Abstract 17016: Cardiovascular Safety Profile of Gonadotropin Releasing Hormone (GnRH) Antagonist Compared to GnRH Agonist Among Patients With Prostate Cancer: A Meta-Analysis

Introduction: Androgen deprivation therapy (ADT) is the cornerstone of advanced prostate cancer therapy. The degree that ADT contributes to cardiovascular disease remains uncertain with conflicting studies. ADT can be achieved through the use of gonadotrophin releasing (GnRH) hormone agonist or, more recently, GnRH antagonists. The objective of this study was to determine whether cardiovascular events differ after the initiation of GnRH agonist compared with GnRH antagonist in randomized control trials. Methods: From PubMed, Cochrane Central, and Embase we identified all randomized studies comparing GnRH antagonists with GnRH agonists in patients with prostate cancer from 2000-2020. Outcomes studied included major adverse cardiovascular events (MACE), coronary artery disease (CAD), cerebrovascular accidents (CVA), atrial fibrillation (AF), and heart failure (HF). A random effects model using the Mantel-Haenszel method was used to assess outcomes. Results: Overall, we identified 7 studies (n = 3298) which reported outcomes in prostate cancer patients receiving GnRH antagonists (n = 2127) compared with those receiving GnRH agonists (n = 1171). When compared to men receiving GnRH agonists, the incidence of MACE (RR 0.52, 95% CI 0.35-0.76, p<0.001) and CAD (RR 0.46, 95% CI 0.27 - 0.77, p=0.004) was lower in men receiving GnRH antagonists. There was no difference in the rates of CVA (RR 0.93, 95% CI 0.31-2.77, p=0.89), AF (RR 0.49, 95% CI 0.09-2.72, p=0.41), or HF (RR 0.55, 95% CI 0.19-1.59, p=0.52) between the two groups. Conclusion: For men with prostate cancer receiving ADT, GnRH antagonists decreased the incidence of MACE and coronary artery disease by half compared to men treated with GnRH agonists. GnRH antagonists have a more favorable cardiovascular safety profile than GnRH agonists.

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

Circulation ◽

10.1161/circulationaha.121.056810 ◽

2021 ◽

Author(s):

Renato D. Lopes ◽

Celestia S. Higano ◽

Susan F. Slovin ◽

Adam J. Nelson ◽

Robert Bigelow ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Gnrh Agonist ◽

Primary Outcome ◽

Gnrh Antagonist ◽

Locally Advanced ◽

Atherosclerotic Cardiovascular Disease ◽

Cardiovascular Safety ◽

Gnrh Antagonists ◽

Clinical Trial Registration

Background: The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease (ASCVD) remains controversial. Methods: In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant ASCVD were randomized 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (MACE) (composite of death, myocardial infarction, or stroke) through 12 months. Results: Due to slower than projected enrollment and fewer than projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From 3 May 2016 to 16 April 2020, a total of 545 patients from 113 sites across 12 countries were randomized. Baseline characteristics were balanced between study groups. The median age 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 assigned to degarelix and 11 (4.1%) assigned to leuprolide (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.59-2.79; p=0.53). Conclusions: 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 smaller than planned number of participants and events and no difference in MACE at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02663908

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Cardiovascular morbidity in a randomized trial comparing GnRH-agonist and antagonist among patients with advanced prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5015 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5015-5015

Author(s):

David Margel ◽

Avivit Peer ◽

Yaara Ber ◽

Sivan Sela ◽

Liat Shavit Grievink ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Gnrh Agonist ◽

