Neal Shore, MD, FACS: That’s a great segue to you, Alicia, and you touched on it a minute ago. We’re all familiar with how for years, we have been talking about the safety and tolerability issues of testosterone suppression. Historically we’ve all said, “Oh, hot flash, hot flush, sexual dysfunction, and bone demineralization.” But you mentioned earlier the issues around cardio-oncology and cardiovascular issues. There’s a warning for the agonists in their labels. But tell me more about how you’re doing things at Northwestern University Feinberg School of Medicine and a lot of the work that you’ve done on understanding these risk factors.

Alicia K. Morgans, MD, MPH: We have to really think about the whole metabolic profile when we’re starting these drugs or in the setting of orchiectomy, because it’s really low testosterone that’s probably driving a lot of the adverse effects we see. Though some of the specifics around cardiovascular disease may be more related to the agonist activity. But I always think about cardiac history. As you said, the GnRH agonists appear to actually raise—it’s not a huge amount, but some amount—cardiovascular risk. There are a greater number of cardiovascular events, and those could be anything from MI [myocardial infarction] to heart failure, or potentially others that haven’t really been teased out in patients, especially those at high cardiovascular risk.

We also know that we disrupt glucose control. Patients, especially those who are on the borderline or prediabetic, can develop overt diabetes, and we’ve seen this a number of times in my clinic, unfortunately. Maintaining that communication with primary care providers [PCPs], or checking glycated hemoglobin A1C levels in our clinic on our own, is an important part of practice. Certainly counseling patients so that they can be alerted that if you’re on this therapy, you may develop diabetes and you may want to make lifestyle changes up front can be really important as well.

We also see that patients can develop abdominal adiposity or fat deposits in their central region. They lose muscle mass more distally, so they don’t metabolize sugar as well when they’re losing muscle mass, and that also is a risk factor for cardiovascular disease. We also see disruptions in lipid profiles. HDL [high-density lipoprotein] goes up, which is a great thing, but that’s not enough to offset the LDL [low-density lipoprotein] and triglyceride increases that we also see, another reason that cardiovascular risk goes up.

Of course, you mentioned bone health. We know that there’s a decrease in bone mineral density with these drugs, which is really a result of the lower levels of estrogen that these patients have because testosterone undergoes peripheral aromatization into estrogens. We see that men actually have levels of estrogen that are lower than postmenopausal women in this setting, and that really upsets the balance of bone breakdown and bone formation to really shift in the direction of loss of bone mineral density.

Neal Shore, MD, FACS: Great points, really good information. This whole notion around cardio-oncology I find absolutely fascinating—how we’re evolving to be better stewards for patients, right? You mentioned a lot of different things to do, for example, just checking hemoglobin A1C. You’re all at tertiary, wonderful academic centers. I have 2 questions. The first question is, do you routinely send your patient with mCSPC [metastatic castration-sensitive prostate cancer] for cardio-oncology consultation? Or does it make a difference if they have a cardiovascular history? Because you mentioned these issues of MACE, or major adverse cardiovascular events, and we’re studying them in a prospective trial called PRONOUNCE looking at agonist versus antagonist therapy. There’s an oral GnRH antagonist that is going to be presented on when compared with an agonist looking at these MACE events, particularly in patients who have baseline cardiovascular comorbidities.

I’d like everybody to weigh in, are you routinely using cardio-oncology referrals? The second part of my question is, if you’re not—in the community, I don’t know how pervasive it is—what would be your recommendation? Should everyone get a hemoglobin A1C and a baseline EKG [electrocardiogram] if they haven’t had one in a while in addition to, obviously, serum chemistries?

Nancy Ann Dawson, MD: I don’t normally send people to cardio-oncologists. Maybe my population, even though I’m in a tertiary center, is a little different. I find that many men who I see who present with de novo metastatic hormone-sensitive disease haven’t been seeing doctors at all. I usually have to start with, do you have a PCP? Have you had your lipids checked at all? Have you had your glucose checked at all? We cover a lot of basic things, including whatever is heart healthy and prostate healthy and if they must lose some weight. We’ve got to get them a primary care doctor. Let’s check all the baseline tests and see where we’re at. Obviously there are other patients who have been getting regular health follow-ups, and if they do have cardiac problems, I do want to have a weigh in from a cardiologist.

Neal Shore, MD, FACS: There’s a spectrum of patients coming in who are getting the monthly executive panel or executive work-up in metropolitan areas versus the people out in the rural suburban areas who may be receiving a real lack of primary care. William, how is it for you?

William Oh, MD: I think this area is still a little controversial. Is it for the patients who already have a cardiologist with underlying cardiac issues and who are already on all these medicines that we should be worried about starting ADT [androgen deprivation therapy] in, or some of these new drugs? Or as Nancy was saying, is it somebody who has never seen a doctor? I actually worry more about the second. But in both cases, am I going to delay therapy for metastatic hormone-sensitive disease?

I really can’t, and my personal experience has been that unless they’re literally having angina in my office—in which case I might delay—I’m going to have to start them on therapy first. Having done that for many, many years, we don’t see a precipitous acceleration of cardiovascular events. We do see that some patients have cardiac events while we’re treating them. What’s hard to separate outside randomized clinical trials is, what was the event that caused it? There’s no question that the data suggest that androgen-targeted therapies, in fact, contribute to this. I do think that after you start therapy rather than before, because there’s a timeline here, I will refer patients. We do have an onco-cardiologist at Mount Sinai Health System, but they can’t always see all the patients. I’ll refer them to a cardiologist because in the end, the cardiology problem is the cardiology problem. Somebody can actually help us with that. But I do think a good internist can manage these issues: cholesterol, high blood pressure, and all the known cardiovascular risk factors.

Neal Shore, MD, FACS: That was a good summary. Anything else to add?

Alicia K. Morgans, MD, MPH: I would also say it’s important to talk to these patients about smoking cessation and diet. I totally agree that a good internist can take care of these things. Some oncologists or some advanced urology groups that have even an APP [advanced practice provider], who focuses on supportive care, can do a lot of this. There does need to be a systematic approach to caring for these patients. But I totally agree, it should never delay your ADT initiation because their metastatic prostate cancer is also a big problem.

Neal Shore, MD, FACS: Pedro, you do a lot of clinical trials. I think we all do. And I’m fascinated by always getting these baseline EKGs and hemoglobin A1C levels, especially in our patients. You serve underserved folks, and I serve a lot of them, too, in my clinical trials. Picking up things such as hemoglobin A1C levels of 11 mmol/L, bundle branch block, and possible prior MIs. That’s really important. You start to realize by just reflexively starting patients on ADT and other therapy, we do put them at risk. But what’s been your experience?

Pedro C. Barata, MD, MSc: I agree. You will find when you look for things, you’re going to find them, right? These patients, despite having metastatic disease, can also have more common disease like high blood pressure, diabetes, etc. I would argue not everybody has a cardio-oncologist next door who can help them. It’s great when we have them, but the reality is that most of us probably don’t have access to one right away. And if we do, it’s not going to be able to help 100% of our patients.

To me, 1 superimportant point is actually to make sure this patient is well engaged with a primary care physician, and we address the 5 factors that we usually quote: blood pressure, sugars—diabetes, if you will—bone health, diet, and exercise. If you start doing preventive medicine there or in case they already have some of those diseases, you already have an expert addressing them. Even though we don’t have level 1 data and we’ve been concerned about patients who already have risk factors for cardiovascular events, the reality of it is that if you control them from the get-go, you’re more likely to be managing them successfully. I think that’s a good message for us.

Transcript Edited for Clarity