ProstACT GLOBAL Trial: Combining PSMA-Targeted Therapy with ARPIs and Docetaxel - Oliver Sartor
January 24, 2025
Oliver Sartor discusses the ProstACT GLOBAL trial design, examining TLX591, a PSMA-targeting antibody bound to lutetium-177 for metastatic castration-resistant prostate cancer treatment. The phase III trial includes a 30-patient safety lead-in followed by a 400-patient randomized study comparing standard of care (ARPI switch or docetaxel) with or without TLX591. Unlike other PSMA-targeted therapies requiring multiple cycles, TLX591 involves only two 76-millicurie doses given two weeks apart. While offering a patient-friendly dosing schedule, the antibody shows increased myelosuppression compared to small molecule alternatives. The trial design allows both ARPI and docetaxel combinations, addressing previous trial design criticisms, with radiographic progression-free survival as the primary endpoint and overall survival as a key secondary endpoint.
Biographies:
Oliver Sartor, MD, Medical Oncologist, Professor of Medicine, Urology and Radiology, Director, Radiopharmaceutical Trials, Mayo Clinic, Rochester, MN
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA
Biographies:
Oliver Sartor, MD, Medical Oncologist, Professor of Medicine, Urology and Radiology, Director, Radiopharmaceutical Trials, Mayo Clinic, Rochester, MN
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA
Related Content:
SUO 2024: A Phase III Study of 177Lu-TLX591 plus Standard-of-Care Versus Standard-of-Care Alone in Patients with mCRPC (PROSTACT GLOBAL)
ASCO 2024: ProstACT GLOBAL: A Phase 3 Study of Best Standard of Care with and Without 177Lu-DOTA-Rosopatamab (TLX591) for Patients with PSMA Expressing mCRPC Progressing Despite Prior Treatment with a Novel Androgen Axis Drug
SUO 2024: A Phase III Study of 177Lu-TLX591 plus Standard-of-Care Versus Standard-of-Care Alone in Patients with mCRPC (PROSTACT GLOBAL)
ASCO 2024: ProstACT GLOBAL: A Phase 3 Study of Best Standard of Care with and Without 177Lu-DOTA-Rosopatamab (TLX591) for Patients with PSMA Expressing mCRPC Progressing Despite Prior Treatment with a Novel Androgen Axis Drug
Read the Full Video Transcript
Zachary Klaassen: Hi, my name is Zach Klaassen. I’m a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I’m delighted, as always, to be joined on your show today by Dr. Oliver Sartor, medical oncologist at Mayo Clinic Rochester. Today, we’re going to be discussing his SUO Trial in progress from 2020 for ProstACT GLOBAL. Oliver, thanks so much for your time on UroToday today.
Oliver Sartor: Great. Thank you, Zach. Pleasure to be here.
Zachary Klaassen: So just walk us through that trial design. It’s an exciting trial. I’d love for you to break down the trial design for us.
Oliver Sartor: Thank you very much, Zach. And really a pleasure to be able to talk about the ProstACT GLOBAL. And this is an interesting trial, at least from my perspective and I think for many others. Let’s talk about the agent first, and then we’ll talk about the trial design.
It turns out that Scott Tagawa, Neil Bander, folks at Cornell did a lot of work with an antibody called J591 and lutetium and also a little bit of actinium. Well, it turns out that TLX591 is the same as J591-lutetium. And this has been worked on by the folks at Cornell for many, many years. They ended up licensing it over to Telix, which is an Australian company. And Telix is going to run and do a phase III.
So let me explain a little bit how it’s going to work. One of the things that they do is pretty typical, and that is in the context of the eligibility criteria. These are people who have confirmed metastatic CRPC. They’re going to have to be PSMA PET-positive in the usual way, just uptake right to the liver and metastatic lesions. Everybody would have had a prior ARPI, and it could have been either for the castrate-sensitive prostate cancer space or the first line of metastatic CRPC space. And docetaxel would be allowed so long as it was used in the castrate-sensitive prostate population.
Now, before they get to the randomization, they’ve got to do a safety and dosimetry lead-in. And that’s where the trial is right now. They’ve got about 30 patients that are going to be accrued. And let me tell you, it’s a little bit unusual.
So one of the things that people have been fighting about and talking about for a long time is the incorporation of both ARPIs and docetaxel into the treatment paradigm when you’re using the radiopharmaceuticals. Well, it turns out that here, both are going to be allowed. So people are going to be able to use the antibody TLX591 to PSMA, and bound to lutetium, and they’re going to be able to use it in combination with either an ARPI switch or docetaxel.
