Latest Prostate Cancer Research Updates: March 2026

Phillip Koo, MD [00:00:00] I’m Philip Koo. It’s an honor to be here again to talk about some of the data from two big meetings, EAU and GU ASCO. We’re focusing on those data, or the information presented that has the highest likelihood of impacting clinical care tomorrow, today, sort of more immediately as opposed to years down the road. So, I do see that there was one question about the T-cell engager trial, the VIR-5500 trial that was presented. We are not covering that because that was a phase one trial, and for that to sort of make it to the clinic, it’ll be a few years because they’ll need to do eventually a phase three. So, we’re not going to cover topics such as that. But to cover these eight or so trials that we’re going to talk about is Zach Claussen. So, Zach, thank you very much for joining us. 
 
Zachary Klaassen MD, MSc [00:00:49] Phil, always great to chat with you and I enjoy these discussions. I know we’ve done a couple of these post-conference discussions, which hopefully are helpful to our patients and their families. And certainly, it’s translating, as Becky said, the work from clinician to clinician to trying to get the information out to our patients and their families 
 
Phillip Koo, MD [00:01:07] That’s great. Yeah, I agree. And this is really the ultimate goal. All the money that we’re able to invest in research, eventually, it has to make it to the patients. It has improve their care in some way for it to sort of really be meaningful, and we’re glad that we have a lot of information to share. So, let’s get right to it. We’re going to start off with PRIMARY2. 
 
Zachary Klaassen MD, MSc [00:01:32] So PRIMARY2, this was presented at the European Association of Urology. That’s one of our probably two biggest urology events, the other one being the American Association of Urology, which will be later this May. So, EAU was in London earlier this month. And PRIMARY2 is a really interesting study. So, this is men that were from Australia, seven Australian hospitals. They had an MRI previously that had a PI-RADS 2 or PI-RADS 3 lesion. And this is sort of the less aggressive-looking lesions on MRI, and then they were randomized to the control, which is standard of care, systematic transperineal biopsy versus PSMA PET scan. And PSMA PETs typically have been for biochemical recurrence, staging high-risk patients. So, this is moving it up to the pre-diagnosis stage. And then patients had a positive PSMA PET scan, then it went to targeted biopsy in that area. If it was negative, they had no biopsy. So, the way we look at this is sort of trying to really identify those patients that maybe didn’t have aggressive features of it on MRI, but maybe on PSMA PET scan there’s something there. So, if you look at, there’s two sort of ways to look at this. Can we diagnose clinically significant prostate cancer, and can we avoid biopsies in men that don’t need a biopsy? So, if you look at the right side of the screen, biopsy avoidance, 49% of patients were able to avoid a biopsy, and they’ll continue to follow these patients for many years to sort of see if these results are truly safe. And the other two outcomes were significant prostate cancer. We wanna make sure if we’re avoiding biopsies, we’re not missing clinically significant prostate cancer. And we saw that the patients that had a PSMA PET versus those that didn’t, there was a non-inferior margin that was met which means that there was no clinically significant difference in the rate of significant prostate cancer. That tells us that PSMA PET will hit that cancer but it’s not going to miss the really bad ones. Insignificant prostate cancer is always a bit of a conundrum, so this is, it sounds like a bit a misnomer, but this is the low-grade low-volume prostate cancer likely to be non-life threatening, but we have to deal with it when we find them and so we want to try to avoid finding insignificant prostate cancer. And we found that PSMA PET was able to decrease the rate of insignificant prostate cancer. So, we’re avoiding biopsies, hopefully appropriately. We’re not missing clinically significant prostate cancer, and we’re avoiding the diagnosis of insignificant prostate cancer with this trial. So very important trial as we see where we can utilize PSMA PET perhaps other places than we traditionally have over the last five or six years. And so, kudos to the Australian folks who put this together. And this study was funded by PCF. Which is really important. And we can sort of see real money being turned into research that hopefully can benefit patients. 
 
Phillip Koo, MD [00:04:29] Thank you, Zach. So yes, exactly. I mean, a little plug here. The money that we’re able to raise from donors, we were able to fund this trial that now leads to this information that will change how medicine is practiced to diagnose prostate cancer. And there’s also another plug, that money raised to award young investigators also came into play here. So, the first author, James Buteau from Australia, he presented the data, he was actually one of the, he is a PCF young investigator and an award recipient. So, it’s really great to be able to invest in projects but also invest in people who are really changing how prostate cancer is diagnosed and treated. So. Zach, this is really awesome. All of our listeners know about PSMA PET. It’s become such an important part of how you stage prostate cancer at initial diagnosis, at biochemical recurrence. It’s also used to treat and find patients who should undergo Pluvicto-type therapies. This is the first time we now have this pretty convincing data about using it in diagnosis, in the prostate itself. So, tell us a little about how you foresee this being incorporated into clinical practice. 
 
Zachary Klaassen MD, MSc [00:05:41] Yeah, it’s still early. I mean, this is a big study. I think we, you know, Australia’s done, over the last 20 years has really been at the forefront of PSMA trials and they continue to lead with this trial. Is it ready for prime time tomorrow? I think, probably not. I think there’s gonna be additional, probably validation following these patients a little bit longer, but we’re certainly seeing, again, you don’t wanna miss significant prostate cancer and you don’t want to over diagnose insignificant prostate cancer and to hit both of those metrics. So, I think- This has promise. Is it ready to be in the clinic tomorrow? Has to go through approvals, has to go through regulatory, and certainly the insurance companies have to pick up on this. And so, I’m hopeful all this gets approved. It’s gonna be in hands of the clinicians. Again, this is PIRADs, twos and threes. This is not for the fours and fives that we know there’s likely prostate cancer there. Patients should get a biopsy. And then if they have high-risk disease, then they certainly qualify for a PSMA PET scan after that. So, I hope it gets approved, we’ll have to use it judiciously. Have to make sure it goes through the appropriate steps to get there. But good quality data and a good trial like this certainly piques our interest and hopefully we’ll see it come down the pipeline. 
 
