Dr. Tagawa discusses PSMA-targeted radionuclide therapy in men with mCRPC

For heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC), researchers continue to investigate treatment options that are both safe and efficacious.

At the recent 2021 Society of Urologic Oncology Annual Meeting, Scott. T. Tagawa, MD, MS, FACP, and co-authors presented favorable outcomes of a study evaluating dose-intense prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy in men with PSMA-unselected, pretreated mCRPC.1 Tagawa is a professor of medicine and urology and medical director of the Genitourinary Oncology Research Program at Weill Cornell Medicine in New York City. He is also an attending physician on the Weill Cornell campus at NewYork-Presbyterian Hospital.

Please discuss the background for this study.

We looked at the effect of pretreatment imaging with PSMA PET vs outcome in those that were getting treated with what we'd call a 'dose intense PSMA-targeted radionuclide regimen.' So, these are patients with metastatic castration-resistant prostate cancer. There's been a vast majority of retrospective, prospective, and now randomized prospective, clinical trials examining different types of PSMA-targeted radionuclide therapy. Almost all of them had some sort of selection for PSMA imaging, but PSMA imaging has never truly been shown to be a predictive biomarker for this type of therapy. In our prior version of studies with lutetium radiolabeled antibody J591, which have been published over the last couple of decades, those that had poor baseline imaging had a chance of responding, but a lower chance. What we looked at now was the use of PSMA PET imaging, which was not available during the prior era of our radiolabeled antibody, with a more dose-intense type of regimen. [They were either given] lutetium PSMA 617, which is a small molecule with lutetium given at a higher radioactivity dose over [a] short course of a dose-intense regimen on day 1 and day 15, [so] 2 weeks apart of a single cycle, or [they were given] the antibody radiolabeled with an alpha emitter [called] actinium-225. Then we looked at baseline PSMA PET imaging. About 50 patients received lutetium PSMA 617 [and] 32 [received] actinium J591. About two thirds had prior chemotherapy—a typical pretreated patient population.

What were some of the notable findings? Were any of them surprising to you or your co-authors?

The outcome of the analysis was that for PSA response as well as progression-free survival, which is driven by PSA, a baseline PSMA PET was associated with outcome, including in both the univariate as well as our multivariable analysis controlling for prognostic factors, such as the Halabi nomogram [and] the radioactivity dose because some of these were phase 1 dose escalation trials. The baseline PSMA PET was not associated with overall survival, [though] the clinical variables as validated in other studies were. Overall, my take is that even with an intense PSMA-targeted radionuclide regimen, I think the chance of a response is higher, at least by PSA, with stronger baseline PSMA imaging. However, about 20% or so of those that we treated wouldn't have qualified for some of the studies, such as the TheraP study, which required at least 1 lesion with a [standardized uptake value, or SUV,] of greater than 20. We had about 1 in 5 that didn't meet [those] criteria. In the smaller percentage, in the low teens, their hottest lesions were either lower than or barely equal to liver, and we ignored any negative lesions. Particularly using an antibody approach with the alpha radionuclide, we saw patients [who] had what people would call 'poor,' or sometimes people would call a 'negative' PSMA imaging [would] still have a response. So, I think we would optimize the patient population for response to PSMA-targeted radionuclide therapy by using PSMA PET; however, we cannot exclude all of those who might benefit, particularly using an antibody with an alpha.

Is further research on this topic planned, and if so, what will its focus be?

We are continuing to, in early-phase clinical trials, treat all comers and analyze PSMA imaging as 1 of the biomarkers. I think it depends on the patient population. [If] there's not much else left, I think it’s justifiable, as well as when we use combinations because the PSMA PET is a moment in time. So, it's nice because we get to look at a lesion-by-lesion analysis. But it's really a moment in time, and if we're doing something such as giving an AR-targeted therapy that might change PSMA expression, then what are we really treating? We will continue to explore that. In the larger studies, such as the VISION study,2 which is a large phase 3 trial, there are not a lot of biomarkers that were prospectively collected. However, there is baseline PSMA PET both in those that got treated with lutetium PSMA 617 as well as those that did not. Even though all [who] were enrolled had to have some positivity within that range, we'll be able to look at both prognostic as well as predictive ability.

What is the take-home message for the practicing urologist?

For a patient population with late-stage, heavily pretreated metastatic castration-resistant prostate cancer, we're expecting lutetium PSMA 617 to be approved sometime in 2022. If approved, we don't know what the label will be, such as a requirement for 'positive' PSMA PET imaging. That being said, it's comforting to know that the vast majority of patients will meet criteria for that, and therefore hopefully be able to receive that type of therapy.

Is there anything else you feel our audience should know about the research?

It's a brand-new world. Even though we in New York have been studying this for almost 2 decades, it remains to be seen if it's going to become part of the standard of care in terms of approval. And there's many different directions that we're going with that. Besides looking at imaging biomarkers, there's other patient selection biomarkers such as genomics that will come into play. As important or more importantly, are earlier patient populations. I don't think that the patient population that is going to have the biggest benefit is going to be those that have received a lot of prior treatment, have bulky disease, and [have] resistance mechanisms, such as P53. [So, we're going to be] moving forward to early lines of therapy, and I also don't think that we're going to be able to cure patients with a single modality. But by using combinations, can we cure some patients? Or, if not, can we [at least] have a much longer progression-free survival period?

References

1. Tagawa ST, Sun M, Thomas C, et al. PSMA imaging and outcome following dose-intense PSMA-targeted radionuclide therapy in men with PSMA-unselected, pre-treated, metastatic castration-resistant prostate cancer. Paper presented at: 2021 Society of Urologic Oncology Annual Meeting; December 1-3, 2021; Orlando, Florida. Poster #97

2. Sartor O, de Bono J, Chi KM, 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