Introduction

DR LOVE: I’m Neil Love from Research To Practice and welcome to hormonal therapy of prostate cancer, a nursing symposium done in conjunction with the ONS Bridge Virtual Conference. We’re really excited to do this today. I think it's the first time it's been done. We have an awesome faculty of docs and nurses who are going to be discussing this topic. We had a couple of other docs who helped put the questions together for what we’re going to talk about today.

And what we tried to really do is we went to our faculty and said, what are some of the questions that come up in a day-to-day basis that you’re answering that we can share? And we’re going to actually show these questions and some of the answers that our faculty gave as we go through the day.

It seems like years and years since we were actually at the ONS meeting, I guess it's actually a little bit more than year. I don’t know if we’re going to get back there in the near future, but we had a lot of fun, a lot of good music played, and hopefully will be back there again next Spring.

So here’s the way we’re going to approach our discussion today. It's going to be case- based. Basically, we made up 3 case scenarios. We’re going to go through each one of those. And one of the things we try to do in our work here, different than a lot of other nursing oncology education, is really get into what we call oncology strategy — what’s going into the decisions that are being made, the recommendations, particularly as it relates to new therapies, new approaches, new data, and how does the team look at all this and try to make a recommendation and then explain it to the patient. In addition, we’re going to focus on the management of side effects and toxicity with various therapies in prostate cancer, but particularly hormonal therapy.

Case: A man in his early 70s with metastatic hormone-sensitive prostate cancer

DR LOVE: So these are the 3 theoretical scenarios, and we’re going to start out talking about a patient, 73 years old, who presents for the first time with metastatic prostate cancer. So no prior PSA, blood draw. No rectal exam. A little disenfranchised from the medical community. His wife died a year ago from breast cancer. He has no close family. He’s currently out of work as a chef in a restaurant. Very concerned about finances as well exposure, and now confronting metastatic prostate cancer.

And just before we dive into the oncology strategy, just curious, Molly, how you’d be thinking through approaching this man in this situation, going from being relatively healthy to now dealing with the same basic illness his wife had? Any thoughts about bringing him into the interdisciplinary team?

MS KIM: There is certainly a lot to address here, psychosocial, and he doesn’t have much background of going to the doctor, being involved in medicine. So, first, I would enforce that we are a team. We’re here for him. And we have social workers as well to help. A social worker can do a psychosocial evaluation, really help us to understand what his needs are. Does he need assistance with transportation? Does he need help in the home? Is he having trouble paying his medical bills? Things of that nature.

DR LOVE: So, Ellen anything you want to add onto that. For people who’ve kind of been away from the medical system — not only is coming into the medical system, but he’s coming in full blown with metastatic disease. Before we get into the specifics of therapy, any general thoughts. Ellen, about approaching a patient like this?

MS LEIDIG: I think I’d want to try and support him to become an active member of his own team. I think sometimes patients expect to come to their appointments to be spoken to or dictated to but rather trying to give them an active role so that he is a participant. And particularly the fact that his wife passed away from breast cancer, he may have some experience in the medical system, in the oncologic system, through her — Was that a good experience? Was that a frustrating experience? — and understanding that so we can better support him.

DR LOVE: So, William, another issue that comes up in these patients, whether they’ll bring it up to or not, of course, is what to expect from the future. People, even with early stage breast cancer, they hear the diagnosis, they think they’re not going to be around in a few weeks. What would you say to this man who says, what do I have to expect? Is this something that's going to take my life in the next few months? Next few years? Can you give me kind of a global picture of what to expect?

DR OH: Neil, I always find that patients have a lot of unknowns about the prognosis. And, in fact, I think for metastatic cancers of different types, people all think that they're going to live just for a few weeks or a few months. And I think it's very important to communicate that, at least for metastatic prostate cancer. There are many treatments available. And, in fact, a patients’ prognosis is generally measured in years. And that's what I communicate to the patients, so that even while we’re dealing with all the treatments that we’re going to be talking about, that they have hope for the future.

DR LOVE: Andy, if you can really get to patients to talk to you, which is always a challenge, what are some of the questions in general you think they want to have answers to, particularly as it relates to, again, what to expect they’re going to go through?

DR ARMSTRONG: Right. Neil, it's a very important question. And I think for a guy like this in particular, it's very important to listen to what his expectations are, what his understanding of his own illness is. To sit down and listen to what his experience with his wife’s breast cancer experience was like, because that may be driving a lot of the fear and anxiety/depression, that he may be experiencing. To engage with him. As Ellen and Molly mentioned that we’re on the same team and that we’re going to be together for many years. We’re going to have a good relationship and that he’s likely to go into remission. And the goal is to talk about quality of life so that he can get back, once COVID’s past, to his restaurant business, so that he can work even despite a metastatic condition, for often many years.

And so a lot of reassurance, listening, and educating about the condition.

DR LOVE: So, we’re going to go through the choices. We picked this situation because the choices are so dramatic, and of course, it's a very important clinical situation. But essentially, we’re going to present to you what choices this man is going to make.

So the interesting thing about this decision is he could get different forms of hormonal therapy, we’ll talk about that in a second. He could get chemotherapy, docetaxel, or he could just get androgen deprivation alone.

So we’re going to talk about what goes into building a strategy for a patient like this. And afterwards, we’re going to come back to you and say, what do you think the best approach would be to a patient like this in particular? And you can try to imagine this man, or a patient maybe you’ve seen that kind of reminds you of that. So it's not just the medical decision, there’s a bunch of things that go into that. We’re going to ask you in a few minutes what you would think might be the best decision.

And then the other thing we’re going to ask you is whether your recommendation or the approach to the patient would be different now in the midst of COVID-19 pandemic? We’re trying to social distance. We’re trying to keep people out of clinic. Is your approach different now than it might have been 6 months ago? So we’ll get into that in a second.

