NCT05465031 Sacubitril/Valsartan in PriMAry preventIoN of the Cardiotoxicity of Systematic breaST canceR trEAtMent (MAINSTREAM)

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What to Expect as a Participant

You will actively receive the study intervention — which may be a drug, biologic, device, or procedure.

Phase 4 studies follow an already-approved treatment in real-world conditions to monitor long-term safety and effectiveness.

This trial targets 600 participants in total. It began in 2024-04-17 with a primary completion date of 2027-12.

Brief Summary

Breast cancer is the most commonly cancer in women in the overall global population. According to the World Cancer Research Fund International, there were more than 2.25 million new cases of breast cancer in women in 2020. Although the modern treatment strategies, based on the complex care, which consists of surgery, radiotherapy, hormone therapy, and targeted chemotherapy directed at specific cancer molecules have substantially reduced the risk of death due to breast cancer, their wide adoption results in the wider prevalence of cardiotoxicity, defined as either symptomatic heart failure, or asymptomatic contractile dysfunction. The occurrence of cardiotoxicity induced by anti-cancer therapies is estimated at 5-15%, and its development is the primary cause of therapy termination, which significantly reduces the probability of the efficacy of treatment. Several attempts have been made to determine the efficacious preventive strategy, which could diminish the risk of cancer-therapy induced cardiotoxicity. The results of the prior studies indicated a trend towards lower risk of troponin elevation, or left ventricular contractile dysfunction with the introduction of drugs interfering with the renin-angiotensin-aldosterone (RAA) axis, which constitute the primary treatment modality in heart failure with reduced ejection fraction (HFrEF). Sacubitril/valsartan, the novel therapeutic agent, has been demonstrated to significantly improve prognosis in patients with HFrEF. Prior retrospective, small, single-center studies have shown that treatment with sacubitril/valsartan may reduce the risk of cancer-therapy induced cardiotoxicity, or reverse contractile dysfunction caused by anti-cancer therapy. However, no large randomized data confirmed these findings. Therefore, the Sacubitril/Valsartan in PriMAry preventIoN of the cardiotoxicity of systematic breaST canceR trEAtMent) study, has been designed to verify, whether the preventive use of sacubitril/valsartan administered in the doses recommended in patients with HFrEF in breast cancer patients undergoing adjuvant chemotherapy with anthracyclines or anthracyclines and HER-2 monoclonal antibodies, will reduce the incidence of cardiotoxicity defined as impaired left ventricular systolic function on transthoracic echocardiography (TTE). In the trial, a total of 480 patients with histologically confirmed breast cancer, who are eligible for chemotherapy with anthracyclines or anthracyclines and HER-2 monoclonal antibodies, will undergo 1:1 randomization to either preventive treatment with sacubitril/valsartan or placebo. The patients will be followed for 24 months, and will have repetitive efficacy and safety examinations, including echocardiography, MRI (optionally), electrocardiography including 24-h Holter monitoring, blood tests, functional capacity tests and quality of life assessment.

Eligibility Criteria

Inclusion Criteria: * Written informed consent * Female gender, aged 18 years and over * Patients with histologically confirmed breast cancer and complete assessment of tumor phenotype (Estrogen receptor - ER, Progesterone receptor - PR, Human epidermal growth factor receptor 2 - HER2, Kiel - Ki67) * Ability to take oral medication and willingness to adhere to the planned regimen * Tumor grade IA-IIIC or oligometastatic grade IV * Radical treatment plan including surgery * Plan of use of systemic treatment (preoperative, postoperative or combined) with anthracyclines and/or anti-HER2 drugs * Eastern Cooperative Oncology Group (ECOG) 0-2 general status * LVEF ≥ 50% as assessed by echocardiography * Sinus rhythm Exclusion Criteria: * Prior anthracycline-based chemotherapy and/or thoracic radiotherapy (prior to diagnosis of the cancer being the present cause of therapy) * Clinically relevant HF (NYHA II-IV) * Myocardial infarction (MI) within the last \< 3 months * Symptomatic hypotension or systolic blood pressure (SBP) \< 90 mmHg * Significant valvular disease, symptomatic coronary artery disease (CCS\>2), significant atrioventricular (AV) block, symptomatic sinus node dysfunction * Expected survival \<12 months * Glomerular filtration rate (GFR) \<30 ml/min/1.73 m2 (screening visit) * K+\>5.5mmol/L (screening visit) * Contraindications to angiotensin converting enzyme inhibitor (ACE-I)/angiotensin II receptor blocker (ARB) or LCZ696 if not listed among criteria * Active untreated liver disease * Pregnancy * Conditions/circumstances that may lead to non-compliance with medical staff recommendations (e.g. active drug/alcohol dependence, poorly controlled mental illness)

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