PSMA as an Actionable Target in mCRPC


Oliver Sartor, MD, reviews clinical data from the TheraP trial looking at the activity of 177Lu-PSMA617 in patients with metastatic castration-resistant prostate cancer.

Ulka N. Vaishampayan, MBBS: How do you think these phenotypic biomarkers are going to impact personalized medicine for patients with prostate cancer in the future?

Oliver Sartor, MD: That will depend on the clinical trials. I wonder if I should go ahead and discuss 1 of the most promising clinical trials called TheraP. TheraP was put together by Michael Hofman and colleagues in Australia, particularly at the Peter MacCallum Cancer Centre. They did a great job of leading this trial. Very simply, they used PSMA [prostate-specific membrane antigen] as a biomarker to select patients for PSMA lutetium-based therapy. 

Let me give a little background because there is more to the story. The use of PSMA with lutetium-177 has developed in part because of the efforts of a variety of German centers, particularly those in Heidelberg, that demonstrated activity, particularly in retrospective settings. The patients were treated and then analyzed, as opposed to setting up protocols going forward. 

When we look at the retrospective data, it was unequivocal that they were active. But then the investigators at Peter MacCallum Cancer Centre, and Michael Hofman in particular, were able to design prospective trials. They used a double-selection criteria, not just PSMA positivity but also FDG [fluorodeoxyglucose] PET [positron emission tomography] discordance. Let me explain that for a brief moment. When you’re selecting patients, you can look for PSMA positivity, and that’s a good thing. But what happens if you run an FDG PET and you find that there are lesions that are not PSMA positive? In that case, you have a PSMA-negative lesion and FDG-positive 1. That patient is not going to respond, so you probably don’t want that patient on the trial.

In TheraP, which is a prospective trial, they screened 291 patients but enrolled only 200. They excluded 91 patients because either the PSMA uptake wasn’t sufficient or there was discordance between the PSMA PET scan and the FDG PET scan. These discordant patients were tossed out. We don’t actually know a great deal about those patients who were thrown out, but it was a priori decided that these patients would not be treated. 

Now we have 200 patients. TheraP is a randomized phase 2 trial. The 2 treatments are the PSMA617 lutetium-177, and the comparative arm is cabazitaxel. The patient population included metastatic CRPC [castration-resistant prostate cancer], and they had to be previously treated with a novel hormone and a taxane. The use of cabazitaxel here is a very good control group. In fact, I’m going to say it’s a tough control group to beat. We already know from the CARD trials, for instance, that cabazitaxel is unequivocally active in this space. 

They found out that the number of PSA [prostate-specific antigen] responses were better with the PSMA lutetium-177. The number of radiographic responses were better with the lutetium-177 treatment. They found that the time to progression-free survival was better with the PSMA lutetium-based treatment. They found that the time to PSA progression was better in the PSMA-targeted treatment. It was a clean sweep pretty much every way they looked at it. They also looked at pain relief, and that was better.

The TheraP trial had a whole variety of end points that were positive for the PSMA617 lutetium-177, and that was in comparison with cabazitaxel, which is a known active agent. This has been published in The Lancet’s brand-new February 2021 publication. It was also presented at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] this year, so you can read about it as well as the article in The Lancet, which was led by Michael Hofman. Survival was too immature to evaluate. There were very few deaths, so it’s not sufficient to assess overall survival yet.

If you don’t mind, I’m going to talk briefly about the VISION trial, because that needs to be covered. VISION is a prospective randomized trial also in that post–abiraterone-enzalutamide, post-docetaxel setting, metastatic CRPC, selected on PSMA biomarkers. You had to be positive on PSMA to get into the trial. You were then randomized between the best standard of care and the best standard of care plus the PSMA617 lutetium-177. It was best standard of care without chemotherapy, so no cabazitaxel. The end point is actually 2 end points. There’s an rPFS [radiographic progression-free survival] and then there’s an OS [overall survival].

Everybody is aware of what happened with COVID-19 and the whole disaster we’ve all been living through. I’m a little concerned about radiographic images being obtained in a timely manner, so we may or may not get great rPFS data because they’re dependent on bone scans, CT scans, etc. On the other hand, the overall survival data will be pretty strong. We’re going to get a look at that in 2021. That important trial is going to report this year, but we don’t know exactly when. That could be pivotal for FDA approval.

Ulka N. Vaishampayan, MBBS: Yes. A lot of people are looking to get access to the PSMA lutetium treatments. The results of the VISION trial will be critical in determining if we can apply this therapy to the next patient we see with metastatic CRPC.

Clearly, the VISION trial had many more pretreated patients. Up to 2 prior chemotherapy regimens were allowed compared with TheraP, but TheraP is a smaller study. It doesn’t quite have the power to show overall survival benefit, unlike VISION, which was a large global trial in which overall survival was 1 of the main end points. I’m looking forward to getting those results.

Oliver Sartor, MD: I should mention that VISION enrolled over 800 patients and is appropriately powered for survival end point. It will be the first real shot on goal for a regulatory approvable trial. TheraP is a great trial, but it will not sway the regulators.

Ulka N. Vaishampayan, MBBS: Do you also want to comment on the toxicities of PSMA lutetium?

Oliver Sartor, MD: I do. I should have mentioned that in the TheraP trial and others. It appears as though the toxicity is quite low. Initially the concern with radiopharmaceuticals of course is you would suppress the bone marrow and have a cytopenia: thrombocytopenia, neutropenia, and the like. It turns out that those are actually quite rare. The cytopenias are basically nonexistent for the PSMA lutetium-177, which is great, but there is an off-target toxicity that can be in the salivary glands and also the lacrimal glands.

It turns out that these small molecules will bind to the salivary and the lacrimal glands, and you can get dry eyes and dry mouth. That is a relatively unusual adverse effect. Usually it’s not too bad, but in some cases, it can be quite bothersome. I have a couple of patients in my practice who constantly complain of dry mouth and are using dry candies and mints and things like that to try to lubricate the mouth. It can be bothersome in some patients. The other adverse effects, like the cytopenias, etc, are pretty minimal.

Ulka N. Vaishampayan, MBBS: I agree. It’s a very well-tolerated regimen in general.

This transcript was edited for clarity.

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