DR LOVE: I’m Neil Love from Research To Practice, and welcome to Recent Advances in Medical Oncology, as this afternoon we discuss prostate cancer, new developments, what happened at ASCO, and a lot of practical issues in terms of taking care of patients in a medical oncology setting. We’re thrilled to have our distinguished faculty with us today, who will not only be discussing the data, but also cases from their practices.

Today we’re going to be focusing on prostate cancer, and really focusing most of our discussion today on the 3 common clinical scenarios that medical oncologists often deal with in their practices, M0 disease, hormone-sensitive metastatic disease, and then castrate-resistant disease. And then we’re going to talk a little bit about some of the papers that were presented at ASCO. Dan Petrylak’s really fascinating oral presentation on ARV-110, the androgen receptor degrader, lutetium, which we’ve all been interested in for a long time, as well as PSMA imaging.

M0 Castration-Resistant Prostate Cancer (PC)

DR LOVE: And I worked with each of the 3 faculty individually. We recorded presentations for all 3 of them on these 3 topics. We’ll let you know when everything’s posted, and you can check out their presentations, which go through these topics in detail. But what we did for tonight is just pick out a few of the slides that were presented just so we can capsulize it, and then really move on to the issue of how this functions in terms of clinical practice.

And we’re going to integrate a survey we just did in the last week or so with 50 general medical oncologists in community-based practice. And maybe we can just start out with that, and maybe just to take a step back before we start talking about scenarios. Dan, maybe you can just talk a little bit about M0 disease. In your lecture you went through the data. We’ll talk about that in a second. But just maybe you can provide a little bit of a broad perspective, Dan, on where we’ve come from in terms of M0 disease, where we were 3 or 4 years ago, where we are today, and where you see us moving in the future, Dan.

DR PETRYLAK: So previously there was really no standard of care for treatments with M0 prostate cancer. We often tried secondary hormonal manipulation, but there was no FDA-approved treatment. So Matt Smith, a number of years ago, looked at zoledronic acid. He did a retrospective analysis of those patients and found that those patients who had a PSA of greater than 13 and who had a rapid PSA doubling time were the ones who got into trouble the quickest. And about half of those patients from his study developed metastatic disease within 2 years.

So the endpoint of metastasis-free survival, which was the endpoint of the apalutamide, enzalutamide, and darolutamide trials, was used for FDA drug approval. And whereas we had no drugs in the past for this indication, now we have 3.

DR LOVE: So let’s talk a little bit about how this is actually playing out in practice. And Chris, you can see this question we ask the panel of 50 oncologists, 65 year old patient, has a prostatectomy, PSA-only recurrence, and further progression after radiation therapy, now with a PSA of 3.4 and a doubling time of 10 months. And you can see that docs in this survey are using antiandrogens. I don’t know how exactly whether it’s 100% representative of what’s going on in the United States in terms of the choice. But Chris, any thoughts about these answers?

DR SWEENEY: I want to say I suspect that might be driven by having a more active marketing project out there for the use of apalutamide in this situation. It’s approved now for this nonmetastatic CRPC setting, and hormone sensitive, so people may be interested in trying out a new drug. We know enzalutamide very well from its use in castration-resistant disease. I’m a little bit surprised about darolutamide. That may be a lack of familiarity because in all honestly, I would be interested to hear if Rob and Dan agree.

All 3 drugs have the same efficacy. They both delay the time to PSA progression, time to appearance of disease on a scan, and also the side effect profile is possibly less with darolutamide in terms of less fatigue. 10% of patients have trouble with apalutamide or enzalutamide from fatigue and cognitive changes, which we don’t see with darolutamide.

DR LOVE: Rob, any comments on that? General medical oncology’s an incredible challenge nowadays. We’re trying to do CME, and we can barely keep up with everything going on. It’s not that easy to keep up nowadays. It looks like the perception in the general medical oncology community is that the efficacy is about the same, in terms of tolerability, it’s interesting that people have different impressions. I don’t know whether they get them clinically or from the data. What’s your approach to this situation, Rob, in terms of choice of agent?

DR DREICER:  Well, as my colleague have said, I mean the data’s the same. If you look at all 3 papers and you just look at them by themselves without comparison, the bottom line is the darolutamide trial suggested that in the placebo arm there was not a lot of difference. That’s not the case with the other 2 agents. Therefore, for me, if I’m going to treat a patient in this clinical setting, based on Level 1 evidence and my interpretation of the toxicity, darolutamide is what I would use. Abiraterone, despite the fact that it may have utility here, has not been tested here, nor is it approved.

DR LOVE: So we’re going to dig a little more deeply into this, but I want to also get into some cases. And here’s a question that we want to pose to the audience to answer, and this is really based on a case that Dan presented in his session. When he recorded his presentation, he recorded 2 cases that we’re going to show today. But we just want to know from the audience if you have an 84 year old patient whose got a history of atrial fibrillation, sick sinus syndrome, pacemaker, and hypertension, and you’re going to use hormonal therapy, any preferences as to which one? And while they’re thinking about that, in a second, we’ll look at the case.

But Chris, how would you answer that question, any preferences in terms of choice of agent in this situation?

DR SWEENEY: I think the first question would be to ask does he need anything? What’s his rate of rise? Because his chance of dying from his comorbidities is substantial. The other issue is dollars to donuts he’s probably taking an anticoagulant, maybe a DOAC, with drug-drug interaction issues. So I would have to be hard pressed to actually start anything. And if I were to start, it would probably be darolutamide for the less of the cognitive issues, less drug-drug interaction, less frailty-inducing if he needed therapy.

DR LOVE: So Dan, this actually was based on a case that you presented in your individual session. Can you talk a little bit about what happened with this man? He actually had M0 disease. What happened with him?

DR PETRYLAK: So basically we started him on enzalutamide. He’s doing fine right now, had a PSA decline. Interestingly, we did try darolutamide first, but we were denied by the insurance company because they wanted us to try enzalutamide first. Their line was “he had to fail enzalutamide before going on daro.” So he’s not on an anticoagulant at this point. He does have sick sinus syndrome. He’s got a pacemaker in place. So he’s not on any anticoagulant, at least when he came to my care.

