A multicenter, randomized, controlled trial comparing the occurrence of major adverse cardiovascular events (MACEs) in patients (pts) with prostate cancer (pc) and cardiovascular disease (CVD) receiving degarelix (GnRH receptor antagonist) or leuprolide (GnRH receptor agonist).

Abstract

TPS395 Background: Epidemiological studies showed an association between GnRH agonists and a long-term increased risk of CVD, early after treatment initiation and with a higher risk seen in pts with pre-existing CVD. Retrospective pooled safety analyses of 6 randomized trials showed that significantly fewer pts treated with the GnRH receptor antagonists, degarelix, had a CV event or death compared with pts receiving a GnRH receptor agonist. In those studies showing an increased CV risk, Androgen-Deprivation Therapy (ADT) was primarily with GnRH receptor agonists. The mechanistic differences between GnRH antagonists and agonists, including testosterone surge and time to suppression at initiation, effect on follicle-stimulating hormone and on GnRH receptors e.g. T-lymphocytes in atherosclerotic plaque, raises the possibility of different CV risk profiles. The PRONOUNCE trial is the first to prospectively assess whether a GnRH agonist/antagonist can worsen pre-existing CVD; assess the impact of GnRH agonist/antagonist on CV risk biomarkers; and effects of hormonal therapy on immune system. Methods: PRONOUNCE is a multi-center, randomized, controlled trial of 900 men with pc and concomitant CVD, assessing adjudicated MACEs, i.e. myocardial infarction (fatal, non-fatal), stroke (fatal, non-fatal), or death in pts randomized 1:1 to either degarelix or leuprolide according to label recommendations for up to one year. Eligibility include pre-defined CVD, metastatic or locally advanced pc; high-risk disease with plan for definitive radiation therapy (RT); recurrence after local therapy with PSA doubling time <12 months; or salvage RT with neoadjuvant/adjuvant ADT for at least 12 months. Serum samples are collected for the analysis of various CV, inflammatory, and immune biomarkers. The primary endpoint will be based on Kaplan-Meier estimator of survival function and stratified for age group and region. Interim analysis is scheduled when 50% of MACE events have occurred allowing the DSMB to recommend for sample size correction. Clinical trial information: NCT02663908.

Association between medical androgen deprivation therapy and long‐term cardiovascular disease and all‐cause mortality in nonmetastatic prostate cancer

“…Results are currently awaited from the PRO-NOUNCE trial, a large randomised trial of 545 people evaluating major cardiovascular events between LHRH agonist vs antagonist treated patients. 50 To summarise, in this unique study using registry-based data, there is evidence of an association between ADT for nonmetastatic PCa and a higher risk of CVD events, especially in those with some CVD risk factors present at the time of their diagnosis and longer duration of treatment. We also found higher all-cause mortality among patients receiving ADT.…”

“…These findings need further investigation but could offer a biomarker for clinicians to identify patients more suitable for treatment with an LHRH antagonist. Results are currently awaited from the PRONOUNCE trial, a large randomised trial of 545 people evaluating major cardiovascular events between LHRH agonist vs antagonist treated patients 50 …”