LuTectomy, a Single-Arm Study of the Dosimetry, Safety, and Potential Benefit of 177Lu-PSMA-617 Prior to Radical Prostatectomy - Declan Murphy & Renu Eapen

July 5, 2022

At the 2022 EAU meeting, Declan Murphy presented the initial results of LuTectomy, a single-arm study of the dosimetry, safety, and potential benefit of 177Lu-PSMA-617 prior to radical prostatectomy. Biochemical recurrence rates remain very high for men undergoing either surgery or radiotherapy for localized prostate cancer and no neoadjuvant strategies have succeeded this far in changing that. In this conversation with Matthew Cooperberg, Drs. Murphy Renu Eapen discusses progress thus far in the LuTectomy trial, a neoadjuvant protocol using Lutetium PSMA for men with high-risk prostate cancer, and highlight the initial results of the first 10 patients where Lutetium PSMA was given prior to surgery. In closing, the group looks forward to Cohort B which is set to read out in the beginning of 2023 along with the expected publication of the full paper. 


Declan Murphy, MB, BCh, BaO, FRACS, FRCS Urol, Professor, Urologist & Director of GU Oncology, Peter MacCallum Cancer Centre, Associate Editor, BJUI, Honorary Clinical Professor, The University of Melbourne

Renu Eapen, MBBS, FRACS (Urol), Consultant Urologist, Genitourinary Oncology Service, Peter MacCallum Cancer Centre, Melbourne Australia, Olivia Newton-John Cancer Centre Austin Health, Heidelberg, Victoria, Australia

Matthew Cooperberg, MD, MPH, FACS, Professor of Urology; Epidemiology & Biostatistics, Helen Diller Family Chair in Urology, The University of California, San Francisco, UCSF

Read the Full Video Transcript

Matthew Cooperberg: Good morning, I'm Matt Cooperberg, and it's a pleasure to bring you a special edition of the URO Today Center of Excellence for localized prostate cancer. I am joined today by two friends and colleagues, Declan Murphy, and Renu Eapen, from the Peter MacCallum Institute in Melbourne Australia. But it is really a pleasure to be here at the EAU meeting, in person, in Amsterdam. And what we're going to be talking about today is some very exciting research, which Mr. Murphy, and Ms. Eapen As even will be presenting about the LuTectomy trial, a neoadjuvant protocol using a lutetium PSMA for men with high-risk prostate cancer. So welcome.

Declan Murphy: Thank you.

Renu Eapen: Thank you. Great to be here.

Matthew Cooperberg: Tell us a little bit about this trial. What was the inception, how did this come to pass, and what will you be presenting at this meeting?

Declan Murphy: Well, two things, Matt. As you well know, unfortunately, biochemical recurrence rates remain very high for men undergoing either surgery or radiotherapy for high-risk localized prostate cancer. We've known that for years and years. And unfortunately, no neoadjuvant strategies have succeeded in changing that. So lots of randomized trials combining ADT with AR pathway inhibitors, or chemotherapy and so on, have not really shifted the dial. So standard of care remains, surgery or radiotherapy, and then wait for the biochemical recurrence, which happens in 30 or 40% of patients.

And at the same time, of course, Lutetium-PSMA has emerged as a very exciting option for men with more advanced cancer, as URO Center of Excellence and UroToday has really documented very nicely. So we know men with mCRPC have very good tolerability and good outcomes from two large trials now, TheraP in Australia, and VISION in the US. So of course, the question is, could we merge both these issues? The unmet need of high-risk prostate cancer and the exciting emerging therapeutic option with lutetium. So there are a number of trials, including in our center, bringing Lutetium-PSMA forward, but this is the way forward one, the LuTectomy trial. So this is a neoadjuvant study where we give Lutetium-PSMA prior to surgery. And at this meeting, we're presenting our initial results for the first 10 patients.

Matthew Cooperberg: First of all, has this been an easy recruitment? Have patients been excited about the concept?

Declan Murphy:Well, patients have been excited, and we've been excited, I think it's fair to say. But we opened, bang in the middle of COVID, in Melbourne. We opened in May 2020 when Melbourne was totally shut down. We had a really, really prolonged lockdown. But despite that, this trial recruited way ahead of expectations. So we're now fully recruited. It's a Phase I, 220 patient study. The first 10 patients get one cycle of Lutetium-PSMA-617, so from Novartis, followed by prostatectomy and node dissection, six weeks later. And the second cohort of men, they get two cycles separated by six weeks, followed by surgery. And it recruited really well. We had no issues. And at this meeting, we're reporting the data from cohort A, so those first 10 men who received one cycle, but the other men are fully recruited, and the last chap will undergo surgery in about three months time.

Matthew Cooperberg: Right. And what can you tell us so far? How's the experience been with those 10?

Declan Murphy: Yeah. The primary endpoint of the study was dosimetry. So that's what we wanted to see is, could we deliver a meaningful dose of radiation into the prostate and oral lymph nodes, with this strategy of giving 5 GBq of Lutetium-PSMA six weeks prior to surgery? So they had three point dosimetry done, over the 72 hours following the lutetium injection. So that's the primary endpoint.

And then of course, other important secondary endpoints like safety. The safety of the lutetium, but also the safety of the surgery. Is it safe to do the surgery was very important. And of course, pathological response rate, PSA response rate, and so on, and so forth. So dosimetry, that's what we're presenting here at the EAU for the first time. And what we showed is, yes, we can certainly get an adequate dose of radiation into the prostate and the lymph nodes. We showed the total maximum median absorbed dose is about 50 grey into the prostate, and about 50 grey as well into the lymph nodes. So that's a meaningful dose. That's what we were aiming for with one cycle. We'll see what two cycles will bring, or more cycles in the future, perhaps. And also it's very safe. Because we measure to see, are we also getting dose into other places, like salivary glands, or the kidneys? And what we also report is very, very low dosages getting in there, very low exposure to the marrow, and so on.

