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Personalizing Cancer Care in Nonmetastatic Castration-Resistant Prostate Cancer

  • Authors: Alicia K. Morgans, MD, MPH; Steven P. Ludlow, PharmD, BCOP, BCPS; Frank dela Rama, RN, MSN, CNS, AGN-BC, AOCNS
  • CME / ABIM MOC / CE Released: 1/25/2022
  • Valid for credit through: 1/25/2023
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Target Audience and Goal Statement

This activity is intended for oncologists, urologists, nurses, and nurse practitioners.

The goal of this activity is to improve the knowledge and confidence of oncologists, urologists, and other members of the healthcare team in creating more patient-centered treatment plans for nonmetastatic castration-resistant prostate cancer (nmCRPC) and actively engaging patients and caregivers in care-planning discussions to balance clinical outcomes with maintenance of quality of life.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Benefit of shared decision-making (SDM) in optimizing outcomes for patients with nmCRPC
    • Potential adverse effects of oral anti-androgen agents used in the management of nmCRPC
  • Have greater competence related to
    • Improving adherence to life-prolonging oral anti-androgen therapies
  • Demonstrate greater confidence related to
    • Interprofessional team collaboration when using SDM to empower patients with nmCRPC and their caregivers to be engaged in care decisions


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  • Alicia K. Morgans, MD, MPH

    Medical Oncologist
    Medical Director, Survivorship Program
    Harvard Medical School
    Dana-Farber Cancer Institute
    Boston, Massachusetts


    Disclosure: Alicia K. Morgans, MD, MPH, has the following relevant financial relationships: 
    Advisor or consultant for: AAA; Astellas; AstraZeneca; Bayer; Blue Earth; Clovis; Dendreon; Janssen; Lantheus; Merck; Myovant; Myriad; Novartis; Pfizer; Sanofi; Seagen Inc., formerly Seattle Genetics, Inc.
    Grants for clinical research from: Astellas; Bayer; Dendreon; Sanofi; Seagen Inc., formerly Seattle Genetics, Inc.


  • Steven P. Ludlow, PharmD, BCOP, BCPS

    Medical Oncology Clinical Pharmacy Specialist
    H. Lee Moffitt Cancer Center and Research Institute
    Tampa, Florida


    Disclosure: Steven P. Ludlow, PharmD, BCOP, BCPS, has no relevant financial relationships.

  • Frank dela Rama, RN, MSN, CNS, AGN-BC, AOCNS

    Clinical Nurse Specialist
    Palo Alto Medical Foundation
    Sutter Medical Network
    Palo Alto, California


    Disclosure: Frank dela Rama, RN, MSN, CNS, AGN-BC, AOCNS, has no relevant financial relationships.


  • Davecia Ragoonath-Cameron, MS

    Medical Education Director, Medscape, LLC 


    Disclosure: Davecia R. Cameron, MS, has disclosed no relevant financial relationships. 

  • Christin Melton, ELS

    Scientific Content Manager, Medscape, LLC 


    Disclosure: Christin Melton, ELS, has disclosed no relevant financial relationships. 

Compliance Reviewer/Nurse Planner

  • Stephanie Corder, ND, RN, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Disclosure: Stephanie Corder, ND, RN, CHCP, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

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Personalizing Cancer Care in Nonmetastatic Castration-Resistant Prostate Cancer

Authors: Alicia K. Morgans, MD, MPH; Steven P. Ludlow, PharmD, BCOP, BCPS; Frank dela Rama, RN, MSN, CNS, AGN-BC, AOCNSFaculty and Disclosures

CME / ABIM MOC / CE Released: 1/25/2022

Valid for credit through: 1/25/2023


Activity Transcript

Alicia K. Morgans, MD, MPH: Hi, my name is Alicia Morgans, and I'm a genitourinary medical oncologist at Dana-Farber Cancer Institute. Welcome to this program titled, "Personalizing Cancer Care in Nonmetastatic Castration Resistant Prostate Cancer." Joining me today are Dr Steven Ludlow, medical oncology clinical pharmacy specialist at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida; and Mr Frank dela Rama, clinical nurse specialist at the Palo Alto Medical Foundation, Sutter Medical Network, Palo Alto, California. Welcome.

