Background: Immune checkpoint inhibitors (ICI) have transformed the prognoses of patients with advanced melanoma. However, the pro-inflammatory effects of ICIs have been associated with increased long term risk of atherosclerotic cardiovascular disease (ASCVD) in cancer survivorship. Statin therapy is commonly used for primary prevention of ASCVD but its efficacy in preventing coronary atherosclerosis among melanoma patients treated with ICIs is uncertain.
Methods: The SOCRATES trial is a multicentre prospective, randomised, open-label, blinded endpoint study to investigate the effects of statin therapy in mitigating coronary plaque progression in melanoma patients treated with ICIs. Potential participants will undergo screening computed tomography coronary angiography (CTCA) to assess suitability for recruitment. Key exclusion criteria include ICI use for more than three months, clinical requirement or contraindication to statin therapy, known cardiovascular disease, or significant coronary artery disease on screening CTCA (calcium score >400 or any severe coronary artery stenosis). Eligible patients will undergo 1:1 randomisation to statin or no therapy. Follow-up CTCA will be performed at 18 months to allow comparison of coronary plaque progression between groups.
Results: The primary endpoint is progression of non-calcified coronary plaque volume. Allowing for 30% drop out, the trial requires 180 participants to achieve 80% power to detect a 15mm3 difference in non-calcified plaque progression between groups. Major secondary endpoints include progression of total and calcified plaque volumes and melanoma-specific quality of life. Exploratory endpoints include death, myocardial infarction, stroke, and melanoma progression-free survival.
Conclusion: SOCRATES will provide new scientific evidence regarding statin therapy to reduce ASCVD risk among melanoma patients treated with ICIs. The results of this trial may guide cardiovascular risk reduction among the growing number of melanoma survivors and provide insight into prevention of ASCVD among other cancer cohorts treated with ICIs.