Cardiovascular risks of androgen receptor targeted agents in prostate cancer: a systematic review and meta-analysis “PCAN-23-0763R”

Summary

The androgen receptor targeted agents (ARTA) typically used in prostate cancer treatment include:

1. Abiraterone
2. Enzalutamide
3. Apalutamide
4. Darolutamide
5. Orteronel

The article mentions that these were the ARTA agents used in the studies included in the systematic review and meta-analysis conducted by Ong et al. It's worth noting that these agents are often used in combination with androgen deprivation therapy (ADT) for the treatment of metastatic prostate cancer.

The article also points out that in many countries, including the author's, the use of an ARTA in combination with either an LHRH (luteinizing hormone-releasing hormone) agonist or antagonist has received Medicare funding for patients with metastatic prostate cancer. This is due to the observed benefits in long-term prostate cancer-specific survival and freedom from progressive disease.

Each of these agents may have different risk profiles and efficacy, but the article suggests that more research is needed to definitively determine which ARTA might be safest in terms of cardiac risk.

This article is a commentary on a systematic review and meta-analysis conducted by Ong et al. regarding the cardiovascular risks associated with androgen receptor targeted agents (ARTA) in prostate cancer treatment. Here are the key points:

1. The meta-analysis found that using ARTA in prostate cancer treatment increases the incidence of cardiac-related adverse events.

2. Specific findings include:
   - 69% increased risk of hypertension
   - 143% increased risk of hypertensive crisis
   - 84% increased risk of ischemic heart disease events
   - 38% increased risk of arrhythmia

3. Despite these increased risks, ARTA did not significantly increase the incidence of cardiac arrests or deaths.

4. The authors note that the mechanisms of interaction between hormonal agents and the cardiovascular system are complex and multifaceted.

5. The commentary highlights the need for cardiac assessment before starting ARTA treatment, especially for patients with known cardiac history.

6. It's noted that real-world data may differ from clinical trials due to more restrictive selection criteria in trials.

7. The article concludes by emphasizing the need for more research to identify at-risk groups and provide better guidance for clinicians on managing cardiovascular risks in prostate cancer patients treated with ARTA.

8. The commentary also mentions that the meta-analysis couldn't provide robust information about which ARTA is safest in terms of cardiac risk, due to limited studies and the novelty of some drugs.

This summary provides an overview of the key findings and implications discussed in the article regarding the cardiovascular risks associated with ARTA in prostate cancer treatment.

Q&A

As a patient undergoing ARTA treatment for metastatic prostate cancer, you should consider asking your oncologist the following questions:

1. What is my individual cardiovascular risk profile?
Expected answer: Your oncologist should discuss your personal risk factors, including age, existing cardiac conditions, blood pressure, cholesterol levels, and other relevant medical history.

2. Should I undergo a cardiac assessment before starting ARTA treatment?
Expected answer: Based on the article, your oncologist might recommend a baseline cardiovascular risk assessment, especially if you have a known cardiac history or risk factors.

3. Which ARTA are you recommending for me, and why?
Expected answer: Your oncologist should explain the choice of specific ARTA (e.g., abiraterone, enzalutamide) based on your cancer characteristics and overall health status.

4. What cardiac-related side effects should I watch for during treatment?
Expected answer: They should mention potential symptoms of hypertension, ischemic heart disease, and arrhythmias, providing specific signs to be aware of.

5. How will my cardiac health be monitored during treatment?
Expected answer: Your oncologist should outline a plan for regular monitoring, which may include blood pressure checks and periodic cardiac evaluations.

6. Should I see a cardiologist before or during my ARTA treatment?
Expected answer: If you have existing cardiac issues or significant risk factors, your oncologist might recommend a cardiology consultation.

Regarding coordination of care:

1. Multidisciplinary approach: Your prostate cancer therapy should ideally be coordinated among your oncologist, urologist, cardiologist (if needed), and primary care physician. This ensures comprehensive care that addresses both your cancer treatment and overall health.

2. Shared decision-making: Treatment decisions should involve input from all relevant specialists. For example, your cardiologist might provide recommendations on managing cardiovascular risks while undergoing ARTA treatment.

3. Regular communication: Ensure there's a system in place for your various healthcare providers to communicate about your treatment progress and any emerging issues.

4. Proactive management: Your care team should work together to optimize your cardiovascular health before and during ARTA treatment. This might involve adjusting medications, lifestyle modifications, or closer monitoring.

5. Patient-centered care: You should be kept informed and involved in all decisions, with clear explanations of the risks and benefits of different treatment options.

6. Follow-up plan: There should be a clear plan for follow-up appointments with all relevant specialists to monitor both your cancer progression and overall health status.

Remember, the goal is to balance effective cancer treatment with maintaining your overall health and quality of life. Don't hesitate to ask for clarification or express any concerns to your healthcare team.

