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Zachary Klaassen: Hi. My name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center.

I'm delighted to be joined for a breaking news discussion on UroToday with Dr. Oliver Sartor, who is a Medical Oncologist who is kind enough to join us from Zimbabwe. A historic day for Lutetium and PSMA radioligand therapy. Oliver, thanks so much for joining us.

Oliver Sartor: Thank you, Zach. Delighted to be able to join you.

Zachary Klaassen: So we are talking today. Earlier this morning, we heard about the FDA approval of Lutetium/PSMA-617 in the mCRPC taxane-naive setting. Take us through this press release and then some of the data from PSMAfore that led to this approval.

Oliver Sartor: Yeah, thank you. So this is really a big day for patients. As it turned out, the VISION trial was a great trial, and it got the FDA approval for PSMA-617/Lutetium 177. I'll just call that Pluvicto, because that's the trade name.

And what I'll say is that a lot of patients had to undergo chemotherapy in order to receive the PSMA/Lutetium therapy. Now it turns out that a good 40% to 50% of patients in the United States will never receive chemotherapy before they die. And so here you have a well-tolerated therapy, an effective therapy that was contingent upon receiving chemotherapy before the PSMA/Lutetium could be administered.

Well, today we had a change, and the FDA granted an FDA approval for the taxane-naive metastatic CRPC patient. Now all of these patients are PSMA PET positive. And I'll just mention that 92% of the patients that have PSMA PET qualified by image based criteria for the trial.

So let's go through a little bit of the data. But the context is very important. This is going to dramatically expand the utility of the Pluvicto in the context of metastatic CRPC disease. So here we are.

All the patients have been previously treated with ADT and an ARPI. And an ARPI could either be apalutamide, darolutamide, enzalutamide, or abiraterone. So all the patients were pretreated with ADT and an ARPI.

All the patients had a PSMA PET-positive disease with uptake in the metastatic lesion greater than [inaudible] and no evidence of any exclusionary lesions, which would be things like visceral lesions that had an uptake less than [inaudible]. So the patients all had progressive disease. And then they were randomized to either an alternative ARPI in the control arm or the PSMA-617/Lutetium.

The primary endpoint was rPFS. And of course, there was an OS as a secondary endpoint. Very importantly, by the way, crossover was allowed and a full 60% of the patients in the intent to treat analysis actually crossed over. So here's the patient disposition.

You ended up screening over 500 patients, eligible and actually randomized for 468, 234 on each arm, half to the ARPI, half to the PSMA with Lutetium. And then after the treatment, if there was eligibility for crossover, then it turned out that 60% of those on the control arm actually did cross over and receive the PSMA-Lutetium.

So that's very, very important because that will not affect the rPFS, but it will affect the OS. You're giving an effective therapy either way. Next slide.

So here's the data on the rPFS. The hazard ratio was 0.41. So a 59% reduction in the risk of progression.

And the risk of progression, the median was prolonged by six months in the patients treated with the PSMA/Lutetium. So a six-month prolongation in the median, a hazard ratio of 0.41. Clearly, we're looking at a very successful trial. And this was cited by the FDA.

Now, next slide, is the overall survival. Please remember this. 60% in the intent to treat analysis actually crossed over and that is going to confound the analysis. As it turned out, the crossover hazard ratio was 0.91.

So it was favorable. But the upper limits of the confidence interval did in fact cross one. So it's OK because the crossover that was inherent within the trial design.

Now that's the basics of it. And by the way, let me say that the therapy was very well tolerated. We have experience with this agent in the commercial setting, in the VISION setting, and we know that the PSMA-Lutetium is well tolerated.

A little bit of dry mouth, a little bit of myelosuppression, but overall very well tolerated by the patients. And a very few number of patients, only about 5%, actually having had dose holding or problems with the administration that result in a dose alteration. So over to you, Zach.

Zachary Klaassen: Yeah. Congratulations, Oliver. I know this is a huge day for our mCRPC patients. It's been a long journey for you and your team as well from ESMO 2023, almost 18 months now getting FDA approval. So congratulations to all of you.

