Matt Cooperberg: Hi, I'm Matt Cooperberg. Welcome to another installment in the Uro Today. Localized Prostate Cancer Center of Excellence video series live at ASCO 2022. It is my great pleasure to be joined by Michael Hofman, who is professor in nuclear medicine at the Peter MacCallum Institute in Melbourne Australia, and has been one of the major international drivers of progress in PSMA diagnostics and therapeutics. So welcome.

Michael Hofman: Thanks, Matt. It's a pleasure to be here in Chicago with you.

Matt Cooperberg: It is wonderful to be breathing the same air.

Michael Hofman: Yes.

Matt Cooperberg: And so always lots of exciting news in the world of PSMA. And of course, your center and your group in Australia have been one of the major drivers, I think, of progress over the last several years. Just to start off and to paint the broad picture, what do you find are the most exciting areas of development going on right now in both the diagnostic and theranostic spaces?

Michael Hofman: Well, PSMA 617 has recently been FDA approved, so we're into the implementation phase, which is an exciting period, because up till now it's been research dominated and available in a few places around the world, but now it's going to be globally available. But that's coming up with its own problems. So there's a lot of work around the education, implementation side of things. And it's kind of a hype curve with any new technology. So I've been on that hype wave, and we're probably reaching the top of that wave now. And it's been a fun journey, but as people use PSMA theranostics widely, perhaps they're going to find that it doesn't work in everyone as well as that society of nuclear medicine image of the year we produced demonstrates. So it's going to be about patient selection. And also about, well, how can we do it even better, because it's not a curative treatment, it's still a lethal disease.

And we are trying to combine PSMA 617 with other agents to improve its efficacy, bringing it earlier, and looking at next generation theranostics. Both new targets like alpha emitters and also next generation targeting molecules. So a lot of work. And then the imaging side also has a lot of progress, also FDA approved in the last year or two. And I think in the US finally it's available. So you no longer have to order that CT and bone scan. And I think we're going to see a surge in PSMA PET as a standard of care for imaging. And that's also got its implementation phase in a lot of nuances of how to interpret findings there. So there's a lot of education to be done there as well.

Matt Cooperberg: Well, let's talk about some of the big news happening at ASCO here, which of course is the theraP trial. Maybe just give us a brief outline of major findings and any of the discussion that's been going on even in advance of the meeting, of course.

Michael Hofman: Yeah. So ASCO 2022 I think the prostate session's actually dominated by PSMA theranostics. Half the presentations in the session are centered around lutetium PSMA, either related to the VISION trial or the theraP trial. And I present the three-year follow up of the therapy cohort. This is a cooperative group trial run by the ANZUP Cancer Trials Group. I had the pleasure of chairing this trial. It was conceived back in 2015, 2016, so it's been a long journey. But we've got the three-year follow up, so mature follow up. The primary findings were published in The Lancet last year, as you know, and that showed that most of the primary and secondary endpoints favored lutetium PSMA 617. So primary endpoint being PSA response, and there was almost a double of the PSA response with lutetium PSMA 617. And we also showed longer or delayed radiographic and PSA progression free survival by 12 months, almost everyone in the cabazitaxel arm had progressed, whereas around 20% had not progressed with lutetium PSMA 617.

So we were really following up secondary endpoint of overall survival, and we were never powered for overall survival. And we neither show a statistical nor a clinically significant improvement in overall survival, which is not surprising, given some of the nuances of the study. And these nuances are that there was crossover. Lutetium PSMA was available in Australia as a sort of off trial option. So men who progressed after cabazitaxel, some of them around 20% accessed lutetium PSMA 617 after cabazitaxel and vice versa. People in the Lutetium arm accessed cabazitaxel. So there was crossover in both directions. We also had 16 out of the 100 men randomized to cabazitaxel drop out at time 0.0. They were randomized to cabazitaxel and said, "No, I don't want chemotherapy." And we are doing an intention to treat analysis. And most of those men sought lutetium treatment.

So we think, one, it demonstrates that cabazitaxel is a very effective treatment. I think the key message is that Lutetium is an additional treatment option, that it performs as well as cabazitaxel, but the key benefit being much lower side effects. So grade three, four toxicities, I think it was 33% for lutetium compared to 54% with cabazitaxel. So big difference. And that translated to a lot of improvements in patient reported outcomes and quality of life. So yeah, there's been a lot of Twitter discussion even before the presentation has happened.

