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Alicia Morgans: Hi and welcome to UroToday, and our online medical education program Beyond Androgen Blockade: to New Pathways and Novel Treatments in Metastatic Hormone-Sensitive Prostate Cancer and Metastatic Castration-Resistant Prostate Cancer. I have the honor of moderating today's discussion following a presentation by nurse practitioner Brenda Martone. The topic is treatment decision-making in metastatic hormone-sensitive prostate cancer, the medical oncologist and patient, what the patient needs to know about his disease and treatment options. Thank you so much for being here today with me, Ms. Martone.

Brenda Martone: Thank you. It's nice to see you, and I really appreciate being invited to discuss this with you.

Alicia Morgans: Well, it's always great to see you too. Let's get to the talk.

Brenda Martone: We're going to be talking about metastatic castration-resistant prostate cancer and what patients should know when speaking with their providers. I love this slide. It really shows us, basically, the explosion of treatment options that we have for our metastatic prostate cancer patients. Not only those that are hormone-sensitive with high-volume disease, we have new treatment options available. Most exciting to me is the treatment advances we have in the metastatic CRPC setting. This is basically the terminal part of the disease, and having options that delay progression and extend overall survival and choices help us tailor our treatments to each individual patient. Every metastatic CRPC patient who has bone mets should be on a bone-strengthening therapy, either zoledronic acid or denosumab. Data shows this delays a skeletal-related event, the most serious being a fracture, but of course this also includes delaying the development of bone pain.


Are they taking calcium and vitamin D? Because we know these agents can lower calcium levels. I would expect, or I would hope, that most of our metastatic CRPC patients have undergone both germline and somatic tumor testing. If they have not, then we need to get this ordered for them to identify if they have a DNA repair mutation or a BRCA mutation that would provide them extra treatment options that wouldn't be available if they didn't have those mutations. Obviously, the backbone of treatment is ADT, and we add things to that. Again, just part of my checklist. Are they on ADT, making sure they're up-to-date? And of course, looking at our medications for potential drug-drug interactions, not just with the AR inhibitors or the PARP inhibitors, but also checking that patient's supplement list. There are quite a few supplements that patients may be taking that may interact with our treatment or cause extra stress on the liver.


And then again, with the somatic tumor mutation, this would also provide an opportunity for pembrolizumab. It's a checkpoint inhibitor. Most of the time, this is given in an oncology office but could also be coordinated with urology in terms of managing labs and things a little more closely, and getting their infusions and symptom management also with oncology. Here are the two second-generation AR inhibitors we have in metastatic CRPC. These include abiraterone and prednisone, as well as enzalutamide. Both of these agents, second-generation AR inhibitors, reduce the risk of death, regardless if they're given pre-docetaxel or post-docetaxel. There is a study, though, that suggests sequencing these agents. If you have a patient with metastatic CRPC, let's say they're on abiraterone prednisone, and they have progression of disease, the role for sequencing AR to AR, you don't get the same sort of efficacy.


Ideally, if possible, you want to avoid that sequence and kind of throw in a different treatment mechanism of action, if possible, to help maximize the potential for delaying disease progression. Some of those second-generation AR inhibitors do carry some side effects with them, and I think it's important that we're at least aware of them. Our patients don't usually come to us with just prostate cancer; they may have underlying hypertension and diabetes. That doesn't exclude them from these agents, but we need to make sure that we're monitoring that closely. Both agents may cause some hypertension; making sure that, if they are on antihypertensives before treatment, their hypertension is well controlled and those treatments are maximized. Making sure we're encouraging our patients to remain active, adopt a heart-healthy diet, limit salt— all the good information and recommendations we should all be following.


There is an increased risk of falls and fractures. Usually assessing the patient to see if they are having any trouble with gait, stability. The get-up and go test is super easy. You can do it before and periodically throughout. It's a really good indicator that's objective to see how things are going. Fatigue is a common side effect with enzalutamide. I encourage patients specifically to take it prior to bedtime because sometimes that helps with the fatigue. Usually the fatigue with abiraterone and prednisone isn't that bad, so patients can dose that in the morning. While these second generation AR inhibitors don't have a lot of GI toxicity, obviously we keep monitoring for nausea, diarrhea, and constipation, and then treating them as we would any other patient, with antiemetics or antidiarrheals or helping them with constipation with bulk forming laxatives. Again, increasing fiber and hydration. I think one of the most significant side effects with enzalutamide that was seen in the clinical trials was the risk of seizure.


Right now, the practice is making sure your patient has a good neural history, making sure that you're asking them, have you ever had a seizure in your past? If they've ever had a transient ischemic attack. Describing what that is, closed head injury, or if they're on any medications that might lower the seizure threshold, this may not be the first choice for you. Obviously, if there's a seizure history, this is not recommended. But again, making sure we include that as part of our review of systems and history taking. And then again, telling patients that if they have no seizure history and we put them on enzalutamide, if they do have a seizure or some sort of transient ischemic attack, to let us know immediately because that medication, the enzalutamide, should not be restarted. Headaches and dizziness can happen. Again, making sure that we're ruling out the more serious causes of headache, and then, if tolerable, just manage with analgesics as needed, and making sure we're investigating for other causes of headache and dizziness, and seeing if there are simple things we can do to help fix that.