DR LOVE: That’s interesting, though, putting aside the cardiovascular history. So you had them deny darolutamide for M0 disease, and here we’re talking about what your preference is, and yet it sounds like you weren’t able to actually execute that. How’s he been doing on the enzalutamide?

DR PETRYLAK: He’s doing fine. He’s doing fine right now.

DR LOVE: Great. So Dan, when you went through the data, I love this slide that you put together. Can you comment a little bit on it?

DR PETRYLAK: So basically, what it’s showing us, it’s comparing apples to bananas, the structure of enzalutamide. In fact, enzalutamide and apalutamide came out of the same laboratory. They’re very, very similar. There’s a variation on the middle ring, but pretty much it’s the same otherwise. If you look at darolutamide, it’s structurally very, very different from the 2, and that may account for the reason that we have a different distribution in the central nervous system crossing the blood-brain barrier with these drugs. Apalutamide, 19%, enzalutamide 29%, whereas darolutamide has only a 3% penetration rate.

So that, I think is a very interesting observation. It may explain some of the toxicities that we’ve seen.

DR LOVE: Anything you want to say about the trial? We’ve been looking at these for a while now. You put together the first 2. Anything you want to say about the data there, Dan?

DR PETRYLAK: They’re very similar in their hazard ratios, as well as their medians. I think what’s striking is the control arms are very, very similar as well. So you really can’t tell the difference between these 2.

DR LOVE: What about the ARAMIS study?

DR PETRYLAK: Same thing with ARAMIS. Very similar hazard ratios.

DR LOVE: And here’s maybe a comparison of the 3. Anything you want to say about this, Dan?

DR PETRYLAK: Again, the hazard ratios for overall survival at this point are the same. The estimated survivals, there is a difference at this point in the median overall survival, but again, this is estimated. We now have close to 4 to 5 years of follow up in these patients.

DR LOVE: And here’s where it gets really interesting, and you put this together comparing the toxicities, Dan.

DR PETRYLAK: Again, enzalutamide has higher rates of fatigue, falling, dizziness, and mental impairment than darolutamide does. And certainly this could be a differentiating factor between these drugs.

DR LOVE: So Rob, can you comment a little bit more? It’s one thing to look at clinical trial data and see the evaluation of toxicity, but what do you actually see in your clinical practice? And maybe talk a little bit about what’s been called fatigue, but maybe is more of a central nervous system syndrome that you see with these agents.

DR DREICER:  Yeah, all of us have used these drugs a lot, and what you see is there’s fatigue, and then the patients who complain of I forgot how to get home. But the fall and fracture rates are surrogates for this. Patients who lose their balance and have fractures. And as our patients get older, and the sarcopenia that’s associated with some of these therapies, those are real issues. So to me, those of us who know this data, we look at the fall and fracture rate as a true surrogate of harm for the cognitive issues.

And in the darolutamide trial you see less of that. And since our patients are 60, 70, 80 years old, this is a real issue.

DR LOVE: Chris, any comments on that, and again in terms of clinically in your experience, what you see with patients? This isn’t just an issue in M0 disease, obviously. But can you talk a little bit more about, again, this syndrome of “fatigue” that you see, and the pathophysiology of it?

DR SWEENEY: Two things, yeah. So obviously it would appear to be something crossing the blood-brain barrier. Interestingly enough, we know the drugs enzalutamide and apalutamide were both designed off the back of a benzodiazepine-like structure, so there is some GABA reaction. And we know they also have this rare incidence of seizure. So there’s some pathophysiology and molecular biology that makes sense.

Interestingly enough, I just saw some data hot off the press today. We have presented the results of the quality of life from the ENZAMET study, and the specific question I’ve asked is how many patients on enzalutamide have a 10% drop? Some people have a mild drop in their quality of life and their fatigue and their cognition, but it is actually 10% who have a clinically significant decline, which plays out as a subtle overall impairment for everyone as a group, but it's the 10% who drive that subtle difference between placebo versus drug.

DR LOVE: That’s really interesting, and also I’ve never heard about the connection of benzodiazepine. That’s really interesting.

So Dan has another case that gets into a different issue in terms of M0 disease that we haven’t really talked about as much. But the more I listen to Dan talk about this case the more I realize how important it is. And to get into that we have another question that we want to put out to the audience here, which is what systemic treatment, if any, would you add onto an LHRH agonist in a 74 year old man with M0 disease who has disease progression, but still negative imaging while receiving enzalutamide? So it’s a patient with castrate-resistant disease, M0, gets enzalutamide, responds to it, but now the PSAs going back up, but still no evidence of metastatic disease.

And we’ll see how the audience, in general, thinks that through. Rob, any comment, in general, about this space, so to speak? In general, the audience is split between not doing anything and maybe trying another form of hormonal therapy. 20% of people say docetaxel in the M0 setting, which I don’t know about that. But Rob, any comments?

DR DREICER:  Remember, some of these patients got hormonal therapy for biochemical failure who may not have needed hormonal therapy. So if you treat enough of those patients you’re going to make castrate-resistant PSA-only disease. And then if you treat them, they’re going to progress. So here’s a guy who, probably conventional imaging, maybe if you used next-generation imaging you find disease. I think we need to be thoughtful about how much we treat a parameter PSA and how much we’re treating the underlying disease and how much we’re treating ourselves. I think there’s a real danger to that. This is a data-free zone, and I think we just need to be careful about this.

DR LOVE: Well let’s see how this plays out in real life with Dan’s patient, a 74 year old man. So Dan, he presented, I guess initially in 2007.

DR PETRYLAK: 2007, right.

DR LOVE: Can you talk a little bit about this case, Dan?

DR PETRYLAK: So he had a radical prostatectomy at that time. He had T2c N0 disease. I’ll go onto the next slide. He started to have a rising PSA in 2013. I couldn’t treat him with salvage radiation therapy at that time due to the fact he had severe incontinence. And we monitored him until his PSA went up to 12, and he wanted to start hormone therapy at that point. So he started degarelix, and he was treated intermittently, basically, for the next 4 years.

And his PSA started doubling rapidly early in 2018. We put him back on androgen blockade at that point. His PSA was 18, and he did not respond to androgen blockade at that point. His testosterone was 20. So we imaged him. He was negative. And he went on enzalutamide when his PSA reached 26. And his PSA doubling time at that point was 8 months.

