Oliver Sartor: Thank you, Andy. Big day yesterday.
Andrew Armstrong: And I'm Andrew Armstrong. I'm a professor of medicine at Duke and a medical oncologist, and I fully intend to implement some of this practice-changing data sets into my practice next week. So, let's just start off.
First off, congratulations on a positive long-term journey bringing radioligand therapy, starting with radium, really starting with samarium, but evolving into alpha particle therapy and now beta particle therapy across the disease landscape. So I wonder if you could just tell us a little bit about the FDA approval. There's some new data in the FDA approval that healthcare professionals would like to know about. And I wonder if you could update us on the rPFS and the survival data that led to the FDA approval in this hormone-sensitive setting.
Oliver Sartor: First of all, we actually have a little bit of new nomenclature that was introduced and it can be a little confusing.
Andrew Armstrong: Yes.
Oliver Sartor: We're going to call it metastatic hormone-sensitive, but actually the label, they're using the new prostate cancer working group for, which you're very intimately familiar with-
Andrew Armstrong: Yes.
Oliver Sartor: And talking about APMR-sensitive or naive. And these are the androgen receptor pathway modulator, which are ARPIs, the abiraterone, darolutamide, enzalutamide, apalutamide-type drugs, naive. So, first of all, these are basically the upfront settings with metastatic disease.
And it's been really exciting to be able to move from the vision setting, which is really the last of the last, into the PSMA-4 setting, which was after the metastatic CRPC and that nomenclature was used there post-ERPI, and now to the upfront setting. So, huge transition.
You mentioned a little bit about the data and I'll just mention it. It turns out that the rPFS final has had a ratio of 0.67.
Andrew Armstrong: Really exciting.
Oliver Sartor: That's good. That's good. And please remember, the control group is the ADT and the ARPI of choice. So this is not an ADT control group. This is best standard of care with a doublet that we all endorse. And again, you can choose abiraterone, enzalutamide, darolutamide, apalutamide, and that was the control arm by physician choice.
So, now we're in a new triplet era, okay? Yes, we have other triplets. And I think the important triplets out there, docetaxel triplets, the triplets with the PARP inhibitors like niraparib, which is approved for BRCA2, cafusertib for those with P10 deletion. This is another triplet. But the beautiful thing about it in my mind is it's a well-tolerated therapy.
And then I'm going to mention the OS. Still immature on the OS.
Andrew Armstrong: With crossover, even?
Oliver Sartor: With crossover. Thank you for mentioning because there is crossover here. The hazard ratio is 0.80 at this interim analysis two for the OS.
Andrew Armstrong: Right.
Oliver Sartor: But very cool. Upper limits to the confidence interval, 1.01. There's more information fraction to go. I think we're going to end up with the positive OS trial depending on how much alpha is available.
So, remember, every time you look at OS, you have to spend some alpha. We've spent some, but we still have some more to go. And we have a final OS that'll be following probably next year. It'll take a little while to get to those events. And then we'll see if the OS is truly positive or not in a predefined statistical fashion. But it's positive now on the rPFS, approved by the FDA, and presumably available quite soon, as soon as the insurance company as well will make their adjustments, for that upfront patient that we want to intensify.
Andrew Armstrong: So, congratulations again. It was a great testament to perseverance. This is a very popular study. We participated in it. I have patients that have had durable remissions.
But let me put you on the hot seat a little bit. How do we translate this on Monday to the patients in front of us? PSMAddition comprised patients that had synchronous disease, metachronous disease, high volume disease, low volume disease, no prior docetaxel, a variety of genetic alterations that are yet to be described, a variety of PSMA uptake, oligo, polymetastatic progressors. There's all sorts of flavors of patients in that group. All patients had to have PSMA-avid disease. So, obviously-
Oliver Sartor: Avid metastatic disease.
Andrew Armstrong: Metastatic disease.
Oliver Sartor: Could be just prostate or pelvic nose. That'd be avid metastatic disease.