Labs are very important with second generation AR inhibitors. You have to monitor the LFTs, renal function, and obviously, the PSA helps with disease monitoring. CBCs with diff aren't usually recommended that often, but checking periodically, especially if the patient has more profound fatigue, to make sure that we're assessing everything and doing a complete evaluation. This is the most exciting, I think, that first-line PARP inhibitors with a second generation AR inhibitor has now been moved into the first line setting in metastatic CRPC. That again, is why testing for a BRCA1/2 is important, looking at DNA mutations. All three of these PARP inhibitors are approved either with abiraterone and prednisone or with enzalutamide, the talazoparib. They were all approved, again, a little bit differently. Some are specifically for BRCA1/2, some include germline or DNA mutations. Some options won't be available based on the package insert, but there are other options. I do know talazoparib is approved for BRCA1/2 and other DNA mutations. Niraparib and abiraterone and prednisone, the median radiographic progression-free survival was 16.5 months, which is significant. And the radiographic progression-free survival in both the olaparib and abi, and talazoparib and enza, has not yet been reached, whereas in the control arm, it was reached.


PARP inhibitors have their own unique side effects, often very different than the second generation AR inhibitors. They're a little bit easier to identify. PARP inhibitors do cause quite a significant amount of profound fatigue. Watching for increased activity, good oral hydration. We do need to keep a lookout on the blood counts for anemia. Also, making sure that, if it is enzalutamide, we are trying to tease out which agent is causing it. Nausea and vomiting, again, is something that isn't usually seen with the second generation AR inhibitors. Making sure that patients have antiemetics, if needed, taking them before their dose of PARP, which is given twice daily. And then again, checking LFTs to make sure we're not having LFT elevation, which might be a cause of that nausea and vomiting. And again, watching for anemia, neutropenia, and thrombocytopenia. Unlike just our second generation AR inhibitors, CBCs with diff need to be monitored very closely at the start of therapy.


There are a lot of guidelines and tables that help us measure what sort of intensity it is. And along with the grading, it has recommendations for what to do, such as obviously transfuse when you think you need to, but depending on neutropenia and thrombocytopenia, if you should hold the dose, which is a common way to manage these side effects. And if you restart, what is the dose level or reduced dose that you would restart at? And there's always the rare but serious side effects of MDS or AML. Again, another important reason that we're following those CBCs very closely. Strategy just to promote adherence. These are all oral therapies. It's finding out how patients like to learn and manage their treatments, what works best for them, how can we provide them with information that is a reminder. Emphasizing the importance of adherence, trying to simplify that regimen as much as possible and always ensuring a caregiver is present really does help to be a second set of ears.


And I've learned the hard way, but instead of asking, "Are you taking the abipred or are you taking the olaparib twice a day?" they may say yes, or if you don't ask them the interval, they may say, "Oh yeah, I'm taking that." But when you ask them how they're taking it, they're doing some totally different schedule. "Tell me how you're taking it" tells me in a very non-threatening manner, how they are taking it. And then I can provide them education and guidance. And unfortunately, in today's date and era, medications are expensive. Finding out the cost of the medication to the patient and if they're not dosing correctly, are they doing so because of cost and they're trying to make things last longer. And again, it's a multidisciplinary approach. There is no way one provider can manage all these things and it really does take a lot of coordination with PCPs, other specialties to help manage comorbid conditions and also to help them stay informed.


When they see the patients, they have the full picture. Looking up prescriptions, over-the-counter supplements that I talked about and not waiting for patients to call you. Reaching out to that patient soon after starting and just asking how things are going, going through a review of systems, I think, allows them permission to tell you how they actually feel. A lot of patients don't want to tell you either because they think they're bothering you or they don't want to have a dose reduction. I think just evaluating all potential barriers, reaching out to patients and really just encouraging them to be part of their care and that we're here to help them.

Alicia Morgans: Thank you so much. That was wonderful, Brenda. And I love all of the tricks that you gave. I love the trick, "Tell me how you're taking it." I think that that's such a practical piece of advice that we can use whether we're in a medical oncology clinic or a urology clinic, but it really is non-threatening. And so many of the ways that you approach patients and the way that you draw that out is not threatening. And of course, that's what we want to be. One thing that can be challenging for patients, though, is blood transfusions or thinking about having low blood counts. And I wonder when you're specifically thinking about that side effect, which can happen with PARPs, but also with chemo and with other agents as well, how do you talk to patients about that? Because we may feel pretty comfortable saying, "Oh, we'll just give you a transfusion or we'll hold your drug," but that can be scary sometimes for patients.