Ong et al. have performed a systematic review of 24 randomised control trials involving 22,624 patients, with the aim to identify any difference in the incidence of cardiac-related adverse events after treatment of prostate cancer with androgen receptor targeted agents (ARTA) and androgen deprivation therapy (ADT) versus placebo and ADT [1]. The ARTA used in the studies were abiraterone, enzalutamide, apalutamide, darolutamide, and orteronel. In my country, like other nations, the use of an ARTA in combination with either an LHRH agonist/antagonist, has obtained Medicare funding in patients with metastatic prostate cancer, in view of the benefit in long term prostate cancer specific survival and freedom from progressive disease. Therefore, the results of this meta-analysis will be very important to clinicians treating advanced prostate cancer.

Ong et al. found the use of ARTA in prostate cancer increases the incidence of cardiac-related adverse events (RR: 1.56, 172 95% CI: 1.29–1.90, p < 0.00001). The risk of hypertension following ARTA increases by 69% and hypertensive crisis by 143%, with the highest risk in the enzalutamide group. Ischaemic heart disease adverse events, defined as acute coronary syndrome, acute myocardial infarction, myocardial ischemia, coronary artery disease, coronary artery stenosis, chest pain, and angina were increased (RR: 1.84, 95% CI: 1.36–2.50, p < 0.0001), with subset analysis identifying increased risks with Abiraterone, enzalutamide and darolutamide. Arrhythmia risk increase by 38%, possibly by the loss of testosterone protective effect against ventricular arrhythmias by decreasing the action potential duration. Sub-group analysis identified the increased risk with abiraterone and orteronel. Abiraterone mineralocorticoid activity may explain the increased arrhythmia events. As discussed by the authors, although not a direct comparison, the increased risk of cardiovascular disease with abiraterone compared to enzalutamide could be due to the addition of prednisolone when prescribing abiraterone. ARTA did not appear to statistically increase the risk of cardiac failure, valvular disease, or pericardial disease. Reassuringly, despite the increased cardiac-related adverse events, ARTA did not increase the incidence of cardiac arrests/deaths (RR: 1.28, 95% CI: 0.87–1.88, p = 0.21). As the authors point out, the mechanisms of interactions between hormonal agents and the cardiovascular system are likely multi-faceted and complex. It must be noted that thromboembolic events or transient ischemic attacks were not classified as cardiac-related adverse events and not included among the outcomes.

In this meta-analysis some studies were considered by the authors at risk of bias. It is therefore pleasing that a subset analysis was performed of the 15 studies considered at low risk of bias. This sub-group analysis did not identify a major difference compared to the overall results, although some results were not statistically significant. This included the subset analysis for arrhythmia, abiraterone for hypertension and hypertensive crisis, ischaemic heart disease, arrhythmia and cardiac failure, subgroup analysis of enzalutamide for a total number of cardiac events and subgroup analysis of orteronel for hypertension.

Other factors can influence the risk of cardiovascular adverse events in androgen suppression of prostate cancer, including the different forms of ADT. Real world data has shown a decreased risk in cardiovascular adverse events with GnRH antagonists, compared to GnRH agonists [2, 3]. The PRONOUNCE randomised clinical trial [4] did not identify a difference in major adverse cardiovascular events at 1 year between patients assigned to the GnRH antagonist degarelix or the GnRH agonist leuprolide. However, the trial was terminated prematurely, resulting in wide confidence intervals and low statistical power. Therefore, the relative cardiovascular safety of GnRH antagonists compared to agonists remains unresolved. Hence, it is possible some of the results in ARTA randomised controlled trials may be influenced by the form of ADT used, above the influence of the ARTA agent alone.

The Ong et al. meta-analysis cannot give any robust information about the best ARTA in terms of cardiac safety. They have relied on multiple subgroup analyses, but due to the limited number of studies and the novelty of certain ARTA drugs that have not been in the market long enough, most results were not statistically significant. It must be acknowledged that other publications have identified a lower cardiovascular risk with enzalutamide as compared to abiraterone [5]. Data from level 1 clinical trials do not always provide adequate information on risks in a real-world setting. The differences between the results of clinical trials and outcomes in real-life clinical practice may be explained by the restrictive selection criteria of RCTs, such as good prognosis and minimal comorbidities [6]. De Nunzio et al identified that both enzalutamide and abiraterone have a low and similar risk of death from any adverse event (~ 4%) and commented that while both agents can be safely prescribed in elderly patients, those older than 85 treated with Abiraterone presented an 80–90% increased risk of cardiac disorders, compared to patients younger than 65 years [6].

The obvious question for clinicians is which patient to send for cardiac assessment prior to commencing an ARTA? This meta-analysis is unable to provide clinician guidance on this question, including whether patients with no cardiac history are at a decreased risk of a cardiac event compared to patients with a known cardiac history. Cardiology and oncology professional society guidelines and expert position statements on CVD in cancer patients uniformly recommend baseline CV risk assessment for oncology patients scheduled to receive potentially cardiotoxic cancer therapies, including ADT [7]. Given the increased risk of cardiac related adverse events after commencing an ARTA, it would seem pertinent that patients with a known cardiac history are referred to their cardiologist to optimise cardiac status before or soon after commencing an ARTA. For patients without a cardiac history, triggers such as incidental finding of coronary artery calcification on staging PSMA-PET/CT scan, known high blood pressure, smoking history, diabetes or abnormally high cholesterol levels could also trigger cardiac referral. Until research clinicians provide more information on the at-risk group, asymptomatic patients will need to be informed of the increased risk of adverse cardiac events after commencing an ARTA.

