Key Challenges in the Administration of Leuprolide for Advanced/Metastatic Prostate Cancer

Dr Paul Sieber, a urologist based in Lancaster, Pennsylvania, recently discussed the nuances of administering leuprolide, a medication for advanced prostate cancer, in a conversation with UROLOGY TIMES®. Dr Sieber highlights the need to be aware of potential adverse events, particularly the increased risks of cardiac events and osteoporosis. Emphasizing the importance of patient-centric care, Sieber underscores the significance of monitoring and managing side effects, like weight gain leading to insulin resistance and altered lipid profiles. He advocates for a team approach in clinics, integrating the expertise of nurse practitioners and physician assistants to ensure comprehensive patient monitoring and to optimize treatment outcomes.

PAUL SIEBER, MD: I'm Dr Paul Sieber. I'm a urologist in Lancaster, Pennsylvania. I work at Keystone Urology Specialists and my specific role as the Medical Director for Clinical Trials.

UROLOGY TIMES®: What are some adverse events you expect to see with leuprolide? Are the expected adverse events similar to what you see in practice?

PAUL SIEBER, MD: Well, there's two answers to that question. One is, are there differences among the lookalike products in terms of adverse events? And that comes specifically to injection technique. So, you have products that are both subcutaneous in terms of how they're injected and intramuscular. So, what I do sometimes see as a problem is patients who are in a coagulated you run into issues with an intramuscular injection with a bleed afterwards. So, I get a little bit nervous when I'm injecting an intramuscular shot, especially the six-month depo, which is a reasonable volume, and someone hasn't coagulated and I'm going to lean towards giving them a subcutaneous injection. So, I don't have that issue. I can apply direct pressure on the injection site after that's completed. The more generalized question is, are there other side effects from leuprolide slide or adverse events? That is more unique to just androgen deprivation therapy in general for them, for those agents that we've come over the years to say that it's not benign to give an agent that's going to deplete testosterone. And they run into all those side effects, which consists of aggravated or worsening risks of cardiac events. They run into osteoporosis, and those are the two biggest things that we have to really be on the lookout for to be aware of. So, you want to be managing cardiovascular events more carefully. You want to be looking out for us to process. And those are specific adverse events that happen to anybody, whether they're having some type of pharmacologic manipulation of androgen deprivation or going back to an old fashioned or key activity for androgen deprivation. So that's a very generalized topic for all interested in a reduction in.

UROLOGY TIMES® Could you discuss some adverse events seen with leuprolide?

PAUL SIEBER, MD: Well, I’ll back up a little bit on adverse events. So, there's also some thought process at adverse events when you look at an antagonist versus an agonist. And I think what we've seen across the country is a migration to more advanced disease at presentation. And I'm seeing more and more men walk in the door with symptomatic metastatic disease at presentation. And that, at least at the start, makes me pause and think what I'm going to pick. So, if I pick a typical super agonist, a liberal ad, it will pick. You have to worry about that first 14 days, you're going to see a slow rise in testosterone before you see it fall off and you have the potential risk of a flare. So, I think I'm concerned about a patient who walks in the door in terms of thinking about giving them an agonist that I might flare the disease. You can give them an anti-androgen and that will blunt that effect, but that's not 100% guarantee. So, I think that very symptomatic patient, you may lean towards an antagonist at the start versus an agonist. After they become castrate, that issue disappears. So that's not necessarily a long-term issue, but certainly a short-term issue that makes that initial decision making about what going to give a patient important in the long run. There's a difference in terms of what I'm thinking in terms of managing those patients, because the agonists have a long acting depo, which is kind of nice, whereas the antagonists either come at a short acting depo, which is a bit of a nuisance, it's a monthly depo and there's no long acting depo or there's a pill, and that gets into an issue not so much related to the drug itself in terms of efficacy, it becomes an issue in terms of insurance. So, all of the injectables fall into the Medicare Part B umbrella, for which most people have standard insurance. Whereas if you give them an oral agent, which is one of the antagonists, you rent to a Medicare Part D, which can run into a problem with finances for patients. So, there's a number of issues that show up that aren't necessarily pure science. There's a whole issue about how do we have coverage for the patient. So, there’s certainly differences between the agonists and the antagonists in terms of insurance coverage. It makes you sometimes pause as well when it comes into the long run, low term for these patients. I think the thing that's particularly near and dear to me is we monitor bone density. So, I think that's the one thing that bone health is the easiest thing for us to manage when it comes to a long-term adverse event. And that comes out of either agent no matter which one you pick and against or antagonist. So, you have to be on top of saying we have to pay attention to bone density and use bone targeted agents as appropriate for those patients.

