(UroToday.com) The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) meeting featured a session on the identification, assessment, and management of side effects of systemic therapies, and a presentation by Dr. Charles Ryan discussing how to select ADT and an ARPI based on cardiovascular risk profile. When assessing cardiovascular risk and your initial treatment decisions, there are several considerations:
- Survivorship science issues:
- The risk may manifest after they are no longer under your care or receiving active anti-cancer treatment
- Most important in using adjuvant ADT/ARPI in patients receiving curative intent therapy
- Adverse event issues:
- Our ongoing management of patients affect outcomes while the patient is under your care
- Most important during ARPI therapy and for long-term care in advanced disease
It is important to remember that for patients with localized disease in follow-up, cardiovascular disease is the leading cause of death, and for advanced disease, as survival improves, cardiovascular disease is becoming an increasing cause of death:1
For patients receiving ADT, the cardiovascular threat lingers:
A 2020 meta-analysis provided specific risks of GnRH agonists with regard to cardiovascular outcomes:2
- Cardiovascular death: HR 1.36
- Nonfatal cardiovascular disease: HR 1.19-1.38
- Myocardial infarction: HR 1.20-1.51
- Stroke: HR 1.20-1.51
Why is ADT so cardiotoxic? Dr. Ryan posed several additional potential questions:
- Does testosterone have a cardio-protective effect?
- Are there physiologic endocrine adaptions to a low testosterone milieu?
- Is there direct toxicity of the drugs? Ie. Chronic GnRH agonism
- Is it secondary to lifestyle factors related to reduced physical activity?
- Perhaps FSH levels are the culprit. Mouse studies suggest that FSH drives monocyte adhesion to endothelial surfaces
Dr. Ryan notes that our choice of initial therapy (GnRH agonist versus antagonist) may have lasting impacts. Previous work from Albertsen et al.3 showed that degarelix is associated with lower cardiovascular risk versus GnRH agonist among patients with cardiovascular history:
Dr. Ryan then discussed the HERO trial,4 which was a 48-week, global, phase 3 trial that randomized 934 patients with androgen-sensitive advanced prostate cancer in a 2:1 ratio to receive relugolix 120 mg orally QD (n = 624) or leuprolide acetate 3-month depot injection (n = 310). Total cardiovascular risk factors included 91.6% of those receiving relugolix compared to 94.2% of those receiving leuprolide. In a prespecified analysis, the incidence of major adverse cardiovascular events (MACE) was lower in the relugolix group than in the leuprolide group (2.9% vs. 6.2%, respectively), otherwise, the safety and tolerability profiles were generally similar. Among a subset of patients with a history of MACE, a MACE event occurred in 3.6% of patients on relugolix compared to 17.8% of patients on leuprolide. Taken together, patients receiving relugolix had a 54% reduction in risk of MACE:
Importantly, there was sustained FSH levels in the leuprolide arm, but no difference in LH levels:
When considering the ARPI era, does cardiovascular risk reduce the benefits of these novel therapies in some patients? In a SEER database study,5 both abiraterone and enzalutamide were associated with increased all-cause mortality in patients with three or more cardiovascular comorbidities:
As this is a SEER database study, Dr. Ryan notes that no comparison was done and no causation can be proven, however, this study does highlight this at-risk population. Kulkarni and colleagues previously looked at the risk for stroke and myocardial infarction with abiraterone versus enzalutamide in metastatic prostate cancer patients in the MarketScan claims database.6 Among 6,294 patients, 4,017 (63.8%) patients used ADT + abiraterone, and 2,217 (32.2%) patients used ADT + enzalutamide. In multivariable analysis, abiraterone use was associated with a 31% increased risk of myocardial infarction or stroke compared to enzalutamide (HR 1.31, 95% CI 1.05-1.63; p = 0.01). The incidence rate was similar in patients who switched initial therapy from abiraterone to enzalutamide or vice versa (5.0 versus 5.6 per 100 patient-years, respectively). The cumulative incidence curve of the composite endpoint is as follows:
Dr. Ryan then discussed the phenomenon known as “abiraterone cardiac syndrome” which is secondary to hypokalemia, hypertension, heart failure, edema, and atrial tachycardia. This is thought to be caused by mineralocorticoid elevation via suppression of CYP17 and upstream shunting of steroids to mineralocorticoid precursors. Recent data from the EMBARK trial7 suggest that even with enzalutamide monotherapy, 5.6% of patients have Grade 3+ hypertension, 5.9% Grade 3+ ischemic heart disease, and 2.3% Grade 3+ other selected cardiovascular events:
Enzalutamide drivers a hyper-mineralocorticoid state via suppression of 11Beta-HSD2 conversion of cortisol to cortisone, with both enzalutamide and apalutamide increasing circulating glucocorticoid exposure in clinical trials. Additionally, both apalutamide and darolutamide have warnings on the package inserts, including “mild hypertension signal” but no ischemic language for apalutamide, with the darolutamide insert including language on ischemic heart disease.
Dr. Ryan provided the following table for choosing the type of systemic androgen deprivation:
Dr. Ryan concluded his presentation discussing how to select ADT and an ARPI based on cardiovascular risk profile with the following take-home messages:
- Data are compelling enough to support GnRH antagonists in patients with cardiovascular risk factors
- High-level evidence in prior MACE
- Extrapolating to less severe points on the risk spectrum is reasonable
- Cardiovascular risks in CRPC are higher than in CSPC
- Should you switch a stable agonist patient to an antagonist?
- There is no data to make the switch
- If a cardiovascular event occurs, it may be a consideration
- Survivorship science saves lives – reducing cardiovascular mortality in ADT/ARPI patients could have significant impact on outcomes overall
Presented by: Charles J. Ryan, MD, University of Minnesota, Minneapolis, MN
Written by: Zachary Klaassen, MD, MSc - Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Advanced Prostate Cancer Consensus Conference (APCCC) Meeting, Lugano, Switzerland, Thurs, Apr 25 - Sat, Apr 27, 2024.
References:
- Weiner AB, Li EV, Desai AS, et al. Cause of death during prostate cancer survivorship: A contemporary, US population-based analysis. Cancer. 2021 Aug 15;127(16):2895-2904.
- Hu JR, Duncan MS, Morgans AK, et al. Cardiovascular Effects of Androgen Deprivation Therapy in Prostate Cancer: Contemporary Meta-Analysis. Arterioscler Thromb Vasc Biol. 2020 Mar;40(3):e5-e64.
- Albertsen PC, Klotz L, Tombal B, et al. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol. 2014 Mar;65(3):565-573.
- Shore ND, Saad F, Cookson MS, et al. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2187-2196.
- Lu-Yao G, Nikita N, Keith SW, et al. Mortality and Hospitalization risk following oral androgen signaling inhibitors among men with advanced prostate cancer by pre-existing cardiovascular comorbidities. Eur Urol. 2020 Feb;77(2);158-166.
- Kulkarni AA, Rubin N, Tholkes A, et al. Risk for stroke and myocardial infarction with abiraterone versus enzalutamide in metastatic prostate cancer patients. ESMO Open. 2021 Oct;6(5):100261.
- Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med 2023 Oct 19;389(16):1453-1465.
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