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AEs from Novel Hormone Therapy in Nonmetastatic Castrate Resistant Prostate Cancer


In Urology Times’ monthly installment of Around the Practice, experts discuss adverse event management from various treatments for prostate and bladder cancer.

Raoul S. Concepcion, MD, FACS: Let's go to case 3. So this will probably be a little bit of an easier discussion. So this is a hormonal therapy for nonmetastatic castration resistant prostate cancer. And as we look back, this is sort of what started all of this about a decade ago as urologists really got more involved into the management of advancing prostate cancer.

So this is a 76-year-old white male. Biopsy proven Gleason Group 5, 5+4 prostate cancer. His primary was treated with external beam radiation therapy and 2 years of androgen deprivation therapy. In 2016, he progressed despite being on ADT to nonmetastatic CRPC. He had a PSA doubling time of 5.2 months. Fluciclovine PET imaging was negative for metastatic disease.

He was started on [apalutamide (Erleada)] 240 mg, PO daily, and then 2 weeks later developed a rash over his anterior chest and abdomen, but covering less than 30%. This is a representative picture of the rash. Let's talk about management of this rash. We know there are a number of different antigen receptor targeting agents out there. Much of this will be a recapitulation for most, but Dr. Ethirajan, tell us about your experience with [apalutamide] and rash.

Sukumar Ethirajan, MD: So, skin rash in these androgen receptor inhibitors, the novel agents, is reported in all 3 trials: AMARIS, SPARTAN, and PROSPER. And each one has a slightly different variation of when it comes and how intense it is. With apalutamide, as you saw there, significant rash is a good qualifier that is it less than 30%, more than 30% body surface area? How intense is it? Qualifying the rash, whether it's visual or maculopapular. Is it acneform, is it just pruritus, and what is the distribution? Is it trunk? Is it arms? In trying to define this as a baseline, was it coincidental to the starting of the [apalutamide]?

Once we get that established and follow these patients, you'll notice that, most common, is topical relief, either cortisone or something similar, before going to systemic medications. And if it's quite symptomatic, we hold the medication and re-challenge it. And sometimes it clears up. And my experience is that we need to be patient with taking care of symptoms on one side and watching the rash closely, so they need a close monitor. And the key is to not let this evolve into something more serious. It's uncommon, but, you know, Stevens-Johnson or erythema multiforme or toxic epidermolytis is also ion my radar.

So we monitor this closely, as often as possible to the point where my communications tools with the patient they're able to send me pictures of this as often as they want to. I can look at them, I can bring them to the office, we can do telehealth to take a look at it. So it's not this spread out, once-a-month visit on these patients. Follow-up monitoring, and then trying to adjust the dose, interrupt it, go back to treatment, re-challenge it, and see if it clears up. I've rarely had to use any significant systemic intervention, and I think once I might have used the Medrol dose pack, so it's not common.

Now from a clinical trial, which is real world experience, most of these patients on trials are not the ones we treat. Patients are older. There are about 34 different adverse events reported on these 3 trials. Only 10 commonly mentioned in all 3, and rash was one of them. A bigger issue is what happens to the placebo group? What percentage of the placebo group had some of these issues? And then, of course, exposure is in their context. So we also want to keep in mind, although a patient would say, "Hey, this happened right after I started [apalutamide]," or the family insisted, we need to be a little more critical about when did it happen. Are there other reasons why this rash could have been there, and watch it closely.

So I hope I answered your questions, but given that we have so many patients in the nonmetastatic hormone resistant prostate cancer and this area's blossoming, I would say, based on all the newer imaging techniques, this is going to be more common. But drug-to-drug interaction is something which is popping up and becoming more significant. So I tend to cross check on every drug, and apalutamide has issues with anticoagulants, the factor 10 inhibitors, and the platelet drugs. So we always want to make sure it's not competing in efficacy. I like when it's not competing or enhancing toxicity of other drugs.

