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Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urological oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today by Minal Padden-Modi and Professor Nick James from the Royal Marsden Hospital. Thank you both so much for joining us today.

Nicholas James: Pleasure.

Minal Padden-Modi: Yeah.

Nicholas James: Great to be here.

Zach Klaassen: So we're going to be discussing some great ESMO data from your trial in progress, looking at STAMPEDE2, specifically the lutetium compared to Arm P. So why don't you guys pull up your slides and walk us through this important trial design.

Nicholas James: Sure. So while Minal is putting us in screen share mode, STAMPEDE2 is, as you might guess, a follow-on from STAMPEDE or STAMPEDE1, as I guess it kind of has morphed into. And we're very excited to have started this earlier on this year. We're recruiting to two of the three planned comparisons at the moment. And we're going to talk today about Arm P, which is PSMA-lutetium.

We are using a different schedule to the other trials like PSMA-UpFront or PSMAddition. And one of the things that we were very keen to do is to understand exactly how the dosing was working, and also what was happening to the imaging during the schedule. So I'm going to hand over to Minal, who's the research fellow who's heading up the linked translational research. And she's going to run through what we're doing, and then we'll wrap up with a summary of the broader trial aims. So Minal, over to you.

Zach Klaassen: Outstanding.

Minal Padden-Modi: So yeah, we're discussing STAMPEDE2: Comparison P, which is a randomized controlled trial testing upfront accelerated lutetium-PSMA-617 in metastatic hormone-sensitive prostate cancer. And that's part of a platform protocol, which is STAMPEDE2.

So this is our presentation outline. And so STAMPEDE2 is testing three research questions, testing three new treatments in metastatic hormone-sensitive prostate cancer. So on the left-hand side we have Comparison S, which is for SABRE-eligible disease, which is low-volume disease. And they can be randomized to receive standard of care, or standard of care plus SABRE to metastasis-directed therapy.

And then on the right-hand side, we have Comparison P, which is testing upfront accelerated lutetium therapy with standard of care, versus standard of care, in patients who are SABRE-ineligible or have high-volume disease, which is more than five metastases.

And we also have Comparison N, which is testing niraparib, abiraterone acetate, and prednisone in patients who have biomarker-positive disease.

So the main thing that STAMPEDE2 Comparison P hopes to address is whether the addition of lutetium-PSMA-617 to standard of care in the upfront accelerated setting will help to improve outcomes in patients with metastatic hormone-sensitive prostate cancer. And the patients will be randomized one-to-one to Arm A, which is standard of care, and Arm P, which is standard of care plus upfront accelerated lutetium-PSMA therapy. And standard of care in this context includes long-term androgen deprivation therapy and androgen receptor pathway inhibitors, plus or minus prostate radiotherapy, plus or minus docetaxel as part of triplet therapy. And our dual primary outcomes are radiographic progression-free survival and overall survival.

So our eligibility criteria are that patients should have more than five metastases or be ineligible for the SABRE trial. They need to have baseline blood tests exhibiting normal liver, bone marrow, and renal function. And they must have biopsy-confirmed adenocarcinoma of the prostate. We also mandate that patients should have had a maximum 12 weeks from starting their androgen deprivation therapy to being randomized to receive lutetium therapy. And ideally, the smaller the timeframe, the better.

And our key exclusion criteria include prior treatment with radioligand therapies, symptomatic cord compression, and also impending cord compression on radiological findings, but also unmanageable bladder outflow obstruction or urinary incontinence.

So this is the main visit schedule for Comparison P. And you can see that there is the standard of care arm and then the lutetium arm, which is delivering 7.4 gigabecquerels at day one and day eight of treatments in six-weekly cycles. So that's how it's different from other upfront metastatic hormone-sensitive prostate cancer disease trials testing lutetium-PSMA-617.

And we also mandate a baseline CT and MRI bone scan prior to eligibility to assess the eligibility, and then also pre-treatment baseline PSMA PET CT. And we'll assess progression with CT or MRI and bone scans so that we can assess progression according to RECIST and Prostate Cancer Working Group 3.

And then embedded within this is the imaging sub-study, and this is the visit schedule for these patients. We aim to recruit up to 100 patients. And these patients will receive next-generation imaging, which includes whole-body diffusion-weighted MRI before, during, and after treatment. And also PSMA PET CT before, during, and after treatment, but also dosimetry scans. So three time-point dosimetry scans after every dose received, which will give us an idea of the dose received after every treatment.

And so in summary, STAMPEDE2 is an open-label multi-center Phase III trial. It's testing metastatic prostate cancer in patients with metastatic prostate cancer, starting long-term hormone therapy. In Comparison P, men are randomized to standard of care, or standard of care plus lutetium-PSMA-617. And standard of care includes long-term androgen deprivation therapy, androgen receptor pathway inhibitors, plus or minus prostate radiotherapy, plus or minus docetaxel as part of triplet therapy. We're giving lutetium-PSMA-617 in 7.4 gigabecquerels on day one and day eight, in three six-weekly cycles. And there's also an embedded imaging sub-study, which will provide a lot of exploratory information about what this novel treatment schedule will do.

And our take-home message is: Does the addition of lutetium-PSMA-617, when given upfront and in an accelerated schedule with standard of care, improve outcomes in patients with metastatic hormone-sensitive prostate cancer? To achieve our understanding of this question, we aim to recruit 1,756 patients. Our dual primary outcomes will be rPFS and OS. And in order to reach this big recruitment figure, we want to recruit internationally. So our current plan is to recruit until midway through next year, start recruiting EU countries and then beyond from then on.

So thank you for listening, and any questions?

