Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urological oncologist at the Georgia Cancer Center. Welcome to ESMO 2024, Prostate Cancer Insights on UroToday. I am delighted to be joined for discussion with Dr. Oliver Sartor, who is a medical oncologist at Mayo Clinic in Rochester, Minnesota. Oliver, thanks so much for joining us today.

Oliver Sartor: Oh, delighted to do this, Zach. Looking forward to the discussion.

Zach Klaassen: It was a historic ESMO for many reasons. We saw multiple huge trials across the GU landscape, but specifically among prostate cancer. And so I'm going to pull up some slides for our discussion today, to go through three really important trials that we had presented in Barcelona.

Oliver Sartor: Thank you very much, Zach. And I'm going to be presenting some of the highlights from three particularly very important trials presented at ESMO 2024. This will be the ARANOTE, the PEACE-3, and the SPLASH.

The ARANOTE is hormone-sensitive prostate cancer. Here we go. And it's a Phase 3 trial, and this is presented by Fred Saad. One of the things—a little bit of background—so the ARASENS trial laid the foundation for darolutamide in the metastatic hormone-sensitive space, but the control group was ADT/docetaxel, and it was plus or minus darolutamide. Here we have a lot of simplicity, because it's just going to be ADT plus or minus the darolutamide. And again, Fred Saad presented this very important study.

Here's the design: metastatic hormone-sensitive prostate cancer, some stratification factors are visceral mets, prior local therapies. Randomized to ADT plus darolutamide in a two-to-one ratio, versus placebo plus ADT. And looking at the primary endpoint, rPFS, along with a variety of secondary endpoints including overall survival.

Primary endpoint—you can see, hit it really nicely. rPFS gone from a median of 25.0 months in placebo plus ADT, not yet reached in the darolutamide plus ADT. Hazard ratio very strong, 0.54. p-value less than 0.0001. Very nice primary endpoint. Now think a game changer here.

Pre-specified, there are a variety of pre-specified endpoints. You can see almost everything is going to be favoring darolutamide. A little bit of a call-out on disease volume—a little bit interesting. The lower volume patients seem to do particularly well. Look at that hazard ratio down in the 0.3 range, exceptionally strong for the low-volume subset.

Secondary endpoints: the overall survival is trending in the right direction. Hazard ratio is 0.81, still relatively immature, relatively small number of events—only 23.1% of the patients to reach an OS endpoint. Time to metastatic CRPC, positive. Time to PSA progression, positive. Time to initiation of subsequent systemic therapy, positive. And also positive for time to pain progression. So it's nice to see this trend across the multiplicity—the endpoints all favoring the darolutamide arm.

TEAEs of special interest: we have become accustomed to seeing a very good darolutamide AE profile, and we see it again here. There's very little differences between the placebo and the darolutamide arm, whether or not you're looking at mental impairment, hypertension, cardiac arrhythmias, etc., etc. You know, we have a very persistent good AE profile with darolutamide. And also not shown here, but it doesn't have much in the way of drug interactions, which is also important in these particularly elderly patients, often with polypharmacy.

Next, moving on to PEACE-3, presented at the Presidential by Silke Gillessen. Silke's great, as you all know—she had a fabulous presentation. Here we're going to be looking at the first-line metastatic CRPC space, but without a prior ARPI. And the randomization, as I'll show you in just a second, is everybody's going to get enzalutamide plus or minus the radium.

Here's the trial design: everybody had to have bone metastatic disease, which we would expect for a radium trial. Asymptomatic or mildly symptomatic—a little bit interesting there, because of course, radium had been approved for those who are symptomatic in the past. Good performance status. No prior treatment with enzalutamide or radium-223. No known visceral metastases, and ongoing ADT. I will say that there are very, very few patients with a prior ARPI of any type, not just the enzalutamide. Very few patients, so any type of ARPI.

Randomized to receive enzalutamide in both arms or the radium plus the enzalutamide. Primary endpoint rPFS, with a variety of secondary endpoints, including safety and overall survival. Very, very important.

Initially, the trial did not include bone-protecting agents—things like zoledronic acid or denosumab. In the initial phases of the trial, there were a substantial number of fractures, and as a consequence, the DMC mandated the inclusion of bone-protective agents in both arms of the trial. This is not just radium/enzalutamide/ADT, it's radium/enzalutamide/ADT and a bone-protective agent.

Primary endpoint, very clearly positive, hazard ratio of 0.69. Interestingly, you can see as time goes beyond the median that the curves split even more. But nevertheless, you have a good log-rank p-value, 0.0009. So unequivocally positive here for the rPFS primary endpoint.

If you look across the multiplicity of parameters within the forest plots, again, you see everything pretty much favoring the enzalutamide/radium arm. Important to see these pre-specified subgroups all being positive.