Let's talk first about the definition of nonmetastatic castration resistant prostate cancer (nmCRPC). This is a patient population with no radiographic evidence of metastatic disease on conventional imaging, which is a bone scan or computed tomography (CT) scan or perhaps magnetic resonance imaging (MRI). These patients have a rising prostate-specific antigen (PSA) level despite having a castrate level of testosterone because they're on androgen deprivation therapy (ADT). The estimated incidence of nmCRPC in the United States is approximately 60,000 cases per year.

Historically, within 2 years of becoming castration resistant, one-third to one-half of patients develop metastatic disease. That is critical to know because this is the time when patients may experience symptoms and ultimately die of prostate cancer. Less than 5% of prostate cancer patients have metastasis at the time of diagnosis, so this patient population is a population that was treated initially with intention to cure their disease and has had a recurrence.

Second-generation androgen receptor inhibitors (ARIs) can delay progression to metastatic disease in the nmCRPC setting. This is important because these drugs not only delay time to those patients developing potential pain from their metastatic disease, but they also prolong overall survival (OS). As more men live longer with nmCRPC, it's important for physicians and clinical teams to be prepared to manage their care. This involves optimizing their outcomes, which we do by shared decision-making (SDM) with patients and their caregivers to ensure that patients are receiving treatments that they agree with and are invested in taking. This improves treatment adherence, particularly for patients who are receiving treatments that involve oral agents.

We must also always think about a multidisciplinary (interprofessional) approach. This includes nurses, pharmacists, physical therapists, specialists in nutrition, and others who might provide psychological or psychosexual counseling for our patients along the way. Sometimes, we even need to include experts in cardiology or endocrinology to help with complications of the disease. All these providers are important in ensuring optimal outcomes for our patients.

Let's start with a patient case to illustrate the importance of this patient-centric approach. Mr RB is a 57-year-old man who's presenting with his wife of 25 years for evaluation after developing a rising PSA after prior prostatectomy for Gleason 4 + 5 prostate adenocarcinoma. He was diagnosed with high-risk localized prostate cancer in 2019 and underwent treatment with prostatectomy followed by adjuvant radiation therapy for pT3b disease with a positive margin. He received concurrent ADT with his radiation and is still on ADT at the time that you see him.

His PSA initially became undetectable but increased approximately 5 months after he completed radiation. Of course, he's still on ADT and is now 6.8 as of October of 2021. His PSA doubling time (PSADT) is 9 months, which was calculated using a PSADT calculator online using values from the preceding 12 months. He underwent a bone scan and CT scan of the chest, abdomen, and pelvis to restage at the time just before you're seeing him in October of 2021, and there's no radiographic evidence of metastatic disease. His Eastern Cooperative Oncology Group performance status is 0, and his testosterone level is in the castrate range, so less than 50 ng/dL. It's time to consider next steps for treatment.

First, let's talk about his treatment options. The FDA has approved 3 second-generation ARIs or androgen receptor antagonists for the treatment of men with nmCRPC. These are apalutamide, darolutamide, and enzalutamide. All are preferred treatment regimens for nmCRPC in the National Comprehensive Cancer Network guidelines. Steve, can you start by telling us the efficacy data and reviewing those clinical trials for nmCRPC?

Steven P. Ludlow, PharmD, BCOP, BCPS: Absolutely. They were approved by 3 trials: the ARAMIS, PROSPER, and SPARTAN trials. Those included darolutamide, enzalutamide, and apalutamide, respectively. In terms of study design, they randomized patients 2:1 in a placebo-controlled environment. Sample sizes were all quite large, with a sample size of 1509 in ARAMIS, 1401 in PROSPER, and 1207 in SPARTAN. They all included patients with high-risk nmCRPC and a PSADT of less than 10 months.

Looking at the data, in terms of metastasis-free survival (MFS), the median in months for apalutamide was 40.5 months vs 16.2 months with placebo; for darolutamide, 40.4 months vs 18.4 months; and then for enzalutamide, 36.6 months vs 14.7 months. Hazard ratios (HRs) all look good in the MFS setting.

