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Thomas Hope: When we put this together, we thought, "Hey, let's do a session. We compare these three trials," because it's interesting that there are nearly three identical trials in the same space and there's obviously a lot of discussion about these three trials. We tried to find speakers for each of them.

Mike Morris is obviously very involved in PSMAfore. Oliver's involved pretty much in everything but also SPLASH, and I've been involved in ECLIPSE. We're going to very briefly go through each of the three trials and slides, and then we're going to sit down, in essence, have a discussion amongst ourselves. And hopefully, people will come to the podium and ask questions about the three trials to sort of understand why there are three of them, what are the differences, etc., and learn from each other.

And I'm going to keep talking until Michael decides to walk back into the room. There's one slide before... That's not the next slide. Okay. That was the right arrow. Can you just hit the next button for me? Okay. That's unusual. Can you just go to the second slide? There we go. Okay. That's now too far. There we go. Okay. Just to remind ourselves, Michael, we're coming up here.

Michael Morris: Will do.

Thomas Hope: Yep, you will do. Right now, Lutetium PSMA end stage, post-chemotherapy, post-abra, Enzalutamide, last line of therapy VISION trials compared to a control arm with minimally effective therapy. Very useful trial because it led to the approval of the drug. And the goal here is to move the drug earlier in the stage of disease. Okay. We're trying to move this pre-chemotherapy, post-RC, and that's where these three trials are sitting. I'm going to have Mike come up now and talk for the next three slides.

Michael Morris: It's funny how when you're at a conference, the patients don't respect that. Alright. PSMAfore, and once again, I'd have to say that there are many, many people who participated in getting this trial done and the success of this trial. And just want to express everyone's gratitude in terms of working together to get this done. And it was a successful study. And also to the sponsor of the study.

PSMAfore is a registration trial for looking at Pluvicto in the metastatic CRPC pre-chemotherapy context. And the way that this trial worked was patients progressed prior to study entry on an ARPI. And then they were randomized to either Lutetium-177-PSMA-617 at 7.4 GBq once every six weeks for 10 cycles, or to an alternative ARPI. Either enza-to-abi or abi-to-enza for the majority of patients, but there was no exclusion on apalutamide or daro as well.

They needed to meet basically VISION criteria for their PSMA PET selection criteria for study entry. And they could not have received chemotherapy except for the unusual circumstance of having neoadjuvant therapy for their primary disease. Importantly, if these patients were HRD, they were not eligible to go on this trial; it was felt more appropriate for them to receive a PARP inhibitor in that early context based on other clinical trials. And it was felt that going on to this study would not be an appropriate alternative to getting treated with their PARP inhibitor.

The primary endpoint was radiographic progression-free survival by the Prostate Cancer Working Group 3. Stratification factors were the prior ARPI that was used, i.e., whether the sequence was abi then enza, or enza then abi. And the BPI-SF, i.e., were they in pain?

A consolidated slide looking at all of the outcome measures, the primary outcome measure is rPFS. You can see that you can really drive a truck through that airspace there between the two lines, essentially doubling the median rPFS from 5.59 months to 12 months with a hazard ratio of 0.43. And the second look that Oliver had presented at ESMO, that primary look was in the context of the press release, the SEC required press release back in December of last year, pretty consistent and without change.

Now, the crossover rate between these two arms was 84%. That is one of the highest crossover rates in prostate cancer. You would not expect necessarily to see an OS benefit in this context since this really ended up being a Pluvicto early or a Pluvicto later study. And remember that the median rPFS was six months for the control arms. There's a six-month difference between that crossover.

And there was an OS-adjusted look at the crossover versus the ITT analysis of OS. And they both are really preliminary. This reflects only 45% of the anticipated deaths that were pre-stipulated to be necessary for an assessment of overall survival. I just caution everybody, these curves here are immature, very early. What you're looking for here with an 84% crossover, though, is essentially no difference in OS as opposed to really expecting to see OS play out.

This consolidated slide shows all of the interim endpoints as well as the safety data. You can see again there is a 50% combined CR and PR rate from a radiographic response perspective. Although the ratios are different than VISION here. Instead of a 10% CR rate, we saw a 20% CR rate. PSA50 is in favor of Lutetium as opposed to the ARPI. And the quality of life once again is also in favor of treatment with Lutetium rather than the ARPI.

What's important to recognize, especially when you're talking about an endpoint of disease control, is that the ARPI arm had a more difficult time in terms of toxicity than the patients receiving Lutetium. If you look at the SAE rate, the grade three to four event rate, or the dose adjustment rate, all really in favor of Lutetium. Three and a half percent of patients needed a dose adjustment with Lutetium. 15% needed a dose adjustment with the ARPI.

The side effect profile is one which again, one would expect with Lutetium. But what's of note is how much lower the hematologic toxicity side effect profile is in this earlier patient population relative to VISION. That's it for that summary of PSMAfore.

Thomas Hope: Okay, Oliver, you're up.

Oliver Sartor: Thanks, Mike. One of the things I did want to draw a contrast with actually was the VISION versus these three particular trials. VISION had a standard of care plus or minus Lutetium. The FDA actually forced the issue into the alternative ARPI. There is no utilization of a standard of care in combination with Lutetium arm in these three trials. That was an FDA decision. It was not necessarily an investigator decision. I think that's pretty important.