Now, there has to be a lead-in because you don’t have a lot of experience with this design. So people can use concomitant hormonal therapy along with the PSMA-targeted lutetium. But because of the docetaxel issues and the possibility for myelosuppression, that’s going to have to be done sequentially. And so they’re going to give the antibody label to a tissue targeting PSMA and then follow that with docetaxel. And they’re going to be looking at things like the dosimetry, safety, the tolerability as a lead-in.
Now, assuming that everything goes OK during the lead-in, there’s then going to be this randomized phase III trial with 400 patients. And everybody’s going to get standard of care. And there’s going to be a randomization beforehand. And people are going to be randomized to a chosen standard of care either to get an ARPI or they’re going to get docetaxel.
Then they’re going to go into the randomization. And two to one, they’re going to be getting the TLX591 PSMA-targeted lutetium-177. As mentioned, if they’re getting docetaxel, this is going to be sequential. If they’re getting the standard of care alone, then they’re just going to go straight to docetaxel.
And then people are going to be followed for rPFS, radiographic progression-free survival. And assuming that everything goes standard in an interim analysis, they’re going to take it out to the 400 patients. Primary endpoint, again, is rPFS. Key secondary, the overall survival and safety.
So Zach, that’s basically the design. It’s pretty simple, because it’s going to combine the hormones. It’s going to combine the chemotherapy. It’s going to combine the lutetium, all into one trial design. And I think a lot of people are going to enjoy this.
Oh, the other thing about the antibody, people have gotten used to the PSMA-617-lutetium, where you’re dosing every six weeks. Here, you get two doses of antibody. 76 millicuries. And two weeks later, 76 millicuries again. So the design on the dosing is very, very different than what people have gotten accustomed to for the PSMA-617-lutetium, otherwise known as Pluvicto. So there you go. Let’s go into some questions. I’m going to stop sharing.
Zachary Klaassen: Before you stop sharing, I just want to ask a quick question, because you mentioned a great point, and it was going to be my question about the two doses. So when I looked at this trial, Oliver, it has very similar inclusion criteria to PSMAfore. We know that the PSMAfore trial had six cycles. The SPLASH trial with PNT2002 had four cycles. Now, we’re down to a very patient-friendly two cycles. And so is it fair to say that based on this trial design that you have laid out here, that we’re going to be taking these results into context with PSMAfore and SPLASH?
Oliver Sartor: Absolutely. Now, let’s talk a little bit about the trial design. PSMAfore excluded prior docetaxel. So none of those patients in PSMAfore had prior docetaxel. On SPLASH, it was allowed, very similar to here. So when we look at this, this is going to be kind of a head to head, if you will, although it’s not head to head, with the PSMAfore and SPLASH population. So same population essentially, but different dosing and different entity. This is an antibody, not a small molecule.
Zachary Klaassen: Excellent. Excellent. So again, with ProstACT GLOBAL, there’s overall survival as a secondary analysis. We’ve seen fancy crossover analysis for overall survival for PSMAfore as well as SPLASH. Do you anticipate, in this trial design, a similar adjusted crossover analysis?
Oliver Sartor: The idea is probably to avoid the crossover here. Now, please realize that patients in the control arm in particular can go on to receive FDA-approved agents, like Pluvicto. All you need, you need ADT. You need docetaxel. And you need an ARPI, and then progression with PSMA PET-positive. So patients could leave this trial and go on to receive an FDA-approved agent like Pluvicto.
Now, that is obviously going to muddy the waters, but we’re going to keep track of all the sequential therapies. And one of the things in prostate—and I know you’re aware of this—is the overall survival endpoint is going to be increasingly problematic as we have more and more active agents. And we’re using things like the PSMA-targeted therapies early on.
So this is a big issue because we’ve gotten used to overall survival. And we should. But on the other hand, those late-stage trials are not necessarily where the drug development is now. As you move earlier, I think we’re going to look for trends in OS and a powerful rPFS. That’s what people are hoping for now.
Zachary Klaassen: Yeah. Great explanation. I think in your early experience with TLX591, what’s the tolerability been like in comparison to some of these other agents?
Oliver Sartor: More myelosuppressive. It turns out that you end up with the antibody having a longer circulation time. Some of that hangs out in the marrow. Thrombocytopenia is a real issue. And this is one of the bugaboos in this trial. You’re giving an antibody, and then you’re setting people up for docetaxel, if they’re choosing to be treated with docetaxel, and there could be some myelosuppression. So I don’t really know.
Now, the reason, I think, that the antibody has generated some degree of enthusiasm, if you look at what was published out of Cornell—and I will cite Scott Tagawa again. Great guy. Did a lot of this early work. I want to make sure he gets the credit. It turns out that some of the survival was just crazy good. I mean, people with metastatic CRPC living three, close to four years. And so there is this concept that maybe the antibody is going to be able to deliver the isotope in a little more efficient way, hence the two doses. But downside, myelosuppression, particularly thrombocytopenia.
