Low-Dose Aspirin Cuts CRC Recurrence

Low-dose aspirin reduced colorectal cancer (CRC) recurrence rates by more than half in patients with tumors harboring mutations in the PI3K signaling pathway, according to findings from the phase 3 ALASCCA trial.

These results stress “the importance of upfront genomic testing” in patients with CRC, said Anna Martling, MD, PhD, from Karolinska Institutet, Stockholm, Sweden, who reported the findings at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium 2025 in San Francisco.

This is the first trial to show that mutations in the PI3K signaling pathway, beyond PIK3CA alterations, predict aspirin response, “expanding the targetable patient population substantially,” Martling added. Genetic mutations along the PI3K signaling pathway are found in about 30% of CRCs.

While aspirin as chemoprevention in CRC has been studied, data confirming its effectiveness as well as uptake of this approach in practice have been lacking, explained ASCO expert Pamela Kunz, MD, with Smilow Cancer Hospital and Yale Cancer Center, New Haven, Connecticut.

“It’s really clear that this is a practice-changing study,” said Kunz. The findings indicate that this approach “checks all of the boxes: It’s effective, it’s low risk, it’s inexpensive, and it’s easy to administer.”

The trial included 626 patients (median age, 66 years; 52% women) with stages II-III colon cancer (67%) or stages I-III rectal cancer (33%) across 33 hospitals in Sweden, Denmark, Finland, and Norway.

Patients were stratified into two groups based on specific PI3K pathway alterations Group A (n = 314) included patients with PIK3CA mutations in exon 9 and/or 20, and group B (n = 312) included those with other PI3K pathway mutations, including PIK3CA mutations outside exon 9/20, or mutations in PIK3R1 or PTEN genes. 

Participants in both groups were randomly allocated 1:1 to 160 mg/d of aspirin or placebo for 3 years. The primary outcome was CRC recurrence; disease-free survival was a secondary outcome.

Compared with placebo, aspirin reduced the risk for recurrence by 51% (hazard ration [HR], 0.49) in patients with PIK3CA mutations, with a 3-year recurrence rate of 7.7% in those taking aspirin versus 14.1% in the placebo group.

“Interestingly,” Martling noted, in the exploratory arm that included other mutations along the PIK3 pathway beyond PIK3CA (Group B), the effect was even stronger. Patients in this group had a 58% (HR, 0.42) lower risk for recurrence than those in the placebo group, with a 3-year recurrence rate of 7.7% in the aspirin group vs 16.8% recurrence rate in the placebo group.

Aspirin also had a disease-free survival benefit in both groups, but it was significant only in group B.

While the study was not specifically designed for subgroup analysis, the benefit of aspirin was observed in all subgroups examined, including men and women with colon or rectal cancer, those who did and did not receive neoadjuvant or adjuvant treatment, and those with stages I, II, and III disease.

The incidence of adverse events was as expected and severe side effects associated with 160 mg/d aspirin were rare, Martling said.

Both Martling and Kunz predicted that these findings will change clinical practice. “I anticipate that we’ll be seeing adoption of this [strategy],” Kunz said.

This study received funding from the Swedish Research Council, Swedish Cancer Society, ALF (a regional agreement on medical training and clinical research between the Stockholm County Council and Karolinska Institutet), and the Stockholm Cancer Society. Martling disclosed various relationships with Bactiguard, Smartcella, CarpoNovum and Pfizer. Kunz disclosed relationships with BMS, Novartis and TayzeBio.