References

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Authors and Affiliations

Wesley Urology Clinic, Brisbane, QLD, Australia
J. W. Yaxley
University of Queensland, Brisbane, QLD, Australia
J. W. Yaxley
Advara HeartCare, Wesley Hospital, Brisbane, QLD, Australia
B. Fitzgerald

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Yaxley, J.W., Fitzgerald, B. Cardiovascular risks of androgen receptor targeted agents in prostate cancer: a systematic review and meta-analysis “PCAN-23-0763R”. Prostate Cancer Prostatic Dis (2024). https://doi.org/10.1038/s41391-024-00873-5

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Received: 24 March 2024
Revised: 04 July 2024
Accepted: 10 July 2024
Published: 29 July 2024
DOI: https://doi.org/10.1038/s41391-024-00873-5

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Abstract

Androgen deprivation therapy is a cornerstone of prostate cancer treatment. Pharmacological androgen deprivation includes gonadotropin-releasing hormone agonism and antagonism, androgen receptor inhibition, and CYP17 (cytochrome P450 17A1) inhibition. Studies in the past decade have raised concerns about the potential for androgen deprivation therapy to increase the risk of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular mortality, possibly by exacerbating cardiovascular risk factors. In this review, we summarize existing data on the cardiovascular effects of androgen deprivation therapy. Among the therapies, abiraterone stands out for increasing risk of cardiac events in meta-analyses of both randomized controlled trials and observational studies. We find a divergence between observational studies, which show consistent positive associations between androgen deprivation therapy use and cardiovascular disease, and randomized controlled trials, which do not show these associations reproducibly.

Highlights

•

As a pooled group, androgen deprivation therapy had positive associations (although not always significant) with cardiovascular events, cardiovascular death, and myocardial infarction among the 3 meta-analyses of observational studies but among none of the 3 meta-analyses of randomized controlled trials.

•

Gonadotropin-releasing hormone agonists had strong positive associations with cardiovascular death, cardiovascular disease, myocardial infarction, and stroke, among the 3 meta-analyses of observational trials.

•

Gonadotropin-releasing hormone antagonists had mixed associations with cardiovascular disease and myocardial infarction and no associations with cardiovascular death and stroke, among the 3 meta-analyses of observational studies.

•

Combined androgen blockade had positive associations with cardiovascular death, cardiovascular disease, and stroke, among 2 meta-analyses of observational studies.

•

CYP17 inhibitors had positive associations with cardiovascular events and hypertension, among 2 meta-analyses of randomized controlled trials.

Introduction

Prostate cancer (PCa) is the second most common cancer in men, with an estimated incidence of 1 276 000 cases and 359 000 deaths globally in 2018.¹ In the United States, 174 650 new cases and 31 620 deaths are projected to have occurred in 2019.² The cornerstone of systemic treatment for PCa is pharmacological or surgical androgen deprivation therapy (ADT). Pharmacological ADT traditionally refers to treatment with a gonadotropin-releasing hormone (GnRH) agonist (eg, leuprolide) or GnRH antagonist (eg, degarelix). Suppression of androgen signaling can also be accomplished with AR (androgen receptor) inhibitors (eg, enzalutamide) or CYP17 (cytochrome P450 17A1) inhibitors (eg, abiraterone). The inhibition of testosterone secretion by ADTs and AR-directed therapies results in a state of low plasma testosterone—a condition referred to as androgen deprivation. As advances in therapy improved the survival of patients with PCa, growing reports have suggested a contribution of ADT to cardiovascular adverse sequelae. These reports led the American Heart Association, American Cancer Society, and American Urologic Association to jointly issue a science advisory on the increased cardiovascular risks of ADT.³ This review will summarize existing meta-analyses of the cardiovascular adverse effects of traditional ADTs, as well as meta-analyses of AR-directed therapy. While the state of low testosterone may arise from a multitude of etiologies, in this review, we will focus on androgen deprivation resulting from the drugs used in the treatment of PCa for patients with PCa.

Physiology

PCa is an androgen-sensitive cancer that relies on signaling from the hypothalamic-pituitary-gonadal axis. The hypothalamic-pituitary-gonadal axis begins at the hypothalamus, which releases GnRH in a pulsatile manner (Figure). Binding of GnRH to the GnRH receptors on the anterior pituitary causes release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates LH receptors on Leydig cells in the testes to produce testosterone.

Figure. **The hypothalamic-pituitary-gonadal axis and targets for androgen deprivation therapy in prostate cancer.** 17-OHP5 indicates 17α-hydroxypregnenolone; AE, androstenedione; AR, androgen receptor; ARE, androgen response elements; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; P5, pregnenolone; and T, testosterone.

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In the testes, and to a lesser degree in the adrenal glands, testosterone synthesis from cholesterol relies on a cascade of CYP17-dependent reactions involving the conversion pregnenolone to dehydroepiandrosterone and progesterone into androstenedione, both of which are converted to testosterone and subsequently dihydrotestosterone (Figure). Dihydrotestosterone binding to the AR in the ligand-binding pocket causes translocation of AR from the cytoplasm to the nucleus, where it binds to DNA and promotes transcription of cancer growth–promoting genes. When testosterone levels are depleted during PCa treatment, PCa cells can continue to respond to androgens synthesized in the adrenal gland. This pathway was the rationale for developing CYP17 inhibitors, which block synthesis of androgens in adrenal gland.