Gnrh Antagonist ◽

Absolute Risk ◽

Absolute Risk Reduction ◽

Cerebrovascular Event ◽

Gnrh Agonists ◽

Open Label ◽

Gnrh Antagonists

5015 Background: Androgen-deprivation therapy (ADT) used in prostate-cancer may increase risk of cardiovascular disease (CVD). Limited preclinical and retrospective clinical data suggest that use of gonadotrophin-releasing hormone (GnRH)-antagonist may be associated with lower risk of CVD compared to GnRH-agonist. Methods: We conducted a randomized open-label study comparing the one year incidence of major cardiovascular and cerebrovascular event (MACCE) in prostate-cancer patients with pre-existing CVD commencing on GnRH-agonists or antagonists. Patients were followed every 3 months for the development of MACCE defined as either death, myocardial infarction (MI), cerebrovascular event (CVA), or percutaneous-coronary intervention (PCI). Serum levels of N-terminal pro-B-type natriuretic peptide (NTproBNP) were analyzed at baseline, 3, 6 and 12-months. Results: Eighty patients were enrolled (41 randomized to GnRH-antagonist, 39 to GnRH-agonist). Patients in both arms had similar age, baseline cardiovascular and prostate-cancer characteristics. During follow-up 15 patients developed a new cardiovascular event. Of these, nine patients developed MACCE (two deaths, one MI, two CVAs, and four PCI). Twenty percent (n = 8) of patients randomized to GnRH-agonists had a MACCE compared to 3% (n = 1) randomized to antagonists (log-rank p = 0.013). The absolute risk reduction for MACCE at 12 months using GnRH-antagonist was 18% (95%CI 5-31). Baseline levels of NTproBNP predicted events (AUC = 0.73 95%CI 0.54-0.91 p = 0.03) and increased over time only among patients with CV events. Conclusions: This is the first prospective study to test cardiovascular outcome among prostate-cancer patients receiving ADT. We demonstrated that in patients with pre-existing CVD, GnRH-antagonists was associated with development of fewer cardiovascular events compared to GnRH-agonists. Clinical trial information: NCT02475057.

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The cardiovascular effects of gonadotropin-releasing hormone antagonists in men with prostate cancer

European Heart Journal - Cardiovascular Pharmacotherapy ◽

10.1093/ehjcvp/pvab005 ◽

2021 ◽

Author(s):

Filipe Cirne ◽

Nazanin Aghel ◽

Jo-Anne Petropoulos ◽

Laurence Klotz ◽

Daniel J Lenihan ◽

...

Keyword(s):

Prostate Cancer ◽

Cardiovascular Events ◽

Gnrh Antagonist ◽

Cardiovascular Effects ◽

Cardiovascular Death ◽

Gonadotropin Releasing Hormone ◽

Gnrh Agonists ◽

Gnrh Antagonists ◽

Releasing Hormone ◽

Gonadotropin Releasing Hormone Antagonists

Abstract Aims The aim of this study was to determine whether gonadotropin-releasing hormone (GnRH) antagonists (an emerging class of drugs to suppress testosterone synthesis in the treatment of prostate cancer) cause less adverse cardiovascular events than the more commonly use GnRH agonists. Methods and results We conducted a systematic review to identify all randomized, controlled trials in which a GnRH antagonist was compared with a GnRH agonist in men with prostate cancer. We identified 10 eligible studies including two different GnRH antagonists, degarelix (n = 1681) and relugolix (n = 734), which were compared with the GnRH agonists, leuprolide (n = 714) and goserelin (n = 600). The pooled risk ratios (95% confidence intervals) among GnRH antagonist recipients for adverse cardiovascular events, cardiovascular death, and all-cause mortality were 0.57 (0.39–0.81); 0.49 (0.25–0.96); and 0.48 (0.28–0.83), respectively. Important limitations of the included trials were their short duration of follow-up, unblinded study design and (in most of the studies) the identification of adverse cardiovascular events through safety reporting mechanisms rather than as a pre-specified outcome. There was no evidence of heterogeneity of findings among the studies. Conclusions There is consistent but methodologically limited data to suggest that GnRH antagonists—a relatively new class of androgen deprivation therapy for prostate cancer—cause significantly less cardiovascular adverse effects than the more frequently used GnRH agonists.

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