But let’s just talk a little bit about the science of what’s involved here. And William, of course the key thing with prostate cancer are the androgens, the male hormones. Can you talk a little bit about the hormonal system and where there are places where we can make an intervention that's going to be helpful?

DR OH: Sure. This is one of the first targeted therapies, Neil. That's the way I describe this. We know that prostate cancer, like breast cancer, is an endocrine-driven disease, and we’ve known that since the 1940s. So drugs that block testosterone production clearly inhibit the growth of the cancer. And over the past few years, as you can see from this slide, we’ve known for many years that orchiectomy or LHRH agonists or antagonists, do the first wave of blocking the testosterone production. But over the past decade or so, we’ve understood that there are additional sources of androgen, including in the adrenal glands and actually, interestingly, the tumors themselves.

So many of the next-generation androgen targeted therapies actually get rid of the little bit of leftover testosterone that's not made by the testicles. And sometimes I describe it to patients like this, I say cacti grow in the desert with small amounts of water. And these next-generation drugs block that little bit of water and can actually kill the cactus. And that's our goal is to try to get rid of that last big of testosterone and in doing so, these men actually live longer.

DR LOVE: Ellen, the whole idea of testosterone suppression, I think would be very foreign to most people, not even imagine that that would be done. Before we get into some of the toxicity issues, the misconceptions about what removing testosterone does. Do you find men feel that this is a challenge to their manhood, so to speak?

MS LEIDIG: We see that often. What I hear, at least in my practice, is that I’ll have a patient come in and say I hear I’m going to go through male menopause due to some of the adverse effects that can come from these treatments that we give. And so, either a patient will come in and they’ll say my wife doesn’t have much sympathy for me because I’m going to have hot flashes and she already has them. Or, worried about sexual dysfunction, I think is a really significant concern for many of your patients. And so, many will come almost with a preconceived fear of these treatments and maybe a resistance to wanting to start them. So that can be something we really need to discuss with them before they're even willing to start therapy.

DR LOVE: So, Andy, what we’re talking about today is almost unique in oncology, in the fact that at different stages we have different approaches. And it's pretty subtle, and we’re going to try to get into some of the subtleties. And a good way to start it is to take a look at this slide here in terms of the disease states, the model of how prostate cancer grows and eventually can kill people. Can you talk a little bit about how you think about this and how you would explain where the patient fits in?

DR ARMSTRONG: So, Neil, prostate cancer in the United States particularly, is most commonly screened detected, and we talk about localized disease as disease that's detected before it leaves the prostate gland. And the good news is about 6 out of 7 men are cured of prostate cancer with local therapy and it's the number 1 survived cancer in the Unites States.

The PSA stands for prostate-specific antigen and is one of the first signs of a relapse after a local treatment like radiation or surgery. And we have a group of men where the PSA is going up despite no evidence of the disease on imaging, and that's called non-metastatic disease. And some patients will continue to have non-metastatic disease despite treatment with hormonal therapy where they’ll have a great response and then a relapse, and that's that disease state of non-metastatic castration-resistant disease where we have 3 approved hormonal therapies.

For men who have very aggressive disease where screening has not been performed in parts of the world, like third world countries, and many parts of the world where early detection’s not commonly practice, about a third to half of patients will just start with metastatic disease as their first manifestation of disease. And so, that's what this circle is around, is patients who present with metastatic disease, like the case you’ve described.

We treat these men with hormonal therapy, sometimes chemotherapy. And they will go through periods of remissions and relapses to the point where castration-resistance develops, which is defined as the disease getting worse despite that hormonal treatment.

DR LOVE: So, we want to talk about the new developments in this field. In the past, patients would get androgen deprivation, you remove the source that's stimulating the cancer. Most of the patients responded and did well. Nobody really thought you could do any better until we started to do studies where we added things. And William, maybe you can through what was seen in terms of adding chemotherapy? So you can see this trial, the control group at the bottom just had androgen deprivation, but the strategies that have been used is to add either chemotherapy or different forms of hormonal therapy. Let’s start out talking about hormonal therapy, William. Can you talk about the ENZAMET study and what that showed?

DR OH: This was a Plenary session at ASCO that really demonstrated that adding enzalutamide to androgen deprivation therapy improved overall survival. And you can see the hazard ratio, that means there was about almost a 40% improvement in overall survival with a very significant p-value. What it really suggests is adding a drug like enzalutamide at the time the patient presents, rather than the way we had been using enzalutamide until this study where we would wait for the cancer to become hormone resistant or castration-resistant, adding it upfront has a better benefit than waiting. And this was in spite of the fact that some of these patients in fact, did get chemotherapy. Interestingly, if you got chemotherapy the effect didn’t seem to be as strong. So it really suggests that chemotherapy or enzalutamide would be powerful in improving overall survival if you don’t wait for the cancer to become castration-resistant.

DR LOVE: So, just to pick up a little bit on this curve, because we talk about, whenever we do a program, we go back through this idea. You look at those curves and it doesn’t look like there’s much of a difference, but if you look down there where it says hazard ratio .67, what it means is that at any given point in time a patient’s actually 33% more likely to be alive if they are taking this therapy.

Ellen, how do you find men responding to the idea of adding something on top of androgen deprivation? And what are some of the things that you go through with patients who are about to start androgen deprivation?

MS LEIDIG: Certainly, there are patients who are very hesitant when they hear that the word chemotherapy, or they’ll present to their appointment and say, I don’t want chemotherapy. I think chemo and cancer go hand and hand, and so many people walk into the office with that expectation or concern. Or those who are potentially already on an androgen deprivation and we’re adding a secondary hormonal therapy, they say, I’m already having these side effects. How much worse are they going to get? And my quality of life, how will that be impacted?

