Activity Transcript

Neal D. Shore, MD, FACS: Hello, I'm Neal Shore, MD, FACS. I'm the medical director at the Carolina Urologic Research Center in Myrtle Beach, South Carolina. And welcome to this program entitled, Prostate Cancer Clinic Multidisciplinary Team Approach To Oral Therapies. Today we have great faculty, joining me are Jennifer Sutton, RN, BS, the director of nursing and administration at Carolina Urologic Research Center in Myrtle Beach, South Carolina and Katie Morgan, PharmD, BCOP, CPP, a hematology and oncology clinical pharmacy specialist at the University of North Carolina Medical Center in Chapel Hill, North Carolina. Welcome to you both. This is a really great opportunity for us to talk about our different expertise and approaches to advanced prostate cancer care. What are we going to focus on today? I think we want to talk about the oral oncolytics or what many of us call the novel hormonal therapies in the management of prostate cancer. This has really changed how we take care of these patients.

We are going to review the drugs abiraterone acetate, enzalutamide, apalutamide and darolutamide. What we want to do first is review their mechanism of action and from our own perspectives in a multidisciplinary team approach, we'll talk about the unique mechanisms of action some similar, some not and the key adverse events of interest. Importantly, I think for our audience, which is not just clinicians, medical oncologists, urologists, but also nurse practitioners, nurses, pharmacy specialists, our team members in the clinic, our team members in clinical trials departments. How are we doing the best education that we can to ensure safe use of these therapies? How do we pick certain therapies as well? And I think we would all agree it's a team based approach. We have different drugs that we've talked about, these four different oral agents that we're going to focus on and we need to think about what some of their approvals are.

Let me start with you Katie. We have these four different oral therapies and maybe if we go in order of the timeline of approval. So, abiraterone acetate, maybe you want to talk about the mechanism of action, how that drug works and then we'll talk about the AR inhibitors and talk about the key adverse events of interest and how we dialogue with patients about it.

Katie P. Morgan, PharmD, BCOP, CPP: Abiraterone acetate is an anti-androgen in the way that it decreases the synthesis of androgen. It inhibits the biosynthesis of androgens, namely testosterone and dihydrotestosterone through inhibition of CYP17A1. And what that does, is decrease the amount of testosterone that's being produced from the adrenal glands as well as the prostate cancer cells themselves. Another aspect of the mechanism is that CYP17A1 also inhibits cortisol production. What you get is actually an excess of mineralocorticoid that can lead to some of the side effects requiring prednisone, the co-administration with the drug to balance that out so that you're getting less ACTH production feeding back through the steroids synthesis pathway.

Dr Shore: Because we have to add to this drug, what some have described as a physiologic dose of prednisone five milligrams twice a day, which makes it different from the AR signaling inhibitors, thus they are unique drug by themselves. This is two drugs, prednisone plus abiraterone acetate. What are some of the safety side effect issues that we have to learn about when to safely administer this drug?

Dr Morgan: In the original trials, steroids were not originally put into combination with abiraterone acetate and they found that you do get this mineralocorticoid excess syndrome, which can lead to increased hypertension, low potassium and fluid retention. And so by administering a physiologic dose of prednisone that can decrease those side effects. It doesn't eliminate them completely because we do still see patients have those side effects even with the steroid administration. But it definitely can lessen them for the patients.

Dr Shore: And Jennifer, we've done a lot of these trials together that led to these approvals in the post-chemotherapy area and then pre-chemotherapy, which now abiraterone acetate is approved and even now in metastatic hormone sensitive prostate cancer. It has a wide spectrum of indication. What has been your approach in talking with patients and their caregivers when they're taking abiraterone acetate and prednisone?

Jennifer M. Sutton, RN, BS: Patient education is important and the first thing to talk about is dosing. Taking the abiraterone acetate in a fasting state, but then also reminding them that prednisone is best taken with a meal. We tell patients to wake up in the morning and take their abiraterone acetate and wait an hour till they have breakfast. And then with breakfast take the prednisone. And then with dinner take their prednisone. And it seems to be better tolerated that way and they need to make sure that they are seeing their healthcare provider regularly so that their liver function can be monitored and also their potassium.