Phillip Koo, MD [00:06:48] Yeah, I agree. I think there’s probably a subset of patients that it really could make a huge impact today. And there was a question about the cost difference between PSMA PET and biopsies. And that’s a really hard question to answer because the way procedures are reimbursed in the U.S. gets very tricky based on location and whatnot. In the end, I think avoiding biopsies, avoiding the complications related to biopsies, being more sure when you go in for a biopsy and get a result, I think will lead to overall just downstream cost benefit for the whole healthcare system. But any thoughts you have there as well, Zach? 
 
Zachary Klaassen MD, MSc [00:07:24] Yeah, no, I think, Phil, I tell my patients, I only want a biopsy if I really think you have prostate cancer. And so, if this helps me make that decision in these patients with sort of these equivocal findings on MRI, that’s going to help tremendously. And so, I think as clinicians, if we can get a tool that will help us make those decisions, that’ll be helpful. To your point, the cost thing is always tricky. I mean you’re talking about different states, different, you know, Medicare versus commercial insurance, whether they’re doing the prostate biopsy in the clinic versus the acute surgery center. These are all tricky questions and they’re good questions, it’s just hard to answer. 
 
Phillip Koo, MD [00:08:01] You know, there’s a question about insurance companies and I will say that, you know, patients and loved ones and people have a lot of power here. Power locally, you now, given your U.S. House of Representatives members or your Senate, whoever it might be, your voice speaks volumes. And we know when things like this occur, being able to mobilize and help sort of tell that story and get insurance companies and federal policy and Medicare can’t underestimate the power that patients have in this whole continuum and this whole process. So just, I think the fact that you guys are all here listening is one step and then afterwards, just continue talking about this and getting this into the ears of the right people. So, we’re gonna move on to the second study called the CAPTAIN study. So, this really talks about focal therapy, which is something many of us are familiar with, but we don’t know too much about. So, fascinating trial I’ll turn it over to you Zach 
 
Zachary Klaassen MD, MSc [00:08:59] Yeah, a really interesting trial, again, presented at EAU a couple of weeks ago, and so this was led by actually one of my mentors, Laurence Klotz, who’s at the University of Toronto. He was one of the PIs on this study and certainly a multi-center study. And so, this is basically the first head-to-head in a really well-designed trial of a focal therapy to one of gold standards, which is radical prostatectomy. So, this was intermediate risk patients randomized to TULSA, which was a basically It’s a form of ultrasound treatment directed to the prostate gland. Typically, not treating the whole prostate, but part of the prostate versus the gold standard of prostatectomy. And so, they have many end points here. Safety end point is essentially whether this is safe, which is important. And then oncological end points, as you can see here, will be followed for three, up to 10 years. And so, we’ll really get a lot of information. This was just the first presentation of CAPTAIN. So, they focused on the safety. And this primary composite endpoint was pad-free survival, so leakage of urine, as well as erectile function. So, we see here that, not surprisingly, if you’re treating part of the prostate, not taking all of it out, 50% primary composite end point versus 24% in the prostatectomy group. So, this wasn’t a surprising finding for us. And then we look also at the quality of life in the bottom left. Quality of life was higher with the TULSA procedure. So usually this is an outpatient procedure, versus maybe one night in the hospital, quicker time back to work, less pain, less discomfort. So that was, you can see here, that almost gets back up to baseline within several days of treatment. And then early results for continence and erections in the bottom right. And we see that with pad-free continence, over 75% for TULSA versus just under 50% for prostatectomy and then erectile function, about 55% versus just under 50%. And a lot of this has to do with what kind of function the patients come into the trial with, whether they’re already leaking urine, whether they already have some sexual dysfunction. So very encouraging early, early results from this. I think all of us are not surprised by these results, but we’re looking forward to seeing some of these oncological endpoints. We don’t wanna miss a window for a cure from a cancer standpoint, but certainly. We know that these side effects of erectile dysfunction and incontinence can be very debilitating, so we’ll be looking forward to seeing more information from this trial over the next several years. 
 
Phillip Koo, MD [00:11:32] You know, this is really powerful. I think a lot of us hear about focal therapy. We see ads direct to patients about focal therapy in every city, every billboard. But we really need trials like this to help inform us on how does it really perform against the current standard of care? So, it sounds like right now, so far, we’re seeing that in terms of some of the side effects, it’s better, but the true sort of endpoint would be, all right, does it control the cancer as well as what we’re currently doing? And when do we expect to see those results, Zach?
 
Zachary Klaassen MD, MSc [00:12:04] Yeah, probably the first oncological endpoints at about three years, so it’ll be some time and then they’ll follow them long-term for four to ten years. So, I anticipate we’ll see several presentations on this trial even before that three-year point, but really, we’ll start to see some of those important oncological outcomes. It’ll take several years still. 
 
