Cardiovascular Risk Assessment and Management in Prostate Cancer Survivorship - Ravi Parikh

Ravi B. Parikh: I'm Ravi Parikh. I am a GU Medical Oncologist at the Atlanta VA and at Emory University.

And so I guess maybe just to start, how many of you have had a patient where you're treating them, you're their primary urologist, radiation oncologist, oncologist for their prostate cancer, and they don't see their primary care doctor nearly as much as they see you? That's pretty much all of my patients.

It's a question of whether they even see their primary care doc at all. And so usually, I think that the point of this talk is that very frequently we, as their definitive treatment manager, or as their systemic therapy giver, we are oftentimes their primary care doc. And so we shouldn't lose sight of the type of things that will cause them to run into problems when and if they get long-term disease control.

So I'm going to touch on five or four major topic areas that have to do with survivorship care, consequences of the treatment that we may give patients or emerging concerns that oftentimes get ignored. I realize that there are far more domains of survivorship care than cardiovascular health, vasomotor symptoms, bone health, and sexual health.

These are the ones where I think there have been some interesting updates in current practice so I wanted to touch on these. These are also areas where I oftentimes have something to say to my fellows rather than other elements of their survivorship care plan, like check their PSA every three months, or get screened for colorectal cancer.

Those guidelines really haven't changed much. So I'll focus on these four, but if there's any other elements of survivorship care you want to talk about during the discussion, we can talk about those as well. So I'm a medical oncologist, so I'm a little biased towards talking about consequences of the type of therapy that I give, ADT, but I'm going to play a urologist during the sexual health part and talk about things that I have no business giving patients.

And so we can have a more in-depth discussion than if you've had good experiences. Okay. So cardiovascular health, this is one of the...

For most of our patients, the leading cause of mortality, regardless of whether they are localized, early stage metastatic, it's in the castration-resistant period where they have a high likelihood of dying from direct prostate cancer-related adverse effects. But even nowadays in the hormone-sensitive setting, if you look at the average leading causes of death for metastatic castration-sensitive prostate cancer in the modern era, you'll see that cardiovascular disease is right up there with prostate cancer, which just tells us how well we've been doing with treating their metastatic disease and how potentially toxic their therapies can be.

So I wanted to give a little bit of an overview of how androgen suppression injures our cardiovascular system because I think it gives insight into what we should be doing to control it. So this comes from a review that was written by Vivek Narayan and Alicia Morgans. And so we know that hypogonadism that we induce leads to loss of testosterone and estradiol, and it's really that estradiol loss that leads to a lot of the adverse cardiovascular effects that we see.

You can see samples of what we, I won't go through the mechanisms of how our different agents tend to cause cardiovascular dysfunction, but you can read those on the pathway figure on the right. But central adiposity, sarcopenia, dyslipidemia, glucose intolerance, these are all mechanisms of how we induce cardiovascular injury.

And the point is that it used to be thought that a lot of the side effects of ADT were atherogenic in nature, but the adverse effects that you see from ADT happen a lot faster than it takes to develop a coronary artery plaque or a vascular plaque. And so most of this we think now is happening as a result of hormonal-related changes outside of plaque formation, things that have to do with the FSH surge at the initiation of a therapy like Lupron or abrupt transitions between hormonal states, especially when we do things like intermittent hormonal therapy, which there are some case reports that have higher cardiovascular-related side effects than giving continuous ADT, so you can read about some of that.

I don't know the exact mechanism by which that happened, but it's thought that some of the hormonal imbalances that we induce through an intermittent approach may lead to some adverse cardiovascular injury as well. And so you've read a lot recently about how there have just been increasing attention to cardiovascular screening for our patients so that we can recognize injury when and if it happens.

But unfortunately, we don't screen our veterans in particular for cardiovascular risk factors enough. So this comes from a study that was led by Lova Sun, who's now a thoracic medical oncologist at Penn, but has done a lot of VA-related research. And so she took a national cohort of veterans and actually coded using administrative data a series of ACC- and AHA-recommended cardiovascular screening measures.

