Update on cardiovascular and metabolic risk profiles of hormonal agents used in managing advanced prostate cancer

Androgen deprivation therapy (ADT), a mainstay of therapy for advanced prostate cancer (CaP), may raise patients' risk of cardiovascular disease (CVD) and related adverse events. The new androgen receptor (AR)-targeted agents are associated with hypertension and cardiovascular events. The most common non-CaP cause of death in men with CaP is CVD. The purpose of this review is to raise awareness of the metabolic and CV risks of ADT and to encourage proper monitoring of patients treated with hormonal agents.

To review the cardiovascular and metabolic risk profiles of hormonal agents in managing patients with advanced CaP, the author searched PubMed, meeting abstracts, and clinicaltrials.gov from 1941 through early 2020 using search terms such as locally advanced CaP guidelines, gonadotropin-releasing hormone (GnRH) agonist/antagonist, ADT, CaP, CVD, abdominal obesity metabolic syndrome, and cerebrovascular disorder. The author ultimately selected 42 of the most relevant publications for inclusion in this paper.

Data regarding cardiovascular risk in patients with CaP on ADT are inconsistent, though there may be evidence of less risk in GnRH antagonists than GnRH agonists in men with pre-existing CVD. Observational post hoc studies generally show higher risks for GnRH agonists than GnRH antagonists. A review of 6 phase 3 trials found that patients treated with GnRH antagonists had lower cardiovascular risk than those treated with agonists during the first year of ADT, and these differences were especially significant among men with pre-existing CVD. Additionally, a small prospective randomized phase 2 study, as well as a large phase 3 trial, showed that there were significantly more major adverse cardiovascular events in patients treated with a GnRH agonist compared to a GnRH antagonist. In addition, the AR-targeted agents in conjunction with ADT have been shown to have more hypertension and/or cardiovascular risk than ADT plus placebo in numerous phase 3 trials.

Whether there is a difference in CVD risk between GnRH agonists and antagonists is the subject of an ongoing phase 3 trial with cardiovascular endpoints. Addition of newer AR-targeted agents may confer additional risk over ADT alone. Clinicians treating advanced CaP should be aware of underlying comorbidities of their patients before choosing either conventional ADT or adding AR-targeted agents. Physicians should monitor patients for hypertension, diabetes, and cardiovascular side effects that may require intervention in order to minimize downstream adverse events and should communicate with other colleagues on the patient's health care team to ensure the best outcomes.