Phillip Koo, MD [00:12:22] Alright, and you know there are a lot of different ways in which focal therapy can be performed. I presume we’ll need trials using each of those different types of therapies, but what’s sort of your thoughts in general on the types of therapy, focal therapy? 
 
Zachary Klaassen MD, MSc [00:12:36] I think they all generally work pretty well. So, we talked about ultrasound with TULSA. There’s also HIFU, which is very similar to TULSA, there is cryoablation, which freezes the tissue rather than heats it up. There’s NanoKnife or IRE, which uses electricity. There’s laser ablation. They’re all kind of similar. They damage the cancer cells in different ways. But I think the thing I always talk about with focal therapy is it’s all about patient selection. So, this is not for the person who has disease on both sides of their prostate, high-risk, Gleason 9 prostate cancer. That’s not the patient. It’s typically for unilateral three plus four, four plus three areas we can see on the MRI. Those patients are likely good candidates for considering it. So again, patient selection for everything we do is super important. It’s very important for focal therapy. 
 
Phillip Koo, MD [00:13:24] So there are some questions about the names, what is TULSA? I think TULSA, I believe it’s a brand name. Electricity is a technique, HIFU is a different technique. So, a lot of different ways, but they all fall underneath the umbrella of focal therapy. So, I think this is exciting. I think it’s definitely informative. Probably not practice changing today. Is that correct? 
 
Zachary Klaassen MD, MSc [00:13:46] I think that’s fair. I think it’s great to see a head-to-head trial against gold standard, such as removing the prostate. Focal therapy itself in those selected patients we talked about is being done, and I think in the right hands of the physicians and the providers that are counseling patients, I think it’s reasonable. But to see head- to-head data and eventually to see the oncological outcomes. We’re looking for non-inferior here. We’re not looking for better, we’re looking for the same, and I think that’s important. 
 
Phillip Koo, MD [00:14:18] All right, good. And this is where I think patients really need to sort of be an active participant in those discussions. Like, if those side effects, getting one of those side-effects is really, really so, they live in fear of that, then maybe you would sacrifice some oncologic control because you would have less risk of some of these complications. So, you know, just be vocal and make sure you share your concerns upfront with your physicians when thinking about these different treatments. Alright, we’re going to move on to metastatic hormone sensitive disease and these genomic classifier tests, which we’ve heard a lot about, we’ve learned a lot about through these webinars, and we’re gonna talk about some new data from Decipher. 
 
Zachary Klaassen MD, MSc [00:15:03] Yeah, thanks, Phil. So, Decipher is a genomic classifier, been around for a long time. I think we’ve talked about it several times on these events and really exciting. It gives us an under the hood look at the genetics of the tumor. And so, what we’re seeing here is a big cohort of patients presented at ASCO GU in San Francisco at the end of February. And what we are seeing at the top is the M1 or the metastatic patients are in that dark red sort of color, purple color, localized is in gray. And what we’re seeing is that the Decipher score, not surprisingly with higher risk, is actually a higher score in the metastatic patients than the localized patients. So not totally surprising if you have metastatic disease, there’s likely to be more genomic alterations that are picked up on this test. And so, when we look at the bottom left, we’re getting into a little bit of the nuance of this test, the metastatic patients, which is on the left. The green boxes, luminal B, these are some of the bad actors in terms of the genomics. We see more in the M1 versus the localized. So not too surprising there. What’s really interesting is the pTEN inactivity. This is the middle part of that slide. We see that there’s more pTEN loss in M1 compared to localized. And this is clinically relevant because we have a targeted treatment of pTEN that’s currently being evaluated for FDA consideration based on a trial we’ve previously discussed as well. So, this is certainly very contemporary and relevant to our discussions today. And again, not surprisingly, we see more pTEN loss in an M1 patient than localized. And then when we move to the very far right side, this is the very high risk Decipher group. Again, not surprisingly over 50% of the patients with M1 disease have a very high-risk Decipher score compared to the localized patients. So, I think this is nice. We always like to see big data sort of confirm what our thoughts are when we’re looking at these genetic defects. And certainly, the Decipher folks have done a great job of testing their test in a number of settings and really informing, you know, for this PAM50 and the pTEN, as well as looking at the genomic classifier score, you know in metastatic versus localized. 
 
Phillip Koo, MD [00:17:20] Great, so I think this is interesting. Clearly, there’s some questions about the aggressiveness of prostate cancer, how some are not aggressive, some are more aggressive. In this study, they’re showing that those who have pTEN loss and the luminal B subtype are more aggressive. Obviously, there are other markers, too, that show that patient’s cancer might be more aggressive, Zach, what advice do you have for patients when they’re seeing, let’s say, their medical oncologist to request this test, and how should they request it? 
 
Zachary Klaassen MD, MSc [00:17:49] Yeah, the genetic testing can be very confusing, not just for patients, but even for providers in terms of how we should test, what we should test. I’ll break it down simply. We could probably talk about 30 minutes on this trial really getting into this, but there’s genomic, which is this Decipher test. This is testing the tumor with a specific test. There’s somatic testing, also testing the tumor, perhaps a different gene profile that they’re looking, and then there’s germline. Germline is what you’re made of. This is the DNA in your body. Typically, with a blood or saliva test. That has implications for maybe hereditary risk. So, what you can pass down onto your children. I typically tell patients, it’s okay to ask about, am I a candidate for any of these tests? I use Decipher when I’m talking about active surveillance or intermediate risk patients. We talk about somatic and germline, typically in more higher risk patients, so ask the question. There probably is a potential, at any interval of your diagnosis and prostate cancer journey, where you may be a candidate for one of these tests, it’s just figuring out what the right one is. 
 
