In the phase III ALASCCA trial, the use of adjuvant daily aspirin for 3 years reduced the risk of recurrence in colorectal cancer harboring PI3K pathway alterations by 51%, according to research in a Scandinavian population presented at the 2025 ASCO Gastrointestinal Cancers Symposium by Anna Martling, MD, PhD, of the Karolinska Institutet and Karolinska University Hospital in Stockholm.1 Dr. Martling estimated that implementation of daily aspirin “could change clinical practice for around one-third of patients with nonmetastasized colorectal cancer.”
The randomized placebo-controlled trial met its primary endpoint, showing that 3 years of adjuvant daily aspirin reduced recurrences by 51% in patients with PIK3CA exon 9/20 mutations (hazard ratio [HR] = 0.49; P = .044) and by 58% in patients with PIK3R1/PTEN/other PIK3CA alterations (HR = 0.42; P = .013).
“ALASCCA is the first biomarker-driven randomized study on adjuvant aspirin in patients with colorectal cancer that meets its endpoint. It is also the first trial to show that somatic alterations in the PI3K signaling pathway, beyond PIK3CA, predict aspirin response, which expands the targetable patient population substantially,” said Dr. Martling. The findings indicate there may be a benefit to repurposing a safe, inexpensive, and globally available agent and emphasize the importance of genomic testing in colorectal cancer, she added.
The PI3KCA pathway is a relevant target, Dr. Martling said, as it is involved in tumor progression and the development of metastasis. Its interaction with aspirin is multifaceted, related to COX2 expression in the tumor, platelet inhibition, the microenvironment, and inflammation. Aspirin has been shown to reduce the number of colonic polyps in high-risk patients, as well as to lower the incidence of colorectal cancer in individuals taking aspirin for cardiovascular reasons. Research based on retrospective, unselected colorectal cancer cohorts has also found that aspirin may improve disease-free survival postdiagnosis.
About ALASCCA
Across 33 hospitals in Sweden, Denmark, Finland, and Norway, 3,508 patients with early-stage colorectal cancer were screened for alterations in the PI3K pathway, revealing that 37% harbored such alterations. Group A (n = 515) had PIK3CA exon 9/20 mutations, whereas group B (n = 588) had PIK3R1/PTEN/other PIK3CA alterations. Of the 626 patients who continued to trial, half in each population received 160 mg of aspirin daily for 3 years, and the other half received placebo.
The time to colorectal cancer recurrence in group A served as the primary outcome of the study, and the secondary outcomes included disease-free survival in group A, time to recurrence in group B, disease-free survival in group B, and safety.
The 3-year recurrence rate was 7.7% in aspirin users vs 14.1% in aspirin nonusers (HR = 0.49; P = .044). In patients with PIK3R1/PTEN/other PIK3CA alterations, this rate was 7.7% vs 16.8%, respectively (HR = 0.42; P = .013). In group A, there was no significant difference in disease-free survival at 3 years, which was 88.5% vs 81.4%, respectively (HR = 0.61). However, the improvement in disease-free survival, to 89.1% in aspirin users from 78.7% in aspirin nonusers, was statistically significant in group B (HR = 0.51; P = .017).
The trial was not originally powered for subgroup analyses. However, aspirin use was found to be protective in all subgroups of patients with colon cancer and rectal cancers; those who received or did not receive neoadjuvant and/or adjuvant treatment; across stages I, II, and III disease; and for both females and males.
Among the 626 patients in the study, severe adverse effects occurred in 57 aspirin users and 38 aspirin nonusers and led to death in three patients in the aspirin group and one in the placebo group. The most common adverse events were late postoperative complications (15 vs 8). Fewer than 10 patients in each arm experienced deep vein thrombosis, embolism, infection, hemorrhage, heart disease, and inflammatory disorders. Dr. Martling noted that aspirin is a well-established and safe medication with well-known side effects, and the safety profile was as expected.
Expert Point of View
Kristen Ciombor, MD, Associate Professor of Medicine (Hematology/Oncology) at Vanderbilt-Ingram Cancer Center, Nashville, said she welcomes the first randomized clinical trial to show a protective effect of aspirin in colorectal cancer. She was also impressed that the ALASCCA study showed a significant difference in recurrence despite the inclusion of not only patients with stage III disease, but patients with stage I and II disease, whose risk of recurrence is much lower. “In this larger population, we saw a difference in patients beyond those who might traditionally benefit,” she said.
Dr. Ciombor pointed out, however, that the findings may take time to be implemented, because patients with early-stage disease have not traditionally been molecularly profiled. “I think it will require some time and adaptation by the insurance companies,” who will need to understand the importance of selecting patients, she said. [The National Comprehensive Cancer Network has updated its Guidelines to recommend aspirin for patients with PIK3CA mutations, so insurance companies may now allow such testing.] Although aspirin is inexpensive and easily available, since it carries the potential for side effects, she “would not give it indiscriminately without the presence of the appropriate PIK3CA alteration.”
ASCO expert Pamela Kunz, MD, FASCO, Professor of Internal Medicine (Medical Oncology) at Yale, also commented on the ALASCCA trial at a press briefing: “Aspirin as chemoprevention has been around for years, but data demonstrating its effectiveness have been lacking. The more than 50% reduction in risk of recurrence in both these populations [patients with PI3K pathway alterations] is very important, and I anticipate we’ll be seeing adoption [of aspirin]. These findings change the treatment paradigm…, and it will be important in our practices to think about the early upfront use of somatic profiling.”
DISCLOSURE: Dr. Martling reported financial relationships with Bactiguard, SmartCella, and CarpoNovum. Dr. Ciombor reported financial relationships with Pfizer, Incyte, Exelixis, Bayer, ALX, Tempus, Taiho, Agenus, Merck, BeiGene, and Summit Therapeutics. Dr. Kunz has received institutional research funding from RayzeBio and Novartis.
REFERENCE
1. Martling A, et al: 2025 ASCO Gastrointestinal Cancers Symposium. Abstract LBA125. Presented January 25, 2025.