It took a lot of work because EHR data is very messy, but she came up with probably the most up-to-date data on how well we do with cardiovascular screening. And this is across med oncs, urologists, rad oncs. Only about 68% of patients who were diagnosed with prostate cancer received comprehensive cardiovascular risk assessment.

Of those, 54% had uncontrolled risk factors and of those 54%, 30% were not receiving risk reducing medication at the time. You can see that from the graph here, what was really interesting, what she found was that rates of cardiovascular screening had much more to do with whether they had baseline cardiovascular disease, but essentially nothing to do with whether they started ADT or not.

And so what that told us was that maybe the fact that they may have been in primary care was a strong determinant of whether they got screened because oftentimes your ASCVD risk factors are triggering primary care docs to screen for cardiovascular risk factors. But the baseline cardiovascular risk assessments that are recommended by our NCCN and ACS survivorship guidelines were just not necessarily doing enough when we start ADT.

And so I think studies like this have really prompted me to think about survivorship care and cardiovascular risk screening as a bit of a bundle, like a go/no-go when I start ADT on patients because it would be terrible if these patients went through and they're not seeing their primary care doc for them to not be monitored for this kind of stuff.

I mean, so there are structured approaches for cardiovascular risk assessment and mitigation. This comes from an ACC, AHA guideline-based statement that came out in 2016, and it's sort of a simple mnemonic for us to remember. A, awareness and aspirin, doing a formal ASCVD risk assessment, so plugging in the variables in that calculator that you see online and discussing cardiovascular risk explicitly at the ADT consent conversation.

I even recently started a statin on a patient a couple of months ago when I was seeing them and it was a big moment for me, I hadn't done that since my internal medicine residency. But the point is that we oftentimes ought to be doing this for our patients because they're not getting seen by their primary care docs or cardiologists.

Blood pressure management, measuring at every oncology visits. I can't tell you, the default state for my vets when they come in is a state of hypertension during their visits, and so it's just a question of how much. But the decision can't be, okay, BP 180, we got to refer them to the ED or we do nothing.

There are ways for us to manage their blood pressure, increase their baseline antihypertensives, and then ensure that they have close management with their PCP who they may or may not be seeing. Cholesterol and cigarettes, so at least measuring lipids at baseline. Diet and diabetes, we'll talk a little bit about diet later.

And then exercise we'll talk about later as well. These guidelines actually recommended a formal cardiology, or if you have one, a cardio-oncologist referral if they have greater than two uncontrolled risk factors out of these that you see here. And so that probably constitutes a large proportion of what we see, and so we should be a little bit more forward about either managing or referring.

There are guidelines about what we should do and how often. I'll share these slides but won't necessarily go through them. I think one of the points that we should mention here is that there is added cardiovascular risk largely through additional hypertension risk from our ARPIs that we're increasingly giving to our metastatic and our localized patients.

And this is treatable, but often ignored. And this is common across all of our ARPIs, even though abi might have an increased risk, this is pretty much a uniform risk factor that we ought to be aware of. ADT can cause insulin resistance within months.

New onset diabetes does happen. And then sarcopenic obesity is the earliest, most visible change as we know for our patients. Not every patient needs a stress test, so that's not necessarily what we should be referring our patients for, it's more so measurement of these risk factors.

Okay, so now let me get to things beyond just risk factor assessment. So one of the foremost areas that in cardiovascular risk prevention, one of the formal studies that came out was the HERO trial that showed that there was a reduction in major adverse cardiovascular events with the use of relugolix as opposed to GnRH agonists like Lupron for someone's primary hormonal therapy.

And so for those of you who haven't used relugolix, it's an oral non-peptide GnRH receptor antagonist, not an agonist like Lupron is. There's no initial receptor antagonism, so we don't need to give the Casodex lead-in when we use this drug. It's rapidly reversible, and it has some SIPS inducer exposure or interaction as well.

The points about relugolix that I want to come across, because increasingly I find that I use it a lot in my Emory clinic and not as much in my VA clinic and I sometimes wonder why. It has to do sometimes with our formularies, but there is a reason why we often not ought to be defaulting to relugolix for everyone.

