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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the United States. I'm so excited to have here with me today, two friends and colleagues, Dr. Declan Murphy, who is a Professor of Urology at the Peter MacCallum Hospital in Melbourne, Australia, as well as Dr. Michael Hofman, who is a Professor of Nuclear Medicine, also at the Peter MacCallum Hospital. Thank you both so much for being here with me today.

Michael Hofman: Thanks, Alicia.

Alicia Morgans: Great. I wanted to speak with you a little bit about the recent Lancet publication that you have on TheraP, and you're an author on that, Michael, and Declan, just here to really get the urologist's perspective as we consider the use of lutetium in advanced prostate cancer and the way that multidisciplinary teams can come together to support that. Michael, can you tell us a little bit about the TheraP trial?

Michael Hofman: Thanks, Alicia. The TheraP trial is the first randomized controlled trial of lutetium PSMA-617. This was an investigator-initiated trial, really, a great collaboration of nuclear medicine investigators and medical oncologists right around Australia. The trial was put together by the ANZUP cancer trials' group, very early on when, perhaps, even few people had heard of lutetium PSMA.

For those listening who aren't aware of this treatment modality, it is a radioactively-labeled small molecule that targets prostate-specific membrane antigen. It has some analogies between a systemic therapy like chemotherapy and external beam radiation, but essentially we give it intravenously and it delivers high doses of beta radiation to sites of prostate cancer, wherever they happen to be. Now, some similarities to radium-223 that the GU oncology audience will be familiar with. But unlike radium, which is a bone-seeking targeted treatment, this is a tumor-seeking targeted treatment. So it treats both soft tissue and bone disease. We get much higher doses of radiation to tumors with this treatment, compared to something like radium-223.

We designed this trial back in 2016, and we chose cabazitaxel as our control arm. A 200 patient study conducted at 11 sites around Australia. A 1:1 randomization in men who had progressed after docetaxel, and almost all of them after a novel anti-androgen, such as enzalutamide or abiraterone. These men were all suitable for cabazitaxel. They underwent FDG and PSMA PET/CT, which was centrally reviewed, and then randomized 1:1.

The results really showed that lutetium PSMA-617 was more active with a higher PSA response rate, longer progression-free survival, better objective response rates on [inaudible], but also had fewer grade 3 to 4 adverse events and better patient-reported outcomes. So although only a phase 2 study, we like to think of it, maybe, as a phase 2-and-a-half study, because I think the patient-reported outcome and other endpoints are pretty compelling to suggest that this is a new treatment option for men with prostate cancer. It looks favorable compared to cabazitaxel. And in any event, it's another line of treatment for these men who we can't cure with any treatments, but having a whole new line of therapy will hopefully improve the quality of life and prolong life in these men.

Alicia Morgans: I completely agree, and I think it's really important, certainly, to see these PSA responses, and of course to have men tolerate the treatment very, very well. I'm curious, just to confirm, the progression-free survival endpoint, was that a PSA progression or was that radiographic? Was that a combination of progression by any type? What was that progression-free survival?

Michael Hofman: Yes, so it was the first secondary endpoint, and it was radiographic or PSA progression-free survival, and that had a hazard ratio of 0.63. Another way of saying that would be a 37% delay in progression. This increased over time. So at 6 months, there actually wasn't much difference between the two arms, but by 12 months we started to see quite a large difference. So at 12 months, virtually all men in the cabazitaxel arm had progressed. In fact, only 3% had not progressed, whereas, in the lutetium PSMA-617 arm, 19% had not progressed.

Now, we also did some sub-analyses of both radiographic and PSA progression-free survival on their own, that is in the supplementary appendix, and they were pretty similar, with hazard ratios of 0.64 for radiographic PFS, and 0.60 for PSA PFS. So it doesn't really matter which one of those you look at, they are all quite favorable towards lutetium PSMA-617.

Alicia Morgans: But really important and interesting too, that it is a radiographic progression as well. And to have almost 20% of patients on the lutetium arm not have either PSA or radiographic progression at 12 months is highly unusual for this type of patient population, and I think really, really important. So it will be very interesting to see how that sorts itself out. I imagine, given that I know ANZUP, that you will have some molecular testing and some biomarker data at some point to tell us exactly if we can sort it out that cleanly, who these patients are that might respond for so much longer. That is going to be really, really interesting to us, but wonderful that we can have that kind of response.