Raoul S. Concepcion, MD, FACS: Kelly, in your experience, when you see a rash like this, does this happen fairly early in the course of therapy or is it somewhat idiosyncratic and can pop up within weeks, or within a few days, or it may be delayed?

Kelly L. Stratton, MD, FACS: You know, in my experience, patients tended to present fairly early in the course. Although I had a patient who was on drug for what seemed like over a year and then developed a rash. What, from my perspective, is important is to try and keep the patient on treatment, if possible, by using topical treatments or antihistamines, and then making sure that the patient understands that this rash may not persist and it may not come back once we clear it up. I've really tried to keep patients on treatment if they're benefiting from it.

Raoul S. Concepcion, MD, FACS: Dr. Ethirajan mentioned distribution and the volume. Does- this tend to be more truncal versus extremity? Is that your experience?

Kelly L. Stratton, MD, FACS: I've seen it in both. To me, it seems like I haven't really come up with one specific area. I've also seen patients who have exposures to other family members who develop rash and so it is important to get a history that expands away from the patient, because, from that perspective, that patient probably didn't get rash [from apalutamide], that was probably something else, either detergent or new laundry soap or something. So, I mean, a little bit of it is a detective work to figure out what may really be causing the rash.

Raoul S. Concepcion, MD, FACS: Drug-related rashes are somewhat hard to decipher. Mersadies, what's been your experience up until this point with rash relative to these antigen receptor targeting agents?

Mersadies Orr, CRNP, FNP-C: I have actually seen the rash with [apalutamide] several times, especially the more that we're using this medication. Typically with my patients, oftentimes this rash is on their chest and upper extremities, but I have seen it on the back. I had a patient yesterday who had a little bit on his legs. I've been able to manage this with a topical steroid and re-challenge the medicine. Oftentimes patients are able to continue with treatment. Now, if the rash reoccurs, then I anticipate that I may have to switch to a different oral, but I have not had to prescribe any oral steroids, and generally this has been managed and treated with just a topical.

Raoul S. Concepcion, MD, FACS: For the most part, my understanding, is this tends to be sort of a nonpruritic rash?

Mersadies Orr, CRNP, FNP-C: In my experience, yes. So patients oftentimes are not complaining of itching, rather just this red, kind of raised rash that they're seeing, that's kind of diffuse. And again, I've seen it most often on the chest and the arms.

Raoul S. Concepcion, MD, FACS: Part of this is obviously the antigen receptor targeting agents, whether they be synthesis inhibitors or they be receptor antagonists, have been around, although we continue to call them novel hormonal therapies. They've been around now for about a decade. So, relative to your practice, the one thing that I think the guidelines don't really tell us is when to use the drugs, what certain phenotypes are appropriate for what agents. We know there are approvals whether they be metastatic or nonmetastatic castration resistance, but it's not always laid out for the provider, especially for those viewers out there that are not as experienced as the 3 of you. What sort of monitoring is seen, whether it's lab, whether it's imaging, when you start a patient on an androgen receptor targeting agent? What are your typical lab and imaging protocols that you guys have put in place at urology clinics around them?

Mersadies Orr, CRNP, FNP-C: With any oral agent, the patient is going to be seen in office 1 month later to assess their tolerance to the medication, and we will check a PSA and a testosterone. If you're on [abiraterone acetate (Zytiga)], you have a CMP every 2 weeks for the first 2 months, and then monthly. And then with [apalutamide] and [enzalutamide (Xtandi)], we often will get a CBC and a CMP at a baseline, and then if there's anything abnormal, continue to monitor that.

Patients are typically seen 1 month after starting the medication. If they're stable and doing well, we'll see them 6 weeks later, and we repeat our imaging 3 months into treatment. After that first set of scans, if disease is stable, if it's [enzalutamide] or [apalutamide], you can go to every 3 months. If it's [abiraterone acetate], we see you 1 time a month for the first year.