And his PSA nadired at 4 in October of 2018. And then in January of 2019 it started rising again. We imaged him again, found nothing. Actually, I think we imaged him twice during the next 8 or 9 months, and both of those imagings were negative. But he was concerned about his PSA rise, and he reached 71 in December, and he said look, I don’t want to continue on with enzalutamide.

And through the VA we were able to get him apalutamide, and his PSA continued to rise. Reached about 240 in February of 2020, and we reimaged him at that point again. At that point he had metastatic disease in bone, and he’s on docetaxel. He’s actually responding very, very nicely at this point.

And you told me he actually was becoming symptomatic with pain.

DR PETRYLAK: Correct.

DR LOVE: And that that responded.

DR PETRYLAK: That responded nicely.

DR LOVE: So Rob, I know you’re very conservative about managing these patients. You already mentioned that. But when I look at this case I go if you think about it, in December he was clearly progressing. A lot of the audience suggested trying another hormone. I’m curious to know, Rob, whether you think that has any possibility of benefitting. But then 3 months later he was on the docetaxel, and then he’s symptomatic. So if you wanted to do Monday morning quarterbacking, I’d say maybe it would have been better to start the docetaxel earlier. But of course I don’t think we have the data.

But just in general, Rob, any comments about this scenario?

DR DREICER:  Yeah, I think this is a case that in a year, maybe, when we have PSMA PET more broadly available, Dr Petrylak knew that the patient had metastatic disease, he just couldn’t prove it, right? So it’ll move leftward where we are, especially in a patient like this. And this wasn’t the patient I was really referring to. It’s more of a patient that may have a very prolonged PSA doubling time, and it’s more about chasing numbers as opposed to bad disease biology.

DR LOVE: So again, would you use a second hormonal therapy, Rob, in this situation? What would you do in that situation? Again, looking in retrospect at December.

DR DREICER:  There obviously is no right answer, and I probably wouldn’t have been inclined to do so because I would have thought that the cross resistance to the drugs was such that there’d be a problem.

As Dr Petrylak I know did is, would now say we might find oligometastatic disease at some point with these patients. So I think this is the kind of patient whose management is going to change a fair amount over the next bit because of just better imaging.

DR LOVE: That’s really interesting, looking for oligometastatic disease that maybe you’d be able to treat locally, I guess. Chris, any thoughts about this scenario? Have you ever seen a response in a patient who’s progressing on one antiandrogen to the next one? How do you manage these patients?

DR SWEENEY: There are 2 thoughts on that. One is I would start with encouraging this patient, saying yes, your PSAs going up, and we’re going to watch this closely, not necessarily need to change from an amide to an amide. But we will watch you, and we’ll do scans, and we will switch therapy when we need to. The PSAs telling us we need to watch him more closely and engage them in that and to try and address their fears that way.

The second issue is I have seen patients respond well to an amide after abiraterone, and that’s a patient who’s been on abiraterone for 2 years, 3 years, lymph node only, you switch them over, they get another 18 months on the amide. I’ve not seen patients really benefit from amide to abiraterone. So the hormone switch does work in a minority of patients who have got good, long, durable responses to abiraterone in some of them. So you can try a switch, but you’ve got to watch them closely, knowing when to change them over.

And one of the questions in the chat is about AR-V7. We know who are the AR-V7 patients without testing. They’re the ones with rapid progressive and newly progressive disease on an amide. The patients who have a slow progression on abiraterone, lymph nodes slightly larger, PSA going up, they’re AR-V7 negative. So I use clinical parameters rather than AR-V7 testing.

Metastatic Hormone-Sensitive PC

DR LOVE: So we’re going to move on now and talk about hormone-sensitive metastatic disease, and I hear a lot of investigators telling me that this strategy that we’re talking about today, of adding something to ADT, is not done as much as it should be in practice. I find that surprising. Maybe it’s the oncologists we’re dealing with because you’ll see every time you ask people they kind of give the right answer. So anyhow, I’m just kind of curious whether that accusation, so to speak, is actually really true.

But I refer you to Chris’ Talmudic talk going through so many different aspects. It is really fascinating. We’re just going to pick out a couple of points that Chris has made, but I really recommend that you check out the talk.

So here’s the introduction to this, Dan. A patient who’s had a radical prostatectomy, presents 3 years later with 3 asymptomatic bone mets that are not amenable to ablative therapy. So first of all, it looks like the audience in general is on board, certainly to do something in addition to ADT. And you can see their preferences, and mainly antiandrogens, interestingly also a little bit of chemotherapy in this lower-risk situation.

Rob, any comments about this scenario and these answers?

DR DREICER:  Well, I would point out that I think you attract a subset of really pretty sophisticated folks.

DR LOVE: This is random, dude. Random.

DR DREICER:  Random smart people.

DR LOVE: These are random people.

DR DREICER:  Yeah, my colleagues would agree, we see, not in significant numbers of patients who don’t have the conversation. And I think part of it’s because you’re also querying mostly medical oncologists.

DR LOVE: Right. This was medical oncologists. You think it’s the urologists?

DR DREICER:  Well, in fairness, there are folks who manage metastatic prostate cancer to start with, with hormonal therapy, who are urologists. And perhaps the uptake of that data’s a little less sophisticated in some groups. I mean, I don’t want to throw stones, but I think it’s a real phenomenon. And I think what you see there is what we see in practice, is that abiraterone is broadly used, and the other agents are data driven. I don’t really think there’re too many patients that should not get additive therapy. So today essentially all patients should, with really few exceptions.

DR LOVE: So we’ll talk about that and some of the exceptions that maybe could be considerations. Dan, any comments? Also, another strategy not too many people use, but you see 10%, 15% of people doing, is starting out with just ADT, see how the patient does, and then if they don’t have a great response, adding something in. Any comment on that, Dan? And also how you approach the choice between chemotherapy and endocrine therapy in this situation, Dan?

DR PETRYLAK: If you’re going to take that approach you have a limited timeframe. The trials that have implemented chemotherapy and the next-generation agents do that within 3 months of starting treatment. And my feeling is try to do it early. Drugs like apalutamide, enzalutamide, if you’re having trouble tolerating you discontinue it. I’d rather see the benefit given upfront.

