Introduction: Overview of Prostate Cancer; Hormonal Therapy

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice and welcome to “What I Tell My Patients.” This is our Part 11 of the ONS Congress series this year and we’re going to be focusing tonight on the management of prostate cancer. We have a great faculty. Dr Andy Armstrong from Duke University in Durham, North Carolina, and Ms Brenda Martone from Northwestern Memorial Hospital in Chicago, Illinois.

If you have any questions or cases you’d like to run by us, just type them into the chat room and we’ll talk about as many of these as we have time. There is a 1-minute premeeting survey for you to take in the chat room and we’ll put it up there at the end of the meeting. If you take these 2 surveys, you’ll get a lot more out of the experience here tonight.

So we’re just coming back from being in Washington, DC, for the 16^th consecutive year doing the ONS Congress. And all these meetings had mixtures on the faculty of nurse practitioners and medical oncologists and gynecologists. Today we’ll be completing this series and all 11 programs will end up getting posted online in the next week or two. We’ll let you know if you weren’t at ONS when that’s available.

We’re actually heading out to the AUA, American Urologic Association, meeting this year. We’re doing a program on prostate cancer. It is particularly oriented towards urologists but it’s this Friday morning, 8:00 AM central time, 9:00 eastern time. We have a great faculty. We’re going to get into a lot more depth about prostate cancer there if you’re interested. We’re also going to be doing an AUA-related webinar next week on bladder cancer. We have a great faculty there as well to talk about all the new developments there. And next week, we’ll also be doing another Year in Review program. This time we’re going to focus on non-small cell lung cancer and actually a topic we did a program on at ONS, which is targeted therapy. At ONS, we actually focused just on EGFR.

We know a lot of people end up listening to our webinars and other programs. If you’re into audio, check out our Oncology Today podcast series including a recent program with Andy and actually Brenda’s partner there at the Robert Lurie Comprehensive Cancer Center, another leader in prostate cancer, Dr Maha Hussain.

So we did something different this year at ONS just to have a little bit more fun. And I actually did interviews with 8 nurse practitioners who we had worked with in previous years at ONS and we couldn’t work out a way to work with them this year, either their tumor we weren’t covering or they weren’t available. So I did interviews with all of them about some of the themes that we’ve had over the years at ONS, things like listening to patients, evaluating the family, minor children and grandchildren, avoiding burnout, a lot of themes that we integrate throughout this. And this time we put together a series of videos and, in fact, you’ll see the link down there below. We produced 85 short-form videos, less than 90 seconds. We’re going to just show 2 of them tonight. We showed about 25 last week just as a little tasting menu both to stimulate discussion and also to get your thoughts about what could we do with this content and particularly how do we get these things to patients, but that’s for another time.

We are going to talk about patients just like we did all last week at ONS, Brenda and Andy. And one of the things that we’re going to be asking them is in addition to getting into the oncologic angle, just briefly kind of talk a little bit about why was it different to take care of this patient than another person in the same situation oncologically but a different person. So age, comorbidities, attitude, family situation, et cetera, what in your mind stuck out about this patient and we’ll get into that as we get into some of these patients that our faculty has taken care of.

As always, we will be talking about unapproved agents in therapies so please refer to package inserts for more information. Usually we spend most of our time or a lot of our time talking about the first therapy that patients get with prostate cancer or at least systemically, which is hormonal therapy. Today we’re going to emphasize more some of the new developments beyond hormonal therapy once hormonal therapy has really been utilized. Just in breast cancer usually these patients receive as much hormonal therapy as they can before they go on to other forms of treatment. So we’re going to talk about that. But then we’re really going to focus on two of the most dramatic changes that have occurred in this field and actually talk a little bit and even show you a picture of one of Brenda’s patients who has been able to benefit by this. And then we’re going to talk about radiopharmaceuticals, particularly the lutetium, the PSMA-targeting agent, but also radium, the bone targeting agent. And then we’ll finish out talking about a theme that we talked about constantly last week at ONS, biomarkers. I kind of made the joke that the subtheme for the entire week was biomarkers, biomarkers, biomarkers. It was constantly coming up and this is something that is really important for you to know about in terms of educating your patients. So we’re going to demonstrate why, as we did all week, but particularly as it relates to the use of these really fascinating agents, PARP inhibitors.

So we’re going to start out talking about hormonal therapy. So Andy, why don’t we start out with just kind of an overview of sort of how it usually presents, the stages of the disease and how we think about interdisciplinary management at each one of these stages.

DR ARMSTRONG: Yeah, thanks, Neil, and it’s a pleasure to be with you and Brenda tonight. Prostate cancer is not one disease. I like to explain that when I’m talking to patients with newly diagnosed cancers. There are some patients that present with localized disease and in America that’s the vast majority. And most of those patients can be cured of their disease either with surgery or radiation. Some men don’t even need treatment at all. We have probably half of our patients just require active surveillance when they have low-risk disease. And then it’s also the number two killer of men from cancer. So while we see that prostate cancer is the number one survived cancer, it’s also a life-threatening cancer for many patients. And most men who pass away from prostate cancer do so with hormone resistant prostate cancer that’s spread beyond the prostate, that’s metastatic disease. So prostate cancer can be cured but it often will relapse or present with metastatic disease and it starts off hormone sensitive hormones, the male hormone testosterone is like a fuel for prostate cancer. And I explain to patients when I’m talking to them that one of the fundamental discoveries back in the ’40s, first Nobel prize in cancer, was for that discovery of that dependence of breast and prostate cancer on testosterone and estrogen. And so manipulations, whether its surgical or medications, that lower testosterone really fundamentally alter the disease, patients do live longer with more intensive forms of hormones, but ultimately the cancers that have spread will progress despite those hormones. And that’s where we’re going to talk about some of the newer strategies.

