Christopher Wallis: Hello, and welcome to this UroToday Journal Club. Today we're discussing a recently published review paper entitled Androgen receptor inhibitor treatments: cardiovascular adverse events and comorbidity considerations in patients with non-metastatic prostate cancer. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt, and with me is Zach Klaassen, an assistant professor in urology at the Medical College of Georgia.

Here's the citation for this recent publication, Urologic Oncology led by some of the real thought leaders in this disease space including Dr. Morgans, Dr. Shore, Dr. Cope, and Dr. McNatty as well as Javid Moslehi, who's a cardiologist focusing on cardio-oncology, Dr. Gomella and Dr. Sartor.

By way of background, the vast majority of patients diagnosed with prostate cancer present with non-metastatic disease, and following treatment of their localized disease, a non-metastatic CRPC may affect up to 34% of these patients. In the last few years, there've been a number of new approval of androgen targeting agents in non-metastatic CRPC including apalutamide in February 2018, enzalutamide in July 2018, and subsequently, darolutamide in July 2019.

Apart from their treatments, cardiac disease is a significant problem in prostate cancer patients. This is in part due to the overlap of demographics involving older men who have significant cardiovascular comorbidities and risk factors, and nearly half of all patients with prostate cancer have cardiovascular disease or risk factors. And so you can see in the table here, taken from Dr. Morgans' paper, that these risk factors including hypertension, hyperlipidemia, diabetes, metabolic syndrome, and kidney disease are very common in the patients we see in comorbidities including atherosclerosis, ischemic heart disease, heart failure, stroke, coronary artery disease, arrhythmias, atrial fibrillation, cardiomyopathy's, and valvular disorders are also similarly frequently seen in our patients.

However, it's very notable that many of these were deemed exclusion criteria, and as a result, patients with these conditions were not included in the seminal trials leading to approval of androgen access targeting agents in a non-metastatic CRPC.

So when we think about the pathophysiology of androgen inhibition and cardiovascular disease, Dr. Morgans and her colleagues remind us that androgens have a generally cardioprotective effect with antiarrhythmic effects, there is a dilation and protection from ischemic injury. And reduced androgens contribute to many risk factors for cardiovascular disease. And when we use androgen deprivation therapy in a therapeutic setting for patients with prostate cancer, we again can see the adverse cardiac effects. And so this is associated with end effects, including atherosclerosis, thrombosis, and ischemic cardiovascular disease mediated through a variety of mechanisms, including dyslipidemia, insulin resistance, and direct atherosclerosis.

In terms of real-world evidence and observational studies, numerous analyses have demonstrated increased rates of cardiovascular disease among patients who receive conventional androgen deprivation with GnRH agonists or anti-androgens. Patients who have advanced prostate cancer, those receiving abiraterone or enzalutamide, nearly two-thirds had pre-existing cardiovascular disease. And these patients had an increased six-month mortality compared to those who did not have preexisting cardiovascular disease at the time of initiation of abiraterone or enzalutamide. Additionally, the adverse cardiac effects of anti-androgen therapy appear to be independent of a history of cardiovascular disease, though with a greater magnitude among those who do have pre-existing history.

So when we look at the clinical trials, as everyone knows, there are three seminal trials assessing the use of these agents in non-metastatic CRPC. A total of seven publications and I've highlighted the first and last for each trial. But in addition to the outcomes we focused on, including MFS and OS, we can also gain significant insights into the cardiovascular burden of these treatments and this data.

And so this is a summary of phase three trials, just highlighting the oncologic endpoints. And as we know that metastasis-free survival and overall survival has significantly improved with the use of enzalutamide, apalutamide, and darolutamide in this disease space. However, it's worth noting that at the present date toxicity profiles in these included trials are somewhat less mature than the data available for conventional ADT. And it is important to consider the prevalence and incidence of cardiovascular disease taking into account that the duration of treatment is substantially longer among patients in the experimental arm than it is on the control arms. And finally, we must remember that there are no direct comparative data published to date between enzalutamide, apalutamide, and darolutamide.

So when we look at cardiovascular-associated adverse events in these seminal phase three trials, the authors highlighted key endpoints here, including hypertension, major adverse cardiac events, heart failure, and cerebral ischemia. And when we look at the PROSPER study of enzalutamide, we can clearly see that there are increased rates of high-grade major adverse cardiac events, as well as adverse events leading to death. When we look at SPARTAN, in the table we see rates of hypertension, which are somewhat higher, but although not hugely so, but the authors point out that adverse events leading to death occurred in 10 patients receiving apalutamide as compared to one who received a placebo.

And finally, when we look at ARAMIS examining darolutamide, we interestingly see that differences between the placebo and drug groups are somewhat lower, although rates of grade three or greater hypertension are somewhat more common in the experimental arm. And at this point, I'll pass it over to Dr. Klaassen to continue taking us through these data.

Zachary Klaassen: 
Thanks, Chris. So looking at the relationship between ARIs and CV toxicity, as Chris mentioned, there is no direct head-to-head comparison of this data, but several studies have looked at this in various fashion. This meta-analysis of PROSPER, SPARTAN, and ARAMIS found that there was a relative risk for hypertension of 1.21 for apalutamide, 1.45 for darolutamide, and a higher for enzalutamide at 2.15. Looking at the relative risk for cardiovascular events, much higher for apalutamide, relative risk of 4.47, 2.71 for darolutamide, and 2.13 for enzalutamide. It's also important to note that enzalutamide has a known association with QTC prolongation. Previous studies have shown that there's maybe a modest QTC prolongation with apalutamide and to date, there's no effect on QTC with darolutamide that's been reported.