In choosing agents, I try to select them based upon potential side effect patterns, and also the extent of disease. I do use chemotherapy for the high-risk, high-volume patients, also, for those patients who may have de novo prostate cancer, as opposed to somebody who was diagnosed with localized disease first, who may be rapidly progressive, younger patients, high Gleason score, Gleason 9, Gleason 10. That, I think, is somebody who’s going to get into trouble fairly rapidly. As far as choosing between the different hormonal agents, I used to use a lot of abiraterone. I’ve been shying away from that based upon some cardiovascular effects I’ve seen in some people who have been completely asymptomatic.

And if we look at the data that was presented last year by the Fox Chase group, there’s actually a much, much higher than expected rate of cardiovascular events in patients treated with abiraterone and prednisone.

Remember that the original trials excluded those patients with significant cardiovascular disease. So we’ve got to be wary of that fact in our patients and how we select our drugs.

DR LOVE: What’s the presumed mechanism of increased cardiovascular risk with abiraterone, Dan?

DR PETRYLAK: I think it’s three-fold. Firstly, you have hypertension which can develop. Secondly, fluid retention. So if somebody’s got a borderline ejection fraction they may not handle the extra fluid load as well, and there can be a direct cardiac effect of the drug on the myocardium.

DR LOVE: So Chris, in your talk you go through in detail a bunch of concepts I think are really interesting, but there are 2 in particular that really struck me. First let’s just take a look at a couple other scenarios we presented to the same group. So now we’re saying the patient has widespread moderately-symptomatic disease, a lot more docetaxel. We say there’re liver mets, a lot more docetaxel.

And then Chris, in your talk you went through the key trials that were the groundwork for looking at these issues. But what I really wanted to focus on is your interpretation of them. And what really came across as you were doing this presentation was kind of what Dan just alluded to, not only factoring in volume, but the other factor that you mentioned that kind of hadn’t been on my radar enough, was again, de novo versus recurrent or asynchronous, Chris. Rather than going through all the details on the slides, maybe you can just conceptually talk about how you think through these variables and how it translates into what you do in practice, Chris.

DR SWEENEY: I think it’s your clinical intuition on a patient. So if someone presents with a PSA of 50 right out of the gate, you check a scan, and he’s got multiple bony metastases, this is the de novo high volume, and we know their median survival is 3 years. They do poorly, in general. If that same person presents with 2 bony metastases, a lower burden, but still de novo, their outlook is 4 and a half years. So some of them do well, some of them do poorly. So the de novo low volume is a bit of a watershed.

And then the patient you presented first, late relapse, has low volume, has a median survival of 8 years from the start of the hormones alone. So you can really start to get a feel for what the trajectory is, what the rapidity of its presentation is.

And they’re much more familiar with cytotoxics for visceral crisis for breast cancer. And so I recognize when you’ve got a general medical oncology audience, I liken it to that you need to get more urgent control and get the chemotherapy out of the way. So think of it like how we think visceral crisis breast cancer as opposed to indolent bone-only breast cancer as an analogy.

DR LOVE: That is a good analogy. And you showed a slide that I’m going to show in a second, but first I want to ask the audience a couple more questions related to your slide. So 2 scenarios for the audience. You’ve got a younger patient, no comorbidities, de novo metastatic, high-volume disease, okay? So generally how would you approach that patient? And Chis, I’ll ask you, in general, how would you approach a patient like that? And then I’m going to ask Rob.

DR SWEENEY: Generally, I sit down with them and say you’re chemo fit and you have all of these are your options, except darolutamide. Darolutamide’s not approved and not available in this setting yet. ADT alone, I do not think is the right answer. You can go docetaxel, get him to a remission, just continue the hormones, and then add on the new hormones later.

Or you can add in the potent hormones with it, and then add docetaxel later. By getting the docetaxel in you’re getting it in and out of the way when they’re fittest. They can have a treatment break with just the castration alone, the testosterone suppression. So I actually have the patient help me make the decision. I don’t make it for them. I give them the pros and cons.

DR LOVE: Rob, any thoughts on what Chris said?

DR DREICER:  My approach is very similar to Dr Sweeney’s. I think that’s exactly spot on.

DR LOVE: Here’s the other end, an older patient, congestive heart failure, coronary artery disease, 2 asymptomatic biopsy-proven rib mets. I’m going to ask Dan in a second how he’d think this through. Would you add anything onto ADT? What would you do with a patient like that? Dan, can you talk a little bit about how you approach situations like that?

DR PETRYLAK: So this is not somebody I would give chemotherapy to. He’s got 2 asymptomatic bone mets. I would give him ADT plus apalutamide. I think that that’s reasonable. I would stay away from abiraterone because of his cardiovascular disease. So either apalutamide or enzalutamide. I prefer apalutamide in this situation. I think it’s a little better tolerated. If darolutamide were available, as Chris said before, I think that probably would be the best choice, given fatigue issues, but right now I would go with apalutamide.

DR LOVE: You always see a little darolutamide sneaking in there, but I don’t think you can even get it paid for. Chris, what about this situation? Would you consider not adding anything to ADT?

DR SWEENEY: It depends how poorly he is, recognizing his median survival with ADT alone is 8 years, and his median survival from his age and comorbidities is probably a lot less. I have started ADT alone, see how they tolerate that as the first instance, have them come back in 3 months. And I’ve actually radiated a few of them, their bony metastases, and just said let’s just see how you go with that. And if their PSA gets to less than 0.2 I just continue with the ADT alone.

So this is the rare patient where I would go with less may be more and risk-adapted approach. If they’re not getting a good response, then I would add in one of the more advanced hormones.

DR LOVE: So there were a couple of slides that you had the summarized some of your thoughts, Chris, about approaching hormone-sensitive prostate cancer. Again, I really recommend you check out the talk. But can you just comment on this slide, Chris, and kind of distill a little bit more about how you think through this decision.

DR SWEENEY: So yes, so I’ll walk through this. The patient walks in the room. First question, are they fit for chemotherapy? Yes or no? That helps you know. Is docetaxel on the table at all? What’s the extent of their disease? We’ve got very consistent evidence of benefit with the hormones in the low volume and the high volume, and metachronous and de novo. So that covers the waterfront, whereas the docetaxel, the signals are mixed. There’s absolutely no benefit seen in the subgroups with the metachronous low volume, mixed signals with the de novo low volume, speaking again to them being a hybrid of patients in their disease.