DR LOVE: So Brenda, I’m curious, every nurse practitioner, particularly the ones that we work with like you and some of these other people are just so amazingly experienced and have such great insights, I’m curious how you explain, you know, kind of like the same model for breast cancer and estrogens, how you explain to a patient this idea that we’re trying to decrease or counteract the androgen receptor. How you explain it to them in terms that are understandable to patients?

MS MARTONE: Thanks. Basically when I’m talking about prostate cancer and treatment with ADT or androgen deprivation therapy, I’m highlighting, just as Dr Armstrong, said that testosterone is really the fuel for the prostate cancer and how we treat that is we decrease that amount of testosterone in their body so that isn’t available for the prostate cancer cells. And it’s basically the backbone of therapy and to that, depending on the diagnosis and how they’re presenting, we may add agents, but throughout the course of their prostate cancer continuum, they’re always going to be on this androgen deprivation therapy.

DR LOVE: So Andy, in a second we’re going to hear about Brenda’s patient, but I just want to go back to this model here because, as you were saying, most people present, you know, hopefully they’re going to get picked up with PSA screening, but most people are being picked up with localized disease and now we’re concerned about whether it’s going to recur and develop metastatic disease and kill them. But there are patients including, Brenda, this 68-year-old man that you’re going to talk about who’s kind of going public with his disease, he’s singing “Take Me Out to the Ballgame” at the Cubs. He’s been living with metastatic disease comfortably for 5 years. But he actually was different. He actually presented — he was having back pain and by the time he actually got — and I know it was before they got to you all out in the community — he actually ended up being admitted acutely with, you know, “question mark” spinal cord compression oncologic emergency. But again, this is a completely new diagnosis. Obviously, he hadn’t had any screening so that’s kind of the other end of the spectrum. Any thoughts, Andy, about those patients and that type of presentation as opposed to patients who develop metastatic disease after local therapy?

DR ARMSTRONG: So right now in 2024 only about 10% of American men when they have prostate cancer will present like Brenda’s case with metastatic disease. And some of the factors that play a role in that is access to care, having screening, having early detection. Getting a PSA test regularly can reduce that chance that men will die of prostate cancer and develop metastatic disease. Some cancers are very horribly aggressive though right away and they can even develop in-between screening sessions and that can be caused by hereditary predispositions or through no fault of a patient’s own can just happen through bad luck. But for these cases, we rely on systemic therapies to control the disease and that is dramatically improved, 5-year survival now.

DR LOVE: And, in fact, this patient that we’re going to ask more about from Brenda as we go along throughout this meeting because this patient actually got one of the therapies that we’re talking about today, a PARP inhibitor. But I want to just spend a few minutes talking about one other thing that really applies to pretty much every patient with certainly metastatic disease and many other patients, which is let’s just call it, life on androgen deprivation therapy. So as Brenda talked about and as Andy explained in terms of the biology it makes sense. It’s like taking a woman’s ovaries out or giving her an LHRH agonist with breast cancer. You’re getting kind of rid of the fuel but, of course, the problem with that comes a lot of potential comorbidities that hopefully we can try to prevent. But also comorbidities that are psychologic and spiritual. Here’s Kathy Burns who is a GU nurse we’ve worked with many years before talking about some of the issues that come up and how she talks to patients during androgen deprivation.

MS BURNS: Talking to a gentleman that is going to start on ADT, and we’re taking away their testosterone either permanently or intermittently, it’s a complicated story. I think if you keep it very medical and black and white, it’s you’re going to experience this side effect, that side effect.

It might be your mood, your reactions to things, your emotions, how you see your partner, how you see your significant other.

A gentleman explained it to me at one point and said it’s like I see my wife of 20 years, and it’s like the light switch has gone off. I see her in a whole different way. Not a bad way or a good way, but the sexual way has kind of — it’s gone right now. So in a way I can relate to my wife in a way I never had before, but in a way I grieve the loss of the relationship we had before.

So it’s a bit of a conversation. Not everyone’s ready for that right away.

As challenges come up, I think it’s our obligation to really make sure that we have networked and relationships with other professionals in the area, be it sexuality, psychology, physical therapy, occupational therapy, back to urology, and we need to be generous and open up their care to whoever can be helpful.

DR LOVE: And we need to keep in mind that we’re talking about PARP inhibitors, lutetium, et cetera. These people are still on androgen deprivation, usually for life. So Brenda, actually this is a slide that I saw when we were getting ready for the AUA meeting on Friday that I mentioned and Dr Laurence Klotz had this slide in his deck and I’m like, “This is such a great slide. Let’s use this on Wednesday.” It’s just a list of some of the issues, some. And not some of the subtle ones that Brenda was talking about. So I just want to put it up there. We’re not going to cover everything. We’ll just talk about it for a few minutes. So Brenda, again, any thoughts about some of the things you think about as you’re getting ready to meet with people who are on this therapy that to me is really unique in oncology, unique in oncology. Brenda?