Phillip Koo, MD [00:18:49] And you alluded to this earlier, I think this is exciting, pTEN, we talked about it I believe in the post-ASCO webinar and hopefully we have a drug that can be used for patients with pTEN loss, again because we know those patients have higher risk more aggressive disease and I love the fact that the whole field is moving towards this, you know, precision a little much more targeted and identifying the bad actors and giving them certain regimens, and those who don’t need it, they don’t need to get it. So, I love the sophistication that’s sort of being brought to the whole field, so this is great. All right; we’re going to go on to the next study about DNA damage repair gene variants and some interesting data presented. I believe it was GU ASCO. 
 
Zachary Klaassen MD, MSc [00:19:37] Yeah, so sort of on the same line of thoughts, we’re seeing, you mentioned precision medicine, we’re hopefully gonna have a pTEN target here soon. We’ve had BRCA mutations, talked about these for 15 years now, roughly. We have PARP inhibitors that do well with these patients. So, to your point, Phil, we’re starting to see target, target, target, can we treat with certain medicines? And this is a little more information based off of that sort of line of thought. So, this is metastatic patients, as you mentioned, ASCO GU. Looking at these three specific ones, BRCA, ATM, and CHEK2. This was 3,000 patients with metastatic prostate cancer. And what’s interesting is, of those 3,005, 9% of them had one of these mutations. Most commonly was BRCA2, 2.8%, ATM, 1.2% and CH2, 1,1%. And so, we’ll turn our attention to the bottom left of the slide. The BRCA mutation patients were historically younger than those that did not have a BRCA mutation. We kind of knew that already, and we see that the Gleason grade group is significantly higher with BRCA2 compared to other patients that don’t have these mutations. Again, not too surprising. What I think’s interesting is the CRPC progression in less than one year. 26 out of 46 patients with BRCA2 had CRPC progression, which means that their cancer went from a hormone sensitive state to a hormone insensitive state and into another category of more aggressive and more potentially lethal prostate cancer. Over half of those patients in less than one year. And then the final thing on the right side is looking at the different mutations. We can see that purple dot is the BRCA2. This was the strongest predictor of worst mortality when looking at ATM and CHEK2 and some of these other mutations. And then that clearly correlated to the overall survival curve on the right. Median overall survival for BRCA2 was about five years compared to ten years with the patient that did not have BRCA2. So really kind of already sort of confirming what we knew about these mutations but looking at it again in a big cohort of patients, this is an opportunity to always talk about genomic testing and genetic testing with our patients. And we’ve known for a while BRCA2 is important, and this continues to highlight that. 
 
Phillip Koo, MD [00:21:54] Great. So, you know, to clarify for the patient’s online, this is germline testing. This is the genes that you might have inherited from your parents. And it’s showing that having these DDR variants, BRCA, ATM and CHEK, means you probably have a more aggressive prostate cancer. There was a question about Decipher and Polaris, they’re similar there’s some subtle differences, but those fall into the genomic classifiers, which is different from the germline So different testing but similar concepts of trying to identify the aggressives from maybe perhaps the intermediate versus not as aggressive So where do you foresee this going? I mean, I know we talk about BRCA a lot, you know BRCA then allows you to receive certain treatments. How will this impact what treatments are they’re given? 
 
Zachary Klaassen MD, MSc [00:22:45] Yeah, I think, you know, we typically, if you look at our guidelines, everybody with clinically localized high-risk prostate cancer, that’s Gleason 8 and above, and everybody metastatic should have a discussion about somatic, testing the tumor, or doing germline testing on these patients. The way I think about somatic versus germline is if you’re the only person in your family that has this cancer, I typically start with somatic. If your brother had it, your uncle, your dad, your son even has it potentially, there’s something going on there. I typically will talk about getting both somatic and germline testing because this is implications for family members. How should we inform this? I think just because you have a localized prostate cancer that has a BRCA2 mutation, doesn’t mean you’re immediately gonna get a PARP inhibitor, but it will tell your provider that this is a higher risk tumor. We’re gonna treat this aggressively. We know we have this in our back pocket when we get to a point where PARPs are already approved, which was down the line. And so, it’ll inform maybe surveillance regimens, maybe how aggressive the initial treatment is, and then subsequently will be a bullet in the holster when we need it in perhaps a metastatic setting. 
 
Phillip Koo, MD [00:23:56] Great, I love that. I think it’s important to have the information to have a plan, work the plan. It’s so informative and you’re right, being two steps ahead all the time. So, all right, we’re gonna switch gears and now talk about, which is interesting because we’ve had webinars in the past that talked about doublet therapies, triplet therapies. And now there was data presented looking at these different treatments in the VA population, which I think all of this stuff really helps us learn about the validity of the trials, how it actually translates into the real world. But this study from the VA I think was pretty informative. 
 
