Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Maha Hussain, who's a medical oncologist at Northwestern University in Chicago, Illinois. Maha, thanks for joining us on UroToday today to discuss your ASCO work.

Maha Hussain: Thank you very much, and it's my pleasure.

Zachary Klaassen: So we're going to discuss an abstract you guys presented this weekend looking at the clinical, environmental, genetic, and genomic profiles of patients that rapidly progress to mCRPC. And so when we look at this from just a high-level background, we know we have lots of options for treatment intensification for metastatic hormone-sensitive prostate cancer. But there are those that will rapidly progress to mCRPC. So maybe just tell us what we know or what we don't know about these patients, and why you guys looked at this in the study.

Maha Hussain: So thank you very much, Dr. Klaassen. And this is the-- really, what prompted this project-- this project has two parts to it. What prompted it, I started my observation from my clinics maybe over 10 years ago when I began seeing two sets of cases. One is younger men presenting with very aggressive disease that's already metastasized as de novo metastatic disease, or literally, they had radiation or surgery-- radical prostatectomy for their disease. In a very short period of time, they progressed to metastatic disease.

But the other group is-- I began seeing them, who basically would have seen a doublet treatment with the more newer AR inhibitors or doublet with chemotherapy, docetaxel. And as you know, these both sets of combinations have been very potent. And we began doing the triplet again early, with the trials going on. And sadly, again, in a short period of time, they started to progress to castration-resistant disease.

So I wrote essentially an application. And basically, this was a Prostate Cancer Foundation supported work. Two cohorts-- the one cohort, the ones that developed advanced disease at young age or progressed to metastatic disease, we presented it last year. At this ASCO, we submitted the abstract, and it should be published, the abstract, basically looking at this cohort of patients.

Now, one thing to clarify, basically that the group is a small group. And really, it's driven by different reasons. But the bottom line is basically we recruited 22 men who had metastatic castration prostate cancer, progressed to metastatic disease, and then progressed to castration-resistant disease in a relatively speaking short period of time.

And interestingly, when you look at the patients' characteristics, which is in the abstract, as you can see, it's a very aggressive group of patients with aggressive disease. Essentially, 55% of them had Gleason score 9 or 10, which, as you know, is very aggressive. 73% had de novo metastatic disease that was high-volume disease at the time, when they developed metastatic disease de novo.

And so essentially, these are a group of men that have seen essentially chemotherapy with ADT and chemotherapy or AR inhibitor. And fascinating also, because I wanted to know if, in fact, somehow exposure to different poisons, if they were in the military, as it turned out, that only about 9% of these patients had served in the military. So this is really what prompted this whole thing.

The number one strong factor that we saw is that the majority of the patients reported-- literally, over 80% reported family history of cancer. Yeah. And breast and colon were the different family history of cancer. And somewhere about 27% of them had family history of prostate cancer.

Zachary Klaassen: I see. And talk a little bit about-- you did some genomic analysis, I think, too with this. Just go over some of those highlights because that's really where we're probably going to start to identify these patients is through those analyses, isn't it?

Maha Hussain: Yes. So interestingly, again, the testing that we did was both germline and somatic. And the germline mutations were found in only about 10% of the patients, roughly. And more common usually were BRCA and ATM. But again, the numbers are very small.

The most common, what I would call clinically significant somatic mutations, were, again, pathways that we don't really have great targeted drugs. TP53 was actually 42% of the patients. PTEN or RB2 in like 16%. And NY-ESO-1 was in 21%.

Now, there was also other co-occurring mutations in between these two groups of patients. Again, these sets of genes are still like-- aside from the BRCA genes, there is not-- or ATM-- we don't really have targeted treatments there.

Now, when it comes to somatic mutation, the most common were TP53, PTEN, and TTN, and RB3 and NY-ESO-1. So again, none of these things we have targetable-- agents that target them at this point. And the question is why?

Zachary Klaassen: Yeah. It's great-- it's almost hypothesis generating data to see we have environmental, clinical, genomic, genetic. Let's take it a step back and say, OK, you see these patients in your clinic. From your vast experience, with what we know from this study, when are you starting to get worried about a patient? And when you are getting worried, how do you maybe change follow-up? Is there a different trigger to change treatment? How do you manage these patients?

Maha Hussain: So I think the first thing is when you're seeing a patient, whether they're de novo metastatic hormone-sensitive or metachronous, whatever it was, I generally monitor them very closely in the first few years. And I have my own strategy. There aren't really any specific guidelines based on level 1 evidence as such. But I would say the first couple of years I monitor them with visits, labs, and imaging. The imaging, I would do it every three to four months just to verify what's going on in there.

Some of these patients actually, surprisingly, you begin to see the PSA beginning to gradually go up. So with these cases, I actually have them repeat the PSA at a sooner interval, maybe a month after. Of course, checking the testosterone to make sure it's adequately suppressed because a lot of these patients are either getting relugolix or LHRH injections, and then monitor closely. And then obviously, imaging at a sooner interval.

The issue comes up sometimes, as you know-- again, I'm sure you see this situation-- is that there are times where the PSA is going up, but the scans are stable. And this is where you have to balance risk and benefit of switching treatment.

Zachary Klaassen: Yeah. No, it's a great point. I think the work that you're doing here, I think-- I like the fact you look at environmental because there is some aspect of that. I looked at Agent Orange was looked at in your study.

Maha Hussain: Right. Yeah.

Zachary Klaassen: So a great discussion. Anything we haven't hit on that you want to talk about, maybe a concluding statement or two?

Maha Hussain: No. I think, again, ultimately, there is what I call what we know, and there's a lot we don't know. And I do think these kinds of observations are going to be important for us to delve deeper into it. And as you can imagine, as the disease is evolving, the biology is becoming important.

When I was in training, basically there was mitoxantrone and ADT for castration-resistant disease. That was it. And then you got-- Casodex came in, and flutamide and bicalutamide and so on. Now we've moved into a different space. And I do think the cancer evolves. And I do think understanding the molecular biology of it and observation--

Ultimately, I would say my dream is we have a combination, like BEP for testis cancer, to basically give it uniform to everybody, cure the majority, and get done with it. But I do think there's a lot of research going on that is important.

Zachary Klaassen: Well, I think you hit on it during your presentation as well. There's a whole subset of genes that aren't targetable yet. Hopefully, they are someday. Maybe they're part of the equation. But really enjoyed, as always, talking with you on UroToday today, Maha. Thank you so much.

Maha Hussain: Thank you so much, Zach. Much appreciated. Thank you.