Declan, I'm curious from your perspective as a urologist, this is not necessarily the patient population that you are going to see on a day-to-day basis, but lutetium is interesting, I think, in earlier stages of the disease as well, and I'm sure that there are trials in progress that we would love to hear from you about, actually, some that were presented as trials in progress at GU ASCO 2021. Can you share a little bit about that?

Declan Murphy: Thanks, Alicia. So as we've seen all the way along, I suppose, in metastatic CRPC, we often test out the new intervention in the far end of the disease in men with very advanced cancer, and then we start bringing it forward if we see signals of success and tolerability. And I think that is exactly what we are seeing now with lutetium PSMA. Michael and other early studies in far-end CRPC show tolerability and some signs of efficacy. Now we have the TheraP study in a randomized format, really reaffirming that. So, it clearly makes sense to bring this therapy into the earlier and earlier paradigms.

At ASCO GU this year, we had two trials in progress from our group, which show exactly that. The first is the UpFrontPSMA trial, which is a randomized trial of newly diagnosed metastatic high-volume hormone-sensitive prostate cancer. So I suppose our classic population who might benefit from ADT plus docetaxel or early pathway inhibitor.  And in this multicenter trial in Australia led by our colleague professor Arun Azad, we are taking newly diagnosed metastatic hormone-sensitive men and randomizing them to ADT plus docetaxel or ADT plus docetaxel plus four cycles of lutetium. So we opened that study six months ago, and we are recruiting very well, and that is a trial in progress.

Then the second trial in progress we presented at ASCO GU this year is very far forward into really the neoadjuvant space, I suppose you would say. These are newly diagnosed high-risk men with what appears to be localized cancer or indeed, no positive locally advanced cancer. And in this study of men who are scheduled for radical prostatectomy plus lymph node dissection, we are offering them one or two cycles of lutetium PSMA, 6 and 12 weeks prior to surgery to see if we can measure a good dose getting into these prostates and lymph nodes. That is our primary endpoint, dosimetry. And then, of course, secondary endpoints are around safety and pathological response, biochemical response, imaging response, and so on. So I think that it is very familiar to those of us working in prostate cancer for many years to [inaudible] with some signs of progress or optimism in the far end space and bring them forward. And look, we will just have to wait and see how these earlier disease spaces pan out.

Alicia Morgans: I completely agree. I'm sorry, Michael, go ahead.

Michael Hofman: Yes. I might just add three other trials that we have open at the moment. At Peter Mac, we have a trial called the ENZA-p trial, also run by the ANZUP cancer trials' group running around Australia, randomizing men to either enzalutamide or enzalutamide and lutetium PSMA in a combination. That is in the castrate-resistant population. And that is run by Louise Emmett in Sydney.

Then we have two trials that I run with Dr. Shahneen Sandhu, which are combination trials, one combining lutetium with pembrolizumab, that is actually finished recruitment and in the follow-up phase, hopefully, we will have some results to present maybe later this year, and another trial combining lutetium PSMA with a PARP inhibitor, olaparib. We are using olaparib in this trial as a radiosensitizer that is run through a PCF Challenge Award. So we are going to have a whole array of Australian data on lutetium PSMA-617 coming out over the next few years.

Alicia Morgans: That's fantastic. I know that the rest of us are so eager to learn from the experience, and continue to learn from what you are already showing us. One thing that I think is not necessarily consistent in all of the trials, certainly different between TheraP and VISION, is that patients are selected differently for these trials. I would love to hear your thoughts, Michael, as a nuclear medicine physician, on how you think this can optimally be done, and maybe some comment on whether this would be different in a more advanced metastatic CRPC setting than in an earlier setting, like a de novo metastatic hormone-sensitive setting, or even in earlier patients who have high-risk localized disease and maybe neoadjuvant typesetting. What are your thoughts there?

Michael Hofman: Yeah, that's a great question. When we designed the TheraP study, one of the great features is that we had nuclear medical oncology and actually radiation oncologists all in the same room with expertise in this area designing this trial, and patient selection was a key criterion. I think one of the advantages of an investigator-initiated trial is we were really thinking, "Well, what is the best for our patients." Not, "What is the broadest group of patients that we can potentially target."

