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Rana McKay: Hello, everyone. My name is Rana McKay and I'm a GU medical oncologist at the University of California in San Diego. It's a pleasure to be here with you today. I've got my esteemed colleague, Dr. Oliver Sartor, really a giant in the field, Director of Radiopharmaceuticals at Mayo Clinic and Chief of GU Cancers at the Mayo Clinic as well.

UroToday is developing a program that will highlight the state-of-the-art, interdisciplinary management of prostate cancer. And as an esteemed leader in research and patient care, we are just so honored to have you with us today, Dr. Sartor, to join us as a faculty member on this topic. Our goal with this program is to highlight the need to understand treatments for patients with advanced prostate cancer and understand the risk of recurrence and how to sequence therapies in the castration-resistant setting based on prior treatment. So we'd love for you to take it away.

Oliver Sartor: Great, thanks so much, Rana. It's a delight to be here today. And I'm just going to give a really simplistic overview of castrate-resistant prostate cancer because we actually could talk about this for about three days. What I'm going to do is just give some bare bones and a couple of cases. Please interrupt me at any time because this is not really a formal presentation; this is just a way to get a little information out and give the opportunity for people to see a little bit about how we think.

When we look at the standard therapies today, and I'm going to put everything on one slide in the beginning, we kind of divide the patients into castrate-sensitive and those who are castrate-resistant. And castrate-sensitive typically means that they're going to be responsive to hormones, never seen hormones, whereas castrate-resistant means that they've seen some hormones along the way.

Now, one of the things that have really changed over the last decade is what it really means to be castrate-resistant. Because if we go back a decade ago, we would use something like leuprolide or goserelin, androgen deprivation therapy, if you will, and we'd lower the testosterone, and at some point, there'd be progression in the number of patients, and that was castrate-resistant.

However, it's gotten so much more complicated because now we have all of these novel hormones that are showing significant and positive effects when they're brought earlier. Things like Abiraterone, Apalutamide, Enzalutamide, Darolutamide. And one of the things that is potentially important is the utilization of chemotherapy, and that's been around for a while. But then more recently we're even talking about triplets, where we use normal androgen deprivation and then something like Abiraterone or Darolutamide, and combine that with docetaxel chemotherapy. So these patients when they progress, are very, very different than the ones that used to progress and we called castrate-resistant because then it was just ADT alone. Now it's ADT, Abiraterone, Apalutamide, Enzalutamide, Darolutamide, or maybe even chemotherapy too.

Now if I move this thing forward, I'm going to talk just for a brief moment about what I call the multi-modality skills that are necessary to manage prostate cancer today. In the old school, it was kind of surgery, radiation, hormonal therapy, chemotherapy. But today we really have to be cognizant about the genetics, both germline and somatic. Germline means that which is derived from the DNA you were born with, and somatic means the tumor, and both of these are potentially important.

We have molecular imaging, PSMA PET being the one that is the prototype now. Artificial intelligence, new things just added to the guidelines, but not for castrate-resistant disease yet. Targeted therapy, that would be things like PARP inhibitors, immunotherapy. In selected cases, we use things like the PD-1 antagonist, but there we're going to be looking for particular alterations, and I'm going to be focusing on that a lot today. And molecularly targeted radiation, this will be things like the new PSMA lutetium-targeted agents.

So, a huge evolution in the space and a lot of fun for patients because we're getting better at what we do. Now one of the things that is important is to think about the guidelines, but to understand that sequence matters. In the old-school sequencing where people had no prior docetaxel, no prior novel hormonal therapy at the time that they were initially diagnosed, just went on androgen deprivation therapy, we have preferred regimens such as Abiraterone, Enzalutamide, docetaxel, it might be entertained. But depending on the genomics in certain settings, kind of useful in certain circumstances, we have the PARP inhibitors like Niraparib, Olaparib, Talazoparib. We have immunotherapies like Sipuleucel-T, bone-targeted isotopes like radium, and even some other secondary hormonal therapies.

But if you have had docetaxel and ADT in the initial setting, then we entertain a slightly different group of options for those patients. Abiraterone, Enzalutamide, yes, but now we're going to be talking about Cabazitaxel as a second-line taxane. And again, we think about the PARP inhibitors, radium, Sipuleucel-T in certain circumstances, but yet again, if we're using the novel hormones upfront, and almost all the patients are getting the novel hormones before they're castrate-resistant today, then it turns out that we have a narrow list of the preferred regimens, really docetaxel and we'll come back and talk about this, and then a whole variety of other possibilities that I've talked about before, and then a few more.