Brenda Martone: It is very scary, and oftentimes when I'm teaching patients about, let's say, the new medication that they're starting, especially if we know it's associated with anemia or neutropenia, I let them know that these are the common side effects. We're going to follow them. If the hemoglobin or whatever becomes a certain amount or a level, we're going to want to hold the medication and then we definitely want to transfuse you if you're symptomatic. And I always say not all patients need a transfusion, but I want to let you know before you start that sometimes holding medications and trying to find that exact right dose for you may not be the starting dose and your body may tell us what that dose should be so that we're not having these side effects repeat. We continually do not want to be giving red blood cell transfusions. We definitely need to do a better job with dosing with our patients and reducing the doses if necessary because it's still working; it's efficacious.


That's how we manage a lot of our side effects. I think just making it kind of part of the talk at the beginning, talking about how we would address that, it wouldn't be a surprise. They're not going to go from a hemoglobin of 12 to six. It doesn't work that way. And if that were to happen, there's other things going on, and we should be better at following the CBCs. I often tell them they're going to be managed very closely, and if needed, we would do what we need to do to help support them.


Alicia Morgans: I think that's great advice. that Giving them the warning before the drug even starts is the same approach that I use to normalize it and to make sure that as we continue to do follow-up, look at CBCs, we're talking through it, and there aren't as many surprises. This can, I think, really improve the ability of patients to kind of process over time and then not be as scared. I guess to that end, how often do you see patients who are on these medications where we might see cytopenias develop or other complications, and we, of course, would want to make sure we were engaging with them to identify these complications and manage them. What do you think about with mCRPC patients?

Brenda Martone: In terms of how often we see patients, we follow them very closely at the initiation of treatment. Basically, getting labs the first two weeks, seeing them back in four weeks with labs, depending on if there's any abnormalities in liver function, you may want to decrease the interval. And then after that, if they're tolerating it, about every four weeks for approximately the first three months. A lot of these side effects can be more profound at the beginning. That's not to say they can't occur later, but just kind of getting an idea because you're starting a new agent or a new therapy combination that they haven't seen before, so we don't know how their body's going to react. So we just follow closely and maybe go to every six weeks, and then at some point, if things are stable, maybe every three months. But that's kind of what we do in my clinical practice.

Alicia Morgans: I think that sounds great and a great rule of thumb for mCRPC patients because there can be such a heterogeneous development of side effects, certainly response to therapies, and just patient heterogeneity in terms of comorbidities and other issues. These are great rules of thumb, and I would say I certainly feel like I follow the same thing. One thing that you mentioned too, though, that I would love to dig into a little bit more is supplements. And our patients tend to take, some of them, all kinds of things because they really want to make sure they're doing everything that they can for their health. How do you approach supplements, and how do you think through drug-drug interactions? Because there can be combinations that can be dangerous, especially if we don't even ask patients and find out.

Brenda Martone: Yes. I have the luxury, which I don't know if every center does, but we work with a GU pharmacist who is outstanding. And so when we're talking about treatment initiation and looking at their meds, we make sure we understand all the meds they're on. We go through any supplements. There is a supplement website that tells you a little bit more information, but our pharmacists really do look at the metabolism of these supplements and whether it would increase or decrease. Is there any sort of stress to the liver? Because a lot of these supplements may seem, because they're supplements, they must be healthy, but they still get metabolized through the organs. I'll tell you that sometimes if we see LFT elevations where things haven't been before, just asking them, did you have a really great evening? Was there a football game? Did you party the night before? And then just making sure they haven't started anything new.

Alicia Morgans: I think that's great advice too. As we wrap up, what are your three main points for consideration for practitioners who work in a medical oncology clinic and are thinking about starting new agents, whatever the agents are for mCRPC?

Brenda Martone: Looking at the data, number one, and the overall response as well as delay in progression, seeing if they have a BRCA or germline mutation to make this a potential option. And then just follow up closely, letting patients know the labs, the visits. This isn't something that you can just start and then see them back in three months if they're due for an injection or if they're on oral therapy. I think the data is exciting. Monitoring side effects and making sure there's no drug-drug interactions and then close follow-up. And because education occurs at each follow-up visit. They're not going to absorb everything at the first visit. If they're back and I go through a review of systems, I'll be like, "Oh, okay, great. Are you nauseated? A little queasy in the morning," and then we can talk through it. Education keeps going throughout, and so I think even though that's probably four points, I think they're all very important.

Alicia Morgans: I certainly agree and always appreciate your learning points. I think that there are so many new agents that you discussed today that are coming in the future and our care of patients in medical oncology continues to evolve. We just need to support the patients, make sure that they're aware of what's coming as best we can, because it does help them process and certainly cope with some of the challenges that they face. And I so appreciate you sharing your pearls and your knowledge with us today. Thank you so much, Brenda.

Brenda Martone: Thank you, Alicia. It was a pleasure to speak with you.