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Zach Klaassen: Hi, I'm Dr. Zach Klaassen, the urologic oncologist at the Georgia Cancer Center in Augusta, Georgia, and I'm pleased to be joined today for a UroToday discussion with Dr. Aaron Berger, who is a urologist at Associated Urological Specialists in Chicago, Illinois. Dr. Berger, thanks so much for joining us today.

Aaron Berger: Thanks for having me. Looking forward to the discussion.

Zach Klaassen: So we're going to focus on non-metastatic CRPC, and as a urologist, certainly, this is an interesting disease space. How often are you seeing non-metastatic CRPC in your practice?

Aaron Berger: It's definitely decreasing. I think that's probably true for all of us that treat a lot of prostate cancer, whether it's recurrent, metastatic, whatever, in our advanced prostate cancer clinic it's definitely been on the decline over the last couple of years, and that's really gone hand in hand with the increasing use of advanced imaging, PET scans, specifically PSMA PET scans, which have really been game changers as far as determining if patients truly have metastatic disease. I think a lot of the patients historically that we were treating as, quote-unquote, non-metastatic CRPC, if they had those types of scans available previously probably would have actually been metastatic. So, just looking at our numbers over 2022 and 2023, the new consults I saw for non-metastatic CRPC that were actually scanned and verified as non-metastatic was right around 8%. So it's definitely the bulk of it is now becoming the metastatic castrate-sensitive patients that are taking up most of our new consults.

Zach Klaassen: It's a good point. It leads me into my next question. So we know, just by way of background for the listeners, the three key studies of the ASRIs in this disease space all roughly around 2015 to 2018 accrual. So pre-PSMA PET, and in fact, the inclusion criteria were negative conventional imaging. So as you mentioned, how do we rationalize this, and when we see these patients, are you ordering PSMA PETs if they haven't had one? And we know from Fendler's study in 2021, 96% of these patients will have some lesion on their PSMA PET, patients that would have been candidates for this trial. So how are you operationalizing when you see these patients? Are they all getting PETs, are you treating them based on negative conventional imaging?

Aaron Berger: It's a great question, and I think it is a bit of a conundrum about what to do because clearly, the three medications from the trials you mentioned are all great drugs, they do a great job, and most of them have multiple indications even for metastatic disease. So the issue becomes if you do a scan and it does show metastatic disease, you may be eliminating a couple of those choices just because of FDA indications. And if the insurance provider or the PBM is astute enough to go through your chart and say, "Oh, this patient does have metastatic disease, why are you ordering drug X when it's not approved for metastatic disease?" Even though we know that it's going to work because it works for metastatic disease in the hormone-sensitive space, so why would it not work?

So it's really just an indication and labeling problem. What we've been doing a bit, and certainly in other parts of the country, the PSMA PET scans have been more of a challenge of getting coverage for PSMA PET scans. Talking to my colleagues around the country, I don't know how it is in Georgia, but some people do have a difficult time in a lot of cases. Illinois, for whatever reason, has been relatively easy. And I think what I've actually been doing now is having my partners who refer me patients actually not order the PET scan and let me see them and counsel them first.

Obviously, it's always good to have more information, but in this particular case, I think when you're potentially eliminating one or two potential drug options for a patient, especially if they have other comorbidities, if they're on other medications that may interact with one drug better than another, or if they have other medical history that may say, "I want to use this drug versus this drug," that may take it away from you if you scan them and it shows metastasis. So certainly having the information, finding out if they're truly metastatic is never a bad thing, but in this case, it may actually limit your choices. So I'm at least discussing it with the patients first and going over the pros and cons of getting a scan.

Zach Klaassen: Great answer. I think when you're thinking about patient selection, whether you're treating or not treating, or whether you're selecting an agent, how closely are you looking at, say, PSA doubling time? Obviously, these trials had a PSA doubling time of less than 10 months for inclusion. How closely are you looking at performance status when you're selecting whether you're going to treat them, what you're going to use?

Aaron Berger: Yeah, I think it's multifactorial. Certainly, the three trials all had the same inclusion criteria with doubling times of 10 months or less, that's not what the FDA has in their label, so you certainly can use it. If it's 11 months, it doesn't mean they can't get one of these drugs. But certainly, if you've got an especially older patient or really any patient whose PSA doubling time is 18 months, two years, three years, whatever, yes, you could order it, but really what are you accomplishing there? That's a patient that very well may just be better off remaining on ADT monotherapy or potentially even discussing intermittent therapy or other options given the potential long-term toxicities of ADT that keep coming out as more research is done.

So certainly PSA doubling time is a factor, as are age, performance status, and just how aggressive patients want to be. Other medications and polypharmacy are always a concern. Financial toxicity is always a concern, although somewhat that's getting a little bit better at least with some of the legislative changes this year and moving into the next year with the Inflation Reduction Act and things of that nature. So getting medications that we want to provide will hopefully be a little bit easier. But obviously, if you've got an 80-year-old guy with a doubling time of 24 months, probably someone could certainly have the discussion, but I would certainly opt to observe that patient like that.

Zach Klaassen: Great insight. So going back to those three trials, if you look at MFS OS, it's all very similar. Are there nuances to the trial data or even the side effect profile of these medications that help you when selecting therapy?

