Kim Chi: Thanks so much for having me, Oliver.
Oliver Sartor: You presented a really provocative trial, Canadian trial, and it's called the PLUDO trial. And here you looked at lutetium, you looked at docetaxel, metastatic CRPC, did a crossover, gave us some really interesting results. I wonder if you could take us through that. I think our readers will really be interested.
Kim Chi: Happy to do that. And I'll do a quick 5-minute summary of the presentation I did at ESMO 2025 just this past month or two. So the PLUDO study is a randomized phase-II study of lutetium versus docetaxel in patients with metastatic CRPC. Now, here's a summary of the study design, and it's fairly straightforward. Patients with metastatic CRPC that were chemotherapy-naive and progressing after an ARPI, as well as having PSMA PET-positive disease, were randomized 1:1 to receive either lutetium at standard dosing or docetaxel, again, at standard dosing and schedule. The primary endpoint was radiographic progression-free survival. But what's interesting about this study design is that we allowed crossover on protocol. So patients were actually followed on protocol afterwards on the crossover to look at rPFS2. And reason being is that we wanted to get an idea of what is the effect of sequencing, if any, of these two agents. And as I mentioned, the primary endpoint was radiographic progression-free survival with the first-line treatment. Here's the patient disposition, and it's a complicated and dense slide, but I just wanted to pull out a couple of key points.
One is that for patients that had to discontinue treatment prior to completion, there was only one patient on the lutetium arm, 1%, that had to discontinue because of a treatment-related adverse event. Versus on docetaxel, there was 15, or 15% of patients, had to come off because of a treatment-related adverse event. Another key point in the patient disposition is that more patients on the docetaxel arm crossed over to receive lutetium, 56 patients, versus 38 patients on the lutetium arm crossing over to docetaxel. This is almost a 20% difference between the two arms. Here are the baseline characteristics, and essentially they are as expected for a patient population going on to chemotherapy, and roughly 20% of them had visceral metastases. And also of note is the PSMA PET SUV mean, it was around 9.1 for the entire population. The median SUV mean was 9.1. This is pretty similar to the VISION trials as well as the PSMAfore trials. For the primary endpoint of radiographic progression-free survival, there was no difference. Hazard ratio 1.01. We looked at various subgroups and there was no differential treatment effect across subgroups, and we even looked at median SUV mean. And previously in the TheraP trial, for example, a higher SUV mean led to better responses with lutetium versus patients with a lower SUV mean.
However, what we found is that there was no difference, actually, between docetaxel and lutetium, regardless of the SUV mean. And in fact, for patients that had a low SUV mean, the point estimate hazard ratio was 0.78 in favor of lutetium over docetaxel. So again, no differential treatment effect. Interestingly as well, the median SUV mean was also prognostic, meaning patients with a higher SUV mean had better outcomes than patients with a lower SUV mean, regardless of the treatment. Disease responses were twice as high in the lutetium arm compared to the docetaxel arm, both for PSA decline as well as objective response in patients with measurable disease. As could be expected from the number of patients coming off protocol treatment early because of adverse events, there were more adverse events in the docetaxel arm. In fact, 34% of patients on the docetaxel arm had grade 3/4 treatment-related adverse events versus 13% in the lutetium arm. Furthermore, there were 2 treatment-related deaths, both of them in the docetaxel arm. I think what was the big surprise for myself, as well as everybody else that we presented this to, is the overall survival results, and the hazard ratio was 1.64, and the nominal 2-sided p-value was 0.02.
Patients randomized to docetaxel first had a median overall survival of 18.2 months versus those with lutetium, the median overall survival was 14.3 months. So just to sum up the primary endpoint, there is no difference in radiographic progression-free survival between lutetium and docetaxel. However, other endpoints favored lutetium, including a higher proportion of patients with a response, either PSA or measurable disease, almost twice as high as docetaxel, and much fewer grade 3/4 adverse events and treatment discontinuations. There were no subgroups that seemed to benefit preferentially from one treatment or another. Now, the overall survival is longer in patients initially randomized to docetaxel, and my hypothesis is that this is possibly due to the higher treatment crossover rate from docetaxel to lutetium. And I guess the big question is, well, why is that? Why was there that differential and crossover treatment? So that's a quick summary of the result, and I'm happy to discuss further.