Zachary Klaassen MD, MSc [00:24:34] Yeah, no, I like this study a lot, Phil, because it doesn’t tell us anything new from the trials, but it really sort of reinforces what’s going on in the real world, but not just in the world, in the VA system, where we know we have a higher proportion of minorities in the system. And so, seeing this data presented really sort of was a take home for me that how this is performing in trials actually performs in the real world in this setting, like you mentioned, is the VA. And so, when we look at this study, This was about 300 patients each receiving triplet therapy. So, this is docetaxel chemotherapy, plus ADT, plus an ARPI. This is either darolutamide, apalutamide, enzalutamide, et cetera, or the ARPI doublet therapy. So, this not chemotherapy and they match them sort of to make them look comparable when they’re doing the analysis. You can see here median age is around 70, about three quarters of patients are high-volume. About 80 to 85% are synchronous, which means they showed up with metastatic disease versus having metastatic disease after initial treatment. And you can see, these are high PSAs. This is much higher than the clinical trials. The clinical trial PSAs are roughly 20 to 30. This is around 100. So, this is what we’re seeing in the real world. And I think this is important. So, the first graph on the left shows that the patients that had a doublet, or excuse me, a triplet with docetaxel had an improved overall survival. Which we can see here the median has not been reached in the triplet therapy patients versus about three years in the doublet. And then when we look to the right, they get into some more of the nuances. So synchronous, which is showing up with metastatic disease versus metachronous having metastatic disease later, we see a benefit for triplet and synchronous and not a benefit to metachronous. So, it tells me that for the majority of metachronous patients, we may be able to consider the doublet therapy not have to do chemotherapy. On the bottom is looking at volume of disease, and we can get a discussion how this is defined, but the way they defined it is typically with about four or less bone lesions versus four or more. Patients with disease in the liver or the lungs are typically classified as high volume. Not surprisingly, and we’ve seen this in the trials as well, that the docetaxel benefit is quite important for these high-volume patients. And not surprisingly as well as it’s not as important in the low volume patients, so I think. This is exactly how I think about treating my patients. It’s great to see VA data in this situation and it mirrors very similarly the clinical trials. Clinical trial patients are often, the entrance criteria is very rigid, and we often wonder how will this perform in the real world. We’re seeing here exactly how it performed in the world is how it perform in the clinical trial. 
 
Phillip Koo, MD [00:27:15] I think that’s great to see that it works in the real world. I think for patients oftentimes they want to avoid chemotherapy, but clearly in certain patients in the synchronous population and high volume, there is a real significant clinical benefit. So, I know we all want to avoid it, but when it’s indicated, you should really, really consider getting that chemotherapy. And then for those who are metastatic hormone-sensitive. Everyone needs to be on an ADT plus an ARPI. And unfortunately, there are still so many patients out there that are just getting ADT, even though they’re metastatic, and we need to see that stop. And it’s kind of sad that we’re even talking about that today. 
 
Zachary Klaassen MD, MSc [00:28:00] Yeah, the one thing I’ll just say quickly about that is this is, and I always try to make this point with chemotherapy in this setting. It’s not chemotherapy forever, it’s not chemotherapy till the disease progresses. It’s six cycles of chemotherapy, docetaxel, takes about five months to get and then it’s done. So, I think that’s important when I talk to patients about, particularly these patients with the PSAs in the hundreds, we start off the conversation right away at triplet because that’s where we see the most benefit and really them understanding that it’s a finite time period of chemotherapy. 
 
Phillip Koo, MD [00:28:33] So, we’re going to move on now to metastatic castration-resistant prostate cancer, and we’re going to talk about the ARTO trial, which is long-term, well, I’ll let you describe it, but this is an mCRPC. 
 
Zachary Klaassen MD, MSc [00:28:48] Yeah, so this is patients that have metastatic disease that have already become resistant to hormone therapy. And so, this low volume MCRP. So, you can see the definition at the top, less than three lesions, no visceral lesions which means nothing in the lymph nodes, or excuse me, nothing in, in the bone, or the lungs or the liver. And then no prior therapies for mCRPC, so this sort of, when they first get diagnosed. So low volume, less than 3 lesions. These patients were then randomized to abiraterone. Which is one of our common treatments for mCRPC. They continue their ADT. And then the treatment or the experimental arm was adding SBRT, which is a very short course of high dose radiation to all of these three sites that were identified on imaging. And so, this trial has been going on for a while. So, we talked about previously the CAPTAIN trial we’ll be following on for long time. This trial has going on for over seven, eight years, I believe. And what we’re seeing now is we can start to see these longer-term outcomes. So overall survival was improved. With this combination of continuing ADT plus abiraterone plus SBRT, as well as cancer-specific survival on the right, again improved with the combination of all of the abiraterone and SBRT and ADT. And important to note, Phil, this is a phase two trial, so a smaller trial, you know, I think it was about just over 100 patients, I believe. And so, they probably will move this into a phase three setting. We’re already sort of seeing some of this done in the clinics, but it’s nice to have some data that if these are amenable to SBRT, it’s not unreasonable to treat them, and certainly this is a very practice-informing trial with these longer follow-up results from the ARTO trial. 
 
Phillip Koo, MD [00:30:31] You know, this is interesting because I think a lot of the patients on the line are listening and watching have seen something similar and we do this Mets-directed therapy for oligometastatic disease in patients who have biochemical recurrence. So, after you get radiation or surgery, your PSA starts coming up and then you start zapping some pelvic lymph nodes or whatnot. But in those trials oftentimes we’re delaying ADT, we’re putting it off because you could control the disease with just the lasers and radiation. This is a little different and I think it’s real important to recognize that these patients, I believe, are receiving ADT plus abiraterone plus that radiation treatment. So, it’s different because I think obviously the disease is different. It’s more aggressive in that castration-resistant state. Is this something that, you mentioned it is something that’s sort of happening already, how should patients approach this when they might have, let’s say, three Mets and they’re diagnosed as CRPC? 
 