Andrew Armstrong: M1 disease beyond the pelvis.
Oliver Sartor: Yeah.
Andrew Armstrong: Soft tissue metastases. So, obviously a lot of patients are going to be very interested in living longer and having their disease progress less abruptly and having durable remissions. Is there a patient population with PSMA-avid metastatic disease that you think would be inappropriate for Pluvicto?
Oliver Sartor: That's a great question. I've been very, very impressed with the BRCA2 guided therapy with the PARP inhibitors. And I think if I had a patient with a BRCA2 mutation, I would probably shunt them over to the PARP therapies, simply because I think that data's really, really strong, beautiful hazard ratios.
Andrew Armstrong: Yeah, beautiful hazard ratios. Right now we have niraparib. We probably have talazepara based on the TALAPRO-3 trial very soon.
Oliver Sartor: Coming, yes.
Andrew Armstrong: And again, stunningly positive data. I was also impressed, and we're going to divert from the direct question, but if we look at the CDK12 data that came out of the TALAPRO-3, I was mightily impressed. Hazard ratio like 0.27. Also amazing.
Oliver Sartor: Super strong. And we've actually published data that CDK12 mutants actually do not do very well with lutetium. So I'm going to be looking at my genetic subsets and I'm kind of prone to do that anyway. And there may be some patients that I would shun off into the PARP world rather than into the world of the lutetium.
The capivasertib is a little bit interesting. There are a couple of relevant data points. Number one is we definitely have activity in the P10-deleted patient from other studies that don't-
Andrew Armstrong: Therapy study showed that very nice.
Oliver Sartor: Exactly. We don't have it here, but we have it there.
Andrew Armstrong: Yeah.
Oliver Sartor: So it's an extrapolation. But also remember that the docetaxel actually is quite active in the P10 deleted as well. And then we have the capivasertib. The capivasertib is dependent really on the degree of the deletion and the 90% was required -
Andrew Armstrong: IHC loss?
Oliver Sartor: On the IHC. Not genomically, IHC for the capivasertib study. And as you got even higher, it looked like the effect was even more. So to me, there's a little bit of a quantitative effect on the P10 loss that can influence me in that hormone-sensitive setting.
Andrew Armstrong: So, you're going to have choices there.
Oliver Sartor: Absolutely.
Andrew Armstrong: No head-to-head comparisons. We don't know which one helps you live longer.
Oliver Sartor: Well, you asked me the difficult question.
Andrew Armstrong: Yes.
Oliver Sartor: I'd give you the easy answer if I had comparative data. So, unfortunately we have the difficult.
But I think this is going to be suitable for the majority of patients. And unlike the docetaxel where we don't have the data to show that docetaxel adds to an ADT and ARPI, here we have the unequivocal data. And it's positive on the rPFS before the crossover. And even the crossover, as mentioned, is not mitigating overall survival benefit. They're still early stage. We have more data on the OS to come.
So, I think this is going to be a great choice. I'm going to be using it in my patients. Metastatic hormone-sensitive prostate cancer, PSMA/PET-positive metastatic disease, and I'm also going to be using SBRT for a number of these patients to clean things up. Let's not forget about SBRT. It's important.
Andrew Armstrong: So, let me talk about that group.
Oliver Sartor: Yep.
Andrew Armstrong: So the oligo-metastatic PSMA-avid disease, if you're doing SBRT, would you still give Pluvicto?
Oliver Sartor: It's an interesting question. And I think based on the LUNAR trial and a little bit of other data, that I'd be open to the use of Pluvicto. And by the way, Fred Saad presented some nice data with high volume, low volume, [inaudible 00:08:48] sickness.
Andrew Armstrong: It did very well with low volume.
Oliver Sartor: And it actually did pretty damn well. And I was interested to see, and of course I didn't know until the results were there, how consistent those hazard ratios were between high and low volume.
Andrew Armstrong: Right.
Oliver Sartor: But I do like the SBRT to clean up those lesions.