But now we have triple therapy, and with triple therapy, we have androgen deprivation, docetaxel, and an AR pathway inhibitor, Abiraterone, Enzalutamide, Apalutamide, Darolutamide, then we have the possibility of the PSMA lutetium being used as category one, because currently the PSMA lutetium requires utilization of docetaxel or another taxane and at least one AR pathway inhibitor in castrate-resistant disease, and PSMA PET-positive metastasis.

Okay, so enough of the broader overview, let's talk about a case. And, Rana, this is a 69-year-old guy. He was diagnosed with Gleason 7, PSA 22 prostate cancer back in 2015. Initial staging, which was with a CAT scan and bone scan. He had a couple of bone mets, he had some retroperitoneal nodes, got treated with ADT. Appropriate for the day. PSA went to undetectable, stayed undetectable for three years, nice response.

Then his PSA began to rise, and it got up to about two or so, and in 2019 got staged with conventional imaging, bone scan, CAT scan, didn't see anything. Then he got started on Darolutamide. Well, there were also Enzalutamide, Darolutamide, Apalutamide, all could have been potential choices, what we call non-metastatic CRPC. His PSA went undetectable again, then began to rise. Now, in November 2023, his PSA is 0.3. In January 2024, his PSA is 0.5. Did some germline and somatic testing. Germline was negative, somatic testing showed p53 mutation, the most common mutations, and some AR amplification, and we got a PSMA PET.

Now, this is what we showed on the PSMA PET. I'm going to use my arrow here. These two little dots up where the eyes would be are called the lacrimal glands, and that's normal uptake. These big blotchy things up around the face are the parotids and submandibular glands. These are salivary glands which have a lot of uptake, but there's a little spot right there that's not supposed to be there. That is actually a transverse process within T1, that's a spinal lesion. Here's the liver, his spleen, there are some kidneys, a little bit of intestine, a bladder, a little bit of ureters right there. That's normal. And bingo, something in the prostate.

So what do we do? His PSA is starting to go up. Still relatively low, it's only 0.5. We scan him up. He's got two areas of abnormality. Oh, I should point this out. This is not thought to be a metastatic lesion; this is thought to be a little hemangioma in his spleen. So he has two areas, one here and one here. So what do we do?

Rana McKay: I love this case because I think this is something that we encounter in clinical practice all the time. We have these individuals who have a slow-rising PSA, and half of our tumor board discussions are, "Can we pull up the PET and can you tell me if you think that that spot is real?" That's like half of our tumor board conversations, but I think this is a gentleman who has nmCRPC, has been on ADT with Darolutamide, has oligoprogression. And I think a strategy to consider, if it's not going to be too toxic, is to retreat in his prostate, radiating both areas of disease, and then maintaining him on his existing therapy. See if he's going to have a response to the oligometastatic SBRT.

The question is, can we target what's in the local prostate area, pending his prior therapies? A clinical trial is always near and dear to my heart. Everybody's always a candidate for a clinical trial at every single intersection. It's important to be talking about clinical trials and assessing. And now there are a lot of clinical trials that are looking at actually answering the question of how do we integrate SBRT into the context of our systemic therapies or even without our systemic therapies.

Oliver Sartor: Well, Rana, you pegged it. What we did is use the SBRT. We reviewed these images. He had not had any prior prostate radiation, by the way. He got put on ADT; he's diagnosed with metastatic disease. And then there was some interesting stuff out of the STAMPEDE trial that said, "Oh, yes, we should radiate the prostate." But that STAMPEDE data was after he was diagnosed, and he never got it.

So now what we're looking at is a prostate lesion down here below the bladder and this T1 lesion, and precisely what was recommended was SBRT, stereotactic body radiotherapy, some people call SABR, S-A-B-R, as well. But SBRT is what we call it. And what I'll simply say is getting these lesions radiated, oligoprogression, just kept everything else going, kept doing ADT, darolutamide. And guess what? His PSA is already starting to go down. So it looks like we made a good choice. We're radiating the oligoprogressive disease, and I think we're going to have a good response to that.

Rana McKay: That's fantastic. Yeah, I think integrating SBRT is, now that we have PSMA PET, that's our hammer for every PSMA PET scan we have.