Matthew Cooperberg: And the lymph node dose obviously, depends on how much cancer is involving the nodes, presumably. To the 50 grey, this is for patients with relatively significant nodal involvement, is that right?

Declan Murphy: Yes. 40% of the patients had node involvement on PSMA PET-CT, but there are challenges in measuring the doses. We're very experienced at measuring dosimetry in patients with very metastatic cancer in our center, but there are these partial volume effects when you're trying to measure small organs like prostate, and especially, lymph nodes. But it's still very interesting, because Renu is doing a PhD on the immunology of this. What is the effect on the tissue? Which is very exciting, and we'll see that. But we definitely measured some very high doses, up to close to 100 in some patients. And we saw dramatic images, as you saw here at the meeting, with these lymph nodes almost disappearing, PSAs coming down in about 40% of patients, and importantly, the surgery was not compromised.

Matthew Cooperberg: Right.

Declan Murphy: So of course, being a surgeon yourself, if you are getting 50, 60, 70 grey into the prostate, where there's a big Grey Group V cancer, does that mean surgery is going to be more difficult? Is the prostate going to be all, fall to pieces, be all mushy? And thankfully, that's not what we saw. And we showed some examples here at the meeting, where even despite the high doses of radiation that's getting into these tumors, surgery is not compromised. The surgery was all very straightforward. Patients recovered very well, thankfully. No compromise from their functional outcomes.

Matthew Cooperberg: Right.

Declan Murphy: So I think, that's the conclusion for me is that, we showed we can get adequate doses in there, and we see some very interesting responses, the surgery's very safe. And I think it makes us feel more determined, I think, to see, where would you take this now? Higher doses, more cycles, combine with something else. And this is probably the start of that journey.

Matthew Cooperberg: Very exciting. Now tell us about the correlative. So obviously, one of the huge advantages with the neoadjuvant strategy is access to tissue before and after.

Renu Eapen: Yeah.

Matthew Cooperberg: Right? So what have you been doing with this, and any preliminary findings, or excitement you can share with us?

Renu Eapen: Yeah. So yeah, some exciting findings. The findings from the trial itself have been fantastic, but the translational work that the trial allows is really exciting. As you know, prostate cancer really typically has a very immune cold microenvironment, and external beam radiotherapy has a bit of an annihilating effect. And what we want to see is, whether this kind of novel radioligand treatment that targets just the cells, but with little collateral damage, can activate the immune system. And is there antigen presentation happening?

Matthew Cooperberg: Yep.

Renu Eapen: Is there T cells that are trafficking back to the tumor and having an effect? Is there a systemic effect with the tumor draining lymph node? So, I think, looking at the tumor microenvironment, looking at gene expression, what immune subsets are now present after treatment, is really exciting. So far, we're seeing some very heterogeneous results, the patient numbers are low.

Matthew Cooperberg: Yep.

Renu Eapen: But the tissue that we have access to is just incredible, and allows us to do these, to do such amazing experiments on them. And being able to compare pre-treatment biopsies to post-treatment radical prostatectomy specimens, it's an investigator's dream. Right? The ample amount of tissue that's available. And then, being able to have access to these lymph nodes, and looking at what happens to the tumor draining lymph nodes, is really exciting.

Matthew Cooperberg: Is there anything you can say yet, about this heterogeneity? Is this driven by differential PSA uptake, or is this innate biology, or differences in immune response? TBD.

Renu Eapen: We don't know. It's TBD, exactly. And I think, and when we run the second subset of patients, the second group of 10 patients, we'll get a lot more information. I think, it'll really solidify the changes that we're seeing. And the comparisons we're making, is not just pre and post treatment, but also, one dose versus two doses of Lutetium-PSMA. And then, the really exciting thing is, to be able to correlate all those translational changes, to see what's happening. Does it correlate with the clinical findings?

Matthew Cooperberg: Yeah.

Renu Eapen: So yeah, really exciting work.

Matthew Cooperberg: Very exciting. And then, what's next? So assuming, safety from both phases of this, will you go on a Phase III in Australia? Will there be a multinational? What's next on the horizon here?

Declan Murphy:Yeah, I suppose that's what we're excited to do now. We have the cohort B, the second part of LuTectomy, we'll read out in the first couple of months of next year, along with the full paper on this experience. But now, we've seen some stuff, and we're sharing it here. There's a lot of discussion, we're talking to you and many others around the world, about what you might do next. But I think, there's certainly enough there to say, in these high-risk men, who have high biochemical failure rates, Lutetium is safe. Some very interesting signs, signals. We should probably be planning some sort of randomized trial up against standard of care, which is nothing, and let's see.

Matthew Cooperberg: Right.

Declan Murphy:And whether we should combine it. Lots of questions I think. But I think Lutetium has got certainly, a research opportunity in early prostate cancer, that we should do our best to explore.

Matthew Cooperberg: Very exciting. Well, congratulations to you, both on a very exciting trial, and lots of great work ahead. So thanks for sharing your-

Renu Eapen: Thank you.

Matthew Cooperberg:... time and your audio equipment.

Renu Eapen: Fantastic. Thank you.

Declan Murphy: Thank you.