Alicia Morgans: Hi, my name is Alicia Morgans and I'm an Associate Professor of Medicine and a GU medical oncologist at Northwestern University in Chicago in the United States. I am so excited to have here with me today, a friend and colleague, Dr. Michael Hofman, who is a Professor of Nuclear Medicine at the Peter MacCallum Hospital and Cancer Center in Melbourne, Australia. Thank you so much for being here with us today.

Michael Hofman: Thanks Alicia, a real pleasure to be with you again.

Alicia Morgans: Wonderful. So I think we're all so excited to hear updates on the TheraP trial, which you have provided to everyone at the GU ASCO virtual meeting 2021, as well as a recent Lancet publication. Can you tell us a little bit about what this is all based on before we get start getting into the TheraP trial? What is lutetium and how can we think about that medication?

Michael Hofman: Yeah, so this is a small molecule that is labeled to a radioactive substance called lutetium-177. So the small molecule binds to PSMA, or prostate-specific membrane antigen, this is a cell surface glycoprotein that's overexpressed in prostate cancer, particularly metastatic castration-resistant disease. So it's a target for both imaging and therapy with nuclear medicine. So for the treatment, which this study is focused on, we're using lutetium-177, it's a beta emitter with a one-millimeter half-life. A little bit similar actually to iodine-131 that's been around in nuclear medicine for a very long time. So it enables us to deliver very high doses of radiation to sites of tumors, probably similar or sometimes even higher doses, than what you can achieve with external beam radiation.

But obviously, it's a very different type of radiation. It travels only one millimeter, so it targets tumor tissue, has a seven-day half-life. So it actually sticks to the tumors and irradiates them actually for several weeks after each dose of treatment. And because of its short path length, there is limited damage to normal tissues, but we do get some uptake in organs that also take up this substance, like salivary glands and kidneys that can potentially cause some toxicity as well. So we've done a lot of research in this area since 2015, we did the first Phase II trial, a single-arm small trial at Peter Mac a few years ago. And this is the first randomized, controlled trial off lutetium PSMA.

Alicia Morgans: Wonderful. And really to just reiterate, this is a targeted radiopharmaceutical. This goes into soft tissues, it goes into bone, there's no real bone tropic effect here. It goes everywhere that the cancer is expressing, this prostate-specific membrane antigen protein, and then will admit this radiation. So, fantastic. Can you tell us a little bit about the TheraP trial?

Michael Hofman: So this is a randomized Phase II study. It's a cooperative group trial. It was run by the ANZUP Cancer Trials group in Australia at 11 sites. Designed back in 2016, when not people had heard of lutetium PSMA, and at that time after careful consideration, we chose cabazitaxel as our control arm. So in this trial, we took 200 men with metastatic castration-resistant prostate cancer who had progressed after docetaxel, and the majority, 91%, had progressed after enzalutamide or abiraterone as well, who was suitable for cabazitaxel. And they were randomized to either six cycles of lutetium PSMA-617, delivered every six weeks, or cabazitaxel at a standard dose.

And we carefully screened these men with PSMA and FDG PET to see if they were suitable. With that test, we're really looking for high PSMA uptake at all sites of metastatic disease. And around 30% of men were screened out, so deemed unsuitable, because our predefined thresholds were not met. These were centrally reviewed. And if you were suitable, you were randomized one-to-one to lutetium or cabazitaxel. We did report the initial findings at the ASCO 2020 meeting, but this is the updated, let's say final result, along with the publication. So we've got all the endpoints reading out.

Alicia Morgans: Wonderful. Well, before we get into those endpoints, just to really emphasize, you actually used a screening process that included both a PSMA PET scan as well as an FDG PET scan, to really find the right patients that had that balance of higher expression of PSMA avid disease, and maybe a lower expression of FDG avid disease. Or at least you didn't want a predominance of FDG avid disease that was not also standing for PSMA. Can you tell us a little bit about that selection process and about that 30% of the patient population that would not have been included in the TheraP trial?