Types of ADT

GnRH Agonists

The most common type of ADT are the GnRH agonists. GnRH agonists bind to GnRH receptors on gonadotropin-producing cells in the anterior pituitary.⁴ The resulting continuous (nonpulsatile) release of GnRH causes a transient surge in LH and FSH and increase in testosterone production from Leydig cells. Subsequently, the negative feedback downregulates GnRH receptors on gonadotropin-producing cells, decreased pituitary production of LH and FSH, and testosterone is reduced to castration levels. Leuprolide, goserelin, triptorelin, buserelin, and histrelin are examples of GnRH agonists. Their pharmacology has been described previously⁵ (Table I in the online-only Data Supplement). All are available as intramuscular or subcutaneous formulations and are typically administered once every 1 to 6 months.

GnRH Antagonists

GnRH antagonists bind to GnRH receptors on gonadotropin-producing cells in the anterior pituitary to inhibit release of LH or FSH without an initial increase in testosterone release.⁶ Degarelix is an example of a GnRH antagonist. Degarelix is administered as a monthly subcutaneous injection. Degarelix causes a rapid fall in testosterone levels within 2 to 3 days, which is significantly more rapid than GnRH agonists.^7,8 Degarelix causes greater and more rapid prostate-specific antigen reduction than GnRH agonists and has a lower rate of prostate-specific antigen failure.⁹ Degarelix also causes greater and more rapid LH and FSH reduction than GnRH agonists.⁹ Degarelix is more likely to cause injection site reactions than GnRH agonists, while flushing is equally common in both groups.¹⁰ Interestingly, degarelix causes improved health-related quality of life compared with GnRH agonists.¹¹ GnRH antagonists are less susceptible to the resistance that GnRH agonists may experience because of decreased sensitivity of the GnRH receptor from continuous exposure to GnRH agonists.⁸

AR Antagonists

AR antagonists, also known as antiandrogens, competitively inhibit dihydrotestosterone binding to the AR at the androgen-binding site.¹² These agents inhibit nuclear translocation of the AR and interaction of the AR with the promoter at the AR response element. The inhibition of AR-dependent transcription impairs cell proliferation and triggers apoptosis. Nonsteroidal AR antagonists, discussed below, spare the patient from antimineralocorticoid, antigonadotropic, and progestogenic effects. Flutamide, nilutamide, and bicalutamide are first-generation AR antagonists. Enzalutamide, apalutamide, and darolutamide are next-generation (more potent) AR antagonists.⁵ They are administered orally. A new compound that is a hybridization of abiraterone and enzalutamide has shown promising results for treating enzalutamide-resistant PCa.¹³ AR antagonists are commonly used with GnRH agonists to alleviate the effects of the testosterone surge that occurs with a GnRH agonist. Extended AR antagonists may be used with GnRH agonists or antagonists to achieve combined androgen blockade (CAB).

CYP17 Inhibitors

CYP17—an enzyme found in the testes, adrenal glands, and prostate tumor tissue—possesses both 17α-hydroxylase and C17,20-lyase activity, which generate testosterone from testosterone precursors.¹⁴ CYP17 inhibitors block these reactions. Additionally, CYP17 inhibition reduces cortisol synthesis and may induce increased adrenocorticotropic hormone release promoting synthesis of mineralocorticoid precursors, leading to hypertension, edema, and hypokalemia. Corticosteroids are thus coadministered to prevent unwanted adrenocorticotropic hormone release. Ketoconazole and abiraterone are CYP17 inhibitors. Although AR antagonists and CYP17 inhibitors are androgen axis–directed therapies rather than strictly ADTs, they have been grouped under the umbrella of ADTs in many studies and will be treated as such in the data synthesis below.

Cardiovascular Adverse Effects of ADT

Keating et al¹⁵ first identified an increased risk of incident diabetes mellitus, coronary heart disease, myocardial infarction (MI), and sudden cardiac death in association with GnRH agonists in a Surveillance, Epidemiology, and End Results-Medicare database. This finding has spurred numerous observational studies and retrospective studies from randomized controlled trials (RCTs).

Cardiovascular Adverse Effects of ADTs as a Pooled Group

Among the 3 available meta-analyses of observational trials, ADTs had positive associations (although not always significant) with cardiovascular events, cardiovascular death, and MI (Table 1).^16–18 The comparator (non-ADT) group in these studies could include radical prostatectomy, radiotherapy, or watchful waiting. When the comparator group was watchful waiting, ADT was significantly associated with any nonfatal cardiovascular disease and stroke.^17,18 The strengthened effect size when the comparator group was restricted to watchful waiting suggests that there is cardiovascular risk associated with some non-ADT therapies, which may be minimizing the true cardiovascular effect difference between ADT and non-ADT. Among the 3 available meta-analyses of RCTs, there were no significant associations with cardiovascular outcomes except for a positive association with nonfatal cardiovascular disease compared in one analysis.^16,19,20Therefore, in patients with low cardiovascular risk enrolled in RCTs, there is a suggestion but no conclusive increase in risk of cardiovascular adverse effects from ADT.

