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Zach Klaassen: Hi, my name is Dr. Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center and a guest of Georgia. And I'm joined today for a UroToday discussion with Dr. Hanan Goldberg, who is an assistant professor and urologic oncologist at SUNY Upstate in Syracuse, New York. Hanan, thanks so much for joining us.

Hanan Goldberg: Thanks so much for having me. It's a real pleasure being here. Thank you.

Zach Klaassen: Fantastic. So, we are going to talk about nonmetastatic CRPC, and certainly, this has been a disease space over the last four or five years, which has morphed into three great clinical trials, the advent of PSMA PET coming in, and so we're excited to get your thoughts on some of these topics. But just off the top, as a urologist, how commonly are you seeing this? How frequently are these patients coming to your clinic?

Hanan Goldberg: Yeah. So, I think before the introduction of the new novel PET PSMA scans, I think this was a much more common scenario that we would see as urologic oncologists. But to be completely fair, this is a decreasing space. Because at least in my practice, and I know other practices similar to mine, PET PSMA is the first test that is being ordered for these.

For anyone who is high-risk prostate cancer, especially if he's metastatic prostate cancer, of course, that's the first imaging test he will get. And all these great three trials that you mentioned, the PROSPER, the SPARTAN, and the ARAMIS, they all used conventional imaging, which really, we don't really do that today. So, this space is diminishing significantly. So, we see less and less of these patients.

Zach Klaassen: Yeah. Absolutely. And so, let's talk about those three trials, and you're right, they were accruing between roughly 2015 to 2018 with conventional imaging as you mentioned. We know the drug works in these patients. You're at an academic center, I'm at an academic center; most patients will come to us with imaging already. How do we rationalize what would've been a perfect nmCRPC patient that now has a couple of very small areas, which are probably picked up on PSMA PET, but never would've been picked up on conventional imaging? How do you treat these patients? What's your thought process there?

Hanan Goldberg: Yeah, so it's a little bit of a double-edged sword because we are seeing a significant intensification of treatment for prostate cancer in general. We're giving all these medications that used to be given later on, we're giving them much earlier now. We're giving in hormone-sensitive. We're doing triplet therapy now. Biochemical recurrence. We have the EMBARK trial. We're giving these medications very early. And when we look at these three medications, enzalutamide, apalutamide, and darolutamide, so two of them, apalutamide and darolutamide, are actually not approved yet for metastatic CRPC. They haven't been tested in that setting yet.

So, we want to give it earlier. And if we use PET-PSMA and find some metastatic disease, they're already metastatic CRPC and we don't have any FDA approval to give it to these patients. So, it's a dilemma about what to do. But when we do have these patients, we try to give one of these three medications. They all work great. The trials were fantastic, all of them with very similar hazard ratios for MFS and overall survival. There are small nuances between the medications that we can talk about later on if we want, but the general idea is to hit them hard and hit them with everything we have. The earlier, the better. I think that's where the world is going.

Zach Klaassen: That's a great point. And so, you're right, these patients have been on ADT. If you look at the trials, they've had prostate cancer for roughly a median of seven years. So, they've been on ADT for a long time. Their quality of life is good. How do you look at performance status when you see these patients? So, let's say there's an 85-year-old with an ECOG of two, but there's a 57-year-old with an ECOG of zero. Does that play into whether you're going to treat and what kind of treatment you're going to give?

Hanan Goldberg: Yeah. That is an excellent question and one that we battle every day in our clinic. And I can say, when you look at these trials, if I remember correctly, all of them had ECOG zero one. So, they looked at patients with pretty good performance status. And I think, thankfully, that's the majority of patients that we do see. And I've got to be honest, all three drugs, they're really well tolerated, at least from what we know from studies published and from our own clinical experience. Patients do really well with these medications. So, we do try to give it, even to those patients who are a little bit sicker, maybe with performance status a bit worse. We do try to monitor.

It's important when we look at these three medications, the important distinction is with darolutamide chemically, it looks different. It's built differently than enzalutamide and apalutamide. There's also some preclinical data showing it doesn't cross the blood-brain barrier. So, that has an effect on the side effects, cognitive decline, mental impairment, seizures, and things like that. So, that is probably my go-to drug in those older, sicker patients who have some issues with cognitive decline. Then, I probably would prefer to give that drug. That's probably the only distinction I would make with patients whose performance status is a bit worse and who are a little bit older, to your question.

