Radioligands in the Treatment of Metastatic CRPC: Lutetium-177–PSMA-617


Focused discussion on the role of lutetium-177–PSMA-617 as radioligand therapy in patients with metastatic castration-resistant prostate cancer.


Rana McKay, MD:We’re going to shift gears a little and talk about radioligand therapies. We’ve seen the approval of lutetium–PSMA [prostate-specific membrane antigen], which has been long awaited by our prostate cancer community. We began to open the field of radioligand therapy in 2013, when the ALSYMPCA trial was conducted with the approval of radium, the first radioligand therapy to improve overall survival for any solid-tumor malignancy. Now look at where we are. Where does lutetium play in the field?

Scott Tagawa, MD, MS, FACP:Are you asking me?

Rana McKay, MD:Yes. You’re the radioligand man, so you’re in charge.

Scott Tagawa, MD, MS, FACP:Right now, clearly there’s a label. There’s clearly less off-label use because there’s not a big supply. That emphasizes that we’re sticking to that label.

Rana McKay, MD:What’s the label? Tell us about the label.

Scott Tagawa, MD, MS, FACP:PSMA positive is a whole can of worms, but there are things that light up more than the liver. There are all sorts of SUV [standard uptake value] means and SUV maxes, but they’re brighter than the liver in that at least all the soft-tissue lesions are a certain size. I’m not going to go into great details. You can have something that lights up on the scan but is negative on the PSMA PET [positron emission tomorrow]; that is 1 part of it. [The other part is] prior exposure to at least 1 AR pathway inhibitor and at least 1 taxane chemotherapy in any setting. That could be first-line mCRPC [metastatic castration-resistant prostate cancer] if someone got a triplet [therapy] up front. That’s in the general patient population [for patients] healthy enough to receive any drug.

That’s on the label. It’s fairly clear that the drug works in that setting. It’s important to know that was a combination therapy. It was the best standard of care, which is mostly hormonal therapy with or without. In post hoc analysis, those who got an AR pathway inhibitor as the best standard of care had an overall survival benefit. Post hoc analysis doesn’t have to do that but, when we want to use combination therapy. That’s reasonable; that’s level 1 evidence. I don’t think we have to. We can deviate because there are plenty of phase 2 data to use the single agent. It’s fairly clear that it’s no different from abiraterone-enzalutamide. It’s not that the drug requires a taxane to work. So far we have 1 positive trial that, in a news release, moved it up in the metastatic CRPC [castration-resistant prostate cancer] prior to 1 line of ARPI and no prior chemotherapy exposure. I expect at least 2 or 3 other trials to be positive. Then we’ll have that flexibility for metastatic CRPC to use it across the board with some positivity on PSMA PET scans. Depending what they’ve had before, we’ll choose whether to use it later or earlier. It’s unclear if moving it all the way forward is going to work out. There are 2 randomized trials: 1 is completed in terms of accrual, and 1 is completing accrual soon. One uses the docetaxel backbone, and 1 uses an ARPI backbone. We’ll see.

Rana McKay, MD:Those are very exciting data. What’s your experience with lutetium–PSMA in the clinic from?

Arash Rezazadeh Kalebasty, MD:We had the vision, and we treated the patient and vision. Among the other treatments that we’re doing, it’s not a hard therapy to deliver. It’s been fairly easy compared with other things. If the infrastructure is there to give it, then it’s not that hard. There are some problems with kidney function, but not much with cytopenia. Cytopenia can be a problem, but not as bad as we thought. For patients with prostate cancer, sometimes kidney function gets tricky. They have up-and-down creatinine clearance. You order the dose, and the next day the creatinine is high, so you have to hold it [and decide] what to do with the dose, how to decay it, and all that. [There have been] some minor problems, but overall it has been great. Can I ask Scott 1 question?

Rana McKay, MD:Yes.

Arash Rezazadeh Kalebasty, MD:He mentioned a combination with AR-targeted therapy. Do you think it’s possibly because of the PSMA upregulation? Do you think that’s probably the case?

Scott Tagawa, MD, MS, FACP:It’s a dual hypothesis. There’s a PSMA addition, which is the frontline [therapy]. What’s the rationale for that? It’s hormonal therapy. It would have to be dual hormonal therapy, which would hopefully do 2 things. We only need 1 to work, but hopefully 2. One is to upregulate PSMA, and the other is to … That has the potential for both mechanisms to work. There have been many looks at sequential PSMA imaging following the addition of hormonal therapy, including a poster presented at ASCO [American Society of Clinical Oncology Annual Meeting] 2023…. [In the presentation], if there was PSA [prostate-specific antigen] control, there weren’t necessarily brighter scans. It was average about 3 weeks later. The problem with using imaging as a readout—these are effective drugs—is that if you decrease the volume, the PSMA per cell could be going up by logs; you may not see it. It’s an unknown issue in the clinic, especially in the noncastrate setting, With every cell line, PSMA always goes up with whatever AR inhibitor, including in castration-resistant cell lines.

Arash Rezazadeh Kalebasty, MD:Thank you.

Rana McKay, MD:Those are very exciting data about lutetium. We’ve heard a lot of subset analyses from VISION, from the therapy trial about the best patient selection markers. Do you think we’re going to get better than just a PSMA alone? We’ve seen SUV max and SUV mean. We’ve seen sites of metastases data getting presented around liver metastases vs not. Any thoughts about that?

Scott Tagawa, MD, MS, FACP:I don’t know how many of you saw the VISION nomogram. When we can [look at] a number of factors, which is relatively easy to do, that can tell us something. And there are different factors, depending on what end point we’re looking at: response, rPFS [radiographic progression-free survival]. One of them—I’m interested to get Sumit’s viewpoint—looked at NLR [neutrophil-lymphocyte ratio] and just lymphocyte counts. I’m also thinking about stroma and the immune system. That’s often prognostic, but that includes this radiation. We’ve seen some patients do well. Whenever I see that, I’m thinking, is that immune? Someone who was treated on trial is now about 4 years out with normal testosterone and no end disease…. It’s not like radium where it may be acting only on the stroma, but there’s an interaction with the immune system as well.

Sumit K. Subudhi, MD, PhD:I agree. There are data from the radium trial. The radium combination with sipuleucel-T that Emmanuel Antonarakis ran when he was at [Johns] Hopkins [Medicine]. The trial was sipuleucel-T monotherapy vs the combination with radium-223. They show not just a radiographic progression-free survival benefit but also an overall survival benefit, suggesting that there’s a synergy because neither drug gives you a PFS benefit or even a PSA response. In combination, it was able to do those things. If you look at another field, like esophageal cancer, the radiation doctors tell us that when they give chemoradiation therapy, the NLR level is prognostic for recurrence. So there’s an interaction between radiation and the immune system.

Transcript edited for clarity.

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