I think most people are hesitant to start a new medication or a second medication for the same indication. And so, explaining the rationale of why we would be adding that secondary therapy, whether it's chemo, whether it's another hormonal agent, is really important so that they can feel some power in their decision and agreement to proceed with our plan of care.

DR LOVE: And there’s kind of a consistent message you see in these various trials, for example, here you have another trial with enzalutamide, now apalutamide, another anti-androgen. Also you see benefit compared to just taking androgen deprivation alone.

In the LATITUDE study, they looked at the effect of adding another hormonal therapy, abiraterone. We’ll talk about that. The CHAARTED study looked at adding docetaxel.

Andy, all of these studies showed a benefit. And I guess one of the questions is how do you compare them? Here’s a comparison of some of the hormonal therapies as well as chemotherapy. When you look at this, how do you think through the decision?

DR ARMSTRONG: Yes, the good news for men is that these increments in survival are measured in years, not months, unlike in the castration-resistant setting where these same agents are effective and the improvements in survival are measured in months. When you use these agents earlier, before the disease becomes resistant, you’re seeing extra years of life and long periods of remission. But there’s no differences generally, in efficacy between these agents. They’ve not been compared head to head, but hazard ratios for survival are generally pretty similar. There are some nuances and differences such as docetaxel may not be as active in patients with lower volume or oligometastatic disease, as we call it. While these AR therapies seem to be very active regardless of the number of metastatic sites. But generally, you’re making decisions based on the comorbidities of the patient, the financial toxicities that may be experienced by the patient, the side effect profile. So it's nice to show that slide around the different toxicity profiles.

Docetaxel is done in about 18 weeks, so it's not a long-term therapy. So there are some cost considerations and some efficiency to the completion of 6 cycles of docetaxel there. And worldwide, that may be the most cost-effective option. But many patients, particularly during COVID, are fearful of the immune suppression, the side effects, the impact on quality of life for 6 to 12 months during chemotherapy.

We’re now integrating therapy to the primary as well. So, even though men may have metastatic disease, we used to say you don’t need to worry about your prostate. The horse is out of the barn. And now we actually have Level I evidence that we didn’t show, showing improved survival with treatment to the primary. So that's a new thing. We’re involving Radiation oncologists in the management of men with metastatic disease.

DR LOVE: And that is really interesting too, this is a new development treating the primary in the face of metastatic disease. But, getting back to the basic decision here, Ellen, to me, this was one of the most provocative decisions in oncology because you see about the — and we’re going to let you vote on this in one second, but just to come back to Ellen — really, you see the same treatment benefit whether you get 6 months of chemotherapy or long-term hormonal therapy. And there are upsides and downsides. You would think that people, in general, would not want to get chemo, but I hear some people say, at least before COVID, get it over with in 6 months. What did you see in terms of how people were processing this, let’s say before COVID?

MS LEIDIG: Prior to COVID, I actually think, despite what we as providers look at, which is the concern for immunosuppression on chemotherapy, patients don’t necessarily take that as much as a consideration as they do the quality of life, with their energy level, loss of hair. That sort of piece —- the chemo patient that they imagine, whether it's from someone that they knew and loved or in entertainment perhaps. So patients prior to COVID, really didn’t take the immunosuppression into consideration I would think to the extent that they do now. Now this risk of infection at all times, concern with being around other people, getting treatment every 3 weeks, that kind of exposure that they would get if they were going to proceed with chemotherapy is really playing a greater role and is actually, in some of our clinical studies, affected whether or not we’re giving chemotherapy to some of our patients.

And then, again, like I said earlier, the concern with quality of life and fatigue and hot flashes and sexual dysfunction that come with ADT, patients really tend to have their Googled perception of ADT management when they come into the appointment. And so, after COVID, that perception has not changed as much as the chemo perception with immunosuppression.

So it's been interesting to see kind of the drift where I think patients are taking chemotherapy not more seriously, but just as a bigger risk to their health, to their overall health.

DR LOVE: Yeah, and people are trying to avoid neutropenia nowadays in almost everybody because of COVID.

Molly, I’m curious how you saw — I always thought this was just so interesting, chemo versus hormonal. And we’re going to talk about the different hormonal therapies, but chemo versus hormonal therapy. How did you see people processing this, let’s say before COVID, and did that change after COVID?

MS KIM: So, you’re right that patients sometimes view it as 6 cycles every 3 weeks. Get it over with, get it out of the way and see that PSA decrease versus hormonal therapy. I think it really depends on the patient’s lifestyle as well. Patients would be more interested in maybe an AR therapy if they’re working every day, if they’re unable to come in for treatments and also unable to have the downtime after treatments; whereas, they feel pretty consistently well when on an AR therapy.

Patients who are receiving the chemotherapy, they do have to come into the clinic every 3 weeks. So that was a consideration, both before and during the pandemic of, are they willing to come into the clinic versus would they rather have their treatments at home, with lab work at home or nearby?

DR LOVE: So, before we ask the audience to again vote on what they think they might want to see a patient receive, William, maybe you can go through a little bit about the differences in the various hormonal therapy options? In this particular situation, we’ll talk about the other two situations, in each situation there are different drugs where we have data on, different drugs approved. But in this situation, there are 3. And can you talk about, William, in terms of some of the key clinical differences, particularly as it relates to tolerability with these 3 drugs and what goes into your thinking in terms of choice?

DR OH: Well, first of all, let me start by saying we’re really lucky to have more than one choice. I mean it's been a very active time for these patients. I remember when all we could do was start them on androgen deprivation therapy and that would work for a year or 2 and then they progress, and we didn’t have a lot of options. So the fact that we have 4 options here, chemotherapy versus 1 of these 3 androgen targeted drugs, means that we have to make a choice for the patient.

And just to look at this, many patients do prefer oral therapies; these are all oral. Abiraterone, I think one of the key things about abiraterone is there is a generic version which I think is an important consideration for some of our patients because of the copays can be significant.