Dr Shore: Yeah. And that's something that’s new for the urology community, something that we had to get comfortable with. It is important to manage that and to check those labs.

Ms Sutton: Right.

Dr Shore: Recently, there's been some recommendation where you can take a reduced dose in a fed state. And some folks are looking at that as well. It's actually worked its way into the NCCN guidelines. We've mentioned that you want to check for low potassium, you want to check for LFT abnormalities, fairly uncommon, but they still do need to be checked per the label. And then some patients who have glycemic issues, diabetics, whether they're type two or one, even with a low dose of prednisone, you can see that. Any thoughts about glucose management or concerns?

Dr Morgan: Comorbidity monitoring is really important not only blood glucose but hypertension as well. A lot of these patients are older gentlemen who have a central hypertension at baseline and educating them that monitoring blood pressure routinely after they start this medication is important because that is one of the main side effects that we do see. The blood glucose monitoring is important as well. Again, older gentlemen, lots of people with diabetes and making sure that those patients are not only connected with us, but they're included with their primary care physician so they can work closely with them to manage those comorbid conditions at the same time.

Dr Shore: One of the things that's very important is communication. You mentioned the PCPs, the primary care physicians, whether it's the family physician, the internist, getting them involved. I think it's really important when you take on advanced cancer care, you don't have to feel that the weight of the world is on you as the clinician, be it you're the physician or the nurse, that we can reach out and regularly call the primary care physician or the endocrinologist or the cardiologist or the gastroenterologist. Katie, what about now as we move over to this class of the AR receptor inhibitors and maybe because they're similar, there're some different molecular moiety differences, but as a general rule, their mechanism of action?

Dr Morgan: We have enzalutamide, apalutamide and now darolutamide that are all advanced forms of androgen receptor blockers. They not only block the interaction of testosterone at the AR receptor, but also inhibit the translocation of the AR receptor from the cytoplasm to the nucleus as well as inhibiting the AR from binding to DNA to promote protein synthesis. So, there's a threefold mechanism there, little subtle differences between them. One big one is that darolutamide does have a different molecular moiety that decreases its blood brain barrier penetration. A problem with enzalutamide and apalutamide, enzalutamide more than apalutamide is that it does cross the blood brain barrier and can have some cognitive effects as well as risks of seizure.

Dr Shore: I think you've summarized nicely the different mechanisms of action. And we know that enzalutamide is approved in mCRPC, whether before or after chemotherapy. Enzalutamide is also now approved in nmCRPC or what we used to call index case 1M0CRPC. It's also approved in hormone sensitive metastatic prostate cancer. Apalutamide is approved initially first approved in the nmCRPC space and now most recently in hormone sensitive metastatic disease. So, we now have those two AR inhibitors approved in nmCRPC, hormone sensitive prostate cancer metastatic. Enzalutamide has the approval in full mCRPC whether before or after chemotherapy. And then the third one, darolutamide is now approved in the one area of the nmCRPC arena. And it's really fascinating how this has all come upon us really quickly, relatively so just a couple of weeks ago, the two trials that led to the approval of darolutamide in nmCRPC and enzalutamide in nmCRPC the ARAMIS and the PROSPER trials respectively, they announced that they met their overall survival endpoint.

These drugs in the nmCRPC space were approved based upon an endpoint of metastasis free survival, which is a co-primary endpoint of radiographic progression and survival or deaths. But at the time of their approval on the time of their New England Journal publications, the data on OS was immature. That's recently been announced. And it hasn't been presented in a public forum nor published yet, but I think those two are coming very soon in 2020. And I'm pretty confident that apalutamide and SPARTAN data that will also... we'll wait and see. But I'm cautiously but optimistic that that will also report positively. So, let's talk about these three drugs.

Katie I'd like you to talk a little bit about something in terms of the drug-drug interactions and maybe the mechanism. You alluded to it already, blood brain barrier. And Jennifer maybe talk to us about how some of the key adverse events that may separate these three drugs.

