LAUSR

Since the early 1980s, androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonist or antagonist therapies has remained the primary systemic therapy for men with prostate cancer, owing to the fundamental reliance of the disease on oncogenic androgen signaling. While the intense androgen suppression achieved with ADT imparts near-universal initial therapeutic response in prostate cancer, it is also associated with numerous adverse cardiometabolic health consequences.1 In particular, GnRH agonist therapies have carried an advisory from the US Food and Drug Administration, warning of increased treatment-related cardiovascular risks, including myocardial infarction, stroke, and sudden cardiac death. However, risk differences related to ADT treatment selection may exist, as several retrospective studies have suggested an improved cardiovascular risk profile with GnRH antagonist therapies compared with GnRH agonist approaches. A 2020 large phase 3 randomized trial further indicated similar potential cardioprotective benefit with GnRH antagonist therapies, particularly in those patients with underlying cardiovascular disease history.2 Until recently, however, no prospective studies directly comparing the cardiovascular risks of GnRH agonist vs antagonist therapies as a primary end point have been published, and the relative cardiovascular safety of GnRH antagonist vs agonist therapies remains unresolved and a topic of clinical interest in contemporary prostate cancer management. Wallach and coauthors3 report results from a retrospective study comparing the cardiovascular safety of GnRH antagonist (degarelix) vs agonist (leuprolide) therapy using a data set of individuals with commercial insurance and Medicare Advantage beneficiaries. Importantly, the study population and clinical outcomes of interest, derived from this real-world data set, were selected to emulate the Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease (PRONOUNCE)—a randomized phase 3b clinical trial comparing the cardiovascular safety of degarelix vs leuprolide as a prespecified and centrally adjudicated primary end point in men with prostate cancer and underlying atherosclerotic cardiovascular disease (NCT02663908).4 At the time of this real-world data set analysis, the primary study results from PRONOUNCE were not yet published, and the authors therefore sought to estimate clinical outcomes from an ongoing and unreported randomized clinical trial. Among 2226 propensity score–matched patients, Wallach and authors3 reported no significant difference in the risk of major adverse cardiovascular events for patients initiating degarelix when compared with patients initiating leuprolide (10.18 vs 8.60 events per 100 person-years; hazard ratio [HR], 1.18; 95% CI, 0.86-1.61). Moreover, while degarelix was associated with a higher risk of any-cause death (HR, 1.48; 95% CI, 1.01-2.18), it was not associated with increased risk of myocardial infarction (HR, 1.16; 95% CI, 0.60-2.25), stroke (HR, 0.92; 95% CI, 0.45-1.85), or angina (HR, 1.36; 95% CI, 0.43-4.27). The authors’ selection of the PRONOUNCE study represents a compelling application of this novel methodologic approach. Indeed, several aspects of this international randomized trial lend nicely to a real-world data comparative analysis. First, neither leuprolide nor degarelix is a novel therapeutic, and both are commonly used in routine clinical practice. Second, while the prospective randomized PRONOUNCE trial represents the criterion standard of comparative evidence, the actual conduct of the study was unfortunately plagued by restrictive patient eligibility, truncated projected enrollment, and potential loss of power to address the clinical end points of interest. (While 900 + Related article