Reviewer: Dr. Murat ÇAP

Name of the study: Cardiovascular Safety of Degarelix versus Leuprolide in Patients with Prostate Cancer: The Primary Results of the PRONOUNCE Randomized Trial

Published Congress: ESC 2021

Link: https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.121.056810

Background:

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of non-cancer death in patients with prostate cancer. Androjen deprivation therapy (ADT) by orchiectomy or medical therapy has been a cornerstone of treatment for patients with advanced prostate cancer for decades. Both GnRH agonists and antagonists inhibit testosterone production by inhibiting luteinizing hormone secretion through gonadotropin-releasing hormone-receptor (GnRH)-mediated mechanisms. It has been shown in previous studies that the use of ADT is associated with higher cardiovascular morbidity and mortality in patients with prostate cancer and pre-existing ASCVD. The relative cardiovascular safety of GnRH antagonists compared to GnRH agonists is controversial.

Objective:

The PRONOUNCE study aims to compare the effect of degarelix, a GnRH antagonist, and leuprolide, a GnRH agonist, on the development of major adverse cardiovascular events (MACE) over 12 months in patients with prostate cancer and pre-existing ASCVD.

Methods:

PRONOUNCE trial was an international, multicenter, prospective, randomized, open-label trial with blinded endpoint adjudication comparing the effect of the GnRH antagonist, degarelix, with the GnRH agonist, leuprolide, on adjudicated MACE in patients with prostate cancer and concomitant ASCVD. The primary outcome was the time to first adjudicated major adverse cardiovascular event (MACE) (composite of death, myocardial  infarction, or stroke) through 12 months. Key secondary outcomes were the time to the first occurrence of cardiovascular-related death, nonfatal MI, or nonfatal stroke.

Results:

The study was discontinued without the inclusion of the planned of 900 enrollment participants due to slower than predicted recruitment and fewer primary outcome events than predicted. From 3 May 2016 to 16 April 2020, a total of 545 patients from 113 sites in 12 countries were randomly assigned to receive open-label degarelix or leuprolide. The median age in the study population was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease and 20.4% had metastatic disease. MACE occurred in 15 (5.5%) patients in the degarelix group and 11 (4.1%) patients in the leuprolide group ([HR] 1.28, 95% [CI] 0.59-2.79; p=0.53). Overall, there were few secondary outcome events. The composite outcome of cardiovascular death, non-fatal MI, or non-fatal stroke occurred in 9 patients in the degarelix group and 7 patients in the leuprolide group (HR 1.20, 95% CI 0.45-3.23). Disease progression occurred in 24 patients given degarelix and 27 patients given leuprolide (HR 0.89, 95% CI 0.51–1.54).

Conclusion:

PRONOUNCE is the first international randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely due to fewer participants and events than planned, and no difference in MACE at 1 year was observed between patients given degarelix or leuprolide. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved.

Interpretation:

Although the Pronounce Study was terminated early and patient number was low, it did not resolve the effect of GnRH agonists and antagonists on cardiovascular events, but provided a model for interdisciplinary collaboration among urologists, oncologists, and cardiologists with the common goal of evaluating the impact of cancer treatments on ccardiovascular outcomes.