So are they fit for chemotherapy? And then start choosing between the hormones versus the other, and also choosing the abiraterone versus the amide based on seizure and blood sugar, as Dan described earlier.

DR LOVE: So just to finish this out, Chris, I’d like you to talk about your 66 year old patient initially diagnosed in 2010, pretty interesting and different case.

DR SWEENEY: It is, yes. So this is a patient who came in. He was a pilot for one of the major airlines doing transatlantic flights, wonderful personality, and he came in with this discomfort in his pubic bone. High-volume Gleason 8 on a biopsy. He got a nasty lesion there. We treated him with hormones and radiation. And I said, do you know what, I reckon this is relatively isolated, maybe we can get some really decent radiation to the prostate and the bone met. Stopped the therapy after 2 years and said let’s see how you go.

And lo and behold, 10 years later he is basically still in a complete remission of sorts. But his testosterone is declining with age, and he’s still in a great remission. So there are some patients who are extreme responders who can come off of hormonal therapy, and there’s this whole new conversation about is there a role for radiation to oligometastatic lesions. And I like to not use the term cure because I’m not sure about long-term event-free survival with PSA normal and testosterone recovery, and see if they have a better quality of life.
DR LOVE: Now this is a situation that maybe we should have more exposure to, more people aware of, Dan, in terms of oligometastatic disease. I mean, this is a theme in oncology in general you hear more and more about. But I don’t know that there’s enough awareness about this. Any comments, Dan?

DR PETRYLAK: Well, I have several patients in our practice just like this, where they have had documented metastatic disease, 2 or 3 metastases, we’ve treated them with abiraterone, radiation therapy to those particular spots, and then 2 years out we reimage them, and they have no visible disease on scans. I’ve actually counseled the patients in that situation to stop their androgen blockade. And we’ve actually had a couple of patients whose testosterone returned to normal and have not had, at this point, any disease yet.

That’s nonstandard treatment, but the question is what do you do about these patients, particularly if they’re young men, and you’re going to be subjecting them to the long-term side effects of ADT. If you’re looking at treating these people for 10 years, for example, that’s going to have significant effects on their bone health, their cardiovascular health. So I think we really need a good series to really evaluate what the role is of stopping treatment if they have been treated for oligomets, and then they have nothing left.

DR LOVE: Have you stopped patients, Dan?

DR PETRYLAK: Yes. Again, with the caveat that this is nonstandard, that they’ve actually told me they’re refusing therapy at that point. But we’ve made a mutual decision to stop and then to observe them.

DR LOVE: So interesting.

Metastatic Castration-Resistant PC

DR LOVE: So we’re going to now move on and talk about castrate-resistant metastatic disease, and also hear another case from the faculty. These are the issues we want to talk about fairly briefly. But let’s take a look at some of the poll questions. So Rob, we have a patient who’s getting androgen deprivation for M0 disease, found to have asymptomatic bone mets. So we’ve been asking this question for a while, and not too much SIP-T in this situation, but Rob, how do you approach a patient like that?

DR DREICER: Well, I mean, as you point out, I would probably think about SIP-T since my center is a SIP-T place. But aside from that, most of the time, in my practice, if a patient has bone metastases he needs to be treated. I think the issue that my colleagues have raised is, is this an oligometastatic patient or are we going to be doing other things? But conventionally for castrate-resistant metastatic disease I would think about abiraterone and prednisone. I think it’s the best tolerated therapy. So while I would probably offer him SIP-T, if I’m going to use an AR drug it’ll be abiraterone.

DR LOVE: I really like Chris’ term in his talk of polymetastatic. That kind of reminds us to think about oligometastatic, I think. Dan, here’s another situation which I think the answers are kind of interesting, too. Now we’re saying that the patient has moderately symptomatic disease. And of course, there’s a lot of individuality. We can make the patient have a little more pain and people might think differently. So it’s not rocket science here, we’re just kind of getting people’s impressions. But I do find it interesting that in spite of the fact that the patient’s moderately symptomatic, most of the people in the survey still would stick with hormones. How do you think that through, Dan?

DR PETRYLAK: Well, you can get significant pain relief with abiraterone, as well as enzalutamide. So my experience is the pain relief is probably better with docetaxel, more rapid. Certainly, you don’t see pain relief with SIP-T, and we done give SIP-T to those patients who are symptomatic. But all these drugs do have a pain effect.

DR LOVE: Getting back to Rob’s point about SIP-T, Chris, are you using SIP-T? Do you believe in it, so to speak?

DR SWEENEY: I do. I do use it. Do I believe in it? I want to believe in it. The question is with all the new therapies, is the survival effect actually washed out with the abiraterone, the enzalutamide, the docetaxel, the radium, which we may or may not see anymore.

Having said that, I do use it because there is data to support it. And I use it in the patient who doesn’t need another therapy, so the asymptomatic patient, you’ve got some time. And we actually do have some data from Dana-Farber, for whatever it’s worth. The more patients who can get more therapies in the longer they live. And so I sequence through all of them, and whether that’s biology or the actual therapies.

We see that we’re not having 20% 5-year survival rates, 25%, with all these new therapies in Dana-Farber registry, whereas before 2010 we were only up around 10%. So we’ve moved a few patients out to the 5 years, and I think we see that clinically. Is that great clinical data? No. Is it some encouragement that we’re making some real advances? Yes. Are all these therapies additive on top of each other? Heck no.

DR LOVE: So Rob, here’s an interesting one. We said you have a patient who got asymptomatic liver mets, and still you see the majority of people going with hormonal therapy. Any comments?

DR DREICER:  Probably not my choice. I mean, liver metastasis in prostate cancer tends to not end well, and obviously we’re going to talk a little bit about genomics and whether or not this patient may be a DDR-mutant patient. But the alternative is also the neuroendocrine phenotype. I’m likely to use systemic therapy, and I may think about a platinum-based regimen on top of docetaxel. That would typically be my approach.

There’s less error biology going on here typically, and I worry about that patient.