Matt Cooperberg: Which itself is kind of an interesting phenomenon, right? I mean the old way is you give the talk a couple days later, some article comes out and ask a post, and there might be some ongoing discussion outside the room. Now, you can snap a photo of the main presentation and it gets tweeted around the world. But it's an interesting phenomenon, the discussion, even before the presentation, based on a published abstract. I mean, what's been your sense of that conversation?

Michael Hofman: Yeah, it is really interesting. I mean, some people take the abstract off the ASCO website and they put it on their own slides and it kind of looks like your presentation, and then they tweet it out and people think they're your slides, but it hasn't actually been presented yet. And there's a conclusion slide, and they think that's my words, but it's actually the words of the tweeter. So the messaging can get a little bit confusing, but it's great to see this discussion. You can modify your slides up till two hours before your presentation, so you can tweak some of the discussion slides, and change the messaging. But there's been a lot of, "Oh, there's no overall survival benefit, does that mean. This is a useless treatment." And I think it's probably going to be a little bit like when enzalutamide and abiraterone came around in the hormone sensitive space. There was no overall survival benefit compared to docetaxel-based chemotherapy, but the world moved towards antiandrogen-directed therapies because there's so much better tolerated. And that's the same situation we have here.

 You can choose kind of the toxic chemotherapy, or the really well-tolerated lutetium PSMA 617, and it still doesn't obviate you getting cabazitaxel down the track. So the other thing that made me think about is just to compare maybe the CARD trial, or the TROPIC trial, and look at the overall survival from those trials with cabazitaxel to what we're seeing in theraP. And theraP overall survival in the cabazitaxel arm, I think it's 18 and a half months. So it's much longer than the CARD trial. And I think what we're seeing is the addition of lutetium to the treatment armamentarium. You may have lutetium post-cabazitaxel post-protocol, or you may have it the other way around. So when you look at the OS data in the theraP trial, in part you're looking at the addition of lutetium as a treatment option.

Matt Cooperberg: But that's sort of the whole point, right? Is that we're heading into this era of multiple treatment lines. The question is no longer abi versus chemo necessarily, as which patients should be getting double therapy, triple therapy up front. So I'm curious how you think, it's hard to have a crystal ball on this, but how do you foresee lutetium ultimately slotting in terms of the timing and combinations with other treatments, which I know it's hard to do based on existing data, but what's your sense of where it will ultimately find its optimal space? Early, late combination?

Michael Hofman: Well, at the moment it's late, it's post-docetaxel, post enzalutamide abiraterone. That's the current space. And I think there's an exception to that, which is elderly men or people with comorbidities that can't tolerate docetaxel. We know that lutetium works in these men. So at Peter Mac at the moment, in our center, we will use it in that setting, and we will use it pre-cabazitaxel. But we do select our men very carefully. And I think another piece of data that we presented at ASCO GU, and more information being presented from the VISION trial, is using PSMA PET/CT as a biomarker. And there's now strong data, both from VISION and theraP, that higher PSMA expression is a prognostic and predictive biomarker. So in that way, depending on what sort of access you have to lutetium PSMA 617, because it's not widely available yet at the moment all around the world, we have really good access at Peter Mac. We're treating sort of 10 to 15 patients a week with lutetium PSMA, but that's not the case everywhere.

But I think if you're in that sweet spot with really high PSMA expression, which is a much smaller group of men, then you really want to prioritize those men for access to lutetium. So I think that's where we're at now. And maybe we'll see some more personalization of that. So in the era where it's not widely available, where you can't get it next week, but maybe you can get cabazitaxel next week, you'll might want to select your patients very carefully. But now we have an array of other trials open that are going to read out. So we have just read out the PRINCE trial, which is lutetium in combination with pembrolizumab, interesting results. It's really a phase two safety study, phase one, two safety study, it looks promising.

So we'll probably see some larger trials of that probably early next year. Our trial of lutetium in combination with olaparib, a PARP inhibitor, that will read out that's using it as a radiosensitizer. And then we see all these myriad of studies bringing it earlier, either pre [inaudible 00:10:13] and chemotherapy or even into the hormone sensitive space. Now we have our own upfront PSMA trial, which is using it as a first line treatment in men with newly diagnosed high volume disease. We're giving lutetium, two cycles followed by docetaxel randomized trial compared to docetaxel alone. And we've randomized, I think, patient number 100 yesterday out of 140. So we're doing well, and there'll be larger industry sponsored trials that do this on a phase three trial level as well. So lots of interesting data coming in the next few years.