Dr Morgan: The drug interactions are very interesting. Two of the medications, enzalutamide and apalutamide have significant drug interactions. Not only are they 3A4 substrates, but they also induce 3A4 which in the majority of medications are metabolized by that enzyme. And there are a lot of drugs that are going to be rendered almost ineffective by co-administering them with enzalutamide and apalutamide. They do have other nuances between them as far as drug interactions go. But that is the major one that we do get into a little bit of trouble sometimes because if you imagine a patient on all of these drugs will be induced by these drugs. By apalutamide, enzalutamide. If you imagine a patient on a statin, a calcium channel blocker, a PPI, all of... You could imagine-

Dr Shore: Some proton pump inhibitor.

Dr Morgan: Yes a proton pump inhibitor.

Dr Shore: But there are days when people come into the clinic and I say, "Oh my gosh! Polypharmacy." Right?

Dr Morgan: Right.

Dr Shore: Long list and they're on anticoagulants, they're on proton pump inhibitors, things like omeprazole, et cetera. They're on antidepressants, they're on antihypertensive, they're on anti-lipid drugs, oral hypoglycemics. So, it's complex.

Dr Morgan: It gets complex because somebody could be on all of those drugs and enzalutamide and apalutamide would decrease their concentrations by up to 80%. So, then you have chronic conditions that are now not under control anymore. A lot of times what we have to do as pharmacists is fix those things before we can even start the patient on the drug. And that takes an extreme effort by a lot of different players to be able to do that.

Dr Shore: Yeah, it absolutely does. And maybe some drugs based upon their hepatic metabolism are inhibitors, some are inducers, some not as well studied as others. But this notion of drug-drug interaction is really important now. I mentioned it a minute ago, polypharmacy. There're some data that this geriatric population of patients with advanced prostate cancer, they're on sometimes four to eight different medications.

Dr Morgan: And some of these drugs may be unnecessary. The 10-year rest reduction that you get from an anti-lipid drug may not be relevant anymore in a patient. Do they really need to be on that? And thinking about apixaban, one of those anticoagulants for A-fib, are we looking at their CHADS score and seeing maybe they can just be on aspirin. These are the types of questions that come up that we have to work together to try to figure out what is the safest for the patient's chronic medications, so that we can start them on one of these targeted therapies or second generation anti-androgens.

Abiraterone, one of its main drug interactions that we find in a practical clinical setting is its inhibition of 2D6, which actually is the enzyme that metabolizes beta blockers. Usually, you can get away with this pretty frequently. But if somebody's baseline heart rate is in the 50s, high 50s or even low 60s, you put them on abiraterone acetate, that could drop them into the 40s and make them symptomatic. So that's something that you really do need to look out for when starting somebody on abiraterone, because almost everybody is on a beta blocker, so making sure their baseline heart rate is high enough that they could tolerate that. Otherwise, there would have to be some manipulation in the front.

And for darolutamide, actually there aren't really many drug interactions with darolutamide. It does inhibit BCRP, which is an enzyme that is responsible for specifically rosuvastatin as a practical drug example. But other than that, it's pretty clean from a drug interactions perspective. So that is one thing that's unique and sets it apart from apalutamide and enzalutamide

Dr Shore: Maybe Jennifer if you can focus a little bit on when you're talking to families and a lot of these men, some of them could be middle-aged, many of them are elderly. How do you think about the different drugs Are there any particular ways you think about these four drugs, abiraterone, enzalutamide, apalutamide, darolutamide in terms of specific things you say about AE management to the patients?

Ms Sutton: The most common possible side effect is fatigue. And so it's important to make the patient and their caregiver aware of this possibility and to educate them on keeping an exercise routine. Regular exercise will help combat fatigue. A body in motion wants to stay in motion. And sometimes they'll say, "Well, I'm too tired to do that." You have to fight that and it ends up making you feel better. Also a heart healthy diet, so a diet high in vegetables and fruits, low in fat and sugar will also help battle that fatigue.

Dr Shore: I think that's great. When I was in medical school and residency we just didn't give that any sort of discussion and I'm certainly hopeful now that we're doing some larger trials showing that directed exercise is really very beneficial and encouraging patients at any age that exercise both cardio fitness, but also some muscle building activity is super important even if you're not on an oral oncolytic therapy.