MS MARTONE: So when a gentleman hears they’re going to go on androgen deprivation therapy and testosterone is going to go down, I basically let them know that they are going to have some side effects. The most common are hot flashes or hot flushes. They may feel a little bit more tired. Because testosterone is what gives them the sexual function ability, that will be most likely impaired as well as libido. They may experience increased irritability or changes in mood. And I let them know that the onset is usually several weeks after starting the androgen deprivation therapy, but I also tell them, unlike women who go through menopause and actually get a gradual decrease in the hormones with the adaptability of the body, we’re taking them from 100% to 0 in a relatively short period of time. So some of these side effects can be much more intense at the beginning of therapy and over time they may kind of mitigate. In terms of just counseling, letting them know that their bones may get thinner because the testosterone is their engine. It also keeps their muscle mass up and so that’s why they may feel a little bit weaker, may gain weight around the midsection, but because of the lack of testosterone their bones may thin a little bit. So we always start them on calcium and vitamin D. And then we kind of readdress that at each visit just to make sure they’re taking that. And then depending on where that patient has been diagnosed, localized or locally advanced, et cetera, some of these patients, if they don’t have metastatic disease, we also do a bone density test to make sure that their bones aren’t thinning while on ADT and if there are additional things we need to consider if this is seen.

DR LOVE: I was just thinking, we need to do an hour just on this topic. It’s so deep. But Andy, maybe you can touch a little bit on some of the issues lower down on the list, metabolic syndrome, thromboembolic disease, cardiovascular disease, there’s a really wild graphic, maybe you can comment on in terms of that. But before you get into that, any thoughts about some of the more, I don’t know, subtle issues that come up in terms of sexuality, self-perception, and some of the things that we heard on that video and what you say to a man when you’re suggesting androgen deprivation therapy in terms of what to expect not just sort of biologically but at a deeper level?

DR ARMSTRONG: Yeah, it’s a great point and I completely agree with the nurse who is emphasizing that this is an impact on a patient’s mood, on their relationships. Even just being diagnosed with cancer is very stressful. And so men go through different periods of grieving. Grieving their former self, their losses of function. They can be proactive though. They can take their own health into their hands and focus on things that will improve their health.

Enjoying intermittent therapy, as that speaker mentioned. Taking breaks or holidays from hormones can kind of balance the yin and yang of cancer control with breaks in their treatment to allow some return of sexuality and return of muscle mass, return of feeling normal again without those hot flashes. So for men without metastatic disease, we definitely spend a lot of time talking about how we can get the cancer into remission but then take planned breaks. And that’s become very important with the EMBARK data and maybe some of these combined regimens where you can actually get a much longer break if you do more intensive therapy right up front. And the reason for that is because all of these secondary effects of low testosterone. Men tend to gain weight if they’re not proactive. And without a change in diet or healthy lifestyles, you can see obesity develop, metabolic syndrome, waist circumference increasing. Lipids can go up and that can promote atherosclerosis or a hardening of the arteries, which can then predispose to cardiac events. That’s not an inevitable side effect, it’s just something that can happen to some men and again being proactive and developing a strategy to reduce those cardiac risk factors to be more active, to follow a heart healthy diet, I think that that requires a lot of survivorship counseling over all these visits. Sometimes we’ll refer a patient to a nutritionist, a psychologist, counselors to help with the grieving and the coping of this diagnosis and situation. We actually have exercise therapists as well that can help write an individualized prescription for men about what to do if they’ve not been used to exercising.

DR LOVE: So let’s hear a little bit about this patient. Here he is. Actually, again there is an interview with him linked to that posted in the chat room. Anything you want to say about this? I guess one of the issues here is this patient has a BRCA germline mutation. Anyhow, I’m just curious in general what’s it like taking care of him, Brenda? What makes him different?

MS MARTONE: Actually, I’ve been with him since he came to see us and just how much he has grown and adapted and accepted his diagnosis and he lives life. And the stories he would tell me, you know, coming into clinic he would tell me how he met this cab driver and then after being brought numerous times to Northwestern by the cab driver, the cab driver offered him to bring him free for the remainder of all of his and ongoing appointments. And he just demonstrated that there’s a lot of kindness out there. And then we also had this joke that he hates — so the way our exam room is set up, the chair with the computer is facing the door and then the two chairs that the patient and family members sit in have their backs to the door. And he always hated that. So we had a joke where we would kind of like switch places. So he would sit behind the desk, and I would come in and he would welcome me to his office. And so now he does that all the time and we just talk about things and he feels much more comfortable in that setting than he did sitting in the other chair. And he’s been so great about sharing things and letting me know how best I can help him in what he needs.

DR LOVE: Actually, we talked a lot about humor last week at ONS. Andy, anything you want to add to that?

DR ARMSTRONG: Yeah, BRCA2 is one of those mutations that predisposes to many cancers but prostate cancer is a common one. And I’ve had patients walk into my clinic and say, “Doc, my sister had breast cancer and a BRCA2 mutation. Do you think that could affect me?” Because they never made that connection. And, in fact, I think we did a disservice to men by naming the BRCA2 gene after breast cancer. It’s really a cancer gene, you know, predisposes to many cancers including pancreatic cancer, melanoma. And so having a genetic counselor involved, especially if it’s germline, counseling patients’ family members, talking about how you might screen patients and intercept cancers before they spread or prevent those cancers even better.

DR LOVE: It’s funny you mentioned BRCA in breast. Dr Emmanuel Antonarakis, who you both know well, one of the leaders in the field, says they should call it PRCA because it’s more relevant — it is, it’s actually more relevant in, I mean it is relevant in breast cancer of course. One thing just before we move —

DR ARMSTRONG: I like the idea, Neil, of — go ahead — of renaming it the King Syndrome after Mary-Claire King who discovered BRCA.

