Gonadotrophin-releasing hormone (GnRH) agonists, such as leuprolide, goserelin, histrelin, or triptorelin, are most often used and induce responses in approximately 85% of men with metastatic hormone-sensitive prostate cancer.6,7 Unfortunately, these drugs are associated with clinically significant toxicities, many of which overlap, such as cardiovascular disease, hypertension, adiposity, sarcopenia, and a variant of metabolic syndrome.6,7 In response, researchers are studying alternative mechanisms of medical castration as well as behavioral strategies to reduce the cardiometabolic risks of ADT.
At the same time, our treatment armamentarium has expanded and is shifting toward the earlier use of docetaxel, second-line ADT, and combinations. This diversifying treatment landscape heightens the need to understand the cardiovascular and metabolic risks of ADT and how best to manage them.
Evaluating cardiovascular and metabolic risk
Older age is associated with diabetes, cardiovascular disease, and prostate cancer, so it’s not surprising how often these conditions overlap. Indeed, cardiovascular disease is the second leading cause of death in men with prostate cancer and the primary cause of death in men with T3 or lower-stage disease.8
We have known since the 1970s that estrogens such as diethylstilbestrol (DES) are associated with cardiovascular risks.9 More recently, studies have linked bilateral orchiectomy, GnRH agonist therapy, and combined androgen blockade to increased risk of cardiovascular morbidity and mortality.5,10
We have the most data on GnRH agonists since they are most often prescribed. Most studies have found that these drugs carry a greater cardiovascular risk than other types of ADT. In a recent review, GnRH agonist therapy was associated with a 20% to 25% increase in the risk of cardiovascular morbidity compared with no ADT.11 In another study of Surveillance, Epidemiology, and End Results (SEER) and Medicare data, GnRH agonists were associated with a significantly higher risk of coronary artery disease, acute myocardial infarction, and sudden cardiac death compared with orchiectomy.12 In another recent meta-analysis, GnRH agonists were associated with a greater risk of incident cardiovascular disease compared with orchiectomy or antiandrogen monotherapy.13 Not all data point the same way, however. In a large observational study in Sweden, men with prostate cancer who received a GnRH agonist had a statistically similar risk of incident cardiovascular events and mortality as men who underwent orchiectomy.14
For patients with a history of cardiovascular disease, we have limited evidence that degarelix is cardiovascularly safer than GnRH agonist therapy. Most data comparing GnRH agonists and antagonists are retrospective and observational,15 but recently, a randomized, two-center, open-label trial assessed the cardiovascular safety of degarelix and GnRH agonists in 80 men with prostate cancer and pre-existing cardiovascular disease.16 After a median follow-up time of 10 months, rates of incident cardiovascular events were 7% for degarelix versus 28% for GnRH agonists (P = .008).16 Additionally, patients whose FSH level had dropped by less than 60% during the first 3 months of treatment were at significantly increased risk of cardiovascular events.16
Other studies generally confirm these findings. In a pooled analysis of data from clinical trial participants with prostate cancer and pre-existing cardiovascular disease, degarelix was associated with an approximately 50% lower rate of incident cardiac events at 1 year compared with GnRH agonists (FIGURE 1), even after controlling for confounding factors.17 In another recent analysis of hospital discharge data and insurance claims, GnRH antagonist therapy was associated with a significantly lower risk of myocardial infarction or ischemic stroke compared with GnRH agonist therapy.18
Based on these data, I am more likely to consider degarelix than GnRH agonist therapy for men with cardiovascular disease or established risk factors. In addition to its (likely) reduced cardiovascular toxicity, degarelix typically achieves castrate levels of testosterone within 72 hours, leading to faster PSA suppression without testosterone flare or microsurges.19 Additionally, GnRH antagonist therapy has been linked to improved PSA progression-free survival and less joint and musculoskeletal pain than GnRH agonist therapy.6,20,21