Toxicity-wise, I find abiraterone to be generally well tolerated. You do have to check their liver function tests every 2 weeks for the first 3 months and a certain percent, 10 to 20% percent will really have a bump in their liver tests. So it's very important to make sure that you’re monitoring that. High blood pressure is an issue with abiraterone as well. And so, a patient who has a lot of blood pressure issues may not be an ideal candidate for this.

But, in general, I think men do tolerate abi pretty well. They have to get prednisone. If there’s a contraindication with prednisone, that's also very important to consider, like the brittle diabetic that may not be a good choice.

Enzalutamide is a very good choice that doesn’t require prednisone, as is apalutamide. I’d say the biggest issue with enza is that men do feel more tired with enzalutamide. I think that's probably the most important consideration, although many men do tolerate it quite well. But that is one of the things you want to look out for.

The seizure risk, there was a lot made out of it, but it's turned that enzalutamide does not really cause seizures in anybody who doesn’t already have a significant underlying seizure risk. So if they do have a history of seizures, I’d avoid it. But otherwise, I think it's available for most of these patients.

And apalutamide has a couple of unique side effects, besides fatigue and some of the other class effects of these drugs, it can cause a rash in about a quarter of these patients. Usually it's very mild and can be managed. I find that you just hold the drug and then rechallenge at a slightly lower dose, it's not a problem.

And then the thyroid issue is a pretty rare one, but if somebody is having persistent problems with tiredness, it's worth checking a thyroid function test. But apalutamide is also, I think, a pretty well tolerated drug.

DR LOVE: All right, audience. You’ve heard the back and forth. And particularly what I’m curious about is the basic strategy here, would you want to add something on top of androgen deprivation? And if so, chemo or hormonal therapy? We can talk about which hormonal therapy. But I’m must kind of more focused on the strategy.

It looks like the audience in general, has been sold on using a hormonal therapy as a secondary therapy.

And then the next question I want to ask you, again based on your decision, do you feel more strongly about that now than let’s say 6 months ago before the COVID pandemic? Do you see this decision as being affected by issues related to social distancing, etc?

And I’m just kind of curious, Molly, what’s it's been like to deal with patients nowadays, a lot more telemedicine is being used.

Obviously, masks and personal protective, all kinds of other things, literally every part of the country is affected. And it looks like most people feel that it's been affected in this decision. Any comments about how it's played out where you are, Molly?

MS KIM: In our clinical setting, we are receiving more phone calls from patients. They are asking what we’re doing to protect them. We’re having screening at the door in the lobby. Patients have their temperature checked. Of course, they have to wear masks. They aren’t allowed to bring guests with them in most situations, which is quite challenging for patients. So, we’re trying to be creative. We’re trying to use FaceTime and call in the patients’ spouse or family member so they can still be involved and understand treatment decisions. That, of course, is to protect the patients and have more room for social distancing in lobbies and areas like that.

In addition to that, we are implementing obviously, video visits. So these patients who are on AR therapies, we’re able to see them less frequently. If they get their labs done locally, we’ll see them in video visits, be able to discuss their side effects; manage them over the phone and over video visit.

DR LOVE: So a couple of questions coming into the chat room. Ellen, can you explain why you need to use a corticosteroid like prednisone with abiraterone? And what are some of the issues that come up in patients who are getting prednisone? Andy mentioned diabetics, etc.

MS LEIDIG: So, the reason that we are going to replace essentially some of the steroid that a patient is losing from their adrenal glands when they’re on abiraterone is because they can have secondary side effects from that deprivation. So, for example, hyperkalemia. They may have issues with blood pressure control. So we want to manage, as well as fatigue — so we want to manage those things, that they're not having profound side effects and are able to continue management on that therapy.

DR LOVE: So I want to go through some of the questions that you put out for discussion. The first Molly put out — well, I’ll let Ellen begin here, which is when you have a patient who’s about to begin androgen deprivation, whether it's alone or with some of these other hormonal strategies or even with chemo, what are some of the things that you emphasize on as being most important for the patient to know about?

MS LEIDIG: So, we always talk about the side effects that come with ADT, most commonly those are fatigue, potentially change in body habitus. They may gain weight in their abdomen and lose muscle mass. Hot flashes, often sexual dysfunction. And it's important because all of these different factors can kind of layer and impact a patient’s willingness and desire to continue on therapy because it can change — they talk about losing their manhood or not feeling as much a man. Because some of these things tend to be definitive of them as a man, particularly the muscle wasting and sexual dysfunction, I think patients will feel just generally they aged overnight. And I think preparing them, but also working through those different adverse effects so that they can continue on their therapy is really important. I tell patients, we’re going to work together to give you good quality of life because we don't want to just treat your cancer and make you feel horrible the whole time. We want to treat your cancer and continue to work together for good quality of life.

DR LOVE: Molly, any comments about sexual counseling, about sexual function? This is a 72-year-old man. We said that he was sexually active. What are some of the things that you’ll proactively bring up with patients in terms of what to expect and what to do about it?

MS KIM: Yes, it's a very important topic to discuss with patients so that they're able to expect it prior to starting androgen deprivation therapy. I would discuss two primary things with sexual dysfunction which would be erectile dysfunction and decreased libido. In this patient who is sexually active, that's especially pertinent they speak with his partner so that they’re able to have strategies going into this, know what to expect with the decreased libido and strategies for erectile dysfunction.

DR LOVE: So, Ellen, you put out this question at least to begin the discussion. One of the things we talked about earlier is the issue of hot flashes which does occur in men on androgen deprivation and maybe not that much more when you add in anti-androgen. It’s really the androgen deprivation that's doing that.

I see that the faculty has all kinds of different approaches. I see a lot of black cohosh in there and also anti-depressants. Any formulate you have that you’ve found that's been helpful, Ellen?