DR LOVE: Interesting. Yeah, that’s a good one. So we’ve got to do one more thing before we move on because we were preparing something for AUA and I was telling Andy about it and Andy completely corrected me so I want you to explain this to the audience. Because what I was thinking — one of the things that came out when we were preparing for AUA is if you have a patient, a man who has a BRCA germline, usually it’s BRCA2, and they have a son it’s easy to understand why you want to test their daughters, because you can actually reduce the chances of them getting breast or ovarian cancer surgically, but you can’t exactly do that with men. So I was like, “Well, why are we even testing them? All they’re going to get is anxiety.” And Andy educated me. So go for it, Andy. Explain why.

DR ARMSTRONG: Well, first off, shared decision-making is important. Men need to understand what their risks are and then they can decide if they want to be tested. So that’s the first step. The second step is genetic counseling. Getting a real professional genetic counselor involved to tell men they’re at risk of prostate cancer, pancreatic cancer, melanoma, male breast cancer. And there are things we can do to screen you more rigorously for all those cancer risks and then they can take it into their own hands if they want to know. Their children may be at risk if they’re a carrier so his knowledge may save his daughter’s life, his sister’s life. If he doesn’t have the BRCA2, we may back off on the screening recommendations, but if he does, we actually have clinical trials going on right now testing better screening strategies, not just the PSA test but prostate MR. These cancers tend to be more aggressive, they tend to spread more quickly so more rigorous screening at a much earlier age is pretty much recognized by all societies as being impactful here.

Radiopharmaceuticals for the Management of Metastatic Castration-Resistant Prostate Cancer (mCRPC)

DR LOVE: All right. Well, that’s kind of a preface to the 2 topics that we really want to focus on that really have revolutionized the care of these patients and hopefully just the beginning of other therapies that go beyond hormonal therapy, which was really the original therapy that we had in this disease. So let’s talk about the big story in prostate cancer, radiopharmaceuticals. And particularly this very interesting agent targeting a PSMA, lutetium 177. I won’t say the rest of it. I’ll let Andy. Just kidding. You can just say lutetium, Andy. But anyhow, what is it, what is PSMA and maybe just provide an introduction to the whole topic.

DR ARMSTRONG: Sure. So we could start off by going off the hormone dependence of prostate cancer. It secretes PSA, which is a hormonally regulated protein. But on the cell surface is a similar protein called prostate-specific membrane antigen. It’s also hormonally regulated. PSMA is not truly prostate specific and that explains some of the side effects of targeting PSMA with smart bombs, but it is fairly ubiquitous in prostate cancer. About 85% of all prostate cancers have very high expression of PSMA and that makes it a very good target for delivering drugs like radiation, radioligands, chemotherapies directly to the tumor. And so that’s the basis of new PET imaging, PSMA PET imaging to localize where metastatic disease may be for recurrent disease, but also in the metastatic setting to identify patients who are candidates for this new smart bomb type therapy.

So lutetium is basically a small molecule that binds to PSMA like Velcro and then a second part of the molecule is radioactive. That’s the lutetium. So that’s in the periodic table. It delivers that radioactivity to the cancer cell. It goes inside the cell. It causes DNA damage breaks like you can see in the cartoon and that kills many of those cancer cells. If the cancer doesn’t have PSMA, then it’s not a smart bomb. I explain it’s a dumb bomb. So it would go and elicit toxicities in normal organs that express PSMA like your salivary glands and your tear ducts, so you can get dry mouth and dry eyes and you can see kidney toxicity as the renal tubules have some PSMA and a little bit of bowel toxicity. And so it’s a very selective targeted therapy. It improves survival. The VISION study proved that and it’s been approved now for over 2 years. We’re gaining increasing experience first in large academic centers with nuclear medicine colleagues and it’s starting to roll out into many community sites. And it’s become a very popular therapy because of its improved quality of life for our patients, quantity of life, good responses, and it’s delayed the need for chemotherapy, for example, and other therapies that may have increased toxicities. The way we dose it is every 6 weeks for up to 6 doses and we follow patients along their journey with PSAs and imaging to document response and remission and then they can sometimes enjoy long periods of time of remission once they complete this therapy.

DR LOVE: So it really has a lot of the characteristics of a lot of new therapies in oncology in general. Less toxicity, more targeted, a biomarker to go after, you know, kind of typical of the kinds of therapies that we’re seeing. It sounds like a pretty neat story but then you get into actually doing it and that can be a challenge. So Brenda, I’m just kind of curious and we are going to get into more detail about the types of toxicity, et cetera. But at least at your first meeting with the patient who’s about to, you know, you’re recommending lutetium, what are some of the initial things you’re trying to get through to them in terms of how it works, what to expect, how it’s going to affect their family? Again, what are some of the things you usually bring up, Brenda? And I guess you had a patient, a 68-year-old patient you were telling me about, who had got treated with this and seems to be stable with dropping PSA. So what do you say to patients, Brenda?

MS MARTONE: Well, I let them know kind of like Dr Armstrong said there’re are a lot of drawings and targets and puppetry and explaining how it works, then essentially, I give the same explanation about how it’s looking for this protein, that’s why we’re getting this scan to make sure you have it. It attaches and inserts the radiation and I too also highlight the side effects by also stressing where some of the PSMA is also in the normal tissue. So again letting them know about the dry eyes, dry mouth, monitoring labs. If they have heavy bone mets, obviously I let them know because it’s inserting radiation right there and the bone marrow is real close by and we’re going to have to monitor their counts. But then again, when they’re finished, there are special precautions. And so it’s great to kind of go through those before a patient gets the lutetium so they can kind of prep for it. They are radioactive. It doesn’t start immediately after the infusion but they’re monitored for a short time and they’re discharged before they become radioactive at larger distances. They do have to limit close contact with whomever, a family member, or whoever is in their house by about 2 to 3 feet for the first several days. They say you can sleep together as long as you stay 3 feet apart, but when you’re asleep you have no control if you’re rolling or cuddling or whatever, so I recommend separate sleeping areas, keeping themselves well hydrated, avoiding contact with pregnant women or children. They can use the same bathroom, that’s not a problem, but they should double flush. And so often patients are kind of like, “Well, if I’m going to be radioactive and I have to stay 2 to 3 apart from my family member or significant other, how do I get home in a car?” And so we’ve been telling patients if you’re driving, your passenger sits in the backseat in that far corner and again the time that you are radioactive there is time built into after you’re discharged to get yourself home. But again you have to be mindful about that and no traveling and thinking about others. This isn’t the time to go out to a restaurant or the movie and sit in a crowded theater. They have to delay that until after that period is over.