Oliver Sartor: Well, no doubt about it. Now I'm going to briefly just talk through some of these other options for a second and just so we have a little more discussion. So like docetaxel chemotherapy, well, if you look at the guidelines, it's progressed on ADT and a novel hormone, then maybe docetaxel was the right thing to do. Docetaxel has some potential toxicity—

Rana McKay: Some.

Oliver Sartor: —that's got very low-volume disease, relatively slow rise in his PSA, low PSA. I really don't use docetaxel here; I'm going to be looking for something else.

Rana McKay: Yeah, I would tend to agree. I mean, I think as we think about integrating SBRT, I love that you have the list of options here because it's like, okay, what is actually the opportunity cost? You know what I mean? What is everything else that's on the table for this gentleman? And so does it make sense? I agree with you, I would not consider docetaxel in this setting.

Oliver Sartor: Yeah. Now switching to another hormone post-Darolutamide, we don't actually have a lot of experience. I'm not even sure what other hormone we would use. Just not quite sure. It sounds reasonable on the surface, but I'm not really sure which one should be done; we just don't have a lot of data there.

Rana McKay: And this gentleman's got some AR amplification. I think he repeated the genetic sequencing.

Oliver Sartor: Yeah, he did have an AR amp. Thank you for picking that up. And then I'm going to use the term BAT, and that's bipolar androgen therapy, which some people call supraphysiologic testosterone or SPT, basically a high dose of testosterone. I know you use a little BAT; I use a little BAT. And could we have used that in this case, or maybe after SBRT, maybe he comes back, and we consider the BAT. I don't know. I'd turn it around, right, Rana, is that too far... A little bit too crazy, or what do you think?

Rana McKay: No. I do think there are a handful of clinical trials that have investigated BAT. I think the TRANSFORMER trial with Johns Hopkins, COMBAT looked at it with IO. There are other trials. RAVENS is looking at it with radium. There's now a STEP-UP trial that's occurring.

But I think it's certainly not standard therapy; there are things to consider around that. People who have systemic disease or visceral mets or have had a recent cardiovascular event or a thrombotic event, they're not going to be great candidates. So, I think it's not one of those things that is done in, I want to say, inexperienced hands. There can be a flare that can be observed, particularly in people that have diffuse bony metastasis. So, I probably would not go down that road at this juncture. If I did have a trial of that, like STEP-UP, I would enroll this person onto that trial.

But honestly, you want to see if you can radiate his two sites of disease. I mean, he's oligometastatic on PSMA PET in the... While his CRPC, I think he can really get a lot of runway with delaying the need to switch treatment.

Oliver Sartor: Well, absolutely, and that's what we did.

All right, the next little case. And this is a 59-year-old who was diagnosed a little more recently than the other fellow who was way back in 2015. He's got a Gleason 8, PSA 39. Gets staged, he has eight bone mets in his spine and pelvis, so nothing outside of the spine and pelvis. Got a few scattered retroperitoneal nodes, no visceral disease. Gets some germline and somatic testing. And he had a VUS in the ATM. VUS means variant of unknown significance. The vast majority of these, by the way, are non-pathogenic and as a rule, we kind of put them into the, we don't really care about that category.

And he got treated with ADT, Abiraterone. Had a very appropriate, had a great response. PSA declined down to 0.1. You could have had a little bit of debate, do you radiate his prostate or not? We have the STAMPEDE data, but at this point, the STAMPEDE data about prostate radiation was really about using ADT alone. We did not have more recent data with ADT, Abiraterone, and prostate radiation. And so no radiation to the prostate here because he had used Abiraterone and at this time period didn't really have the data.

His PSA begins to go up, 0.2, 0.9, 1.9, and didn't have any symptoms, still feeling pretty good. And we get a PSMA PET scan and now this is what we see. By the way, that spot over the liver that you see is actually a rib, that is not a visceral lesion. What he's got is he's got some scattered rib lesions, a little bit of spine, some mediastinal adenopathy, retroperitoneal adenopathy. But this one is too much for SBRT. I don't think I can get my SBRT artist to come out and do all here. I'm going to do one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve. He's probably at 13, 14 nodes. So this is a different case, so what do we do now?

