Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial

Abstract Background Recent advances in the treatment algorithms of early breast cancer have markedly improved overall survival. However, anthracycline- and trastuzumab-associated cardiotoxicity may lead to dose-reduction or halt in potentially life-saving adjuvant cancer therapy. Early initiated neurohormonal blockade may prevent or attenuate the cardiotoxicity-induced reduction in cardiac function, but prior studies have been inconclusive. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to be superior to traditional treatment in heart failure with reduced ejection fraction, but its cardioprotective effects in the cardio-oncology setting remains to be tested. Objective To assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction. Methods PRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations. Results The study is ongoing. Results will be published when the study is completed. Conclusion PRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy. Trial registration The trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588). Registered 30 November 2018.

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Faculty Opinions recommendation of Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726165826.793550720 ◽

2018 ◽

Author(s):

WH Wilson Tang

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Cancer Therapy ◽

Cardiac Dysfunction ◽

Breast Cancer Therapy ◽

Double Blind ◽

Double Blind Clinical Trial ◽

Adjuvant Breast Cancer

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Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol

European Heart Journal ◽

10.1093/eurheartj/ehw022 ◽

2016 ◽

Vol 37 (21) ◽

pp. 1671-1680 ◽

Cited By ~ 274

Author(s):

Geeta Gulati ◽

Siri Lagethon Heck ◽

Anne Hansen Ree ◽

Pavel Hoffmann ◽

Jeanette Schulz-Menger ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Cancer Therapy ◽

Cardiac Dysfunction ◽

Breast Cancer Therapy ◽

Double Blind ◽

Double Blind Clinical Trial ◽

Adjuvant Breast Cancer

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A Randomized Trial Comparing 3- versus 4-Monthly Cardiac Monitoring in Patients Receiving Trastuzumab-Based Chemotherapy for Early Breast Cancer

Current Oncology ◽

10.3390/curroncol28060427 ◽

2021 ◽

Vol 28 (6) ◽

pp. 5073-5083

Author(s):

Susan Dent ◽

Dean Fergusson ◽

Olexiy Aseyev ◽

Carol Stober ◽

Gregory Pond ◽

...

Keyword(s):

Breast Cancer ◽

Early Breast Cancer ◽

Cardiac Dysfunction ◽

Controlled Trial ◽

Left Ventricular ◽

Cardiac Monitoring ◽

Left Ventricular Ejection ◽

Her2 Positive ◽

Ventricular Ejection Fraction ◽

Trastuzumab Therapy

Purpose: The optimal frequency for cardiac monitoring of left ventricular ejection fraction (LVEF) in patients receiving trastuzumab-based therapy for early breast cancer (EBC) is unknown. We conducted a randomized controlled trial comparing 3- versus 4-monthly cardiac monitoring. Patients and Method: Patients scheduled to receive trastuzumab-containing cancer therapy for EBC with normal (>53%) baseline LVEF were randomized to undergo LVEF assessments every 3 or 4 months. The primary outcome was the change in LVEF from baseline. Secondary outcomes included the rate of cardiac dysfunction (defined as a decrease in the LVEF of ≥10 percentage points, to a value <53%), delays in or discontinuation of trastuzumab therapy, and cardiology referral. Results: Of the 200 eligible and enrolled patients, 100 (50%) were randomized to 3-monthly and 100 (50%) to 4-monthly cardiac monitoring. Of these patients, 98 and 97 respectively underwent at least one cardiac scan. The estimated mean difference in LVEF from baseline was −0.94% (one-sided 95% lower bound: −2.14), which exceeded the pre-defined non-inferiority margin of −4%. There were also no significant differences between the two study arms for any of the secondary endpoints. The rate of detection of cardiac dysfunction was 16.3% (16/98) and 12.4% (12/97) in the 3- and 4-monthly arms, respectively (95% CI: 4.0 [−5.9, 13.8]). Conclusions: Cardiac monitoring every 4 months was deemed non-inferior to that every 3 months in patients with HER2-positive EBC being treated with trastuzumab-based therapy. Given its costs and inconvenience, cardiac monitoring every 4 months should be considered standard practice. Registration: NCT02696707, 18 February 2016.

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Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol

Circulation ◽

10.1161/circulationaha.121.054698 ◽

2021 ◽

Author(s):

Siri Lagethon Heck ◽

Albulena Mecinaj ◽

Anne Hansen Ree ◽

Pavel Hoffmann ◽

Jeanette Esther Schulz-Menger ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Cancer Therapy ◽

Cardiac Dysfunction ◽

Breast Cancer Therapy ◽

Double Blind ◽

Double Blind Clinical Trial ◽

Adjuvant Breast Cancer

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Trastuzumab cardiotoxicity: FDA review of four adjuvant breast cancer clinical trials leading to trastuzumab marketing approvals

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e11520 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e11520-e11520

Author(s):

K. Fedenko ◽

P. Cortazar ◽

P. Keegan ◽

R. Pazdur

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Cardiac Failure ◽

Cardiac Dysfunction ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Adjuvant Breast Cancer ◽

Cardiac Medication ◽

B 31

e11520 Background: Trastuzumab can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure (CHF), and decreased left ventricular ejection fraction (LVEF). Methods: Data was reviewed from 9837 patients in four randomized trials (NCCTG 9831, NSABP B-31, HERA, and BCIRG-06) that supported trastuzumab HER2 overexpressing adjuvant breast cancer approval. Results: Trastuzumab can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death. Herceptin can also cause asymptomatic decline in LVEF. There is a 4−6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving trastuzumab as a single agent or in combination therapy compared with those not receiving trastuzumab. The highest absolute incidence occurs when trastuzumab is administered with an anthracycline. Clinical trials NCCTG 9831, NSABP B-31, and BCIRG-06 included arms with doxorubicin- cyclophosphamide (AC) followed by a taxane plus trastuzumab. Among 32 patients receiving adjuvant chemotherapy from studies NCCTG 9831 and NSABP B-31 who developed CHF, one patient died of cardiomyopathy and all other patients were receiving cardiac medication at last follow-up. Approximately half of the patients recovered to a normal LVEF (defined as ≥ 50%) on continuing medical management at the time of last follow-up. In BCIRG-06 the incidence of CHF was six (6) fold higher in the AC followed by docetaxel plus trastuzumab arm as compared to AC followed by docetaxel. There was a lower incidence of CHF in the non-anthracycline TCH (docetaxel, carboplatin and trastuzumab) arm in BCIRG-06 comparable to trastuzumab monotherapy. Conclusions: Cardiotoxicity manifesting as sub-clinical and clinical cardiac failure is a known side effect of trastuzumab. In an era where trastuzumab is given earlier in the treatment of breast cancer (adjuvant setting), the safety of continuation or resumption of trastuzumab in patients with trastuzumab-induced left ventricular cardiac dysfunction has not been studied. No significant financial relationships to disclose.

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