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Zach Klaassen: Hi, my name is Dr. Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm joined today by Dr. Michael Hofman and Dr. Renu Eapen, both from Peter MacCallum Cancer Center. Thank you so much for joining us today.

Renu Eapen: Thanks for having us, Zach.

Michael Hofman: Pleasure.

Zach Klaassen: So we are talking about LuTectomy today, and this is a very exciting trial. You guys just published it in European Urology, so congratulations on that. Previously presented at the PCF meeting as well as EAU. So just tell us about the background and sort of the genesis for how LuTectomy came to be.

Renu Eapen: I think I'll let Michael take this one.

Zach Klaassen: Sounds good.

Michael Hofman: Thanks, Renu. We did some of the very first trials of Lutetium-PSMA-617 at Peter Mac publishing our phase 2 trial back in 2018. We did see incredible responses in patients that had failed multiple lines of treatment. And as nuclear medicine specialists, we understand that this is effectively a radiation delivery device and we know external beams are very effective in patients with newly diagnosed prostate cancer.

And a grant call came around from November for something a little bit moonshot-like, and we thought let's just move it all the way from last line, which is kind of 2017 to first line, which is a paradigm shift given that the data in between, some of which we've seen presented at this meeting like ENZA-p or like PSMAfore we're undergoing. Let's just do it first line, we'll take a small cohort. And we have a great collaboration with our urologists at Peter Mac, which is a little bit unusual, urologists and nuclear medicine doctors working together. So we thought, let's do a trial where we give one or two cycles of lutetium prior to a prostatectomy and let's see what happens. Maybe you can give a bit more about that.

Renu Eapen: Yeah, so I mean, it was a couple of years in the making. One of our colleagues who's now passed away, John Violet, was heavily involved in the conception of the idea for the trial and was really involved in the earlier stages of the trial. So initially our trial did have a radiation arm and a surgical arm, but after multiple conversations, we decided to focus just on the surgical arm, so as an upfront option prior to surgery. We were all a little bit apprehensive about the trial, operating on patients after radioligand therapy, which has never really been done before, but the results are very reassuring from that standpoint.

Zach Klaassen: That's great. So let's get into the trial design, phase 1/2 trial.

Renu Eapen: Correct.

Zach Klaassen: Just lay out the two cohorts that you guys use.

Renu Eapen: The two cohorts were according to the dose of lutetium-PSMA that they received. We recruited patients in a staggered fashion, so 20 patients all up. The first cohort of 10 patients received one cycle of lutetium-PSMA at 5.5 gigabecquerels per cycle. Once we were assured of safety, the second cohort of 10 patients received two cycles spaced six weeks apart. And then six weeks after the final cycle of lutetium-PSMA, patients underwent a robotic prostatectomy with or without a pelvic lymph node dissection.

Zach Klaassen: Excellent.

Renu Eapen: And the follow-up is for three years in total.

Zach Klaassen: And these were high-risk patients, right? So these are patients, I think there were, what, six patients out of 20 that had lymph nodes positive as well?

Renu Eapen: Correct. So high-risk patients, biopsy proven prostate cancer, no distant metastasis, but regional N1 disease was included and six patients did have pelvic lymph node involvement. And an important inclusion criterion was uptake on PSMA PET-CT. So they had to have an SUV max of 20 or more.

Zach Klaassen: Okay. Great. So very selected sort of high risk, pelvic only, and prostate obviously.

Renu Eapen: Yeah.

Michael Hofman: And we debated about the primary endpoint a lot, as being a small study, we can't really look at oncologic endpoints that's going to need a larger phase 2/3 trial, but we focused on dosimetry, which is unique. How much dose could we get to the primary lesion in the prostate and also the lymph nodes. And we thought carefully about this, and we had a threshold. If we can get above 10 to 20 gray, this may be a useful neoadjuvant approach. And what we saw is that we can get very high doses to the tumor, unlike external beam radiation where you can dial up the exact dose you want. Here, it's unpredictable. It depends upon the uptake in each individual.

So we saw quite a wide range, but some patients received over 100 gray from a single injection. These are quite extraordinary images because you inject the PSMA intravenously, you do a whole body scan, and there's uptake literally just in the prostate gland at 96 hours. So it's quite remarkable to be able to do that sort of targeting similar to external beam in a way, but with an injection. But bear in mind that there's just a very wide range that's uncontrollable and that's going to result in variable outcomes.

Zach Klaassen: Let's talk a little bit more about the dosimetry because I think from, let's say, the urologist and the medical oncologist, just to break it down a little bit more nuanced and a little higher level, how was the dose in the prostate, say, compared to radiation therapy in terms of dosimetry?

