Low-dose aspirin halves recurrence risk in select CRC patients

In colorectal cancer (CRC) patients harbouring mutations in the PI3K pathway, adjuvant treatment with aspirin 160 mg daily reduced the recurrence rate by over 50 percent, according to the 3-year results from the ALASCCA trial.

In study group A comprising patients with PI3KCA exons 9/20, the 3-year cumulative incidence of the primary outcome of CRC recurrence among aspirin-treated patients was only 7.7 percent. For those who received placebo, the corresponding rate was 14.1 percent. A comparison between arms yielded a hazard ratio (HR) of 0.49 (95 percent confidence interval [CI], 0.24–0.98; p=0.044), translating to a 51-percent lower risk of CRC recurrence with aspirin.

Interestingly, a similar trend in favour of aspirin was observed in study group B, which is the subset of patients with PIK3R1/PTEN/other PIK3CA (7.7 percent vs 16.8 percent; HR, 0.42, 95 percent CI, 0.21–0.83; p=0.013).

“The effect was even stronger, with a 58-percent reduction in CRC recurrence,” said Professor Anna Martling from the Karolinska Institutet & Karolinska University Hospital, Stockholm, Sweden, during her presentation at ASCO GI 2025. “This finding considerably expands the target population to almost 40 percent of all [CRC] patients.”

When combining the results for study groups A and B, the HR for CRC recurrence was 0.45 (95 percent CI, 0.28-0.73). This translates to a 55-percent lower risk of CRC recurrence. [ASCO GI 2025, abstract LBA 125]

The effect of aspirin relative to placebo was also observed when looking at the secondary endpoint of 3-year disease-free survival (DFS), both in group A (88.5 percent vs 81.4 percent) and group B (89.1 percent vs 78.7 percent). The HRs for each group were 0.61 (95 percent CI, 0.34–1.08; p=0.091) and 0.51 (95 percent CI, 0.29–0.88; p=0.017).

Subgroup, safety analyses

Although the trial was not powered to evaluate subgroups, subgroup analysis reflected the robust advantage of aspirin over placebo across all subgroups, including patients with colon and rectal cancer, those who did and did not receive neoadjuvant and/or adjuvant treatment, those with stage II and III disease, and both sexes, Martling noted.

The effect was notably more profound among rectal cancer patients in group A (HR, 0.23) and among women in groups A, B, and combined groups A & B (HRs, 0.22, 0.28, and 0.25, respectively). The HRs for the other subgroups ranged between 0.35 (pTNM stage I in the combined cohort) and 0.82 (men in group A).

With regard to severe adverse events (SAEs), apart from the nearly twofold-higher incidence of late postoperative complications in the aspirin vs placebo arm (n=15 vs 8), the rates of all other SAEs were similar between arms. Of note, there were three SAEs that led to death and two life-threatening SAEs in the aspirin arm.

“Aspirin is a well-established and safe medication with known side effects. The incidence of AEs was as expected. SAEs associated with daily low-dose aspirin use were rare,” said Martling.

A potential predictive biomarker

The current findings add to the growing body of evidence reflecting the ability of aspirin to reduce CRC rates among cardiovascular users and the incidence of colonic polyps in high-risk patients, as well as to improve DFS. [N Engl J Med 2012;367:1596-1606] According to Martling, these effects may be linked to the PIK3CA mutations in the tumour.

“Aspirin is one of the most extensively studied and widely used drugs worldwide … A retrospective analysis has suggested that PIK3CA mutations may predict the beneficial response to aspirin, while wild-type tumours do not appear to benefit,” she noted. “However, before this selective strategy can be offered to patients, we need more robust evidence.”

Hence, Martling and her team set out to evaluate the effect of aspirin on CRC recurrence by using alterations in the specific pathway as a potential predictive biomarker.

A total of 3,508 patients from 33 hospitals in the Scandinavian region (Denmark, Finland, Norway, and Sweden) were screened for somatic alterations in the PI3K pathway. Of these, 37 percent had genetic changes in the PI3K pathway (n=515 [group A] and 588 [group B]).

Group A included patients with PI3KCA mutations in hotspot regions, while group B comprised patients with other PI3K mutations, including those outside hotspot regions and other alterations in the same pathway. According to Martling, this has not been investigated before in relation to aspirin; therefore, this was an explorative arm within the randomized trial.

Ultimately, in group A, 314 participants were randomized 1:1 to receive aspirin 160 mg daily or placebo; in group B, 312 underwent randomization to either treatment arm. The regimen was initiated within 3 months postop and went on for 3 years.

The median age was 66 years and 52 percent of the overall cohort were women. Two-thirds had colon cancer (53 percent pTNM* stage II), while the rest had rectal cancer (40 percent pTNM stage II). Half of the colon cancer patients were given additional adjuvant therapy, and half of those in the rectal cancer subset received neoadjuvant therapy on top of the study treatment.

Expands target population

“ALASCCA is the first biomarker-driven randomized study on adjuvant aspirin in CRC patients meeting the primary endpoint,” said Martling. “This is also the first trial to show that somatic alterations in the PI3K signalling pathway, also beyond PIK3CA, predict aspirin response, expanding the targetable patient population substantially.”

“These findings could lead to immediate changes in clinical practice for more than a third of patients with early-stage, non-metastasized CRC,” she continued.

Martling added that the study embodies precision medicine, demonstrating how a safe, inexpensive, globally available drug can be repurposed, and stresses the importance of upfront genetic testing in all CRC patients.