Read the Full Video Transcript

Alicia Morgans: Hi, I'm so excited to be here with Dr. Oliver Sartor of the Mayo Clinic, where he is the director of radiopharmaceutical trials. Thank you so much for being here with me today, Dr. Sartor.

Oliver Sartor: Hi, I am Dr. Oliver Sartor at the Mayo Clinic. Alicia, it's really a pleasure. This is an exciting presentation I'm presenting on behalf of the co-authors and the PSMAfore investigators on the PSMA-617 lutetium phase three trial in taxane-naive patients with metastatic castrate-resistant prostate cancer.

I wanted to say, Alicia, thank you so much for the opportunity to be here today. We just had a great presentation at ESMO, so delighted to be able to see that live, and now we're going to present to UroToday. I think this is going to be an even bigger audience. So thank you for that opportunity. It's really a pleasure for me to be able to present this. I do have a number of conflicts, and I don't necessarily think they're going to influence anything I say today, but nevertheless, I do need to make those disclosures, as is appropriate.

I think most people know a little bit about PSMA-617 lutetium. It turns out that this is exactly the same molecule we used in the VISION trial. And what you've got is a little ligand, PSMA-617, and that is going to bind to the PSMA receptor on the cell surface of the prostate cancer cells, and that PSMA-617 is tagged with a beta matter, Lutetium-177. Once we put it onto the cell, we're going to start radiating that cell. A good bit of it is going to be endocytose. We're going to cause DNA damage, and by the way, we're probably also going to cause some damage in the microenvironment, and then, we're going to kill those cells. That's how it works.

Now, let me go through the schema. I think this is important. So first of all, you had to have progressive metastatic CRPC, not a surprise, you had to have a PSMA PET-positive metastatic lesion, and no exclusionary PSMA-negative lesions, just like VISION. You had to progress on one prior ARPI, and that was typically either abiraterone or enzalutamide and be candidates for a change in ARPI. So if you were considered to be maybe a little more appropriate for taxane, fine. Go to taxane, but no taxanes were allowed in this trial.

You could have been pretreated with taxane, but only in an adjuvant or neoadjuvant since more than 12 months ago. You also should not be candidates for a PARP inhibitor. ECOG performance status, zero to one. Okay. Everybody gets randomized, and this is not standard of care plus or minus lutetium. This is going to be lutetium in one arm given every six weeks or up to six cycles versus the ARPI change, and that's going to be abiraterone, depending on whichever one you were on the beginning. Now, you can switch. Primary endpoint RPFS, and then go into follow-up. A couple of stratification factors.

Now, you have a primary endpoint that's going to be RPFS, and we have a key secondary endpoint. That key secondary endpoint is going to be pre-specified, by the way, crossover adjusted OS analysis. You'd have a primary RPFS, and then an updated RPFS, and then a whole variety of secondary and exploratory endpoints.

Now, 585 patients were screened. 547 got a PSMA PET, of which 505 were positive. It's about 92%. So a lot of patients were PSMA PET positive, qualified for the trial, and did not have PSMA PET negative exclusionary lesions. 234 randomized in each arm, and we treated the vast majority, and it's intended to treat, so not everybody gets treated, even though you may hope that that's the case. And then, looking at radiographic progression, you could see on the lutetium arm there were only 51 progressive events, 21.8% of those enrolled. Whereas, in the ARPI change arm, there were 146 progressive events, 62% of those enrolled. Very, very importantly, if you had RPFS documented on the ARPI change arm, you could cross over to receive lutetium. 84% of those who had RPFS met on the ARPI change arm, went over to lutetium. Very important.

Now, baseline characteristics. I don't think there are any surprises here. Most of the patients were white. Most had a good performance status, but not all. High Gleason scores were common. PSA is about 18 and 15, depending on the arm. Alkaline phosphatase is hemoglobin's equal between the two arms. A little bit of liver match, but not really. 5.6 and 3%. Lymph nodes and bones, pretty much what you've got accustomed to. And the prior ARPI, abiraterone in 50.9 versus 55.6% in the two arms. Enzalutamide, is a little less common, 40.2 versus 35.9.

So what do we see? RPFS primary endpoint. First of all, there's some data that was preliminarily reported in a press release back in December. Hazard ratio was 0.41. Confidence intervals didn't come close to one. P value, less than 0.0001. And here's the updated hazard ratio. Essentially the same. Hazard ratio is 0.43. Confidence interval's pretty tight, and without a doubt, a benefit in the primary endpoint for the lutetium. If you look over the right hand side, you can see the median RPFS for the lutetium arm was about 12 months and about 5.59 for the ARPI change group, so clear differences between the arms ended up being a little better than double for the lutetium in terms of the median RPFS.