MS LEIDIG: I always tell patients to start with behavioral modification. So in other words, most of our patients aren’t necessarily looking to start another medication as soon as they’ve just started on a therapy, so immediately offering another pill usually doesn’t make them happy. We’ll talk about things for this patient that's waking — his hot flashes are waking him up at night. I would say make sure you have a fan that is accessible so that you can turn that on if you have a hot flash. Keep a cold glass of water next to your bedside. If those things aren’t working, we then progress essentially to talking about over-the-counter supplements. Two of the common ones that we talk about are black cohosh and flax seed oil. They have, I would say, variable effect. And some of our patients just never really step towards that because it's something they have to go to the store, find, order for themselves, and start.

If we go through those different — behavioral modification as well as that first supplement and they’re not working and their quality of life is really negatively impacted by the hot flashes, we then talk about prescriptive medications that we could initiate. I try to have that conversation before they start the ADT or in their early days of ADT. Because oftentimes, like I said, they’re not willing to start another therapy that early. But to know that there are options for them, that if they get to a point with their hot flashes that they say my quality of life is not improved, or is really significantly decreased, that there are options like SSRIs, SNRIs. We use gabapentin in some of these patients. Megace. So we would progress to those prescriptive interventions.

DR LOVE: So, Molly, another issue or complementary strategies as it relates to, for example, nutrition, exercise. Again, men who are just beginning hormonal therapy. What are some of the strategies you think about? It looks like a lot of people use calcium. You talked about getting a referral to a nutritionist. Where does exercise and nutrition fit in in this situation?

MS KIM: So all patients who are on androgen deprivation therapy first of all should be started on calcium/Vitamin D. The purpose of this is to decrease bone density and mineral loss. So, in addition to taking the calcium/Vitamin D, which, first of all, I order to the pharmacy so that patient is sure to get the correct order and start that generally twice daily. Some patients will say, oh, I already consume a lot of dairy, that's my calcium/Vitamin D. I still recommend it.

Patients will do their own research on what is best to implement in these situations: Should they make dietary changes? Should they go on a prostate cancer-specific diet, etc? I generally recommend that these patients should be making reasonable modifications
calcium, vitamin D. They shouldn’t be going from a drastic high meat/high processed sugar diet to a ketogenic diet. They should be trying to avoid animal proteins or just decrease their animal proteins, decrease processed sugars to make these healthy lifestyle modifications and feel better.

I would refer them to a nutritionist for further questions that they might have surrounding these specific diets.

DR LOVE: So, Andy, a number of people brought up the concept of so-called intermittent hormonal therapy, where a patient receives hormonal therapy, a lot of times they're going to have side effects from it, and then the hormonal be stopped. The PSA slowly comes back up. And then again hormonal therapy is given. What are the situations where that's an acceptable strategy? And for example, would it be an acceptable strategy in this situation with this man, this 72-year-old man, presenting with metastatic disease?

DR ARMSTRONG: Neil, I’m glad you asked about that. In the non-metastatic setting, where basically the hormone therapy has been started because of an abrupt PSA rise, for example, intermittent hormonal therapy is the standard of care and should be offered to men who have a robust response to that hormonal therapy. And that's based on the improvement in quality of life, with breaks, and men really value those breaks which can often last years in some patients. And there’s no detriment to overall survival. There may actually be a reduction in cardiovascular risks and other side effects like bone density loss, muscle fatigue, the effect on sex life. So intermittent therapy is really a standard of care based on actually thousands of patients in randomized studies.

But in the metastatic setting, basically intermittent therapy is not the standard of care and should only be offered to patients who really are suffering through significant quality-of-life issues and have a really good response to therapy. There are some patients where in my practice I’ve offered intermittent therapy, particularly if you’ve targeted metastatic disease with radiation. That patient’s achieved a complete remission and they want to see how well they can do off therapy. But that's a very select group of patients.

In the randomized studies, patients, in many cases, did worse with intermittent therapy when they had — in terms of overall survival in that metastatic setting.

DR LOVE: So, William, one more question, then we’re going to go on and talk about the second clinical situation. It looks like the audience is pretty strongly favoring hormonal therapy plus androgen deprivation for this patient, but what about choice of hormonal therapy? We mentioned that there are 3 that have pretty similar outcomes. How do you decide which one?

DR OH: It's a very good question and it's really a tricky question to answer because each patient is individual. There are the different side effect profiles that I think are important. There is financial toxicity, some of you have heard that term. The nurses and nurse practitioners and the people in the social work department are very important to help us, along with the pharmacist, I should say, help us figure out what the financial consequences to the patient. But at the end of the day, our goal is to try to extend survival and maximize quality of life.

So once we get to know the patient, because I don't start at the first visit — we start ADT at the first visit. We get to know the patient. We get to know their concerns and the side effects. And soon after their first visit, when they come after they started ADT, we’ll be exploring what second treatment to give. And in general, abiraterone, since it's been around longer, is my default of choice. Obviously, there’s a generic version. But there are a lot patients who can’t get it for the reasons I mentioned earlier: high blood pressure, diabetes. And in those patients, I may choose apalutamide or enzalutamide.

So it is a very personalized choice. I have my favorites. I think other people have theirs. But I think that the good thing is we have choices.

DR LOVE: So, Andy, what’s your favorite?

DR ARMSTRONG: There’s a lot of individualization, as William mentioned. For an elderly man, over the age of 75, who is more `, I tend to pick abiraterone because enzalutamide/apalutamide cause a little bit more fatigue and fall risk, bone loss, effects on muscle mass.

In the younger man, I tend to try to avoid prednisone for as long as possible, particularly with the emerging role of immune therapies. The avoidance of metabolic syndrome. In a patient with obesity and metabolic syndrome I try to avoid prednisone. I think enza and apa are equally good. And all of these choices are winners for the patient. That‘s the good news.