Oliver Sartor: Thank you. It is really fascinating. And I wanted to ask a couple of questions and I'll probably reflect much in the community in these questions. Chemo fit, these patients were obviously a little different than PSMAfore patients who were kind of appropriate for a second-line ARPI. In your mind, you mentioned the visceral metastases, which is pretty high, but were there patients that you would say would've been appropriate for second-line hormones, or is it just really chemotherapy-type patients who also managed to cross over on the Pluvicto arm?
Kim Chi: Yeah, patients had to be agreeable and being considered for chemotherapy in order to go on this trial. So again, this is very different from the PSMAfore population where patients really had to be candidates for an ARPI switch. And yes, there's overlap between that. So there's some patients that we know that there was about 5%, 10% of patients on PSMAfore that had visceral metastases, and most of these were probably lung metastases. Well, in our trial, a lot of the visceral metastases were liver metastases, which is something you don't want to wait for. So I think it is a patient population that's 6 months down the line from the PSMAfore kind of population. The question of crossover is an interesting one. My initial hypothesis is that patients went on this trial to get lutetium. Lutetium was not available at the time, except for on trial, and I think patients went on this trial to get lutetium.
So if they got randomized to docetaxel, they were very motivated to get lutetium. And honestly, I think lutetium is easier to give after docetaxel. Now, for those that had gotten lutetium first, they were happy and I suspect that many didn't want to go on to the docetaxel afterwards. Also, docetaxel can be harder to give after a subsequent line of therapy once patients have progressed. So I think that might be the reason for the difference in crossover.
Oliver Sartor: Yeah. Really interesting. It was pretty distinct. 56 versus 38. Now, it looks like, even for docetaxel, there were probably patients who did not cross over. And maybe they were too sick, maybe they were traveling from a long way away and it was just difficult to be on the trial. I don't know. But even 56 out of the original docetaxel group is not nearly complete, whereas 38 is really low.
Kim Chi: So this is at the time of the analysis, and at the time about 80% of patients had progressed, so a proportion of those, 20%, have not progressed yet, and so are not eligible to crossover. So I think that's one factor, some of those. And so that ends up, if you look at the numbers, generally we see if crossover is freely given, 60-80% of patients end up crossing over in all our previous phase-III trials that we've done. Because about 20% of patients haven't progressed yet, so they're not eligible to crossover, and then another 20% of patients just progress so quickly they don't get that next line of therapy. So I think it's about in line with what I would expect, that 50%, 60%. I think where it didn't meet the expectations is crossing over from lutetium to docetaxel. And really the question becomes, is it because they didn't want to or were they not able to clinically? So we're diving into that question now.
Honestly, this was unexpected. We did not expect to see this differential in crossover. So getting at the answer as to why they didn't crossover is actually not that straightforward. We didn't have a specific question in the case report forms as, "Is the patient not crossing over? Why?" And so we will have to look at that in a circumstantial manner or indirect way. So looking at their performance status after they came off protocol therapy and so on. I think the other question is also, how effective was the second-line therapy? Is there a biologic difference? The analysis I showed was all intention-to-treat. So what we're doing is a per-protocol analysis. For the patients that actually receive both lines of therapy, what was the outcome with second-line therapy? What was the outcome of both first and second-line therapy? So hope to present that in an upcoming meeting. We're just doing the analysis now to look at it. So what are the reasons for not crossing over or crossing over? And then also, what's the per-protocol analysis for patients that got both lines of therapy?
Oliver Sartor: Yeah. No, great questions. And I think the prostate cancer community would be very interested. I couldn't help but notice, in the PSA response for docetaxel, it was only 16% was really low. And for the lutetium is 36%. Low, but goodness gracious, what were your thoughts about that very low response rate? I was surprised by that.
