Carmel Pezaro: So I have the absolute pleasure of speaking today with Professor Ian Davis. Ian is a Medical Oncologist working at Eastern Health and a Professor of Medicine at Monash University in Australia, a place very close to my heart. Thank you so much for sitting down with me, Ian.

Ian Davis: Thank you, Carmel. It's a pleasure.

Carmel Pezaro: So you just did a wonderful talk at APCCC regarding the pitfalls of PSMA PET CT scans. Now that's not a topic that may have come to mind, so can you give us an overview of what you see as pitfalls?

Ian Davis: Yes. I was very grateful to be given that topic and I felt like I was pouring cold water on everybody's enthusiasm, which is never fun. But PSMA PET is a bit of a mixed blessing for us. There are situations clinically where it's clearly of value, probably most clearly of value when we're trying to make decisions about not treating people. If we're looking for a reason not to give radiation to the prostate bed, for example, in biochemical occurrence after prostatectomy. In that situation, seeing a nice hot lymph node somewhere else diverts our attention and we might treat that instead. We might see a PSA response. We might think we've done well for that patient, and certainly spared them the toxicity of radiation to the prostate bed, but we don't actually know if we made any difference to them in their outcome.

The real challenge with PSMA PET, I think at the moment, is that there's massive enthusiasm for it. It's a beautiful technology. The pictures are impressive and very pretty. It's a technology that allows us to think about the theranostic applications as well as the imaging applications, so if you target a different isotope, you can kill the cancer cell as well as image it, so there's a lot of aspects to this which are very attractive. I think where we're starting to fall into problems is where we're extrapolating from what we knew previously. And the big issue here is this is a very sensitive technology, so we're moving everything forward. You're seeing lead-time bias issues coming into consideration here. We're finding cancer at lower volumes and much earlier than we normally would and we're making treatment decisions based on that, which might be correct, but we don't actually know. So I think that's the real challenge for us at the moment. How do we take this new technology and bring it into clinical practice in a meaningful way? It's eventually going to give benefit to our patients.

Carmel Pezaro: Great. So you made the point in your talk that the PSMA PET is, of course, a PSMA PET CT and that the CT component of that was really important. Can you explain what you mean by that?

Ian Davis: Yeah, the technology's moved on a bit. So previously in the early days with this sort of PET imaging, there was a low-quality CT scan done, which really just helped to localize the areas of uptake anatomically, really not sufficient to give diagnostic quality information about the characteristics in the lymph node or the bone lesion that you might be imaging. Now that's changed. We're seeing much better quality CT coming along with the PET images, but I think it comes down to who's interpreting that and if we don't have a radiologist interpreting the CT component then we're working with one arm tied behind our back. We need to have both sets of information in order to draw the right conclusions.

Carmel Pezaro: Okay. So in your practice at the moment, obviously Australia is a place where there is a lot of PSMA PET CTs being done. In your practice are you recommending PSMA PET CTs and in what settings, at the moment?

Ian Davis: So this comes up in our multidisciplinary meetings every week and in Australia, we've got the mixed blessing where PSMA PET is pretty much available on every street corner. It's not free, but it's at a manageable cost, particularly compared to other parts of the world. So the sorts of scenarios where we're seeing it, men with high-risk localized disease who might be a little bit older, a little bit more frail, and where the surgeons are thinking perhaps we are not quite so keen to do a prostatectomy on this person. If we find a node outside the pelvis, we might give this person ADT and further them onto the radiation oncologist. So in that situation, I think that's probably not a bad outcome for that. We still don't know if that's the right thing to do, but in that situation, I think ADT and radiation is probably a good outcome.

Did the PSMA PET actually help us come to that conclusion? If we hadn't had it, might that have been the right outcome anyway? I would argue that in many cases that probably would have been the right decision, but this is, I think just helping people get a little bit more clarity on what direction they should go. Where we're starting to run into problems though, is where we are seeing findings on the PMSA PET that are unexpected and that's influencing our treatment in a way that is perhaps inappropriate. Perhaps the best example of that would be a man with high-risk prostate cancer who might otherwise receive androgen deprivation therapy and radiation therapy to the primary. The negative from the tests by CT scan and bone scan, but the PSMA PET shows up disease in a vertebra or a node somewhere. That person's then deemed have metastatic disease and is put on ADT alone, perhaps without treatments and the primary. We're seeing this happen on several occasions. We know that that is not the right treatment for that patient. We know that these men should have ADT and radiation, but because they've been reclassified into the metastatic box, then they're not getting radiation. Now with the recent data from STAMPEDE, perhaps that's going to change and we'll see less problems from them.

