ASCOLT trial explores aspirin’s role in preventing colorectal cancer recurrence

A large-scale, international, multicentre, phase 3 clinical trial of aspirin for the secondary prevention of colorectal cancer has concluded. Led by Singapore clinician-scientists, the ASCOLT (Aspirin after completion of standard adjuvant therapy for colorectal cancer) trial is the first phase 3 study to assess the efficacy and safety of aspirin in preventing the recurrence of colorectal cancer after standard of care surgery and adjuvant chemotherapy treatment. The study was published in The Lancet Gastroenterology and Hepatology online in January 2025, and is featured on the cover of the March 2025 print issue of the journal.

ASCOLT’s results report that aspirin does not statistically improve disease-free survival in all patients. Still, they clearly show a consistent trend of aspirin improving disease-free survival and overall survival across the years. In January 2025, the same month that ASCOLT’s results were published, positive results of a Phase 3 study of colorectal cancer patients in Northern Europe with a PIK3CA mutation – using aspirin for secondary prevention following surgery and adjuvant chemotherapy – were announced, indicating that aspirin taken for up to 3 years is efficacious in those with the mutation. The ALASCCA trial showed that aspirin use in this specific colorectal cancer population could reduce recurrence by over 50%, a very significant benefit. Together, these two landmark studies herald a potential role of aspirin in reducing colorectal cancer recurrence in a specific subgroup.

Why aspirin for cancer recurrence?

For over the past 20 years, there has been no therapeutic advancements to treat resected colorectal cancer in order to reduce recurrence risk. All trials, including those led by major pharmaceutical companies that added biologic antibodies to standard chemotherapy, have failed to further improve on survival outcomes in these patients.

In 2008, National Cancer Centre Singapore (NCCS) senior clinician investigators, Professor Toh Han Chong and Dr. John Chia, conceptualized ASCOLT as a randomised, controlled trial to test the efficacy and safety of using aspirin to prevent the recurrence of colorectal cancer in patients who had completed standard of care surgery and adjuvant chemotherapy. The ASCOLT trial was driven by three main motivations, (1) aspirin is inexpensive and widely accessible, (2) an urgent need to test repurposed drugs, such as aspirin, for chemoprevention as cancer drug costs soar, and (3) research showed aspirin’s potential to reduce colon polyps and risk of developing colorectal cancer.

Aspirin works by inhibiting the activity of the cyclooxygenase (COX) 1 and 2 enzymes, which are responsible for causing inflammation. Previous observational studies have shown aspirin reduces intestinal polyps in healthy individuals with prior polyps, as well as reducing polyps in colorectal cancer survivors. Aspirin has been proven to reduce colon cancer incidence in patients with Lynch syndrome in a large, randomised Phase 3 trial. However, there was little data regarding aspirin’s potential to reduce cancer risk in patients who had already been diagnosed with colorectal cancer.

ASCOLT: A global trial driven by clinician-investigators

The ASCOLT trial, an international, multicentre, randomized, double-blind, placebo-controlled Phase 3 clinical trial recruited and randomly assigned 1,587 patients with colorectal cancer who had completed standard therapy to one of two groups – one receiving 200 mg of aspirin daily, the other a placebo – for three years or until they experienced severe side effects, cancer recurrence, death or discontinued from study. Of these patients, 1,550 participants were included in analysis population.

ASCOLT ran between 2009 and 2021 and was conducted in 66 hospitals across 11 countries and territories including Australia, China, India, Indonesia, Malaysia, New Zealand, Saudi Arabia, Singapore, Sri Lanka, South Korea, and Taiwan. Two large consortiums: INDOX Research Network, a partnership between the Institute of Cancer Medicine at the University of Oxford and India’s top nine comprehensive cancer centres including AIMS (All India Institute of Medical Sciences) and Tata Memorial Hospital in Mumbai, and The Australasian Gastro-intestinal Trials Group (AGITG) were key members of the ASCOLT trial.

The ambitious large-scale global study faced many challenges, including coordinating trial logistics across multiple countries and territories, navigating COVID-19 pandemic restrictions and raising sufficient funds. As ASCOLT was an investigator-initiated trial, additional funding support secured by Prof Toh and Dr Chia was a vital lifeline to support operations, completion and follow up of over 15 years.

A negative result with a silver lining

The results of the ASCOLT trial did not meet its primary endpoint as no statistically significant difference was seen for disease-free survival for patients with colorectal cancer who had completed standard therapy, when compared to the placebo. Still, ASCOLT did demonstrate a clear and consistent trend across the years, albeit a small one, of disease-free and overall survival benefit of aspirin versus placebo. Importantly, ASCOLT showed that aspirin for up to 3 years was well tolerated with no significant side effects. In fact, the side effect profile for aspirin was comparable to that of the placebo group.

Previous data suggested that specific molecular features, including the PIK3CA mutation and COX2 expression in colorectal cancer tissue, could identify individuals who could potentially benefit most from taking aspirin to reduce colorectal cancer recurrence. In January 2025, results from the ALASCCA trial, which recruited patients in Sweden, Denmark, Finland, and Norway, showed that aspirin use in patients with PIK3CA-mutated colorectal cancer reduced the recurrence risk by over 50% compared to placebo. This is the first prospective trial to demonstrate that aspirin can effectively target a selected biomarker-identified subset to reduce colorectal cancer recurrence.

Together, ASCOLT and ALASCCA provide crucial insights into the use of aspirin as adjuvant therapy for colorectal cancer and catalyse next steps for further research and validation. Leaders in the field anticipate that in the near future aspirin will become part of the treatment regime for early-stage colorectal cancer in a biomarker-identified subset – reducing recurrence and improving cure rates. This will be an impactful global health benefit that makes a positive difference in one of the commonest cancers in the world.

Next steps for ASCOLT clinical investigators and researchers

“ASCOLT lays the foundation and identifies the role of aspirin in a more selected biomarker-identified population to reduce the risk of colorectal cancer recurrence after standard surgery and chemotherapy,” said The Lancet Gastroenterology and Hepatology study’s senior author Professor Toh, Senior Consultant, Division of Medical Oncology, and Deputy Chief Executive Officer (Strategic Partnerships), NCCS. “We have already started analysing promising molecular targets, such as the PIK3CA mutation and COX2 expression in ASCOLT’s patient cohort, working closely with ASCOLT consortium colleagues from Australia and New Zealand. The results from ALASCCA are exciting for its striking benefit with aspirin in a Scandinavian population, but it is still important to confirm whether these findings can be validated in more diverse ethnic populations.”

It is imperative that global academic consortiums continue to build and lead large trials asking key questions such as whether affordable, off-patent drugs can bring benefit to cancer patients and patients across many disease types. If proven useful, such drugs will provide powerful global health benefits especially for patients in low- and middle-income countries (LMIC).”

Professor Toh Han Chong, Senior Consultant, Division of Medical Oncology, and Deputy Chief Executive Officer (Strategic Partnerships), NCCS

“With all our combined efforts, we are going to define the role of aspirin in the treatment of established cancers,” said study’s first author Dr Chia, who is now a medical oncologist in private practice. “This is incredibly significant because aspirin is very affordable and may well prove to be the most cost-effective cancer treatment of the future.

Story first appeared on News Medical