Dr Morgan: The main thing that we talk to patients about is just trying to maintain that standard recommendation of exercise at least 30 minutes a couple times a week.

Ms Sutton: Strength training is really good to maintain that bone health and keeping the bones healthy and strong will then also minimize the risk for fractures and falls, which is a very important to have that conversation with patients in this disease state as well because they are at risk for fractures and falls and making sure that they're aware of that.

Dr Shore: Yes, and one of the things that we've come across now and recently in some different trials where we were combining therapies, is the importance of looking at adding bone health agents starting with zoledronic acid and now with denosumab in combination with making sure the vitamin D and calcium levels are appropriate. When we're adding on these other oral therapies and other approved mCRPC therapies such as taxanes as well as radiopharmaceuticals, it helps reduce the risk of skeletal related events. So very, very important. Now, let's talk a little bit more about some other management and concerns regarding these therapies. I know we were talking earlier about cognition. What about cognition and how do you address that Jennifer?

Ms Sutton: Cognitive impairment is something that can happen when taking these oral therapies, especially enzalutamide because we talked about the blood brain barrier penetration. It's important to educate the patient and their caregiver about the possibility of cognitive impairment and you want to make sure that you screen at baseline for cognitive function and then periodically throughout treatment. And you want to make sure you also engage the caregiver because a lot of times patients don't notice that they have changes in their cognitive function and their caregiver will. So, it's important to involve them in the conversation.

Dr Shore: I completely agree and some of these men who come in by themselves, we try to encourage them to come in with their partner or family member. What about some unique things for example, seizures or rash?

Ms Sutton: Along the lines of cognitive impairment with enzalutamide is also the risk of seizure because of the blood brain barrier. Patients who are predisposed to seizures should not take enzalutamide and if they have a seizure while an enzalutamide should be stopped right away. Rash is something to note with all of them, but especially apalutamide. Early detection of rash is key. Educating the patient that it's possible, that they may develop a rash, if they notice any redness or a scaling of the skin to notify their healthcare provider right away because as soon as we can start to treat the rash, the less severe it could be and the chance of recurrence could go down.

Dr Shore: I think you're right. And fortunately the level of really severe rash for apalutamide is very low single digit percentage. And similarly, both apalutamide and enzalutamide in their studies have always excluded patients who have seizure history. An interesting difference with darolutamide, is that they've allowed patients into all of their trials and even in their approved label, patients who have a seizure history or not contraindicated in the trials or in taking the medication. I think we don't yet have any direct comparator trials that have been reported. I think they'll probably be forthcoming. People start to rely more and more on their real world experience. The good news is these drugs are very effective for survival prolongation and delaying progression of disease. So, that's the good thing. Well, I think we talked about some of the metabolic changes and the cardiovascular effects potentially of concern. Any thoughts about additional comments on that?

Dr Morgan: With all of our androgen deprivation therapy, including leuprorelin or GnRH agonists and antagonists, we do see an increased risk of metabolic changes and cardiovascular risk over time. These medications definitely contribute to that, especially with abiraterone with its mineralocorticoid excess, that puts another wrench in it for patients on that medication. I think the main thing as we touched on before, is making sure that we're all working together as a team, including the primary care provider to ensure that we're doing the proper screening. Baseline screening is recommended for all of these comorbid conditions before starting these medications. I think working closely with the patient as well as the primary care provider and the medical oncologists or urologists or nursing as well helps with maintaining these patient's health over time because they will be on these medications for years.

Dr Shore: Absolutely. Some of these drugs you can't write a prescription for and get them in the corner of drugstore and you have to either have an in-house dispensary or use what's called a specialty pharmacy. What are some suggestions in terms of the interdisciplinary team, you've already mentioned it both of you really nicely. The physician, the nurse, the nurse practitioners, the physician assistants, but when it comes to getting more pharmacists involvement, how do we do that effectively? And maybe comment on whether it's in a community practice or in an academic center.