Kim Chi: I was surprised by that too. And first thing, is the data right? So just making sure we're going back and going back through all the individuals. This was a late-breaker abstract, so I got the data in September and basically the data's the data from the statistical analysis plan. So we are going back to look at individual patient data all through that again to confirm if that is true. Because it's low for both of them. With the lutetium consistently, the PSA response rate, it's about 50%. And similarly with docetaxel, if you look at most recent trials, it's about 30-50%. So one question is, is the data accurate? Was it calculated accurately from the databases? So we're going back and looking at that specifically. But if it is low, it could just reflect really this was a practical study and really, I think, enroll the very representative population of patients. And so essentially if they were eligible for chemo or eligible for lutetium, they could go on this study. And so there wasn't that strict criteria sometimes that we can see with industry studies. This was a cooperative group study. So I think it does represent real life. But yes, first thing to do is confirm if the data is correct.
Oliver Sartor: Yeah. Just for thinking out loud, for the VISION study, I think PSA confirmed 50 was 46% and the others was a little over 50. I think the initial report was 54, it may have drifted down a little bit. But yeah, even the lutetium was a bit low. The survival also sort of surprised me. In PSMAfore, people were coming in about 24 months. Here in lutetium arm, it was actually only 14.3. Also, I looked at that, I said, "Oh, my goodness, that was a little unusual." I wanted to hear your thoughts about why the overall survival seemed to be even worse. I mean, that's worse than VISION. VISION was 15.3 on median, but these patients were chemotherapy-naive. Whereas for VISION, everybody had one taxane and many people had two. So let me hear your thoughts on that a little bit, if you don't mind.
Kim Chi: Yeah, first of all, let's take the docetaxel arm, even though they got lutetium afterwards. If you look at that docetaxel arm, it's about 18 and a half months. Docetaxel outcomes have been very consistent. The initial TAX 327 study median overall survival of q3-weekly was 18.9 months.
Oliver Sartor: 18 months. Yeah.
Kim Chi: And this past KEYNOTE study with docetaxel and pembrolizumab, the docetaxel every three-weekly arm was 19.0 months. That one just got published this past year. So it's been very consistent over 20 years. And so the docetaxel arm was consistent with what we've seen. A little less, but really consistent with other phase-III trials. So yeah, the lutetium arm did worse. And I suspect it's because, again, it's reflecting a real-world population that's going to receive lutetium and going into this trial and not getting the selection criteria. PSMAfore, of course, was very early pre-chemo patients. And you can tell that by the control arm. ARPI switch, they got 6 months. No trial has ever seen 6 months from an ARPI switch before. It's always been around 3 months. So I think it really tells the population it's a slower, progressive, earlier population.
And then I think VISION is doing better because those patients made it through one, two, three, four lines of therapy. And as we talked about earlier, usually after every line of therapy, there's 20% or 30% of patients that just don't make it to the next line of therapy. And so that's what we're capturing here. I think we're capturing real-world first-line therapy. I also think it stresses the importance of subsequent therapy. Like, if you don't get your next good lines of subsequent therapy, you're sacrificing your chances of better survival. And why I really think it's crossover that's affecting the survival difference is because if you look at post-protocol subsequent therapy like radium-223, cabazitaxel, and so on, it was the same in both arms. There was no difference. First-line therapy is the same. Post-protocol subsequent therapy is the same. The only difference is that difference in crossover. So it really does emphasize that subsequent therapy is important, we need to be capturing that in our clinical trials, but also it influences survival.
Oliver Sartor: Kim, that's a really beautiful overview of a study that, again, has engaged the prostate cancer community. People are talking about it. Congratulations for running the study. It was not easy in its overall design because so many people really do want the lutetium. They may just say no to the chemo. Nevertheless, you pulled it off. It's a great addition to the literature. Thank you for leading. And I'll simply say thank you for being on UroToday and enlightening our audience.
Kim Chi: Thank you, Oliver. Happy to be here.