Zachary Klaassen: Hello, my name is Zach Klaassen for UroToday. I'm a urological oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined by Dr. Emmanuel Antonarakis, who is a Professor of Medicine, Medical Oncologist at the University of Minnesota. Today, we're going to get Dr. Antonarakis's take on advanced prostate cancer, what's been impactful over the last several years, and what's important to him going forward. So, Emmanuel, as always, thanks for your time on UroToday.

Emmanuel Antonarakis: Thanks so much.

Zachary Klaassen: So, the last five years of prostate cancer really in, as we say, prostate cancer year is like 50 years. It's been so much going on. What's been impactful in your opinion in the last, say, the last five years?

Emmanuel Antonarakis: So I'll just pick two or three things; there are so many. The molecular genetics and the genetically targeted therapies, I think that has to be number one. So we're not treating all prostate cancers as one disease, we know that there are subsets, molecular classifications that can help us decide about PARP inhibitor sensitivity. We've seen that story unfold. We have the small but very profound subset with a mismatch repair deficiency, which can have very profound responses to drugs like pembrolizumab. And as we've heard recently, we'll get into this in a moment, now PTEN deletion or loss might also be an actionable biomarker. So that's number one.

Of course, theranostics, it's important, it's hot at the moment, but we can't omit it. That has changed both the way that we diagnose advanced disease, but also select patients for lutetium-PSMA-617 and others in the pipeline, and there are going to be many of those. So that has made a huge impact. And then of course, moving those lutetium and other actinium agents into the earlier disease space.

And then I would say the third, and we can keep it brief for this question, is that the liquid biomarkers, we no longer now need to do a tissue-based biopsy at every disease state for every patient. It's always nice to have one tissue biopsy at the beginning; of course, we need that to make the diagnosis as well, but the liquid genomics, transcriptomics and even proteomics I think is now taking off. As a special interest of mine at the University of Minnesota, we have been working to quantitate the prostate cancer proteome in blood. And we can do that either from circulating tumor cells, but more so from the circulating extracellular vesicles, the exosomes. And the fascinating thing about the circulating exosomes is they are composed of the cell membrane of the cancer cell, and that cell membrane should theoretically contain proteins such as PSMA, which is a cell surface protein, proteins such as STEAP1, KLK2, B7-H3. And by the way, those four specific proteins I mentioned, those are therapeutic targets. So I think the field is going to evolve now where we're not going to be relying only on immunohistochemistry from tumor biopsies, but other ways to interrogate the proteome in blood or plasma.

Zachary Klaassen: Yeah, great answer on the last five years of prostate cancer; that was perfect. Let's focus a little more recently. We just came off the heels of ESMO, lots of data at ESMO. What were sort of the highlights in prostate cancer for you at ESMO 2025?

Emmanuel Antonarakis: So I'll pick two things that I think are going to be the most impactful. Of course, PSMAddition, that was a highlight. We were waiting for that data. We had seen the press release that rPFS was positive; we had not seen the numbers. So the option of using lutetium-PSMA-617 in the metastatic hormone-sensitive setting in conjunction with doublet hormone therapy, that was exciting. I do have to say though that the data is immature and incomplete. I think many of us would view this as a great start and it might make it to the finish line. We hope that it does for the benefit of our patients, but we have to see more mature OS data, but also I would say PFS data as well.

Now, one thing that that trial did not address, of course, is how many doses of lutetium-PSMA-617 are sufficient in that setting. And one potential concern that I have, which I'm sure my colleagues may share, is after two or three doses of the lutetium-PSMA-617 in those patients, their PSMA positivity will likely go away or be significantly reduced. So is this a scenario where we could omit six doses and stop at three or two or use PSMA PET scans or SPECT scans to tailor that? So I think that's going to unfold in an interesting way over the next few years.

The other one, which you might not have expected me to mention, is the CAPItello study. I had an interesting revelation myself. My first reaction to that was, okay, we have a PFS hazard ratio of .81. Yes, it was statistically significant. It appeared modest, but the more I looked into that, especially when I was paying attention to the control arm, and Dan George mentioned this during his talk at PCF just today, is that the PTEN-deficient patients with metastatic hormone-sensitive disease, they have a worse prognosis. So they will be developing rPFS or time to castration resistance in about two years, 24 months or so, and that is relatively short in the current era. And so that is something that does represent an unmet medical need. So in the context of an unmet medical need, the bar for improvement could potentially be a bit lower, especially when it's linked to a biomarker that is going to be relatively easy to assess with immunohistochemistry looking for PTEN protein loss. So I think that will make an impact.

Of course, neither of the two trials that I mentioned from ESMO have led to FDA approval yet. They might, I think they will both be filing for that and we'll see how that goes.

Zachary Klaassen: No, great summary, and I think you mentioned too, just highlighting on moving lutetium up in the disease space and really highlighting the need to screen these patients for PTEN. So on the heels of the ESMO discussion, we're moving into 2026 soon and another great set of oncology meetings coming up. What trials maybe in the next year or two are you really looking forward to reading out?

Emmanuel Antonarakis: So with the radiotherapeutics, we have the ECLIPSE trial, we haven't heard much about that. This is a PSMA-I&T. Also, lutetium-177 is the delivery agent there. And, of course, we know about PSMAfore and we know about SPLASH. We know that PSMAfore did lead to an FDA approval in the pre-chemotherapy setting despite a lack of overall survival advantage. We know that SPLASH had a more modest PFS benefit and the sponsor decided not to file for regulatory approval. So ECLIPSE is going to be the third in that same space looking at the first line metastatic CRPC who have not previously received docetaxel. And I think that one is going to be reading out probably in the next 12 months.

Then moving into the PARP inhibitor combination space, we heard about the AMPLITUDE study in metastatic hormone-sensitive HRR-mutated disease that's now published as well. But we have the TALAPRO-3 study in that same space and we have the EvoPAR study in that same space. So can alternative PARP inhibitors with alternative AR pathway inhibitor combinations also yield the same type of benefit that we saw in the AMPLITUDE study?

Zachary Klaassen: Yeah. It seems like 2026 could be the year of continued PARP understanding of where we're going to treat these patients, for sure. Always a great discussion. Any take-home messages, anything we haven't hit on that you want to share with our listeners before we wrap up?

Emmanuel Antonarakis: One quick thing, which is also a University of Minnesota centric.

Zachary Klaassen: Sure.

Emmanuel Antonarakis: Please pay attention to B7-H3.

Zachary Klaassen: Yes.

Emmanuel Antonarakis: It's a relevant target. We don't yet have any B7-H3 therapeutics in any cancer type. Prostate cancer could be the first one. It's not a prostate cancer specific protein; it's expressed in other cancers as well. But the phase three landscape, using that target with, for example, antibody drug conjugates, ADCs, is probably going to hit in prostate cancer before the other cancer types. And we have a young investigator, Nick Zorko, who's developing a trispecific natural killer engager, so-called TriKE, targeting B7-H3, which can be a new form of immunotherapy. That trial will be launching in the next six months, so please invite me back next year or better yet, invite Dr. Zorko.

Zachary Klaassen: Absolutely. And we actually talked to Dr. Zorko, so look for that on UroToday as well; it'll be coming out soon too. Absolutely phenomenal. I mean, we're going to be seeing those new cell-surface targets and I think that's going to be exciting over the next years as well. So, Emmanuel, always great chatting with you in UroToday. Thanks for taking time to do it.

Emmanuel Antonarakis: Thank you. It's been fun.

Zachary Klaassen: Thanks.