Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We are at AUA 2025, in Las Vegas. I'm delighted to have on your show today, Dr. Mike Cookson, urologic oncologist, Dr. Jason Efstathiou, who is a radiation oncologist. And we're going to talk about hot topics and metastatic hormone sensitive prostate cancer and mCRPC as well. Gentlemen, thanks so much for joining us today.

Jason Efstathiou: Great to be with you.

Zachary Klaassen: When I was putting this together, I was thinking about how to do this. We could talk about hot topics for a whole conference if we wanted to but I really wanted to just divide it up by time frame. So maybe in the last year or so, hot topics in HSPC, mCRPC. And then we'll move into maybe ongoing trials or things coming down the pipeline that you're interested in a little rapid fire. I'll start with Mike, maybe in HSPC in the last year or so. What's exciting to you?

Michael Cookson: Well, thanks for having me. Yeah there's been a lot going on with metastatic disease. One of the things that we found is that patients with rising PSA, even after failed primary therapy, we used to call them biochemical recurrence. But we are now using PET imaging, that more than half of those patients, even with very low PSA, will have nodal disease or M1a, which I think is the new horizon. What do we do with these M1a patients. But I think that's an exciting area where the EMBARK study, for example, showed that there was benefit to adding combined hormonal therapy and then giving the opportunity for a break. So some intermittent therapy.

I think when you look at the truly de novo presentation for metastatic disease, looking at doublet therapy, triplet therapy and trying to decide who gets what, that is also a very exciting area. There's been, now pretty much you agnostic to what you can use in that space from our targeted therapy. We have abiraterone. We have the three "mides". So those with the new studies that have come forward, even darolutamide is in the game now in that setting. So those are some exciting areas for us in the metastatic space.

Zachary Klaassen: Yeah, absolutely. How about you, Jason, from a radiation oncology perspective?

Jason Efstathiou: Yeah. I mean, it's been as Michael said, it's been a rapidly evolving standard of care landscape in metastatic hormone-sensitive prostate cancer. And really what we're seeing is that more aggressive treatment, treatment intensification is leading to improved outcomes, improved survival. And just building on what Michael said, what about local therapy. What about treating the primary and STAMPEDE really set the stage for a survival advantage in low volume, low burden, metastatic hormone-sensitive prostate cancer to treat the primary with radiation. And PEACE-1 built on that.

And that's been published within this past year where it showed that in low volume disease, there was an improvement in radiographic progression-free survival, in castration-free survival by adding radiation to the primary. There was even advantages regardless of metastatic burden and avoiding serious GU events. And that was all without any increase in late toxicity or toxicity really from adding radiation. So it's sort of setting a new standard of care where certainly in low volume metastatic disease and maybe in select high volume metastatic disease, we should consider treating the primary with radiation.

In just a little more data that's building in recent years is what about SBRT to sites of metastases. Those are all phase II trials, but have generally suggested ADT-free survival or progression-free survival advantages. And so that's another very interesting space.

Zachary Klaassen: Yeah. Great examples. Let's switch now to the same time frame. But mCRPC what about-- what's exciting you in that area, Mike?

Michael Cookson: Well I'm old enough to have seen the very beginnings of the first drugs that came in for castration resistance. End-stage patients heavily pretreated. Everything's moving back. And so, this year, we saw the emergence of first-line PARP inhibitors combined with ADT. So that's exciting not only for the best results in patients who are germline mutated, but even in some of the studies have shown benefit in all comers. So sort of a one-two punch. The ADT makes the cells susceptible and the PARP inhibitor kind of finishes it off. So that's exciting. Moving up lutetium, for example, in that first line. You don't have to go through chemotherapy, for example.

So I think those are exciting. We're seeing the movement upward. Of course, we'd like to get to the other side where it's not yet castration resistant I think testes tumor, finding the right combinations early could provide us with the best chance for a cure, but it is an advancement to see these therapies that were approved of after second and third line now moving into first line in metastatic CRPC.

Zachary Klaassen: Great summary. How about you, Jason, mCRPC.

Jason Efstathiou: Yeah, exactly. I mean, the combination of let's call it PARPis and ARPIs, right. Certainly has been very exciting and probably the biggest area, I think, of advancement, recently. I think the other real important thing is that we should be doing somatic and genomic molecular testing on all patients when they become metastatic and before castrate resistance. This is going to inform not only prognosis and familial risk, but it's going to inform risk benefit ratios with the combination of these therapies. And it's going to help with of treatment selection. And I think that's a very important point for us all to.

Zachary Klaassen: I'm glad you mentioned that because anytime we have these conversations, if we can promote germline and somatic testing, it's super important. And we know it's underutilized for sure. Great conversation on what has been and what we are excited about. Let's move to maybe perhaps even more fun is, what's coming down the pipeline? What are you excited about? I'll maybe switch the order and start with you, Jason, for metastatic hormone sensitive prostate cancer.

