Adjuvant Aspirin Trial in CRC Inconclusive

BARCELONA, Spain — A higher disease-free survival (DFS) rate was seen for patients with stage II/III colon cancer given adjuvant aspirin than for those given placebo in a randomized, double-blinded study.

Ulrich Güller, MD, Kantonsspital St.Gallen, St.Gallen, Switzerland, presented the results of the phase 3, Swiss SAKK 41/13 trial, involving patients with a mutation linked to cyclooxygenase 2 (COX-2), at the European Society for Medical Oncology (ESMO) Annual Meeting 2024 on September 15. The study was stopped early due to a lack of funding.

This is the “first prospective, randomized trial to provide clinical evidence of a protective effect of adjuvant aspirin in patients with resected, PIK3CA-mutant stage II and Ill colon cancer,” said Güller.

“Even though these results are not statistically significant due to premature study closure, adjuvant aspirin warrants individual consideration” in these patients, he added.

Güller began his presentation by noting that retrospective data published more than a decade ago provided “suggestive evidence” of a protective effect of aspirin as an adjuvant treatment in patients with colon cancer.

Moreover, a study from around the same time indicated that a PIK3CA mutation is a predictive biomarker of a benefit from aspirin therapy.

Considering these previous studies, the investigators in the new trial selected patients from 55 sites in four European countries with stage II/III colon cancer who had undergone complete resection of their tumor and who had an activating PIK3CA mutation in exon 9 and 20 and an ECOG performance status of 0-2.

They excluded patients who were already receiving aspirin or a COX-2 inhibitor, had upper gastrointestinal bleeding within the past 12 months, or who had multiple colonic malignancies or rectal cancer. The primary endpoint was DFS.

Güller said that the trial was closed early due to financial constraints, when they had enrolled 112 out of the 185 patients estimated to be required to show a significant difference between the study arms.

Study Methods and Results

Among 74 patients given adjuvant aspirin and 38 given placebo, the median age was approximately 66 years, and around 45% were women. Approximately 46% patients had stage II and the remaining patients had stage III disease.

The 5-year DFS among patients given adjuvant aspirin was 86.5% vs 72.9% among those given placebo, at a nonsignificant hazard ratio (HR) of 0.57 (P = .11). There was also a nonsignificant difference in recurrence-free survival between the groups (HR, 0.49; P = .089).

Güller reported that compared with placebo, adjuvant aspirin was associated with a nonsignificant improvement in overall survival (HR, 0.71; P = .3).

He added that aspirin had a “very favorable side effect profile,” with no serious adverse events recorded.

Adjuvant Aspirin ‘Looks Like’ It Improved Outcomes

“People were looking forward to this prospective data,” said Christine M. Parseghian, MD, of the Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, during an interview.

“The thought was that adjuvant aspirin would improve outcomes,” Parseghian continued, “and it looks like it did,” particularly as it was focused on the PIK3CA, a downstream target of COX-2.

She noted the study included only just over 110 patients and speculated that with a larger cohort of patients, it could have achieved a significant benefit.

Parseghian, who was not involved in the study, pointed out that “a lot of these patients are taking it anyway: They’re hearing about it, they’re wanting to take it.”

She added: “Most patients will come and say, ‘Well, doc, what can I do to improve my outcome?'” While Parseghian recommends lifestyle interventions, such as reducing red meat consumption, exercising, and eating a low–saturated fat diet, she said her patients will often ask about taking low-dose aspirin. “In my opinion, there’s no downside to giving it,” she said.

However, Parseghian noted that she and her colleagues do not check patients’ PIK3CA mutation status, particularly in the adjuvant setting.

Clinical Relevance of Benefit Questioned

Sebastian Stintzing, MD, who is professor of medicine and head of the Department of Hematology, Oncology and Cancer Immunology, at Charité – Universitätsmedizin in Berlin, Germany, questioned the authors’ conclusion that the benefit seen in the trial was clinically relevant.

“From a formal standpoint, there is still no compelling data in favor of adjuvant aspirin,” continued Stintzing.

Stintzing, who was not involved in the research, underscored that questions remain over the benefit of aspirin in elderly patients, in whom the risks vs the potential benefits are unclear.

More multinational collaborative trial efforts to “personalize adjuvant treatment to reduce toxicity and increase efficacy” are needed, he said.

The study was funded by the Swiss National Science Foundation, Swiss Cancer League, Merck Grant for Oncology Innovation, ProMedica Stiftung, and Fédération Francophone de Cancérologie Digestive; Aspirin and placebo were provided by Bayer.

Güller declared no relevant financial relationships. Stintzing declared relationships with Amgen, AstraZeneca, Bayer, BMS, CV6, ESAI, Isofol, Lily, Merck KGaA, MSD, Pierre Fabre, Roche, Sanofi, Servier, Taiho, Takeda, LEO Pharma, Medscape Foundation, and CORZED. Parseghian declared a relationship with Merck.