Zachary Klaassen MD, MSc [00:31:34] Yeah, I think these are always important discussions because nothing’s ever free when you’re getting the treatment. So, you have to worry about side effects. You have to worry about what’s the ramifications of getting a treatment. The way that we’re able to tailor this radiotherapy to these spots is actually pretty sophisticated these days. And so, this can often help with symptoms too, if people having some bone pain from one of these spots. It’s often resolved quite quickly with radiation to those areas. So, in our institution, we typically will discuss these at our multidisciplinary tumor board where all the experts from all the different fields get together and discuss these cases. And I think for the most part, this is, even though it’s phase two data, it’s nice to have that because we’re already sort of seeing it. If you have a radiation oncologist that has SBRT, for them, it’s easy to give it. It’s typically quite well tolerated, especially when it’s given to the bone. And so, we know there’s gonna be continued side effects with the abiraterone, et cetera. But to see some benefit there, I think this has already sort of snuck into the clinic in a good way and now we have some data to perhaps support it. 
 
Phillip Koo, MD [00:32:40] So this is a question that comes often and it makes a lot of sense, this question. Why are patients still put on ADT even though it’s failing and they’re castration-resistant? 
 
Zachary Klaassen MD, MSc [00:32:52] Yeah, it’s a great question. One we get asked all the time, I typically discuss it as follows, is that the majority of your cancer is still probably responding to that ADT. There’s just a portion of it. It’s always harder to depict whether it’s 10% or 5%, but there’s clearly a portion of it that has had mutations that is now resistant to it. So, we’re still treating the majority of it with the ADT, but we need extra to get the cells that have sort of escaped that mechanism. 
 
Phillip Koo, MD [00:33:20] Great, and you know it’s interesting, because I think we’re seeing a lot of, and we’re gonna talk about this with the last trial, but we’re see the side effects of ADT, and I think there’s a movement towards how do we get to treatments that don’t incorporate ADT in the future, and I that’s gonna be sort of the next horizon. Before we get that trial, we’re going to talk about the PEACE-3 trial, which I think is really, really exciting, and sort of puts new energy into a drug that we’ve heard about treating the bone. So, Zach, PEACE-3.
 
Zachary Klaassen MD, MSc [00:33:50] Yeah, PEACE-3, as you mentioned, Phil, we heard about this a couple of years ago. There was initial results presented and this is an interesting population. So, you mentioned that we’re still seeing some lack of treatment intensification in that metastatic hormone-sensitive prostate cancer setting where men are just getting ADT alone, which is how we did it prior to 2015, but things have changed dramatically in the last 11 or 12 years. So, what’s interesting of these patients is they were enrolled if they were mCRPC with bone metastases. And had not received the prior ARPI. They were then randomized to enzalutamide plus Radium-223 versus enzalutamide alone. So, enzalutamide, one of the standards of care for first line mCRPC. The question was, could we add Radium 223? This is an injection. It’s usually given six cycles every four weeks that targets specific areas in the bone, and could we improve outcomes with this combination? And so, the answer is yes. We saw initially a couple of years ago this radiographic progression-free outcome was positive. And on the bottom right, we see that with continued follow-up, that still is the case. There’s a 29% reduction in progressing radiographically or dying of cancer in these patients. But it’s important now that we have overall survival data with a 24% reduction of mortality for these patients. The one thing I’ll mention is it’s extremely important. It’s not on the slide. But if you’re taking Radium-223 and enzalutamide in this setting, you have to add a bone protective agent because, what we’re doing is we’re treating these bone lesions with a radiopharmaceutical, which is Radium-223, plus enzalutamide can be hard on the bones too. We saw a significant reduction in fractures or symptomatic skeletal-related events if patients are getting a bone protective agent at the same time. So, I almost think about this as triplet therapy if you think about radium and enzalutamide and that bone protective agent. 
 
Phillip Koo, MD [00:35:44] I think that’s such a great point and I’m going to repeat it because patients need to remember this. And I love the way you call it triplet here as well. You need to protect the bones, get the radium and the enzalutamide. This is practice changing. So, I think once the label has changed, I imagine we’ll start seeing it being used very regularly in patient treatment. 
 
Zachary Klaassen MD, MSc [00:36:04] Yeah, I agree. This was a European trial, and I think, you know, I know our regulatory boards will look at it as well. It can sometimes take a little bit longer in those situations, but I agree, I think this is talking about practice changing versus practice informing or early data. This is definitely something that could, could be, could be approved here hopefully soon. 
 
Phillip Koo, MD [00:36:24] All right, so we’re going to go to the last area of survivorship, and we’ve talked about this, we’ve talk about ADT and how there are side effects and cardiovascular events are something significant. So, there’s some data presented at GU ASCO on cardiovascular events and ADT. 
 