Michael Hofman: Look, it's very difficult to compare because the radio biology is different. When we give lutetium as a beta emitter, it's got a seven-day half life and it's emitting radiation constantly over that period of time for actually several weeks after the dose, whereas external beam's given in fractions. So actually we don't have good comparable data. So when we say we measured 100 gray, that's not equivalent to 100 gray from external beam radiation in whatever fractions, and maybe as a rough guesstimate, you need to halve the values that we spit out. So if we say 50 gray, that's equivalent to roughly 25 gray of external beam. But data from other cancers with theranostics, so iodine for thyroid cancer or lutetium-dotatate for neuroendocrine tumors, which have been around for longer than lutetium-PSMA, we know that if you get above 80 to 100 gray, then you start to get lethal doses to the tumor.

Zach Klaassen: I see. Okay. So let's talk about the surgical outcomes. Surgeon on surgeon here, I mean, when I read this, I thought we hate giving salvage radical prostatectomies after external beam. We know those tissue planes are changed. Sounds like this wasn't an issue for lutetium-PSMA.

Renu Eapen: Yeah, it was nothing like a salvage prostatectomy. The tissue planes were largely preserved. It's important to keep in mind that these are all patients with high-risk prostate cancer, so they're difficult operations anyway. But out of the 20 patients, 15 was basically a stock standard sort of robotic prostatectomy.

Zach Klaassen: That's great.

Renu Eapen: And this was all very subjective evaluations, but we graded five slightly more difficult, but again, really not particularly difficult. But we saw that there was just a little bit more fibrosis in the tissues compared to what we may expect in a normal patient or a normal situation. No real increase in complications at all-

Zach Klaassen: That's great.

Renu Eapen: ... and no complications that we attributed to lutetium-PSMA treatment. So all our patients left hospital the next day-

Zach Klaassen: That's great.

Renu Eapen: ... catheters were removed at the appropriate times, so we were very pleasantly surprised and systemically also, it was very well tolerated. There were no grade 3 to 4 adverse events. So it was a very safe drug to give-

Zach Klaassen: That's great.

Renu Eapen: ... the two doses at least.

Zach Klaassen: Did you notice anything surgically between one and two doses or was it pretty much the same?

Renu Eapen: We didn't really, we only waited six weeks before operating on these patients. And again, this is a first time done study and we didn't want to leave these high-risk prostate cancer patients without surgery for too long. But we didn't notice a significant difference between one and two doses.

Michael Hofman: And conceptually, lutetium-177 has a one to two millimeter path length. So if you envisage-

Zach Klaassen: Great point.

Michael Hofman: ... a prostate cancer that's inside the prostate gland, not on the surface, you're not going to have any effect on surrounding tissue. But it may be if it's right on the surface, you might get a little bit. But we also have experience with other tumor types, lutetium-dotatate with salvage pancreatic operations in patients with neuroendocrine tumors. And this is our experience that after lutetium, the surgeons go in and go... I think if we blinded you, I don't think you'd be able to tell.

Renu Eapen: You wouldn't be able to. Yeah.

Zach Klaassen: And you mentioned high risk is going to have its own challenges, EP and all that stuff anyways.

Renu Eapen: Exactly. That's right, exactly.

Zach Klaassen: Some of the other outcomes I thought were interesting. When they looked into the microscope, just tell us about the PCR rates as well as what did the cells look like?

Renu Eapen: Yeah, so histological response, again, it wasn't a main end point of our trial, but the majority of our patients, about 80% had evidence of partial response. So this is more fibrosis in the stroma, there was more gland atrophy, less density of tumor cells. There was extracellular mucin deposition, and these all seem to be markers of some form of response. Most patients still had disease at the six-week mark. One patient in fact had minimal residual disease.

Zach Klaassen: Wow.

Renu Eapen: So the majority of our patients seem to have some histological response to lutetium-PSMA.

Zach Klaassen: That's great. And so obviously small cohort, early in terms of follow-up from an oncological standpoint, but I know we had PSA 50 results. Just tell us about some of those early results on the oncological side.

Renu Eapen: Yeah, so the median PSA reduction was 49% and 45% of our patients achieved a PSA reduction of 50% or more. And we had a median follow-up of 13.8 months, and the biochemical recurrence-free survival was 80% at that time.

Zach Klaassen: That's pretty good.

Renu Eapen: So we've seen encouraging responses throughout. Like you said, it's an early phase trial, it's a limited cohort of patients, so it definitely does make the case for further research in the area.