And that changes based on the patient and how they're tolerating the medication. If they're having side effects, if we're having issues with blood pressure control, etc. When we're looking at these medicines, there's a lot that you have to take into consideration before even prescribing 1 just with the interaction with blood thinners, etc.

Raoul S. Concepcion, MD, FACS: Kelly, what do you guys do? I know abiraterone, because of the potential hyperkalemia as well as the blood pressure issues, liver function tests, there's a specific recommendation for following that, but relative to the androgen receptor antagonist, is that sort of your [plan] as well?

Kelly L. Stratton, MD, FACS: Yeah, I think with [apalutamide] the one thing that we'll add on is a thyroid function test just because there are that group of men who had thyroid changes, particularly if the patient has a history of thyroid dysfunction. Then we would to be mindful of that. So, similarly, we follow the [abiraterone acetate] labs every 2 weeks for the first 3 months, and then monthly for the next 3 months. So, a patient on [apalutamide], we would get baseline labs and then check them at least quarterly.

Sukumar Ethirajan, MD: I would agree with all these best practices. We see a fair number. We also have in office dispensing, which I think integrated dispensing is very helpful, where we check on the patient every month before they get the next refill. So, they're not given and gone away and we're not seeing them. A good baseline assessment is excellent. Making sure that they are not risks for falls, fractures, or fatigue. And as I mentioned, there were 34 different adverse events mentioned on the 3 clinical trials. Only 10 were reported commonly on 3. So we need to constantly look for other things which patients complain about, things change, lab work monitoring, and see if there is any need for dose adjustment or interruption in treatment.

I tend to ask them every month, and I can understand that that can get to be a heavy practice just watching these patients when they're doing well, but an advanced practice provider is very helpful. A nurse visit is very helpful. And so we have some redundancies where you have a patient portal where the communication is live, so I'm constantly addressing any questions from the patient or their family.

Now, the abiraterone is slightly different. You know, the initial trials are every 6 weeks evaluation, a little complicated in the outpatient setting to do a 6-week and then refill the medication every month, so I try to stick to 1-month visits, either nurse visit or follow-up. Once it's stable, I see them every 3 months with the monthly nurse chats and prescription refills. Lab work is a little more often initially, and stable. Once they are stable, cut back on them. It also depends on the patient reliability. So if you have someone who is reliable and easy access and they know they'll call you, it's different than someone who is living 100 miles away and doesn't have any companion to help report things out there. So, patient context is also very important in managing these patients.

Raoul S. Concepcion, MD, FACS: Let's stick with the various androgen receptor targeting agents, and we know there are a number of them out there. You've mentioned, obviously, multiple side effects that have been associated. What are the ones that are kind of sticking out in your mind and you can classify it either as a drug class or by individual agents that the viewing audience needs to be really aware of as they start to utilize and prescribe these drugs?

Sukumar Ethirajan, MD: Yeah, I'd be glad to address the 4, which are approved in the metastatic hormone-sensitive setting, and, of course, the 3 which we are talking about in the nonmetastatic setting. Abiraterone, prednisone, with patients with diabetes, congestive heart failure, blood sugar changes, hypokalemia, as you mentioned, these are important things to watch. Every now and then we see liver function changes, so that's a different class.

In patients with apalutamide, obviously this one we're looking for a rash, but falls, fatigue, and fractures are more commonly reported to be watched. We had 1 of our patients on bone health management, which means they've got a baseline DEXA scan, they've got calcium with vitamin D, they've got either denosumab or some form of bone modifying agent, so our fracture rate is low, and our bone management rate is very high.

Then we get into the cardiac issues, which most of them have comorbidities and some cardiac issues, whether it's hypertension leading to something else or patients who have had coronary artery disease. I watch them closer, and if someone is frail and elderly and there is a whole NCCN guideline on adult oncology, so if I have a 90-year-old who is frail and I have to give him something, I'm reluctant if they have any CNS issues and fall issues to add enzalutamide. And, likewise, um, [apalutamide] is a little more comfortable in polypharmacy because it doesn't interact with other drugs and doesn't cross the blood/brain barrier. And each drug has its own strengths and weaknesses, and you try them, but you monitor them. You come up with a monitoring plan.

