In this final segment, the panel discussed additional PSMA-targeting agents currently being assessed. While the main topic of this series has focused on PSMA-617-Lutetium-177 (assessed in the VISION trial), Dr. Oliver Sartor mentioned PSMA-I&T-Lutetium-177, which represents a different moiety for binding to PSMA. Moreover, Dr. Rana McKay touched on the PSMA Addition study, which is designed where patients are not to receiving chemotherapy. Rather, the study is assessing the combination of an AR targeting agent with or without Lutetium.

Daniel George:

Okay. So we’re back now to talk about this last section of this roundtable, and it’s really around the current trials and maybe some of the additional agents that are being studied around PSMA and directed therapies. And I want to start Rana with you and the PSMAfore trial. Can you walk us through sort of the basic scheme of this study and where that is? What do you think of the study?

Rana McKay:

Absolutely. So, this study is basically being designed in the pre-chemotherapy CRPC setting for patients with prostate cancer. So, VISION was really in the treatment refractory setting, we demonstrated that we could make people live longer. Well, actually, if we move therapy earlier on in the CRPC course, prior to receipt of chemotherapy, docetaxel, taxane chemotherapy, can we still see the same benefit? And so essentially the trial is looking at, I believe it’s the combination with abiraterone, though I could be wrong. Oliver, I’m going to volley it over to you.

Oliver Sartor:

It’s very similar to the PROfound study.

Rana McKay:

Randomized to the sister drug and then single agent, Lutetium.

Oliver Sartor:

Yeah, you get the physician’s choice and the control arm. It was interesting, it was proposed initially as a standard of care, plus or minus, and even though the FDA accepted the standard of care, plus or minus, in the VISION, they did not accept it here. So it’s an alternative AR pathway inhibitor versus the Lutetium.

Rana McKay:

And then I think thinking about PSMA Addition, which is now looking at things in the hormone sensitive setting, and I think in that context, that study is designed where patients are not to receive chemotherapy. So it’s really designed at looking at the combination of an AR targeting agent with or without Lutetium in that context. And then, I know we’ve got Preston here on our video, you got to bring it back to the infamous luteectomy, looking at PSMA in the neoadjuvant setting. I’m sure you can comment on that.

Daniel George:

Yeah, Preston, let’s go to you because I think that, particularly that PSMA Addition study is going to give us some insights into the local treatment effects of this agent and I’d be curious, from your perspective, [inaudible 00:02:40] perspective, how you view that.

Preston:

I am intrigued by it. I think, there are many side effects to treating localized prostate cancer. And we are seeing that Lutetium is very effective in men with this high risk disease. We can only hope that it’s going to be even more effective when you don’t have all those mutations and different selected bad actor types of cancer in later metastatic resistant prostate cancer. So potentially treating earlier, we’ll have even more effect.

It seems to be pretty well tolerated, it’s obviously different side effects than urinary incontinence and erectile dysfunction, which is what we see with surgical prostatectomy. But I think, quite honestly, we’re going to be trying to find a balance. If we can do Lutetium based diagnosis and treatment with local therapy, control the prostate. It may not be perfect, but if it can be effective enough to give people additional time away from surgery, away from some of the other significant quality of life deficits that we cause with local treatment, I’m very excited to see how it plays out.

Daniel George:

Excellent. Yeah, I think there’s a lot of uncharted waters here and really opportunities to learn from multiple trials here, where this fits in these, as you can see, the earlier stages of the continuum of this disease. And it’s not the only agent, right Oliver? There’s another phase 3 going on with another PSMA targeted strategy, want to walk us through that?

Oliver Sartor:

Yeah, there is. We’ve been talking about PSMA-617-Lutetium-177, and that’s one that’s got most of the press because of the VISION trial and all. But there’s another one that’s proceeding right now, and that one is called PSMA-I&T-Lutetium-177. It’s a different moiety for binding to the PSMA, it’s still a small molecule. And the PSMA-I&T is very similarly being studied as a PSMAfore, they call their trial, the SPLASH trial. And the SPLASH trial is going to be looking at kind of an alternative AR targeting agent, metastatic CRPC in the prechemo setting, if you will, also an RPFS endpoint.

And there’s another one coming by the way, there’s another PSMA-I&T-Lutetium-177 that’s been announced. And we’re just going to have to wait to see, it’s not up and running yet. But there are lots of ways to be able to attack PSMA, and then of course, ways in which novel isotopes are being used as well. I’ll just mentioned things like Actinium-225 and we don’t have enough time to really talk about all the different isotopes in all the different moieties that are binding, but this a very active investigational area. It’s not just PSMA-617-Lutetium-177, but that’s in the lead, that molecules in the lead.

Daniel George:

That is fantastic Oliver, thank you. And I think, this really, I think really frames the fact that this likely to be a whole paradigm shift in the way we think about the treatment modalities for prostate cancer. When you think about where we’ve gone from [inaudible 00:06:03] and samarium, to radium, really targeting bone with alpha particles, but really limited to bone. And now moving on to really more direct tumor targeted approaches with PSMA. And thinking about that, changing those warheads and changing those small molecules, it really does sound like there’ll be, potentially, a portfolio of choices to build off of. And as Rana mentioned, as Preston mentioned, the clinical context in which we’ll study these drugs and earlier disease states and in earlier setting, that if we’ve learned anything from prostate cancer in the last couple of years, including GU ASCO, it’s timing matters. Timing with hormonal therapy, timing with AR targeted agents, and some of that timing will be studied now in some of these earlier disease settings.

I can’t thank you all enough for this really interesting, inspiring discussion around Lutetium-177 PSMA and the potential rollout of this in the near future, what implications we have for this year, and things to look forward to in the years to come.