Cardiovascular Safety of Degarelix Versus Leuprolide for Advanced Prostate Cancer: The PRONOUNCE Trial Study Design

Chiara Melloni, Susan F Slovin, Allan Blemings, Shaun G Goodman, Christopher P Evans, Jan Nilsson, Deepak L Bhatt, Konstantin Zubovskiy, Tine K Olesen, Klaus Dugi, Noel W Clarke, Celestia S Higano, Matthew T Roe, PRONOUNCE Investigators, Chiara Melloni, Susan F Slovin, Allan Blemings, Shaun G Goodman, Christopher P Evans, Jan Nilsson, Deepak L Bhatt, Konstantin Zubovskiy, Tine K Olesen, Klaus Dugi, Noel W Clarke, Celestia S Higano, Matthew T Roe, PRONOUNCE Investigators

Abstract

Objectives: This study will compare the incidence of major adverse cardiovascular events (MACEs) with androgen deprivation therapy (ADT) among men with advanced prostate cancer who are being treated with a gonadotropin-releasing hormone (GnRH) antagonist versus a GnRH agonist.

Background: Treatment of advanced prostate cancer with ADT might increase the risk of subsequent cardiovascular events among men with known atherosclerotic cardiovascular disease (ASCVD), but a recent meta-analysis suggested that this risk might be lower with ADT using a GnRH antagonist versus a GnRH agonist.

Methods: PRONOUNCE is a multicenter, prospective, randomized, open, blinded endpoint trial that will enroll approximately 900 patients with advanced prostate cancer and pre-existing ASCVD who will be treated with ADT. Participants will be randomized to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide as ADT for 12 months. The primary endpoint is time from randomization to first confirmed, adjudicated occurrence of a MACE, which is defined as a composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke through 12 months of ADT treatment. Baseline cardiovascular biomarkers (high-sensitivity C-reactive protein, high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide), as well as serial inflammatory and immune biomarkers, will be evaluated in exploratory analyses.

Results: As of October 1, 2019, a total of 364 patients have been enrolled. The mean age is 74 years, 90% are white, 80% have hypertension or dyslipidemia, 30% diabetes mellitus, 40% have had a previous myocardial infarction, and 65% have had previous revascularization. Regarding prostate cancer features at randomization, 48% of the patients had localized disease, 23% had locally advanced disease, and 18% had metastatic disease.

Conclusions: PRONOUNCE is the first prospective cardiovascular outcomes trial in advanced prostate cancer that will delineate whether the risk of subsequent cardiovascular events associated with ADT is lower with a GnRH antagonist versus a GnRH agonist for men with pre-existing ASCVD. (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease [PRONOUNCE]; NCT02663908).

Keywords: ADT, androgen deprivation therapy; ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; DSMB, Data Safety Monitoring Board; GnRH, gonadotropin-releasing hormone; MACE, major adverse cardiovascular event; cardiovascular safety; outcomes; prostate cancer.

© 2020 The Authors.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Mechanism of Action Mechanism of action of GnRH agonist and antagonist. FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone.
Figure 2
Figure 2
Trial Design The trial design, from the initial screening period through treatment and/or follow-up, and the end of the trial. CVD = cardiovascular disease; i.m. = intramuscularly; MACE = major adverse cardiovascular event; s.c. = subcutaneously.
Central Illustration
Central Illustration
PRONOUNCE Study Population, Allocation, Follow-Up, and Analysis The study population for the PRONOUNCE trial for initial inclusion, allocation, follow-up, and analysis. ASCVD = atherosclerotic cardiovascular disease; GnRH = gonadotropin-releasing hormone; MACE = major adverse cardiovascular event.

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