Zachary Klaassen: Excellent. Great discussion, as always, Oliver. Maybe just a couple take-home messages for our listeners today.
Oliver Sartor: Yeah. Number one, I think the isotope field is alive and well. We have small molecules. And now, we have an antibody coming into phase III. This will be the first phase III with an antibody.
I can’t say if it’s going to be positive or negative, but I like the shot on goal. I like the choices. I like the dosing scheme. Just two doses is patient-friendly. I like the opportunity to be able to use docetaxel in both arms, which will mitigate some of the criticisms that have come against PSMAfore and SPLASH. And I’ll simply say, let’s hang on for the ride. Let’s see what it shows.
Zachary Klaassen: That’s absolutely true. And I think it’s nice to know that the dose lead-in is ongoing. And hopefully, the phase III accrues well and accrues quickly, and we’ll get some results. So as always, thanks so much, Oliver. Thank you very much for joining us.
Oliver Sartor: OK. Thank you, Zach.
Zachary Klaassen: Hi, my name is Zach Klaassen. I’m a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I’m delighted, as always, to be joined on your show today by Dr. Oliver Sartor, medical oncologist at Mayo Clinic Rochester. Today, we’re going to be discussing his SUO Trial in progress from 2020 for ProstACT GLOBAL. Oliver, thanks so much for your time on UroToday today.
Oliver Sartor: Great. Thank you, Zach. Pleasure to be here.
Zachary Klaassen: So just walk us through that trial design. It’s an exciting trial. I’d love for you to break down the trial design for us.
Oliver Sartor: Thank you very much, Zach. And really a pleasure to be able to talk about the ProstACT GLOBAL. And this is an interesting trial, at least from my perspective and I think for many others. Let’s talk about the agent first, and then we’ll talk about the trial design.
It turns out that Scott Tagawa, Neil Bander, folks at Cornell did a lot of work with an antibody called J591 and lutetium and also a little bit of actinium. Well, it turns out that TLX591 is the same as J591-lutetium. And this has been worked on by the folks at Cornell for many, many years. They ended up licensing it over to Telix, which is an Australian company. And Telix is going to run and do a phase III.
So let me explain a little bit how it’s going to work. One of the things that they do is pretty typical, and that is in the context of the eligibility criteria. These are people who have confirmed metastatic CRPC. They’re going to have to be PSMA PET-positive in the usual way, just uptake right to the liver and metastatic lesions. Everybody would have had a prior ARPI, and it could have been either for the castrate-sensitive prostate cancer space or the first line of metastatic CRPC space. And docetaxel would be allowed so long as it was used in the castrate-sensitive prostate population.
Now, before they get to the randomization, they’ve got to do a safety and dosimetry lead-in. And that’s where the trial is right now. They’ve got about 30 patients that are going to be accrued. And let me tell you, it’s a little bit unusual.
So one of the things that people have been fighting about and talking about for a long time is the incorporation of both ARPIs and docetaxel into the treatment paradigm when you’re using the radiopharmaceuticals. Well, it turns out that here, both are going to be allowed. So people are going to be able to use the antibody TLX591 to PSMA, and bound to lutetium, and they’re going to be able to use it in combination with either an ARPI switch or docetaxel.
Now, there has to be a lead-in because you don’t have a lot of experience with this design. So people can use concomitant hormonal therapy along with the PSMA-targeted lutetium. But because of the docetaxel issues and the possibility for myelosuppression, that’s going to have to be done sequentially. And so they’re going to give the antibody label to a tissue targeting PSMA and then follow that with docetaxel. And they’re going to be looking at things like the dosimetry, safety, the tolerability as a lead-in.
Now, assuming that everything goes OK during the lead-in, there’s then going to be this randomized phase III trial with 400 patients. And everybody’s going to get standard of care. And there’s going to be a randomization beforehand. And people are going to be randomized to a chosen standard of care either to get an ARPI or they’re going to get docetaxel.
Then they’re going to go into the randomization. And two to one, they’re going to be getting the TLX591 PSMA-targeted lutetium-177. As mentioned, if they’re getting docetaxel, this is going to be sequential. If they’re getting the standard of care alone, then they’re just going to go straight to docetaxel.
And then people are going to be followed for rPFS, radiographic progression-free survival. And assuming that everything goes standard in an interim analysis, they’re going to take it out to the 400 patients. Primary endpoint, again, is rPFS. Key secondary, the overall survival and safety.