Zachary Klaassen MD, MSc [00:36:41] Yeah, I know, Becky mentioned off the top that one of my interests is survivorship and this sort of falls in that line. I think the reason survivorship is important, I’m just going to take a step back, is we know that the prevalence of prostate cancer, people living with prostate cancer is about 3 million people in the United States. We know that about 35,000 a year will pass, unfortunately, from prostate cancer. But survivorship’s important because most men will live with prostate and likely pass from something else. And that something else oftentimes is cardiovascular issues. We know that cardiovascular disease is number one cause of mortality in the United States, and it’s very high for men that have prostate cancer. Part of that is just being a male in this country and those risk factors that are inherent, but also a lot of the treatments that we give increase the risk of cardiovascular disease. So, I spent a lot of time on discussing that and making sure they’re either plugged in with their primary care provider. Or even better, a cardiologist. We have a cardio-oncologist at our institution that we use very liberally, particularly in people that are starting some of these treatments, have risk factors that are gonna be on ADT. We’ve talked about enzalutamide, we’ve talk about chemo. All this can increase the risk of cardiovascular disease. So, this study looked at, it was a claims database, so big numbers. As you can see here, they were sort of divided into agonist initiators. This is commonly your Luprons, your leuprolides, antagonist initiators, which is commonly your Degarelix, your Orgovyx, and then looking at baseline cardiovascular disease versus no baseline cardiovascular disease. So, what this study showed us on the right, the two-point MACE was a scoring system that they looked at either a heart attack or non-fatal stroke. The three-point MACE was those two plus any other cause of mortality. So that’s why there’s the two metrics that they looked at. What this tells me is on the top, overall rates of change in two point or three-point MACE per 100 patient years, the highest risk is in those with baseline cardiovascular disease. So, this is not surprising. If you have predisposed conditions, that’s gonna be your biggest risk of having a MACE event once you’ve started therapy. What’s interesting too, is that if you look at the agonist, versus the antagonist and the relugolix initiators. We know that the antagonists likely have a less cardiotoxic effect. We’re seeing that in this real claims-based study. And then if we look at the bottom, again, this is change in the prevalence before and after relugolix approval. Relugolix is the oral pill, the antagonistic. And we see, again, the biggest benefit is in those with a baseline cardiovascular disease. And so, the take home for me in this is, it’s super important to know your risk factors going into starting treatment. And so that may be, again, partnering with your primary care provider, making sure you’re on a statin if you need to be, making sure your blood pressure’s controlled, making sure not smoking, making sure you’re exercising, eating a heart-healthy diet. I send men to the American Heart Association website, and I usually give it to their family members because they’re the ones paying the most attention at these sorts of things too. And really helping them follow that because at the end of the day, we wanna treat their prostate cancer. We don’t want them to die of prostate cancer, but we know the elephant in the room is the cardiovascular disease. 
 
Phillip Koo, MD [00:40:10] That’s very helpful, very interesting. Cardiovascular disease and those side effects are real significant. Give us some counsel on the antagonist versus agonist. The way you presented, does this mean everyone should be on an antagonist, not an agonists? 
 
Zachary Klaassen MD, MSc [00:40:25] Yeah, it’s an interesting debate, Phil. I don’t know if I have a perfect answer for you. I think that there’s some aspect of the antagonist injection is typically every month. The antagonist pill is obviously a daily pill. The Lupron or the leuprolide is typically every three months. Some of it’s convenience if somebody’s driving four or five hours away. I think the way I look at it is that most people will be just fine on an agonist such as a Lupron injection, but we do have those patients that have a cardiovascular risk factor or two or three, and those are the ones that we probably need to push insurance companies for coverage for Relugolix or getting them on that monthly injection that’s the antagonist because I think that’s, we’re seeing more data and we’re saying it in this study that they have less cardiovascular risk with that treatment. 
 
Phillip Koo, MD [00:41:17] Can you tell us, so we’re just gonna go through, we have some extra time, some questions and answers that were submitted. Can you us about the bone protective agents? Which are the agents that they should be on? 
 
Zachary Klaassen MD, MSc [00:41:29] Yeah, there’s a few out there. I think, you know, there is Prolia, there are some of these other pills that are out there, there there’s three or four different ones. I think probably the easiest is whatever your physician is comfortable with. Xgeva is another name for one of them and they’re given in different doses, they’re given in either injections or IV. There’s no perfect answer for which one you should be on. Just make sure that you’re asking your physician, am I, should I be on this? Particularly if you’re on that combination we talked about, I think it’s an absolute must. And certainly, when we talk about people being on hormone therapy for let’s say localized disease, it’s not metastatic. You don’t need to be on a bone agent in that situation. But what you do need to be on is calcium, vitamin D supplements, making sure you’re exercising, keeping your muscle strength, keeping your bones healthy. And so, there’s a whole discussion around that, but that’s sort of a quick one-off in terms of just knowing that this is part of that process and that all those treatments will deteriorate bones and certainly will deteriorate skeletal muscle as well. 
 
Phillip Koo, MD [00:42:35] So there are questions about Radium versus Pluvicto and PEACE-3 and those patients could be eligible for Pluvicto, which they’re correct, as long as it’s PSMA positive. I sort of shiver a little because I don’t think it’s, like just because Radium and Pluvicto are both radiopharmaceuticals doesn’t mean they’re interchangeable. So, can you sort of help clarify that and who might be better to undergo sort of that PEACE-3 regimen versus someone who might get Pluvicto in that pre-chemo setting? 
 
Zachary Klaassen MD, MSc [00:43:04] Yeah, great question, Phil. I think, I’ll spin off just a second, come back to that. There is some data that you can get both, and it is safe. We’re not sure what the timing of that is between the two, but I think that’s important as radium has been around for nearly 20 years, and obviously, lutetium or Pluvicto is somewhat newer. So, we’re feeling out that timing of sequencing therapies and what the safety net is for that. But going back to your question, generally anybody with bone lesions especially in that PEACE-3 cohort is a candidate for radium-223. Now, whether that’s with visceral or not visceral, it’s predominantly for bone lesions. So, if you have five bone lesion, nothing else, I think you’re a great candidate for Radium. There’s an important criteria for radioligand therapy. We talked earlier about PSMA PET and the utilization of that. The patient has to have PSMA PET positive lesions lighting up on that scan to be into that criteria of whether you could get lutetium or Pluvicto. So, I think that’s the easiest way to sort of that first delineation. There may be some other nuances you need to discuss with your clinician, but I think that’s one of the easier ones. It’s more of a catchall for radium and it’s a little more specific for radioligand therapy. 
 