Table 1. Cardiovascular Mortality and Cardiovascular Disease Associated With ADT as a Pooled Group Compared With Non-ADT, According to Results of Meta-Analyses From 2010 to 2019

	Type	Treatment Agent (No. of Patients)	Comparator Agent (No. of Patients)	CV Mortality	Any Nonfatal CVD	Myocardial Infarction	Stroke
Nguyen et al¹⁹	RCT	ADT (n=2200)	Nonimmediate ADT (n=1941)	RR, 0.93 (CI, 0.79–1.10; P=0.41; I²=0%; N=8)
Bourke et al²⁰	RCT	ADT (n=1065)	Nonimmediate ADT (n=814)	RR, 1.06 (CI, 0.80–1.40; P=0.69; I²=0%; N=4)
Zhao et al¹⁸	Obs.	ADT (n=129 802)*	Non-ADT (n=165 605)*	HR, 1.17† (CI, 1.04–1.32; P=0.01; I²=57%; N=6)	HR, 1.10 (CI, 1.00–1.21; P=0.06; I²=72%; N=6)	HR, 1.10 (CI, 0.97–1.26; P=0.14; I²=68%; N=6)
Zhao et al¹⁸	Obs.	ADT (n=39 465)*	Watchful waiting (n=43 648)*	HR, 1.30† (CI, 1.13–1.50; P=0.0003; I²=0%; N=4)	HR, 1.19† (CI, 1.08–1.30; P=0.0004; I²=0%; N=3)
Carneiro et al¹⁶	Obs.	ADT (n=52 308)	Non-ADT (n=74 590)	OR, 1.92 (CI, 0.79–4.68; P=0.15; I²=97%; N=3)	OR, 1.06 (CI, 0.70–1.61; P<0.78; I²=100%; N=2)	OR, 2.05† (CI, 1.93–2.17; P<0.00001; I²=100%; N=2)	OR, 1.07 (CI, 0.66–1.72; P=0.79; I²=99%; N=2)
Carneiro et al¹⁶	RCT	ADT (n=8388)	Non-ADT (n=8411)	OR, 0.97 (CI, 0.81–1.18; P=0.79; I²=0%; N=6)	OR, 1.55† (CI, 1.09–2.20; P=0.01; I²=0%; N=3)	OR, 1.23 (CI, 0.92–1.64; P=0.16; I²=0%; N=2)	OR, 1.02 (CI, 0.71–1.46; P=0.93; I²=0%; N=2)
Meng et al¹⁷	Obs.	ADT (n=74 538)	Non-ADT (n=85 947)				HR, 1.12 (CI, 0.95–1.32; P=0.16; I²=85%; N=6)
Meng et al¹⁷	Obs.	ADT (n=39 029)	Watchful waiting (n=42 073)				HR, 1.16† (CI, 1.03–1.31; P=0.01; I²=0%; N=2)

n, total number of patients examined in the meta-analysis; N, number of studies or trials available for that outcome in the meta-analysis. ADT indicates androgen deprivation therapy; CV, cardiovascular; CVD, cardiovascular disease; HR, hazard ratio; Obs., meta-analysis of observational studies; OR, odds ratio; RCT, meta-analysis of randomized controlled trials; and RR, relative risk.

The exact participant count in the study by Zhao et al¹⁸ varies by outcome.

†

Pooled effects that were statistically significant.

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Cardiovascular Adverse Effects of GnRH Agonists

Among the ADTs, the strongest cardiovascular adverse event signal comes from observational studies of the GnRH agonists. In the 3 meta-analyses of GnRH agonists compared with non-ADT, positive associations were found between GnRH agonists and cardiovascular death, nonfatal cardiovascular disease, MI, and stroke (Table 2).^17,18,21 There are currently no meta-analyses of RCTs of GnRH agonists and cardiovascular adverse events.

Table 2. Cardiovascular Mortality and Cardiovascular Disease Associated With GnRH Agonists Compared With Non-ADT, According to Results of Meta-Analyses From 2010 to 2019

	Type	Treatment Agent (No. of Patients)	Comparator Agent (No. of Patients)	CV Death	Any Nonfatal CVD	Myocardial Infarction	Stroke
Zhao et al¹⁸	Obs.	GnRH agonist (n=89 865)*	Non-ADT (n=126 219)*	HR, 1.36† (CI, 1.10–1.68; P=0.004; I²=91%; N=4)	HR, 1.19† (CI, 1.04–1.36; P=0.01; I²=86%; N=3)	HR, 1.20† (CI, 1.05–1.38; P=0.008; I²=82%; N=4)
Bosco et al²¹	Obs.	GnRH agonist	Non-ADT		RR, 1.38† (CI, 1.29–1.48; P<0.001; I²=85%; N=16)	RR, 1.57† (CI, 1.26–1.94; P<0.001; I²=92%; N=6)	RR, 1.51† (CI, 1.24–1.84; P<0.001; I²=90%; N=5)
Meng et al¹⁷	Obs.	GnRH agonist (n=49 292)	Non-ADT (n=47 309)				HR, 1.20† (CI, 1.12–1.28; P<0.001; I²=0%; N=3)

n, total number of patients examined in the meta-analysis; N, number of studies or trials available for that outcome in the meta-analysis. ADT indicates androgen deprivation therapy; CV, cardiovascular; CVD, cardiovascular disease; GnRH, gonadotropin-releasing hormone; HR, hazard ratio; Obs., meta-analysis of observational studies; and RR, relative risk.

