Louise Emmett: Thank you, Oliver, for having me.
Oliver Sartor: So, why don't we just dive right in? You just gave this presentation at the EAU, and I know our listeners would like to learn more.
Louise Emmett: So the Co-PSMA study is a prospective comparison of a new PET agent, 64Cu-SAR-bisPSMA, directly compared in the same patients, to Ga-PSMA-11 PET/CT in men with biochemical recurrence of prostate cancer following radical prostatectomy. So, we know that PSMA PET has become really important for the staging and management of early prostate cancer, particularly in biochemical recurrence. But at really low PSA levels, a high proportion of PSMA PET scans remain negative. And there hasn't been much of a leap between Gallium, or Fluorine, or the other peptides, in terms of detection rate or sensitivity. So, this 64Cu-SAR-bisPSMA is an interesting agent. It's actually... It's got a sarcophagine cage around a 64Cu, which is a long half-life. It's got a 12-hour half-life. And then it's actually got a bifid structure. So it's got two peptides, not one, which leads to much higher binding affinity, certainly preclinically. So, it looks encouraging in terms of a higher detection rate in this group of men. So what we did was we did both the Ga-PSMA-11 and the 64Cu-SAR-bisPSMA at... The SAR-bisPSMA, we did at two time points, 1 and 24 hours. And the two PET agents, the two different PET agents were undertaken within two weeks of each other. We took 50 patients who had biochemical recurrence following radical prostatectomy. The PSA had to be between 0.2 and 0.75 nanograms per mill with no prior salvage radiotherapy. So, these men were being considered for salvage radiotherapy.
The primary endpoint was the number of lesions detected per patient for 64Cu-SAR-bisPSMA and for the Ga-PSMA, and that was powered with a 50 patient for detection rate. And then secondary endpoints, we actually did management impact questionnaires between the Gallium and the Copper in all patients. We looked at reporting certainty with blind experts reading the scans three times, and looked at Cohen's Kappa in reproducibility. And we looked at accuracy using a composite reference standard. That was a composite of biopsy, response to targeted treatment without hormones, and PSA rise without treatment. So when we look at the difference between the two scans in this patient population, the median PSA was 0.43, and the majority of these patients actually had quite high-grade disease, as you would expect with biochemical recurrence. The primary endpoint was really positive. So the mean per-patient detection rate was 1.26 for 64Cu-SAR-bisPSMA and 0.48 for Gallium, and strongly statistically significant. When you look what that actually means, it means that we detected positive findings in 36% of patients with Ga-PSMA-11 compared to 78% of patients with 64Cu-SAR-bisPSMA, and the number of lesions for Gallium were 24 versus 63. And that led to a consequent, quite significant management change.
So, management actually changed in 44% of the patients. And then we also looked at accuracy, the reproducibility, the Cohen's Kappa for Ga-PSMA was 0.75, which is pretty standard actually for Gallium between three readers, but went up to 0.94 with the 64Cu-SAR-bisPSMA. And when we look at our reference standard accuracy, true positive, 71% true positive for 64Cu-SAR-bisPSMA compared to 29% for Ga-PSMA-11, and false-negative 21% for 64Cu-SAR-bisPSMA compared to 65% for Ga-PSMA-11. So, pretty interesting result. And also, just show a couple of the images that were representative of what we saw in the study. So on the top here, this patient, we had a 64Cu-SAR-bisPSMA 24-hour image compared to the Gallium underneath. So, the Gallium scan that was taken and undertaken in this patient, all three readers called it negative. The Copper scan on the top had a clear recurrence in the prostate fossa, with an SUVmax of 15, and all three readers called this positive. So a scan was undertaken within five days of each other, clearly positive and clearly negative. This study is also interesting. This patient had a positive scan on Ga-PSMA-11. You can see a lymph node here in the pelvic side wall that was reported by all three readers, but what was missed and then detected on the 64Cu-SAR-bisPSMA was the local recurrence that you can see in the prostate fossa. That's very clear on 64Cu-SAR-bisPSMA. And the other three nodes that were identified on 64Cu-SAR-bisPSMA, identified by all three readers. So, it does look like it's much easier to identify lesions. It's very important to understand that this is on the 24-hour image. The one-hour image with 64Cu-SAR-bisPSMA detected the same number of lesions. We did have one false-positive lesion with the 64Cu-SAR-bisPSMA in addition in bone compared to the Gallium, and that's just seen here.