Zach Klaassen: For sure. And I think, as you mentioned, the efficacy among these three is basically the same, hazard ratios for MFS, OS. Other than performance status, are there any other aspects of either the clinical trial data or your clinical experience that would maybe lead you to treat a population with X, Y, or Z?

Hanan Goldberg: Yeah. So, from what we know from the data, people who have issues with seizures, I would tend to less give them enzalutamide, probably more darolutamide again because of that blood-brain barrier issue. Also, there's an issue with thyroid hypothyroidism and adverse effects with that, that we've seen with enzalutamide and a little bit with apalutamide, and I think much less with darolutamide. So, whenever we have patients who have known issues with seizures or thyroid issues, again, probably darolutamide would be the drug of choice. But other than that, all three are very well tolerated and well taken.

Zach Klaassen: Yep, absolutely. We see these patients as urologists. Maybe we take their prostate out or we radiate them, and we treat them with ADT, and then they become nmCRPC. Is this really a urology space? Do you think we're sharing this with medical oncology? Should we be sharing this with medical oncology? How do you look at this, even though it is a shrinking space, is it something that urologists should be comfortable with, and that we are pretty much seeing the majority of these patients?

Hanan Goldberg: Yeah, that's a great question. And I think it really depends on your level of comfort and where you trained and what experience you have. I think you and I, we both trained at the same place, and we were very hands-on with what we can do. And we were very much involved in treating the advanced prostate cancer patients. We also have advanced prostate cancer clinics. So, I feel very comfortable with my colleagues as urologists treating them. We do have a very good relationship with our medical oncologist colleagues, and of course, we have a multidisciplinary tumor board where we discuss these patients.

But really, the majority of these patients, I think the urologist should be leading this. Of course, I'm biased, so that's clear. But I do think the urologist has a very important role here. And I really think the only time that I really hand it off to the oncologist is when I'm giving chemotherapy, let's say for mHSPC, triplet therapy. So they are the ones administering. But I know it's not the same everywhere. And I know some urologists prefer to give this more to their medical oncologists. So, I do think it varies. It depends. As long as there's a multidisciplinary team, I think discussing these patients on a regular basis, then it's less critical as long as the patient gets the right treatment. Me personally, I do think the urologist, urologic oncologist should take the front lead here and guide this patient.

Zach Klaassen: Yeah, great answer. I think you hit on a couple of good points. Your comfort level has to be there and obviously multidisciplinary because at some point we're all going to be involved, whether it's geneticists, radiation oncology, urology, medical oncology. So.

Hanan Goldberg: Absolutely.

Zach Klaassen: It's been a great discussion. Anything we haven't hit on you want to discuss? Maybe a couple of take-home messages for our listeners as well?

Hanan Goldberg: Yeah. First of all, I think it's a great discussion. Great topic. I think it's important to mention, we didn't really touch a lot on that, but we see as an academic center... I'm sure you as well, referrals from other places, other oncologists, urologists, and it's a huge ongoing problem that we talk about in meetings about, unfortunately, the lack of implementation of guidelines that we see by a lot of the community medicine.

And I see that on a regular basis, as I'm sure you do too. And I think the education part here is really important. So, I think we need to get this to the community: the dual therapy for metastatic hormone-sensitive, and of course, this therapy available for nonmetastatic CRPC, and know that there are other options available and not just ADT. I think that's one of the key take-home messages.

And the last one, I would say, is very important. It doesn't happen a lot, but there are a lot of things that sometimes you can see, like neuroendocrine differentiation and differentiation of the disease itself with time. So, even if the PSA is undetectable, I think it's critical to do imaging on a regular basis like the NCCN Guidelines recommend. 'Cause sometimes you see some surprises. The PSA stays very low, but the disease keeps on spreading because it's mutated, and there are different mechanisms at work here. So, I would say remember to do those images on a regular basis and education to the community.

Zach Klaassen: Yeah, that's a fantastic answer. And you're absolutely right. That's the beauty of these discussions that we're having, and the UroToday platform in general is all about educating. So, Hanan, thanks so much for your time. Always great catching up and appreciate your time and expertise today.

Hanan Goldberg: Perfect. Thank you so much. Thanks for having me.