I think what's coming more to light these days is the other side effects that we get with addition deprivation therapy, such as weight gain, which leads to a diabetic tendency. So, if we look at something like insulin resistance, we're seeing at four months significant differences in terms of where the patient was at baseline or where they are at that point in time or things like their lipid profile, all things that are contributing to cardiovascular risk. And I think one thing urologists haven't been aware of is when we put somebody in a state of being castrate, we need to pay more attention to their diabetes. Looking at a hemoglobin A-1 C as an example, we need to pay more attention to their lipid profile. We need to pay more attention to hypertension, which comes along with all of the weight gain that we see. So, I think there's more involved in managing energy deprivation today than there was 25 years ago because the side effects are becoming something that we're now aware of. And quite frankly, people are living longer in the world of metastatic disease, and we have to pay attention to the baseline of treatment of metastatic disease. Androgen deprivation causes side effects that we really need to manage more carefully.

UROLOGY TIMES®: What are some strategies to manage the adverse events in leuprolide?

PAUL SIEBER, MD: You know, I think the strategies and managing these patients really involves some type of additional help in terms of the office. You know, urologists are hard pressed to keep up with their workload. And I think the idea of adding a nurse practitioner or pay to your team is vital. I mean, these patients need more careful monitoring and we're having busier and busier days as the number of your order seems to be shrinking and our caseload is going up. So, it's really at least at me from my perspective, a team involvement in terms of managing these patients. Some are sitting down besides the urologist helping you to say, “Have you had your blood sugar checked? Have you had your cholesterol checked? How's your weight management coming along? How are you doing?” These other problems that I think that's something that's new for us to think about, a team approach. I think we're used to saying, here's your injection. I'd see it six months or see it three months, and we really need to pay more attention to the details. And that is an ideal situation. So, in my practice I have a formal, formal process where anyone receiving androgen deprivation therapy is routinely monitored. I have two sets of people that are actually monitoring these people on a regular basis because I think we're just too busy to pay attention to the detail. And I think that's a critical part of taking care of these patients is the details. And again, as I talked about earlier, you know, the life span of a man with widely metastatic disease, even widely metastatic disease is now measured in years, not in months. And they have an opportunity to run in trouble. If we don't pay attention to the details. Then again, I think an ideal situation for an APP, as we refer to them, to help manage that situation.

UROLOGY TIMES®: How does the toxicity profile of leuprolide factor in when you are deciding on a treatment for your patients?

PAUL SIEBER, MD: You know, I think the toxicity of provide or any energy deprivation therapy is all the side effects that we didn't pay attention to in the past. You know, I think back to 30 years ago and a patient would have a biochemical recurrence as an example after radiation that you would very quickly think about adding, Lou, provide to drive that PSA down or what he used to joke as drive the prostate specific anxiety score down and think everyone felt better. The PSA test was better. Everything was wonderful. What we didn't see below the surface was, “Oh, now I know why you had your heart attack, Mr. Jones,” or why you had that stroke. So, I think the toxicity of androgen deprivation therapy these days is much better appreciated in terms of who needs medication and who doesn't. I think that patient who has a recurrent cancer that is very slow growing, you're going to pause before you add androgen deprivation therapy because of the toxicity in general.

That said, we're facing an onslaught of patients presenting with more advanced disease. So, I don't think I read any paper in the last couple of years that someone has commented on higher grade disease at presentation. Higher stage of presentation isn't part of your practice. So unfortunately, there are a whole lot more people walking in the door with worse disease. I read a study that the day that was the current estimated growth rate of metastatic disease is 5% a year. So, there's a number of people that must be placed on therapy and then you have to start to balance. Okay, I'm placing them on therapy. Am I paying attention to the detail? You have to pay attention to the detail. So, I had a patient recently, actually I just saw yesterday in the office who was started on androgen deprivation, but had already had seven stents, hypertensive diabetic hypercholesterolemia, and within two months he had reinfected, had had two new stents put in. So, we have to pay ultimate attention to that. And I think getting our cardiology friends on board to say, hey, listen, we're starting a medication on your patient. Are you aware of the concerns about that? I mean, the whole world of oncologic cardiology, that especially unto itself. And unfortunately, here I actually have a guy who's now coming out from residency trained in oncologic cardiology. One of the things they're looking at is androgen deprivation therapy in men on and B, being treated with a drug that's going to aggravate their underlying cardiac situation.

UROLOGY TIMES®: How did the AEs seen with leuprolide compare with other ADT?