The exact participant count in the study by Zhao et al¹⁸ varies by outcome.

†

Pooled effects that were statistically significant.

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Cardiovascular Adverse Effects of AR Antagonists

The cardiovascular adverse effect signal from AR antagonists was mixed. In the 3 meta-analyses of observational studies of AR antagonists compared with non-ADT, there were mixed associations between ADT and nonfatal cardiovascular disease and MI^18,21 and no associations between ADT and cardiovascular death and stroke^17,18 (Table II in the online-only Data Supplement). There are currently no meta-analyses of RCTs of AR antagonists and cardiovascular adverse events.

Cardiovascular Adverse Effects of CAB

CAB, which refers to the use of a GnRH agonist together with an AR antagonist, showed increased risk for cardiovascular adverse effects. In 2 meta-analyses of observational studies that examined CAB compared with non-ADT, there was a positive association with cardiovascular death, nonfatal cardiovascular disease, and stroke^17,18 (Table III in the online-only Data Supplement). The association with MI was not statistically significant.¹⁸

Cardiovascular Adverse Effects of Orchiectomy

Individuals undergoing orchiectomy may have increased risk of cardiovascular events. In 3 meta-analyses of observational data examining orchiectomy compared with non-ADT, there was a positive association between orchiectomy and nonfatal cardiovascular disease^17,18,2 (Table IV in the online-only Data Supplement). Individual associations between orchiectomy and cardiovascular death, MI, and stroke were positive but did not achieve statistical significance. There are currently no meta-analyses of RCTs of orchiectomy cardiovascular adverse events.

Cardiovascular Adverse Effect Differences Between ADT Types

The mechanism of specific ADTs may differently affect cardiovascular event risk. In one meta-analysis, GnRH antagonists were associated with lower cardiovascular events than GnRH agonists (hazard ratio, 0.44 [CI, 0.26–0.74]; P=0.002; I²=42%; N=3).²² In a broader meta-analysis comparing all types of ADT with each other (Table V in the online-only Data Supplement),²³ orchiectomy had the most unfavorable cardiovascular risk profile. Orchiectomy had a near-doubling of MI risk compared with CAB, which appears to have the least harmful cardiovascular risk profile. Differences were modest among the other ADT types. GnRH antagonists were associated with a 58% decreased risk of MI compared with GnRH agonists.^22,23 Between continuous ADT and intermittent ADT, there was no difference in the development of cardiovascular events or thromboembolic events, but there was a marginally significant increase in cardiovascular death from continuous ADT.²⁴

Cardiovascular Adverse Effects of Abiraterone and Enzalutamide

Two agents, enzalutamide (an AR antagonist) and abiraterone (a CYP17 inhibitor), have drawn specific attention for their association with cardiovascular risk. In a meta-analysis of observational studies and a meta-analysis of RCTs, enzalutamide did not increase risk of cardiac events but increased the risk of hypertension (Table VI in the online-only Data Supplement).^25,26 Abiraterone was associated with increased risk of cardiac events and the risk of hypertension in both meta-analyses (Table 3). The strength of abiraterone’s association with any cardiac events and hypertension suggests that further scrutiny should be given to the CYP17 inhibitors in future clinical trials. Furthermore, pharmacovigilance studies show that abiraterone has increased risk of atrial tachyarrhythmias and heart failure compared with other ADTs²⁷—an area that should be studied in future meta-analyses.

Table 3. Cardiovascular Events Associated With Abiraterone (a CYP17 Inhibitor) Compared With Non-ADT, According to Results of Meta-Analyses From 2010 to 2019

	Type	Treatment Agent (No. of Patients)	Comparator Agent (No. of Patients)	Any Cardiac Events	CTCAE Grade ≥3 Cardiac Events	Any Hypertension	CTCAE Grade ≥3 Hypertension
Moreira et al²⁶	RCT	Abiraterone and prednisone (n=1343)	Prednisone (n=940)	RR, 1.28* (CI, 1.06–1.55; P=0.01; I²=0%; N=2)	RR, 1.76* (CI, 1.12–2.75; P=0.01; I²=0%; N=2)
Iacovelli et al²⁵	RCT	Abiraterone and prednisone (n=2878)	Prednisone (n=2496)	RR, 1.41* (CI, 1.21–1.64; P<0.001; I²=0%; N=4)	RR, 2.22* (CI, 1.60–3.27; P<0.001; I²=0%; N=4)	RR, 1.79* (CI, 1.45–2.21; P<0.001; I²=68%; N=4)	RR, 2.19* (CI, 1.73–2.78; P<0.001; I²=34%; N=4)

n, total patients examined in the meta-analysis; N, number of studies or trials available for that outcome in the meta-analysis. ADT indicates androgen deprivation therapy; CTCAE, common terminology criteria for adverse events; CYP17, cytochrome P450 17A1; RCT, meta-analysis of randomized controlled trials; and RR, relative risk.