Matt Cooperberg: It's an amazing body of trials and of evidence. Actually, I do want to focus on that newly diagnosed space and the LuTectomy trial, maybe drill down a little bit. And I know Declan Murphy's going to be presenting this at EAU, but what can you share now about, first of all, the study design and kind what you've done, and any preliminary findings?

Michael Hofman: Yeah. So LuTectomy is one of my favorite trials. I did come up with the name.

Matt Cooperberg: That's a great name.

Michael Hofman: We're kind of combining lutetium and prostatectomy. And this is an investigator initiated study that Declan and I have led. John Violet was involved in the trial design as well, together with many folks at Peter Mac. And what we're doing is taking patients with high PSMA expression, newly diagnosed, high-risk prostate cancer, N0 or N1. They have to have an SUVmax over 20, so very high PSMA expression. And then the first 10 patients had one cycle of lutetium PSMA 617. Six weeks later, prostatectomy. The second cohort, which has now completed recruitment, has two cycles of lutetium followed by prostatectomy. So Declan Murphy will read out the first 10 patients at EAU. So unfortunately I can't share the results with you, but no doubt you'll be doing one of these sessions with him in just a few weeks time.

But the data is really exciting. And the idea here is that we can get a very high dose of radiation. And the primary endpoint of the study is a dosimetry endpoint. It's what gray can we get to tumor and/or lymph nodes. So really interesting study design. And the hypothesis here is really twofold that will get large amounts of radiation, maybe similar to what we get with external beam radiotherapy, but in a highly targeted fashion with a single intravenous injection. If you can get doses that high with a one millimeter path length, that's pretty game-changing. And that may be used potentially in the future on its own. We know external beam radiation can cure patients with prostate cancer. So can a few doses of lutetium PSMA 617 cure prostate cancer? And t's just a hypothesis at the moment. This should not be done outside of clinical trials. There's a lot of concerns about long-term toxicities. Unlike external beam radiation, your whole body is seeing some radiation, and we could see some long-term side effects.

So we need to do this cautiously, or it might just be that it's a neoadjuvant or adjuvant treatment either in combination with surgery or external beam radiation. But I really do think it's a highly promising approach.

Matt Cooperberg: Do you think the doses that will be received by micro metastatic disease will be sufficient? In other words, PSMA invisible disease that we do know exists from some of the recently published studies. Will the dose of lutetium taken up by sub millimeter, nodal implant be sufficient for cytotoxicity?

Michael Hofman: Yeah. Now...

Matt Cooperberg: Hypothetically. Obviously we'll see data, but just from a radiation physics standpoint.

Michael Hofman: Yeah. Well, I mean, theranostics is not new. We've been using it for over 80 years for treating thyroid cancer. And in thyroid cancer the rationality is treating micrometastatic disease. And we know that you can cure patients with metastatic thyroid cancer, or small volume residual, really microscopic disease, post-thyroidectomy. So I think the answer is yes. The challenge is not everyone. And I think this is the problem. If you look at the radiation dose delivery, and maybe the EAU presentation will show this, but we've already shown our dosimetry results just from treating patients with metastatic disease. And it's widely variable. So if you inject lutetium PSMA 617 and you do doses, you actually get very consistent doses to the kidneys in the order of sort of one to three gray. You get very consistent doses to salivary glands. So your normal organs actually get a very narrow dose, but tumors have a really wide dose in the order of sort of 10 to 20 fold difference. So massive differences.

And we see this when you do a piece of a PET. Some patients have SUVmax of 10, and other patients have an SUVmax in the extreme setting, I've seen SUV viewing maxes as high as 330. So that means you're kind of getting 30 fold differences in radiation delivery in different patients. So this is where I think the challenge lies. And we can't predict this, but if you want take a blunt, a blast approach, and just give this to everyone, I think your results are going to be pretty average. A lot of patients are not going to cure. And perhaps in this micrometastatic disease setting, it's a minority of patients that we can cure. But I think we probably can see that on a PSMA PET.

Again, you can go back and look at the pro PSMA trial, an imaging trial, where we have 300 men with newly diagnosed prostate cancer. We've presented just the SUVmax data in the primary prostate cancers. And again, we see this huge variation from as low as one to two, and some negative all the way up to SUVs of in the hundreds. So quite extraordinary. So you're going to have to take those patients with the super high SUVs, and I think those patients actually are sweet spot. And I think even with small volume disease, meaning sub millimeter or microscopic deposits, I think we will eradicate them with the lutetium.