Zach Klaassen: Absolutely. That leads me to my next question, sort of the $64,000 question, what's coming next with this disease space and what you guys are planning?

Michael Hofman: So I think it's potentially a great therapy in this setting as an upfront treatment, either in combination with surgery or with external beam radiation, and potentially even in a highly selected population lutetium on its own could be useful. I think as you move this earlier, we do need to be mindful of potential delayed toxicity.

Zach Klaassen: Sure.

Michael Hofman: So we're continuing to follow up everyone on this trial. Will they develop any long-term toxicities? We haven't seen any to date, but we'll follow that up carefully. Given the big range of tumor doses that we see in this 20-patient cohort, I think it's going to require careful patient selection. Don't treat everyone. Everyone, at least in Australia, is now having a PSMA PET-CT for staging of high-risk prostate cancer. So then you know the intensity of uptake on the scan, you can quantify it with an SUV max. So I would advocate that this approach is useful only for those patients with very high expression. We can debate what that is, but you don't just want to treat everyone because you're not going to have much effect.

Zach Klaassen: Right.

Renu Eapen: Yeah, I think patient selection is going to be really key. The other important thing we're doing out of this trial is the translational work.

Zach Klaassen: Yeah, absolutely.

Renu Eapen: It just gives us such a unique opportunity to study tissues, so the pre-treatment biopsies and the post-treatment prostatectomy samples. So we're trying to understand the changes in the tumor microenvironment in response to lutetium-PSMA. Prostate cancer has always traditionally been considered a cold tumor environment, but what we're seeing is that there is still a subset of patients that are immunologically hot at baseline, and these are the patients that even if you're looking not even in the localized setting, even in the more advanced setting, these are potentially the patients that could have lutetium-PSMA combined with some form of immunotherapy, but it doesn't work for all patients. We're seeing that this is a very heterogeneous group of patients.

Zach Klaassen: Well, I think it's exciting. I mean, we look at the neoadjuvant trials before surgery. They've been pretty disappointing to date. So we have something here with proof of concept, looks exciting. And I think, as you alluded to in the beginning, we have VISION, basically third line mCRPC, we just saw PSMAfore at ESMO, we have PSMAddition, hopefully will come in the next little bit for metastatic hormone sensitive. We jumped all the way to the front, which I think from a surgeon standpoint is very exciting because we may have something in the neoadjuvant setting, as you mentioned, maybe we combine this with other modalities as well that may help our patients even at the beginning of their journey essentially.

Michael Hofman: So I think a different approach here is with VISION, PSMAfore, we're looking at palliation, extending survival, extending quality of life. But when we bring it back here, we're actually trying to increase the cure rate.

Zach Klaassen: That's right.

Michael Hofman: And maybe in combination with surgery this high-risk population may have a failure rate of 40% in five years' time. Maybe we can reduce that from 40 to 30 or 40 to 20. If we can halve that failure rate, this would be a major advancement in prostate cancer.

Zach Klaassen: Different goals for sure.

Renu Eapen: And I think this is where the toxicity really matters, because in this space, these are healthy men who will live potentially a long, long time. So we just don't have that long-term toxicity data yet. And as we get that, I think that will also add a lot of importance to this data.

Zach Klaassen: Absolutely. It's been a great discussion. I want to give you guys each a moment to either hit on something we haven't hit on or maybe a couple of take-home messages from each of you.

Renu Eapen: I mean, it's been a very exciting trial to run, but it wouldn't have been possible without an amazing team.

Zach Klaassen: Sure. Multi team.

Renu Eapen: So I think I want to just acknowledge the incredible multidisciplinary team at Peter Mac and ProsTIC, all our funders, in particular Movember, Novartis and all the patients and their families who helped us with the trial. We recruited into this trial during COVID during the toughest of restrictions in Melbourne.

Zach Klaassen: For sure.

Renu Eapen: So really, I'm very proud of the effort by the whole team.

Zach Klaassen: Outstanding. Dr. Hofman, any final thoughts?

Michael Hofman: Echo everything that Renu has said, and we really hope that this trial's an impetus for many other groups. There are so many different phase 2, phase 3 combinations you can do off the back of this with surgery, with radiation, BlueSky even on its own in highly selected people. We just would like to see, I'd like to see a myriad of combinations of early use of lutetium.

Zach Klaassen: Congratulations again on the publication and for the conversation. I'm very grateful. Thank you.

Renu Eapen: Thank you, Zach.

Zach Klaassen: Thanks.

Michael Hofman: Thank you.