Mike, there's one small point I wanted to add, not a clarification, but just an addition to PSMAfore. If you actually look at the number of events in the survival, it turns out that only about 27 to 29% of the overall potential events have been reached. Even though it's about 45% of the statistical analysis plan, your note on immaturity is absolutely correct. These are pretty immature data and that 84% crossover is remarkably high.

We're going to see that same, by the way, 84% crossover in SPLASH. I'm going to draw a couple of distinctions between PSMAfore and SPLASH. And there were some small differences. Number one, and I'll just compare and contrast for a brief moment. The selection criteria were basically the same. It's basically VISION criteria on the PSMA PET.

You could take docetaxel in this particular trial, in the SPLASH trial if it was given more than one year preceding. Now, within the use of the PSMAfore patients, it could only be adjuvant or neoadjuvant. And here you could actually receive Taxotere in a more advanced setting. There were, I think, about 27% of the patients or so who had more advanced disease when they received the Taxotere, but it was more than one year ago. That's an important distinction. The no prior treatments for the PARP inhibitors are also there. And I'll simply say that the rest of the features are pretty similar.

One other small addition to Mike's comment, and I think this is a little bit important, the emphasis was on making sure that the patients were not really candidates for chemotherapy. If you saw in the PSMAfore trial, it was 5.56 months for the control group rPFS. Here you're going to see 6.0 months. These are pretty good for rPFS change. If you go to some of the trials like the Ambassador 250s, you can see lower ARPI PFS changes.

For instance, we're going to be looking at 3.4, 4.1. I'm quoting different trials. But the bottom line is these trials turned out to be a little bit different. And I think these patients were in fact chosen to be appropriate for a second line to ARPI. Same rPFS by Bicker, same crossover on confirmation. Now we don't actually have the full scientific presentation, so I had to lift from the press release. And I'm going to say that the rPFS was 6.0 versus 9.5. That compares to 5.56 versus 12.02.

The hazard ratio here turns out to be 0.71. And I think there's, I'll just say it, disappointment in that 9.5. And the 6.0 turned out to be a little better than expected. If I were to project beforehand, I would've probably said somewhere around four to five, maybe 4.5 in the control arm and it came out six. The control arm was better.

And then when you have a 9.5, there's actually a lead-in, and that lead-in was presented at ESMO. And the ESMO data in the lead-in was 11.0 months. I think the expectation going in was somewhere around 11.0 to 4.5 or five, which would get a hazard ratio much closer to 0.45 or 0.5, somewhere in that area. The 0.71 was a bit of a disappointment. And we're going to talk about why. I think it's probably dose. And it's dose and interval both because I didn't really mention but should have the dosing is different here. And the dosing was 6.8 Q eight weeks instead of 7.4 Q six weeks. I should have mentioned that on the previous slide, but forgot to do so.

The crossover, and it's rather remarkable, 84%. Mike had mentioned how high the 84% was in PSMAfore. Here it is again. It's rather unbelievable. If you go to other trials in the space, it's really incredibly high to see this type of crossover. If you look at another really high crossover trial, for instance, the PROfound trial with Olaparib, that was around 66%. A little bit different for these patients, who really want to get the isotopes.

Hazard ratio for OS in the intent to treat, 1.11. That compares to 1.16 for PSMAfore. Almost identical. Now, "almost identical" refers to the 27% of events of the totality. That's not the statistical analysis plan. That's of the total patients randomized. Still a pretty early look. You end up with 46% of the SAP finalized events. But actually, I prefer to look at it in the totality of events because I think it gives a little better picture. It's still pretty early.

I don't have all the listings of the AEs. One of the things that's remarkable about the PSMAfore trial is how the AEs were less than hormonal therapies. The AEs are fantastic here. This is a really, really well-tolerated regimen. And I think with that, that's pretty much what I wanted to cover. Thanks.

Thomas Hope: Okay. Well, I get the easiest job here. I present the one trial that doesn't have any results to talk about, but it's also very interesting in comparison. The ECLIPSE trial. ECLIPSE is run by a company called Curium, which is actually the largest distributor of radiopharmaceuticals in the world. Not really a pharmaceutical company in terms of developing therapeutic drugs historically. But moving into this space.

And it's interesting because it's very similar to SPLASH. It uses Lutetium PSMA-I&T. It's unusual because this is a generic drug. It wasn't patented. Anyone can go out there and run a trial. We got two companies at the exact same time running the same trial in the same patient population. It's interesting to see that. Now, there are a couple of really important distinctions here.

First of all, you can see that the dosing here is 7.4 Gbq per cycle every six weeks. It's actually the dosing that is in PSMAfore. There's a difference between SPLASH and ECLIPSE in terms of the dosing. But otherwise, the inclusion criteria for ECLIPSE are actually similar to SPLASH. Again, it allows docetaxel in the CSPC setting as long as it's 12 months out. It does have this, if you have an HR mutation, you've had to previously have had PARP. You could have had PARP inhibitors but requires you to have had it if you have a DNA repair defect in your genetic analysis.

Overall, completed enrollment. Oh, the other difference here is there's a two-to-one randomization. If I'm not mistaken, SPLASH had a one-to-one randomization. This is a two-to-one randomization. But right now, we completed enrollment at the end of last year. And so, we'll be finding out where this sits in between. And I think to me, you have these two spectrums of SPLASH and PSMAfore. And where we're going to fall out with ECLIPSE, we don't know. And essentially, it's a remarkable circumstance you don't see very often in drug development where you have a generic drug being run in two different trials at the same time. We'll see where it ends up.