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Zach Klaassen: Hi, my name is Dr. Zach Klaassen, I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm pleased to be joined today by Dr. Alan Bryce, who is the chief clinical officer at City of Hope in Arizona. Thanks so much for joining us today.

Alan Bryce: Thanks for having me, Zach.

Zach Klaassen: We're going to talk today, we just had a really exciting ESMO Meeting, we heard about PSMAfore, and just to summarize for our listeners, this was lutetium versus, essentially, abi or enza. In, essentially, the second line, so this is pre-chemo for mCRPC. We already have, obviously, the VISION post-chemo, this was pre-chemo. Very exciting trial, people were excited about looking at the results, so we saw a very significant rPFS benefit for the lutetium arm hazard ratio in the second interim analysis was 0.43.

Alan Bryce: Yeah.

Zach Klaassen: Overall survival, immature data. The adjusted hazard ratio was 0.8, maybe trending towards benefit, but obviously, early results. Just based off of that, thinking about the data, what are your initial thoughts on this trial and the data?

Alan Bryce: Yeah. Absolutely, it was an exciting trial, we've been anticipating this. This is a trial that was very easy to accrue through, right? Patients wanted to get their lutetium. I think the results are as expected. I'm not the least bit surprised, lutetium is a good drug, or Pluvicto, lutetium PSMA is a good drug.

Zach Klaassen: Yeah.

Alan Bryce: It works in the appropriate patients, right? With PSMA-directed therapies, we need to do the PSMA PET scan first, make sure the lesions express the target, and if they do, the drug works at a very high level. No surprise, I think we all expected a positive study. There's the nuances that we're going to talk about in terms of the trial design, and then there's clinical questions we have to think about in terms of, "All right, so how does this apply to clinical practice?" I think we all expected the drug to work, we expected the study to be positive. No surprise, it's really strong results.

Zach Klaassen: It is strong results. I think you alluded to some of the nuances, and I think that's the beauty of this platform, talking about those and getting your opinions. I'll start it off by just saying that, obviously, the crossover that Dr. Sorter presented was 84% in the control crossing over to lutetium. Let's talk about that and what the implications of that are.

Alan Bryce: I think there's a few key design elements to think about here. The crossover is one of the most important pieces, no question. Patients wanted this drug.

Zach Klaassen: Yeah.

Alan Bryce: They still want this drug clinically, they want it on clinical trials, "Get it in the pre-chemo space."

Zach Klaassen: Yes.

Alan Bryce: As you know, I was involved in the TRITON study where we had a high crossover as well, and when I presented that study, I said at the time, "I absolutely believe that this design is patient-centric, it's patient-friendly, and it's ethical and appropriate."

Zach Klaassen: Yeah, that's all right.

Alan Bryce: I think the same arguments apply here. I think it would've been very difficult, and I would've been ethically bothered by the idea of saying, "You can go on this study, but if you get randomized to the control arm, then you've got to go get chemo before you could get your Pluvicto," because that's what it would've been.

Zach Klaassen: That's right.

Alan Bryce: Now, the problem with this, and the reason that most studies don't do this is because when you cross over, if you have an early crossover, there's a strong chance you're going to lose your OS signal.

Zach Klaassen: That's right.

Alan Bryce: That's exactly what happened in this study. The OS is non-significant at this point.

Zach Klaassen: Right, right.

Alan Bryce: Is it going to trend? Is it not? I'm not going to be the least bit surprised if this ends up as a non-significant OS, because of 85% crossover.

Zach Klaassen: Everybody got it at some point, right?

Alan Bryce: Absolutely, right? Really, in that sense, the OS is testing second-line Pluvicto versus third-line Pluvicto. I think we, as a field, have to take a position and we have to have some principled clarity here about, "Do we believe in crossover designs or not?" Because you remember, in the VISION study, there was no crossover.

Zach Klaassen: Right

Alan Bryce: Frankly, a lot of us criticized that, I certainly did. Patients were denied the drug, and what ended up happening is, as we know, people went around the country trying to enroll in the study over and over again until they got randomized to the Pluvicto. That undermined the study and delayed the results by a year or more, but because there was no crossover, you have an OS signal.

Zach Klaassen: Yeah.

Alan Bryce: Now, if we say from a regulatory perspective, "We absolutely have to have OS," then industry will necessarily respond by saying, "We will never cross patients over."

Zach Klaassen: Yeah.

Alan Bryce: I don't think that's the right answer. If I have a vote in this, I would say, "Allow the crossover, accept it, and accept the consequences that we know are going to manifest in the OS result."

Zach Klaassen: Yeah.

Alan Bryce: I am very comfortable with the OS signal that we see in this study, that's what I'm saying.

Zach Klaassen: I think, too. They knew that it was going to be a crossover, they had a pre-specified adjusted OS, so statistically, I think they did the right thing. I think from access and in real world, patients want the drug. This is a pragmatic way of doing a big clinical trial.

Alan Bryce: I agree.

Zach Klaassen: Now, I think the next question, a little bit on the same line of thought, is it's a very strong rPFS benefit.