So Zach, that’s basically the design. It’s pretty simple, because it’s going to combine the hormones. It’s going to combine the chemotherapy. It’s going to combine the lutetium, all into one trial design. And I think a lot of people are going to enjoy this.
Oh, the other thing about the antibody, people have gotten used to the PSMA-617-lutetium, where you’re dosing every six weeks. Here, you get two doses of antibody. 76 millicuries. And two weeks later, 76 millicuries again. So the design on the dosing is very, very different than what people have gotten accustomed to for the PSMA-617-lutetium, otherwise known as Pluvicto. So there you go. Let’s go into some questions. I’m going to stop sharing.
Zachary Klaassen: Before you stop sharing, I just want to ask a quick question, because you mentioned a great point, and it was going to be my question about the two doses. So when I looked at this trial, Oliver, it has very similar inclusion criteria to PSMAfore. We know that the PSMAfore trial had six cycles. The SPLASH trial with PNT2002 had four cycles. Now, we’re down to a very patient-friendly two cycles. And so is it fair to say that based on this trial design that you have laid out here, that we’re going to be taking these results into context with PSMAfore and SPLASH?
Oliver Sartor: Absolutely. Now, let’s talk a little bit about the trial design. PSMAfore excluded prior docetaxel. So none of those patients in PSMAfore had prior docetaxel. On SPLASH, it was allowed, very similar to here. So when we look at this, this is going to be kind of a head to head, if you will, although it’s not head to head, with the PSMAfore and SPLASH population. So same population essentially, but different dosing and different entity. This is an antibody, not a small molecule.
Zachary Klaassen: Excellent. Excellent. So again, with ProstACT GLOBAL, there’s overall survival as a secondary analysis. We’ve seen fancy crossover analysis for overall survival for PSMAfore as well as SPLASH. Do you anticipate, in this trial design, a similar adjusted crossover analysis?
Oliver Sartor: The idea is probably to avoid the crossover here. Now, please realize that patients in the control arm in particular can go on to receive FDA-approved agents, like Pluvicto. All you need, you need ADT. You need docetaxel. And you need an ARPI, and then progression with PSMA PET-positive. So patients could leave this trial and go on to receive an FDA-approved agent like Pluvicto.
Now, that is obviously going to muddy the waters, but we’re going to keep track of all the sequential therapies. And one of the things in prostate—and I know you’re aware of this—is the overall survival endpoint is going to be increasingly problematic as we have more and more active agents. And we’re using things like the PSMA-targeted therapies early on.
So this is a big issue because we’ve gotten used to overall survival. And we should. But on the other hand, those late-stage trials are not necessarily where the drug development is now. As you move earlier, I think we’re going to look for trends in OS and a powerful rPFS. That’s what people are hoping for now.
Zachary Klaassen: Yeah. Great explanation. I think in your early experience with TLX591, what’s the tolerability been like in comparison to some of these other agents?
Oliver Sartor: More myelosuppressive. It turns out that you end up with the antibody having a longer circulation time. Some of that hangs out in the marrow. Thrombocytopenia is a real issue. And this is one of the bugaboos in this trial. You’re giving an antibody, and then you’re setting people up for docetaxel, if they’re choosing to be treated with docetaxel, and there could be some myelosuppression. So I don’t really know.
Now, the reason, I think, that the antibody has generated some degree of enthusiasm, if you look at what was published out of Cornell—and I will cite Scott Tagawa again. Great guy. Did a lot of this early work. I want to make sure he gets the credit. It turns out that some of the survival was just crazy good. I mean, people with metastatic CRPC living three, close to four years. And so there is this concept that maybe the antibody is going to be able to deliver the isotope in a little more efficient way, hence the two doses. But downside, myelosuppression, particularly thrombocytopenia.
Zachary Klaassen: Excellent. Great discussion, as always, Oliver. Maybe just a couple take-home messages for our listeners today.
Oliver Sartor: Yeah. Number one, I think the isotope field is alive and well. We have small molecules. And now, we have an antibody coming into phase III. This will be the first phase III with an antibody.
I can’t say if it’s going to be positive or negative, but I like the shot on goal. I like the choices. I like the dosing scheme. Just two doses is patient-friendly. I like the opportunity to be able to use docetaxel in both arms, which will mitigate some of the criticisms that have come against PSMAfore and SPLASH. And I’ll simply say, let’s hang on for the ride. Let’s see what it shows.
Zachary Klaassen: That’s absolutely true. And I think it’s nice to know that the dose lead-in is ongoing. And hopefully, the phase III accrues well and accrues quickly, and we’ll get some results. So as always, thanks so much, Oliver. Thank you very much for joining us.
Oliver Sartor: OK. Thank you, Zach.