DR LOVE: So here’s another scenario. And Dan, this is a 65 year old patient, minimally symptomatic disease, he’s gotten docetaxel, ADT, enzalutamide, but still has disease progression. So the CARD-type situation that I’m going to ask Rob to comment on. So most of the audience is saying cabazitaxel. Dan, any comments?

DR PETRYLAK: Yeah, I would agree with that. This patient does not have a DNA repair mutation. I don’t think further hormonal therapy will be that effective in this patient. I think cabazitaxel’s a reasonable choice.

DR LOVE: Do you take into consideration AR-V7, for example, if somebody else ordered it, Dan?

DR PETRYLAK: Well, as Chris said before, I don’t. I’ve seen some very strange results with AR-V7 that have popped up because we’re doing next-generation sequencing, and we see it in some of our specimens. But it hasn’t correlated. And there was a trial done a while ago with a drug called galeterone, where they tried to get asymptomatic AR-V7-positive patients on it, and they couldn’t find them. So it’s an indicator as to how rapidly the disease is progressing.

DR LOVE: So Rob, you went through the CARD trial in your talk. I pulled a couple slides out for you to just comment on. Clearly, it was practice changing, as you can just see. Can you comment on what they looked at there, Rob?

DR DREICER:  So we’ve know, as you heard Dr Sweeney mention before, that there is cross resistance between abi and enza, and we’ve known that for some time. This is one of the prospective studies that pretty much prove it, basically. This is a pretty heavily pretreated group of patients either receiving abi or enza, most also receiving docetaxel, who have progressed within the year of receiving docetaxel. So bad biology. And then they were randomized to get the alternative AR drug versus cabazitaxel. And there was a survival benefit.

There’s other data that’s prospective, but this is a definitive study, not so much to tell us that you have to use cabazitaxel, here, more to tell us that switching to the alternative agent in patients with bad disease is not a good strategy.

DR LOVE: So I’m not sure, when you went through this I was noting what you just said about the idea that these people progressed within a year. I don’t even know that that’s typical, and I’m not sure that’s on everybody’s radar. So Dan, any thoughts about that? And do you approach the patient differently if they progressed after 2 years?

DR PETRYLAK: Well yeah, I think Chris pointed that out before. There are these patients that do respond to multiple hormonal manipulations. They tend to have a long duration of response to their initial therapy. So the patient who may be on abiraterone for 3 years as opposed to somebody who’s on it for less than a year. It’s different biologically. They may respond again to another hormonal agent. There’s not a lot of data on that, but there’s a lot of anecdotal stories that all of us have shared in that situation.

I’ve had a couple of patients who’ve been on 5 hormonal manipulations over an 8- or 9-year period. And they’ve done well. Eventually they do progress, but I was able to get fairly good mileage out of that. The question is biologically what’s different.

DR LOVE: I just think we need to emphasize more that point in our CME because I didn’t realize that. That’s really, really important.

So we got a great case here. When I saw the case, I was just trying to think what actually Rob did with this patient. It turns out to be pretty interesting. So Rob, let’s hear about this 72 year old man.

DR DREICER:  Sure. Five (5) years out from a Gleason 7. He got salvage radiotherapy for a detectable PSA about a year out. Eventually progresses, develops bone metastases, and then started on abiraterone. He has actually a reasonably nice response for 18 months and now is progressing, and he’s got bone pain. His performance status is good. He has no actionable mutations.

DR LOVE: So let me just turn to Chris. This is certainly a common situation. How would you be thinking through this one?

DR SWEENEY: So he’s fit. And I think the answer is reach for chemotherapy sooner rather than later, from what I can see there.

DR LOVE: So did he have docetaxel at that point? I don’t think so, but you’d be thinking about chemotherapy?

DR SWEENEY: Yeah, so what’s the status of disease? Is he castration resistant? That’s not completely clear.

DR DREICER:  Yes. He’s castrate resistant.

DR SWEENEY: So he’s progressed on ADT and abiraterone, has been on it for 18 months.

DR LOVE: Only bone disease.

DR SWEENEY: Bone-only disease. So radium definitely has a role here, as well, and that’s the thing, is when can you layer in the radium? And so this probably the patient you can get it in. You don’t want to wait too late. Chemotherapy you can get some debulking with the symptomatic patient, as the one that Dan described earlier, Dr Petrylak, so this is the one chap I would think about sneaking in radium, sandwiched between the hormone and the docetaxel, is one thing there that we haven’t talked about, how to sneak that in.

DR LOVE: Dan? Are you up for sneaking some radium in?

DR PETRYLAK: You could sneak some radium in. I don’t think it’s unreasonable. One thing I’ve tried in these patients who’ve progressed on abiraterone is we will switch steroids. So I’ve switched from prednisone to dexamethasone. I’ve gotten some mileage out of that in some patients, 20% maybe. There’s some publications by Dr Attard on that, where they’ve done that in 45 to 50 patients. But that’s one thing I would also consider in this patient.

DR LOVE: That’s neat. I haven’t heard of that one. So Rob, let’s talk about what happened. Kind of interesting.

DR DREICER:  So here is your evidence radiographically of progression. And again, it’s hard on a slide. I mean, the gentleman basically is highly functional. He’s got a little pain, but it’s being managed with minimal doses of nonsteroidals.

DR LOVE: So, go for it guy. Tell them what happened.

DR DREICER: This is the patient that I think that radium was actually quite useful for, and that’s what I opted to give him. Dr Sweeney has trained me well. And I think it’s important, as my colleagues have inferred, the radium-223 wasn’t approved as a pain drug. It’s actually not documented to be a pain drug. It’s a drug to improve survival and probably impact on symptomatic skeletal events.

I think radium is underutilized. It’s very well tolerated. There are some patients who get symptomatic benefit. Not very many, but some do. This patient actually happened to get it. He felt better, and his PSA dropped for a few months. And the other thing that most of us do is in between cycle 3 and 4 I tend to do CT scans to just make sure that there’s not visceral progression, especially in patients who typically have PSA progression.

DR LOVE: That’s a really interesting situation. And he tolerated treatment well? No cytopenias? Do you ever see cytopenias with radium, Rob?