Michael Hofman: Yeah, so our experience here actually stemmed from lutetium dotatate in neuroendocrine tumors where we've used dotatate, which is sort of the PSMA equivalent, for that tumor and FDG for many, many years. And what we often see is tumor heterogeneity with some sites of disease with one phenotype and other sites with another phenotype. This is really not unique to PSMA therapy, it's probably true for all treatments that we use in oncology, but we have a unique ability to image the target with this theranostic approach. Because we are imaging with exactly the same PSMA, but it's liable to either gallium-68 or fluorine-18 as opposed to lutetium. So this enables us to really make sure that that target is expressed. My analogy would be checking for estrogen receptor expression in breast cancer, if you're going to use that sort of approach, that's done with immunohistochemistry and you can do it at a single site. Here, we're using an imaging method to essentially tell us a similar expression phenotype, but we can look at the whole body.

So as you pointed out, we had to have PSMA uptake above a certain threshold. We actually used a quantitative PET measure in this study. We said you have to have an SUV max above 20 at one site of disease, not at all sites, but just at one site. And then the FDG was really to look for sites that were FDG positive and PSMA negative. And some of those hide in bones, which is a frequent site of metastasis, so you can't see them on the CT scan. So if they're PET negative on the PSMA, you wouldn't know unless you had the FDG. Sometimes it's obvious on the CT, you have a liver metastasis that you see on the CT that's PSMA negative, you don't really need the FDG. But I will point out that some of these patients had really very FDG avid disease, but they were also PSMA avid. And actually, the majority of men in this castrate-resistant phenotype with rapidly rising PSAs do have FDG avid disease, it is an aggressive phenotype. So we're really just checking to make sure that all those sites do express the PSMA.

Alicia Morgans: And I think that's so important as we think, from a patient perspective and a clinician perspective, about how to really match the right treatment for the disease. It helps us to interpret the trial results, of course, so thank you for going through that. So what did you find as the result of the TheraP trial?

Michael Hofman: So the primary endpoint was a PSA decline of 50% or more, and we actually reported this at ASCO 2020 last year, and the updated results are no different. There was a large difference in the intention to treat analysis, 66%, with lutetium PSMA-617, compared to 37% with cabazitaxel. So that's a large difference. In this readout, we now report progression-free survival and for a combination of radiographic and PSA PFS, the hazard ratio was 0.63 in favor of lutetium PSMA 617. So that's a 37% delay in time to progression. And if we knock that down to either radiographic or PSA, it's not very different, it's similar. And in our intention to treat versus our per-protocol analysis, it's similar. And the differences were seen increasingly over time. So at 12 months, 19% in the lutetium arm were progression-free, compared to only 3% in the cabazitaxel arm.

Whereas the median PFS was actually similar in the two arms at 5.1 months. So when we look at that Kaplan-Meier survival curve, which you'll see in the Lancet publication, it separates after six months. And now to 12 months and beyond, we're starting to see a significant separation of those curves. And we also report objective response rates, so CT RECIST response. So this is in a sub-population of men that had measurable soft tissue disease at baseline, so we saw a partial response in 49% of men, randomized to lutetium, compared to 24% of men randomized to cabazitaxel. So again, just showing us that there's greater activity with the lutetium compared to cabazitaxel.

Alicia Morgans: So that's really fascinating. And just to think about this splay of responses and the disparate responses that you see, do you have any sense of which patients seem to respond to the lutetium for longer and which patients may not be as responsive?

Michael Hofman: Yeah, it's a complicated pattern when we look at those Kaplan-Meier curves, that may be a function that the radiation doesn't work overnight. You tend to get slow shrinkage of tumors over many weeks with radiation, so maybe just a function of some of the kinetics of response between the two arms. It may be an effect of so-called exceptional responders, where some patients with lutetium are exquisitely sensitive. Maybe that's similar to some immunotherapy trials where you have a proportion of patients who are really responding. And therefore you see that at a delayed time point, those survivors. Whereas at 12 months, really 97%, almost everyone with cabazitaxel, had progressed. But you've got 20% of men with lutetium that haven't progressed. So I think that might just reflect the subset that's very sensitive to the treatment. I'm not sure that we can isolate those patients at the moment and identify a predictive marker.