When we're looking at data like this, it's important to note that the ARIs were all studied against placebo and not against each other. Although you see differences in data, it's important that you don't slate these against each other because there was no head-to-head study that compared these individual agents against each other. It's important not to draw conclusions.

Median OS for apalutamide was 73.9 months vs 59.9 months with placebo. This data hasn't been reported for darolutamide, being the third agent to come on board for this indication. Enzalutamide was 67.0 months vs 56.3 months with placebo. The HRs again looked quite strong.

Dr Morgans: It's important that, as you mentioned, all those HRs showed consistent efficacy for the primary endpoint of MFS and for the secondary endpoint of OS with all these agents, really prolonging survival in this population of patients who not have metastatic disease until time of progression. Most of them, as we saw in these trials, presumably received subsequent therapies that certainly continued to play into their overall outcomes.

What's also important, from what I saw of what you presented, is that there's no clear winner. All of these ARIs have a very consistent signal, and the HRs are all similar. When we think about choosing a treatment with our patients, we have to consider not only the efficacy outcomes, but also the safety profile. Frank, I wonder if you could you tell us what the safety profile looks like for these agents.

Frank dela Rama, RN, MSN, CNS, AGN-BC, AOCNS: Yes, sure. Thanks, Alicia. Some of the symptoms are kind of running across the board, where fatigue may be an issue with any of these agents. You'll notice that with enzalutamide, asthenia is mentioned in addition to fatigue. I usually tell my patients asthenia is kind of like when you wake up in the morning, and you've already run out of gas; whereas, with fatigue, you have some gas in the morning, but as you are active throughout the day, you get a little more tired. We're educating our patients to make these decisions about fatigue.

Perhaps the risk with one of these agents, like apalutamide, is falls and fracture. If the patient is already at risk of falls for some other reason, maybe that will help them make a decision about which agent to pick. Definitely as clinicians, we can help them measure blood pressure. Are they having any problem with intake and output (diarrhea)? These are all things to consider. Ultimately, it's about quality of life.

As these patients are thinking about these 3 medications, their healthcare provider or their physician, especially, is going to give them advice about how to decide, but they may not tell them exactly what to do. The tools we're going to give them to help them understand the treatment they may be undergoing will be helpful for them moving forward.

Dr Morgans: I could not agree more. It's also important to mention specifics around cognition and fatigue. At this point, there are only minimal head-to-head data to help us understand the effects of these agents, but I want to mention the ODENZA trial, which was recently reported. This is a study out of France. It's a phase 2 trial that looked at enzalutamide vs darolutamide in patients to try to understand whether there's a difference in the degree of fatigue patients experience or a difference in certain cognitive domains identified as being important and potentially affected by inhibitors of the androgen receptor in the central nervous system.

The study demonstrated that there might be slightly more fatigue associated with enzalutamide, but it wasn't so much that patients felt they wanted to switch from one drug to the other in this trial. These are really interesting and early days, I would say. It's also important to note that all the data we have on this are not from large or head-to-head trials. At present, it’s just from this 1 phase 2 trial that's been reported.

As clinical teams, when we're trying to help patients choose between agents, we often think about drug-drug interactions. These can be critical because patients have multiple comorbidities that affect them day-to-day and that involve medications that can interact with whatever we use to treat their prostate cancer. Steve, can you talk to us a little about drug-drug interactions for these 3 agents?

Dr Ludlow: Sure. The metabolism of these medications is quite complex. As we see, they are typically substrates of cytochrome (CYP) 3A4 and CYP2C8. They're also inhibitors of CYP2C8 and inducers of CYP3A4. That all leads to a very complex picture when you're dealing with what is generally an older crowd of patients who are already on a lot of medications for health maintenance. The thing to remember, for the most part, is that the second-generation ARIs are rarely the victims of this metabolic effect in these pathways.