I think we've seen some keynote data at ASCO GU with pembrolizumab, and the results don't look very good overall, but it was a non-selected group. I think if they had selected the patients more carefully based on genomic analysis, you would see a highly positive trial. And so what we've done here is we know the target is PSMA, and we can measure that with a PSMA PET scan, so we can visualize how intense the PSMA activity is at all sites of disease. And we know from vast experience with theranostics in other domains, like lutetium dotatate for neuroendocrine tumors or radioactive iodine for thyroid cancer, that this principle of seeing what you treat works.  And if a site of disease is not lighting up on the PET scan, then when we give the treatment, that site will progress very predictably.

So we had quite strict criteria and we used some quantitative PET parameters. We said you have to have an SUV max, a standardized uptake value, above 20. That is quite an intense uptake on the PSMA PET. That didn't have to be at every site of disease, just at a single site of disease. And then we also incorporated FDG PET, because, after several lines of therapy, we developed tumor heterogeneity and not all sites will express PSMA. That allowed us to visualize, let's say, bony metastases that you can't see on the CT, but that are FDG-positive PSMA-negative. And then we didn't treat those men.

I think this is a great approach. It means around 30% of the men that we screened were not suitable, but they are men that we do not think will derive a huge benefit from this treatment. That's not to say that they won't benefit at all. The VISION trial has a much broader population, so that will be of interest because perhaps we've been too selective. But that is where we started with a 200 patients study. We really wanted to narrow it down.

Alicia Morgans: Great. Declan, I'll ask you, when you are treating patients who are maybe earlier in the disease, for your neoadjuvant study, for example, are you selecting patients differently than Michael did with the team in TheraP? Are you using one scan, both scans in terms of those two different types of PET scans? Or are you using no scan, as some have proposed for some of these trials, to some criticism, perhaps? But what is your approach?

Declan Murphy: Yes, it's a little different, Alicia. For the neoadjuvant space, newly diagnosed high-risk or locally advanced prostate cancers, we are not doing an FDG PET, because these men are not metastatic.  They haven't been pretreated, and we think the value of doing an FDG PET, compared to the metastatic or CRPC population, will be much less. However, on the other hand, we are pretty much sticking to our guns and setting the bar quite high for what the imaging shows us and how we select these patients. So these patients have to have an SUV max of greater than 20 in the primary or the lymph nodes to be considered eligible for this study. So unlike a classic neoadjuvant study where we pick them based on traditional disease risk stratification.  For high risk or unfavorable, intermediate risks, yes, we are doing that. But in addition, we are making sure that there is a good target for the lutetium, by making sure that this is high SUV expression.

So I think that makes perfect sense, doesn't it, from a precision oncology approach? We are not just taking the traditional risk stratification characteristics. We are taking what the imaging shows us because this is an imaging-directed therapy.  So I think it makes sense to set the bar high from that point of view, and especially in such an early disease stage.  It's not at all clear to us whether giving lutetium to these men prior to a prostatectomy will make much difference.

And certainly, in this early phase 1 and 2 study, we're just trying to assess dosimetry as the primary endpoint plus, of course, safety and other characteristics to see, is there enough there? Can we learn lessons to say, "Let's go on to do a phase two randomized study. Let's consider whether we should be adding in ADT or going against ADT," and so on? But it's a very nice disease space, and because our imaging trials, like ProPSMA, showed us, we learned a lot about the way these tumors appear in a prospective study. We think that it is the perfect group to bring forward the theranostic side of it and see, "Can we help some of these men?"

Alicia Morgans: I love that because I don't think in our normal clinical practices, at least here in the US, we are not typically making a lot of decisions based on SUV max. Now, that, I would say, is, of course, an FDG PET. We don't have PSMA PET and we don't usually use those in the prostate cancer space. So this is, in general, in a solid tumor, we are not so reliant on the SUV max, as this clearly is, which is really using all of the data that the PET has to offer. It's using not only the location but really the intensity. So really informing those decisions based on that too. It makes a lot of sense.

I also want to commend you for being flexible about how, or not just flexible, actually very thoughtful, about how you're using these different imaging modalities in different spaces, knowing that the biology of the cancer is changing and is different along the spectrum of prostate cancer. And so we have to use the imaging modality that makes the most sense, and I think as we integrate the imaging side of things into our practices, we will have to be really thoughtful about that too. More advanced disease is more heterogeneous. FDG PET, in addition to PSMA, may make a lot of sense in earlier stages. Perhaps it's more of a setting where we will see more PSMA expression, and perhaps this PSMA-targeted approach will be more important and more worthwhile.

