Phenotypic Biomarkers in Advanced Prostate Cancer

Alicia K. Morgans, MD, MPH: Let’s move on and ask Phil a question, because Phil’s a nuclear medicine physician, a true expert in our field in prostate cancer, and has collaborated with us over the years to try to help us understand some of the biomarkers that we find in imaging, particularly with PET [positron emission tomography] imaging. Phil, can you tell us a little about radiotracers in prostate cancer? What are your thoughts on some of the different agents that exist?

Phillip J. Koo, MD: Sure. Thanks, Alicia. Radiotracers in nuclear medicine are the backbone of our specialty. We specialize in the use of these unsealed sources of radiation to diagnose and treat tumors. And in prostate cancer, they’re not new. We’ve been using various radiopharmaceuticals to diagnose and treat disease in the past. What we’re seeing in prostate cancer is this elevation and huge step forward with the validation and FDA approval of PSMA [prostate-specific membrane antigen]-targeted diagnostic agents. To me, this is shepherding a new era in precision medicine that’s focusing on the phenotypic precision medicine, which looks at the expression of a specific biomarker in patients with prostate cancer to help us guide treatment decisions.

When we talk about precision medicine, we focus so much on the genotype, which is obviously very important. But the phenotype in PSMA is now opening up a whole new world of opportunities. To me, this is extremely exciting, and we’re only scratching the surface. A lot of times, the focus has been on detecting disease. But now, the idea of using imaging to select patients for treatment is real. It’s with us today, and we’ll talk about that later. The idea of using imaging to help us understand prognosis is another area where we’re just scratching the surface.

All of this is really exciting. Clearly, a lot of the people at this table have done groundbreaking work to help us answer a lot of these questions. One other point I’d like to add is the fact that imaging has always shed light on heterogeneity. We talked a little about this earlier, but heterogeneity is something we’ve seen so often on imaging, but we couldn’t explain it. In the past, we used FDG [fluorodeoxyglucose] glucose analogues to image, and we’ve seen various tumors have more glucose expression vs less glucose expression. Even with sodium fluoride, there were some tumors that would be really bright, and some that would be less bright. It was telling us something. It’s incumbent on us to search more, because heterogeneity is going to be a big driver of how our patients respond to these various therapies in the future.

Alicia K. Morgans, MD, MPH: Absolutely. And in a later conversation, we’ll get to the way that we can use several different PET tracers, FDG and PSMA perhaps, to find a bit of a different phenotype of the disease in the same patient, with different areas of metastatic spread. It’s really important and interesting. Sandy, how commonly do we see PSMA expression? We’re really interested, as one of the newer technologies is PSMA-directed PET technology. How commonly do we see that protein expressed in our patients?

Sandy Srinivas, MD: It depends on the type of patients you see. In my practice, for patients with more advanced disease, we’ll talk a little more about the VISION trial. But in the VISION trial, all patients ended up having a positive PSMA as an inclusion. It turned out that close to 85% of patients with advanced disease do have a positive PSMA expression. We know this from earlier studies showing us that PSMA is prognostic. As you get more treatment, perhaps with AR [androgen receptor]-directed therapy, there’s increased expression of PSMA. You can even see in patients with localized disease, those with more aggressive disease have a higher PSMA expression. It’s going to be interesting to see how we utilize this imaging, and in which patient population it is going to add the most value. It’s remarkable that it’s prognostic, and now we’re able to target it both therapeutically and diagnostically.

Alicia K. Morgans, MD, MPH: I agree. I heard a talk once that compared our ability to target PSMA with imaging as a light bulb, and our ability to target it with theragnostics as a little bomb, and to think about PSMA being utilized in both ways, allowing us to image our patients potentially more sensitively or accurately, as well as potentially to treat our patients. It’s really interesting, because both of those characteristics are there. But we should be very careful and also explain that there are different ways for us, at least in imaging, to target PSMA. There are also multiple ways to target it therapeutically. Phil, I’d love to hear from your perspective a characterization of some of the different agents that we can use to target PSMA with imaging. Let us know how those approvals—because they’re approved at this point—have panned out.

Phillip J. Koo, MD: Sure. As of today, speaking for the diagnostic perspective, there are 2 approved PSMA-targeted diagnostic agents. Gallium 68 PSMA-11 was approved at UCSF [University of California, San Francisco] and UCLA [University of California, Los Angeles] in December of 2020. Then we have the F18 [fluorine-18]-based PyL compound that was approved in May of 2021. Both of these agents, for all intents and purposes, are the same. There are subtleties in image quality, biodistribution, and dosimetry. But for all the users out there, the end product is pretty much the same, and the output will be pretty much the same.

What we’re seeing right now, especially in the United States, is a relatively rapid rollout of these agents. With the Gallium 68 PSMA limited to UCSF and UCLA, there was clearly a limitation in access. Patients would only be able to get access at those 2 sites. Now, we’re seeing nationwide commercialization of the PyL compound because of the isotope, which allows it to be distributed across the United States pretty easily. This is going to really change what we see in terms of access. Then we have other compounds, such as the Gallium 68 PSMA-11 kit, which will also help us increase the access for patients across the United States. But again, the performance is pretty much all the same. So if we say PSMA-targeted PET or PSMA PET, they’re all going to be roughly the same.

Alicia K. Morgans, MD, MPH: Great, thanks. That’s so helpful. It’s also helpful to understand that these are different compounds between the gallium and the fluoride, and that the gallium agent at this point, also a very good agent, is only available at 2 sites in the United States, so we were very excited when it was approved. It’s showing a shift in our paradigm and opportunities to potentially identify patients for these therapeutic agents that we’ll discuss later. But it wasn’t necessarily something that we could see at all sites, and so that’s a bit of a challenge for some of our patients who do not live near those particular sites.

Transcript edited for clarity.