In looking at the most common interactions, with enzalutamide, you're going to see effects on calcium channel blockers, direct oral anticoagulants, and things like losartan, where the induction of CYP3A4 -- particularly, a strong induction of CYP3A4 -- is going to lower the efficacy of most agents listed to the right there that are associated with drug-drug interactions. Apalutamide is the same, where you see decreases in efficacy. Darolutamide is a little different from the others. Its metabolic pathway is somewhat different in terms of inducing CYP enzymes. It does affect rosuvastatin, so many people cap rosuvastatin at 10 mg or 20 mg.

Dr Morgans: Great. Well, thank you for talking us through that. I know from a physician's perspective, I really rely on my team to help me with those drug-drug interactions, and the specialty pharmacy is so critical. For this particular patient, he's young -- he's less than 60 years old -- really active and engaged, married, and very active at work. I'm wondering how you would help him choose a treatment. Frank, maybe you can talk us through that a little bit. How do you think through this process with the patient? What do you consider for patients like him?

Mr dela Rama: Thankfully, today we have evidence-based kind of practice. This is a nice example of SDM, where there is an acronym: SHARE. It's a step-by-step process to help patients do their due diligence as they're making these decisions. The first step, S, is really for seeking your patient's participation. Hopefully, we'll have a session where we sit down and address these issues. We don't want any distractions, and we definitely want to set the stage for talking about this particular decision. Then we're going to revisit how we're going to help them in that second step: help them explore all these options. Again, we look over the side effects of one drug vs the other vs the other to kind of set the stage, giving them the pros and cons of each one.

The next step, assessing the patient's preferences, is key. If we kind of get a feel for their patient preference, they're not going to "woulda, coulda, shoulda" later. Maybe for them, the most important part is avoiding falls and fractures, so we avoid one of the medications. In some studies that we have seen, if the OS is less with one agent, but maybe it has less risk for cognition issues or rash or falls, some patients may pick that and be comfortable with that decision despite whatever side effect they might get.

The next one is R, reach the decision. We don't want to let this decision go on and on for months. We want to help them. "Let's reconnect in about a week or less, so we can kind of see where you're at about this decision." They may be gathering more information from the team, from the pharmacists, from the physicians, or from the practice nurses.

The last step of SDM is evaluating the patient's decision. As a navigator or as a clinician, especially, we're always reconnecting with the patients, asking, "How do you feel about this?" It's going to be a cyclical process, so we will probably want to repeat SHARE all over again just so they're comfortable with the decisions as they move through the treatment course.

Dr Morgans: I really appreciate you going through that. I think it's so critical that we clinicians in oncology really understand the SDM process. One reason this is so important is that studies really do show that patients with cancer want to be involved in these treatment decisions and that they can feel left out if they're not included. Importantly, too, caregivers are a critical part of the decision-making process and should be involved as much as the patient and the caregiver want them to be included. Frank, can you tell us your thoughts specifically on including caregivers and partners in the process?

Mr dela Rama: Yeah, definitely a great point in SDM. Prostate cancer is affecting the whole family unit, especially the caregiver or the partner, and a lot of these choices may affect them pretty much directly. Now, I know guys are warriors and want to take care of everything by themselves, but I think in this situation, you need someone else there to learn about the possibilities and to kind of help keep an eye open for when the patient is more tired one day and to ask the patient about fatigue or things that can't be measured with a blood test. So, you're going to recruit that caregiver to be your help at home. Again, regarding outcomes: if they're both on board and given a choice, they're going to be comfortable with that choice in the future.

Caregivers are really an important part of the process. We want to recruit them, and we want to educate them as much as possible because we're giving care as a team, and that definitely does include the patients and caregivers.

Dr Morgans: When we're working with patients and their loved ones, we sometimes encounter obstacles to SDM. These barriers may come up because of communication issues. Maybe we don't speak the same language or maybe we don't have materials that have been translated into a particular language. More commonly, there are barriers based on medical literacy. Frank, do you have some guidance for us there? What methods do you have for getting around some of these barriers?

