tumors. EPISODE-III evaluates whether low-dose aspirin improves disease-free survival (DFS) in unselected stage III CRC receiving standard adjuvant chemotherapy. Methods: EPISODE-III is a multi-institutional, two-arm, randomized, double-blind, placebo-controlled phase III trial at 36 institutions in Japan. Eligible patients (20–80 years; ECOG PS 0–1) with histologically confirmed, R0-resected stage III adenocarcinoma from the cecum to upper rectum (lower rectum excluded) after D2/D3 lymph node dissection were randomized 1:1 to low-dose aspirin (100 mg once daily) or matched placebo for 3 years, in addition to standard adjuvant chemotherapy (capecitabine, mFOLFOX6, or CAPOX). Randomization was balanced by institution, sex, stage (IIIA/IIIB/IIIC), and planned oxaliplatin use. The primary endpoint was DFS (event: relapse, second cancer, or death). Secondary endpoints included overall survival (OS), relapse-free survival (RFS), relative dose intensity (RDI) of aspirin and placebo, and safety. The planned sample size was 880 (279 DFS events), providing 80% power with a one-sided α = 0.05 to detect hazard ratio (HR) of 0.741 (assumed 3-year DFS 74% vs. 80%). Results: Between Mar 2018 and Oct 2022, 882 patients (placebo 442; aspirin 440) were enrolled. At the data cutoff (Oct 2025), the median follow-up for all randomized patients was 4.0 years, with 231 DFS events (placebo 124; aspirin 107). Baseline characteristics were balanced (median age 65 vs. 64 years; pIIIA/IIIB/IIIC 19/63/18% vs. 19/62/19%; planned oxaliplatin-containing regimen 70% vs. 71%). Three-year DFS was 75.4% with placebo and 78.8% with aspirin (+3.4%); the primary endpoint was not met (HR 0.84, 95% CI 0.65–1.09; one-sided p=0.0987). DFS, RFS, and OS are shown in the Table. Grade ≥3 adverse events were similar between arms, and grade ≥3 aspirin-related adverse events were <1% (lower GI bleeding n=4). One treatment-related death was observed in the aspirin arm during chemotherapy (ischemic heart disease). RDI was high and comparable (median 98.6% in both arms). Conclusion: Low-dose aspirin added to standard adjuvant chemotherapy did not significantly improve DFS in unselected stage III CRC. However, a numerical DFS improvement with good tolerability was observed. Exploratory biomarker analyses including PI3K/PIK3CA are ongoing and will inform a planned collaborative meta-analysis of randomized trials. Clinical trial information: jRCTs031180009. 3-year (%)placebo vs. aspirin HR (95% CI) P (one-sided) DFS 75.4 vs. 78.8 0.84 (0.65–1.09) 0.0987 RFS 77.2 vs. 79.5 0.87 (0.66–1.14) - OS 96.6 vs. 95.2 1.02 (0.65–1.60) -