So for one, the sustained castration rate is a less than 10% difference, but it is higher with relugolix and there is a quicker on and off for testosterone suppression with relugolix that was seen in the study. But the major point that got a lot of attention was the fact that the cumulative incidence of MACE was about three absolute percentage points, but the hazard ratio was over 50% lower when you use this drug.

So on one hand, this is a real effect. On the other hand, the smaller absolute effect, it can be justified that you should be careful about using this much more expensive drug, and one that depends on oral adherence to achieve sustained castration. And so I'll usually reserve this if someone has a prior history of MACE.

I won't usually defer to that if they have just a baseline risk factor like hypertension or hyperlipidemia. If they've had prior coronary artery disease, or a prior heart attack or stroke, that's usually when I'll make the push to the VA formulary folks to really push for this. But I realize practice is different, and it is a lot easier to get this approved sometimes in the commercial insurance setting.

Some of my colleagues at Emory, Sagar Patel and Anant Mandawat, two PCF-funded investigators, did this really interesting randomized trial where they tried to uncover the mechanism by which relugolix may lead to lower cardiovascular risk factors. And it did look like plaque volume buildup was one of the major mechanisms of this effect.

And so this is interesting because we know that Lupron-induced cardiovascular effects isn't necessarily plaque buildup, but it does look like the reason why relugolix has some improved MACE benefit does have to do with long-term plaque buildup, and they used some really interesting techniques in this randomized trial to elucidate that.

So this is a summary of recommendations around cardiovascular care. I think it largely has to do with risk factor assessment, recognition of uncontrolled risk factors to refer to a cardiologist if need be, and then use of relugolix if someone has a history of prior MACE or significant uncontrolled cardiovascular risk factors.

There are some controversies in cardiovascular management that I'll want to just call across. One is that many of the risk calculators that are prompted to be used are primarily trained in non-prostate cancer populations, and so we don't, sometimes the exact thresholds that are used for triggering say statin use are not necessarily tailored for our population.

I already mentioned the fact that I'm not completely convinced that we ought to be using GnRH antagonist for everybody. There have been trials with prior GnRH antagonists like degarelix that were negative, like the PRONOUNCE trial, and so this isn't necessarily a uniform benefit, although I do think there's a mechanistic possibility here.

There've been a lot of trials in particular from the STAMPEDE group around metformin use, but many of these have not necessarily shown super meaningful effects on metabolic syndrome, and so I don't routinely offer metformin for my patients. And then there's cardio-oncology referrals, which may or may not be available at your centers.

So now, let's talk to vasomotor symptoms, which is the main reason why my patients hate me when I start ADT. I under-screen for the significance of vasomotor symptoms. I'll just tell you up front, and I think we routinely do this for patients on ADT.

It's not just a question of whether they are or whether they aren't having hot flashes. It's also a question of are they daily? Are they multiple times per day?

Are they resulting in functional deficits? And then when during the day are they happening? And I think that all can play into your management strategy as I'll tell you about in a little bit.

This is a summary of what our current guidelines offer for vasomotor symptom management. Venlafaxine probably has the best established prospective data for use in men. Gabapentin, because it's additionally sedative, is sometimes preferred for when men have significant nighttime hot flashes.

And then I'll tell you a little bit about a randomized trial that was published this past year on use of oxybutynin for control of hot flashes that's led to it to be my preferred agent for managing hot flashes in several men. We'll talk a little bit about Veozah or fezolinetant, but I've never treated a patient with it yet for hot flashes.

Some of you may have, I have not. I think we tend to under refer for behavioral- and lifestyle-based therapies, which compared to some of our medication-based therapies, acupuncture has some of the best prospective data for hot flash management. And unlike in commercial settings, many of us can actually refer veterans for acupuncture a little bit easier.

I know at the Atlanta VA, there is dedicated acupuncture centers that we can refer to. So something that I'd encourage some of you to think about. And then there are hormonal-based therapies like low-dose estradiol because it should be remembered that hot flash symptoms are a result of estrogen withdrawal, not testosterone withdrawal that have shown effect, particularly for the low-dose estradiol, although I'll usually refer to endocrinology and not administer that myself.