DR LOVE: So, Ellen, rash was mentioned as maybe a little bit different that's seen with apalutamide. What’s your experience with that?

MS LEIDIG: It really varies. It's not the majority of patients who will experience a rash. And the rash is actually typically quite treatable. It depends on the gradient of the rash. If it's greater than 30% of the body is covered, that's a Grade 3, and we would typically discuss maybe a dose interruption. We’ll talk about use of oral antihistamines, potentially some topical treatments. And then we can always try restarting the drug and seeing how they are able to tolerate.

So, it's an interesting side effect because it is pretty unique to the apalutamide, but thankfully, it's very treatable.

DR LOVE: So we’re going to go on to other situations. And I think if you come away with nothing else from this discussion, I think it would be an appreciation for the granularity of this topic. It's not just hormonal therapy. There are different types of hormonal therapy with different consequences to patient. It really requires some thought.

Case: A man in his mid-50s with metastatic castration-resistant prostate cancer

DR LOVE: So we’re going to talk about this second case, a younger patient now, less typical. This is a patient who we’re saying has a 4-year-old grandson that lives with him and his wife. Something to think about in a patient with metastatic disease. We think a lot about children, but this is a grandchild. This particular patient is interested in alternative complementary strategies to assist in his course.

He’s previously gotten a radical prostatectomy. Had PSA recurrence. Like a lot of those patients, they get radiation therapy to the pelvis, but he still had progression. Was put on ADT and docetaxel. And now has widespread bony mets.

And so there are actually a number of choices, not just hormonal therapy, that we’re going to go through. There are several hormonal therapy, or at least 2 that have been approved, but chemotherapy is an option, sipuleucel-T, the immune therapy, and Radium-223, which is used specifically in patients with bone mets.

So here’s the question that we’re going to ask you in a minute, what do you think would be best for a patient like this? Here’s this younger patient. You can imagine, like all patients, wants to live as long as possible, but particularly with a young grandson. Would you start out with Sip-T? Would you start with more chemo? Would you use one of the hormonal therapy options? And then we’ll also ask whether you think that's affected by the COVID pandemic?

So, William, can you talk a little bit about the overview of the so-called metastatic castrate-resistant space that this man finds himself in? What’s the prognosis in a situation like that compared to the first patient, presenting for the first time with metastatic disease? And what are some of the choices that you think through?

DR OH: So remember, mCRPC is all the way at the right side of that first graph that we showed. And this is believed to be the state before a patient dies of prostate cancer. In other words, they’ve been on androgen deprivation for many years. Their cancer is now becoming resistant and their metastases are spreading. And actually, as you see in this 1 bullet, we’re using some of these drugs earlier. So if we’re using enzalutamide or abiraterone or we’re giving chemo upfront, the same drugs were first proven to work in mCRPC. So you’ve now, in a way, exhausted that option.

So one of the questions in this type of setting is, what are your goals with therapy? Most patients, they want to live longer. I think having done this for many years, you can’t underestimate that drive to live. People want to live longer, men want to live longer, but they also want to live better. They don’t want pain; this is often a very painful disease state. They don’t want to be so weak and tired they can’t do things that they want to do. So, now you have a situation where you may have fewer therapeutic options. This man’s only received chemotherapy in this case, but many men have received 2 or 3 other therapies even at this point. And then you have to make a decision about what you think is going to be the best and most effective treatment that he can tolerate.

So that's how I approach these patients. And you see some of the other factors: What have they received? How long have they been on ADT? Do they have symptoms or not? And then really customize the treatment to what I have left in terms of standard therapies.

DR LOVE: So, we’re going to drill down a little bit on some of the specifics, Andy. And this is a timeline for the approval of drugs used in metastatic castrate-resistant, sort of an overview of the drugs that are used. We’ll go through some of the data. But maybe you can just provide more of an overview of, particularly the other therapies, Sip-T as well as cabazitaxel?

DR ARMSTRONG: So, Neil, the timeline that goes right up until 2004 was largely based on a palliative care goal of pain relief. We did not have life-prolonging agents until docetaxel became approved for men with metastatic castration-resistance disease.

One thing I would point out is that just because the disease is resistant to drugs like ADT, doesn’t mean that it's actually hormone resistant; it just means it's resistant to the castrating effects of an LHRH agonist or antagonist. That's where these novel agents like enza or abi are very effective at extending life, improving palliation, delaying resistance. And you can see abi and enza are approved in the metastatic castration-resistance setting as well.

We also have approval of Sip-T, which is the only immune therapy broadly approved for prostate cancer. We have bone-targeting agents that provide improved survival. And each of these are used in specific patient populations defined on what the pattern of spread is, the symptoms of a patient. The goal is to get all of the life-prolonging agents for a patient so they can live as long as possible, if it's appropriate.

To add to that, from this past summer we have 2 new targeted agents, the PARP inhibitors, which are important to mention.

DR LOVE: Yes, we should mention that, too. Because there are a lot of DNA repair damage alterations that you see in prostate cancer. And these drugs can be effective.

Molly, any comments about Radium-223? It's actually given really to try to extend survival as much improve symptoms. What do patients go through who get this type of therapy?

MS KIM: So these are injections that are given in Radiation Oncology. Patients need to know about some of the side effects. There are some GI toxicities. But besides that, patients are generally feeling quite well with this. We do keep a close eye for cytopenias. So the patients will be coming in, most likely to ask for labs prior to getting the injections.

DR LOVE: And the great thing about radium is it only goes into the bone, so you don’t see much toxicity from it. But on the other hand, it only treats bone.

William, what about secondary chemotherapy? One of the questions has been when you have a patient — most patients will get started with hormonal therapy, but when they have disease progression, what do you? Do you go to another hormonal therapy? So, for example, abiraterone in a patient who got enzalutamide or vice-versa?

