Louise Emmett: Hey, Oliver.
Oliver Sartor: We're going to be talking about some of the implications of your recently presented Co-PSMA trial. And to me, it's a very important trial. I'll lay a little foundation, but then I want to get your perspective, of course. So everybody with a radical prostatectomy that recurs, it depends on where you actually do the PSAs and how often and what sensitivity test you use as to what you find. But let's put it this way. The majority of patients that I see have a PSA below 0.5 when they recur. And in my experience, the majority of the PSMA PET scans that I run in these patients are negative. Yet, you found the majority of these patients are likely to have positivity on the PSMA PET. Let's look at those implications. What do you believe are the implications of this more sensitive scan for the literally hundreds of thousands, if not millions of men who have a PSA recurrence post-radical prostatectomy?
Louise Emmett: You know, to me it's an important space. These men, the post-radical prostatectomy, the prostatectomy has failed, they've got a rising PSA, and then you do a scan and it's negative. So I think standard of care really is salvage fossa radiotherapy, but the disease may still be elsewhere. I think PSMA PET has actually induced a little bit of a change in management. Certainly in Australia, it has. If the PSMA is negative, they just wait and they repeat the PSMA until it becomes positive. But we know the disease is there at this very low PSA level, and we also know that these patients can actually be cured if you get them early enough. So in a sense PSMA PET has derailed us a little bit, I think, from good management when it's negative by a lot of these patients not being treated. So what I think with this study is because we went from a 36% detection rate up to a 78% detection rate between gallium PSMA and 64Cu-SAR-bisPSMA in this very low PSA level, median PSA of 0.43. It means that those patients have a positive scan. They go for more active treatment earlier. And I think that has implications for those patients for their wellbeing and also for their potential cure in the long-term. Obviously, we need to do other studies to look at that and make sure that we look at patient outcomes have actually improved, but to me, that's what it looks like.
Oliver Sartor: You know, there is good data with salvage radiation, and there's a certain article I recall by Emmett and colleagues that looked at the negative PSMA PET as being a predictive marker for a positive outcome after salvage radiation. So let's talk about the negative PSMA PET implications and the outcomes. But also, if you don't mind, can you discuss how many of these detected lesions would've been in a normal radiation salvage port as opposed to the abnormal port that might've been induced by the findings in the copper scan?
Louise Emmett: I think that's, first of all, talking about the negative PSMA PET, that's actually been a thing of mine for a while since when we did the first study. What we found was that if patients who had a negative PSMA PET, their chance if they went for salvage fossa radiotherapy of having a three-year freedom from progression was 85%. So we know the disease must have been in the fossa even though we couldn't see it, and that treating it led to very high rates of disease-free progression. But less than half of the patients were actually referred for salvage fossa radiotherapy in that patient population. And the surgeons were going, "If we can't see it, we don't want to treat it because we don't want to induce toxicity." So that led to a lot of patients ... In that study, the median rise in PSA in the patients who did not get the salvage fossa radiotherapy were 1.6 nanograms per mil, so well beyond curative levels. So I sort of felt strongly that we might be harming patients with PSMA PET. And that's why I'm super excited by this result because just being able to see it meant that they were being treated. So 78% and then 90% of patients going for active management is a change. That is important because psychology is super important in medicine. If you can see it, you're more likely to treat it. If you can't see it, a surgeon is not going to want to send for treatment of an area that's going to get long-term toxicity if they're not sure it's there. So big certitude about knowing where the disease recurrence is, I think is important for clinicians.
Oliver Sartor: Well, I certainly agree. And I wanted to raise the point because you made important issues about the PSMA negative implications previously, and I'm circling back around to now a more positive stance from Louise Emmett on the detectability of the disease now in the vast majority of the patients. 78% is a remarkable number. I thought this was outstanding.