A practical sequence for thinking about hot flash management is to start with venlafaxine or gabapentin if a patient has a co-indication for them like mood, neuropathy, or insomnia. If they don't have a contraindication, then oftentimes I'll start with oxybutynin because it's cheap, generic, and now has randomized evidence.

Although as I'll mention, there are anticholinergic side effects that we need to worry about with oxybutynin. And then there's a pathway now that's present in some guidelines to escalate to NK3 antagonists like Veozah for refractory symptoms. And I'll show you a recent New England Journal article about that.

So let's talk a little bit about oxybutynin, which is my new preferred agent for hot flash management. I usually start with 2.5 milligrams BID, although in someone who you're really concerned about confusion or dry mouth or who may have anticholinergic interactions with some of their meds, sometimes you can start with two and a half milligrams at night.

In this randomized trial published in NEJM, they ran a three-arm study, oxybutynin five versus oxybutynin 2.5 versus placebo. And at each increased excessive dose, there was a significant reductions in the percentage of baseline hot flash scores. You can see on the graph on the right, it averaged out to about two to three less total absolute hot flashes per day, which for our patients is pretty meaningful.

As mentioned, it is a potent anticholinergic and the general population has been linked to falls and cognitive impairment so we don't want to take this drug lightly, although it could be argued that some of those side effects are similarly present for some of the SNRIs that are currently recommended as well so we have to just weigh out our potential side effect burden.

Usually the thing that prevents me from using it is med-med interactions. So I always try to talk to my pharmacist before prescribing this. Some of you may have come across this New England Journal of Medicine case report around Veozah or fezolinetant, which is a 45-milligram once-daily medication that is approved for women with vasomotor symptoms, but does not have a current prostate cancer approval, although there are some patients I've heard about getting it off label.

This is a remarkable case that they described about a patient who is refractory to many different types of medication management who got started on Veozah and had a profound reduction in their proportion of severe hot flashes that they had. And so something interesting to think about, it is quite hepatotoxic, and so you have to watch out for that.

And so I'll oftentimes, if I was going to use this drug, I would do it under close surveillance with an endocrinologist. Many of you may have seen the PATCH trial that came out earlier this year in New England Journal. This was a randomized trial that randomized individuals to getting their primary hormonal treatment with either transdermal estradiol, so four patches switched twice-weekly, versus Lupron.

This was non-inferior for metastasis-free survival. And essentially, the side effect profile was trading off hot flashes for gynecomastia. So that has to do a little bit with the mechanism of action.

As I mentioned, hot flashes are a symptom of estrogen withdrawal, and so if you're providing direct estrogen through this patch, then you're often able to mitigate hot flashes. That's also the reason why Casodex is associated with less hot flashes than Lupron, but that direct estrogen can cause gynecomastia.

And so the rates of gynecomastia here, 85%, were larger than is typically seen even with Casodex. So this isn't approved yet in the US. I believe it's available in Europe.

It may be coming and something to think about if it does come out. I'll skip over this a little bit. I'll just touch on this question about is the best drug to address vasomotor symptoms actually ADT choice.

So there's a lot of patients with refractory hot flashes that are difficult to control with medical management that are just on single-agent Casodex in my clinic. And either that's a relic from a prior treatment or something that I've done just because otherwise they would not be on any ADT at all because of the hot flashes.

And so as to whether that's a great strategy or not, I'm not sure, but hopefully with some of these additional hormonal therapy agents, we may have some better options. Okay, so vasomotor symptoms, what to take back to your clinic, ask about them. Oxybutynin is an agent that I would recommend trying.

Respect its anticholinergic burden though. When there's a co-indication for giving venlafaxine or gabapentin, consider those, and then for refractory hot flash symptoms, think about referral to endocrinology. Okay, let's talk a little bit about bone health, which I would argue is the largest gap in prostate cancer survivorship.

