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Neal Shore: You look great. Well, hi everyone and welcome to UroToday and our online medical education program Beyond Androgen Blockade: to New Pathways and Novel Treatments in MHSPC and MCRPC. I'm Neal Shore and I have the honor to moderate today's discussion following a presentation by Brenda Martone, who's an advanced nurse practitioner from Northwestern Medicine specializing in GU oncology. I've had the privilege to be involved with her on multiple educational multidisciplinary programs. So with that, it's a pleasure to have Brenda further discuss.

Brenda Martone: Thank you, Dr. Shore. So I'm going to be talking about Beyond Androgen Deprivation therapy and those patients who have metastatic CRPC. This timeline, I think it really kind of just visualizes and really sort of drives home how many different treatment options we now have for those with advanced prostate cancer. Basically, since 2011, we've gotten second-generation AR inhibitors. We've got some radio labeled pharmaceuticals such as radium 223, checkpoint inhibitor therapy for those who have MSA high or TMB high or MSI instability, as well as other AR targeted agents along with AR in docetaxel. A lot of different combinations as well as new molecular imaging, which is helping to diagnose metastatic disease earlier on, as well as new combos with PARP inhibitors and second-generation AR inhibitors. These agents are all associated either with an overall survival benefit or a delay in disease progression.

I call this my checklist for metastatic CRPC patients. Basically in this setting, if they have extensive bone mets or bone mets at all, all metastatic CRPC patients should be on some bone strengthening therapy and I'm looking for either zoledronic acid or denosumab. The rationale for this is it delays a skeletal related event. It's also very important that we're making sure our patients are taking calcium and vitamin D because we want to monitor for hypocalcemia and especially with zoledronic acid and actually denosumab also, keeping an eye on the creatinine and the creatinine clearance.

I want to make sure that these patients have both germline and somatic tumor testing results available because we know in men with advanced prostate cancer, one out of 10 actually have a germline mutation regardless of family history. So identifying these is not only prognostic but predictive for future therapies. And again, if they do have a germline or a somatic DNA repair mutation, this would open up the door for adding in PARP inhibitors in the metastatic CRPC setting as well as any TMB high or MSI high. That would also give them an opportunity to receive pembrolizumab, which is a checkpoint inhibitor.

Obviously making sure all patients are still on androgen deprivation therapy, either injectables or our one oral agent called Relugolix. This remains the backbone of therapy and we're basically just adding on. Again, if they're taking oral medications, making sure there's no drug-drug interactions with either Relugolix and what they're currently taking or any of these second-generation AR inhibitors or PARP inhibitors. And it's important that we don't forget to look at the supplements. A lot of our gentlemen come with different supplements thinking because they can buy them over the counter or they're natural that there's no sort of consideration for harm and it's important that we're looking at those drug-drug interactions.

This slide shows that there is an overall survival benefit with our two second-generation AR inhibitors in the metastatic CRPC setting, and this includes abiraterone and prednisone and enzalutamide. It also shows that there is activity either in patients receiving these pre-docetaxel as well as post-docetaxel. There is a trial though that in the metastatic CRPC patients, if they're on a second-generation AR inhibitor and they have disease progression within 12 months, generally you would try to avoid sequencing AR by AR. The efficacy is a little bit lower. You might want to consider if they haven't seen chemotherapy, maybe referral to oncology to receive chemotherapy. And if they're not chemo fit, looking at some other options, if they are eligible for a PARP or seeing what else you could offer that patient.

Managing key AEs with these second-generation AR inhibitors. Abiraterone you can see more of a tendency for hypertension. You're going to want to look at the blood pressure. If they're already hypertensive or on anti-hypertensive medications, making sure that you get these maximized with the most control of the blood pressure and treating any risk factors. Even those patients who are on enzalutamide, you may not see a lot of hypertension, but there are some cardiovascular risks involved and I think it's important that we're always practicing and promoting preventive strategies for cardiovascular disease and the increased risk of diabetes in those patients with metastatic CRPC.

There is an increased risk for falls and fractures, so assessing fall risk at each of the visits. Something as simple as the Get Up and Go test, you can do it at baseline and then at different visits throughout. It gives you an objective way to kind of measure that patient's mobility, making sure that they're using a walker or a cane if that's necessary for them. And then removing rugs, using nightlights, just doing anything in the home to reduce that fall risk.