Louise Emmett: It's cool. And then 78%, but with a kappa reproducibility between readers of 0.94. So I think it's there and it's reproducibly identified by the readers as being at that site. I think that's important. And then the true positives ... Admittedly, our composite reference standard in this study is weak because it's not based on a biopsy and biochemical recurrence is very hard for biopsy. We didn't have many biopsies. So it's predominantly based on response to targeted treatment without the presence of hormone therapy, so PSA response. But it really correlated very strongly. The higher detection rate was associated with a much higher true positive rate in terms of PSA response.
Oliver Sartor: When we talk about standards of truth and you're detecting smaller and smaller lesions, I agree 100%, the biopsies become more and more problematic. So how do you prove it's real? And the answer is use targeted radiotherapy and then have a PSA decline. So in this study, do you have preliminary data on the patients for whom targeted radiation therapy was used and the results after that use?
Louise Emmett: We do. So more than half of the patients in the composite reference standard had salvage radiotherapy with a PSA response without ADT. So 16 patients in this study out of 50 actually went on to hormone therapy, ADT, and were not evaluable in terms of PSA response. The remaining patients were. And that's largely what we use for the composite reference standard in this study. So it's not a strong composite reference standard, but I think it's an important thing. If you identify a lesion and then it responds to salvage radiotherapy with a PSA response, at a clinical level, that's important. That's what you need to know. So not only is it a reference standard in terms of true positive, it's a reference standard in terms of are they going to respond if you treat that area? And I think it's a clinically relevant endpoint.
Oliver Sartor: Were any of these lesions able to be detected on conventional imaging? UROscan, CT scan, MRI? Just out of curiosity.
Louise Emmett: So the MRI, we don't do a lot of MRI for biochemical recurrence in Australia. And we previously published a prospective international trial, actually, called the PROPS trial where we compared MRI to choline and to PSMA PET. And what it found was the detection rate for local disease with MRI was pretty well the same, but the detection rate for distant disease, lymph nodes and bone, was much, much lower. It was about 9% detection rate compared to 66% detection rate with the gallium that we used in that study, slightly higher PSA at that stage and at more aggressive patients. So we didn't do MRI. We wouldn't do CT. And these were very small lesions that were discovered. This is low-volume disease that we're talking about.
Oliver Sartor: Right. And I guess what I'm driving at in an indirect way is I still see conventional imaging being used in certain patients in this biochemically recurrent setting. And it sort of drives me a little crazy because why are they doing it?
Louise Emmett: We didn't look at conventional imaging. We've done that, it didn't work, and we don't use it. And MRI is great for characterizing the local recurrence if you need to for guiding salvage radiotherapy fields and things like that, but it's not good at detecting nodes, and nodes are predominantly the site of recurrence distantly in these patients.
Oliver Sartor: Absolutely. And I saw that clearly. Louise, the implications for me is if the copper has the potential in this setting to be able to displace the conventional PSMA PET. Is that an overstatement? I don't want to be an overstatement guy. I want you to exercise your-
Louise Emmett: We have a lot more work to do to say that, I think. So copper is interesting. It's a 12-hour half-life. We know with PSMA PET that you get this slow, continuous uptake within the cell, so it's probably continuing to uptake beyond the half-life of fluorine, beyond the half-life of gallium. And then this addition of a bifid PSMA agent seems to double the binding capacity and affinity of the agent within the prostate cancer cell. So I think it's the combination of the copper and the bifid agent. And I do think it increases detection, but we have no idea what it does in metastatic disease. We have no idea what really ... I think the company is doing work on looking at accuracy in terms of sensitivity, specificity, negative and positive predictive value with histopathology studies. That's important. We don't have that data yet. And then we also don't have data on outcome. If we find more, did the change outcomes for the patients, and that's a big stretch in terms of being able to do that kind of study. But personally, as a person who could potentially be a patient, I'd like to know that not just are we detecting more, but that it actually improves my outcome long term.
Oliver Sartor: Well certainly you're asking the right questions, and that study may take years, decades to even do. But in the meantime, Louise, we're going to wrap it up, but I'd like to say thank you for your many, many contributions in the field. I think they're enormous and important, and thank you for being on UroToday.
Louise Emmett: Thanks so much, Oliver.