Alan Bryce: Yeah.

Zach Klaassen: I think I know your answer to this, but that's enough to basically use this drug, assuming FDA approval and everything else, but I think that's a strong signal. Would you agree with that?

Alan Bryce: A couple of things. Look, the drug works.

Zach Klaassen: Yeah.

Alan Bryce: It absolutely works. The rPFS is one of the strong signals that it works, okay, but the other signal is the objective response rate.

Zach Klaassen: Yeah.

Alan Bryce: A CR rate over 20%.

Zach Klaassen: Yeah.

Alan Bryce: The partial plus CR rate was over 50%.

Zach Klaassen: Yeah.

Alan Bryce: Drug works.

Zach Klaassen: Yeah.

Alan Bryce: That's not in question. Now, fair criticism, and a fair criticism I ascribe to is the randomization was against patients who got their second androgen receptor pathway inhibitor.

Zach Klaassen: Yeah.

Alan Bryce: The eligibility is patients had to have already had abi or enza.

Zach Klaassen: Right.

Alan Bryce: Then they were crossed over to the one they hadn't already had.

Zach Klaassen: Yeah.

Alan Bryce: Now, look, we've seen this in study after study, right.

Zach Klaassen: Yeah, doesn't work.

Alan Bryce: The second one doesn't work.

Zach Klaassen: That's right.

Alan Bryce: Right?

Zach Klaassen: Not just in this country, Canada as well. There have been studies from all over the place. Yeah.

Alan Bryce: Abi after enza, your response rate is 10%, and enza after abi, it's higher, so it's a little bit better when you do that sequence. Nevertheless, you see it, you see the CRPR rate on the control arms like 15%.

Zach Klaassen: Yeah.

Alan Bryce: Right? It's terrible.

Zach Klaassen: As expected.

Alan Bryce: As expected.

Zach Klaassen: Yeah.

Alan Bryce: They chose a weak comparator, so you get a great HR of 0.4, but what is the other option in this setting?

Zach Klaassen: Yeah.

Alan Bryce: We did this in the TRITON study, this could have been randomized against docetaxel.

Zach Klaassen: Right.

Alan Bryce: That would have been appropriate, and docetaxel is the better drug in this setting.

Zach Klaassen: They still could have crossed over and gotten-

Alan Bryce: They still could have crossed over.

Zach Klaassen: Yeah.

Alan Bryce: Right. The FDA allows this, right?

Zach Klaassen: Yeah.

Alan Bryce: They approve the design, so we've got what we got, but we could stop and look. You could go back and look at the data that I had presented from TRITON, where we had dosing the control arm.

Zach Klaassen: Right.

Alan Bryce: Now, remember in TRITON3, the patients were all BRCA1 or two mutated. The disease was BRCA-mutated. We know that that's not just predictive of response to PARP, it's also prognostic.

Zach Klaassen: That's right.

Alan Bryce: That is more aggressive disease. On TRITON3, the dosage control arm had a rPFS of about eight and a half months. Extrapolating from that to PSMAfore, you might say, "All right, all comers, not quite as aggressive. Maybe the rPFS would've been nine and a half or 10 months estimate."

Zach Klaassen: Yeah.

Alan Bryce: We saw Pluvicto here was a little over 12 months, probably still would've been a positive study.

Zach Klaassen: Yeah, absolutely. It's a great point.

Alan Bryce: Right?

Zach Klaassen: Yep.

Alan Bryce: Just to finish the thought, because we want people to think about this comprehensively. VISION was the same thing, they didn't randomize against cabazi. In fact, they excluded cabazi.

Zach Klaassen: Yeah.

Alan Bryce: Cabazi would've been appropriate.

Zach Klaassen: Right.

Alan Bryce: TheraP did Pluvicto versus cabazi, and what you ended up seeing was rPFS benefit to Pluvicto, overall survival equivalence.

Zach Klaassen: Yes.

Alan Bryce: Okay? With doce in this study, the argument is accrual, would've been more difficult, because some patients would've said no.

Zach Klaassen: Yep.

Alan Bryce: Okay, understandable. We get that, and the study might have had to have been bigger.

Zach Klaassen: Yeah.

Alan Bryce: More patients to achieve a statistically-significant result. I get that.

Zach Klaassen: Yeah.

Alan Bryce: That's why it wasn't done. Fine. I think it's a fair criticism, but then in terms of application to clinical practice today, I absolutely think the drug is effective, and as long as there's FDA approval, absolutely, it's a reasonable choice.

Zach Klaassen: Yeah.

Alan Bryce: Okay? No one should say that it's better than doce, we have no evidence to support that claim.

Zach Klaassen: Yeah.

Alan Bryce: Right? It is entirely plausible that doce gives the same OS, we just don't know, okay?

Zach Klaassen: That's fair.

Alan Bryce: What I would say to the practicing clinician is, you're in good standing to doce or Pluvicto in this setting based upon this data. There's a toxicity issues we think about, right? There's patient preference issues. There's access, though. Not everyone has easy access to Pluvicto at this point, and can they ramp up production that high?