DR LOVE: It’s really interesting. Every time I hear people discuss things I always think of things I’ve never thought of before. And Andy, I was just thinking about this. In terms of the risk to other people — so I can certainly understand going out in public and dealing with grandkids, et cetera, but if you have, for example, an elderly couple, the patient is 78, the wife is 78 and they want to sleep together, like how much of a risk is it to an older person like that, Andy?

DR ARMSTRONG: That’s a great question, Neil. It’s really a theoretical risk and radiation exposure is all about distance and duration. So you’re allowed to hug your loved one and it’s more the prolonged period where you’re close. And we’re not talking about the whole 6-week period. For those kind of more intense exposures as it decays, we’re talking about 3 days of sleeping in separate rooms and maintaining that distance and for pregnant women and children it's 7 days. So it’s a small sacrifice to have better quality of life. And so certainly in an elderly situation it’s a tradeoff. These radiation induced cancers and risks may not occur for 10, 20 years and so you may counsel them and they may be like, well forget it. But it’s only a week.

DR LOVE: Yeah, I mean, when you go to get an x-ray and they put a shield around you and as I get older and older I’m like, well, why am I doing this? But anyhow, Brenda what about the dry mouth? How often is that actually a clinical problem that patients are aware of? There’re a few drugs out there in oncology that have dry mouth. What do you do? Is there anything you can do to prevent or manage it?

MS MARTONE: There really isn’t anything you can do to really prevent it. It is one of the most common side effects but, of course, you can use mouth rinses without alcohol, sucking on candies, making sure of your food choices, you have a lot more liquid, you know, not eating dry toast. I mean, if your mouth is dry, you know, it’s terrible. So the patient that I have currently is part of this case for tonight, he has dry mouth and he’s sort of altered some of his dietary choices to be, not necessarily soup 24/7 but he’s doing things with sauces and good hydration and even though it’s annoying he is managing to deal with it. And I think it was good to kind of prophylactically tell him so he could be at least prepared and not like shocked because none of the chemotherapy agents that we really currently use in prostate cancer or the oral therapies really cause dry mouth. So this would be the first time for this kind of unique side effect for a patient to experience.

DR LOVE: So Andy, in a second I would like to hear about your 67-year-old man who went on lutetium, but first I just want to flip back a little bit more in terms of efficacy with this type of strategy and this is a graphic from one of the trials that was done on lutetium. Andy, you can explain what it is, but I want to ask first of all, Andy, of course symptomatically you see, of course, bone pain, for example, is a common symptom of metastatic disease. We’ll mention later we had another radioligand radium in extended survival, but it didn’t necessarily improve symptoms. What about lutetium? Do you actually see tumor shrinkage? Do you see symptom improvement, Andy? Do you see better quality of life related to the cancer?

DR ARMSTRONG: Yes, thank you, Neil. The initial data was for the VISION study. It required chemotherapy and an AR inhibitor and then you could get lutetium and compared to a second AR inhibitor you did see better objective shrinkage of tumors, PSA declines, delays in deterioration and pain and pain responses and that’s what makes it more popular than older radiopharmaceuticals that may not have as dramatic of a response even though they improve survival. This Kaplan-Meier plot here are the survival curves from an earlier disease trial. It’s not yet published but it’s been presented. It’s called PSMAfore and when you counsel patients a common question I get is, what do you mean I have to get chemotherapy to get to the PSMA lutetium? And this is an attempt to evaluate the risks and benefits of lutetium prior to docetaxel. And this is the primary endpoint here was that progression or death was delayed almost two-fold from about 6 to 12 months. And so it’s very active whether you’ve had chemo or not. A 60% delay in the risk of progression on imaging or death is substantial for patients. The FDA hasn’t ruled on this. That’s something that we’ll hear about this summer. But we expect that we’ll have this as an option for many patients. Instead of having to give chemo to get to the other side, we may have this as a choice between chemo.

DR LOVE: Right, and you can imagine much better quality of life then chemo. But I just want to point out one other thing about this graphic because again it’ll pick up on a theme that almost every single one of these meetings we got into, which is how to look at these types of studies. So as Andy pointed out if you look over there on the left this is event-free survival. So, I mean, I look at it as the chance that you need to switch to another therapy because the disease is getting worse. Does that sound right, Andy?

DR ARMSTRONG: Yeah, so everybody starts at 100% and as events happen an event would be death or you’ve progressed and a progression event is often life-threatening for many patients. It can cause symptoms. It can cause morbidity, pain. And you see that red line dropping very quickly. That’s like enzalutamide after abiraterone or vice versa and that’s not a very effective strategy. Patients tend to blow through that or progress within 6 months.