And here's the overall survival. And I'll mention, there's a little bit of controversy about the early quote, potential crossover in the arms in the initial phases prior to 18 months. I do want to make a statement, and that statement is, that differential that you see visually is not statistically significant. It was looked at—the confidence intervals are going to overlap completely between the two arms during these first 18 months. Then you go on and you see the split. And you see the hazard ratio of 0.69. The log-rank p-value is 0.0031. This does meet the pre-specified endpoint. And I'll simply say that it looks positive from a clinical perspective to me.

Now, statistical issue: there was some non-proportional hazards in the testing, and that is part of the pre-testing in the log-rank value analysis. So there are those statisticians who believe that we need to look further with more follow-up. I'm fine with that. But to me, this is a positive study right here, right now.

Safety: we do notice that there are more fractures—you can see in the arrow, 5.1% versus 1.3%. Please remember that initially the bone-protective agents were not included; later on, they were. When the bone-protective agents were included, this all seemed to balance out quite nicely. Otherwise, I think you see a very well-tolerated radium therapy. And I'll simply say that for those patients without a prior ARPI, that this is a practice-changing trial in my mind.

SPLASH trial: actually, I presented the SPLASH trial in Barcelona. This is the lutetium-177-PNT2002. This is also known as PSMA-I&T, and it is the SPLASH trial. All of these patients had PSMA-positive disease, and all of these patients have prior progression on an ARPI.

The SPLASH trial incorporates a trial very similar to what was seen with the PSMAfore trial. Here we get the PSMA-I&T with lutetium. Please note, the control arm, alternate ARPI, enzalutamide or abiraterone. Please note that the PNT2002 is being given as monotherapy, unlike, say, the ENZA-p trial that was presented by Louise Emmett, where she used enzalutamide plus or minus a lutetium-based therapy. rPFS is the primary endpoint.

The crossover—the crossover is really important here. Patients on the control arm who progress by central radiographic progression review could be allowed to cross over to the lutetium arm. 84.6% of the patients eligible for crossover in fact did cross over. So what we're going to see is we're going to see an rPFS that is not particularly altered by the crossover, but subsequent events, such as the overall survival, are going to be altered by this 84.6% crossover.

Primary endpoint, positive rPFS. You can see the hazard ratio, 0.71. p-value is 0.008. Confidence intervals do not overlap 1.

rPFS across a variety of pre-specified endpoints are positive. I'm going to do a little bit of a call-out. If you go down, second from the bottom, and look at the baseline PSA. If the baseline median is going to be on the low side for the PSA, the hazard ratio is pretty close to 1. That's because the patients on the control arm did exceptionally well, even with the secondary hormone. With these low PSAs, people do quite well with the secondary hormonal manipulation. On the other hand, if the PSA was greater than median, you can see that the hazard ratio was down to a 0.5, so very strikingly positive. So there was a distinction, in my mind, between those with the higher and the lower PSAs in this particular trial.

Overall response rate, again favoring the lutetium arm. You're going to have 38.1% versus 12%. p-value 0.0021. So again, favorable.

Interim overall survival analysis, first in. Hazard ratio is 1.11. We're looking at median around 20.8, and no distinction between the arms. But please remember that 84.6% crossover, which I think will dramatically alter the overall survival assessment. There's going to need to be more follow-up here.

Treatment-emergent adverse events favoring the lutetium arm. Here you can see those greater than grade 3, 30.1% versus 36.9% for an alternate ARPI. The serious TEAEs, 17.1% versus 23.1%. TEAEs related to death, I mean, 1.9% versus 3.8%. This is a very, very, very well-tolerated therapy. TEAEs with discontinuation, 1.9%. And lutetium, 6.2% in ARPI. Reduction in the dose, 1.1%. So again, very well-tolerated therapy.

Clinical implications: ARANOTE—a second pivotal trial of darolutamide, but this one is not inclusive of docetaxel. So we have a second metastatic hormone-sensitive prostate cancer-positive trial, this time without docetaxel, which I think will have clinical utility, because not everyone gets chemotherapy in hormone-sensitive disease.

PEACE-3: combination of enzalutamide and Ra-223 and a bone-protective agent is a new first-line metastatic CRPC treatment option, in my opinion, for those that had not received a prior ARPI. This is going to have to go to the regulators, and they're going to have to give an opinion.

SPLASH trial: second radioligand option. Here we have lutetium-PNT2002, otherwise known as I&T, presenting with a positive study in patients progressing after an ARPI. And I'll simply say, also have to see how the regulators will approach this one.

Thank you very much, Zach, for the opportunity to present three large, three important trials that came through at ESMO 2024.

Zach Klaassen: Yeah. Great job, Oliver. Thank you so much for your insight and expertise. It really was a wonderful meeting. It gets us excited for what's coming up at GU-ASCO in 2025. But we've seen some practice-changing data at this meeting, and your concise expert opinion was awesome today. Thank you so much.

Oliver Sartor: Glad to be able to do it. And I was in Barcelona, I was able to personally attend all the presentations. Fred Saad did a great job. Silke Gillessen did a great job. So it's really a pleasure to be able to see it firsthand at ESMO.

Zach Klaassen: Absolutely. Thanks again, Oliver.

Oliver Sartor: Okay. Bye-bye.