A patient who has a history of falls, I'm watching him very closely for falls. A patient who has a history of diabetes or hypertension, I'm watching that close. A patient who has a history of any CNS or a fair number of them have dementia or what they call cognitive dissonance these days. We try to document a baseline and watch what changes over time, because these things can creep up on you if we're not monitoring them well.

Raoul S. Concepcion, MD, FACS: Kelly, Dr. Ethirajan brought up an interesting point, relative to the cardiovascular toxicity, obviously related to some of these agents, but obviously we know that there's an increased incidence of cardiovascular disease with the generalized use primarily associated with ADT as LHR antagonist. So, at your institution, are you guys developing a pretty stout cardio-oncology program as well?

Kelly L. Stratton, MD, FACS: You know, cardio-oncology is something that's becoming more popular and, and certainly we can see the benefits of having that program. Now that we have new agents available like relugolix [Orgovyx], we have started to stratify patients. Those who have cardiac comorbidities we discuss with the patients that there are different androgen deprivation therapy options. Some of them may have a better cardiac profile. We encourage them to talk with their cardiologists, make sure that they understand that androgen deprivation therapy is not a cardiac-friendly regimen, and we try to optimize them as best as possible. We have seen some issues with insurance coverage and difficulty getting patients started on some of the newer drugs, but oftentimes with a peer-to-peer we can sometimes convince them to consider some of the newer agents.

Raoul S. Concepcion, MD, FACS: That's great. Mercedes, what are you guys doing? Because I know this is a big issue. Cardiac toxicity, we've used LHRH analogs for years and we've given them like water, and it's only now the data is becoming more and more available. Dr. Ethirajan mentioned bone health, cognitive dysfunction, but the cardiovascular events, how are you guys managing that at Urology Clinics of Alabama?

Mersadies Orr, CRNP, FNP-C: Yes. So I stress the cardiovascular risk with every patient, and we really go over the ABCDs of heart health, which includes: an aspirin if no contraindications and the primary care doctor is agreeable, blood pressure and cholesterol management. I just really make sure my patients are plugged in with their primary care doctor that's checking the cholesterol, because we're not. And that we keep that blood pressure managed and controlled. Diet and exercise. We really just go over low carbohydrate, healthy fat diet, and about 30 minutes of exercise 5 days a week. And I just try to stress that at every visit, and just make sure that the patient is keeping the blood pressure where it needs to be. All of our oral agents, they can make that harder to control and interact with some of the blood pressure pills, so that's really something I focus on.

Raoul S. Concepcion, MD, FACS: Dr. Ethirajan, I'm going to punt this to you. A question came in. Can we use erythropoietin injections to treat anemia once we have ensured normal ferritin, vitamin B12, folic acid levels? I'm assuming that was probably related to case 1.

Sukumar Ethirajan, MD: Yeah, so erythropoietin stimulating agents were really popular initially in chronic kidney disease because of low erythropoietin levels, and then eventually while being treated with chemotherapy-induced anemia. And then they found significant toxicity with those patients, so that indication was withdrawn by CMS and others who supported it. Having said it, we have a new erythropoietin stimulating agents for chemotherapy-induced anemia. There are a couple of indications where you could try it, and that is if there is chronic kidney disease and we know the patient is anemic, and that's an approved indication. That's worth a trial to see if it improves. And there's a fair number of older patients who benefit. You'll have to document creatinine clearance, which is decreased, and chronic kidney disease … but they do benefit. And watch for side effects, especially hypercoagulable states.

There are some primary bone marrow disorders where you don't have enough erythropoiesis, so it does stimulate them. That's assuming that these patients are prone or have a diagnosis on that basis before they come to us with prostate cancer. So, quick statement would be, no, it's not standard, but there might be a couple of exceptions where you will be able to use them, like chronic kidney disease.

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