Neha Vapiwala: I'm well, thank you so much, Zach.
Zachary Klaassen: We're going to talk today about the INDICATE trial, and I know you've been on UroToday discussing it. It's a big cooperative group trial. Before we get into that phase-3 trial, maybe just take our listeners through why it's important to consider treatment intensification, particularly for these high-risk biochemical recurrent patients, but also the oligometastatic patients.
Neha Vapiwala: Sure thing. Well, I think all of us in GU-oncology appreciate the ways in which PET imaging has really redefined the way we look at our patient populations. And for the individual patients sitting there in your clinic, who's got biochemical recurrence after prostatectomy, it can be a really confusing time. It can be distressing, thinking about, "What's my chance of a second shot at a cure?" I think in this population where we are increasingly getting PET scans and finding lesions in many cases outside of the pelvis, what we would consider metastatic, but not necessarily seeing that on traditional imaging, on what we call conventional imaging, we're in this conundrum. Do you offer this patient still that opportunity for definitive second shot at cure, what we colloquially refer to as salvage therapy? Or do you treat them as metastatic or some hybrid in between? So really what the INDICATE trial tried to do since its conception, and is still aiming to do, is offer some clarity in this nebulous space and really help us to figure out where do we actually benefit patients by doing more directed treatment without withholding that definitive salvage therapy.
Zachary Klaassen: Yeah, absolutely. That's well said. I think this trial now is what? Roughly three years enrolling. So maybe just lay out the trial design, there's a couple layers to it, and some of the primary objectives for INDICATE.
Neha Vapiwala: Sure thing. For starters, we really wanted this to be open to patients with biochemical recurrence regardless of their pathology findings. So of course, we collect that, but you can have any findings on pathology as long as you meet the PSA criteria for recurrence and are a candidate for salvage pelvic radiotherapy and six months of standard androgen deprivation therapy. So really all comers. And then where things get a little complex is the double randomization. So we randomized then based on what the baseline standard-of-care PET scan revealed. If it was at all positive anywhere outside of the pelvis, outside of your typical pelvic radiotherapy field, then you entered the randomization that's currently still open. That's arms C and D. Arms A and B were the randomization for patients who did not have findings outside of the pelvis. They could have been positive within the pelvis on the PET, and we collected that info, but those arms are done to enrollment. They've been completed since January, so we're letting that data mature. But getting back to arms C and D, really the question here is, okay, you have something on PET.
Any number of lesions, by the way. There's no upper limit, because I think we're all agreed that the traditional definition of oligometastatic disease was based on conventional imaging. And we don't know if the appropriate upper limit, if you will, in a molecular era should be six, should be seven, should be 10. We don't know. So we collect that info, any number of lesions, as long as the PET shows disease outside the pelvis, but the conventional imaging is equivocal, indeterminate, or straight up negative. So here you have this population where they're not technically M1, but you want to treat them as M1 based on the PET. We randomize them to receive metastasis-directed radiotherapy to those PET-positive lesions. And everyone essentially gets the standard of care, the salvage radiotherapy, the six months ADT, and also everyone gets six months of apalutamide provided by Janssen. So we're trying to say we're not withholding definitive treatment in this population for salvage, but at the same time, we're questioning the role of focal therapy intensification. What value does it add? So the primary endpoint of progression-free survival is intended to hopefully be a clinically meaningful one and really get at that point of, do we just treat everything you see for the sake of it or are we actually helping our patients?
Zachary Klaassen: Yeah, really well laid out. I think you kind of alluded to a little bit of my next question in terms of where we are with the trial. It's exciting that arm A and B already accrued. Just give us maybe an update on where C and D are at with recruitment and maybe when we may see data. Obviously these trials take a while to accrue events, but what's your thoughts on when we may see data?
Neha Vapiwala: Yeah. So as you can imagine, it's a little bit of a bespoke population that we're trying to accrue in arms C and D, so it takes a little bit longer. But I'm excited to say that we're actively working on an amendment as we speak that should be making its way through the bureaucratic process. And as soon as that's activated, hopefully in the next month or so, we are essentially over halfway done with arms C and D. And with the new sample size that we plan to have in the amendment, if all goes well and it's approved, the hope is, hopefully by the summer, that we can be done with accrual and really start looking at letting that data mature and seeing what we can learn from that randomization.
Zachary Klaassen: Absolutely. I think when we look at this trial, and the fun part about doing these conversations is we can hypothesize a little bit. So let's assume this is all done. We see the results. It's a positive trial. We've heard about EMBARK. Obviously in the last several years you heard about PRESTO. Where may INDICATE fit into this whole landscape of high-risk biochemical recurrence/oligometastatic disease?
Neha Vapiwala: Sure, absolutely. Well, I think for starters, there's a ton of exploratory endpoints that are built into this study as well as the potential for future secondary analyses. So first of all, we're bringing in as much as possible a pragmatic element to this study. At every step of the way where we could be pragmatic, we are, within the confines of a very tightly controlled randomized phase-3. So we have PET scans that are just whatever's FDA-approved, whatever you use, as long as it's consistent through follow-up. We did not place upper limits on the number of lesions. We allow for a variety of different doses for the radiotherapy and fields as long as they're all within what's considered guideline-accepted. So I think some of that element will be a bit of a nuance to essentially complement EMBARK and PRESTO.
But there's also, again, within PRESTO, we did not have that molecular imaging. So I think we're really saying this is modern treatment with modern imaging and decision-making that best reflects the conundrum we face in clinic. Again, in EMBARK, radiotherapy was not the focus. What we're saying here is, we're not treating these patients as if they're metastatic. We don't want to put them on a year, two years, an indefinite amount of therapy. We're trying to do intensified six months of ADT and ARPI with apalutamide, definitive pelvic radiotherapy that they would've gotten had that PET not shown anything, and really redefine how we look at M0, and whether conventional imaging should remain the standard. And I think we all agreed it shouldn't, and yet all of our studies, all of our data, and our decision-making has historically been based on that. So we're really trying to move to that next frontier. I hope that it's going to enhance and complement all of the data that we already have, but it has a lot of unique angles that are distinct.
Zachary Klaassen: Yeah, no, well said. I think the point you made about pragmatic is exactly that. PET scans, not putting on patients for months and years of intensification, and really trying to answer two questions within one trial based on those populations. So I think that's really well said. Anything we haven't hit on? Anything you want to leave our listeners with before we wrap up?
Neha Vapiwala: Well, listen, I'm always grateful for any time with my UroToday colleagues.
Zachary Klaassen: Aw, thank you.
Neha Vapiwala: You guys do such incredible work. All I would say to patients is, there's so much that's happening, and of course bringing in the genomic signatures and all the other stuff we're doing in this study. So we thank all of our patients who have already participated, because it's with their time and their dedication to science and their altruism that we get the satisfaction of doing what we do and being able to help future patients. And then to all of those sites that have INDICATE open and all of our enrolling investigators, please help us through this final push, keep an eye out for these eligible patients, and just know that when that data comes out, hopefully we'll all be better for it, whatever it shows. So thank you.
Zachary Klaassen: Perfect summary. Yeah, thanks so much for joining us. Appreciate it.
Neha Vapiwala: Absolutely. My pleasure. Always great to chat with you.