PSMA-Targeted Treatment Considered in mCRPC After AR Inhibition

Robert Dreicer, MD, MS

Deputy Director, UVA Cancer Center

Director, Solid Tumor Oncology

Division of Hematology/Oncology

Professor of Medicine and Urology

UVA Health

Charlottesville, VA

DISCUSSION QUESTIONS

• What are your impressions of the VISION trial (NCT03511664) data for patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously been treated with taxane and androgen receptor (AR) inhibitor regimens?
• What real-world challenges are there to using Lutetium Lu-177-PSMA-617 (¹⁷⁷Lu-PSMA-617; Pluvicto) and the PSMA [prostate-specific membrane antigen]-PET scan?

HARVINDER SINGH, MD: It provides another option for patients in the difficult scenarios, where there are not a lot of options.

ROBERT DREICER, MD, MS: What do you think the greatest challenge to introduce ¹⁷⁷Lu-PSMA-617 into your practice is going to be?

QAMAR ZAMAN, MD: I’m in a small, rural town, so access, time, and insurance are always an issue. A lot of patients now have Health Maintenance Organization Medicare.

DREICER: Yes, it’s the worst of both worlds.

SINGH: In the community, it’s hard for me to send patients to a university to even receive Lutetium Lu-177-dotatate [Lutathera], which is for carcinoid or neuroendocrine tumors. But we have a practice by a nuclear medicine radiologist in the community, and he does all that.

DREICER: Do you anticipate that it would be relatively seamless?

SINGH: I would think so. I have not talked to him yet…to see when he plans to use it.

YACOUB FAROUN, MD: I think the most important question that we have to ask is, what is the sequence of therapy after progression on docetaxel [plus androgen deprivation therapy]? Should we use cabazitaxel [Jevtana], the taxane with the 36% decrease in the death rate, versus ¹⁷⁷Lu-PSMA-617?^{1 177}Lu-PSMA-617 has an overall survival benefit, but it’s minimal, [though] I know it has short-term follow-up.²

DREICER: That is a good point, in terms of sequence. There is a study called TheraP [NCT03392428], which was published and was updated at the 2022 American Society of Clinical Oncology Annual Meeting. This was a relatively small randomized phase 2 study, where the randomization was between ¹⁷⁷Lu-PSMA-617 and cabazitaxel. Because it was a randomized phase 2 trial, it was not a survival study. The primary end point was PSA [prostate-specific antigen] response. So, you might see something about the follow-up of that trial. The bottom line is, that trial doesn’t tell me anything. The question that you raise about what the optimal sequence is, is unknown.

Now, there are studies that are ongoing that will eventually give us some insight, but if you had access to ¹⁷⁷Lu-PSMA-617 today, and you said, “Am I doing my patient a disservice by treating with cabazitaxel versus ¹⁷⁷Lu-PSMA-617,” nobody is going to be able to tell you you’re doing them a disservice. We don’t know. So, that’s part of the issue…where do you feel that this therapy might fit in?

If it’s a hassle for you—meaning if it’s not straightforward, unlike our other colleague who has a colleague in the community who makes it pretty seamless—you’re going to make different decisions, because of how hard it is for your patients to go to [an academic center]. These are real issues, and I’m sure you’ve given it a bit of thought. But those are very legitimate questions.

KAMALESH BALA, MD: There is a real need for this therapy, especially now that we are using AR-targeted agents even in the castration-sensitive stage, before patients even become castration resistant. We are running out of options for patients with CRPC. So, hopefully this will become widely available, and easy to use.

DREICER: Yes, I understand what you’re saying. Not that it’s going to be imminently available, but there are 2 other randomized trials that are ongoing. One is the PSMAfore [NCT04689828] study of ¹⁷⁷Lu-PSMA-617 in patients who have just had an AR inhibitor but not a taxane, and they progressed. And there’s an even earlier study called PSMAddition [NCT04720157]. It is for castration-sensitive metastatic disease, so patients get androgen deprivation therapy and docetaxel, [meaning] intensification with or without ¹⁷⁷Lu-PSMA-617. So, they’re asking the question of adding it even earlier. Those trials are ongoing, so we are not going to have data for a while, but those are legitimate questions. They want to move it up earlier in the paradigm; you’re interested in making sure that you have additional therapy options for patients when they progress. So, they’re not mutually exclusive, but they’re different issues.

SINGH: [In terms of scans], where does the fluciclovine F18 [Axumin] assay fall? Where do you see it in your practice?

DREICER: I don’t think I’ll ever order another fluciclovine study; there’s no reason. In the Gallium 68 PSMA-11 and fluorine-18 PSMA-1007 scans, the imaging quality is pretty similar. Both PSMA-PET assays are significantly better than fluciclovine, so I’m not going to use fluciclovine anymore.

Interestingly enough, the fluorodeoxyglucose-PET [FDG-PET] in prostate cancer is not particularly useful. Although, in some studies of ¹⁷⁷Lu-PSMA-617, they have increased the rigor by basically doing both studies. They do FDG-PET and PSMA-PET, because they try to identify the FDG-avid, non–PSMA-avid disease sites. That’s more of a biological construct; we’re not going to do that clinically.

But I think there is going to be work done along those lines, because we don’t know what to do with those patients if they’re not PSMA-avid but they have progressive disease. If most of their disease is not PSMA-avid, when you use a PSMA-targeted therapy, it’s likely to work less well. But ultimately, we’re going to be using PSMA PET as our standard going forward. It will replace conventional imaging. It’s going to take time, because right now—I don’t know about in your neck of the woods, but our 2 commercial carriers will not pay for PSMA PET-CT scans. I can’t get it in the appropriate indications, so the only patients I can do PSMA-PET for are Medicare patients because our carriers won’t pay for it. Eventually, I think they’re going have to [allow it], but right now they are not and [this is true] pretty much around the country.

ARUN BHANDARI, MD: If you order PSMA-PET scans and you are the authority, even then they are not paying?

DREICER: The reality is…that I cannot tell. If you say to me, “Can you show me evidence that if you do a PSMA-PET on this patient with biochemical failure, he’s going to do better and live longer than if I let you do a bone scan and a CT scan?” The answer is, I can’t.

Even though the data are compelling, the reality is that the data have not caught up with outcomes yet. So that’s why, even though I’m frustrated about this, I tell my colleagues to [relax] a bit because in fairness, we spend [millions] of dollars on lots of things, and I’m not sure that I can tell people, at least in biochemical failure, that I have to do that. That said, 5 years from now we’re going to be doing PSMA-PETs.

Right now, the choice for most colleagues in the community when the patient has received a taxane and an AR inhibitor or 2—you’re making a decision between cabazitaxel and ¹⁷⁷Lu-PSMA-617. Even if you were able to get a gallium PSMA-PET, and they were PSMA-avid, you may feel more comfortable about the timeline of getting cabazitaxel started. Since you control that, you can move that along. Unless you have a readily-available nuclear medicine colleague who can move this fast, it may take a few weeks to get patients imaged and [prepared for therapy]. So, you’re going to use some of those clinical parameters to make your decisions, until such time that there is a CARD study [NCT02485691] equivalent where the data are so compelling that you are going to think differently. But those data are not available [currently].

_References:

_{1. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206}

_{2. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322}