Pooled effects that were statistically significant.

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Impact of Study Population on Cardiovascular Risk

Several factors related to trial design could partially explain these divergent results between meta-analyses of RCTs and meta-analyses of observational studies. RCTs may underestimate cardiovascular risk because the primary end points in RCTs are measures of PCa disease control, not cardiovascular events. First, cardiovascular events in RCTs for PCa therapies are not defined or adjudicated in a standardized way as done in large prospective cardiovascular outcomes trials. Second, these RCTs are not sufficiently powered to look for unexpected cardiovascular events. Third, the duration of follow-up is rarely as long as in observational studies. Fourth, patients in the control arm in some trials did end up receiving ADT as well, just in a deferred time frame, thus attenuating any positive effect of ADT on cardiovascular risk. Fifth, PCa RCTs suffer from selection bias as they exclude patients with high cardiovascular risk from enrollment.

On the other hand, observational studies have greater susceptibility to confounding, less control over adherence to treatment, and may have outcome reporting bias, potentially leading to an overestimation of cardiovascular risk. Population-based databases, such as Surveillance, Epidemiology, and End Results, do not exclude elderly patients or those with concurrent cardiovascular disease or cardiovascular risk factors, thus more closely resembling the population of patients who develop PCa.²⁸ The critical role that baseline cardiovascular risk factors and comorbidities play in overall survival was demonstrated in a study on a long-term follow-up of a PCa RCT.²⁹

Finally, the heterogeneity varies widely between the studies, ranging from 0% to 100%; so results should be interpreted with caution. Studies varied greatly in follow-up time and regions included (Table VII in the online-only Data Supplement). On balance, the data support a cardiovascular risk association that needs to be further characterized. Pragmatic trials may overcome these limitations and offer the methodological innovation needed to address this research question.

Mechanisms

The increased risk of adverse cardiovascular outcomes from ADT is thought to be related to its role in promoting atherosclerosis, dyslipidemia, adiposity, and insulin resistance.

ADT and Atherosclerosis

Multiple murine models of androgen deprivation have supported the hypothesis that androgen deprivation worsens atherosclerosis lesion formation. First, orchiectomized LDLR^−/− mice consuming a high-fat diet developed larger atherosclerotic lesions as compared with sham-treated mice.³⁰ Testosterone supplementation in the orchiectomy model significantly reduced atherosclerotic lesion size compared with placebo, but this reduction did not occur if testosterone was administered in the presence of an aromatase inhibitor, which blocks conversion of testosterone to 17β-estradiol. This suggests that testosterone may inhibit atherosclerosis indirectly through its conversion to 17β-estradiol. Indeed, 17β-estradiol supplementation reduced atherosclerotic lesion size to the same degree as testosterone treatment.³⁰

Second, ARKO (AR knockout) in the context of an apolipoprotein E deficiency model led to larger atherosclerotic lesions in the aortic root compared with animals with an intact AR.³¹ As in the LDLR^−/− model, testosterone supplementation reduced lesion size in both ARKO and wild-type mice, although the effect was blunted in ARKO mice. This suggests disruption of testosterone signaling is atherogenic via both AR-dependent and AR-independent mechanisms.

Third, in vitro, testosterone dose dependently augmented cholesterol efflux from human monocyte–derived macrophages via upregulation of scavenger receptor B1, thereby providing a possible mechanism for how testosterone can reduce the cholesterol content of atherosclerotic lesions.³² Collectively, these preclinical models support the hypothesis that androgen deprivation drives atherosclerosis.

ADT and Adiposity

ADT increases visceral and subcutaneous fat³³ while decreasing lean body mass.³⁴ This may occur via loss of androgen-mediated inhibition of stem cell differentiation into adipocytes,³⁵ as well as loss of androgen-mediated stimulation of lipolysis and androgen-mediated reduction of lipid accumulation.³⁶ Of note, 90% of the gain in adiposity is subcutaneous rather than visceral.³⁷

ADT and Insulin Resistance

ADT leads to insulin resistance. Among men without diabetes mellitus, ADT has been associated with worsening fasting insulin, fasting glucose, leptin, and homeostasis model of insulin resistance.^38,39 More importantly, ADT has been associated with increased risk of developing diabetes mellitus.⁴⁰ Among men with diabetes mellitus, ADT has been associated with worsening A1c control.⁴¹ This is plausible as testosterone has dose- and time-dependent effects on increasing cellular expression of insulin receptor substrate-1 and glucose transporter 4.⁴²

ADT and Metabolic Syndrome

In a meta-analysis of 9 studies of men treated with ADT for PCa, ADT was associated with an increased risk of developing metabolic syndrome (relative risk, 1.75 [CI, 1.27–2.41]; I²=0%).⁴³ However, ADT raises both LDL (low-density lipoprotein) and HDL (high-density lipoprotein) levels, instead of decreasing HDL levels, as in metabolic syndrome.^43–46 The fat accumulation in ADT is primarily subcutaneous, rather than the visceral accumulation of metabolic syndrome.³⁷ Moreover, there is no significant increase in waist-to-hip ratio. These data suggest that ADT acts via pathways other than the traditional insulin resistance–mediated development of metabolic syndrome.

