Dr. Sartor, always so generous with your time. Thank you for joining us on UroToday.
Oliver Sartor: Oh, pleasure to be here and enjoy doing it.
Zachary Klaassen: AcTFirst is a really interesting trial. We'll get into the design and the background and the outcomes, et cetera, but just set the stage. You do such a good job of explaining PSMAfore/VISION. What sort of led to what we're going to talk about today?
Oliver Sartor: Yeah, let's talk about radio iodine therapy and let's leave off for a minute things like the old Samarium-153 and Radium-223. This is the new lutetium-177-PSMA-617.
So the initial trial led to overall survival improvement was conducted basically in sort of the last stage of patients, people who had gone through multiple ARPIs, taxanes, and didn't have any other choices, and the VISION trial turned up positive and that led to the FDA approval of lutetium-177-PSMA-617, otherwise known as PLUVICTO.
So then the idea was to get it moved up so you didn't have to wait so long before giving the lutetium. And we did another trial called the PSMAfore trial. And the PSMAfore trial was people with taxane-naive metastatic CRPC who had progressed on an ADT and ARPI. And the idea was, could you show rPFS advantage? And there was a crossover built in, so OS was not going to happen there. But the bottom line is we did it again. So we got good rPFS and a second approval, and that's where the approvals are today.
Now we're going to pivot a little bit to AcTFirst, but I want to talk a little bit more about actinium.
Zachary Klaassen: I definitely want to pivot to that. We have lutetium, which is different than actinium 225. So just break down for our listeners what that difference is in terms of the mechanism.
Oliver Sartor: Sure. So when you start looking at the isotopes, there are a bunch of different particles that can be emitted by these unstable nuclei that we call the radioisotopes. And one of the things that we're very familiar with are so called beta particles, which lutetium is one, samarium is one, yttrium 90 is one. So there are a bunch of beta particles out there that have been used in medicine.
Now you need to pivot to the alpha particles. Basically the betas are an electron. It's basically a little tiny particle, but now you're talking about two protons and two neutrons, which basically turns into helium nucleus, which is over 7,000 times as large and carries huge energy. Well, the alphas are things like actinium-225, Lead-212, astatine-211. It's a whole new class of radiopharmaceuticals.
So that's what we're studying in the AcTFirst trial is the actinium-225 alpha-emitter targeted to PSMA using PSMA-617 as a ligand, which is going to bind to that PSMA on the expression of cells and going to target the radioactivity to those cancer cells.
Zachary Klaassen: It's a perfect background leading into AcTFirst. So just take a minute to lay out the trial design, who these patients are and what the primary and secondary outcomes for AcTFirst are.
Oliver Sartor: Yeah. So these are very similar patients to the PSMAfore trial. The idea is that they would be taxane-naive in the castrate-resistant space. They could have had some chemotherapy in the hormone-sensitive space.
That being said, these are patients who are moving through after having ADT and an ARPI and they need additional therapy. Well, right now lutetium is in that space, docetaxel is in that space or even second-line ARPIs are in that space. So there are a number of alternatives.
So first of all, let's consider the control arm. The control arm is actually a taxane, a second-line ARPI or you can actually use lutetium in the control arm. The experimental arm is a PSMA-617 actinium-225. And that is the essence of the question, can the actinium be better than the control arm for these patients who are initially progressing with ADT and ARPI, taxane-naive in the CRPC space. So it's a nice little design, rPFS endpoint. If it's positive trial, then what's going to happen is you'll put actinium into this space.
Now, there are things about actinium that we don't fully understand. First of all, what are the consequences of these early treatments? We have some preliminary data in the late stage that looks quite good. There is some salivary toxicity, some xerostomia that occurs from the salivary binding of the PSMA and it turns out that that could be an issue and there could also be other problems that we're not fully aware of.
But I'll simply say this, the trial is going to move forward and I think it's a very, very good trial to test the PSMA-617 actinium hypothesis and I think it's likely to be a positive trial.
Zachary Klaassen: Yeah, it's a great background. My thoughts are this, we've looked at actinium at least in some data sets after lutetium.
Oliver Sartor: Yes.
Zachary Klaassen: What's sort of that hypothesis that it's going to be better than lutetium, not head to head, but it is one of the potential controls, to bring it up into that disease space?
Oliver Sartor: So there's going to be a trial presented here called the Action Trial by Louise Emmett and Mike Sathekge out of South Africa. And it turns out that the preliminary data from that trial is really, really strong.
Zachary Klaassen: I see.
Oliver Sartor: And the actinium with the alpha particle has got a really good punch on the tumor, and we know that. We have experience from German studies, from South African studies, now the Australian studies, and it turns out that the alpha particles just got a lot more punched than the beta and it's probably a better cancer-killing machine.
Zachary Klaassen: I see. That's great. Where are we at with the trial right now? What's the accrual looking like?
Oliver Sartor: Yeah, just underway.
Zachary Klaassen: Perfect.
Oliver Sartor: Way too late too early to really talk about anything other than accruals underway.
Zachary Klaassen: Awesome.
Oliver Sartor: I think it's going to accrue very nicely because you have a good control arm. Patients given a choice and say, look, you can even get lutetium, which is a great choice. And some people need a taxanes and get a taxane. Some people don't want either one. They can go on a second line ARPI. So the way the trial is designed is pretty flexible control arm, which means the patients are always going to feel like that they have something that they can move toward that's reasonable for them. And also important to recognize you could potentially get if you go on to an ARPI or a taxane, you could potentially end up being treated with lutetium. There's no built-in crossover. The patient could then move on to a lutetium-based therapy if that's what they wanted to do.
So I think one of the attractiveness of the trial design is the flexibility that it gives. And I think the accrual is going to be very robust. I think people are going to say, "This is a good trial. I can win either way and let's go ahead and give this a shot and see what happens."
Zachary Klaassen: I like the fact that the lutetium's in the control. I mean, you probably won't be powered to show head-to-head differences with actinium, but it'll be interesting to see those sort of secondary analyses.
Oliver Sartor: Absolutely it will. And that was one of the debates in putting the trial design together is, okay, this is a lutetium space today, it's an ARPIs space today, it's a taxane space today, well, let's just give people the choice and they can do what they want. And I applaud Novartis for being able to strengthen up that control arm, including the lutetium, to give people really good choices to go forward.
Zachary Klaassen: And that'll help with accrual for sure.
Oliver Sartor: Absolutely. Yeah.
Zachary Klaassen: Oliver, always great chatting with you in UroToday. Thanks for your time as always.
Oliver Sartor: Thanks, Zach. Appreciate it.