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Charles Ryan: Hello, I'm joined today by Professor Michael Hofman, who is a Professor of Nuclear Medicine at the University of Melbourne, who's really a leading voice in the development of theranostics for advanced prostate cancer. Thanks for joining us today.

Michael Hofman: Thank you.

Charles Ryan: You have a lot of interesting things going on. It's been exciting to see your presentations and read your papers on this topic. What I first thought we should focus on is the use of new imaging techniques in prostate cancer. Australia really the place where this is happening first, and we'll talk about the sensitivity of the new imaging, and then we'll talk about the therapy.

Michael Hofman: Sure. So PSMA PET imaging has really taken off very quickly in Australia, so this is a radioactive tracer that binds to prostate-specific membrane antigen or PSMA. There's a few different ligands now. The main one in use is radiolabeled to gallium 68, so we call it gallium PSMA, and there's a few fluorinated derivatives that have also come into the market, the main one being DCFPYL, and they're very similar. In our institution, we actually use a range of different PSMA tracers and they're all extremely good, but as you allude to, they're highly sensitive. So on conventional imaging, bone scan, and CT, you're often using a size criteria to decide if something is abnormal, so it has to be enlarged. On a bone scan, you're just looking for the bone reaction around the tumor. It's not a direct tumor imaging agent, whereas PSMA binds to the tumor so it's very specific. 

It gets taken up into the tumor, it lights up very brightly, and we have quite extraordinary tumor-to-background contrast that allows us to do whole body imaging and really see very accurately where prostate cancer has spread to, but it's also very good for looking at the prostate gland itself and tumor within the gland.

Charles Ryan: Could you address a controversy at least we're seeing in the United States, which is the widespread use of FDG PET in oncology in general, has many oncologists feeling very comfortable with that modality when evaluating patients with lung cancer, bladder cancer, et cetera, and so it's not uncommon for FDG PETs to be performed for prostate cancer. How would you compare what you see with a PSMA PET versus what one would expect to see with an FDG PET?

Michael Hofman: Sure. So prostate cancer really has this huge spectrum, from your early disease to your late-stage castration-resistant, and it's really hard to lump them all together. FDG is a radioactive sugar, so tumors that are growing rapidly use sugar for their growth and they light up very brightly on FDG. So FDG is actually quite a good tracer in a patient with castration-resistant metastatic disease and rapidly rising PSA. They will light up very brightly, and in fact, we use FDG in that population, whereas if you go back to early stage prostate cancer, low PSA doubling times, these tumors are not growing quickly, so they're not lighting up on the FDG PET scan. So FDG is not useful in all this early prostate cancer, early biochemical recurrence, a limited role for FDG.

When I say that, it's still a useful test in that early setting, because a negative scan, it's providing you prognostic information. It's telling you that this is an indolent phenotype, that it's growing slowly. Normally you would have to perhaps do a biopsy to look at some of those markers of aggressiveness. You can do it noninvasively with FDG, so we use FDG a lot in prostate cancer. It's something that we actually use. What probably differentiates us from many of the other centers, we do it with PSMA PET, and we use the combination to characterize the disease rather than just-

Charles Ryan: Interesting, interesting.

Michael Hofman: Count lumps and look at where they are. So our analogy would be that conventional imaging, anatomic imaging, CT, bone scanning, MRI, it's sort of the lumpology paradigm. You're looking at lumps on a scan and you count them, and you can guess whether that lump is a tumor. Sometimes there's some specific anatomic features that make you strongly suspect that it's a tumor, but you're really just seeing lumps, whereas PET/CT is really the molecular imaging. We're imaging some metabolic process. With FDG, it's sugar metabolism. With PSMA, it's PSMA expression. It's essentially like doing whole body immunohistochemistry with PSMA and seeing where it is, so it's characterizing disease.

Charles Ryan: But the leverage with PSMA is that it can help somebody who thinks the patient has localized disease to determine that he does not just have localized disease, and this may change a radiation plan or even a surgical plan. Conversely, it may help us to look at patients who have known castration-resistant disease for example, and we may be thinking should we go on with more systemic therapy, but we get a PSMA result that might suggest that maybe a focal radiotherapy to a metastatic site can be determined or it can be administered, and that's something that's being studied at a couple of places around the world, and probably more than a couple of places.

And then, of course, your introduction to PSMA-targeted radioligands leads us to the conversation around lutetium and the ability to not only do imaging, but to do therapy, and this is a really exciting area. You've published some beautiful pictures again and cases with lutetium, and tell us where we are right now worldwide with the use of theranostics or therapy-directed PSMA-targeted therapies.

Michael Hofman: Yeah, so this is lutetium radiolabeled to PSMA. So it's essentially the same or very similar small molecule that we use for imaging. We label it with a beta emitter for therapy, so the principle there is we know exactly where it's going to travel in the body because it mirrors what we see on a PSMA PET scan, so that's a nice feature of this theranostic paradigm being able to do a scan, see where the drug's going, and then give a therapeutic dose of this. This is very different to conventional oncology when you're giving chemotherapy or a novel anti-androgen therapy. You really can't see where it's going. Here we can visualize it upfront. So all our patients get a PSMA PET scan first. If the tumors show high PSMA expression, and we like to see that at all sites so that we know that we can target all the disease, then we can go ahead and treat, and our approach has been to do this as part of prospective clinical trials. 

You know, the innovators in this area were in Germany where these molecules were discovered, but they largely gave the therapy as compassionate access therapies, and they've helped a large number of men through their efforts, but they haven't produced the type of data that our oncology colleagues demand in order to know that this is an effective therapy. 

So back in 2015, we designed a prospective trial at Peter Mac which was published last year in Lancet Oncology as a 30-patient series, and at this meeting yesterday, we presented the outcomes of an expanded 50-patient cohort. It's largely showing us what that 30-patient cohort demonstrated, but with a higher degree of confidence. So in that study, we had 50 men that largely failed chemotherapy and second generation anti-androgens, and despite that, we saw a PSA response over 50% in 64% of the patients with really a very good safety profile.

Charles Ryan: And it even showed that some patients who had received lutetium and then developed progression of disease could be retreated with lutetium with some effect, right?

Michael Hofman: Correct, so 14 patients of that series, they had good responses, but then at some point, anywhere between sort of nine months and two years later, their PSA was rising. We repeated the PSMA PET. They had PSMA-avid disease, so we gave them further cycles of lutetium, and these patients actually had a response rate of 64% when retreated, so this is a treatment we can give more of, and four cycles, which is what we did in that trial, is probably not enough. We're not seeing much toxicity, so moving forward, most of the trials currently underway have moved towards six cycles every six weeks.

Charles Ryan: Yeah. Six cycles every six weeks is the standard schedule in the studies ongoing.

Michael Hofman: Yeah.

Charles Ryan: Well, we're going to look forward to further updates from you and others down the road on this exciting area. I know that speaking personally in my own practice, I am continually facing questions from patients of should I go to Australia and get lutetium, and it's almost like people are using it as an excuse to go down and visit Australia, get some cancer treatment-

Michael Hofman: So how do you deal with that?

Charles Ryan: Well, you know, I would say that you and your colleagues have been very gracious in responding to American patients, and some of them have actually been able to go and be treated, and that's okay, but really what we need to do is do what we do with all therapies, which is try to make access available around the world as we develop these. Thank you so much for your efforts, and thanks for joining us today.

Michael Hofman: A pleasure, thank you.