Prevention of Cardiac Dysfunction with LCZ696 in Early Breast Cancer Patients Receiving Anthracycline-Based Adjuvant Therapy: Randomized Placebo-Controlled Trial (PRADA‑II)

Primary objective: To determine whether administration of LCZ696 (sacubitril/valsartan) prevents or attenuates the reduction in left ventricular systolic function measured by cardiovascular magnetic resonance in patients with early breast cancer receiving anthracycline‑containing therapy. Secondary objectives:

• Evaluation of the effect of LCZ696 on left ventricular systolic function using echocardiography or CMR.
• Assessment of the incidence of a clinically significant decline in left ventricular systolic function by imaging.
• Determination of the incidence of cardiotoxicity as defined by imaging criteria.
• Investigation of early, acute and chronic cardiac injury through serial cardiac biomarkers.

The trial enrolled adult female patients with histologically confirmed invasive early breast cancer who were scheduled to receive anthracycline‑containing neoadjuvant or adjuvant therapy; all participants were required to have an Eastern Cooperative Oncology Group performance status of 0–1 and to be in sinus rhythm. The sponsor did not provide the total number of participants or specific age range, and the study population was described only as female and classified under age‑range codes 3 and 4. Inclusion required eligibility for the planned chemotherapy regimen, while exclusion criteria were not detailed in the provided information. Participants potentially had comorbid Heart Failure, reflecting the dual focus on oncologic and cardiac outcomes. Lifestyle factors such as diet or physical activity were not specified.

The PRADA‑II trial is a phase 4, multicenter, randomized, placebo‑controlled study evaluating whether oral sacubitril/valsartan (LCZ696) administered during anthracycline‑containing adjuvant breast‑cancer therapy can attenuate the decline in left ventricular ejection fraction (LVEF). Women with early invasive breast cancer scheduled for anthracycline therapy, ECOG performance status 0‑1, and sinus rhythm are screened for eligibility, then randomized to receive titrated doses of Entresto (24 mg/26 mg, 49 mg/51 mg, or 97 mg/103 mg) or matching placebo tablets taken orally for a blinded treatment period of 18 months. Follow‑up visits are scheduled at baseline, 3, 6, 12, and 18 months to obtain cardiovascular magnetic resonance, echocardiography, strain imaging, cardiac biomarker measurements, and safety assessments. The end‑of‑study visit at month 18 records final imaging and laboratory data, concluding participant involvement, which therefore spans approximately 18 months plus the initial screening visit. Recruitment commenced on 17 December 2018 and is planned to continue until 5 September 2029.

The experimental arm utilizes sacubitril/valsartan (commercially known as Entresto) supplied as film‑coated tablets for oral administration. Three dosage strengths are employed: 24 mg/26 mg tablets (total dose 100 mg per tablet), 49 mg/51 mg tablets (total dose 200 mg per tablet), and 97 mg/103 mg tablets (total dose 400 mg per tablet). Each tablet contains the fixed‑dose combination of valsartan and sacubitril and is taken according to the study dosing schedule.

The control arm receives matching inert tablets designated as placebo. Placebo tablets are provided in strengths corresponding to the active product (50 mg, 100 mg, and 200 mg film‑coated tablets) and are administered orally in the same manner as the active medication.

The primary efficacy assessment is the change in left ventricular ejection fraction (LVEF) measured by cardiovascular magnetic resonance (CMR) from randomization to the end of blinded therapy at 18 months.

Secondary efficacy parameters comprise the change in LVEF by echocardiography, the change in global longitudinal strain (GLS) by both echocardiography and CMR, the change in end‑systolic volume by CMR, the incidence of a clinically significant reduction in LVEF ≥5 % by CMR, the incidence of a relative GLS reduction >15 %, the incidence of cardiotoxicity defined as an absolute LVEF decline ≥10 % to a value below 50 % as measured by either imaging modality, the incidence of clinical heart failure, and the change in circulating cardiac biomarkers.

Imaging assessments are performed at baseline (randomization) and at the 18‑month visit using standardized CMR protocols and transthoracic echocardiography with validated software for LVEF and GLS quantification. Biomarker analysis utilizes high‑sensitivity assays for cardiac troponin I and T (hs‑TnI, hs‑TnT) and for NT‑proBNP, collected at the same time points.