Mr dela Rama: Right. Great question. Being a navigator is all about breaking down barriers, so when it comes to language barriers, you definitely want to tee it up. I want to take as much of the burden off the patient and the caregiver as I can. If they speak another language, I can hopefully find someone or do a Google translate on these education materials so we can share them with the patient, the caregiver, and the family. Sometimes the one who speaks the English best may not be the caregiver or the patient; maybe it's someone else in the family. We want to make sure those people are involved so that we can break down the knowledge barrier because language can be key. Different cultures are definitely going to play into that, as well, and it's all about giving them the tools to figure things out.

We're going to be talking about this educational material maybe face to face or by video, but I always want to follow up with giving them something in writing, something they can read. They're going to need to go home and digest that, and they can go over that material together as a family. Video visits are more common now, which could be a good thing or a bad thing. Setting that up at home and technical issues are barriers we may need to help with. Again, video access makes it a little bit easier to connect with our patients, especially in rural areas, and we want to connect with our patients basically as often as we can. I think that's going to encourage adherence and break down the barriers with this process.

Dr Morgans: Those are some great tips. Thank you for sharing those and giving us some guidance on how to use technology to our advantage. I haven't forgotten about you, Steve. How do you and your colleagues in the pharmacy work to overcome those barriers, and how do you engage in supporting treatment decision-making and the shared decisions Frank has talked about?

Dr Ludlow: Well, it's always an individual process. In the beginning, with each patient, I try to get an assessment of where the patient is at and what their support systems are. Even basic communication can be really challenging at times, and you have to be open to the idea that things are not going to be as easy as they are with someone who has good medical literacy or good support systems to get information across clearly.

At the same time, I'm never surprised by how when you present the same data to 3 different people, the preferences and selections are so very different and things that you personally may find important -- possible adverse events -- may not be important at all to the person with whom you're speaking.

I think you always have to include the patient and the family in decision-making and that you have to provide all the available details that you can to them. At that point, you can then tailor therapy to what their needs are as a group and as an individual.

Dr Morgans: Great advice. Thank you for that. As we think about SDM and about treatment choice for nmCRPC patients, some things I think about as a physician are patient factors, disease factors, the different aspects of therapy, and the patient's preferences. Some of the clinical considerations I think about are the patient's age, of course; their life expectancy, which is a consideration you make based on their comorbid illnesses; the supports they have at home; and their relative frailty or lack thereof.

Of course, we also have to think about the stage and grade of cancer. In nmCRPC, this is relatively uniform, but we do have to think about PSAST, even though this is not on the label. Patients with a very short PSADT of 10 months or fewer were included in the clinical trials we reviewed and are really the patients we target most with these medications. Sometimes patients with a very long PSADT of 1 or 2 years may take a lot longer to develop metastatic disease and may have more time before they need to start additional therapy, and that can be part of a shared decision.

Adverse events from medications need to be considered, of course; as well as other patient factors like expectations around quality of life and some of the side effects we've discussed; any symptoms the patient may be having related to the disease or to prior treatments, like incontinence or erectile dysfunction; and anxiety that the patient may have about PSA rising. We also have to think about survival and how treatment may affect that and about the cost of the drug. These oral agents come with copays for many patients, and that can affect access to the drug.

Let's get back to the patient case. Mr RB noted that although his standard imaging, which we mentioned was a bone scan and a CT scan, was negative for evidence of metastatic disease, he wanted to have one of the fancy new prostate-specific membrane antigen (PSMA) positron emission tomography (PET) scans. The PSMA PET was performed and demonstrated small pelvic lymph nodes within the prior radiation field (an area that was already treated with radiation) of approximately 1.8 centimeters, which was relatively small and just met size criteria to be concerning for metastatic deposits; and 2 areas of potential rib involvement: the posterior seventh and ninth ribs. Now we need to think about what to do next and what the treatment options are for this patient.

In my practice, I use systemic therapies and sometimes layer on metastasis-directed therapy, but we know that there is currently no survival advantage associated with metastasis-directed therapy in the absence of changing systemic therapy from a large-scale phase 3 trial in the nmCRPC population.

The added adverse event profile and quality of life changes that happen when we do add one of these androgen receptor antagonists is relatively minimal from what we can tell from both patient-reported outcomes and adverse events. Because of that, I would always add -- unless the patient was unwilling to do so -- one of those androgen-receptor targeted agents onto my ADT to be sure that I had that MFS prolongation and the improvement in OS demonstrated in the phase 3 clinical trials.

