Colorectal cancer (CRC) remains a significant global health burden, with recurrence being a major concern even after standard treatment. The ALASCCA trial, a biomarker-driven randomized study, explored the role of low-dose aspirin (160 mg daily) as an adjuvant therapy in reducing CRC recurrence in patients with PI3K pathway alterations. The study achieved its primary endpoint and provided valuable insights into the efficacy and safety of aspirin in this setting. The findings were presented by Dr. Anna Martling at the ASCO Gastrointestinal Cancers Symposium 2025.
The ALASCCA trial (NCT02647099) screened 3,508 patients with rectal and colon cancer for PI3K pathway alterations. Of these, 515 patients had PIK3CA exon 9/20 mutations (Group A), and 588 had PIK3R1/PTEN/other PIK3CA alterations (Group B). Patients were randomized into aspirin (160 mg daily for three years) or placebo arms. The trial commenced in April 2016, with final three-year follow-up data collected in July 2024.
Among the 626 randomized patients, the median age was 66 years (range 31–80). Fifty-two percent were females, 67 percent had colon cancer, and 33 percent had rectal cancer. Fifty percent of rectal cancer patients received neoadjuvant therapy, while 50 percent of colon cancer patients received adjuvant therapy.
Primary Outcome: CRC Recurrence
The primary outcome, cumulative incidence of CRC recurrence at three years, showed significant benefit in both groups receiving aspirin. In Group A (PIK3CA Exons 9/20), the aspirin arm had a recurrence rate of 7.7 percent (95% CI: 4.2 – 12.5), compared to 14.1 percent (95% CI: 9.2 – 20.0) in the placebo arm, with a hazard ratio (HR) of 0.49 (95% CI: 0.24 – 0.98; p = 0.044). In Group B (PIK3R1/PTEN/Other PIK3CA), the aspirin arm had a recurrence rate of 7.7 percent (95% CI: 4.2 – 12.6), compared to 16.8 percent (95% CI: 11.4 – 23.1) in the placebo arm, with a HR of 0.42 (95% CI: 0.21 – 0.83; p = 0.013). These results indicate that aspirin significantly reduced the risk of CRC recurrence in patients with PI3K pathway alterations.
Secondary Outcome: Disease-Free Survival (DFS)
Three-year DFS rates further demonstrated aspirin’s potential efficacy. In Group A (PIK3CA Exons 9/20), the aspirin arm had a DFS rate of 88.5 percent (95% CI: 82.3 – 92.6), compared to 81.4 percent (95% CI: 74.4 – 86.7) in the placebo arm, with a HR of 0.61 (95% CI: 0.34 – 1.08; p = 0.091). In Group B (PIK3R1/PTEN/Other PIK3CA), the aspirin arm had a DFS rate of 89.1 percent (95% CI: 83.1 – 93.1), compared to 78.7 percent (95% CI: 71.4 – 84.4) in the placebo arm, with a HR of 0.51 (95% CI: 0.29 – 0.88; p = 0.017).
Subgroup Analyses
Subgroup analyses identified key factors influencing aspirin’s effectiveness. Among colon cancer patients in Group A, the HR was 0.75 (95% CI: 0.31 – 1.77). Among rectal cancer patients in Group A, the HR was 0.23 (95% CI: 0.06 – 0.83). Patients receiving neoadjuvant or adjuvant therapy had an HR of 0.42 (95% CI: 0.19 – 0.93), while those without neoadjuvant or adjuvant therapy had an HR of 0.79 (95% CI: 0.18 – 3.52). Among females, the HR was 0.22 (95% CI: 0.06 – 0.77), while among males, it was 0.82 (95% CI: 0.33 – 2.03). These findings highlight aspirin’s varying effectiveness across patient groups, with notable benefits in rectal cancer patients and females.
Safety Profile
Aspirin was generally well tolerated, but some safety concerns emerged. The aspirin arm had 301 adverse events compared to 228 in the placebo arm. Severe adverse events (SAEs) were reported in 57 patients in the aspirin group compared to 38 in the placebo group. There were three SAEs leading to death in the aspirin group, compared to one in the placebo group. The most common SAEs included late post-operative complications (15 in aspirin vs. 8 in placebo), deep vein thrombosis (9 in aspirin vs. 7 in placebo), embolism (6 in aspirin vs. 4 in placebo), and hemorrhage (4 in aspirin vs. 0 in placebo). While aspirin demonstrated strong efficacy, bleeding risks remain a concern, requiring careful patient selection and monitoring.
Key Takeaways and Conclusion
The ALASCCA trial is the first biomarker-driven randomized study showing aspirin’s efficacy in adjuvant CRC treatment. Aspirin at 160 mg daily significantly reduced CRC recurrence rates by over 50 percent in patients with PI3K pathway alterations. Somatic alterations in the PI3K pathway predict aspirin response, expanding the potential target population. One-third of early-stage CRC patients could benefit from this low-cost, widely available therapy. Careful safety considerations are necessary, particularly regarding bleeding risks.
