Sacubitril/Valsartan in PriMAry preventIoN of the Cardiotoxicity of Systematic breaST canceR trEAtMent

MAINSTREAM is a prospective, multicentre, randomised, placebo-controlled, double-blind, parallel-group, investigator-initiated clinical trial. The study is powered to demonstrate the difference between the groups in the primary endpoint, which has been defined as the occurrence of a decrease in LVEF by ≥ 5% assessed by transthoracic echocardiography (TTE) within 24 months. Approximately 600 patients will be recruited in three tertiary supraregional Polish oncology centers. Of those patients, after an estimated dropout, during the single-blinded phase of drug uptitration to the target dose, 480 will be randomized in a 1:1 ratio into sacubitril/valsartan or matching placebo.

In brief, patients with histologically confirmed, and phenotypically assessed breast cancer at an early stage, defined as stages I-III and oligometastatic IV stage, with a radical treatment plan, which includes surgery and the post- and/or pre-operative systemic treatment, will be included in the study. The patients must be classified in the 0-2 classes of the Eastern Cooperative Oncology Group. In the baseline echocardiography analysis, the LVEF must be ≥50% and the patients must be in the sinus rhythm. The patients who underwent prior therapy with anthracyclines and/or left-sided radiotherapy, suffered from myocardial infarction within the preceding 3 months prior to the study, or have symptomatic, clinically relevant heart failure, will be excluded from the study. Similarly, patients with contraindications, or prone to the adverse effects of the studied drug, which includes patients with symptomatic hypotension, hyperkalemia defined as K+ higher than 5.5 mmol/L and estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 on the screening visit, will also be considered ineligible to participate in this trial. Patients must not have been on treatment with ACE-I/ARB/ARNI at least in the 36 hours prior to study enrollment. According to the ESC guidelines on cardio-oncology, the inclusion and exclusion criteria for the trial define the vast majority of the studied population in the low- or moderate risk of cancer therapy-related cardiac dysfunction (CTRCD), however, the inclusion of patients at high risk of either anthracycline- or anti-HER-2-associated CTRCD, such as patients aged ≥80 years, is not impossible. No very high-risk patients will be considered eligible for enrollment.

After assessment of the inclusion and exclusion criteria, and all examinations, including the echocardiography assessment, the patients will begin the single-blinded phase of treatment with sacubitril/valsartan during the screening visit. The MRI study may be performed according to the availability of the method in each participating facility. The initial dosing of the drug will be 49/51 mg twice daily, which should be uptitrated to the target dose of 97/103 mg twice daily at the Run-in-visit scheduled at 6-8 days from the initial evaluation and drug introduction, tolerance permitting. After further 6-8 days of single-blinded treatment with target dose of sacubitril/valsartan, providing satisfactory tolerance of the drug, the patients will undergo randomization at the Randomization visit.

Providing the patient signed informed consent, is fully eligible for randomization, and underwent the single-blinded study treatment regimen with satisfactory tolerance, the patient will be randomized with the use of an electronic, centralized randomization system, blinded to the patient's characteristics, to either interventional group, which will be administered with sacubitril/valsartan, or the placebo group. The system will dynamically randomly allocate patients to the two groups in a 1:1 ratio.

After randomization, the patients will follow treatment with either sacubitril/valsartan or a matching placebo, for a maximum of 24 months. During this period, three study visits are planned, at 3 months, 12 months, and 24 months from randomization. At each visit, the patients will be assessed for the medical presentation, undergo laboratory and imaging studies, and will be assessed for the presence of adverse events. In patients, who will be unable to tolerate the target dose of the study drug of 97/103 mg twice daily, the dose can be down-titrated to 49/51 mg twice daily at the investigator's discretion (after having considered whether there is any other concomitant medication that could act as a parallel contributor to the lower tolerance of the drug). If the dose of 49/51 mg twice daily cannot be tolerated, the dose could be temporarily lowered by half for a period of two weeks. However, if after that period the uptitration of the dose is impossible, the patients will have to be excluded from further participation in the trial. The physicians will be strongly encouraged to foster the continuation of the target dose of the study drug, based on their assessment of the patient's condition.