DR LOVE: What I wanted to point out because you know it depends how people actually plot the graph like how dramatic looking it is but one thing you’re always going to see in a graph like that as Andy was alluding to and you see it up there on the left, HR, hazard rate. So for this it’s either 0.41 or 0.43 but what we were talking about at ONS is what that means is you sort of subtract it from 100. So let’s say you’re going to use say 41. That means at any point in time as these patients were followed and again, Andy, correct me if I’m wrong, there’s a 60% less chance that they’re going to have progressed at any point in time. Because if you look at it on the right you have 12 months versus 6 months it kind of doesn’t seem as impressive but that’s a very good hazard rate. I mean drugs get approved that have 0.75 hazard rate. That’s a 25% reduction in recurrence. This is a 60%, which is much more potent. Andy, any comments? Am I interpreting it the right way?

DR ARMSTRONG: That is right. It’s a measure of risk over time and this is an average risk for a whole population but some men get a much bigger benefit. If you have a more dramatic response, your PSA drops even more, you’re going to see even better individual responses. These curves are the averages for a whole population of men on the trial.

DR LOVE: I’m curious, Brenda, what are some of the questions that patients and family members bring up about this type of therapy?

MS MARTONE: Well, a lot of it has to do with how it works, which we’ve already explained. The side effects and what to do and how to manage them as well as the radiation precautions and there’s a lot of questions around what does that mean, how does that look like, again stressing that this is only temporary. Just making sure that they understand that there’s risks. And then those things that they can do to help themselves, you know, staying hydrated prophylactically, staying active, weightbearing exercises, having either Imodium or some sort of stool softener at home and not waiting until they have — if they are going to have diarrhea, that’s the worst time to not have something. So just having those things available and you may not need them but at least they are there and they kind of understand what to do and then also making sure they understand what isn’t normal. They shouldn’t feel so tired that they can’t get out of bed. So it’s like these things I always say, “Well you shouldn’t be like XYZ and if you are you need to call.” And I also encourage people that they can call and reach out to us at any time either through MyChart, the hospital app, calling and somebody will answer them and call them back. And I really do stress that it’s the patients interpretation. If their side effect they think is severe and their message is urgent, I always ask them to tell the call center that it’s urgent so it flags them. Maybe they page me and then we can work this out together so they’re not feeling that they’re trying to figure this all out on their own. So I think education continues throughout, reenforcing when they do develop a side effect, taking the time to review that again and stress what certain things they can do to give them some control.

DR LOVE: I was just flashing all the things we talked about last week trying to encourage patient proactivity and participation and research in their treatment decisions. Andy, of course another question that always comes up in oncology, you see something that works, particularly a new kind of strategy, is like what’s next? Where’s it going to be? Are oncologists going to start adding things to stuff or moving things up earlier? If you think about that initial graphic we showed of the natural history. So where do you see this heading? What are some of the exciting trials going on? Here's a trial. Of course everybody wants to combine checkpoint inhibitor with everything so you know you’re going to see that. And it actually looks pretty good. This is also a waterfall plot if you want to describe what that is, Andy.

DR ARMSTRONG: Sure, Neil. A waterfall plot is just a measure of the PSA changes, the best PSA changes with the treatment. And so on the x axis is the patients and on the y axis is the PSA change. So if the waterfall is going down, the PSA is going down. If the waterfall is going up, the PSA is going up. So seeing all those yellow bars going down is really reassuring. That means the patient is having a very nice response. Whether this is better than PSMA lutetium alone is unknown, but the strategies that are being employed is to combine rationally with combinations that might increase PSMA, increase DNA damage with the PSMA lutetium. So giving of PARP inhibitors has been tested here, changing the lutetium out for what’s called an alpha particle. Lutetium is a little bit like a BB gun and an alpha particle is like a cannonball. So people are trying new radioligand approaches. This LuPARP trial showed that olaparib plus lutetium was well tolerated as long as you gave it in intermittent schedules and there were some suggestions that maybe there was some radiosensitization or an enhanced efficacy signal but again you’re going to need bigger randomized trials before we would ever recommend this in practice. These are all very early-phase studies right now.

DR LOVE: And Brenda, we had a number of patients we presented last week who went from trial to trial to trial. Any thoughts about, you know, and, of course, you are both at academic centers doing a lot of trials but a lot of other people out in the community need to make a little extra effort to be able to do that. From your point of view, Brenda, I’m curious what your thoughts are about participating in trials. You saw some of these examples where you’re taking something that works and trying to make it better. What are some of the things you talk to patients about in terms of participation in clinical trials?

MS MARTONE: We always encouraged participation in clinical trials and part of our treatment decision making is in reaching out to our clinical research team to see ahead of time, you know, are there any open trials? Are there early-phase trials? So that way when we are discussing treatment changes, we can provide them with opportunities that they may not have that aren’t standard of care. And if there isn’t a trial available, then we just maintain standard of care and then if they do progress, which often they do, then we revisit the clinical trial option. And all patients, I think, should be approached about a clinical trial and then depending on the phase you have to explain what the outcome is, why the trial is being done, so they understand. And I think the biggest thing you need to let patients know is for those patients with advance in metastatic disease, there is never a placebo. So a lot of patients are hesitant because they’re afraid they may not get treatment. So stressing and again focusing on the standard of care and adding the agent and the rationale behind that and based on randomization the question of the trial is to answer is that new agent or that new combination actually as good as what we know already? So they are going to be treated to the maximum extent and letting them know and reassuring them that this isn’t like an obligation. So when they do sign the consent they are informed. They understand what’s going on. But they also have the right to withdraw depending on anything. So this isn’t like a contract that is cemented. So they always have their free thinking and it's mutual decision making and we let them know that they do have choices. And I think that’s the biggest thing, knowing they have choices and again that they have control over some of their care and what’s done.