This study came out and showed that in this particular situation the patients did better with chemo. Any comments?

DR OH: Actually, this is an oncology nursing audience and one of the things that people should be aware of, especially with, let’s say Urology audiences or other doctors who may be involved, is that patients get undertreated with chemotherapy. I heard a statistic, that as many as half of patients with advanced metastatic prostate cancer never get chemotherapy. And we understand it's a disservice, not only because people have myths about chemo that are not quite right, but because they clearly do better — they live longer. They’re palliated if they have painful bone metastases.

So this was a very important study. And as you see, it was published in the New England Journal last year, because it asked the question, in a patient who’s already received docetaxel and at least 1 AR targeted therapy, like abi or enza, they randomly assign them to receive a second chemo, cabazitaxel or the opposite androgen targeted therapy. And you can see, not only did the patients respond better, but they actually lived longer with, again, a hazard ratio of .64. So that's a 36% improvement in survival. Now it doesn’t look like much when you look at medians, but what the message really is that patients really do a lot better with the second round of chemo.

The other lesson that was shown in this study and in other studies is if you keep giving patients another AR targeted therapy after the first one, it doesn’t seem to have much benefit.

So I think the message here is, chemo can be the right choice for patients who’ve already received 2 prior lines of therapy. It might not be the only choice, there are other things, but chemo does keep these men alive longer if you give it in the third line.

DR LOVE: Ellen, any comments about tolerability issues in this setting? We see all these different kinds of approaches. And particularly what you see with the major hormonal therapies in terms of — again, we talked before about the difference in side effect profile, but now we’re talking about a different situation with progressive disease. Often, these patients will get started on hormonal therapy. Can you comment on how you decide which one?

MS LEIDIG: I think it really depends on the patient. Because in metastatic castrate-resistant prostate cancer, as we’ve said, they’ve had now several lines of therapy. And at this point, many of the patients are no longer just symptomatic of the therapies they’ve received, they may also be symptomatic of their actual cancer — bone mets can cause pain, they may be losing weight rapidly. And so some of their baseline stamina that they had — those metastatic hormone-sensitive patients who perhaps aren’t symptomatic of their cancer or still have some resilience that hasn’t demonstrated from years of cancer treatment, I think it's really important because we’re going in already essentially highly symptomatic, a lower level of resilience and ability to tolerate these therapies.

And so, some of our patients who are very frail — for example, if we were discussing a secondary chemotherapy, we need to be really honest about whether or not they can tolerate full-dose chemotherapy, whether or not they’ll be able to deal with the side effects and read on for their cycle of chemotherapy. So you’re looking at a sicker patient when you’re deciding this. And each patient’s sickness may demonstrate differently. And so that creates a very subjective decision-making process in deciding that next line of therapy.

DR LOVE: So we asked you all to submit some clinical scenarios and actually, William submitted a couple. I want to see how Andy responds to. So, Andy, this is William’s case of a 67-year-old man on 3 blood pressure medications for hypertension, metastatic castrate-resistant disease, what we’re talking about here. Moderately symptomatic. Has bone, liver and lung mets. Says he doesn’t want chemotherapy, at least initially. The only hormonal therapy he’s gotten is leuprolide. So we said to these docs as well as our nursing staff, in general, what do you think a patient like this would end up on? And you can see, Andy, everybody said the same thing, just kidding — this is the art of oncology.

So maybe you can talk about — I guess the 2 big choices here seem to be enzalutamide and abiraterone. Can you talk about how you think through those?

DR ARMSTRONG: Sure. A couple of important points for this patient is that these AR therapies actually all do work regardless of the patterns of spread. That when patients have liver metastases, generally the prognosis is worse, and the responses are worse. All of these agents, abi and enza, particularly, cause hypertension. And a patient with severe refractory, 3-drug treated hypertension, kind of the first thing is to get control over the hypertension. Monitor the hypertension, home blood pressure monitoring is something we recommend for all patients treated with these agents.

Both agents, there’s no right or wrong answer here. I would say that a patient who’s not had docetaxel, the PREVAIL study did include men with liver metastases. The abiraterone prechemotherapy trial did not. And if you look at NCCN guidelines, there’s a little bit stronger evidence to support enza in this particular patient scenario. But abiraterone also has activity, particularly after chemotherapy in men with visceral disease.

So there’s really no right or wrong answer. It's about monitoring for toxicities and monitoring carefully for rapid progression. This is a patient with a poor prognosis, unfortunately.

DR LOVE: And it's interesting to see the variation and the choice of hormonal therapy.

Here’s the second case that William had, Andy, an older patient, 82 years old. Was getting leuprolide and enzalutamide. The PSA has come down. Marked improvement. The patient’s doing better. But the patient comes in and the wife says, hey, I’ve noticed he’s more fatigued. He’s weaker. He’s tripped a couple of times. What would you do?

So, Andy, can you comment a little bit about what you would do in a patient like this? A lot of people say reduce the dose of enza. But you say add exercise and physical therapy.

DR ARMSTRONG: Yes, the reason I mentioned exercise, it's important to discuss that from the very beginning with patients starting ADT or any of these AR therapies, is the loss of muscle, sarcopenia, fall risk, is important with all of these particularly enza. Certainly, a dose reduction is reasonable for a patient. But physical therapy, participating in exercise program. I realize during COVID that's particularly difficult, that patients may need home exercise programs and guided exercise programs they can do safely without being in public. But building up that muscle strength and doing exercise reduces many of the adverse effects of hormonal therapy, fall risk, muscle strength, bone strength, actually reduces hot flashes as well.

