Zachary Klaassen: Hi. My name is Zach Klaassen, neurologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We are on UroToday in ASCO 2025 in Chicago. I'm delighted to be joined by Dr. Kristine Lacuna, who is a medical oncologist at Memorial Sloan Kettering Cancer Center. Kristine, thanks for joining us on UroToday.

Kristine Lacuna: Thank you so much for having me, and I'm really excited to be talking about that changing landscape of CRPC in metastatic disease. It's a really exciting time.

Zachary Klaassen: It's so much going on. Every meeting we come to, it's just, there's new data to insert, and this is kind of what our discussion's going to be. Just sort of, how do we position radium-223 in that mCRPC landscape?

So just by way of background for our listeners, maybe bring them up to speed. First on ALSYMPCA, which is now 14, 15 years ago, and then more recently, the PEACE-3 trial.

Kristine Lacuna: Of course. So as we all know, in the prostate community, ALSYMPCA was a trial that was done many years ago. Patients started enrolling in the trial from 2008 to 2011. So a very different landscape than we are really seeing today.

Zachary Klaassen: The dark ages of prostate cancer.

Kristine Lacuna: Exactly.

Zachary Klaassen: Yes.

Kristine Lacuna: But essentially in that trial, the ALSYMPCA trial, patients with metastatic CRPC were enrolled who either progressed on docetaxel, or they were not candidates for docetaxel, randomized in a one-to-one fashion to receive treatment with radium-223 versus placebo. And these patients had to have symptomatic bone disease. And they were given best supportive care at that time too.

And so, the bottom line of that study was that the primary endpoint of overall survival was met. So that was really the first study where we were seeing a survival advantage for radium-223.

Zachary Klaassen: Right.

Kristine Lacuna: Sort of fast-forward to today, where we're seeing the PEACE-3 data, a very different landscape in metastatic CRPC. So kind of just to take a step back, that trial was essentially done between 2015 to 2023.

Zachary Klaassen: Right.

Kristine Lacuna: So landscape had changed. Essentially patients, now we're having approvals of androgen receptor pathway inhibitors, approvals in the pre and the post chemotherapy setting, and certainly PEACE-3 incorporated that.

So just as a broad sense, PEACE-3 was a randomized Phase III study, which enrolled patients with either asymptomatic or mildly symptomatic disease, who did not receive androgen receptor pathway inhibitors, and they were randomized in a one-to-one fashion to receive treatment with enzalutamide versus enzalutamide plus radium-223. And the primary endpoint of that study was radiographic progression-free survival, and overall survival was a secondary endpoint. But as we can remember from ESMO of last year, Dr. Gillessen, she presented such extraordinary data that was sort of surprising to us in the community, where the primary endpoint of RPFS was met with a hazard ratio of 0.69, median RPFS of 16 months versus 19 months. I think what's remarkable is looking at the overall survival, where we're really seeing a seven-month difference with a similar hazard ratio. And so there's further analyses that need to be done with that survival data.

Zachary Klaassen: Sure.

Kristine Lacuna: But certainly, it makes me wonder and question radium, where I think as a community we have fallen out of favor of using it. But now in these days, I think in the setting of Pluvicto, we have to think about it more given these new data.

Zachary Klaassen: Absolutely. It's a great summary of those trials. And just like you said, lutetium, we'll throw another wrench in the armamentarium here, which is good, but I think we have the VISION trial that was post-ARPI, post-chemotherapy. And just recently, we had FDA approval and NCCN uptake of PSMAfore data. This is looking at lutetium after an ARPI, before chemotherapy. So maybe just bring our listeners up to speed on that PSMAfore trial.

Kristine Lacuna: Of course. So this was, again, kind of moving along the timeline, a later study, and it was recently published last year, where patients with metastatic CRPC who were pre-chemotherapy, as you said, pre-taxane, who had already progressed on one ARPI, were randomized in a one-to-one fashion to receive treatment with lutetium-177, or Pluvicto as we know it, versus an ARPI switch. And so in that study, the primary endpoint was RPFS. Also looked at OS as some secondary endpoints. And the primary endpoint was met. So really we're seeing a hazard ratio of 0.49. This brings up, again, another kind of mix into the pre-chemotherapy setting for patients with metastatic CRPC. This sort of comes into play, as clinicians, of who are choosing these types of treatments for our patients?

Zachary Klaassen: Yeah. That's another great summary. And I think this is all set in the landscape for my next question. Because when we look at the landscape now, we have radium plus enzalutamide, we have Pluvicto after ARPI, and we see that even in the United States, up to 50% of patients are just getting ADT before they become mCRPC. I think the radium plus enzalutamide story has a lot of benefit, even in the current landscape with patients getting monotherapy. How do you see radium and radium-223 plus enza in that landscape, and especially with this new nuance with lutetium moving up a little bit?