Several lines of evidence may help explain why degarelix appears to pose a lower cardiovascular risk than GnRH agonist therapy. First, prolonged use of GnRH agonists adversely affects multiple cardiometabolic risk factors, including glucose tolerance, low-density lipoprotein (LDL) and triglyceride levels, waist circumference, and sarcopenia.5 These changes can indirectly induce atherosclerosis and coronary artery disease. In addition, GnRH agonist therapy has been found to promote plaque rupture and thrombosis by stimulating T cell and macrophage activity.10,22,23 (In contrast, GnRH antagonists do not stimulate T cell activity.)23 Furthermore, GnRH agonists primarily suppress luteinizing hormone, while GnRH antagonists suppress both luteinizing hormone (LH) and follicle-stimulating hormone (FSH).5 Follicle stimulating hormone is highly expressed in prostatic adenocarcinoma and appears to promote both atherosclerotic plaque formation and insulin resistance in men receiving ADT.24 Finally, recent evidence indicates GnRH agonists can cause QTc interval prolongation, which might explain sporadic reports of sudden cardiac death in these patients.25
The picture becomes even more nuanced when we consider that the relative risk of various ADTs can vary by race and ethnicity. In a recent study in Taiwan, men with prostate cancer at increased risk for cardiovascular were significantly more likely to experience an ischemic cardiovascular event after orchiectomy compared with GnRH agonist therapy.26 This study was not an anomaly—a study of men with prostate cancer in China reported a similar result.28
Fortunately, a large trial is underway that may help elucidate some of these distinctions. The single-blind PRONOUNCE study (NCT02663908) is enrolling up to 900 patients with prostate cancer and established cardiovascular risk factors who are being assigned on a one-to-one basis to receive either degarelix or leuprolide for up to one year.28 The composite primary endpoint is major adverse cardiovascular events, while secondary endpoints include time to myocardial infarction, stroke, unstable angina requiring hospitalization, cardiovascular death, and all-cause mortality. Patients with advanced prostate cancer and established cardiovascular disease are potentially eligible to enroll if they have no 30-day history of acute cardiovascular disease and have received no hormonal therapy in the past year. The results of this trial could substantially expand our understanding of the cardiovascular risks of ADT. I encourage participation.
When considering risk, it is also important to note that the metabolic effects of ADT differ somewhat from the “classic” metabolic syndrome.29 For example, ADT is associated with increased adiponectin and normal C-reactive protein levels, while the opposite occurs in the metabolic syndrome.29 Also, unlike metabolic syndrome, prolonged ADT increases both low and high-density lipoprotein (HDL) levels and both subcutaneous and visceral abdominal fat.29,30 In a widely cited prospective observational study, men with prostate cancer who received ADT typically experienced a 22% increase in visceral abdominal fat, a 13% increase in subcutaneous abdominal fat, and a 12% increase in insulin resistance.30 The authors hypothesized that insulin resistance might result from visceral fat accumulation, rather than sex hormone deficiency.30.
As our options for GnRH antagonism expand, we will need to continue to ascertain their relative safety. For example, the phase 3 HERO study (NCT03085095) is comparing the investigational oral GnRH antagonist relugolix with leuprolide in men with advanced prostate cancer. Topline results are expected in 2019 and I particularly await the safety results of this trial.
Screening and the ABDCEs of risk management
Based on these data, it is clear that risk management is of primary importance when administering ADT. We need robust, multifaceted strategies to address the diverse cardiovascular and closely linked metabolic risks of these treatments.
The American Heart Association, the American Cancer Society, the American Urological Association, and the American Society for Radiation Oncology have published detailed recommendations on assessing and managing cardiovascular risks in men being considered for ADT.31 Before starting ADT, patients should be evaluated for pre-existing cardiovascular disease and for untreated or undertreated metabolic risk factors.5,31A complete history and physical exam should evaluate patients for current or historical angina, congestive heart failure, valvular disease, arrhythmias, and hypertension.5 Patients with established or suspected cardiovascular disease should be referred to a cardio-oncologist or cardiologist.
