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Dr. Charles Ryan: Today I'm delighted to be joined by Dr. Carmel Pezaro from Monash University in Melbourne, Australia. We're talking today about nuclear medicine and lutetium and PSMA based therapies, where in Australia you've had a fair amount of experience. My understanding is it's not all on clinical trials, and you're able to offer this for patients. Give us your framework about when you think about these trials, what you think are good about ... I should say what you think about these therapies when you think about them, and what are the limitations, and what should we and the rest of the world be thinking about?

Dr. Carmel Pezaro: I think Australia is in a really interesting situation because we actually haven't had easy access to radium 223, unlike most of the rest of the world. There have been some complexities about getting access to that. Instead, we've had a long history of being very interested in PSMA based imaging. That's been something that has essentially moved entirely into clinical space so it is unusual for a patient now not to have at least one PSMA PET. Then this word came out, and I think initially from places in Germany and there were other areas, and then Australia became interested in medicalizing PSMA, particularly with lutetium. 

That certainly is something that people are very passionate about in Australia at the moment. Particular centers, Peter MacCallum, and centers in Sydney, have been working very hard in a research space looking at lutetium based PSMA. Additionally, it is very true that because lutetium PSMA is not regulated in quite the same way, it actually can be given outside of clinical research. One can pay to access lutetium PSMA and some men are choosing to do that. 

Additionally, we have research, initially phase II research that was recently published by Michael Hoffman and team, out of Peter MacCallum. Also, then a randomized trial being led through the ANZUP Clinical Trials Group, which is a randomized trial of lutetium PSMA or cabazitaxel chemotherapy. At the moment, we're essentially referring people on to that clinical trial.

Dr. Charles Ryan: Oh good, okay. With regards to the PSMA PET, before we get to the lutetium again, are you not getting bone scans on patients? Are you just doing PSMA PETs? How are you doing that?

Dr. Carmel Pezaro: We're in a bit of a mess because of course, all of the standard imaging for a trial inclusion remains CT and bone scan. In the advanced prostate cancer space, people are mostly still having CT and bone scan. PSMA PET has been used a lot in terms of staging for men presenting with prostate cancer. In that setting it's often replacing a bone scan. Some people are also using it in more advanced disease and even using it to monitor therapy. IM is not as fast an adopter of new technology and I work in a public hospital, so that's not something we've been doing, but It's fascinating to hear people doing that. I feel a bit anxious about interpreting some of those changes because of course, those are new untested scans.

Dr. Charles Ryan: Yeah. Back to the lutetium. We, in the rest of the world, are seeing data coming out showing really interesting responses and some waterfall plots looking at some potential benefits of lutetium based therapy. Tell us about sort of the other side. Are there things we should be worried about? Are there toxicities that are emerging in the Australian experience that are limiting? What would be the best patient in which to use it?

Dr. Carmel Pezaro: I think answering those in reverse. I think the best patient to use it is someone who has very strong PSMA positive disease on PET, no FDG positive disease on PET, and those patients who actually still have excellent performance status who have perhaps non-bone disease, seem to do very well with lutetium PSMA.

Dr. Charles Ryan: Why do you say no FDG positive disease?

Dr. Carmel Pezaro: That's actually one of the fascinating screening tests is that through the nuclear medicine team in places like Peter MacCallum, they've said that actually if you have a mismatch, where you have FDG positive, as well as PSMA positive disease, or indeed FDG only, those patients do not respond to the PSMA targeting.

Dr. Charles Ryan: I didn't know that, because I would just assume that many metabolically active prostate cancers would have both, and that that would just not ... That the FDG wouldn't tell me any additional information.

Dr. Carmel Pezaro: It seems like the FDG positivity is actually picking up disease that will not respond well to the PSMA targeting, which is really important to know.

Dr, Charles Ryan: That's very interesting. FDG positive may be a resistance marker.

Dr. Carmel Pezaro: Yeah.

Dr. Charles Ryan: Which says something about the ... You know, we've said for years the FDG PET isn't useful in prostate cancer because obviously because of the bone issue, but maybe it's telling us something about a more aggressive disease biology. Interesting.

Dr. Carmel Pezaro: Particularly because these patients have been later stage patients. There is that chance that they're going to have the neuroendocrine D-differentiated phenotype. Those patients do not seem to respond well to PSMA targeting.

Dr. Charles Ryan: Interesting.

Dr. Carmel Pezaro: I think that's an important, so patient selection is going to be very key. I think the data were really lovely, but I would highlight that again, not every patient will benefit. Some patients will have a transient response and then very quickly progress. Some patients have a fascinating trajectory where they do respond, and when they start progressing they can be treated with another dose.

Dr. Charles Ryan: Interesting.

Dr. Carmel Pezaro: That's really, there are fascinating trajectories of the response that seem like they're going to be very patient centric and individualized. I would comment that some patients do not benefit, and that for some people, when their disease progresses eventually, actually they progress with potentially quite difficult to manage resistant cancer. Although some patients have had an excellent prolonged response, there are also anecdotes that are equally important of patients who have not had a good response, or have progressed quite quickly and actually then had quite a poor trajectory afterwards.

Dr. Charles Ryan: I see.

Dr. Carmel Pezaro: Again, patient selection is going to be really important. I think that's where we're going to see the really important data coming out of the next ANZUP trial.

Dr. Charles Ryan: Great. Delightful talking to you. Very interesting times, as always, in prostate cancer and in chatting with you, it's really I'm learning a ton and looking forward to your educational session.

Dr. Carmel Pezaro: Thank you.