DR LOVE: I just love it when new drugs come out that are not very toxic and have a great effect and then you see a bunch of people who’ve been on it for a couple of years already before it’s even approved because they got it on a clinical trial. So everyday that’s happening in oncology. Andy, just to sort of round out this discussion of radioligands. The initial one that we had available was radium-223. Can you explain what that is, why it’s different than lutetium but what its current role is.

DR ARMSTRONG: So Neil, radium was the very first life-prolonging radiopharmaceutical in prostate cancer and radium is in the periodic table right underneath calcium. So I like to explain it as the body thinks of it as calcium, takes it up in areas where calcium is taken up like the bones. And prostate cancer, when it spreads to the bones, starts to form new bones and so it will take up more radium and you see a direct bone-targeting effect with radium. Radium was discovered by Marie Curie in 1898 so it’s been around actually quite a long time. But the life-prolonging data only came out a few years ago. Radium is still important for bone predominant patterns of spread. If patients failed other therapies, maybe they’re not a candidate for chemotherapy or wish to pursue something. The trials that showed that radium was effective actually showed fewer side effects than a placebo because there was better control over the disease. So it is still a valuable weapon that we like to keep in mind. It’s an alpha particle so unlike lutetium, which was that little pea shooter beta particle, this is delivering these little cannonballs to the bone metastases. So very effective. Every 4 weeks times 6. It’s largely getting supplanted by PSMA lutetium because it doesn’t result in many responses. It delays death. It delays progression. But it doesn’t have these dramatic responses or data on pain or quality of life as much as lutetium does and PSMA lutetium extends that radiopharmaceutical efficacy beyond the bones to the tumor directly wherever it’s lurking.

DR LOVE: I just also want to qualify what Brenda was saying about placebos because we still do use placebos in trials, but usually it’s added onto the standard therapy. So I think it’s like they’re going to get at least standard therapy in that situation, but they may be randomized to another drug in addition versus the placebo of the drug so it could be adequately evaluated. But I just want to hear some examples of how radium actually plays out. Brenda, you have a 76-year-old man. How did he do on the radium?

MS MARTONE: Well, he was pretty symptomatic due to the bones, you know the metastatic lesions in the bones, quite a lot of pain. He had fatigue, decreased appetite. So we started the radium because at that time lutetium was approved but unfortunately it wasn’t available due to some short supply. So we started him on the radium and his pain got slightly better. His fatigue still was there. He tolerated it well. No diarrhea, no drop in counts or anything like that. But the whole purpose of this was trying to bridge him to when the lutetium would become available because that’s really what he wanted. So it bought us the time. He was on it for 3 doses so it gave us 3 months’ time. Disease was progressing through that but again who knows if we hadn’t of used radium the outcome may have been different. So we used that. It was well tolerated. Again, he still had bone pain, slightly better, but that provided the opportunity for the next treatment and that’s what we’re always telling patients, you know, we’re going to do this treatment, we’re going to maximize it and this will allow time for something else to become available so that we have options for you in the future.

DR LOVE: And radium actually showed a survival benefit for some reason maybe we don’t always exactly understand, but even though it may not relieve symptoms it seems to improve survival and maybe that’s what was happening with your patient.

Biomarker Testing for mCRPC; PARP Inhibitors for mCRPC

DR LOVE: So I want to finish out talking about PARP inhibitors but particularly biomarker testing. Again, this is such a huge issue in oncology in general nowadays, certainly in terms of PARP inhibitors. We talk about PARP inhibitors — we talked at ONS about PARP inhibitors in breast cancer. We did a huge section on ovarian cancer. You can imagine that’s really PARP inhibitors where they really started. We talk about it to some extent in pancreatic cancer, maybe not as exciting. But prostate cancer, big time, big issue. And Andy, I guess one of the thoughts I have from the point of view of a nurse is, I’d be pretty curious if I had a patient who had metastatic prostate cancer about whether there was germline and somatic testing results on the chart.

DR ARMSTRONG: Yeah, I mean, the reason we do genetic testing, Neil, is a couple of reasons. One is to help that individual patient find actionable alterations that may help them live longer and better. So these BRCA2 mutations and other DNA repair alterations predispose to having a really great response with this class of DNA damaging drugs called PARP inhibitors, olaparib, talazoparib, for example. And now we can combine them with hormone receptor inhibitors, abiraterone and enzalutamide. And so that can change your management directly. That’s now in the NCCN guidelines. We have multiple Phase III studies showing better progression-free survival overall survival in those patients that have BRCA mutations and other similar types of mutations. The second reason, like we talked about earlier, is family risk, family counseling, patients’ siblings, their children may be at risk and figuring out what caused their prostate cancer can also, if it’s a hereditary alteration, can sometimes help save that next generations lives and prevent a cancer in that next generation. The third is for clinical trials also. We’re testing new smart bombs, new targeted therapies, new agents that may work differently depending on the genetics of that patient. If I have 100 patients in clinic, they’re all going to have different things that they bring to the table in terms of how they feel, their medical conditions but their tumors are also unique and different from each other and that explains why some patients may respond differently to establish therapies.

DR LOVE: And the patient where we showed the picture at the Cubs game there as we mentioned has a BRCA2 germline mutation so we have the potential family issues but also, Brenda, you have another 68-year-old man who has BRCA2 somatic mutation. Also got treated actually on a clinical trial as Andy was alluding to. This is a really important trial that combined PARP inhibitor olaparib with abiraterone another therapy that we refer to later. I’m curious, were you working with him when he went on that trial, Brenda?