Fatigue is common. I see it more often with enzalutamide, so I often recommend that these gentlemen take their medications prior to bedtime, keep up with physical activity, weight-bearing exercises, and other sorts of things that can be done, such as staying well hydrated- everything that can be helpful for fatigue. Of course, we have to also look to make sure that there are no other underlying factors such as thyroid dysfunction or anemia. For GI issues, we all know how to manage if patients have nausea, diarrhea, or constipation with appropriate antidiarrheals or bulk-forming laxatives.

With enzalutamide, there is a rare risk, but it does exist, of seizures. So in patients prior to starting any type of AR inhibitor, part of my review of systems is always, "Have you ever had a seizure? Do you remember anyone ever telling you you had a TIA where you had a brief transient ischemic attack? Any falls or closed head injuries?" So if they report any of that, obviously if there's a seizure history, this medication is not to be offered to them or prescribed due to the increased seizure risk. And also finding out if they are on any medications that could lower the seizure threshold.

Headaches and dizziness. Again, I see that more often if they are experiencing them. In patients on enzalutamide, you can treat them symptomatically, but of course work up for other causes of headaches and dizziness and find out how much it's impacting their quality of life. There are labs that need to be followed such as LFTs, renal function, and of course PSA which kind of helps us track the disease and the response in addition to imaging.

I think this is one of the most exciting developments in terms of treatments, these were all recently approved. So we've had PARP inhibitors in second line metastatic CRPC patients, and these were monotherapy and included olaparib and rucaparib. Most recently, we now have a combination of PARP inhibitors with AR inhibitors, niraparib with abi/pred, olaparib with abi/pred, and also talazoparib with enzalutamide. And in niraparib and abi, the median progression-free survival was 16.5 months in the combo compared to those on single agents and the median progression-free survival hasn't yet been reached in those patients taking olaparib and abi or talazoparib/enzalutamide. They also have slightly different indications with niraparib and olaparib being for BRCA1,2, talazoparib includes BRCA1,2 as well as other DNA repair mutations. So it's important that when selecting your combo you are selecting the correct agents for that patient.

The most common side effects with PARP inhibitors include fatigue, nausea/vomiting, and of course anemia, neutropenia, thrombocytopenia. Most often these side effects can be more profound at the beginning of treatment and actually kind of mitigate over time, especially fatigue and nausea and vomiting. Anemia, neutropenia, and thrombocytopenia, again, can be more cumulative. So obviously for fatigue, increase activity, rule out anemia to see if that patient doesn't need a blood transfusion, and maintain good oral hydration. For nausea and vomiting, have antiemetics at home, suggesting they take them prior to each PARP dose. Monitor the LFTs to make sure there isn't anything happening with the liver that might be contributing. And again, close monitoring of CBCs. There are really good guidelines and I'm going to show you just a slight example towards the end about grading some of that anemia, thrombocytopenia, knowing when to hold the dose, knowing when to consider a dose reduction.

So this is basically that slide I promised you. This is from the talazoparib physician's guide. I'm not trying to promote one PARP inhibitor over another. It's just that they had this great resource that shows you looking at toxicities and grades, what you should do about holding the drug and if you should restart at what parameter as well as a dose reduction. Just in general, grade three and four for non-hematologic effects basically mean it's interfering. If there's an activity that's interfering with their instrumental daily living activities or something that is uncontrolled with medications, that's usually on average a grade three. So that helps if you don't have any sort of guideline available, knowing when you should hold.

And again, this is a nice little resource for talazoparib that actually shows what you need to do, how you do those dose reductions with the capsules. And if you've had three or more dose reductions, obviously the medication should be discontinued and these are things that are available for all the PARPs. And I actually use this myself when I'm seeing patients as a guideline and a recommendation. I think it's really helpful in having these resources available.