But, in general, as always, you are very thoughtful, and I love that you continue that also in the imaging as you are selecting your patients. So, as we wrap up, I would love just a comment from each of you on how you work as a multidisciplinary team to really get this done. Because you in Australia are quite the model of really integrating nuclear medicine physicians into the prostate cancer care team in a way that we all aspire to, but are still moving towards, I think, like the rest of the world. We'll start with you, Michael.

Michael Hofman: Yeah, look, it's been a great adventure with our urology, medical oncology, and radiation oncology colleagues. We have a great multidisciplinary meeting where we all get together every week, and I think a lot of ideas stem from that. We've had a cooperative clinical trials group, ANZUP, for the TheraP study, and also a group called ARTnet, the Australian Radiopharmaceuticals Trials Network, and that has helped get everyone together. So once we had some funding and wrote the protocol, really, everyone around Australia was keen to work together. We did have a Co-PI at every site, medical oncology, and a nuclear medicine Co-PI for the TheraP study. For the ProPSMA study, which was an imaging study, we had urology, radiation oncology, and nuclear medicine co-leads at every site, so it really is a great network.

That network was established over the last 5 years. Everyone is working really well together. Everyone's learning from each other. It's a great collaboration, I think it is replicable in other places. We've had the luxury of some different regulatory environments in Australia, which has enabled PSMA PET to be adopted early on. That certainly helped our journey. I'm pleased to see that at least gallium PSMA PET has been approved in a couple of sites in the USA in the last few months. And noting that two pivotal trials, CONDOR and OSPREY, have just been published on DCFPyL. I think that will lead to FDA approval of that agent. So, I expect by the end of this year, you will be rapidly transitioning to a PSMA-positive world in the USA, where this technology becomes widely available, and hopefully, that will enable you to start collaborating more with your nuclear medicine and radiology colleagues.

Alicia Morgans: Thank you. And of course you, Declan. What do you think?

Declan Murphy: Yeah, for sure, Alicia. This whole area of imaging and theranostics using PSMA has really opened our eyes to how much value can be added from embedding the nuclear medicine teams in our prostate cancer multidisciplinary team meetings, and we've been pushing that message out for a number of years now. We wrote a piece of letters in the BJUI a few years ago titled, "Going Nuclear" on why we need to embed the nuclear medicine team in our multidisciplinary team meetings.

And I must say, you must pay tribute to the multidisciplinary teams in Australia that have done that exactly in the past 5 or 6 years. They've embedded nuclear medicine physicians and their allied health professionals in the team, and that has led to really good imaging trials.  It has led to very good theranostic trials because of the knowledge exchanged by people being in the same room, or in the same virtual room nowadays, to look at the problems, the unmet needs for patients, and then people can come up with solutions. But I think that is one of the reasons why these trials have done so well in Australia. We have recruited at a time, very well-founded because they have shown that when Nuc Med and the traditional multidisciplinary team work well together, you can really make some great discoveries.

Alicia Morgans: Absolutely. And as we start to move forward and have access, in the US at least, to some of these PSMA imaging modalities and eventually to PSMA-targeted theranostics, things like lutetium, I think it is  going to be so important to be in the same room together to review scans and to say, "Hey, you've got quite a positive PSMA scan, but if you look over here, this disease," and there is, say, 50% of it is actually not lighting up with PSMA, "So if that is really what you want, if you want the lutetium, you're going to be missing a lot of diseases." These kinds of conversations can happen routinely and easily when we are all meeting together and so many more, like you were saying, to push the envelope and move us forward in terms of our treatment options for patients. This is really just the beginning.

So, thank you both for taking the time today. Congratulations, Dr. Hofman, on the Lancet publication and for TheraP, and congratulations to you both on continuing to find options for patients that makes sense, both in terms of efficacy, but also in the way that the patients feel when they are on these therapies, and hopefully we are moving much closer to being able to cure some more of these patients. Thank you both for your time.

Michael Hofman: Thanks, Alicia.

Declan Murphy: Thank you.