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Zach Klaassen: Hi. My name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We are live at the American Urological Association 2024 in San Antonio, Texas. I'm pleased to be joined today by Dr. Neal Shore, Carolina Urologic Research Center in Myrtle Beach, South Carolina. Neal, thanks so much for joining us again.

Neal Shore: My pleasure, Zach. Thanks.

Zach Klaassen: So today, we're going to talk about a really interesting topic. We've seen a lot of activity in non-metastatic CRPC in the last five or six years, but now we're seeing the installation of PSMA PET scans. So we're going to guide our discussion on what we do with these patients. So maybe by way of background, maybe start by just explaining for our listeners what exactly non-metastatic CRPC is.

Neal Shore: So when we did these three very important trials in nmCRPC, I think historically we called it M0 CRPC. When AUA did their six guidelines index cases, it was called M0 CRPC. Back in the day, we had nothing for it. That's almost antiquated. But most of us will say, "Let's call it non-metastatic castration-resistant prostate cancer." It's based on conventional historic imaging, which means a full-body CT scan with and without contrast and a technetium bone scan. So you fast forward to PSMA PET scans, which have turned everything upside down in terms of what some people call molecular-targeted imaging or next-generation imaging.

But the bottom line is three fabulous trials really changed everything with SPARTAN, PROSPER, and ARAMIS, respectively, looking at this nmCRPC group, negative conventional imaging, rising PSA castrate level of testosterone. So that, by definition, was our population in all three studies. Additionally, the patients had to have a doubling time of less than or equal to 10 months. Data clearly shows that north of that, it's a very slow biology and you're really much better off just observing those patients.

But looking at SPARTAN, PROSPER, ARAMIS, that led to the approval in nmCRPC of apalutamide, enzalutamide, and darolutamide, respectively.

Zach Klaassen: Right. I think... And you're right. 2018 when these papers came out, 2019, seems like ancient times now.

Right, and so we fast forward to 2024. Either these patients are now coming to us with a PSMA PET scan plus or minus negative conventional imaging, or they're asking for one. And if you look at... Fendler from Germany in 2021 did a study around 200 patients of basically index patients that would be involved in this trial, and 96% of these patients had a metastasis somewhere on PSMA PET imaging. So how do we explain this to patients? How do we say, "The drug works great. You have negative conventional imaging. You just happen to get this PSMA PET scan"? What are we going to do? How do we explain that to them?

Neal Shore: Yeah. Great paper, that Fendler paper.

Zach Klaassen: Yeah.

Neal Shore: My good friend, Boris Hadaschik, is the senior author on. I love that paper because to your point, they took countries that really didn't want to participate in SPARTAN, PROSPER, and ARAMIS because they had already had PSMA PET. It's an interesting storyline about how we have disparities in countries that have certain technologies, imaging. We lagged behind in the United States. We were ahead of them in a lot of accessibility to therapeutics, but it was clearly an area that we lagged behind.

And I always like to bring out the fact that our nuclear medicine radiology colleagues, they've really helped us, many of them in Europe and in the United States. So they're really moving us forward because it's not controversial to say that the PSMA PETs, whether it's a gallium tracer or an 18F, are just more sensitive. They're more accurate. There are some false positives, there are some false negatives, but they're just clearly more accurate than conventional imaging.

That said, so now you have nmCRPC. Your PSA is going up. Your T is suppressed. You've got to check the T, make sure the patient is getting adequate delivery, and you get a PSMA PET scan. In that paper, yeah, 98% had positive findings and 55% had positive findings above the pelvis. So there was node only, there was bone, there was even a small percentage that had visceral. So how do you think about that now, which is really a great question? And the answer is, number one, we don't have any trials prospectively that say anything is better than the AR pathway inhibitor drugs. Incidentally, at APCCC a week ago, we had a consensus agreement on that nomenclature that ARPI is the one that was heavily agreed upon.

Zach Klaassen: Thank goodness.

Neal Shore: Not ARTA, not NHA, not SGARI, or ARSS. So maybe we'll all start using that.

Zach Klaassen: That might be the most important thing that came out of the video, honestly.

Neal Shore: I know. Possibly. Other than it was a fabulous meeting.

Zach Klaassen: A fabulous meeting, yes.

Neal Shore: And hats off to Silke Gillessen and Aurelius Omlin.

Zach Klaassen: Absolutely.

Neal Shore: They do just amazing things. But I still think that... And I remember having this conversation with my good friend, Karim Fizazi about this. You know what? You're still probably, in the vast overwhelming majority of patients, going to offer them an ARPI, an apo, an enza, or a daro. Now, if you had somebody who had a lot of disease in the liver, small volume, would you offer docetaxel? Maybe. Maybe. But that's going to be a very small percentage. In the US, which is an interesting phenomenon, you now, because you have imaging positivity, technically some version of M1 asymptomatic, could now offer sipuleucel-T, which is limited to the United States, but I think that's an interesting opportunity. And the opportunity of even combining an ARPI with sipuleucel-T. We can debate costs, etc., but yeah.