Rana McKay: Yeah, no, very excellent case. The first thing that I will say is serial PSMA PET imaging in the CRPC setting hasn't... I feel like it's going to be the new standard, but it's not totally been integrated across the spectrum for disease monitoring, disease assessment. Largely it's being utilized to assess candidacy for radioligand therapy or other clinical trials.

I think this patient clearly has a progression on his Abiraterone and probably, given the multifocality of his disease, both in the bones and in the lymph nodes, probably would favor docetaxel if I didn't have a clinical trial to put this individual on. There's a lot of cross-resistance going from Abi to Enza. In that order of Abi to Enza, there can be some responses that are observed with the subsequent ARSi, maybe PSA responses on the order of 20 to 30%, but probably leaning more towards chemotherapy in this setting.

Oliver Sartor: And again, protocols. So protocols can be through the BAT out, but we've talked about the BAT before. And then anything else. It's kind of interesting.

Rana, one of the things that I think is a real conundrum, and this is just me talking to you about it, and I'm interested in your opinion, so this is an asymptomatic patient. His PSA is now around 1.9. A lot of people will say, "I mean, do I really need to go on chemotherapy now?" And I think that one of the reasons the second-line hormones get used, even though, as you point out, and I agree with you by the way, the response rate to Enzalutamide here is probably 20 to 30%. But in practice, a lot of people get put on Enzalutamide because the patient is not ready to take the chemotherapy.

So you have one sort of option, docetaxel, which is going to be the standard of care, but the toxicity is often not necessarily what people want. But then you've got another option like Enzalutamide, where, quite frankly, the efficacy is not what you want. And it's reasonably well-tolerated, but the efficacy is not really there. So you've got one therapy that has too much toxicity, another therapy that doesn't have enough efficacy. It'd be nice to have something kind of in the middle, be both effective and non-toxic. And of course, that's why we do protocols, trying to figure out maybe we can do that?

And we presented a protocol result on the PSMAfore trial with lutetium. And it's interesting, we delayed progression but not FDA approved, and we're going to definitely be looking at this in more detail, longer follow-up. So that's a little bit interesting. But anyway, not sure if there are any other comments. I don't know if you'd agree with me on the docetaxel—

Rana McKay: No, I mean, I think—

Oliver Sartor: —Enzalutamide question.

Rana McKay: Yeah, I think there is... In our clinical practices, we all have individuals who are probably good candidates for that ARSi switch. Not everybody, but there are good candidates out there. When we look at the CARD data, it's a different patient population. I think these are docetaxel pre-treated individuals. They were required to have progressed on their ARSi within 12 months, so a different cohort of patients.

But we've all seen those individuals who've been on their Abi for many years and then they're starting to have some slow progression. And so thinking about, they're not yet ready for chemo, they haven't seen chemo, so insurance isn't going to approve them to get Pluvicto. And they've got some non-bone metastases, so they're not really great for radium. And you're kind of just, not to say buying time, but you kind of are.

So I think there can be a place certainly for individuals that have visceral metastasis, symptomatic disease, that's not really a way to go. But yeah, this is a very helpful, instructive case.

Oliver Sartor: All right. Well, I have one more slide, and it's complicated, but we'll go through it really fast. I called it clinical decision-making for metastatic CRPC. And I'm just going to hit a couple of highlights.

One of the things that is problematic in the entire world, and the United States is certainly a part of it, is the cost of therapy. And we have a lot of patients that just cannot afford to get the therapies, and sometimes that will actually dictate what you do. Now, there are a lot of programs, there's a lot of help, but nevertheless, if you can't afford to give the therapy, then the patient cannot receive it. And we have to be very sensitive to these financial issues because they're very important.

Now, not everybody with metastatic castrate-resistant prostate cancer is the same. I've got 97-year-old nursing home patients, and I've got 55-year-old marathon runners. And so age and comorbidities, performance status, make a big difference in how we choose our treatments. And laboratory assessments. If you're going to be giving chemotherapy, then you need to make sure that you have an adequate white count, adequate platelet count, otherwise, you might be putting the patient in danger. Symptoms, are they symptomatic or not, and if so, how much and where? Always remember that we can bring in external beam radiation in a palliative way and use it quite effectively.