Dr Morgan: Yes, I think community practice might be a more difficult as far as making sure the specialty pharmacy is closely involved with the oncology practice, just because the resources and support might not be there compared to a large academic medical center. So, I think there are some challenges with that model and... with both models actually, to be honest. Pharmacists should be involved in the monitoring, obviously counseling and management of these oral medications over time, especially working with the provider to make sure that drug interactions are resolved, that those medications can be started safely without any concerns, and also with organ function of course.

Dr Morgan: Monitoring the liver function test as well is really important and being able to communicate closely with the pharmacist to make sure the patient is getting dispensed the medication on time; that the patient's adherent. Usually the pharmacist knows about that more than the physicians do because they're the ones calling the patient and saying, "Hi, do you need a refill?" And the patient might say, "Actually I have a couple of weeks left, so I don't really need a refill right now." Well, that's kind of concerning, they shouldn't have a couple of weeks left because you dispensed it 30 days ago.

Dr Shore: You make a great point, compliance and adherence. And when you start going to orals it's something that comes up a lot as well. How do I know the patient is taking the drug? And there are some strategies for that, but Jennifer, I wanted to ask you about, more practices, such as medical oncology and urology are really being encouraged to do clinical trials research. So, what are some thoughts that you've had over the course of your career in enhancing and optimizing the research team with the clinic team, especially as it relates to just overall adverse event management, adverse event education of the patients and also the pharmacy intervention? What are some things going forward that you would recommend?

Ms Sutton: Being in clinical research, you do get to know the drugs from the ground floor and you learn these adverse events, which ones are most important to educate the patients on. Being in clinical research, we go onto the clinic and say, "Okay, this is after you're approved now and these are the things you should watch out for." And we have a good communication between the research center and the clinic to make sure the patient knows about fatigue, bone health, cognitive impairment, risk of fracture and fall. And also to make sure that they are keeping their appointments. That's very important to make sure for the patients. They don't need to cancel that follow-up, they need to come to the follow-up to make sure that they are being monitored for liver function, potassium when necessary.

Dr Shore: Yes, just because patients are feeling well they still need to be monitored, they still need their lab work, they still need imaging appropriately. You mentioned earlier too, which was a great point, is making sure the caregivers and family support is there. It is a team approach; no one can do it alone anymore. It's complicated. Taking care of patients with advanced prostate cancer, and there are so many things to be thinking about and we've talked about so many of them. So, I think this has been a really great discussion. I think that we touched about the stress that this causes to patients and their families. I'm always struck by how often patients will never say anything to the clinician, whether it's the white coat syndrome or not wanting to disappoint their doctor. But they'll talk to the nurses, they'll talk to the pharmacist and they'll share their concerns. And that back and forth communication on the whole team really makes that optimal care.

Dr Shore: So in closing, any other comments or thoughts?

Ms Sutton: I think it's important for nurses to make sure that they ask the patients open-ended questions to encourage them to talk about what's really going on with their health. Because like you said, they're not always forthcoming when they come to the doctor and so the nurse is their advocate and needs to really figure out, when you say you're doing okay, let's ask them open-ended questions about, have you been feeling tired lately? Have you been having a hard time remembering things? So that they can relay that to their healthcare provider so they can have a discussion about maybe just modification or an interruption changing treatment.

Dr Morgan: Yes, we have similar things as well. Not to any fault of physicians or anybody else seeing the patient, but not a lot of people ask about adherence. To touch on those important points that you mentioned earlier about how abiraterone has to be taken on an empty stomach, some patients will come in and they'll be taking it with food, which actually increases your toxicity. So, then we see those toxicities and wonder why that is. And it's because they're taking it incorrectly. Or I've had many patients take enzalutamide or one of these other medications, we have to take four tablets or capsules at a time, they take one four times a day. And we've seen that a lot. Right? Adherence to these medications is really important in managing the side effects. And I think some of those questions that we all ask differently is really important to that multidisciplinary care as well.

Dr Shore: Yes, that's an excellent point. Jennifer, Katie, thank you so much, really appreciate all the work that you've done and all the suggestions that you've made today. I think it's incredibly helpful. And thank you all for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation. Thank you very much.