Daily adjuvant aspirin failed to reduce disease recurrence in patients with colorectal cancer liver metastases and may actually increase the risk of death, according to results from the randomized phase 3 ASAC trial presented at the 2025 American Society of Clinical Oncology Annual Meeting.
The multicenter trial enrolled 428 patients with colorectal cancer liver metastases eligible for resection or ablation, randomly assigning them to receive either 160 mg aspirin daily or placebo for three years. The study found no significant difference in disease-free survival between the two groups, with median DFS of 1.16 years for aspirin versus 1.35 years for placebo.
Safety Concerns Emerge
More concerning were the safety signals that emerged from the trial. Patients receiving aspirin had a numerically higher risk for death that nearly reached statistical significance, with a hazard ratio of 1.6 (95% CI, 0.99-2.61; P = .057). The probability of surviving beyond 36 months was 76.1% with aspirin compared to 84.9% with placebo.
"The effect is in the wrong direction," said discussant Jason A. Zell, DO, MPH, associate professor in the division of hematology and oncology at UC Irvine School of Medicine.
The toxicity profile further emphasized potential harm. Those who received aspirin experienced more adverse events (85% vs 76%), serious adverse events (24% vs 5%), life-threatening serious adverse events (4% vs 1%), and events leading to death (1% vs 0%). Clinically relevant adverse events in the aspirin group included myocardial infarction (2 vs 0), duodenal ulcers (2 vs 0), and cerebral hemorrhage (2 vs 0).
Metastatic Disease Differs from Primary Cancer
The findings contrast sharply with previous research showing aspirin's protective effects in non-metastatic colorectal cancer. Lead investigator Sheraz Yaqub, MD, PhD, senior surgeon at Oslo University Hospital and associate professor at University of Oslo, emphasized this distinction.
"The protective effect of aspirin in colorectal cancer is not transferable to metastatic disease," Yaqub stated. "Aspirin cannot be recommended as adjuvant treatment for colorectal cancer liver metastases."
The study population had a mean age of 62 years, with 64% male patients and 66% having colon cancer rather than rectal cancer. Approximately 45% of patients in the aspirin group had synchronous liver metastases compared to 42% in the placebo group.
Future Research Directions
Despite the overall negative results, researchers see potential opportunities in specific patient subgroups. The phase 3 ALASCCA trial previously demonstrated that aspirin improved disease-free survival in patients with non-metastatic colorectal cancer harboring PIK3CA mutations (HR, 0.51; 95% CI, 0.29-0.88; P = .017).
Yaqub and colleagues plan to conduct subgroup analyses for PIK3CA, PTEN, and KRAS mutations to identify whether certain genetic profiles might predict benefit from aspirin therapy. This approach aligns with recent updates to National Comprehensive Cancer Network guidelines, which now recommend testing for PIK3CA mutations in all patients with stage II or III colon cancer and treating with aspirin if positive.
Zell highlighted the potential role of circulating tumor DNA (ctDNA) in identifying patients who may benefit from NSAIDs in the future, emphasizing the importance of the planned subgroup analyses to provide further data in this area.
The study underscores the complexity of translating therapeutic benefits from primary to metastatic disease settings, particularly for approximately 25% of colorectal cancer patients who develop liver metastases—the primary driver of cancer-specific mortality in this population.