DR DREICER:  Maybe 1 out of 75 patients you see a little bit of mild anemia and white count. It really is very well tolerated. Most of the side effects are GI, some diarrhea, but really it’s an incredibly well-tolerated therapy.

The key is, and it’s easy for the academics, we coordinate very closely with our nuclear med docs or rad oncs, whoever is administering it. But you’ve got to see the patient monthly because there are patients who will progress on this therapy, and you can’t, with all due respect, have our nuclear medicine colleague think that they’re going to manage castrate-resistant disease. So you really need to see the patient monthly as the patient gets treated.

DR LOVE: And so I think they may be even seeing them more now with lutetium, maybe coming onboard. Just 1 final comment, Chris, going back to radium in terms of the issue of combining it with hormonal therapy. We’ve kind of gone back and forth about that, the issue of bone protection and how important that is if you’re going to combine it. There have been a couple of papers we put in the slide deck looking at patterns of care in the community, at least this was going on before the recent papers came out, there was a lot of combining endocrine therapy with radium-223. Where are we today with that, Chris, and where do you think that’s heading?

DR SWEENEY: Don’t do it. I’ll say that as the very pithy way. Beautiful idea destroyed by brutal facts. The combination was worse. Whether that can be salvaged by giving bone protection with zoledronic acid, or denosumab, unknown. But there was more pain, progression with bone fractures, when you put the abiraterone with the radium. It got a little bit better for the patients who had the bone protection. Same with enzalutamide.

But we’ve got no evidence that there’s a synergy or additive benefit of the doublet. So I’m very confident I’d use them sequentially. Could it be the hormonal therapies are so effective they actually decrease the osteoblastosis? They decrease the radium distribution to the bone? We don’t know. We thought it was going to be better on the cancer, we don’t see it. Don’t do it. Let’s find out. Let’s get real data before we do anything.

DR LOVE: How about radium and SIP-T, Chris?

DR SWEENEY: If we want to send the country broke, that’s one strategy. I don’t think so. The one strategy that I think is a nice clinical trial is CTLA4 inhibition with sipuleucel-T as a trial that’s being done to see if you can boost the immune system. I don’t think radium is going to have enough of an abscopal effect to boost the immune system. I think that’s a bit of a beautiful biological theory yet to be proven. But I would say SIP-T alone, and I wouldn’t put other agents with it because that may alter the immune system that’s being activated if the SIP-T does have a benefit. And again, I want to believe.

DR LOVE: So continuing on in terms of castrate-resistant metastatic disease, Dan, we recently did a roundtable. We spent an hour and a half talking about PARP inhibitors in prostate cancer. I’ll just ask you for a very brief comment. Everybody’s aware of the fascinating data and approvals. Dan, just maybe a summary, a little bit, in terms of clinical practice, how its affected the way you approach genomic evaluation of men with metastatic disease? And where you’re using PARP inhibitors, and which one? 

DR PETRYLAK: So right now all of our patients who come in to see us at Yale are molecularly phenotyped as part of our standard. Just as a standard practice in care they should be having DNA repair checked, BRCA mutations, ATM. They should also have microsatellite stability checked because there are patients who do respond to pembrolizumab with that particular mutation.

So both olaparib, as well as rucaparib, are approved. There’re slightly different indications. Olaparib is for those patients who failed next-generation abi or enza plus androgen blockade. Rucaparib is a little bit more down the line after docetaxel and a next-generation agent.

Both of these drugs, in my hands, have been very similar in their side effects and their efficacy. So really the only way to select one versus the other is the indication, in my mind.

DR LOVE: So Rob, I didn’t show that we asked also in the survey what kind of genomic evaluation people are doing for castrate-resistant prostate disease in practice, and pretty much you see NGS and germline panel. Ideally, Rob, is that the best way to approach it? Or maybe overkill?

DR DREICER:  No, I don’t think it’s overkill. I think, as my colleagues have indicated, I think the standard of care has evolved. We need to do germline and somatic testing. On the somatic side, prostate cancer’s a bone-trophic disease. If you have a prostatectomy specimen from 9 years ago and nothing else, how good is that?

I increasingly rely on liquid biopsies. I understand that there are controversies and issues, but I think from a practical matter, ultimately, we’re going to need to use liquid biopsies in prostate cancer. If you have fresh tissue, wonderful, and that should be sent off for somatic. So germline and somatic mutation in any patient with metastatic disease.

DR LOVE: So I’m going to finish out here with a little bit of a tasting menu of things for the future. And I want to start out with this really fascinating concept. Dan, we’re seeing this in multiple diseases, the idea of combining checkpoint inhibitors with antiangiogenic. Renal cell cancer upfront, endometrial cancer, MSI stable is where you see this combination strategy. And we haven’t seen too much with checkpoint inhibitors in prostate cancer other than MSI high. You might want to comment on CDK11/12, Dan. But this paper looks pretty interesting, employing a similar concept using atezo and cabozantinib. Any comments?

DR PETRYLAK: So this is 1 situation where zero plus zero equals 30. Cabozantinib has a very, very low response rate. I think in the randomized trials it was about 5%. And we had a paper at ASCO GU actually a couple of years ago looking at atezolizumab having a less than 10% response rate. So the thought of an agent such as cabozantinib, where it may have an effect on T-reg cells, showing this response rate in patients with soft tissue lesions, some patients had liver mets, I think it’s extremely exciting and needs further confirmation in randomized trials.

DR LOVE: So Rob, common situation with solid tumors in general, is a patient with advanced disease. They go through all approved therapies. There’s no trial available, and everybody brings up the issue of checkpoint inhibitor. I mean, these drugs are both approved, if you could get it paid for, would you try this in a patient, Rob, who had no other options? When do you use checkpoint inhibitors in general in that situation, Rob?

DR DREICER:  So outside of MSI high, no. I wouldn’t use a checkpoint just to give a checkpoint. I happened to be involved in this study, so I mean I’m interested in the combination. The study is pretty much closed, so the next patient who walks through the door am I going to use cabo/atezo? No, I’m not. I mean, I’ve been doing this a long time, and while I’m very intrigued by this data, and I’d love to see this work out, I’m not smarter than randomized trials. This is not a benign treatment. So forget about the economic issues. I remind my fellows all the time, our patients are not kitchen sinks. This isn’t about throwing everything in and just jostling it around and seeing what works. We’re going to have to be a little bit more thoughtful.

