In 2010, the United States Food and Drug Administration (FDA) issued a warning that gonadotropin-releasing hormone (GnRH) agonists may increase the risk for cardiovascular disease. While this led to many retrospective studies, editorials, and guideline statements, there was a lack of high-level evidence to guide the management of the potential cardiovascular toxicity of these agents. Added to this was the question as to whether GnRH antagonists have a safer cardiovascular toxicity profile than GnRH agonists. This discussion was reinvigorated in 2020 by the HERO trial, which reported a lower incidence of major adverse cardiovascular events (MACE) with relugolix, an oral GnRH antagonist, than leuprolide [1]. Soon thereafter, the PRONOUNCE trial, whose primary endpoint was adjudicated occurrence of MACE in men treated with the GnRH antagonist degarelix verse leuprolide, was stopped early due to the low number of MACE events at 1 year raising skepticism amongst many clinicians regarding the clinical significance of cardiovascular events with either GnRH analogs or antagonists given their low incidence and advanced age of men with prostate cancer [2]. Nonetheless, Dr. Pinthus and Dr. Duivenvooden cite several lines of evidence supporting the argument that GnRH antagonists are associated with a lower incidence of cardiovascular events than GnRH agonists [3]. A persuasive part of this argument is their prior translational study showing that the FSH to testosterone ratio after introduction of androgen deprivation therapy (ADT) is associated with cardiovascular events [4]. Yet, the challenges associated with their use (monthly subcutaneous injection of degarelix and costs of relugolix) are key barriers to the uptake of GnRH antagonist therapies, in the absence of adjudicated, high-level evidence supporting a cardiovascular (or other) benefit. Additionally, GnRH agonists or antagonists are now typically given with an androgen receptor signaling inhibitor (ARSI) that have their own additional cardiovascular toxicity and may negate the potential cardiovascular benefit of a GnRH antagonist.

The manuscript by Dr. Pinthus and Dr. Duivenvooden raises an important question: should an infrequent event that may be mitigated by preventive care change how we select ADT for most men with advanced prostate cancer? Men with advanced prostate cancer have a high burden of cardiovascular risk factors, and ~25% of men with metastatic prostate cancer die from non-cancer related conditions with most being cardiovascular events [5, 6]. Despite the favorable long-term prognosis of prostate cancer, busy clinicians often do not have bandwidth to address co-morbidities and/or silent adverse effects of ADT. In a study from the Veterans Health Administration, over half of men initiating ADT had uncontrolled cardiovascular risk factors [7]. Thus, we face a challenging scenario where many men with cardiovascular risk factors receive ADT in overwhelmed healthcare systems. Do we change to oral GnRH antagonists for everyone or implement systemic changes that ensure cardiovascular risk factors are actively managed for men on ADT? In our opinion, this problem highlights the need to shift the focus of precision medicine from addressing solely the determinants of anti-cancer efficacy to also accounting for toxicity in order to prospectively identify at-risk individuals.

Typically, the discussion about cardiovascular health for men with prostate cancer focuses on how we administer hormone therapy. Rather, clinicians and patients would be better served by an improved understanding of competing cardiovascular risk with hormone therapy and identification of at-risk individuals prior to initiation of and during treatment. Infrequently, clinicians attempt to actively monitor cardiovascular risk for men on hormone therapy using available tools, such as the Pooled Cohort Equation to estimate 10-year primary risk of atherosclerotic cardiovascular disease (ASCVD) [8]. However, the tools to estimate ASCVD were designed for the general population, whereas men receiving ADT for prostate cancer are a refined cohort with unique risk factors and competing health risks unaccounted for by these risk models. Our group is exploring the biology underlying the shared vulnerability to prostate cancer and cardiovascular disease observed in a subset of men under a conceptual framework called the “overlap syndrome.” [9] Indeed men with prostate cancer may have unique susceptibilities, are living longer and are exposed to more intensive systemic therapy earlier in their disease course, leading to an urgent need to identify these at-risk individuals utilizing advanced risk models. To accomplish this, novel tools that identify and monitor the cardiovascular risk for men receiving hormone therapy are needed, and there is early research investigating non-invasive imaging measures, such as coronary microvascular dysfunction, fat attenuation index, or coronary calcium scores for this purpose. Since MACE often occurs after a prolonged latency period from ADT initiation, novel tools that reflect early cardiovascular toxicity may be the most impactful for monitoring and identifying potential toxicity.

In sum, there may be compelling clinical indications to use GnRH antagonists in men at high-risk for MACE, but it is unknown whether that might also be the case for the majority of men who are not at high-risk for MACE. Prostate cancer is the model disease to expand the scope of precision medicine to account for toxicities of treatment in order to meaningfully improve survival.