All patients should have a baseline blood pressure, lipid and metabolic panel, HbA1c, and electrocardiogram. 5,31 Patients with signs of congestive heart failure or structural heart disease should have a follow-up echocardiogram.5 I recommend follow-up screening every 3 months, which should include, at a minimum, a metabolic profile, lipid panel, and blood pressure.31 Regular follow-up monitoring is especially important because patients with pre-existing cardiovascular disease are at greatest risk of cardiovascular events during the first 6 months of ADT.32
In addition to publishing the AHA/ACS/AUA guidelines, experts have tailored the ABCDE paradigm to specifically address ADT.5 Initially developed for survivors of breast cancer, the ABCDE acronym stands for awareness and aspirin, blood pressure, cholesterol, and cigarettes, diabetes, diet, and exercise.5,33
In terms of awareness, patients should be educated to watch for chest pain or discomfort, shortness of breath on exertion, fatigue, nausea, sweating, light-headedness, headache, and sudden onset of chest discomfort or pain that may radiate to the neck and jaw. Limited data indicate that daily aspirin may decrease prostate cancer-specific mortality.5
For managing blood pressure, angiotensin converting enzyme inhibitors may be particularly helpful. I recommend a cardio-oncology consult for patients with pre-existing hypertension, especially if it is not well controlled (a common treatment goal is less than 140/90 mm Hg). For cholesterol, consider cardiology consult for high-intensity statin therapy, especially if patients with hyperlipidemia also have established cardiovascular disease or diabetes.5 In terms of cigarettes, smoking independently increases the risk of death in patients with prostate cancer, and they should be counseled to completely avoid tobacco products and referred for smoking cessation treatment whenever possible.5
In terms of diabetes and diet, ADT can worsen glycemic control, making it important to monitor blood glucose regularly and adjust diabetes therapies as needed. I counsel patients that ADT often leads to weight gain and that their diet should emphasize vegetables, fruits, lean protein, and whole grains. Evidence supports this approach: In a small, single-blind, randomized controlled pilot trial of men receiving ADT for prostate cancer, a 12-week intervention consisting of improved diet and group-based cognitive behavioral therapy led to significant improvements in muscle strength, body composition, and mobility.34
Exercise is one of the most important ways to mitigate the cardiovascular and metabolic risks of ADT. For example, resistance exercise can prevent and even reverse adiposity in these patients. In a year-long multicenter analysis of men starting ADT in the RADAR trial (NCT00193856), early initiation of exercise helped preserve body mass index, lean body mass, bone mineral density, fat mass, and cholesterol.35 In contrast, the control group showed increased adiposity, sarcopenia, dyslipidemia, and bone loss.35 In a single-center study, men receiving ADT who exercised 3 times. weekly for 12 weeks lost an average of 2 cm in waist circumference, while non-exercising controls gained an average of 0.7 cm.36 Notably, none of the exercises developed metabolic syndrome, compared with 8% of controls.36 In a third study of men receiving ADT, 12 weeks of resistance training improved lean muscle mass, body fat percentage, and prostate cancer-specific quality of life but did not significantly reduce the risk of metabolic syndrome over this short time period.37 Data from other controlled studies indicate that resistance exercise improves quality of life and reduces cancer-related fatigue in advanced prostate cancer.38
We can expect more robust data on how to mitigate the cardiovascular risks of ADT from the RADICAL-PC trial (Role of Androgen Deprivation Therapy in Cardiovascular Disease – A Longitudinal Prostate Cancer Study). This study seeks to ascertain risk factors for ADT-emergent cardiovascular disease by following men with newly diagnosed prostate cancer or who are being prescribed ADT for the first time.39 Embedded within this study is RADICAL PC2 (NCT03127631), a randomized, controlled trial that is comparing usual care with an intervention consisting of behavioral modifications (nutritional advice, exercise, and smoking cessation), as-needed antiplatelet therapy, statin therapy, and ACE inhibitor therapy.39 RADICAL PC2 continues to recruit patients, and primary results are expected in 2020. If the RADICAL PC2 intervention is found to negate the cardiovascular risks of GnRH agonist therapy, that would potentially give our patients with prostate cancer and cardiovascular risk factors more options for ADT.
