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Carissa Chu: Morning, everyone. Thank you for the opportunity to speak. My name is Carissa Chu. I'm assistant professor at UCSF in urology, here to provide a surgical perspective on how we're using PSMA PET. We're leveraging PSMA PET in the preoperative setting. We use it in the biochemical recurrence setting. I also want to talk a little bit about how we're using it intraoperatively as well.

So there are some key opportunities here, looking at PSMA PET in our world—using it to improve surgical precision, optimize outcomes after biochemical recurrence, and design neoadjuvant clinical trials with translational impact. And so I'll be talking about an exciting trial that we're opening soon at UCSF with Tom Hope, comparing different PSMA radioligands.

Like I said, we use PSMA PET imaging to stage patients well prior to surgery. Now we're venturing into this whole new world. We're actually using live PSMA imaging intraoperatively during our robot-assisted laparoscopic prostatectomy surgery.

So this is a study really led by Doctors Peter Carroll and Hao Nguyen at UCSF, looking at IS-002, which is a PSMA-conjugated fluorophore. And as we all know, PSMA is overexpressed in prostate cancer cells compared to healthy adjacent normal cells. And so leveraging that overexpression to pull 404-tagged PSMA antibody, administering it intravenously 24 hours prior to surgery allows us to visualize it actively during surgery. And this is a case where the prostate had already been resected. We switch over to this firefly mode, which provides some excitation at 800 nanometers, showing that there is some residual tissue there still at the apex, as you can see from my pointer, hopefully, right there at the apex, which then required the surgeon to go in and resect additional tissue.

Here’s an example of a PSMA-positive lymph node, a pelvic lymph node that was seen preoperatively on PSMA PET imaging and, again, using the PSMA-tagged fluorophore evident intraoperatively to be sure that that particular suspicious area was removed. This was pathologically confirmed to be prostate cancer. And here we see there’s quite a bit of concordance in the fluorescence between the pathologic diagnosis and what’s seen under fluorescence.

So here’s a gross specimen with the prostate, with tumor palpable in this location, corresponding at the same time to increased intensity of PSMA fluorescence. When you look at this in a cross section where the dominant tumor is right here, again you see a corresponding intensity of the fluorescence there. And then diving deeper into an H&E slide, the tumor, which is outlined here in green by our pathologist, corresponds quite well to what’s seen under fluorescence.

So that was our results from the phase I safety dose escalation study involving 24 patients. The PSMA agent was well tolerated, with really just some discoloration of urine, stool, or injection site in a very small number of patients. And so this has since gone on to a phase II study, a multicenter, single-arm study looking now at an endpoint of positive surgical margins and the ability to potentially downgrade that intraoperatively using live imaging.

And so here’s an example, again, of a prostate surgery. This is the prostate, kind of highlighted there in green. And you can see where the tumor is located within that prostate live during our operation. And so the way the phase II study is designed is basically to have—there’s an intervention arm and a control arm. The intervention arm gets the PSMA fluorophore IS-002. And the endpoint here is histopathological assessment for positive surgical margin on the final specimen.

And so here’s a common scenario of how that can occur intraoperatively. The prostate is removed. We suspect a possible positive margin based on residual fluorescence at the time of surgery. Additional deep biopsies are taken. And we think that this is going to improve our positive surgical margin rate and, hopefully, longer-term cancer-specific outcomes.

In addition to improving surgical precision, I want to talk about how we’re using PSMA PET in the biochemically recurrent setting after prostatectomy. We know that patients with high-risk prostate cancer have a 30% to 40% chance of biochemical recurrence at some point, which is strongly associated with worse long-term clinical outcomes. So this is just a retrospective look at our single center and how we’ve been using PSMA PET over the past couple of decades.

This is work by Ariel Ilano, who really led this study of 354 patients with biochemical recurrence who underwent either PSMA PET imaging or conventional imaging. You can see that the positive detection rate was significantly higher in the PSMA PET group, as expected, with the detection rate around 54%, as compared to 10% in the conventional group. The median PSA at the time of imaging was pretty comparable between both groups.

And what we found was that PSMA PET detects more pelvic and nodal disease, probably as expected, when compared to conventional imaging. Conventional imaging showed increased detection of visceral and osseous disease, and that’s likely related to some stage migration and comparable rates of extra-pelvic nodal disease. As you can imagine, the PSMA PET group is a more contemporary group with a median year of recurrence around 2018, as compared to 2013 for the conventional imaging group.

What you can see here is that the PSMA PET imaging was more likely to be performed earlier, and that the PSA value at the initiation of salvage therapy for those who received it occurred at lower PSA values—0.4 versus 0.59. When you then look at what salvage treatment they subsequently received, you see that there was lower use of ADT overall in the PSMA PET group.

So here, this is salvage hormone therapy. In blue, you see patients who received no hormone therapy, orange standard ADT, novel ADT in green, and both in blue. And in general, there are more patients with the blue stripe on the stacked bar chart showing more patients who are not undergoing ADT who had positive PSMA PET findings. In salvage, when you look at salvage radiation, there is a difference in salvage radiation to an extra-pelvic target in patients who underwent PSMA PET scanning.

So far, we have not seen any difference in second biochemical recurrence yet. There are some differences in median follow-up time in the conventional imaging and the PSMA PET group, as expected—about a year’s difference. And so we’ll continue to see how this data matures as we follow these patients out. On multivariable analysis, we saw, as expected, that log PSA at the first biochemical recurrence was a predictor of second biochemical recurrence, but no other independent predictors for second biochemical recurrence, including PSMA PET use.

Lastly, I want to just mention an exciting neoadjuvant clinical trial that we have opening at UCSF. It’s an IIT in collaboration with Novartis, and our goal here is really actually to look at differences in absorbed dose between lutetium and actinium. So these are patients with really high-risk disease, Gleason 4+5 disease with pelvic nodal metastases or seminal vesicle invasion or extracapsular extension with the PSMA PET scan showing a positive signal, who are then candidates for radical prostatectomy and have not received any prior prostate cancer therapy.

Cohort 1 and Cohort 2 are assigned to either lutetium or actinium PSMA radioligand therapy. And interestingly, we do have an intravenous and intra-arterial arm for this study to look at differences in how the radioligand is administered and how that impacts absorbed dose.

Patients will either undergo one cycle or two cycles of treatment and then subsequently undergo radical prostatectomy. And so this gives us two really nice time points, both comparing the presurgical biopsy specimen and the prostatectomy specimen, to look at dosimetry—absorbed dose—interested in other biochemical and pathologic outcomes as well.

So this is a fun, collaborative trial that’s designed by Dr. Hope, as well as Cornelia Ding, pathologist Dave Oh in immunology, myself in urology, and also Ryan Kohlbrenner in interventional radiology. So with that, I’d like to wrap up here, thank my collaborators, and I’m happy to take any questions later. Thank you very much.