Andrew Armstrong: Right, kind of like the LUNAR study.
Oliver Sartor: Exactly. And so I may be using a combination.
Andrew Armstrong: Okay.
Oliver Sartor: You ask me tough questions, Andy, because I guess the easy question-
Andrew Armstrong: Real world questions.
Oliver Sartor: Yeah, real world questions. The easy questions are easy answers, but this is a difficult one. But I'm going to look at this very carefully for particularly the oligo-metastatic aesthetic to be able to use the lesional approach with metastasis-directed therapy and consider the possibility of the lutetium added to an ADT/ARPI backbone.
Andrew Armstrong: Right.
Oliver Sartor: But I'm probably going to get great responses in these patients. And after 18 to 24 months, I'll probably stop the ADT and watch and see what happens.
Andrew Armstrong: Goal is to get patients off therapy.
Oliver Sartor: Exactly.
Andrew Armstrong: I wonder if you might give a little less Pluvicto as well, save a little for later.
Oliver Sartor: That's a great question. And I think I'm likely prone to do so. This whole question of can you treat what you do not see was addressed in part by the LUNAR study. And there are other data out there.
Andrew Armstrong: Right.
Oliver Sartor: When you ablate the visible lesions, there are still subclinical lesions.
Andrew Armstrong: Right.
Oliver Sartor: And please remember, even the PET scans, which are super sensitive and great, not really under two millimeters, maybe three millimeters.
Andrew Armstrong: Right, tip of the iceberg.
Oliver Sartor: Exactly, so there's that iceberg underneath the water you still have to deal with. And the truth is you can treat, with lutetium, lesions that are only about a millimeter. In fact, that may even be optimal for the lutetium. So, there is this idea of treating what you see, but there's also the idea that you can treat what you don't see. We need to learn more about it.
Andrew Armstrong: Last question. Do you think docetaxel is obsolete or is there an ideal patient still for docetaxel in your practice?
Oliver Sartor: That's a good question. First of all, those with the liver metastases in a particularly aggressive disease were actually not systematically excluded from the study, but within the study design, they were saying if you wanted or needed docetaxel to be given, just give it and don't put the patient on the study.
Andrew Armstrong: Right.
Oliver Sartor: And that was very similar to the PSMA-4. And I'll simply say that a patient with extremely high volume, particularly visceral disease like the liver, docetaxel still may be a very reasonable choice.
Andrew Armstrong: The FDA label doesn't exclude prior docetaxel, I would just point out.
Oliver Sartor: No. No, it's an interesting sort of patient-centric view.
Andrew Armstrong: Sure.
Oliver Sartor: And the physicians will have some flexibility.
Andrew Armstrong: Some quadruplets out there, perhaps.
Oliver Sartor: There could be. And as it turns out, we're going to evolve, Andy. And one of the cool things about our field right now, it's evolving very rapidly.
Andrew Armstrong: Yep.
Oliver Sartor: We're going to learn a lot more. And we have more analyses to come from PSMAddition, some genomically, some related to the scans, some related to the number of cycles. And any new trial, which we celebrate when it's positive, also brings questions that we need to bring to the clinical front and try to answer. So, the questions we have now answered lead to more questions we need to answer.
Andrew Armstrong: Absolutely. It's an exciting time to be oncologist right now. Thanks for transforming the lives of our patients and for your successes in this research.
Oliver Sartor: Well, listen, I want to very clearly say, big, big, big team effort.
Andrew Armstrong: Absolutely.
Oliver Sartor: Novartis sponsored the trial, did great. There are actually three of us that are leaders on the trial. I want to mention Scott Tagawa.
Andrew Armstrong: Absolutely.
Oliver Sartor: There are two co-PIs, me and Scott, and then head of the steering committee was Mike Morris. And we all work together. It's a team.
Andrew Armstrong: Right, team science.
Oliver Sartor: It's a team.
Andrew Armstrong: Congratulations.
Oliver Sartor: Thank you.
Andrew Armstrong: Thank you.