The other clinical question is when we're thinking about adding treatments to ADT in a city of metastatic hormone-sensitive prostate cancer. In Australia, the only reimbursed therapy there is docetaxel and the evidence seems to favor that most of the benefit is in men with high volume disease. So if you've got a man with low volume disease by CT scan and bone scan, but a pattern on PSMA PET that looks like high volume disease, how do you treat that person? Is that someone who is or is not going to benefit from docetaxel and we don't know the answers yet.

Carmel Pezaro: So in both of those examples you talk about PSMA PET as adding information over on top of conventional scans. So does that mean you see it as an added test rather than a replacement scan?

Ian Davis: Yes, I think so. But there are limitations on the value of CT and bone scan as well. And bone scan, as you well know, it's something that in which we place a lot of faith, and which is of very little value sometimes. But we quite happily accept that and we use it and it's built in the clinical trial protocols all the time, rightly or wrongly. So I think this is another tool in our armament. We need to know how to use it appropriately. We need to know how to use it without hurting our patients and ourselves. We need to divorce the finding of a PSMA PET scan from a knee jerk response to what the clinical decision should be and put it into context. And then ideally, of course, we need clinical trials to guide us through. It's easy to say that. The challenges in many of the situations we deal with early-stage prostate cancer and the clinical outcomes we want might not occur for many years, so we've still got a lot of time ahead of us before we get the answers to these questions.

Carmel Pezaro: So one of the things that I'm taking away from your talk is that I think we all, as a community, need to separate the issue of scanning for theranostic purposes compared to staging earlier in cancer. If we can think about the staging early in prostate cancer, whether that be at diagnosis or at point of biochemical recurrence, how would you see research moving forward to actually provide the information we need so that folks like me working in Sheffield on the NHS can then justify getting this as a standard scan?

Ian Davis: I don't think there's a straight forward answer to that. And I alluded to lead time bias before. There's a very sensitive technique, so we're finding disease much earlier. What we're now seeing though are treatment decisions being made on that. So you've got biochemical recurrence, nothing on CT or bone scan. Something pops up in a normal size lymph node on PSMA PET. So knee jerk response, that's where the cancer is. You'll give stereotactic therapy to that lesion and think that we've done something useful and perhaps we have, but we don't know and it's going to take following those patients for a long period of time in carefully controlled randomized studies to ascertain, "Is the benefit we're seeing real, or is it a simply an effective lead time bias?", and those trials are very difficult to design. And when you're doing this in an environment where the horse has already bolted, scans are out there, theranostics using the tissue or other isotopes attached to these traces are also out there, they might not have the opportunity to answer these questions anymore.

Carmel Pezaro: So if you were going to give a message to men in countries other than Australia where they do not have routine access to PSMA PET, what would your message to them be? Do you think they're missing out or do you think there is still a way forward?

Ian Davis: This is the real key question. So before PSMA PET came along, we were perfectly able to manage prostate cancer. We are hoping that PSMA PET is helping us manage prostate cancer better than we did then, but we still don't know if that is the case. So my message to people in that situation where you can't go around the corner and get a PSMA PET is, we can still manage your prostate cancer, you're still going to get the very best of care, you're not missing out. There are things that we can do that will help you. We can't guarantee a cure, but we couldn't guarantee that previously. So just because it's not available does not mean that you're going to be missing out. But if you did get the chance to go into a clinical trial, you should certainly talk to your doctor about that because that's where we're going to learn things and that's where you're going to get the best opportunities as well.

Carmel Pezaro: Fantastic. Because there were two PSMA PET talks, do you have any other take-home messages from the talks that you feel are important from today?

Ian Davis: So that's Stefano Fanti gave the opposite talk to me. He was talking about the advantages of PSMA PET. We had a beautiful talk. It's very sensitive and can help direct therapy appropriately or not, it's still to be answered. So there is still a lot of value in that. I think that probably where the clinical practice and research is going to go in the next few years is, as you mentioned, get down the theranostics route. So to try to choose patients for whom uptake on a PSMA PET scan tells you that there's disease there that might benefit from that type of approach. Still, a lot to be learned from that as well.

Carmel Pezaro: Okay. Fantastic. Thank you so much for your time today.

Ian Davis: Thank you, Carmel.