Importantly, for this particular patient, he is still active in his job. He's a financial executive who travels a lot. He does a lot of activities and mathematical calculations for his job, so he really wants to consider a treatment that is not going to interfere with any of that. Taking one of these oral agents each day should not really interfere with these activities. He can take them whether he's traveling or not just as long as he's home to have his ADT when necessary and is being monitored with laboratory tests to make sure he is safe from that perspective.

I want to talk to Steve because this patient has developed high cholesterol and hypertension, so he does need to think about drug-drug interactions. Steve, do you have any comments for how you might think about drug-drug interactions for these pretty common comorbid illnesses in this setting for this patient?

Dr Ludlow: Yeah, I think when you're running into situations like this, it's always important to know that these patients are going to require a bit more finesse. That doesn't necessarily mean that these agents can't be used, but it means that closer monitoring will be necessary.

Agents we might run to initially, like angiotensin receptor blockers or calcium channel blockers depending on the patients' other comorbidities, may potentially be impacted by therapy with apalutamide and enzalutamide. That being said, it doesn't mean that these agents can't be used or that we can't reach the goal. We just have to think of it in a different context, recognizing that the patient will require more follow-up and titration will probably take a little longer. We have to be open to the fact that there are going to be potential changes.

Specifically, when you're talking about statins for hypercholesterolemia, you have to be cautious because apalutamide and darolutamide are really pushing things in opposite directions. Thus, it requires knowing what your starting point is and what your goals are. Are you talking about somebody who is 80 years old and looking at their quality of life and their length of life in terms of whether or not to initiate therapy? That's not the case with this patient, but I think it's important to keep that in mind, overall, and to try to have your best case forward when it comes time to treat. Just know that there's going to be a little more effort needed for patients who are taking drugs in this group.

Dr Morgans: That's great. Thank you for those insights. Considering this patient's travel schedule and his need for energy and mental acuity, he did a lot of research and decided (based on things like the ODENZA trial and other anecdotal evidence he read) that he wanted to try darolutamide. That's a completely reasonable option and has relatively fewer drug-drug interactions, which may be helpful considering his new comorbid illnesses.

As we think about him, he's younger than 60 years, and hopefully hardy -- he tolerated this treatment quite well -- but we do have to think about and take care of patients who are older adults. They may have more comorbid illnesses or other issues such as frailty or a higher risk of falls. From your perspective, Steve, is there anything that we need to think of in particular for older adults who are facing this treatment choice?

Dr Ludlow: Well, it's always wise to look at your adverse effects profile and falls, especially given the high rate. In the older adult, osteopenia or osteoporosis always needs to be taken into consideration. Some patients may have legitimate fears of falls and skeletal-related events associated with that.

Seizure profile was relatively modest with all the ARIs. Even though there's an association between seizure and enzalutamide, it's not quite as strong as it's often led out to be. I think you really have to look at where patients are -- how they live, what their lifestyle is like, and how much support they have. There is some finessing you can do among the agents. Darolutamide has a little cleaner profile in terms of falls and things, but I don't think there's a tremendous difference among them. We're often guided by financial toxicity. That is a very important piece of this that is often left out.

Dr Morgans: Great. Well, thank you. Frank, as we start to wrap up, I wonder if you could give us any guidance on how to think proactively about managing adverse events. What can we do to support education of caregivers and others to avoid any adverse events that might be associated with intensifying therapy?

Mr dela Rama: Yeah, definitely, that's an important point. I want to make the patient and the caregiver active participants. We want to educate them on what to look for when it comes to fatigue and cognition. Some things are obvious. We may want them to get their blood pressure measured and to check their steps every day on a step tracker.

Measuring fatigue is not something they're used to doing, however. It may be something as simple as, "How tired do you feel today on a scale of 1 to 10, or mild/moderate/severe?" The same goes for cognition. It may involve asking questions like, "Are you starting tasks and not finishing them? Are you having some difficulty remembering things?" It's good to kind of get them thinking about it so that maybe they'll reassess themselves at home.

