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Zach Klaassen: Hello, my name is Dr. Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. And I'm pleased to be joined today for this UroToday discussion with Dr. Vahan Kassabian of Advanced Urology in Atlanta, Georgia. Vahan, thanks so much for joining us again today.

Vahan Kassabian: Thank you so much, Dr. Klaassen, for having me.

Zach Klaassen: So, we're going to talk about nonmetastatic CRPC today. And just off the top, it's an interesting disease space, and how frequently are you seeing this in your clinic?

Vahan Kassabian: Yeah, it's a great question. We're seeing it less and less frequently, simply because we perform a lot of novel imaging techniques with PET scans. So, a lot of the trials in the nonmetastatic CRPC space, as you know, in fact, all of them were done with traditional imaging, CT scan, and a bone scan.

So, you'll find some, and because we use a lot of novel imaging, that space has shrunk quite a bit. We'll still see it sometimes, but it's not as common as it once was.

Zach Klaassen: Yeah, you're absolutely right. The three key trials that were published about 2018, 2019, all were conventional imaging negative. And you're absolutely right, since then we've seen an explosion in PSMA PET over the last four or five years. It's a conversation we have in the clinic all the time. I mean, they come in, they're basically definition-perfect nonmetastatic CRPC, but they've had a PSMA PET. They've maybe got one small lesion in the retroperitoneal nodes, maybe a tiny bone lesion.

How do you handle those patients? Because my philosophy is, I still think the drug works in those indications because they were conventional imaging negative. How do you handle those conversations with your patients?

Vahan Kassabian: Yeah, that's a great question. First of all, all these nonmetastatic CRPC patients are asymptomatic, so that's an important point.

Zach Klaassen: Absolutely.

Vahan Kassabian: And patients are like, "Well, why do you want to do this imaging? Why do you want to put me on medication when I feel fine?" I've been practicing long enough where before we had any of this, your PSA would be rising on ADT and you have nothing to offer these patients. You sort of tap them on the back, "You're feeling fine. See you in six months."

Well, now the whole landscape has changed. Since 2010, we've had a tremendous amount of progress in therapies for both CRPC and castration-sensitive prostate cancer. So now we want to find these patients and we want to put them on as many therapies and sequence them or layer them. There's a whole mental shift that we, as urologists, took from 15 years ago, 10 years ago even.

Having said that, you have to look the patient in the eye and say, "Okay, do I want to just get a bone scan, CT scan? Do I want to put this guy on therapy? Or do I really want to look for mets? Am I concerned about something? Does he maybe have visceral mets? What's his family history? What are his comorbidities like?" So, it's not one answer for every single patient.

But getting back to the therapies available in the nonmetastatic space. So, we are taking an asymptomatic patient who has nonmetastatic disease, at least on traditional imaging and hopefully on a fancier PET scan, and then it comes down to PSA kinetics doubling time. If this is a rapid doubling time, I try to encourage the patient to go on therapy.

There are potential side effects to these medications, so it's an important topic of conversation. You take an asymptomatic man with a rising PSA, no evidence of metastatic disease, and now you put them on potential therapy, and you have a few choices. "Do I treat, which AR do I choose," all these questions come into play. And it's not a one-recipe-fits-all; it's really a nice conversation with the patients.

Zach Klaassen: Yeah, absolutely. And you dovetailed nicely into my next question. You mentioned PSA doubling time. We know that the inclusion criteria for the most part in these three trials was PSA doubling time less than 10 months. So, how important, when you're looking at a patient, is performance status, zero to two ECOG, let's say, how do you factor that in? And do you follow that PSA doubling time cutoff of less than 10, or is it a little bit more generic than that?

Vahan Kassabian: Yeah, I think the PSA cutoff is helpful. I mean, the point is rapid PSA kinetics; that's the important notion here. Whether it's eight months or 12 months, I don't think it makes that much difference. I don't necessarily look, "If your PSA doubling time is 11 months, I'm not going to offer this to you." I don't think that's the right answer.

We, who treat this disease on a regular basis, want to treat the disease. We have guidelines in terms of PSA kinetics, what those cutoffs should be. And if you look at the nonmetastatic CRPC space, it's actually a regulatory bucket, it's not a disease bucket. We, as urologists, have known that any patient with a rising PSA, whether it's biochemical relapse after primary therapy or on ADT, has something somewhere; we don't know the extent, we don't know exactly where it is, but these guidelines and these buckets help us differentiate who we should treat and who we perhaps should consider observation on.

Zach Klaassen: Yep. Well said. But going back to these three trials, we have three agents. If you look at these agents, it's remarkable how the MFS curves, the OS curves, all show benefit. They're almost overlapping curves for the most part.

Vahan Kassabian: Correct.

Zach Klaassen: So, when we get in the weeds a little bit, is there specific characteristics of an agent or the data that you're looking for when you're deciding what to put patients on?

Vahan Kassabian: Yep. I think in this bucket, in the nonmetastatic CRPC patient who is asymptomatic, I think we want to choose something that has the least potential side effects. We look at comorbidities, we look at the drugs that the patients are on, are there potential drug-to-drug interactions? Which one am I going to pick? Obviously, all three drugs have not been studied head to head, but we get an idea of which one perhaps is better tolerated, but it may be a b.i.d. dosing rather than a Q daily dosing.

So, all these factors play in the decision-making process. And sometimes it's the insurance company that decides for us which of the three drugs we have to start with and take it from there. But I try to choose the one that I think is going to have the least side effects on that particular patient because they are asymptomatic.

Zach Klaassen: Absolutely. When we look at urologists, and I know you and I are preaching to the choir here in terms of liking to manage advanced prostate cancer, are these patients generally from a urology community that we should hang on to, that we treat? Are we seeing that we should get medical oncology involved? We obviously work very closely with medical oncology and certainly, there are disease spaces of prostate cancer where they're crucial, but what's your take on the delineation of care for M0CRPC?

Vahan Kassabian: Yeah, I think we like to see these patients. We've diagnosed them, we've treated them with local therapy. They progress, we put them on ADT. And it's just nice to continue to take care of them. And we're very comfortable in a large urology group, especially folks like me and you, to take care of these patients.

We pretty much do all the therapies. We offer everything except for chemotherapy. That's the only agent that we don't currently offer in our paradigm. So I love my medical oncology colleagues, I use them on a regular basis, but for the nonmetastatic CRPC, I don't see any reason to involve them. Now, if the patient says, "I'd like an opinion from an oncologist," absolutely, I refer them, and I even offer it to them upfront. But I tell them, "This is something that's easily manageable." And like you, they've been in our office and we've managed them for years, we've had them progress from diagnosis to nmCRPC.

Zach Klaassen: Yeah. And the nice thing is too, when these drugs work, they're still happy with us. It's a nice three-month visit. They like coming in. It's more of a social visit than anything, and they're fun to have in the practice, aren't they?

Vahan Kassabian: They are, they are, because they do well.

Zach Klaassen: They do well. Great conversation as always, Vahan. Is there anything we haven't hit on, any take-home messages for our UroToday listeners?

Vahan Kassabian: No. Again, be familiar with what's out there. The urologists in general in the US tend to be elderly and not so much in tune with all these nuances of all these therapies. And there's usually some champion within a group, a urology group, that has a passion and an understanding of this. And if they're uncomfortable, just refer them internally, would be my recommendation to everybody.

Zach Klaassen: Great points. Dr. Kassabian, thank you as always for your time and during your busy day. We appreciate it, and thank you so much.

Vahan Kassabian: Thank you, Dr. Klaassen.