And just saw a patient in the clinic the other day who's metastatic CRPC, and he was having some pretty substantial focal pain that we could treat with a quick course of external beam radiation and give him good palliation. So you got to think about that. Prior therapies, not just Abi, Enza, and taxanes, you need to consider the PARP inhibitors and more. I have to consider how long did they work. You mentioned the CARD trial, which requires that people progress on their hormones in less than 12 months. That's different than if they took 18 or 25 or 36 months to progress. Tolerance and intolerance from prior therapies have been taken into consideration.

The burden of disease. I showed you one guy with just two metastases, another guy with many more. So the burden of disease, the pace of disease, is it moving quickly, is it going slowly? Is it bone, is it pelvic lymph nodes, or is it liver? Visceral is not what we like to see. So this rapid progression in the liver patient is completely different from a slow progressor in a lymph node. Just two different spectrums there.

Systemic or focal progression. I presented a case where we had 15 new metastases, now I presented a case where we had two new metastases. Those are not the same. I didn't really go into a lot of different genotypes or phenotypes here; these are adenocarcinomas, their genomes were pretty well-behaved, so I didn't have any particular things like the PARP inhibitors to bring out. And image-based biomarkers, I did not talk about the use of PSMA lutetium, even though I potentially might in the future, because these patients are not really eligible to get PSMA lutetium today. They had not had prior chemotherapy.

Clinical trial options we talked about. Adverse event profiles always have to be considered. And then patient preferences. Some patients just say absolutely no to chemo, other patients say absolutely no to hormones. We somehow have to work with our patients in order to accommodate their preferences to the degree to which we can reasonably do so. So that's my clinical decision-making in CRPC in a nutshell.

Rana McKay: I absolutely love this slide, because I think it highlights the complexities that we, as clinicians, are processing whenever we're faced with a patient before us in the clinic, deciding just exactly what to do. When we look at the guidelines, there's like a laundry list of all these different options, and this is where the art of medicine comes into play. You've got the patient before you, what's happening with them clinically, what are their risk factors? Where's their disease? Are they symptomatic? What's going on with them from a psychosocial standpoint? Do they have trouble coming into the clinic? Do they have insurance?

So I think these are all the things that end up coloring just exactly what we do. And in some scenarios, you could have somebody with the same exact clinical phenotype, but you're going to select something different based on the patient's risk-benefit tolerance and their values. So I think this is really important. I think prior therapies are increasingly becoming important in strategizing what we do next. Our mCRPC therapies have entered into the mHSPC setting, and knowing what patients have received previously and in what kind of fashion is going to help drive what they get in the future and what they get at their next treatment fork in the road. So I think it's really important.

I'm so glad that you highlighted the issue around access because it's not just access to the treatment, I think it's access to all of these things. Do they have access to genetic testing, and that could open up a door for additional treatment options? Do they have access to PSMA PET imaging, which is now being used as the imaging biomarker for selection for radioligand therapy? So I think there's a lot of disparities across our healthcare system in the way care is delivered, and certainly inside the US and outside the US as well.

So I love this slide because I think it highlights the complex clinical decision-making that we need to factor in deciding what to do when for any given patient.

Oliver Sartor: Well, thanks, Rana. I do love the guidelines because I think they give us some guardrails, but at the same time, it's a bit of a laundry list, and you do have to make decisions with the patient in the room. And it's more than just a laundry list.

And I mentioned third from the bottom here, the availability of clinical trials. Yesterday I had a patient, and I spent literally an hour covering the variety of clinical trials that he could potentially be eligible for. And he was really interested in some of these novel therapies. And even though I could have talked about docetaxel for 30 minutes, I ended up talking about clinical trials for an hour, and I think he's going to go on a clinical trial.

Rana McKay: That's fantastic. That's awesome. I mean, I do think clinical trials are critically important. That's how we move the needle forward; that's how we help shape the future. I think of where we were a decade ago, and we were not... One, our treatment options have expanded, but we weren't treating mHSPC other than ADT alone; it was just like... And now I feel like it's so archaic for us to think about ADT alone for mHSPC. So I think it's good to see that our treatments continue to expand our patients are in fact living longer and living better, which is a very good thing.

Oliver Sartor: Absolutely. Well, I'm glad to be here, and it's fun to discuss. Thank you for your insights. Thank you for your discussion; it's certainly been a pleasure for me.

Rana McKay: Oh, thank you so much, Oliver. It's really great hearing from you. And for everybody watching, we hope that you found this beneficial and look for more in the series. Thank you.

Oliver Sartor: Thank you.