It's all about encouraging open communication, so they can reach out to their key person on the team, whether it's a navigator or a clinic nurse or a physician as often as they want. "You want to keep us in the loop so we can help you manage those issues." From a prevention standpoint, when it comes to fatigue, we obviously don't want them just staying in bed. Fatigue is best served by exercise and good diet. We want to keep them active so that they can best get through treatment.

Dr Morgans: As we wrap up, I would love to hear your final thoughts on how you can support patients best, but with a little focus on adherence and how we help patients ensure that they are taking their medications as prescribed so they can really get the maximum benefit. I'll start with you, Steve. How do you and the pharmacy team help support that?

Dr Ludlow: Well, the vast majority of it is going to come through education -- speaking with patients and caregivers about what may happen while they're taking these medications. Sometimes you get this phenomenon where patients don't want to let us down by telling us they're not taking their tablets. At the same time, it's telling them, "There are reasonable occasions when you should not be taking your tablets, like if you're having side effects that are too much for you or if the therapy is not working for your personal situation." Having an open line of communication between patients and the treatment team is extremely important and can help mitigate those issues.

Also, perhaps it means moving from one therapy to another. We hope to select our best therapy first, but that's not always the case. When we need to pivot, we need to be able to do that. When we make those changes, It's not without patient input. They need to be able to speak with us freely and openly. It's a lot easier if we can say, "This side effect may happen," and have them say back to us, "Well, it is happening, and it's a really big deal and it's really affecting my life," instead of, "Well, I've got this thing that has happened that I'm not quite sure what it is, but I'm kind of worried that you're going to take my therapy away if I talk to you about it." Putting the information into their hands, allowing them to process it as they will, and then hearing about it from them when it comes up are extremely important.

It's just basic nuts and bolts -- keeping people on therapy with things like pill minders. With darolutamide, the pill burden is a little bigger than it is with some of the other agents, and that can be a problem for some patients. That should play a role, hopefully initially, when we're talking about therapy and what they're able to tolerate in terms of pill burden; also, if they've got good mechanics when it comes to swallowing. I think in the end, it all comes down to just looking at all the pluses and minuses for all the different agents and looking at patient scenarios and what they've got going on in terms of comorbidities. Also, tolerance is paramount to keeping patients on therapy. Hopefully, it's the right therapy the first time.

Dr Morgans: Frank, from your perspective, how do you, the navigator team, and nurses in general help patients with adherence? What are your overarching thoughts on how to get the best outcomes for nmCRPC?

Mr dela Rama: In my role as a nurse, keeping adherence is definitely important. If adherence is poor, we may get an inkling from their caregiver or from the patient as we assess them. You know, asking, "What's going on?" Think about acuity. If you have a patient who has a supportive wife who tells you what's happening every day or sends you online messages, that may be a little less of a concern than a guy who lives alone, is elderly, and doesn't have a lot of resources. As a nurse, maybe I'm reaching out to that guy a little bit more. I agree with Steve that patients don't want to disappoint their doctor, but maybe they're a little bit more comfortable with the nurse. It means reaching out often and making it easier for the patient because we want to make sure they stay on track.

Dr Morgans: Right. Well, I'm really glad that you and the nurses are part of the team, too. We could not do this without that teamwork aspect. Let's conclude. First, the second-generation ARIs delay progression. They improve MFS and improve OS in nmCRPC. Treatment adherence is essential for maximizing the benefits of these ARI therapies. Because the second-generation ARIs have similar efficacy, differences in safety and tolerability are some of the main concerns we think about when we're helping make treatment decisions with our patients.

SDM really requires educating the patient and the caregiver about the risks and benefits of these therapies and integrates and considers the patient's goals and preferences in treatment selection. To promote continued adherence, everyone on the healthcare team, including the patient, needs to be aware of potential treatment-related adverse effects and needs to work together to manage those effects. Clear, consistent communication is absolutely key.

To my colleagues Dr Ludlow and Mr dela Rama, thank you for this great discussion. I appreciated it and learned quite a bit. To the audience, thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.

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