Alicia Morgans: Well and hopefully we'll have some additional correlative analysis to really help us understand that because I think that will be so important as we try to understand who these exceptional responders are and who those patients may be that don't respond so well. Particularly since we've actually initially separated them out, as at least having some PSMA positive disease and not having an overwhelming amount of FDG positive disease that's not actually PSMA positive. So this will so interesting, I think, for us to continue to work out. Now, can you tell us about some of the secondary endpoints that you've also been able to report in the paper, and of course in your publication, or in your presentation at GU ASCO?

Michael Hofman: Yeah, so clearly we show that there's higher activity with lutetium. Also importantly is adverse events and patient-reported outcomes. So adverse events, there were grade 3 to 4 adverse events with cabazitaxel, this occurred in 54% of men with cabazitaxel, that's any cause not necessarily related to the drug. So 54% compared to 33% with lutetium PSMA. So that's physician-reported adverse events. We also did a lot of patient-reported outcomes with the QLQ-C30 patient questionnaire. And also a lot of other validated questionnaires looking at specific symptoms. And what we saw is that the global quality of health, with the QLQ-C30, was actually similar over time between the two arms. But when we looked at specific symptom scores, we saw some large differences in favor of lutetium. So less fatigue, diarrhea, less hair loss, insomnia, skin rash, sore hands and feet, urinary symptoms. These were very large differences favoring lutetium.

And the general direction of all the other patient-reported outcomes, even though many were not statistically significant, were all in the direction of lutetium. And there were no symptoms that were better with cabazitaxel. I think we'll see a treatment that's more active, but also improves the quality of life. An analogy may be docetaxel versus abi/enza in the castration-sensitive space. We've got a treatment that's at least as effective, we don't report overall survival yet in this presentation. There were only 90 deaths at the time of analysis, which was not enough to trigger our pre-specified survival analysis. So we cannot make a claim of improved survival at this point in time. But we do know that the response rates are greater, that's a surrogate outcome, but I think the patient-related outcomes, and also the adverse events, are pretty significant outcome measures in favor of lutetium.

Alicia Morgans: I think that's just so interesting, because as you said, even if the overall quality of life was similar between these arms, we can have differences in certain areas, or within certain areas of quality of life. And sometimes it's the outliers, so the people that have the best quality of life, the worst quality of life, that tend to tell us the most, not just the median. So I think that'll be really interesting to continue to sort through, and I really look forward to digging into those results. And certainly, we'll have to talk with you again about them at some point in the future, too, I'm sure. So if you were to make an overarching summary of what you found in this TheraP trial, which again, congratulations. It's a wonderful way for you to help us bring ourselves, as a community, into this PSMA lutetium spotlight as a therapeutic that might integrate into our framework, maybe even earlier than end-stage diseases, as VISION was designed. What would your overarching summary and conclusion be?

Michael Hofman: Yeah, so thanks, Alicia. I think firstly, just want to thank all the co-investigators involved in this trial, because this was an investigator-initiated trial run by the ANZUP group. So pretty rare to get to this trial investigator-initiated and really a great effort by the investigators and clinical trial staff. And another unique feature of this study was that the radiopharmaceutical was actually made in hospital radiopharmacies in all these hospitals. So a tremendous effort by all. But I think the overarching conclusion is that lutetium PSMA-617 is a new class of effective therapy for men with metastatic castration-resistant prostate cancer. It does seem that it's a suitable alternative to cabazitaxel with greater activity. And that's determined by PSA response, objective response rate, PFS with fewer severe grade 3 to 4 AEs, and patient-reported outcomes favoring lutetium in quite a few relevant domains.

Alicia Morgans: Fantastic. Always good to see our armamentarium increase. Hopefully, we in the United States will have access to these treatments in the future. And I sincerely appreciate the work that you and your team are doing to bring these therapies to the world and to help us understand how to best integrate them. Thank you so much for your time, for your expertise, and your efforts in the ongoing work that you do to try to improve the lives of men with prostate cancer. Thank you so much, Dr. Hofman.

Michael Hofman: Thanks, Alicia.