Now, a whole bunch of pre-specified subgroups. You know? Basically, everything's going in the right direction except for some concurrent radiotherapy, and there, the numbers are extremely small. I mean, look down in the lutetium arm. There are only nine patients. So the bottom line is most of these are going in the right direction pretty strongly, and a few of them have conference intervals that are big, because you've got small numbers.

Now, radiographic responses, are measurable. This is resist criteria. These are soft tissue responses. 50.7% versus 14.9. No doubt about that. It's better. Median duration of response, 13 versus 10 months. I put a little box around the complete response because I thought that was pretty good. 21% complete remission in the lutetium arm versus 2.7. Partial response is right next to that. 29.6 versus 12.2. So objective response rate, is clearly positive.

PSA waterfall plots, are clearly positive. Confirmed decrease of 50% or more. 57.6% versus 20.4%, again, favoring the lutetium. Now, time for asymptomatic skeletal events. And there weren't a lot of these events. You can see the events right there, symptomatic skeletal events or death, 21 versus 54, but the hazard ratio is very favorable to lutetium. 0.35. Health-related quality of life and BPI short form for the pain intensity scale, both of them statistically significant. Hazard ratio 0.59 for FACT-P. 0.69 for the BPI short form. This is positive.

Now, looking at the pre-specified overall survival crossover adjusted analysis, remember 84% of these patients crossed over from the ARPI arm to the lutetium. What we see is a hazard ratio shown up in the upper left of 0.80. Conference intervals definitely overlap one. Median follow-up about 12 to 13 months. Median OS, at this point, about 19 to 19.5 months. What you see is a favorable movement on the interim OS crossover adjusted pre-specified analysis.

Now, it turns out that in the overall survival analysis, intent to treat that, we end up with a hazard ratio of 1.16. Now, when you look at the differences, the median follow up, 12.7 versus 13 months, events are pretty balanced. 69 versus 65, so not a lot of difference, but just a reminder. 84% of these patients crossed over, so the confidence intervals overlap one, but this is what we have that has the ratio of 1.16.

Now, treatment emergent adverse events. I think this is important. Grade three to four, interesting. 33.9% in lutetium arm, 43% in the hormonal arm. SAEs, 20.3 versus 28. If you look at fatal AEs, four versus five, if we look at the dose adjustments, I thought this was interesting, 3.5% of the patients on lutetium had a dose adjustment as compared to 15% in the hormonal arm. Discontinuation was 5.7 versus 5.2. Thought this was interesting data.

Treatment emergent adverse events. Dry mouth, that's what you get with lutetium. It's not grade three to five. It typically is going to be grade one or two. Asthenia was about the same between the two arms. Nausea more common in the lutetium arm, 31.3 versus 12, for all grades. Anemia, a little more common in lutetium arm, 24 versus 16. Fatigue about the same. Constipation a little higher with lutetium. Anyway, I think these are pretty similar to what we saw in the VISION trial, but I'd say it's pretty well tolerated as a whole.

Now, let's look at this in summary. The RPFS primary endpoint was met with a very favorable adverse event profile in these taxane naive patients with metastatic CRPC. No doubt that the RPFS is positive. Hazard ratio down in the 0.43 range. Secondary endpoints, PSA response, objective response, time to symptomatic skeletal events, time to worsening and health related quality of life, time to worsening and pain, all better. Pre-specified crossover adjusted OSS trended favorably. Now, the intent to treat had 1.16 on the hazard ratio, but again, we look at the confidence intervals and they're pretty broad.

I'm going to say the PSMA lutetium has a manageable safety profile, and overall, it's very well tolerated. Thank you very much for the opportunity to present today. I have a lot of people to thank. I have many investigators, their patients, their families, and I want to simply say it takes a village to do this type of study. Thank you for the large village that helped to make this a reality.

Alicia Morgans: Thank you so much for presenting that, Dr. Sartor. That was wonderful and really exciting that this was, of course, just presented at ESMO 2023, so wonderful to be able to share this to an even broader audience. Now, one thing that I think was really interesting from the early parts of your presentation is that a majority of patients actually met criteria on those PSMA PET scans to enter the trial. This was an even higher number, higher percentage, of patients than we saw in the VISION trial. Can you comment on that?

Oliver Sartor: Yeah. A little but earlier in the stage of disease, Alicia, VISION was 87%. Here, were 92. Vast majority in both. I think what you have is a little less heterogeneity in the earlier stages of CRPC, this kind of post hormones as opposed to post hormones and post chemo. But nevertheless, 92%. I was actually surprised how high it was. It indicates to me that the vast majority of these people are going to be eligible, assuming that their counts are okay, and creatinine requirements, et cetera, et cetera.