DR LOVE: Well let me challenge you a little bit on that one. Did you see any patients in the trial who had good responses, Rob, clinically?

DR DREICER: In fact, I have seen some pretty dramatic responses.

DR LOVE: Pretty dramatic responses. You want to see a randomized trial? Really?

DR DREICER:  Neil, having done Phase I trials for a long time, you know that the Phase I trial bible tells you? The first patient always responds.

DR LOVE: Okay. All right. Well, I won’t push you too much on that.

ASCO Journal Club

DR LOVE: But anyhow, I want to pick up a couple of papers presented at ASCO. And this first one that Dan presented, I really recommend you check out the oral. Just go to the ASCO virtual meeting. It is really an awesome presentation, ARV-110: A Protein Degrader. Dan, can you just kind of talk a little bit? I love the graphics you presented there. Can you talk about what this is?

DR PETRYLAK: This is a drug that was developed by Craig Crews at Yale. It is an orally bioavailable PROTAC. And what a PROTAC is, it’s a molecule that will bind to a particular protein and accelerate its degradation through the E3 ubiquitin ligase pathway. And 1 of these PROTAC molecules can actually degrade up to 400 target proteins. So in this case we took the androgen receptor, and this particular PROTAC will degrade everything except AR-V7, and there’s also a second mutation that is nondegradable, as well. So there’re 2 mutations that are not degraded.

We did a standard Phase I trial. We were able to show that there was downregulation of the antigen receptor. And this was a patient who was treated at 280 mg. Six (6) weeks after treatment there was a repeat biopsy. As you can see on the right, there is less expression of the antigen receptor in the tissue, and in those patients, who had actionable mutations, or at least degradable mutations. And also above 140 mg, and this was the dose that we felt was the magic dose, above which is where, correlating with the laboratory, we had activity.

We had 2 patients, both of whom had a T878A and H875Y mutation, which is associated with abiraterone and enzalutamide resistance. Both of these patients had PSA declines, and 1 of these patients had an objective soft tissue response, as you can see, that’s almost complete resolution of that node. And his IVC, which was collapsed, is now patent. And that patient had a 97% reduction in PSA.

So it’s exciting. It’s preliminary, and I will stress preliminary. We’ve got a lot of work to do to figure out exactly who’s the right patient and whether we’ve got broader activity in other mutation, as well. So I think that small numbers, very small numbers, but a first way of targeting a protein with the PROTAC.

DR LOVE: So I was joking with Dan that this is prostate cancer’s answer to fulvestrant in breast cancer. I know it’s different, but the idea of getting rid of the receptor.

DR PETRYLAK: There actually is a PROTAC that’s being raised against estrogen. That’s in clinical trials right now.

DR LOVE: Awesome. So getting back to the other issue in terms of the lutetium PSMA. Rob, there’s actually a randomized trial. We’ve been hearing about this strategy for so long. It was in Europe for a while. Is this coming to the US? Maybe you can just talk briefly about what this is, Rob, and what they presented there at ASCO?

DR DREICER:  Sure. Prostate specific membrane antigen has been a target because it’s pretty ubiquitous in prostate cancer. So for 25, 30 years there have been diagnostic attempts and therapeutic attempts. This is a small molecule that targets PSMA and releases lutetium, which is a beta-emitter. As you point out, there is data from colleagues in Australia and in Germany which demonstrate antitumor activity and a relatively reasonable safety profile, although the data is very, very preliminary.

You referred to the Phase III registration trial, which is referred to as VISION, and that study has been completed, and I think many of us think we may see data later this year. There was a randomized Phase II presented at ASCO comparing lutetium versus cabazitaxel, and it was kind of provocative. The endpoints are not particularly clinically meaningful.

My sense is that this is a real therapy. Again, I don’t think this is a homerun. I would be a little surprised, frankly, based on how the trial was conducted. The control arm was the alternative abi/enza flip over. So I would hope that we’ll see real meaningful benefit from this therapy. Again, as you pointed out earlier when we were talking about radium, this is going to be administered by our nuclear medicine colleagues, and for those of our colleague who practice in the community, you’re going to have to figure out how to work together with your nuc med docs because medical oncologists are going to have to oversee the care.

DR LOVE: So a final comment from Chris. Curious where you think maybe this is going to land in the sequence of therapy in metastatic disease. Do you think it might be given say before cabazitaxel, for example, in the CARD situation? And also, Chris, any comments on where PSMA imaging is going to lead to?

DR SWEENEY: I suspect, in all honesty, if the lutetium PSMA study is proven to be positive, up against modest control arm, it’s going to probably replace radium. You don’t have to worry about bone only versus other. The cabazitaxel study looked like it had more anticancer activity than cabazitaxel in the randomized Phase II small study. But it looked like it had more anticancer benefit in a select patient population, who had PSMA PET positive without discordant disease.

So if you were PSMA PET positive in 1 lesion, but FDG positive in another, you didn’t go on the study. So there was some selection in that study. They had some selection in VISION. So that’s something we’ll have to work out and is a topic for another day. But I’m very encouraged, and if it does come in I suspect we’ll probably end up using it in patients with soft tissue and bone disease, where we would be otherwise using radium.

The PSMA PET imaging, bottom line is we can see more cancer spots with PSMA PET imaging, whether it be the gallium or the other versions of it. We just don’t know how to use it, actually. And I’ve got 2 concerns. One (1) is if you get a PSMA PET in a patient who has high-risk localized disease, conventional scan negative, and they had some disease beyond the pelvic lymph nodes, do not abort the local therapy. Treat them as high risk. They’re micrometastatic patients who may actually benefit from the low hormones in the radiation and be cured. Do not abort just because they have some PSMA PET positivity where we know they have a survival benefit.

The other scenario where I’ve seen a problem, rising PSA post prostatectomy. PSA gets to 0.2, someone sends them off for a PSMA PET, and they say you know what, let’s wait until your scan is positive before we give you your curative salvage hormone and radiation. Don’t do that. The higher your PSA the lower your cure rate. They’re my words of caution. But it sees more cancer.

DR LOVE: So I want to thank the faculty so much for tonight. And thank you all for attending.