Aspirin for cancer prevention in individuals with Lynch syndrome: first results from the CaPP3 multicentre, randomised, double-blind, non-inferiority trial.

Abstract

BACKGROUND In CAPP2, 600 mg aspirin daily significantly reduced the incidence of colorectal cancer and the incidence of all Lynch syndrome cancers among participants with Lynch syndrome. CaPP3 aimed to assess the efficacy of two lower doses of aspirin. METHODS CaPP3 was a multicentre, parallel-group, randomised, double-blind, dose non-inferiority trial that compared 100 mg or 300 mg daily aspirin with 600 mg daily aspirin in Lynch syndrome carriers aged older than 18 years; patients were recruited from clinical genetics centres in the UK, Australia, Finland, Israel, and Spain. The trial was double-blinded for 2 years, and open label on the same dose for three subsequent years with consent for cancer follow-up (except in the UK, where 75 mg aspirin replaced the 100 mg dose in the open phase). Participants from the five countries were randomly assigned by the Newcastle Clinical Trials Unit in a 3:3:4 ratio to receive daily doses of 100 mg, 300 mg, and 600 mg. Participants received blinded doses of aspirin, identically packaged so as not to indicate dose, every 6 months. Information on compliance was collected on a self-report basis. The dose was revealed at 2 years of recruitment; subsequently, aspirin was obtained via hospital prescriptions during this open-label phase. The primary outcome was the number of new primary mismatch repair-deficient cancers (referred to as Lynch syndrome cancers) developing in participants and diagnosed in the period from the start of the intervention for each participant. The safety outcome was the number of adverse events of interest in the first 2 years of blinded treatment. Aspirin-specific adverse events were recorded at regular participant interviews as a measure of harm during the blinded phase. A non-inferiority margin of 1·5 was chosen for each lower dose against 600 mg daily for the primary endpoint. The effects of the two lower doses (compared to 600 mg daily) were examined with Cox proportional hazards examining time to first Lynch syndrome cancer, with the effect being assessed by hazard ratios (HRs), while negative binomial regression examined the relative cancer burden assessed by incidence rate ratios (IRRs). Non-inferiority was proposed with either lower dose if the upper 95% CI of both the HR and IRR in comparison with 600 mg were below the non-inferiority boundary of 1·5. Participants were deemed per protocol if they had adhered to the protocol and continued taking aspirin into the unblinded phase (ie, they agreed to remain in the study at the 2-year review); non-inferiority required consistency of effects within both intention-to-treat and per-protocol populations and for both HR and IRR analyses. CaPP3 is registered on the ISRCTN registry (ISRCTN16261285) and ClinicalTrials.gov (NCT02497820), and was closed to recruitment in March 2019; this analysis was timed for when all participants reached 5 years past recruitment. Further follow-up is planned until all participants reach 10 years past recruitment. FINDINGS Between October, 2014, and March, 2019, 1879 patients with Lynch syndrome were recruited and randomly assigned: 564 (30·0%) to 100 mg aspirin daily, 565 (30·1%) to 300 mg daily, and 750 (39·9%) to 600 mg daily. Following the exclusion of 13 participants, the intention-to-treat population consisted of 1866 participants; 559 (30·0%) received 100 mg, 562 (30·1%) received 300 mg, and 745 (39·9%) received 600 mg. 730 (39·1%) of 1866 participants stopped taking aspirin within the 2-year blinded phase, while 937 (50·2%) completed 5 years of aspirin, taking aspirin during the subsequent 3-year unblinded open phase. The per-protocol population consisted of 1136 participants: 336 (29·6%) on 100 mg, 357 (31·4%) on 300 mg, and 443 (39·0%) on 600 mg. Up to a median of 66·4 months (IQR 32·1-84·0) of follow-up, 176 participants had been diagnosed with 216 Lynch syndrome cancers (57 cancers in patients on 100 mg, 75 in those on 300 mg, and 84 in those on 600 mg), including 83 of 1846 participants with colorectal cancer (21 participants on 100 mg, 30 on 300 mg, and 32 on 600 mg). For Lynch syndrome cancers, the 100 mg dose was non-inferior to 600 mg in the intention-to-treat analysis (HR for time to first Lynch syndrome cancer 0·97 [95% CI 0·67-1·42], IRR for cancer burden 0·94 [95% CI 0·65-1·38]). For the per-protocol analysis, the cancer burden was non-inferior with the 100 mg dose (IRR 0·90 [95% CI 0·55-1·46]) but time to first Lynch syndrome cancer was not (HR 1·00 [95% CI 0·61-1·63]). Non-inferiority was not established for the 300 mg dose for either time to first Lynch syndrome cancer or cancer burden, in both intention-to-treat and per-protocol analyses (intention-to-treat population: HR 1·28 [95% CI 0·91-1·80], IRR 1·12 [95% CI 0·79-1·61]; per-protocol population: HR 1·42 [0·91-2·19], IRR 1·28 [0·82-1·98]). The proportion of participants with any reported adverse events of interest increased modestly but significantly with dose: 140 (25·0%) of 561 participants on 100 mg, 151 (26·8%) of 564 on 300 mg, and 234 (31·2%) of 750 on 600 mg (p=0·03 for heterogeneity). Over the 5 years, serious adverse events due to bleeding occurred in no patients on 100 mg, three (0·5%) on 300 mg, and 11 (1·5%) participants on 600 mg (p=0·004 for heterogeneity). INTERPRETATION Although non-inferiority could not formally be concluded for either 100 mg or 300 mg of aspirin daily by comparison with 600 mg aspirin daily, there was evidence that the 100 mg dose had similar characteristics to 600 mg in terms of cancer risk but with fewer side-effects and less risk of bleeding. FUNDING Cancer Research UK; Bayer Pharma; Newcastle Hospitals NHS Foundation Trust.