Zach Klaassen: I want to be a little provocative here. So let's say you get a patient. You mentioned 55% really outside of the pelvis. If somebody comes to us with this image, we can't ignore it, right? They're theoretically nmCRPC, conventional imaging negative, but they have, let's say, two nodes or maybe a tiny bone lesion. Is there a threshold where you would say, "I see those, but I'm going to treat you like you didn't have the PSMA PET and I'm going to give you X, Y, or Z"? Or is there a threshold above that where you're going to say, "We really have to think of you as true mCRPC"?

Neal Shore: Yeah. Do we think about if it's really lighting up, what is the significance of the SUV, background liver effects? We debated on this. There was no consensus. Do you do metastasis-directed therapy for those patients and see what happens before invoking systemic therapy? We don't have level one evidence for that. I think these are really some of the studies that need to be done.

I think if I had to tell my colleagues who are listening right now, I'd say what we do have level one evidence on is that SPARTAN, PROSPER, and ARAMIS have taught us that these oral ARPIs are very effective. The safety and the tolerability are overall excellent, and you're not obviating any other treatments in the future.

Zach Klaassen: That's right. That's a good point. In terms of the three trials, you could almost line up the MFS and the OS curves. They're all very similar. Are there patient characteristics, whether it be doubling time, age, comorbidities, that may lead you to choose one versus the other when selecting these therapies?

Neal Shore: Yeah, that's a great question, and it goes across the entire spectrum where ARPIs are approved. The one that has the absolute broadest now, since the approval of the EMBARK data by the FDA, expanding their label for high-risk, biochemical relapsed patients, is enzalutamide. It's now approved in combination with ADT and as monotherapy for high-risk PCR but then, of course, with mHSPC and the full spectrum of mCRPC. Apalutamide is approved for mHSPC and for mCRPC. Darolutamide is approved for mCRPC and mHSPC in combination with docetaxel. We're going to have a readout on a large global trial looking at ADT and daro versus ADT mono. Globally, that'll read out.

And we have a large study of model therapy, 200 patients, of ADT and daro, the ARASEC study. Eventually, we'll have a broadening for the daro label. I think there are differences in the adverse event profiles. Some have some rash considerations. Some have more in terms of cognitive issues. Some may have some differences in cardiovascular.

BID versus QD. Assuming that accessibility is there and cost is the same, there may be some differences in drug-drug interaction. But we have an embarrassment of riches, as they say. I think it's a good thing to have. I think our colleagues who use these drugs should be aware of the different pros and cons and then have that full-throated discussion with the patient.

Zach Klaassen: Excellent. One last question before we summarize. In terms of the timing of treating these patients, you mentioned a PSA doubling time. And that's obviously one thing I use in the clinic too. If it's less than 12 months, typically that's a candidate versus maybe more than 12, you think about it. Does a PSMA PET change that thought process about the timing of treating these patients?

Neal Shore: Yeah, I think for me, no. I think the PSA doubling time... And I use 12 months too.

Zach Klaassen: It's a great marker.

Neal Shore: It's a great marker. It gives you a lot of information regarding the phenotypic biology. I'm not going to treat a patient particularly differently based upon the PSMA PET finding, especially with a PSA doubling time north of 12 months.

Zach Klaassen: Yep. That's excellent. Great conversation as always. Any other take-home messages, maybe something that folks can take to their clinic on Monday?

Neal Shore: Oh, I think that the ARPIs are wonderful oral medications. Abiraterone acetate with prednisone or methylprednisolone, not approved in nmCRPC, but is approved in mHSPC and in high-risk localized disease a la PEACE-1, as is enzalutamide now also in that same population. So I think it's important for all of our patients and our colleagues to recognize that the role for monotherapy ADT across the spectrum is essentially non-existent at this point. Can ARPI ultimately become the backbone, as we always typically say, ADT is the mainstay backbone?

I think there's an ongoing conversation and discussion about that. All of our level one evidence has been based upon ADT and combinations. Now, we recognize that ADT mono is essentially relegated to somewhat of a historical purpose.
So, look, if we can get rid of T suppression at some point and the associated toxicities, that's a good thing.

Zach Klaassen: Absolutely. And you mentioned there's a lot of data coming down the pipeline, I'm sure. ESMO and ASCO coming up as well. So as always, this disease space is moving quickly, and it's always great having you on to talk about it.

Neal Shore: Thanks very much.