ADT and Hypertension

ADT was hypothesized to lead to hypertension since androgen-deprived states were shown to increase arterial stiffness.^47,48 However, only abiraterone and enzalutamide have consistently demonstrated associations with hypertension.²⁵ Increased mineralocorticoid production from an increase in adrenocorticotropic hormone resulting from suppression of cortisol has been suggested as a mechanism for abiraterone’s hypertensive effect.⁴⁹

ADT and Endothelial Cell Function

At the cellular level, ADT leads to endothelial cell dysfunction. In endothelial cells from patients with diabetes mellitus, androgen signaling was negatively enriched.⁵⁰ However, despite this previously identified biology, GnRH agonists improved conduit artery flow-mediated vasodilation in men with PCa at 3 months.⁵¹ Discontinuation of GnRH agonist resulted in return of flow-mediated vasodilation to baseline after 6 months. The improvement in flow-mediated vasodilation occurred despite worsening insulin resistance and dyslipidemia. Other cross-sectional studies have described similar effects of ADT on endothelial cell function,⁵² suggesting that endothelial cell dysfunction may not be a major determinant of atherosclerosis from ADT.

ADT and Arrhythmia

ADT, especially enzalutamide, may be associated with increased QT interval and acquired long QT syndrome.⁵³ Testosterone shortens while estradiol lengthens QT prolongation (thus explaining, in part, the long standing observation that men have shorter QT than women).⁵⁴ Similarly, an association between hypogonadism in men and long QT syndrome and risk of torsade de pointes has been observed.^55,56 This association appears to be causal, as correction of hypogonadism by testosterone replacement therapy reduces QT prolongation.⁵⁷ These results suggest electrocardiographic monitoring may have a role in the surveillance of men treated with ADT.

GnRH Receptors Outside the Pituitary

Pituitary cells and cardiac myocytes have increased mRNA expression of GnRH receptor, LH receptor, and FSH receptor compared with other human cells.⁵⁸ In mice, GnRH has been shown to increase cardiac contractility via the PKA (protein kinase A) pathway.⁵⁹ However, further studies remain to be done to characterize the link between GnRH agonist use and GnRH receptor stimulation on cardiac myocytes. There is no evidence yet about whether this may be related to the QT interval prolongation reported from GnRH agonist use.⁶⁰ Intriguingly, FSH levels were positively associated with QT duration in 2 observational studies.^55,61

Synopsis of Mechanisms

The aforementioned atherosclerosis, visceral adiposity, lipolysis inhibition, insulin resistance, and endothelial dysfunction result in an unfavorable cardiovascular risk profile predisposing to MI, stroke, and hypertension.^62,63 In addition to these structural changes, conduction abnormalities arise as androgen deprivation prolongs the QT interval. Plaque destabilization and insulin resistance are further worsened by the increased state of inflammation caused by elevated proinflammatory cytokines and adiponectin from AR-dependent and -independent mechanisms.⁶⁴

Management

The cardiovascular adverse effects of ADT, such as atherosclerotic plaque growth, are insidious. The cornerstone of management relies on prevention. Before initiating an ADT, ideal management involves a multidisciplinary discussion with the patient about the risks and benefits of ADT. Physicians initiating ADT in patients with multiple cardiovascular risk factors or history of cardiovascular events should consider referral to cardiology or cardio-oncology. The components of cardiac prevention in PCa survivors can be remembered by the ABCDE mnemonic: A for awareness and aspirin; B for blood pressure control; C for cholesterol and cigarettes; D for diabetes mellitus and diet; and E for exercise.⁶⁵ These principles do not differ from the principles of cardiac prevention in the general population.

Conclusions

In conclusion, meta-analyses demonstrate a recurring pattern whereby GnRH agonists, GnRH antagonists, AR antagonists (CAB), and orchiectomy for PCa show positive associations with cardiovascular events and cardiovascular death in observational studies. These effects are not consistently reproducible in RCTs. Notably, the CYP17 inhibitor abiraterone increases risk of cardiovascular events in both observational studies and RCTs. Animal and human studies suggest that the mechanisms by which ADT increases cardiovascular risk include increased atherosclerosis, dyslipidemia, metabolic syndrome, and insulin resistance. Our current work can provide the basis for a living network meta-analysis. Further pragmatic trials and meta-analyses are necessary to definitively characterize the impact of ADT- and AR-directed therapies on cardiovascular events.

Footnote

Nonstandard Abbreviations and Acronyms

ADT: androgen deprivation therapy
AR: androgen receptor
ARKO: androgen receptor knockout
CAB: combined androgen blockade
FSH: follicle-stimulating hormone
GnRH: gonadotropin-releasing hormone
HDL: high-density lipoprotein
LDL: low-density lipoprotein
LH: luteinizing hormone
MI: myocardial infarction
PCa: prostate cancer
RCT: randomized controlled trial

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