Jason Efstathiou: Well, I mentioned STAMPEDE earlier. And, in the setting of metastatic hormone-sensitive prostate cancer. I mean, so building on that there's STAMPEDE-2. And I mentioned SBRT earlier. So what is STAMPEDE-2 doing? As I mentioned, there's benefit seemingly in phase II trials to the addition of SBRT to sites of metastases. Showing progression-free survival and some other benefits. But that was really in metachronous disease. And so what STAMPEDE-2 is asking in de novo synchronous metastatic hormone-sensitive disease. Is there a value to SBRT to sites of metastases.

And I think that's a really exciting trial. And it's a randomized phase III trial. So it's going to really, provide level 1 evidence on that question. So I'm looking forward to that. The other thing I would say is there are other pathways than the AR pathway. We've talked about PARP and but there's also. PI3K or AKT and PTEN loss. And there's drugs that are being evaluated there like the CAPItello trial.

There's going to be a role in hormone-sensitive disease for the PARP inhibitors for PSMA-targeted radioligands. And I think that's going to be a lot of interesting stuff coming on those topics.

Zachary Klaassen: STAMPEDE-2 is going to be super exciting. I agree, it's going to be awesome. Mike, how about you?

Michael Cookson: Well, we started with that treatment intensification. So there's some trials really trying to examine that. So I think one of them is called ASPIRE. And it'll be looking at a doublet using apalutamide compared to triplet. And then there's a switch study that I think is going to be a cooperative group trial from SWOG, where we are and looking at starting out with doublet therapy and then based on PSA response, randomization to chemo or not.

We really need to in addition to that, what are the patient profiles. What other new tools can we get to help select who needs that intensification. Who needs doublet therapy. The days of monotherapy really should be exceptional and very few patients. We all have very elderly patients, very frail patients. They need some treatment. But they couldn't maybe handle. But when we look at how we're doing, when we look at pharma data, for example, we just really haven't gotten where we need to be even with that. But I think picking the right patient, how much to intensify, we're going to learn from those type of trials.

Zachary Klaassen: I love that example because we're layering additional trials. We're de-escalating, perhaps even patients that have done really well in a doublet. So those are going to be really informative for the next several years as well. Lastly, let's talk about mCRPC Jason, what's coming that you're excited about.

Jason Efstathiou: Yeah, I mean, look, we've seen seven new indications of new drugs and combinations in mCRPC since 2020. So, we've got PSMA-targeted drugs, we've got novel androgen drugs, we've got PARP inhibitors. And really what that is telling us is that we're moving towards precision and biomarker-driven approaches. I'm really excited about theranostics and what is going to be the role of theranostics. We've got the VISION trial, we've got PSMAfore recently suggesting progression-free survival advantage. But maybe not overall survival advantage to the ARPI switch. So I think the future really is going to look at the optimal timing and sequencing of PSMA-targeted radioligand therapies. And I'm looking forward to that.

Zachary Klaassen: No, that's great.

Michael Cookson: Yeah. And I think I would wholeheartedly agree. I mean, how do you sequence it if they're a germline mutation? Do you do the PARP first? When do you layer in the radium? When do you-- so the sequencing, how much a person can tolerate? All that needs to be sorted out. It's an embarrassment of riches in that we have so many choices now. But on the other hand, we've got to be smart about how we use them, when we use them, what goes first, what goes second, et cetera.

One of the things that's always driven me crazy is whether you can stop a therapy too. Because now we know from some of the newer studies, when we first looked at, could you use radium with NHT? Well, we know now that you can. But you've got to be smart about it. You've got to watch their bone health. You've got to make sure you're looking at the whole patient, not just that individual thing, but as we move forward, learning that. And then, of course, new drug developments that will like androgen degraders and things that we don't have available today, I think those will be advancements. I'm still sad that the pathway is end stage patients first, followed by moving up, and it's just a slow process to get back to where you really need. So hopefully we can do something about that in the future.

Zachary Klaassen: I think just to wrap up, I think terbium is coming, lead coming, copper's coming. There's so much in that radioligand space, which is going to be really cool. And probably seeing some of that data even this year too. So gentlemen, I was really looking forward to this conversation. It did not disappoint. Maybe a take home message from each of you.

Jason Efstathiou: Yeah, I'm happy to start. I mean, I think what we've heard today is there's really no role for ADT monotherapy anymore in metastatic disease. I think that's a take home. Lots of exciting developments. I think the other big take home is that metastatic prostate cancer requires multi-modality management. These patients should be seen in a multidisciplinary environment. We need, of course, medical oncologists, urologists, radiation oncologists, but nuclear medicine specialists and everyone else involved in the care of these patients. And we should work hand-in-hand towards that goal.

Zachary Klaassen: Yeah beautifully said.

Michael Cookson: And I agree. And what I'd really like to see is improvement in the newly diagnosed high-risk patient before we're able to evaluate for any metastasis. Neoadjuvant combination therapies are coming combining six months of treatment ahead, radiation or surgery in the middle, and then a tail with additional therapy. I'd like to catch them before we get beyond the metastatic site. And I'd like to not be talking about castration resistance someday. That would be the most exciting thing.

Zachary Klaassen: Yeah, well said. Thank you again. We'll do it again in AUA 2026. So thank you guys both.

Michael Cookson: Thank you.

Jason Efstathiou: Thank you.