Also, it's important to look at drug-drug interactions among these patients taking ARIs and cardiovascular disease medications, given that these patients are elderly, and a lot of these patients will be on various medications. So to highlight here briefly enzalutamide, we know is a strong inducer of CYP3A4, which has interactions with several anticoagulants, including warfarin. Also of note Losartan is metabolized in the same pathway. In terms of apalutamide, is similar form of pharmacokinetic profile as enzalutamide and there could be a theoretical interaction with vitamin K antagonists, such as warfarin, but there's been no current reports of this interaction.

Darolutamide probably has the most evidence in terms of specific analysis of drug-drug interactions and pre-specified in post-talk analysis of ARAMIS. There was a study looking at pharmacokinetics of darolutamide and other medications, including statins, beta-blockers, anti-hypertensives, and anti-thrombotic. And so far there's been no significant drug-drug interactions between darolutamide and these medications.

So this is a table looking at drugs for cardiovascular disease and their metabolic pathways. And so what I'll do is I'll direct you to the right side of the slide and this table. In the boxes, there's several important things that I'd like to highlight. So in terms of anticoagulants, as I mentioned before, there's a strong potential for apalutamide and enzalutamide with regards to warfarin exposure. In terms of some of the other more commonly used anticoagulants, for the most part, these affect apalutamide with regards to reducing rivaroxaban exposure, dabigatran, et cetera. When we look at the anti-platelets such as Plavix, the authors note that we should monitor for increased apalutamide related adverse events and avoid co-administration with enzalutamide as well.

Moving down the table to the beta-blockers, with regards to propranolol, we should be monitoring for reduced effect if apalutamide or enzalutamide are co-administered. At the bottom of the table with the terms of the calcium channel blockers, such as amlodipine, detussin, nifedipine, and verapamil, we should monitor blood pressure if used with apalutamide or enzalutamide. And so you can see here that the majority of these effects are regarding enzalutamide and apalutamide.

This is a continuation of this table. Looking at the digoxin, we should monitor the digoxin levels of apalutamide as given. Moving to the statins, specifically atorvastatin, we should monitor for decreased efficacy if co-administered with apalutamide or enzalutamide. And rosuvastatin, we should use caution or avoid co-administration with darolutamide. So, in summary, as I mentioned in the previous slides, most of these interactions are with enzalutamide and apalutamide with only rosuvastatin having a bit of a warning label for the coadministration with darolutamide.

In terms of health related quality considerations, these are important when you have essentially similar efficacy data amongst these three medications for non-metastatic CRPC. And in generally, treatment with ARIs did not adversely affect health-related quality of life for these patients. So in PROSPER, these patients for evaluate with FACT-P-EQ-5D-3L and the EORTC QLQ-PR25 metrics and men receiving enzalutamide reported improved or stable health-related quality of life during the followup. Similarly, for SPARTAN and ARAMIS, men receiving apalutamide and darolutamide, respectively had high health-related quality of life during the treatment compared to placebo.

There has been another study looking at matching adjusted indirect comparison of health-related quality of life for patients from the PROSPER and SPARTAN trials. And generally, patients receiving apalutamide had improved fatigue, less hypertension, improved appetite, and less falls, headaches, and nausea. Dr. Morgans and colleagues had a very nice algorithm, which they called the ABCDE Algorithm for managing patients with prostate cancer and cardiovascular disease. And generally, there should be a multidisciplinary approach. So walking through this, in terms of healthcare providers and patients, there should be awareness of these interactions. There should be good control of blood pressure, good control cholesterol, and always a movement towards smoking cessation. As with all patients, diet is important as well as control their diabetes. And especially for patients on ADT plus these ARIs exercise is important for overall wellbeing, as well as bone and muscle health.

So several quick discussion points from this great review paper from Dr. Morgans and colleagues, they note that ARIs are associated with increased risk of hypertension and major adverse cardiovascular events that have been observed in the phase three trials of PROSPER, SPARTAN, and ARAMIS. Complete data regarding cardiovascular toxicity for darolutamide is not available given the fact that darolutamide is only indicated for non-metastatic CRPC at the current time. And thus there's fewer patients with less followup than those receiving enzalutamide or apalutamide.

Interestingly results of the HERO trial, which were published last year in the New England Journal of Medicine by Dr. Neal Shore and colleagues demonstrated a subgroup analysis of patients with a history of cardiovascular events that had lower incidents of major cardiovascular events and those receiving the GnRH antagonist arm at 3.6% versus the GnRH agonist arm at 17.8%. So perhaps these patients with cardiovascular risk factors should be getting a GnRH antagonist.

So in conclusion, ARIs are treatment options for patients with non-metastatic CRPC and cardiovascular comorbidities, and importantly, the complexity of these patients warrants a multidisciplinary treatment approach. And finally, because the ARIs vary with regarding the cardiovascular risk, it is important to take cardiovascular comorbidities into account when prescribing ARIs. Thank you for your attention. And we hope you enjoyed this UroToday Journal Club.