You could see the 24-hour images are a little bit grainy, and this patient had an SUVmax 5 identified in vertebra that was identified by 2 out of 3 readers, and was felt to be probably positive, but nothing at all seen on this. This patient was deemed to be a false-positive on 64Cu-SAR-bisPSMA because they had radiotherapeutic prostate fossa with a marked reduction in PSA. So on the reference standard, false-positive. So really, interesting results. Overall, 64Cu-SAR-bisPSMA identified a higher number of disease recurrences, and the Ga-PSMA PET. It had a substantial management impact. And the composite reference standard true-positive rate was significantly higher in men with biochemical recurrence following radical prostatectomy.
Oliver Sartor: Louise, I think that's a fabulous presentation. What with a lot of impact? We're going to have a second discussion on some of the impacts, but let me just ask you about discordant reads with the Gallium. That was a little higher than what I had previously understood. The discordance was substantial with the Gallium and less so with the Copper. Why-
Louise Emmett: No, it's not discordant. I would say there was an agreement between readers on 80% of readers with the Gallium. So, not pretty, just concordant. The Copper of 0.75 is a substantial Cohen's Kappa. So as an agreement between readers, 0.75 is very, very respectable. The 0.94 Cohen's Kappa with the Copper is the outstanding thing. That's near-perfect agreement, and there was no discordance at all between the readers. That is very interesting. And I think it's really clearly delineated here by the images that you see. The bladder washout is marked. You're not trying to peer around the activity within the bladder to look for a recurrence. And because of the washout from everywhere else in general, you get a very clear signal, because the Copper seems to continue to intensify within the prostate cancer cells. And so, you get a brighter tumor-to-background ratio. That's very helpful for the readers. I don't think the Gallium is the discord or the unusual finding. That's standard for us. I haven't seen higher than 0.75 with Gallium. But the 0.94? I have never seen.
Oliver Sartor: Yes. And I guess, the way I referred to it as discordant was the relative comparison between the agreements was striking to me in the sense that the Gallium, perhaps standard, is not as good as I would've hoped for, whereas the 0.94 seems just perfect or close to it.
Louise Emmett: Yeah, that's interesting too. These readers were blind to the results, clinical results and the other scan results. And it was a triple read. So, 0.94 is the highest we've ever got from any trial in terms of reading between readers. I mean, if you look at MRI prostate, then your Kappa sits at about 0.58. Gallium prostate, we usually sit between 0.7. About 0.75 is perfect for us. I think we've got 0.77 before. And remember, these guys have early prostate cancer. The PSA is 0.2 to 0.75. It's a low PSA. And so the volume of disease that we're looking at is small, and often, particularly on the Gallium, that what we see is low volume and not always very distinct.
Oliver Sartor: What was the median PSA, Louise? Do you recall?
Louise Emmett: 0.43.
Oliver Sartor: 0.43. And so clearly, your Gallium results are going to be compatible with that of others. The control group performs as expected, and this is just far better than expected. I would simply say that this looks like superior imaging to me.
Louise Emmett: It's interesting. So, the PSA was 0.43. It is low. And our detection rate with Gallium was 36%, which is a little bit lower than we would normally expect at 0.43. But I think one of the things that happened on the trial is that a lot of the referrals had a Gallium scan that was negative, didn't know what to do with the patient, so then referred them to the trial, and they ended up having a second Gallium scan for the trial and then the Copper. We didn't exclude prior negative PSMA PET on our inclusion criteria. So, our detection rate is probably a bit lower than you would normally expect because we had preferential referral of negative scans, I think.
Oliver Sartor: Wait, it's a little bit interesting because that coincides with what my expectations were. If you go to between 0.2 and 0.5, then I've quoted, based on the UCLA data, somewhere around 0.37. Now, admittedly, your median was there, meaning you had a number of patients above 0.5, and that translates into a higher detection rate. I typically quote somewhere in the 58 to 60% range between 0.5 and 1. But 0.37 is certainly within expectation for me, but nevertheless, you found just much more lesions, more than double the rate of the patients actually had lesions detected.
Louise Emmett: True. So no matter what the enrollment criteria, there were more lesions detected in this patients who are a difficult patient population. One of the other things, I think, is interesting is the management impact. There was a significant management impact to active management. So, active management in these patients with a rising PSA following radical prostatectomy clearly have recurrence of prostate cancer, went from 66% with Gallium up to 90% after the Copper in terms of active management. So, it did push the investigators to treat these patients more actively.
Oliver Sartor: Louise, we're going to wrap this one up. Thank you as always. I really enjoy seeing your data, and really enjoy speaking with you and hearing your thoughts. And with that, we'll wrap up UroToday segment number one, and quickly go on to UroToday segment number two very shortly, looking at further implications from this important trial.
Louise Emmett: Thank you.