Matt Cooperberg: Do you find that these are generally consistent within a patient? So how much variation do you see from primary to met, or from met site to met site? Do you find that the PSMA expression and the SUVs are consistent enough?

Michael Hofman: Yeah, that's a great question. I think it needs a lot more research. Certainly in the metastatic setting, post multiple lines of therapy, we see a lot of heterogeneity, but not in everyone. Some patients have consistent SUVmax at every site. I saw someone the other day who had wildly metastatic disease with SUVmaxes of 200 everywhere. It was quite extraordinary. So this is sort of a sweet spot where you're going to have some extraordinary results. So fortunately we do have a biomarker, which is your PSMA PET scan. Potentially combined with other scans. We like combining it with FDG to really have sort out does every site of disease. And if we do this carefully, I think you will be able to really select patients very well. But it's a bit of a work in progress.

Matt Cooperberg: And you mentioned earlier alpha emitters. So what do you think is going to be the future role for lutetium versus actinium, or some of the other nuclides that are further up in the pipeline?

Michael Hofman: Yeah. So actinium 225 and alpha emitter has been used off trial for quite a number of years now in Germany, South Africa, and even in Australia. Look, there's really no good published data on actinium. It's a little bit embarrassing from the nuclear medicine community. We have not done actinium in our center because we are keen on generating prospective trial data. And actinium does have some problems. It's got salivary toxicity, small bowel toxicity, and I'm not really sure where it sits. I actually await some high quality clinical trial data. Louis Emin in Sydney, together with Mike Sathekge in South Africa have just started a trial. I think it's called the ACTION trial, looking at actinium 225 and PSMA 617. So finally some prospective data is coming. There are other radionuclides as well. We're about to embark on a trial of terbium 161 at Peter Mac.

Terbium 161 is a dual beta-alpha Auger emitter rather. Auger electrons are another type of radiation. That actually has a path length that's even shorter than alpha emitters. So it actually just kills the cell where the radiation was taken up, whereas alpha emitters will travel sort of several cells. So really short path length. That means it doesn't have the toxicity of alpha emitters, but it is better for eradicating that micro metastatic disease that we were just talking about. So we're going to do the first in human trial of interesting terbium 161. We've just been getting some shipments of terbium, and playing with the radio chemistry, which looks very easy, very similar to lutetium. So lots of isotopes to play with. You can look at the periodic table, and it's going to keep us busy for a long time.

Matt Cooperberg: Excellent. Any other concluding thoughts or anything else we should be particularly excited about looking forward to the next year or so?

Michael Hofman: Well, it's good. It's just going to be an exciting time. I think combinations in earlier use is kind of where we're at. And maybe a bit on how to really personalize patient selection and work out where's the sweet spot, who should definitely get lutetium PSMA 617 and who shouldn't miss out. And I think there's a lot of work to do there.

Matt Cooperberg: Do you think we will get to a dichotomized answer to that question? Well, we have a threshold from a PSMA PET scan, certain SUV above or below, which will make it easy in community practice, or do you think this is going to remain a sort of personalized discussion for the foreseeable future?

Michael Hofman: Look, I think we are getting some thresholds. So there's a magical number 10, which showed up as our SUV mean, which we used in the theraP trial presented at ASCO GU. So this is an SUV mean, which is not that easy to do. It means you have to contour all the tumor, and get the average intensity of uptake. And you need some fancy computer software to do that. It's quite easy in our hands, but it's not easy in a community radiology practice at the moment. But there's a lot of tools coming along to assist that, including some fully automated tools to do that. And we see some data from the VISION trial showing that SUV mean is in fact the best measure as well. And they also find this magical number of 10 from the VISION trials using a completely different data set.

So I think we might be there. SUV mean over 10, which is about one third of patients coming for that we treat with lutetium PSMA therapy at the moment are in that high group. These are patients that just have quite extraordinary responses. Pretty much all the patients we treated in the theraP trial and the VISION trial do well and better than the standard of care arm, either cabazitaxel or best standard of care protocol defined in the VISION trial. But if you want to pick the patients that do extraordinarily better, who really shouldn't be missing out than these SUV means on PSMA PET scans, are really helpful.

Matt Cooperberg: Terrific. Well, thanks again for your time. Always great to hear the progress and I hope we can connect soon with a whole another set of trials to review the data. And a lot of excitement for men with prostate cancer. So thanks for your time.

Michael Hofman: Thanks, Matt. Always great to catch up. Thanks for the opportunity.