Aaron Berger: I think the trials are very similar. Obviously, comparing hazard ratios is hazardous, but as far as the patient populations and outcomes, overall survival data, they all have it; they're very similar, and obviously, the mechanism of action of all these drugs is pretty much the same. So I think it again goes back to the patient and what they can tolerate. Certainly, patients that take a lot of other pills—a couple of these options now are one pill a day or two pills a day versus four pills a day—so that may make a difference. Patients that have difficulty swallowing pills, one of them can now be dissolved in non-carbonated beverages, which may be an option for them. And certainly their medical history; patients who have cognitive issues, I think that one of the medications does have some preclinical data that would suggest that it may have fewer cognitive side effects.

But I think all these things are well tolerated. I'm sure your experience is similar to mine; that for the most part, all three of the drugs in this space are very well tolerated and work very well. But if you do have a patient who has cognitive issues, dementia, things of that nature, then if there is some data from the trial that may suggest less blood-brain barrier impact, that may be a better choice. And then certainly there are drug-drug interactions. If there are certain drugs that they're on that may interact better with one than the other, that certainly plays a role as well. So all those factors go in there, but it's great to have options.

I think these are all fantastic drugs. They all do a great job. I think for the most part they're very well tolerated. Most people come in and say, "Oh, I'm having hot flashes from this." I'm like, "No, it's probably not from that; it's probably from the hormone therapy you're on. This is not really adding much to that." Obviously, each can have some various other side effects, but I think in general they're very well tolerated for the profound impact they have in terms of both progression-free survival, metastasis-free survival, and overall survival.

Zach Klaassen: Yeah, absolutely. So these are typically patients we've had in our practice for years. Maybe we did a prostatectomy on them or we treated them with radiation, and they've been on ADT for usually a median of five to seven years, depending on which trial you're looking at, so we know these patients well. Are these patients that, in your practice, you're sharing with medical oncology? Are you keeping them usually until they progress? How is it operationalized in terms of treatment and referral basis?

Aaron Berger: In this space and the non-metastatic space, or at least those we think are non-metastatic, personally, those are patients that I'm typically managing myself. Certainly, there's more than one way to do it. I think it really depends on your location, whether you're in academia, which is pretty much medical oncology-focused for these patients versus in a large private practice setting where a lot of it is maintained by the urologists, and there are certainly reasons for that potentially in a private practice setting on the business side of things. But I think as long as patients are seeing someone who knows the differences between the drugs, knows the data, knows the different drug interactions, and what drug is appropriate, I certainly think that this is something that can very well be handled by urologists. I think since these drugs are pretty well tolerated, I think this is actually one of those things that probably can be handled by even an APP.

This is not super high-level advanced prostate cancer. We're not talking about PARP inhibition or chemotherapy or things like that. These are pretty well-tolerated drugs. They've been around for several years. I think people understand how they work, what the potential side effects are. There's not a ton of extra monitoring you have to do. A lot of the side effects are not going to be life-threatening; you're not going to have severe anemias or things like that from these medications. So I think this is certainly something that most urologists who are interested in prostate cancer could be comfortable with. I'm a big believer that all these patients with recurrent, advanced, castrate-resistant prostate cancer really should be seen by some sort of prostate cancer champion. It's just that there are so many new drugs and so many new treatments available in the last several years, it really is important to understand the options and what you're dealing with, and whether or not to scan them and all the factors that go into that, but I think as far as this particular space, this is definitely not one of the more challenging areas that we deal with.

Zach Klaassen: Great answer. And I think you said something I want to just touch on briefly is once these patients are rolling, once they've been started on their ASRI and they're really being checked, say, every three months for PSAs, once they get rolling, the APPs can really handle a lot of these patients, and I think it's a great opportunity to utilize those resources. Would you agree?

Aaron Berger: Oh, 100%. I think those of us that do a lot of this, we're getting... Again, it goes back to the imaging. So many of our newly diagnosed, more high-risk patients that are getting PET scans are found to have metastatic disease, which many of them, if you're in a place that requires conventional imaging first before a PET, a lot of those patients are negative. You get the PET, now there's multiple areas of metastasis. So I think at most places, the numbers of metastatic newly diagnosed patients have gone up substantially, and those are complicated patients. You need to have long discussions with them. So handing off some of these patients with non-metastatic CRPC who are cruising along, doing great on their medications, you check on their side effects, you check their labs, I normally see them every three months.

But certainly, the APPs, again, who have an interest in advanced prostate cancer, certainly can take this burden off of the physicians, and then they can focus on metastatic hormone-sensitive patients, metastatic castrate-resistant patients where really that's when you're getting into the options that definitely can have more toxicities and require more of a conversation.

Zach Klaassen: That's great. It's been a fantastic discussion. How about a summary statement or two, maybe some take-home messages for our listeners today?

Aaron Berger: I think it's great to have options. Obviously, we've had a lot of explosions in new treatments in the past 10 years in prostate cancer, so it's exciting to be a part of the ongoing treatment paradigms and learning about what's new and what's next. And as far as non-metastatic CRPC, for those patients who truly have it, we have some great options. I think really the biggest dilemma, as we touched on earlier, is looking for metastasis, because we now have a great tool in PSMA PET scans to find very, very small metastases, and then it's just a question of whether it is best for the patient to treat them as non-metastatic or do you treat them as metastatic? And then that obviously gives you options for other things like immunotherapies or radiopharmaceuticals, things of that nature. But if their PSAs are relatively low and they're otherwise doing very well from a performance status standpoint, do you want to go down that path or do you want to just get them on well-tolerated oral medications that we're all pretty comfortable with prescribing and following patients with this disease?

Zach Klaassen: Outstanding. Thanks so much for your time, Dr. Berger. We really appreciate it. And thanks for sharing your insights on UroToday.

Aaron Berger: Thank you very much.