Prostate-specific membrane antigen (PSMA)–targeted radioligand therapies (RLTs) have improved outcomes for patients with prostate cancer; however, responses are still incomplete and heterogeneous. Biomarkers for treatment response and patient selection are under evaluation, and new PSMA-targeted radiopharmaceuticals are being evaluated. Several studies presented at the recent 2025 ASCO Annual Meeting discussed these and other topics relevant to PSMA-targeted RLT for prostate cancer.

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Following these presentations, featured expert Jeremie Calais, MD, PhD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Calais on these findings are presented here.

Recently, the US Food and Drug Administration (FDA) approved the expanded indication of ¹⁷⁷Lu-PSMA-617 to patients with PSMA-positive metastatic castration-resistant prostate cancer who were previously treated with ARPI therapy and not with chemotherapy based on the PSMAfore trial results. During ASCO 2025, Novartis announced that PSMAddition, a trial in PSMA-positive metastatic hormone-sensitive prostate cancer, reached its primary end point of radiographic progression-free survival. We may expect to have a new label expansion in a couple of years. Circulating tumor DNA in the PSMA-targeted RLT space was also one of the highlights discussed at this year’s ASCO meeting, with a low pretreatment circulating tumor DNA fraction found to predict a superior response to ¹⁷⁷Lu-PSMA-617.

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During my session at ASCO 2025, I discussed a whole-body PSMA positron emission tomography (PET) biomarker substudy of the ENZA-p trial that was also presented at the meeting by Louise Emmett, MD, FRACP, MBChB (abstract 5011). PET is a whole-body imaging modality, and you can contour each lesion to get an estimate of total tumor volume at the whole-body level. So, it tells you, quantitatively, the volume of the total tumor burden and the intensity of the PSMA expression, whether it is low expressing, high expressing, or heterogeneous. These parameters at the whole-body level are related to patient prognosis, but it is important to note that they must be interpreted differently depending on the disease stage. For example, the intensity of PSMA in early-stage, untreated disease is typically a sign of aggressiveness and is correlated with Gleason grade. In advanced late-stage disease, a lower intensity of standardized uptake value (SUV) means that PSMA expression is decreasing due to dedifferentiation, and it is a poor prognostic sign. Whole-body PSMA PET SUVmean was previously investigated in a post hoc analysis of the VISION trial. The higher the SUVmean, meaning the PSMA expression, usually the better the response because of increased treatment delivery to the target.

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The previously mentioned substudy presented by Dr Emmett and colleagues from ASCO 2025 evaluated PSMA PET SUVmean from the ENZA-p study, a randomized trial of enzalutamide monotherapy vs enzalutamide plus ¹⁷⁷Lu-PSMA-617 (abstract 5011). In the group receiving enzalutamide plus ¹⁷⁷Lu-PSMA-617, SUVmean was not significantly correlated with patient outcomes. Likely, cells with low PSMA expression were affected by enzalutamide, and cells with high PSMA expression were affected by ¹⁷⁷Lu-PSMA-617. So, when you combine both treatments, if you look at the SUVmean, you cannot really differentiate. That is why there was no good prognostic predictive value from SUVmean here, which I think is very interesting and different from what was seen with VISION. This means that SUVmean should be interpreted differently for each disease stage and treatment combination. In the group receiving enzalutamide monotherapy, patients with low-volume disease had better outcomes than those with high-volume disease, as usual. However, the combination may work so well that even the tumor volume does not seem to matter, as it was not associated with outcomes in the combination arm.

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I think that something very important to mention is cross talk between ARSIs and PSMA. PSMA can be upregulated by androgen deprivation. People speculate that you can improve PSMA PET sensitivity or ¹⁷⁷Lu-PSMA-617 efficacy if you give a patient an ARSI, and it will flare up, enabling you to see the region better or obtain more drug uptake. We recently did a study at the University of California, Los Angeles in which we pulled scans from 56 patients before and soon after the initiation of an ARSI. The flare effect was only seen in 25% of the patients, and the intensity was rarely above 30%. So, the improvement of outcomes when combining enzalutamide with PSMA is mostly coming from the additive effects of dual-targeting AR and PSMA, rather than through the ARSI increasing PSMA expression, upregulation, or synergistic effects.

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Another study that I discussed during my session at ASCO 2025, the VIOLET study, led by James Patrick Buteau, MD, FRCPC, and presented by Michael S. Hofman, MBBS, FRACP, evaluated the novel PSMA RLT radionuclide Terbium-161: ¹⁶¹Tb-PSMA-I&T (abstract 5010). Terbium-161 emits beta radiation and Auger electrons. Beta particles travel a few millimeters, and Auger electrons travel a few nanometers. With beta radiation, there is a crossfire effect, as it can reach surrounding cells. Beta radiation involves a lower homogeneous dose delivery, whereas Auger electron dose deposition is very concentrated around a very short path. So, to treat microscopic disease that cannot be seen on a PSMA PET scan, you can potentially treat it better with Auger electrons.