Aspirin as secondary prevention for colorectal cancer liver metastases (ASAC): A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial.

LBA3511 Background: Approximately 50% of patients with colorectal cancer develop liver metastases, and while surgical resection improves survival, over half experience recurrence. Evidence from laboratory and epidemiologic studies suggests that aspirin may have antineoplastic effects in colon cancer, but its role in the secondary prevention of colorectal cancer liver metastases remains unclear. Methods: This phase 3, randomized, double-blind, placebo-controlled trial was conducted across 14 centers in Norway, Sweden, and Denmark. Patients (aged ≥18 years old) radically treated for colorectal cancer liver metastases were randomly assigned in a 1:1 ratio using computer-generated blocks to receive aspirin 160 mg or placebo once daily for 3 years or until disease recurrence. Investigators and patients were masked to the treatment allocation. The primary endpoint was 3-year disease-free survival from the start of medication, with analyses performed on the full analysis set. The hazard ratio comparing the two treatment groups was estimated by Cox regression, and the 3-year disease-free survival in each group was estimated by the Kaplan-Meier method. Results: Between Dec 2017 and Jan 2022, 466 patients were randomly assigned to treatment (aspirin, n=234; placebo, n=232). There were 38 who did not start treatment (17/21 allocated to aspirin/placebo). All patients who started medication were included in the full analysis set (aspirin, n=217; placebo, n=211). Of these patients, the mean age was 62 years and 272 (64%) were males and 156 (36%) females. The primary tumor site was in right colon, left colon, or rectum in 98 (45.2%), 37 (17.1%), 82 (37.8%) in the aspirin group and 94 (44.5%), 54 (25.6%), 63 (29.9%) in the placebo group, respectively. Synchronous liver metastasis was present in 98 (45.2%) and 88 (41.7%) in the aspirin and placebo groups, respectively. The 3-year disease-free survival showed a hazard-ratio (HR) estimate of 1.06 (95% confidence interval (CI) 0.77–1.45, p-value 0.64) in disfavor of aspirin. The probability of surviving past 36 months was 76.1% in the aspirin group and 84.9% in the placebo group, with an overall survival HR of 1.60 (95% CI 0.99–2.61, p=0.057) in favor of the placebo. Adverse events were reported in 53 patients in the aspirin group (24.4%) and 42 patients in the placebo 19.9%). Among these, 17 participants in the aspirin group and 4 in the placebo group (7.8% vs 1.9%) had at least one serious adverse event. There were no treatment-related deaths in either group. Conclusions: This phase 3 trial showed that in patients with colorectal cancer liver metastasis, daily aspirin 160 mg after complete tumor removal did not improve disease-free or overall survival. Additionally, aspirin was associated with an increased incidence of serious adverse events. Clinical trial information: NCT03326791 .