PAUL SIEBER, MD: At this point in time, we can't say that we have any differences. There is a signal that one of the oral antagonists may have a slightly safer profile than the Lou provides the world to all the antagonists that is yet unknown or not proven. I think in general it just goes back to the fact that we really have to pay attention to optimizing patient's cardiac status. And when you say what else can you do? There are clear cut guidelines. So, if a patient is being placed at an edge deprivation, I think we could all say they would see needs to be within range. Your blood pressure needs to be within range. Your liver profile needs to be favorable. Maybe a baby aspirin, but do you need a coronary calcification score? Do you need a heart cath? Do you need a treadmill? We don't really have guidelines, so I think the best we can say is you need to pay attention to other things besides their prostate cancer. And I think that's not been on our domain. We've just not thought about that. And I think that's a big first step for everybody to say, “You have risk factors, Mr. Jones; I've started you on this medication, but we need to make sure your family doctor is aware of this. And I need to make sure that your other health issues, particularly diabetes, blood pressure and lipid profile, are being adequately addressed.” And, you know, that's not often the case. Or the patient will say, “Oh, my blood sugar is not bad. Well, we're going to make that a little worse. We're going to make your cholesterol a little worse. We may make your weight a little worse.” All these things add up that you really have to pay attention to monitoring these people. And I think we've been behind the times in the past in terms of treating people. We just didn't know the cardiac issues were such a big part of managing androgen deprivation therapy.

UROLOGY TIMES® How do you balance safety and efficacy in practice?

PAUL SIEBER, MD: I'll go back to saying it's amazing what a difference I've seen in my practice by setting up a formal process for ADT. And that goes back to the importance of ADT and not minimizing it. I mean, I think you're right, as we're used to saying, Get yours out of the way out the door today. See, in three or six months. I think there's more to it. And we've taken, you know, a much more systematic approach to say, I'm taking out of the doctor's hands, Your schedule's too busy to manage this. You need to have somebody dedicated to androgen deprivation therapy that's managing these other side effects. It's paying attention. And I think putting that AP in a pro in a role where they're part of the team and my patients all recognize, hey, I'm going to see in my and my case, my office as an example, “Brent;” You know, on a regular basis, I always see more talking about, you know, other issues. And you get into the other side effect issues of ADT, like depression, like weight gain, like hot flashes, that need at least a little bit of attention. And they have the time, and they have the role to say, I'm managing that problem for them. And I think that's something for too long we've dismissed because we just haven't taken those other side effects is yes, it's just it comes with the territory. So, what your you know, your PSA is great. I think that's too simple an answer you need to pay attention to. There are a lot of side effects that are both symptomatic and there are side effects that are below the surface that that need attention. And for us, handing it off to a formal clinic for us has been the real key to how to better manage this, to make certain my patients are, you know, getting their bone density, having an agency, or having the conversation. And my patients live longer because I am hopefully living in cardiac events as an example that arise might arise in someone who's not paying attention to the details.

UROLOGY TIMES®: Could you talk about your clinical experience with leuprolide in clinical practice? And do you have any advice for other urologists who are managing adverse events related to leuprolide?

PAUL SIEBER, MD: I think there's two steps to providing management. First is determining, is your patient at risk if you give them and I have objection and some concerns about giving them an immediate bleed versus saying I want to go with a subcutaneous product from day one. Second thought is, is my patient accounting to start on this today worry about potentially going to flare their disease? Do I need to think about it, at least in the short term, starting with an antagonist and switching to an agonist in the long run? And the third thing is just the convenience. For us at least, it's much more convenient to have a six-month depot. It gives people more freedom. It also gives us less concerns about potential breakthroughs. I think getting patient on a regular schedule, I think when you look at some of the data out there, what patients are on shorter term treatment, the potential for not staying within the prescribed time frame for getting their next injection goes out of order. And when you have people who are missing their shots on a regular basis, you increase the risk of having breakthroughs of testosterone, which contributes to a less desirable long-term outcome. So, I like the six-month depo, particularly just for compliance’s sake to make sure patients don't get out of window. And I think the last thing the least easy logistics is care of the patient for it. You know, I'm looking at how many times need to stick with my Medicare Part B. I have a lot of people who have trouble obtaining Medicare Part D when it comes to the long term. You know, it's managing these other side effects carefully. And I think I just can't say enough positives about having a formal clinic, a formal process to kind of, as I said, take it out of the doctor's hand and put it in your mid-levels or APS hand to manage these have side effects is a critical part of really having an outstanding program for energy deprivation, which I think people have not really given that a lot of attention.