Overview of the Episode III clinical trial showing aspirin's lack of DFS benefit in stage III colorectal cancer, with a cityscape background.
GI Oncology / Conferences 06/05/2026

EPISODE-III Trial: Adjuvant Aspirin Shows No DFS Benefit in Stage III CRC

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Key Points

  • In the phase 3 EPISODE-III trial, adjuvant low-dose aspirin did not significantly improve disease-free survival compared with placebo in unselected patients with stage III colorectal cancer (CRC).
  • The ALASCCA trial had previously established that adjuvant aspirin significantly reduced recurrence in patients with PI3K pathway–altered tumors, which has been incorporated into National Comprehensive Cancer Network (NCCN) guidelines.
  • The directional trend of the EPISODE-III trial is notable, but without biomarker selection, adjuvant aspirin cannot be recommended as the standard of care for all patients with stage III CRC.
  • PI3K/PIK3CA biomarker analyses from the EPISODE-III biobank are ongoing and will contribute to a planned collaborative meta-analysis.

At the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, Atsuo Takashima, MD, PhD, presented the EPISODE-III trial on behalf of the Japan Clinical Oncology Group. This was a phase 3 study evaluating 3 years of adjuvant low-dose aspirin in patients with stage III CRC after curative resection. While the trial was formally a negative study, its full implications remain to be seen.1

Background and Rationale

Aspirin has been widely studied for its anticancer properties. By inhibiting COX-2 and prostaglandin E2 production, it modulates downstream PI3K-AKT-mTOR signaling. Furthermore, it is thought to limit metastatic spread by reducing platelet-mediated immunosuppression. 

In the recent practice-changing ALASCCA trial, patients with stage I-III CRC who had somatic PI3K pathway alterations were randomized to receive adjuvant aspirin 160 mg daily for 3 years versus placebo.2 

In the combined cohort of patients with PIK3CA hotspot mutations (exon 9 or 20) and PI3K pathway alterations, the hazard ratio (HR) for recurrence was 0.45 (95% CI, 0.28–0.74), with female and rectal cancer patients deriving the greatest benefit. Treatment was generally well tolerated, with only three serious aspirin-related adverse events across the entire treatment arm. Based on these findings, the NCCN updated its guidelines (v2.2026) to recommend routine PI3K pathway profiling for all resected stage II–III CRC cases and low-dose aspirin for 3 years in patients with confirmed alterations.

EPISODE-III Trial Design and Outcomes

The EPISODE-III trial was a double-blind, placebo-controlled, randomized phase 3 study conducted across 36 centers in Japan between March 2018 and October 2022. It enrolled patients who were aged 20 to80 years with ECOG performance status of 0–1 and R0-resected stage III CRC. 

Those who had received prior chemotherapy or radiotherapy, regularly used antiplatelet agents or NSAIDs, or had a history of gastrointestinal (GI) ulcers or bleeds were excluded. 

Within 8 weeks post-surgery, patients were randomly assigned to receive standard adjuvant chemotherapy (modified FOLFOX6 [leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin], CAPOX [capecitabine and oxaliplatin], or capecitabine) plus either daily aspirin 100 mg or placebo for a total duration of 3 years. The primary end point of the study was disease-free survival (DFS), and secondary end points were overall survival (OS), relapse-free survival (RFS), and the effect of aspirin dose intensity on safety.

Of the 882 patients, 440 received aspirin and 442 received a placebo. The two cohorts were well matched in their clinical characteristics. The trial did not meet its primary end point of demonstrating a significant DFS benefit: the 3-year DFS was 78.8% with aspirin compared with 75.4% with placebo (HR, 0.84; 95% CI, 0.65-1.09; P = .099). RFS results were similar (HR, 0.87; 95% CI, 0.66–1.14). Currently, the OS data remain immature, with final results expected in 2028. 

Both groups had identical relative dose intensities. Aspirin was generally well tolerated, although 7 lower GI hemorrhages occurred in the aspirin group compared with 1 in the placebo group. There was 1 treatment-related death because of ischemic heart disease in the aspirin cohort.

Practice Implications

EPISODE-III demonstrates that low-dose aspirin should not be routinely added to adjuvant chemotherapy for unselected patients with stage III CRC. The current best evidence recommends testing PI3K pathway profiling in all patients with resected stage II–III CRC and administering aspirin at 100 mg to162 mg daily for 3 years to those with confirmed pathway alterations. 

In his discussion at ASCO 2026, Alan P. Venook, MD, described EPISODE-III as a “well-designed and well-executed study,” noting plans to analyze biomarker-selected patients and incorporate this data into a pooled analysis; ongoing exploratory PI3K/PIK3CA analyses from the prospectively collected biobank will contribute to a planned collaborative meta-analysis of randomized aspirin trials. These findings could ultimately enhance patient selection, dosing, and treatment duration for adjuvant aspirin in stage II-III CRC.

References

1.Takashima A, Hirano Y, Shiozawa M, et al. 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). J Clin Oncol. 2026;44(suppl 17): Abstr LBA3508.

2. Martling A, Hed Myrberg I, Nilbert M, et al. Low-dose aspirin for PI3K-altered localized colorectal cancer. N Engl J Med. 2025;393(11):1051-1064. doi:10.1056/NEJMoa2504650