Alicia Morgans: I would agree. I mean, I think that was just a higher percentage of patients than I would have expected. So really, really interesting. Now, the other thing that I think is so important to emphasize, that PFS really was quite a substantial benefit there. One of the things that came along with that progression-free survival benefit was a longer time to deterioration of quality of life.

When we think about this patient population, they're not necessarily in dire straits in terms of their quality of life. And so, maintaining quality of life in this population, prolonging that time until there's a decline, is really meaningful. This was quite a prolongation. I wonder. Have you any comments there? How did patients tolerate from your perspective and looking at the data and how meaningful is this maintenance of quality of life and prolongation of pain-free time?

Oliver Sartor: I think it's very important, Alicia. The totality of evidence here, I think, really gives a good story. You know? We're looking at the radiographic progression-free survival. We're looking at SSEs. We're looking at health related quality of life. We're looking at time to pain deterioration. We're looking at AEs. We're looking at objective response rates, and then, the crossover adjusted OS. Taken together, we have radiographic benefit. We have patient reported outcomes. We have the crossover adjusted OS, and again, the AEs, which I think are favorable, so it makes a nice package.

I was very pleased by the way, to be able to present the totality of data. Initially, there was maybe a little bit of misgiving about how much should be presented, but I wanted as much of it out there as possible. I think this really gives a great picture to the audience interested in this type of phase three trial, and we've got some good data here for people to be able to dissect.

Alicia Morgans: One of the things that I think is also so important is that, certainly, the overall survival data is not mature, right? And so that's important to acknowledge. That crossover percentage is something that I think the investigators should be commended on, because in general, we are not good necessarily, especially when it comes to these large registration trials, in terms of getting the patient to that therapy, if it's going to be potentially active for them. So kudos to you and the team, and congratulations on an extremely ethical design of this trial.

Now, one thing that comes to mind, again, immature overall survival data, but I actually take heart in the fact that, even if we don't immediately get that lutetium to patients, say there's a delay, delay in getting the drug, or a delay because you're still trying to figure out if the patient's progressing, or any other reason that you are not immediately getting the drug. It does not look like that amount of time that was spent while patients were having progression events on that alternate AR targeted agent really condemned them to necessarily having substantially shorter survival.

The drug is active, was able to be active, even when there was that time of delay. And to me, that's actually quite a heartening thing for patients and potentially for clinicians who work in the real world and do not have the ability to cross patients over from one treatment to the next in an instant, the way that we sometimes can do more effectively within a clinical trial and its controlled parameters. What are your thoughts?

Oliver Sartor: Well, first of all, I think you gave a really good summary better than I could have. So I'm just going to say kudos to you for bringing out those key points. I have never seen a crossover design that was more embraced than this one. I can't think of any trial where the crossover was above 80%. I mean, even in the olaparib studies, which are pretty high, they were less than 70%. It's the highest crossover I've ever seen. I think I've been trying to emphasize that during the presentation to help people understand that we are crossing these people over. I think your point, maybe even if there is a little delay, it's not terribly harmful, at least on the OS.

Now, I want the patients to be able to get the most effective therapy as soon as feasible, and I'm hopeful that the real world delays will not be so great in the future. I think we all have sensitive issues about some of the delays in the past, but it's getting better. At least for our shop, it's much better. But going forward, I think we have a lot of positives here, and I look forward to being able to get this to a broader number of patients.

Alicia Morgans: Absolutely. And so, again, commend you on your presentation at ESMO, and would just love to have your final thoughts. What's your recommendation to clinicians who have been awaiting this? And certainly, we're excited with your presentation and are excited to hear how today from you on PSMAfore.

Oliver Sartor: Well, thank you. I was really excited to be able to get the presidential at ESMO. You know? Now, it'll move into the hands of the regulators and those who submit to the regulators. I don't have control over that process. I think, as these data are carefully evaluated, that I hope that the totality of data will be reviewed and that some of those safety profiles I thought were excellent. The AEs, the SAEs, and discontinuation rates. You know? I'm hoping that the regulators will pay attention to what I call the total evidence, not just one or another one of these particular items. Anyway, really a pleasure for me to be able to present. A big team and it's an honor for me to be able to present on behalf of all the investigators and all the families and patients who participated.

Alicia Morgans: Wonderful. Well, thank you again. Congratulations to you, to the patients, to all the investigators, for getting some of this work completed and for completing that initial presentation at ESMO. We look forward to further data, and certainly, to regulatory decision-making on this information, but wonderful news that we clearly see an improvement in radiographic progression-free survival with the earlier use of lutetium in this PSMAfore study. Thank you so much for your time and expertise today.

Oliver Sartor: Thank you, Alicia.