Case: A man in his late 70s with nonmetastatic prostate cancer

DR LOVE: So I want to finish out with our third case scenario, this is a 77-year-old man with so-called M0 disease. We talked about before the fact that men may have a situation where they have a recurrence, they’ve had a prostatectomy, like this patient, or they might have had radiation therapy. Then the PSA, it goes up. You do imaging, you can’t find any evidence of metastatic disease. And the patient then has so-called M0 or PSA-only disease. And there are 2 questions that come up in patients like this. The first question is, do you start hormonal therapy at all in a patient who only has PSA? We know that, depending upon the situation, that the doubling time is slow. It may be very indolent, and patient may have that and die of something else. As opposed to patients who have the doubling time is quicker, which might lead to treatment.

What goes into your decision, William, to start hormonal therapy in a patient like this, who’s only had local therapy but has M0 disease?

DR OH: Well this has never been studied prospectively, Neil, so we really don’t know the value of adding ADT. It's presumed. But in a PSA era, there’s been an actual experiment, which is to start ADT on all of these patients. Usually, for me, it's a combination of the PSA doubling time, characteristics of their initial cancer. Did they have a high-grade cancer? How soon did they relapse? What’s their age? Their other comorbid status?

But typically, I am starting most patients on ADT by the time their PSAs hit 5 to 10, depending on how fast their PSA are doubling, even in the absence of metastasis.

The second question is when do you add a second AR targeted therapy? And it's basically the same thing in redux, right. It's the same problem because they still have no metastasis. The difference is that we have Level I evidence here with 3 drugs — apalutamide, enzalutamide and darolutamide — all of them have shown two benefits. One is, they showed prevention of metastasis — metastasis-free survival benefit. And recently at ASCO this year, all 3 of them also improved overall survival.

So, for me, this is a lower bar to start a medicine like this because now I know they're on ADT, their PSAs are rapidly doubling, 10 months or less, I will generally offer them 1 of those 3 drugs.

DR LOVE: So, Ellen, I’m kind of curious. Vicky Sinibaldi put together this slide, I really liked it, on one of our ONS programs, of the challenge of balancing risks and benefits, particularly in this situation where the patient — you can’t even demonstrate the disease other than their PSA. How do you see different patients processing whether to treat in a situation like this? And what to treat with?

MS LEIDIG: It can be very variable because you have some patients who I would say fear their PSA. It can be really important to encourage these patients and say, there is still good news, which is there’s no evidence of metastatic disease, despite the rising PSA. But some of these patients feel very aggressively that when they see that PSA rising, we need to be doing something. We need to be kind of making progress or at least intervening. So, some of the patients have a very strong, kind of predisposition to want to treat regardless of the fact that they’re not metastatic.

And then you have some people who really are about their quality of life and feel more like, hey, I don't have metastatic disease. I feel pretty well right now. I’d like to consider that as an important decision, part of the decision.

So it really depends on the patient because they can come in with very strong opinions about which is more important, longevity of life or quality of life and how do we make those two meet.

DR LOVE: I think the other thing is to try to help the patient get an understanding of what the level of benefit is. It's not easy, but sort of straightforward to look at side effects. But sometimes the benefit, in a situation like this is trickier to explain. You see these curves, in terms of how hormonal therapy affects. And in this situation, William, you have 3 androgen receptor inhibitors or AAs, that have been studied and approved in this situation. Can you comment about what we know about the 3 and for practical purposes, how you choose between them?

DR OH: Well, again, an embarrassment of riches. They’re very similar to each other, but these are some of the key differences. I’d say, as in this case that I mentioned, the patient falling, enzalutamide has been associated with a little bit more fatigue and muscle weakness. I don’t think the seizure risk is a big one that I’ve seen, but, of course, if somebody has seizure history you should avoid enzalutamide.

We talked a little bit about the rash already. Ellen described how she manages apalutamide rash. But it's usually pretty mild.

Darolutamide is an interesting drug. We haven’t talked about it up until now. There’s a little bit of a chat going on around it because it's only approved in this patient setting, non-metastatic CRPC. And what’s interesting about the structure of darolutamide is it doesn’t seem to cross the blood brain barrier. And that might make it a little bit better tolerated. And in our experience, and Molly will agree, that patients seem to tolerate darolutamide a little bit better in terms of their cognitive functioning and maybe their energy levels.

So they all have very significant improvements in MFS and now OS, and you can see these numbers here. And so I think they're all reasonable choices for this type of patient.

DR LOVE: Molly, any comment about this choice? When we compare these drugs, they’re aren’t trials that compare one versus the other, so indirectly, you’re looking at the SPARTAN trial, the PROSPER and trying to indirectly, which is kind of hard to do, although you can see the benefit. It seems about similar. How do you see patients processing this? And do you think you can see a difference in the tolerability profile with darolutamide?

MS KIM: I think that darolutamide, Dr Oh is correct, it is very well tolerated amongst our patients. I think providing the patients with the data can be helpful in making decisions. So, when patients don’t have any pre-existing conditions or any reason that they shouldn’t take enzalutamide, for example, then the decision is there. But, ultimately, darolutamide is well tolerated.

DR LOVE: So, Andy, any comment again about the tolerability profile of these anti-androgens? Again, these are indirect comparisons. Theoretically, you’re not supposed to do that because there’s a different trial, different situation, but that's all the data we have. And we see people looking at these numbers. What kinds of conclusions do you come up with?

DR ARMSTRONG: I think what I communicate to patients is, from all these trials, we have very high levels of quality of life. Almost by definition, none of these patients have symptoms from their disease. And the goal is to prevent those symptoms from their disease over many years and all of these agents accomplish that by keeping the PSA down, keeping the cancer from metastasizing. And all improve survival. And the quality of life in almost all these cases, is very high.

There are some differences with respect to age, fall risk, fatigue. I agree that darolutamide is very well tolerated, particularly in elderly patient with comorbidities, I think that's a fine choice.

DR LOVE: Thanks so much for joining us.