Kristine Lacuna: I think that's a great question, and I think it's a tough question for us as clinicians.

Zachary Klaassen: It is.

Kristine Lacuna: So in my practice, where I practice in the United States, certainly there has been a shift. We're seeing ARSIs being used in the earlier and earlier settings, especially in the metastatic hormone-sensitive setting. And now we're seeing it in the locally advanced and local disease. So these patients who are coming in who have only progressed on ADT, they're becoming fewer and far between.

Zachary Klaassen: Sure.

Kristine Lacuna: I think certainly in kind of a broad, that's a slightly different story, but I still think that looking at the data from PEACE-3, there's certainly still a role here.

Zachary Klaassen: Sure.

Kristine Lacuna: Obviously, if that patient does come in and they're progressing on ADT alone, of course I would use it. I think I still see that sometimes occasionally. We get referrals from the community and they've been on ADT for a while and now they're progressing. I will certainly try to apply the PEACE-3 data there.

Zachary Klaassen: Yeah.

Kristine Lacuna: It becomes a question of, when we have patients who are progressing and they've already been on an ARSI, but with the PEACE-3 data given knowing that the remarkable outcomes that came of it, I might start to think, what about the second-line hormonal therapy setting? What about those patients who have been on enzalutamide and maybe are progressing only in bone?

Maybe I would think to myself, "Oh, what about potentially adding radium-223 to that to increase the longevity of them being on enzalutamide?" Maybe there's an additive or a synergistic effect given Dr. Gillessen's data.

Zachary Klaassen: Sure.

Kristine Lacuna: So I think that as a community here in the United States and places that are incorporating ARPIs earlier on, I think how we'll be applying the PEACE-3 data maybe in more so the ARPI switch setting with the second-line hormonal therapy setting, but specifically in bone only progression disease.

Zachary Klaassen: That's a great answer. And I think these are why these conversations are good, because we're trying to sequence these almost in real time. Every meeting we come to, there's new data, and we'll have these conversations again after ESMO, I'm sure.

I think when we look at the landscape, and you've summarized these trials beautifully, just like a quick hitter. What patient are you thinking about radium-223 plus enzalutamide? What patients are you thinking about lutetium? Just so that's almost like a take home message for our listeners.

Kristine Lacuna: Yeah. No, that's a great question. I think if someone who's presenting to me who's been on enzalutamide, or maybe abiraterone before, and you're thinking of switching them, or you think of... I would consider either adding radium on top of enzalutamide for those who are only progressing in the bone.

Zachary Klaassen: Yeah. Good point.

Kristine Lacuna: Those are the patients that I really think, okay, maybe I can extrapolate the PEACE-3 data for.

Zachary Klaassen: Sure.

Kristine Lacuna: If someone is coming in and they have soft tissue disease, or disease that's outside of the bone, then I think radium is sort of out of the question here, and then I would certainly consider Pluvicto for these patients.

Another factor that I think us as a community, as oncologists and urologists, have to think about is that radium-223 and enzalutamide are drugs that have been around for a really long time. Pluvicto is not as accessible.

Zachary Klaassen: Sure.

Kristine Lacuna: Certainly in the places that I've worked and practiced, it was never a question whether Pluvicto was available.

Zachary Klaassen: Yeah.

Kristine Lacuna: But that is a question in Alaska or some other place.

Zachary Klaassen: Great point.

Kristine Lacuna: And so, when I think of patients who can't get access, I think that it's reasonable to consider radium plus enzalutamide in these cases.

Zachary Klaassen: That's a great point. Anything we haven't hit on? Any concluding statements you want to give our listeners?

Kristine Lacuna: Yes, I do. So PEACE-3, I think one of the great things about the study was that the investigators of that study really learned from prior studies. The ERA-223 study was a similar study that looked at abiraterone plus radium, and in that study there was an increased risk for fractures.

Zachary Klaassen: Yeah. Good point.

Kristine Lacuna: And so, I think that if anyone is considering treatment based on PEACE-3, they need to include that bone-modifying agent. I would actually say that it's more triplet therapy-

Zachary Klaassen: Totally agree.

Kristine Lacuna: ... in that it has to be bone-modifying agent, plus radium-223, plus the enzalutamide. Because that is the way that we're protecting our patients. The safety profile was quite tolerable for the addition of radium-223, but only because the investigators learned from that prior study.

Zachary Klaassen: Yeah. No, it's a fantastic take home point. Anytime we can elevate bone protective agents on this website, we're going to do it. So I love that take home point.

Kristine, great discussion. Thanks for joining us on UroToday.

Kristine Lacuna: Thank you for having me.