Zach Klaassen: Right.

Alan Bryce: I don't know. There's also expense.

Zach Klaassen: Yes.

Alan Bryce: Six cycles of doce is going to be, what? A 10th of the cost?

Zach Klaassen: Yeah.

Alan Bryce: That's not insignificant. That's an important consideration as well. I would say, in this setting, mCRPC, someone who's already had ADT in one of the ARPIs, really at this point, you've got doce, select patients, you've got Radium, and if there's an approval, I would be very comfortable using Pluvicto in this space, based on the PSMAfore data.

Zach Klaassen: That's great. Just to dovetail on that a little bit more, so assuming we get approval, you're sitting with a patient, they've had all these criteria to lead there, and you teed up very nicely the options at this point. Is there any either genetics or patient characteristics that would lead you towards lutetium PSMA versus radium versus docetaxel?

Alan Bryce: Yeah. At this point, we don't know.

Zach Klaassen: Right

Alan Bryce: You know, what I didn't say in that list was, if that person has BRCA-mutated disease-

Zach Klaassen: They get a PARP-

Alan Bryce: I'd put them on a PARP inhibitor, okay? For the non HRR patient, do we have genomic selection? Do we have clinical selection? We really don't.

Zach Klaassen: Yeah.

Alan Bryce: Now, we know with radium, it's bone only. Fine. For the patients who have more than bone only, then you're talking doce or Pluvicto and we don't have any real insight yet. We need to get that. That's one of the things that we, as investigators, will be working on, as a field, will be working on. Is there a way to select for patients? I do think it's important, because you hear this, I get so involved in patient education and patient forums, and patients are discovering that it's not a miracle drug.

Zach Klaassen: Yeah.

Alan Bryce: It doesn't work for everybody. Pluvicto is like most of the other drugs we have in cancer, which is you've got the distribution of patients.

Zach Klaassen: That's right.

Alan Bryce: You have a cohort who have amazing responses.

Zach Klaassen: 21% CR.

Alan Bryce: 21% CR, that is awesome, right?

Zach Klaassen: Yeah.

Alan Bryce: You have that cohort and then you have the cohort who have moderate responses. They benefit, it's perfectly okay, and that's okay, we're happy with that, but you also have the primary refractory cohort. Maybe 15, 20% on this study of early progressors, and they're there too. That's psychologically hard on those patients and their families, when they come in with extremely high expectations.

Zach Klaassen: Yeah, that's a great point.

Alan Bryce: They come in, it's been built up.

Zach Klaassen: This is the miracle drug. Yeah.

Alan Bryce: Then it doesn't work for them the way they'd hoped, and that really hits patients hard. I think it's providers, right? We really have a responsibility to set realistic expectations and try not to let the patients get carried away with the hype.

Zach Klaassen: Absolutely, that's well said. Great discussion. Anything we haven't hit on that you want to touch on? Maybe a couple of points for our listeners to take to their clinic tomorrow?

Alan Bryce: Yeah. If you haven't used radial ligand therapy yet, it is fairly well-tolerated, but there's no question, the dry eyes, the dry mouth is real, the myelosuppression is real. There are absolutely a cohort of patients who don't tolerate it, so when you start out treating patients, just like every other systemic therapy, you want close contact with your patient, ask them how they're doing, call them a couple of weeks into it, see how the side effects are going. Most patients are going to do fine, but for those patients that are not doing well, you really want to intervene early.

Zach Klaassen: Yeah.

Alan Bryce: Dry eyes, dry mouth is very manageable. That's not hard. Xerostomia, we know what to do, but the myelosuppression sometimes is very real. There can be some GI side effects, some GU side effects. Just something to monitor. The other tricky part is the following the imaging throughout.

Zach Klaassen: Yeah.

Alan Bryce: Right?

Zach Klaassen: Yeah.

Alan Bryce: Really, we use conventional imaging to follow patients even though we have PSMA PET scan, but we don't actually know. There's no clear guidance on, how do you interpret a PSMA PET scan in terms of SUV correlating to benefits.

Zach Klaassen: Right.

Alan Bryce: Right? That data is still emerging. I think that's a challenge, I hear this consistently from community physicians who are seeing this for the first time, "What do I do with this scan now? What does this mean?"

Zach Klaassen: Is it working? Is it not working?

Alan Bryce: Right. A lesion disappearing is easy to understand, a new lesion appearing is easy to understand, but if all you have is SUV change, what does that actually mean? I would actually encourage people, don't act on just SUV change.

Zach Klaassen: Yeah.

Alan Bryce: Right? Put everything in clinical context, think about your patient's symptoms. Obviously, you've got PSA, you've got alk phos, you've got the other serum markers, but really, I wouldn't make treatment changes on SUV alone.

Zach Klaassen: Yeah, that's great.

Alan Bryce: Yeah.

Zach Klaassen: Great conversation. Really enjoyed it, I know our listeners will as well. Thank you so much.

Alan Bryce: Thanks, thanks very much. It's a pleasure.