Behavioral and pharmacologic risk management is doubly important because the second-line ADT agents abiraterone acetate and enzalutamide both show cardiovascular safety signals.40 Abiraterone can cause mineralocorticoid excess, which in turn can induce or exacerbate hypertension, hypokalemia, and fluid retention. In a prospective study of patients with metastatic, castration-resistant prostate cancer who also had risk factors for coronary artery disease, 6% of patients developed hypertension after starting on abiraterone, and 30% of patients experienced worsening of pre-existing hypertension.41 Enzalutamide also has been associated with hypertension, and a meta-analysis of more than 8,000 men receiving either abiraterone or enzalutamide reported an 84% increase in the risk of high-grade cardiac toxicity and a more than two-fold increase in the risk of high-grade hypertension. 42 We need more data on the cardiovascular safety of these therapies, but for now, we should assume that they pose a cardiovascular risk and pursue baseline and follow-up monitoring, cardio-oncology referrals, and behavioral risk modifications.
Just three years ago, ADT alone – whether with a GnRH agonist, a GnRH antagonist, or both – was the standard of care for metastatic hormone-sensitive prostate cancer, with docetaxel added after disease became castration-resistant. That changed in 2015, when upfront docetaxel plus ADT was found to significantly extend overall survival by a median of 13.6 months in the CHAARTED trial (NCT00309985) and by a median of 15 months in the STAMPEDE trial (NCT00268476).43,44 In 2017, additional results from the STAMPEDE study and results from the LATITUDE trial (NCT01715285) showed that upfront combination therapy with ADT and abiraterone (plus prednisone) also significantly improved overall survival and radiographic progression-free survival compared with ADT alone in men with hormone-sensitive. metastatic prostate cancer.45,46 Enzalutamide is also under priority FDA review for approval in combination with ADT for men with M0 castration-resistant disease and rapidly rising PSA levels. In the pivotal phase 3 PROSPER trial, these patients had a median metastasis-free survival of 36.6 months with enzalutamide plus ADT, versus 14.7 months with ADT plus placebo.47
The results of these studies are practice-changing,48 but questions remain about sequencing. Most of our patients with advanced prostate cancer will eventually receive both docetaxel and a second-line ADT agent during their disease course. In the STAMPEDE trial, after a median follow-up time of 4 years, abiraterone-ADT versus docetaxel-ADT showed no significant differences in median overall survival, metastasis-free survival, prostate-cancer-specific survival, or rates of symptomatic skeletal events.49 Therefore, the question is not so much which treatment to use, but which to use first.
Unfortunately, STAMPEDE and LATITUDE did not compare different sequences of docetaxel and abiraterone. Physicians might be tempted to use abiraterone first to spare patients the toxicities of chemotherapy. However, this is not necessarily the best choice. Patients who are relatively strong, with good performance status , may better be able to tolerate docetaxel upfront, and data suggest that this sequence can help maximize docetaxel’s benefits. Because of differences in hepatic uptake, castrated men with prostate cancer have been shown to clear docetaxel about twice as rapidly as uncastrated patients.50 Thus, by delaying docetaxel until patients become castration-resistant, we can inadvertently weaken treatment response. As long as docetaxel is part of our prostate cancer armamentarium, we need to consider when to use it relative to ADT.
Fortunately, an ongoing phase 2 study (NCT03069937) should help inform this issue. In this trial, men with metastatic, hormone-sensitive prostate cancer are receiving four cycles of docetaxel, followed by two cycles of docetaxel plus degarelix, followed by five additional doses of degarelix (once every 28 days). If readouts are positive, we can expect a large phase 3 follow-up study. Another question is when and whether to consider upfront triple-combination therapy with ADT, abiraterone, docetaxel. The ongoing phase 3 PEACE1 trial (NCT01957436) is evaluating this regimen in men with metastatic hormone-sensitive prostate. cancer. Primary results are expected in 2019. Other trials, such as ARCHES (NCT02677896), ENZAMET (NCT02446405), and STAMPEDE arm J, also are comparing the efficacy of ADT, docetaxel, and one or more second-line ADT agents with either ADT plus docetaxel or second-line ADT monotherapy. The results of these studies should help us determine the best treatment sequences for our patients with advanced prostate cancer.