Phillip Koo, MD [00:44:16] So there’s a question about liquid biopsies. We hear so many different terms of liquid biopsy, this, CT, circulating tumor cells. It’s confusing. Can you sort of help us understand what is liquid and what is solid? Yeah. 
 
Zachary Klaassen MD, MSc [00:44:29] Yeah, so it’s a huge topic right now, particularly in bladder cancer, where we’re seeing some really interesting data for being able to track patients and how they’re doing with ctDNA. Basically, what it is a blood test that basically looks at the amount of tumor content that’s floating in the blood, essentially. That’s the easiest way to put it, I guess. It’s still somewhat, I don’t want to say new in prostate cancer, but figuring out how to utilize it, I think where it’s helpful is if you have a new diagnosis of metastatic prostate cancer or you’ve progressed and your physician wants to know has there been genetic changes, if a spot is not amenable to a biopsy, such as it’s in a difficult location in the bone or it’s not easy to get to in the liver or the lung, we’re seeing that we’re able to do some of that genetic testing on the ctDNA and there’s a pretty good correlation between what’s going on in that tumor itself in the body and what’s floating in the blood. That’s it. We could do a one-hour seminar on ctDNA though. 
 
Phillip Koo, MD [00:45:31] Yeah, maybe another time. So, there were questions about biopsies. So, we’re sticking to biopsies. And they were saying, all right, if you have something that really looks suspicious on a PSMA PET and an MRI, why do you even need tissue? Why do you need to undergo 12-core biopsy? 
 
Zachary Klaassen MD, MSc [00:45:51] Yeah, it’s a great question. One we get asked quite commonly. I think the short answer is as good as MRI is and as good as PSMA PET is, it’s not perfect. And so, we know that looking at cells under the microscope at least in 2026 is still the definitive way to diagnose prostate cancer. And it also gives us an opportunity to see whether it’s low grade, intermediate risk, high grade, that sort of thing as well, which we still can’t do on an MRI or a PSMA PET. Now, may we get to that point? We might. And I think with continued other agents coming into the market, they may be good enough that we don’t need it. But it does help. The biopsy gives us a lot of information. I think it, like I mentioned it, it’s putting it into the context of you could have a really hot PSMA spot, but it’s only Gleason 6 prostate cancer versus what you may think is Gleason 9. So, we have to restratify. We know the side effects of treatment are certainly real. We don’t want to put somebody through something if they don’t need it. Active surveillance versus a radical prostatectomy, big difference in side effects. And so at least at this point in time, we can avoid the biopsy, but we’re trying to select patients better for who needs to undergo biopsy. 
 
Phillip Koo, MD [00:47:04] So, there’s not much data on GLP-1s and prostate cancer, but I think it’s a question that a lot of people have. And when you start talking about survivorship and cardiovascular events, and then you hear about GLP-1s being the miracle drug for metabolic syndrome and cardiac events and whatnot, how do you counsel that without having any level 1 data? 
 
Zachary Klaassen MD, MSc [00:47:26] Yeah, it’s, again, another common question. And I think that my, I’m going to start by saying each person that they’re interested should talk to their physician because there’s a lot going on with GLP-1, who’s eligible, who’s not. I will say we don’t have a lot of information in terms of does it make your prostate cancer better? But what I will is there’s emerging data from a cardio protective aspect. So, I could see where somebody is really high risk for cardiovascular issues, starts hormone therapy, starts something else with hormone therapy. There’s a multidisciplinary discussion that, yeah, maybe a GLP-1 is worth it for that cardioprotective effect. And so, it’s definitely more to learn from that, I think, particularly how it pertains to the prostate cancer and whether it’s beneficial from that standpoint. But we’re starting to see, because of those things you mentioned, the metabolic syndrome, the heart protective aspect as well, where I could see it coming into aspects of higher risk patients starting on hormone therapy. 
 
Phillip Koo, MD [00:48:21] You know, it’s interesting. We are seeing more research applications being submitted trying to study GLP-1s in prostate cancer. And obviously, the more money we’re able to raise, the more of those studies we’ll be able to fund and get some of those answers, which I think are gonna be extremely important because I don’t think GLP-1s are going anywhere, so. 
 
Zachary Klaassen MD, MSc [00:48:40] No, they’re not, and I think there’s a lot to learn in terms of how this all works, and I think these are really important studies. 
 
Phillip Koo, MD [00:48:49] Well, we are just at time, so wanted to thank you so much. This was fun. I think we got through a ton of stuff, a ton materials. We were able to ask and answer a lot of the Q&A questions as well. So really appreciate the time, Zach. 
 
Zachary Klaassen MD, MSc [00:49:03] Phil, always a pleasure. Hopefully it was helpful to our listeners. Looks like we had great attendance tonight. So, thank you guys for joining and we’ll maybe have to do it after ASCO coming up here in a few months again. 
 
Phillip Koo, MD [00:49:12] Absolutely and everyone on the line tell your friends. This will be recorded if you registered you should get a link to be able to see it on a video on demand and please you know let everyone around you know who might be affected by prostate cancer just so we could all be educated and empowered so appreciate the time tonight and have a good evening.