You mentioned it a little bit at the beginning, that this is going to open up therapy for some patients that may never have seen it. What do you think, just in your estimation, the denominator increases to with this approval for Lutetium?

Oliver Sartor: Honestly, Zach, I think it's going to triple the utilization. If you take people who have progressed after one or two taxanes and an ARPI, you're dealing with many patients who are extremely frail, and many of the individuals who, quite frankly, are almost hospice-type eligible.

So a lot of the patients that we've been treating are very, very far advanced and have exhausted all their alternative therapies. Here, we're going to be having progression after ADT and ARPI. This is a very different patient population. And I think we'll triple the number of patients who actually receive the PSMA/Lutetium.

Zachary Klaassen: Wow. You know, I think we're always looking for treatment sequencing in mCRPC. We got a little bit more clarity today. How do you think this changes, perhaps, the treatment sequencing first line, second line, third line?

Oliver Sartor: Yeah, great question. What we have in the United States, most patients actually receive a second ARPI. That's the data that's come through over many of the real-world settings.

Taxanes are given, but many of the patients we know will never receive a taxane. And if we're going to be looking at the new reality, I think many patients will choose to get the PSMA-617/Lutetium because it's very well tolerated and it is effective.

So if we look at the sequence which you've asked me to opine on, I think that this is going to get a lot of the space that would otherwise have been taken up by either a second line ARPI or a taxane. I think it will be the most popular choice in this space.

Zachary Klaassen: Yeah, great answer. I think as we look to the future, we have trials even further up in the disease space, mHSPC and beyond. How do you think this approval maybe affects subsequent reporting of data, agents how it may get approved downstream in mHSPC? This is another step towards moving it up in the disease space.

Oliver Sartor: Now let me take a variation on that question first, if you don't mind, Zach. One of the things that I love about America and I love about the FDA approvals, it sets a new benchmark that other people can shoot for.

Now we know that if you're going to compete in this space, you're going to have to be as good or better than the PSMAfore data. So this sets a new standard from a conceptual perspective.

Now to your point, we're going to be looking at newer trials, potentially moving up the PSMA-617/Lutetium even more. But the PSMAddition trial, which accrued over 1,400 patients, metastatic hormone-sensitive prostate cancer, and again, with PSMA PET positivity, which almost all the patients were. And we can anticipate some preliminary data from that later this year.

But I think 2026, we'll be able to see some reasonably mature data. Completed accrual in January of 2024, so January 2026 will have two years of follow-up. Remember, these are metastatic hormone-sensitive patients. A lot of them will be starting to progress at that time.

We also have another trial. And this trial, I'm particularly excited about because it doesn't use hormonal therapy. These are patients who are recurrent with oligometastatic disease. And we are going to be treating them with SBRT plus or minus the Lutetium.

And this trial is now accruing patients across the globe and would have the opportunity to move up in this oligometastatic, but recurrent prostate cancer after radical prostatectomy or radiation. But the treatment would not utilize hormonal therapy. And you know how many patients, almost all patients would prefer to avoid castration.

So that trial, if, in fact, it's positive, will be a real game changer as well. But it's only accruing now. We can't say anything about the results, of course.

Zachary Klaassen: And you're talking about the PSMA-DC trial, correct?

Oliver Sartor: Correct. And "DC" stands for delayed castration. Yes, thank you for naming the trial, PSMA-DC.

Zachary Klaassen: Excellent. Oliver, very exciting day, and thank you on last-minute notice for jumping on to discuss with us. Anything we didn't touch on, or any take-home messages for UroToday listeners?

Oliver Sartor: One thing, and I want to be careful to make sure to have a shared credit here. There are many, many individuals who contributed to this trial. I was Chairman of the Steering committee.

Mike Morris was one of the PIs on the trial. We ended up with a large team effort led through Novartis. And I want to make sure we give credit to all those great individuals who helped make this new FDA approval a reality.

Zachary Klaassen: Yeah. Well said. Oliver, thanks again so much.

Oliver Sartor: Thank you.