In the near future, genomic profiling will probably help us better individual patient treatment selections. Demographics are also an important consideration. At ASCO 2018, an analysis of the Abi Race trial (NCT01940276) showed that abiraterone induced deeper PSA responses in black men compared with white men.51 Median time to PSA progression was 16.6 months versus 11.5 months, respectively.51 Adverse events, including hypertension, were mostly comparable between groups, but white men had a higher rate of fatigue (40% versus 26% for black men) and black men had a higher rate of hypokalemia (36% versus 18% for white men).51
Such findings underscore the need for diversity when enrolling patients in clinical trials, particularly because we now have powerful tools to assess the genetics of risk at a granular level. For now, I recommend carefully considering each patient’s fitness, comorbidities, tumor characteristics, and expected disease trajectory.
Androgen deprivation therapy remains foundational in the treatment of advanced prostate cancer. Hormone suppression is associated with a variety of important adverse effects, of which cardiovascular and metabolic complications especially overlap. Multiple studies indicate that GnRH agonists may increase the risk of cardiovascular disease and major adverse cardiovascular events more than GnRH antagonists. In addition, degarelix is associated with faster testosterone suppression without flare and longer PSA-free survival. Pending the results of the PRONOUNCE study, I consider degarelix instead of GnRH agonist therapy for men with a history of cardiovascular disease or a PSA level exceeding 20 ng/mL or metastases. Baseline and regular follow- up monitoring should ascertain cardiovascular and metabolic risk factors and changes. Emerging data indicate that multifaceted behavioral interventions can help positively modify cardiovascular and metabolic risk, although we await results from the RADICALPC2 trial to help quantify their impact. As new therapies for advanced prostate cancer shift toward earlier-stage treatment, we must carefully consider how best to sequence and combine ADT, second-line and next-generation ADT, docetaxel, and other therapies. A tailored, individualized approach should account for patients’ fitness, disease characteristics, and comorbidities. Genomic tools may soon help us personalize treatment and sequencing to optimize both efficacy and safety.
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48. NCCN.org. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines Ò ): Prostate Cancer. Version 3.2018- June 21, 2018. https://www.nccn.org/professionals/physician_gls/pdf/prostate. pdf Accessed June 27, 2018.
49. Sydes MR, Spears MR, Mason MD, et al. Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol. 2018 May 1;29(5):1235-1248.
50. Franke RM, Carducci MA, Rudek MA, et al. Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer. J Clin Oncol 2010 Oct;28(30):4562-4567.
51. George DJ, Heath EI, Sartor AO, et al. Abi Race: A prospective, multicenter study of black (B) and white (W) patients (pts) with metastatic castrate resistant prostate cancer (mCRPC) treated with abiraterone acetate and prednisone (AAP). Presented at: American Society of Clinical Oncology; June 1-5, 2018; Chicago, IL, USA. Abstract LBA5009.
Written by: Thomas E. Keane, MBBCh, FRCSI, FACS, is professor and chairman of the Department of Urology at the Medical University of South Carolina in Charleston. Dr. Keane specializes in managing prostate, bladder, and renal cancers. An avid researcher, Dr. Keane has served as principal investigator or co-investigator on more than 20 major clinical and preclinical studies, funded by grants from the National Institutes of Health as well as industry-funded. Much of his work focuses on innovative concepts in translational research, including utilizing human tumor xenografts to investigate the efficacy of new therapies as they relate to GU malignancies with particular reference to cytotoxic agents, sphingolipids, and boron-containing compounds. He holds a U.S. patent for sphingolipid derivatives and their use.