MS MARTONE: I was, actually. So I was doing informed consent along with the physician, you know, explaining things, getting him started, doing a lot of the education, reassurance, helping him plan visits, et cetera. So yes, I was there when he started that trial. And again because he presented, you know, he was, I think 62, so that’s young for prostate cancer. So because he presented that way that’s what led to the germline and somatic testing to identify a potential target, as Dr Armstrong mentioned, that we could utilize a therapy directed towards that and kind of exploit that germline or somatic mutation. So I guess also to kind of go back and say it’s not just germline. If you have tissue, you should also be testing the tissue because somatic mutations may be in the prostate cancer tissue itself and may not be a germline.

DR LOVE: And Andy, as far as I have heard, you respond just as well to a PARP inhibitor whether it’s BRCA or somatic that’s only in the tumor or they have a germline mutation toxicity, I think is about the same. So can you talk first of all a little bit more, Brenda, about how people tolerate PARP inhibitor therapy? Your Cubs guy seemed to do really well. Did he have any issues receiving PARP therapy? What are the kinds of tolerability issues that come up, Brenda?

MS MARTONE: Well, because we have different PARP agents for different indications, we do know that some of the PARP therapies are associated with more intense side effects but, in general, the most common include fatigue. You have to monitor their blood counts, making sure white blood cells, red blood cells, platelets aren’t going down. Maybe with starting of dose they may have some nausea and so making sure that patients have antiemetics at home and encouraging them to take them prior to dosing, maybe 30 to 60 minutes. And also to remind them because the dosing is bid they need to take the antiemetics prior to each dose. Letting them know they may have changes, they may have diarrhea, they may not. This particular patient that we’re discussing actually tolerated therapy quite well and he symptomatically improved because the PARP inhibitor was actually treating the cancer. So his fatigue improved. He did have some nausea with dosing that seemed to have mitigated over time. Counts have been holding. He never required any blood transfusions. Did quite well. Had no issues with diarrhea. Came to all the clinic appointments and really was very pleased with this therapy with the minimal side effects, the improvement, of course, in the prostate cancer activity, and the fact that he could live his life with minimal impact on what — he’s still working full time and going out. He could do all the things he wanted to do and actually more.

DR LOVE: And thinking about the fact that he actually improved his symptoms, I can imagine him reading in the newspaper, oh this strategy combining PARP inhibitor just got approved, and he’s already been treated on it successfully for a couple of years and there’s a perfect example of clinical trial. So Andy, we’re talking about biomarkers and again we could spend a lot of time but maybe sort of condense down what we’re really looking for in terms of trying to figure out how well PARP inhibitors are going to work. Do you see them moving up earlier, for example, also?

DR ARMSTRONG: Yeah, so these mutations can be germline meaning hereditary or they can be somatic meaning uniquely in the tumor and not hereditary. And about a quarter of men with metastatic prostate cancer will have these types of mutation. And you see this real strong efficacy signal in these subgroups of patients from the PARP inhibitors as well as platinum-chemotherapy by the way. And so the successes that we’ve seen in the castration-resistant setting are now starting to move through Phase III trials into the hormone-sensitive setting. So in the next 1 to 2 years, we’re going to see the results of these trials testing the AR inhibitors, which we’re also now using in the hormone-sensitive setting with the PARP inhibitor. So about 3 different clinical trials. And that’s trying to improve the survival early on by hitting the cancer hard, by delaying progression. But, of course, like Brenda mentioned, there’s some balancing with toxicities. These are DNA-damaging substances so we do worry about what will happen long-term. Are we going to start causing cancer? Bone marrow suppression, is that going to limit our ability to use subsequent therapies like chemotherapy, PSMA lutetium? So we have to see the results of those studies before we start applying that to practice and these are the Kaplan-Meier curves showing the benefits of that combination of the hormone and PARP inhibitors in the blue curves particularly in the patients with those homologous repair, DNA repair defects on the left. There’s still a little bit of a benefit in the right in delaying progression and so the tradeoffs need to be discussed on an individualized patient benefit discussion so that there’s informed decision making. You go in this with your eyes wide open.

DR LOVE: So again, just to look at that curve on the left, which would have applied to your patient, Brenda, so HRR mutated. So this patient had BRCA2 and you can see he’s up there on the curve on the top and we were talking about hazard rates 0.34, 66%. That is very impressive. So at any given point in time, he was 66% more likely not to have a relapse, which I guess at this point he hasn’t, which is fantastic. But I guess we can see why. I guess the other thing, Andy, is we have seen data — there are a bunch of PARP inhibitors out there and they have been and are being studied, talazoparib is another one, for example. Any comments on selecting a PARP inhibitor, Andy? How does that go?

DR ARMSTRONG: Yeah we can’t mix and match these with different AR inhibitors. For example, talazoparib is only linked to enzalutamide. That’s how the study was done and olaparib was mixed with abiraterone. There are other drug interactions. So you can’t mix and match them. So pick the right one for that patient. The PARP inhibitors do differ in their toxicities. For example, talazoparib, niraparib have a bit more anemia. Olaparib, a little bit less. There’s differences in side effects, drug interactions, and so pick the right AR inhibitor for that patient and then follow that with the appropriate PARP inhibitor.

DR LOVE: So Brenda and Andy, thank you very much for working with us tonight. Audience, thank you for attending. Be safe, stay well and have a great night. Thanks so much, Brenda. Thanks, Andy.

MS MARTONE: Thank you.

DR ARMSTRONG: Thank you, Neil. Great program.