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Alicia Morgans: Hi. I'm so excited to be speaking today with Professor Karim Fizazi, who's a Professor of Oncology at Gustave Roussy in Paris. Thank you so much for joining me today.

Karim Fizazi: Thank you so much, Alicia.

Alicia Morgans: Wonderful. So Karim, you and the team, that has worked for years now on VISION, have just recently published in Lancet Oncology, some quality of life outcomes data, for us to really help put the sort of icing on the cake, I would say, in terms of our understanding of how best to understand the effects of Lutetium-PSMA-617, also called Pluvicto, in our patient population, the VISION heavily pretreated patient population with metastatic CRPC.

So, can you tell us a little bit about VISION in general, just sort of set the stage? And then we can dig into these quality of life data that you recently published.

Karim Fizazi: Of course.

So, again, VISION is the first Phase III trial for lutetium-PSMA. It focused on men with metastatic castration-resistant and very advanced disease. They had to have failed on at least one AR PARP inhibitor and one taxane. And actually, most patients had received multiple of these agents. They were randomized to receive... Or, before I forget, you had to also make sure PSMA protein was expressed based on PSMA PET. And then, they were randomized on a two-to-one fashion to receive standard of care, which was basically what was remaining, except chemotherapy, and except a radioligand, with or without PSMA lutetium, for four to six injections, once every six weeks.

So, the trial has two co-primary endpoints, rPFS and overall survival, both were significantly improved. And for overall survival, we saw a 38% reduction in the risk of death, which is, of course, enormous.

The safety was mainly driven by dry mouth, which is usually mild, mostly grade 1, and not necessarily long-lasting. Nausea, vomiting, which probably should be prevented, at least in my practices I'm doing, and citron clearly work. And then, at the end of the day, the most important, I think, safety concern is more about bone marrow toxicity. And especially in the VISION indication because, basically, you're radiating the skeleton, so you have to see, probably, some bone marrow toxicity.

So I guess, it was really important to also assess quality of life data. Given, yes, the efficacy benefit we'll see by rPFS and OS, but also, some toxicity, you have to transfuse some patients. So it was important to figure out whether we were really helping patients, besides prolonging the life duration. And I'm really glad to see that the benefit in quality of life is amongst one of the most important, I think we saw, in men with advanced prostate cancer. Quality of life, time to deterioration, was reduced by more than half. Time to pain, also deterioration, using the BPI questionnaire, was also tremendously improved. I can't remember the exact medians, but it's like two months versus 11 months, or something like that. Something super big.

And also, time to skeletal related events. So fractures, spinal cord compressions, of major pain requiring radiations, all those things which are so important to patients, clinically speaking, were also reduced by health in the trial. So everything you are looking at in this trial is favor clearly PSMA-lutetium. So it's really all pointing to the same direction. It's really an important treatment for the patients.

Alicia Morgans: Absolutely. And I think, so important that we have the reports from the patients on their surveys, from quality of life surveys, talking about pain, talking about these quality of life issues from their perspective, but also these issues that we know affect patients', mobility and function. Things like skeletal related events absolutely affect patients, even in terms of their independence, which certainly, of course, would affect their quality of life.

Are these things that are meaningful, when you're having those conversations with patients, and you're talking about potentially using this as an option to prolong progression-free survival and overall survival, which clearly, are going to be beneficial to the patient? Are these things that even come into the discussion, given the real efficacy for this drug?

Karim Fizazi: They are, because rPFS is an imaging thing. And of course, if you're telling your patient, well, this treatment was shown to improve your time before your cancer will be progressing on a bone scan or a CD scan, they're happy. But if you are telling them that this treatment was shown to improve your pain, and make sure your bone will not break, and of course, on top of that, your life will be longer, this is much more meaningful to a 21. So this is, obviously, the conversation, but this is also simply more convincing to me, and I guess, to us. We are happy to see patients living longer, but we're also happy to clearly provide direct benefit.

I remember this gentleman, who was on pain before he was enrolled in the trial, and he had really nasty disease, a young guy, and his pain was gone. After the treatment, he could act normally, and he was still golfing just a week before passing away. And it was a totally different natural history before and after.

So these things are really important. We know that PSMA-lutetium remains a non-curative option for, at least for these patients with very advanced disease, but it's prolonging life, which is important, but it's also making their life much better.

Alicia Morgans: Yeah. I think in so many ways, it's giving them their lives back, if we can effectively reduce that pain. And to your point, for this patient, to get him back to golfing, and doing the things that made him who he was, I think that is so meaningful. And it is easy to communicate with patients around those kinds of parameters, because sometimes, the things that they want are to remain independent, to not be a burden, to not feel pain, or to be in a wheelchair, because they have such crippling pain. And this is so important-

Karim Fizazi: I agree.

Alicia Morgans: ... in their day-to-day.

Karim Fizazi: I fully agree. Having said that, we need to be also very honest with ourself and with all our patients. Not all patients benefit from PSMA-lutetium. Even though we selected these patients as having PSMA expression in their cancer, and non-PSMA negative cancer as well, based on CT scan. For reasons I ignore, not all patients respond. And I think, this is also something we need to know, to tell honestly patients, and to tell honestly to ourself. Because I would hate colleagues starting their first patients with this treatment, seeing no benefit, and stopping the treatment for the next one. It's just something that exists. We need to understand why. Is that because the treatment doesn't go to the cells? Is that because the radiation doesn't enter the cell, and any other reason? But it's just a true finding.

Alicia Morgans: It is. And that heterogeneity of disease, especially as we get further and further out in mCRPC, is something that we need to continue to acknowledge. Because clearly, there's an unmet need here, even as we find an option that can help control the disease. Another identified population emerges, one that is PSMA PET positive on a scan, but does not seem to benefit from a PSMA targeted radiopharmaceutical, at least this one. And so, I so appreciate that you raised that, because to your point, it's not going to work on everyone. So if it doesn't work for your first patient, that doesn't mean that it won't work in any patient. We should, of course, should continue to try and offer this drug to patients.

So one final comment. At least in our practice, we've had access again to lutetium-PSMA-617 outside of clinical trials, now in our standard of care. Is this something that you're seeing in your practice, and has it made a difference in your conversations in clinic?

Karim Fizazi: Yes. That's much easier right now, as opposed to just some months ago, when we had this long waiting list. And this is shrinking, and it's so good to see, because these patients cannot wait long at least. So that's really good to see. I hope this will continue. And also, I don't know for you guys in the US, but the access to PSMA PET is much easier, as compared to just a year ago. So that's really good for patients. And depending also, on the findings from the coming Phase III trials of PSMA-lutetium in earlier stages, the population to be treated might become even broader. So we need to be prepared for that. But this will be another conversation, I guess.

Alicia Morgans: Absolutely. But certainly, good news for patients with this Lancet Oncology paper, really confirming that there is a quality of life maintenance with this treatment, as compared to the standard of care that was in the alternate arm. And really, prolonging time to pain progression, prolonging time to SRE. These are meaningful and impactful to patients.

So thank you so much for the work that you're doing, and for talking this through with me today.

Karim Fizazi: Thank you so much.