PSMA-PET imaging disrupts prostate cancer paradigm

Urology Times is celebrating its 50th anniversary in 2022. To mark the occasion, we are highlighting 50 of the top innovations and developments that have transformed the field of urology over the past 50 years. In this installment, William P. Parker, MD, explains how PSMA-PET imaging has disrupted the treatment paradigm in prostate cancer. Dr. Parker is a practicing urologic oncologist at The University of Kanas Health System and an assistant professor at the University of Kansas Medical Center.

Urology Times: Please discuss the emergence of PSMA-PET imaging prostate cancer.

Dr. Parker: PSMA-PET is 1 agent in PET imaging and to understand the evolution of PSMA-PET, you have to go back a little bit and look at how PET imaging evolved in prostate cancer. Traditional PET imaging—positron emission technology, or tomography—is using metabolism to find cancer cells. We began by using FDG or a glucose-based tracer, and so we're really trying to identify metabolically active tumors. Unfortunately, prostate cancer doesn't metabolize glucose in the same way that other cells do, and so for a long time, PET imaging was not effective in evaluating prostate cancer.

As we understood the tumor biology better, we gradually found other agents like C-11 choline and then Axumin (F 18 fluciclovine) which were metabolized by prostate cancer. And then from there, we were able to start using these PSMA tags with the isotope attached to it, and even moving beyond that to where we are today, where we're starting to have treatments that are really using that PSMA tag to deliver radioactive elements that are actually delivering radiation to the site of disease. We traditionally termed these “theranostics,” mainly because the term really comes from the idea that we have an imaging tool—PSMA-PET—that can be used to predict response to a therapeutic, in this case it's lutetium-177 PSMA therapy.

What PSMA-PET agents are currently approved by the FDA?

Currently there are 2 FDA-approved, commercially available PSMA-PET imaging agents, which are Gallium 68 PSMA-11 (Ga 68 PSMA-11) and piflufolastat F 18 (Pylarify).

These agents are approved for the initial staging of men with prostate cancer, and really most insurance companies and most guidelines would say that it's really restricted to men who have a very high risk of harboring metastatic disease, and in particular, in those men where we have conventional imaging that would be considered equivocal. For example, if you have somebody with a really high PSA, like 200 for example, and you scan them and you don't find metastatic disease on a conventional imaging study, then the clinical suspicion is, “We're just missing it.” So, that would be considered an equivocal finding. Or, for instance, if you get conventional imaging and you find something that is “suggestive of metastatic disease,” a PSMA-PET image may help in identifying if that's real or just artifact.

The PSMA-PET imaging agents are also approved for the evaluation of men who have recurrent prostate cancer after curative intent therapy. And here really the goal is to ensure that whatever our next therapy is, that it is not harmful, or at least that's the way I think about it. So I use these agents in men in 2 scenarios: So either in men who've had radiation and they are suffering a biochemical recurrence and I think that they're a candidate for further local salvage, so salvage prostatectomy. In that setting, the worst thing that I could do would be to take out a prostate if they're already metastatic, because then I might be exposing that patient to the harms of the treatment without an expected benefit from a cancer standpoint. Similarly, if I've taken out somebody's prostate, and their PSA is recurring and I'm thinking about giving them radiation to the pelvis, I want to ensure that they don't have prostate cancer that's extrapelvic in origin, because then that radiation which is going to be aimed at their pelvis is going to deliver toxicity without an expected advantage.

However, there's this gray area—and we use these scans now in a lot of different settings—is what do you do if you find somebody that has metastatic disease? Do you treat them truly as metastatic disease? All our existing trials to date—CHAARTED, STAMPEDE, LATITUDE—everything is really aimed at men who have conventional imaging–detected metastatic disease, not conventional imaging–negative, PET–imaging positive metastatic disease. And so, while PSMA-PET imaging helps guide the addition of further local therapy, it doesn't really help us understand yet how we should be employing systemic therapies if we identify a metastatic finding.

The other area where PSMA-PET imaging has a role—and this goes to that theranostic setting—is in men who have metastatic castration-resistant prostate cancer who have failed docetaxel-based chemotherapy and at least 1 advanced androgen agent, such as abiraterone acetate (Zytiga), enzalutamide (Xtandi), apalutamide (Erleada) or darolutamide (Nubeqa). For those men, that’s where lutetium-177 PSMA (lutetium Lu 177 vipivotide tetraxetan; Pluvicto)actually has a role and an FDA-approved indication, but it's dependent upon finding a PSMA-PET–positive metastatic cancer.

What are the next steps with PSMA-PET imaging in prostate cancer?

I can envision 3 areas where PSMA-PET imaging is going to be explored further. One is already ongoing, which is in the role of screening. There are some studies out there using PSMA-PET scans to screen men who we think may have prostate cancer. I think we'll find more data on that. I don't know realistically what the long-term clinical applicability of that is. I don't know if that's a scalable approach, just because of the cost.

The second area harkens back to what I was saying about what do we do with this gray area? I think we're going to see a huge advance in the number of studies and trials that are being done in the conventional imaging–negative, PET imaging–positive patient and how we approach those men, be it with metastasis-directed therapy or with studies really looking at the role of systemic therapies like docetaxel, abiraterone, and other androgen receptor–targeting agents.

The final space that I think is going to be really exciting is that the lutetium-177 PSMA product obviously has activity in metastatic castration-resistant prostate cancer. But it would be interesting to know what it is going to do in other disease states, such as localized disease, maybe regional risk disease—that is, somebody who has nodally metastatic disease, but still an untreated primary. I think we're going to see a lot of exciting data coming out about the role of PSMA-PET imaging to select men for possible therapeutic approaches with this agent in earlier stage disease.