About 41% of our men have either osteoporosis or osteopenia prior to ADT start. And it's been shown that ADT leads to at least 3% loss in bone density, or sorry, on average 3% loss in bone density within the first year, and around 20% over five years for those men who are on long-term ADT.

And yet and still, in Medicare populations, and this is not too different at the VA, we only screen for bone density screening for about 8% of men who start ADT, which is just abysmal. Now, the takeaways are that we should be getting DEXAs and calculating FRAX scores for those men who are osteopenic before ADT starts in any man with a risk factor, which is basically anyone who starts ADT.

The guidelines are to treat with an anti-resorptive if either they have osteoporosis or osteopenia with a FRAX score that's greater than 3% for hip or greater than 20% for major osteoporotic fracture. Or if they have a prior fragility fracture, if they have evidence of a vertebral compression fracture, that's also an indication to starting bisphosphonate or a ligand inhibitor.

This is a checklist for bone health I have for every man on ADT, calcium, vitamin D, and then recommending resistance training. I'll talk about structured ways that we could recommend resistance and exercise training for our patients, alcohol and smoking cessation. The dosing distinction to remember, and this is something I often quiz the fellows about, is that osteoporosis dosing, so people who have either osteoporosis or high-risk osteopenia, dosing of bisphosphonates or denosumab is different than when they have bone mets like they in castration-resistant disease.

So you can see, for example, in denosumab, the dose is usually 60 milligrams every six months, but the dose for bone mets is usually every four weeks or three months in some studies. Same thing with zoledronic acid. So the point is that doses for fracture risk prevention are different than when they have bone mets.

And you can see some of the caveats around use of these drugs on the right-hand side. I won't go through all of these. Everyone who gets a bisphosphonate or denosumab, I usually try to get them to see their dentist beforehand, unless they have dentures and they're not planning any dental work and then I relax that requirement.

But there's just a lot of people who have, once they see their dentist, they have planned dental work and then I usually just have to delay the start of their bisphosphonate. Correct their calcium and vitamin D. I have caused hypocalcemia in a patient by giving them a bisphosphonate before because I didn't replete their vitamin D beforehand.

So I always tell my fellows, do that, and then check their renal function because denosumab is usable in renal impairment, but Zometa or another bisphosphonate is not. This is something that I haven't got burned by yet, but I've been told by the endocrinologist to watch out for. And that has to do with when someone uses.

Or actually, that's on the next slide. When someone is on Xgeva or Prolia or on denosumab, stopping denosumab is not a benign activity. Sometimes we think, "Oh, they're done with their ADT.

Let's just stop their Xgeva when they've been on it." And there's well established higher incidence of vertebral fractures when someone stops denosumab because the RANK ligand inhibition is over activated when someone stops. And so if you measure someone's alk phos when you stop denosumab, you'll actually see that it jumps up.

And so it's actually indicated that you cross taper with at least one dose of a bisphosphonate when you stop Zometa. So this doesn't happen all the time, but I do advise this for my patients or for the fellows when they're thinking about stopping denosumab. The best data for fracture.

So all of these halt the progression of bone density loss, but of course bone density loss is in a clinical event. The only agent that has fracture risk prevention is denosumab, and that comes from the Matt Smith HALT trial back in 2009 where they reduced absolute fracture risk by about two and a half percent.

So that number needed to treat translates to about 42 over three years. This hasn't really convinced me to use denosumab preferentially for my patients rather than Zometa. I'll usually base that decision on renal function, but it is something to be aware of when we're talking about using these medications.

And then actually, my PCF YIA was around fracture risk prevention screening using routinely collected CT scans. And so it should be noted that even though these aren't routinely used, there are existing algorithms that are billable and commercially available to measure bone density from routinely collected CTs.

And so this is a study that we ran showing that there's a high correlation between CT-assessed versus DEXA-assessed bone density. And so hopefully in the future we'll get to a point where we don't necessarily have to be ordering DEXAs on everyone starting ADT. We can just get them from their routine staging PET or CT scans.

Okay. So what to take back about bone health? Order the DEXA before your first ADT injection.