Since we are talking about oral medications in this little segment, things that we can do to help promote adherence to these oral therapies, finding out patients' preferences in terms of how they like to learn, how do they like to track medications, what sort of literacy they have in terms of understanding what we're saying. Because it's our job and our goal to make sure patients understand why they're taking things, what to look for and how to do things safely and what sort of support do they have. Kind of asking them open-ended questions. Instead of saying, "Are you taking the abiraterone once daily?" I say, "Tell me how you're taking the abiraterone once daily." Because you'd be surprised how many times I've been told that I take two in the morning and two at night or one every four hours despite the instructions that are written, etc. on the bottle. So just reinforcing that through education each time you see that patient.

Emphasize the importance of adherence and simplify that regimen as much as possible. And again, written information. Maybe some patients prefer more words. Some patients like pictures. I like pictures. Making sure patients have somebody with them to be a second set of ears just to help them hear things. And then I always ask them how much things cost. So you always do a financial investigation at the beginning. Sometimes even though insurance pays, the copay can be high. I often look for patient assistance in that setting, but sometimes even what we would feel is an okay copay may be too much for that patient. So if you find out they may not be taking their medication as prescribed, finding out what that cost is and see if perhaps they're trying to preserve their medication so they don't need to get it as often.

Obviously not one person can take care of these patients. It's a multidisciplinary approach. We have to include PCPs to help us monitor our patients. We need urologists, radiation oncologists, and oncologists, and again, looking at reviews of medication, making sure that there's no drug-drug interactions. You don't want anything that will interfere with the efficacy of the medication, nor do you want that prostate cancer directed therapy to interfere with the efficacy of other medications that that patient is taking.

Reaching out prophylactically, asking them how they're doing, calling them in close follow-up. That kind of, I think, opens the door and gives them permission to kind of say, "Hey, I'm having this," rather than they may not want to call us because they don't want to bother us. So I always go through and do a complete review of systems and symptom assessment to see if I can't help them manage a toxicity or side effect that they may not have shared with me otherwise.

Neal Shore: Well, Brenda, thank you so much. That was fantastic. You are so important to the work that the physicians are able to do. In fact, you're indispensable and your knowledge, your passion, your clarity of communication is really impressive. You've worked with some great uro oncology and medical oncology folks at Northwestern and the folks at that institution and the patients you treat are really lucky to have you.

You bring up so many great things, the importance of reemphasizing education that sort of sometimes just glazes over patients when the physician says it. Probably it is because you say it in a much calmer, clearer, more patient friendly way, but that's still really, really super important. The checklists that you do. Gosh, I wish I could say I'm always 100% on it and I'm not. And my nurses who work with me like you do with your oncologist, the patients benefit because unfortunately folks fall through the cracks on certain things, the way they take their medicines, if they're not getting a bone protective agent, lab work, imaging, genetic testing. The list you presented was great.

My question for you is, given your experience, what are the educational opportunities that you've seen that have been helpful for your colleagues, whether they're nurse practitioners, physician assistants, RNs, who are really key to the multidisciplinary team now in making sure patients get the best care? What are some of the ways physicians who are listening or advanced practice providers, nurses who say, I want to be more like Brenda. How do I raise the bar for that type of multidisciplinary care?

Brenda Martone: I think in this day and age, we have so many different opportunities for learning. There are podcasts available, there's online presentations, so you don't have to go somewhere. Dr. Neil Love does them all the time with the research to practice. And so I think that those are all helpful. Obviously attending conferences, sometimes there's one day conferences like the APPOS summit or the Oncology Nursing Society if they want to join a local membership. There's always education in that way as well as the ability to kind of network and hear other people's ideas.

And then I think asking questions, I would say there are helpful things. Some people can't have drug reps come into their practice and some people can, and oftentimes they offer good opportunities with written materials, some of those brochures I showed you. And now that we are able to go out, sometimes there'll be dinners that are hosted, which is another great opportunity to learn information and get to network with people and kind of figure out who your go-to person, your scientific liaison may be based on whatever pharmaceutical company you're working with. So I think there's a whole bunch of different ways that people can learn.

Neal Shore: Yeah, that was really well said. And for me at least, and I think given your obvious passion and your commitment, this, I think, continues to keep one really invigorated about new targeted therapies and new biomarkers and new imaging and how we can do better for our patients. And frankly, I think it's the absolute perfect antidote to burnout and helping recognize that it's a team approach, which you've clearly wonderfully articulated. So thank you very, very much.

Brenda Martone: You're welcome.