Zach Klaassen: Minal, thanks so much for going through that great trial design. I want to start with Nick. Just without stating the obvious, STAMPEDE has obviously been transformational over the last decade or so, and really shaping advanced prostate cancer management. We've had multiple Lancet, New England papers, and I think my question is for STAMPEDE2: How does it differ from STAMPEDE, and what are you guys hoping to find over the next several years with the new platform?

Nicholas James: Yes. So thank you very much for those kind remarks. Yes, STAMPEDE has been an absolute just amazing ride to run. The main problem we were having is that we were kind of saddled with the baggage of still having to report suicides from arms we shut 20 years ago and stuff like that. And also, we were saddled with the 20-year-old database. So it was just getting quite creaky in terms of managing it. But the core model, as you say, worked really well. It has proven quite a challenge rebooting it. So we're going through the same sites that recruited before, but we're having to reset everybody up, which is proving to be not great. But we are up and running, and we are seeing huge enthusiasm from sites to open it. We're getting great support for this arm from Novartis, in terms of the mechanics of opening it.

And we're well down the road of opening multiple EU sites. And slightly less down the road, but certainly making good progress around opening a whole range of sites in the USA as well. So although our recruitment target is large, and actually we may revise it downwards as well, depending on how we feel that the group is behaving prognostically. So obviously, it's a high-volume group.

We think it is deliverable. That's the first thing. The second thing, and we've got three comparisons, as Minal outlined. So two of those are currently up and running and recruiting nicely.

The second thing is that we were very concerned from our own preliminary research around what happens to PSMA-positive disease when you start what is the highly potent upfront therapy, especially triplet therapy, that your target would disappear before you've got the PSMA-lutetium in. So hence, we've got a schedule that gives us six cycles, as per the VISION dosing, within 13 weeks of starting treatment. Whereas the PSMAddition trial, for example, had them six-weekly, so it's 36 weeks to get through the whole lot.

Whether or not that's important, we clearly don't know, but the imaging study will give us a very good handle on how both control arm and experimental arm imaging behaves. And the whole-body MRI gives us a particularly novel twist on this, as far as where nobody has really looked at dual whole-body MRI PSMA PET imaging, although our center itself is quite a fan of this. Our Phase I drug developers use it a lot, because it allows us to see and measure tumor and look at cellularity with diffusion weighting and so on, which is Minal's project. And so we'll be able to see what's happening in the PSMA-negative disease with quite some degree of detail. And we're looking at doing things like introducing targeted biopsies of resistant disease as part of this.

The second thing is that we're very concerned—well, not very concerned. We're very aware that the dose is going through the kidneys. And potentially, the kidney dose gets worse as your disease volume decreases. Now, you may not be bothered about that in Nth-line CRPC therapy, but in these patients who may live for a long time, it may actually be very important. So this will give us a very detailed understanding of the relationship between GFR changes in the future and measured renal dose. And dosimetry for liquid isotopes is complex, but we can get a reasonable stab at measuring it.

So the imaging sub-study and the dosimetry sub-study will start to give us readouts relatively quickly. And so, we may or may not modify the design once we've got some data. But we are certainly getting fantastic data from the first few patients that we've put through it. I think it's fair to say, isn't it, Minal? We've got discussion around today.

Zach Klaassen: That's great.

Minal Padden-Modi: Every new patient that we get generates a new discussion. So it's actually quite exciting with every new patient, because it's all novel treatment in a novel setting. So yeah, it's important stuff.

Zach Klaassen: Minal, I just want to dive a little more, as Nick said, about that sub-study. So you guys are looking at dosimetry, and Nick mentioned whole-body MRI.

Minal Padden-Modi: Yeah.

Zach Klaassen: Specifically from a dosimetry standpoint, what are you guys hoping to learn? Especially in this upfront dose in these metastatic hormone-sensitive patients.

Minal Padden-Modi: Yeah. So obviously, the dose received by the treatments, or the tumor and the normal tissue, might be different in this setting because we are giving it compressed, in comparison to the six-weekly schedule that we're usually used to. And also, doing dosimetry in the context of hormone-sensitive disease. And there's not that much data out there in comparison to how much data there is on the castrate-resistant setting. So it will give us an idea of how much dose is being received by the tumor, and how much of the dose is being received by the normal tissue. And maybe it might give us an idea of dose toxicity information, or dose-response information. Maybe even highlight some kind of dose constraints that we might need to follow with longer-term toxicity data as it comes through. So yeah, it's important stuff. Yeah.

Zach Klaassen: Excellent. Well, I think congratulations on a great presentation and an awesome platform. Maybe just a take-home message from each of you before we wrap up. I'll start with Nick.

Nicholas James: Yeah. So we're very excited to be booting STAMPEDE2 up, and we're seeing huge enthusiasm for it. And we very much hope we can repeat the success of STAMPEDE1. I'm confident we can. We're getting lots and lots of support. And I think I'll hand over to Minal to talk about just some of the translational work that she's doing and highlight that.

Zach Klaassen: Absolutely.

Minal Padden-Modi: Yeah. So I mean, the imaging sub-study will give us information, not just about the dosimetry, but also the next-generation imaging. So we're going to have the three time-point PSMA PET CT and whole-body diffusion-weighted MRI. The whole-body diffusion-weighted MRI, like Nick alluded to before, gives us an independent assessment of what the disease is doing, not just the PSMA expression. So that might lead for us to work out as to whether there's imaging biomarkers at baseline, next-generation imaging as well. So that's something that we're going to look into. But yeah, I'm very excited.

Zach Klaassen: Fantastic. Especially with that many patients. There's so many spinoff and ancillary studies I'm sure that will come out of it as well. So thank you both again for your time, and for educating our UroToday listeners on STAMPEDE2 lutetium.

Minal Padden-Modi: Thank you.

Nicholas James: Bye.