Cardiovascular Toxicity During Advanced Prostate Cancer Treatment

Corresponding Author

Despite some heterogeneity in the literature, there is overall consensus that androgen deprivation therapy (ADT), most commonly using luteinizing hormone-release hormone (LHRH) analogues, is associated with negative metabolic consequences and increased cardiovascular morbidity/mortality.¹ Urologists and oncologists, whose primary focus is ensuring patients do not succumb to prostate cancer itself, acknowledge that the elevated risk of cardiovascular morbidity may be a necessary compromise. However, it is undoubtedly preferable to simultaneously avoid adverse outcomes due to cardiovascular causes. Thus, the development of LHRH antagonist therapies, with apparently greater cardiovascular safety, represented an important advance in the treatment of prostate cancer.² However, questions have remained regarding the validity of early analyses,³ because the studies were not specifically designed to examine cardiovascular outcomes.

In this issue of JACC: CardioOncology, Nelson et al⁴ review the cardiovascular risk from contemporary studies of LHRH agonists vs antagonists to provide greater confidence in the differential cardiovascular safety of these agents. With a pooled odds ratio of 0.57 derived from an analysis of 4,248 patients, this analysis supports the assertion that LHRH antagonists are associated with a lower rate of cardiovascular events including myocardial infarction, cerebrovascular accident, and death particularly in patients with pre-existing cardiovascular disease (CVD).

As the investigators point out, the mechanism by which LHRH therapy may contribute to cardiovascular risk remains incompletely defined and may be different in the short term (testosterone/follicle stimulating hormone surge) vs during long-term treatment (metabolic syndrome and atherosclerosis).⁵ The analysis was limited to short-term therapy with median ADT duration of the included trials being 12 months. It is possible different results would be seen in patients receiving long-term ADT if the deeper testosterone suppression achieved by LHRH antagonists⁶ would translate into more significant metabolic disruption. However, the differences seen in this analysis speak to the fact that even when short-term use of ADT is planned, cardiovascular morbidity should be considered. Reassuringly, the incidence of overall major adverse cardiovascular events (MACE) was relatively low, at 4.8% in agonist-treated patients and 2.9% in antagonist-treated patients. However, it is important to consider a recent study that reported a 2.1% rate of 1-year MACE among patients without known prostate cancer, but with established atherosclerotic disease (mean age 69 years) and 1.1% among patients with multiple cardiovascular risk factors.⁷ These findings suggest that the event rates among prostate cancer patients on ADT may indeed be elevated, compared with noncancer patients with pre-existing CVD. Therefore, although the benefits of cancer control with ADT often outweigh the associated cardiovascular risk, prostate cancer patients being considered for ADT, in particular those with those with pre-existing CVD or CVD risk factors, should be closely monitored with parallel efforts to optimize their cardiovascular risk.

A limitation of the analysis is the shifting landscape in prostate cancer therapeutics toward greater usage of doublet therapy with agents such as androgen synthesis inhibitor (eg, abiraterone) or androgen receptor antagonists (apalutamide, darolutamide, and enzalutamide). The differential cardiovascular morbidity of the LHRH component may become less significant if there are added cardiovascular toxicities from the partner agents. Although data on this topic are limited, existing evidence suggests a heightened risk of cardiovascular events, including hypertension, associated with abiraterone as well as androgen receptor-targeted agents.8, 9, 10 There are also more drug–drug interactions involving cardiovascular medications including direct oral anticoagulants, antiarrhythmics, and even antihypertensive agents. Thus, it is crucial to foster closer collaboration between cardiologists and prostate cancer specialists to minimize what may be preventable cardiovascular events related to drug–drug interactions.

It is important to call attention to the concern that the lack of equitable access to LHRH antagonists may exacerbate health disparities. A retrospective analysis of a Southern California population found that cost was a significant barrier to use of relugolix in both Medicare and privately insured patients.¹¹ If insurers refuse to cover relugolix, which offers flexibility in the clinic visit schedule given its oral formulation, working patients may find the monthly degarelix injection schedule a barrier in terms of time off work, whereas LHRH agonists can be administered with a 3-, 4-, or 6-month depot formulation. Additionally, considering the relatively recent Food and Drug Administration approval of relugolix, the information regarding the potential differences between LHRH agonists and antagonists in terms of cardiovascular outcomes may not have penetrated into all oncology and urology practices. This knowledge gap can contribute to further disparities in the care of those on ADT. Thus, dedicated efforts should be made to enhance physician education and dissemination of up-to-date information regarding the cardiovascular risks and benefits associated with different LHRH therapies.¹² Furthermore, studies are warranted to assess the practice patterns and barriers to accessibility of LHRH antagonists, especially to patients with elevated cardiovascular risk, which may be enriched for underserved populations.

It is also important to emphasize that the availability of a less cardiotoxic treatment option (eg, LHRH antagonists) does not exempt oncologists and urologists from devoting attention to cardiovascular risk when treating prostate cancer patients. Regular monitoring of blood pressure, lipid panels, fasting glucose levels, and weight changes are still essential and should be done ideally in collaboration with primary care or appropriate specialists. Additionally, appropriate pharmaceutical and lifestyle strategies to mitigate adverse cardiometabolic consequences should be implemented.¹³ As noted by the investigators, there was greater medication prescription for lipid and blood pressure management in PRONOUNCE (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease), in which cardiology consultation was mandatory for each patient, than in other ADT studies. Regardless of the use of LHRH agonist or antagonist therapy, there should be consistent attention to these parameters,¹⁴ and we therefore call for increased educational efforts and patient-empowering innovations to promote comprehensive care of prostate cancer patients receiving ADT.

Finally, although population-based retrospective studies and ad hoc analyses of available clinical trial results such as this work offer valuable insights into the cardiovascular impact of ADT, there is a need for prospective studies and/or randomized trials that specifically examine how contemporary approaches (eg, doublet therapy) influence cardiovascular outcomes. One ongoing study, REPLACE-CV (Randomized Study to Evaluate MACE in Patients With Prostate Cancer Treated With Relugolix or Leuprolide Acetate; NCT05605964) will randomize 2,250 patients with prostate cancer to relugolix or leuprolide, while allowing additional standard treatments, and should provide definitive data given the design with a rigorous, blinded adjudication of MACE by an independent clinical event adjudication committee. Additionally, it would be essential to examine how pre-existing cardiovascular risk factors influence outcomes when undergoing various ADT treatments and, ideally, when there is a standardized approach to risk management. Such studies can enhance our understanding of the cardiovascular implications of different ADT regimens and lead to the development of optimized strategies for identifying and mitigating cardiovascular risks in patients because, for the foreseeable future, ADT will continue to play a crucial role in the treatment of prostate cancer.

Funding Support and Author Disclosures

Dr Dorff has been a consultant for Astellas, AstraZeneca, Bayer, Janssen, and Sanofi. Dr Rhee has received research funding from Pfizer unrelated to the work.