<p>Building on the success of currently available prostate-specific membrane antigen (PSMA)–targeted therapies for prostate cancer, novel strategies and alternative radionuclides are under development with the aim of continuing to improve these therapies. At the recent <strong>2025 Society of Nuclear Medicine & Molecular Imaging (SNMMI) Annual Meeting</strong>, several presentations discussed studies focused on these areas.</p> <p><br></p> <p><em>Following these presentations, featured expert Delphine L. Chen, MD, was interviewed by </em>Conference Reporter<em> Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Chen on these findings are presented here.</em></p>

One novel strategy with PSMA-targeted therapy is moving treatment with ¹⁷⁷Lu-PSMA-617 to earlier stages of disease. The phase 3 PSMAfore trial is probably the largest source of data that we have so far on this approach. The results of PSMAfore show that upfront ¹⁷⁷Lu-PSMA-617 therapy improves progression-free survival, but its impact on overall survival seems to be smaller. While some patients do better with chemotherapy than with ¹⁷⁷Lu-PSMA-617, that seems to occur in the minority of patients; the majority of patients seem to prefer receiving ¹⁷⁷Lu-PSMA-617 to chemotherapy. It is encouraging to see that there is a benefit with upfront ¹⁷⁷Lu-PSMA-617 for patients who want to put off potentially more toxic therapies that could have a larger negative impact on their quality of life.

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Other novel strategies for PSMA-targeted therapies to improve outcomes when PSMA uptake is lower are being evaluated in the phase 2 LPS-Boost study, which is testing the efficacy of an alternative dosing strategy to deliver increased radiation to tumor sites, and the phase 2 VALOR study, which is testing HDAC inhibition to increase PSMA expression in patients with PSMA-low tumors. During my talk on radiopharmaceutical therapy trials at the 2025 SNMMI Annual Meeting, I reviewed these and several other phase 2 trials.

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There is a potential role for Auger-emitting radiopharmaceuticals, which I think do better with targets that bring them close to the nucleus. A presentation by James Patrick Buteau, MD, FRACP, FRCPC, at this year’s SNMMI meeting was focused on the first-in-human results of ¹⁶¹Tb-PSMA-I&T in patients with metastatic castration-resistant prostate cancer (abstract 251535). I think that the theory and physics behind this type of radionuclide could cover what is needed to kill cancer cells effectively. If its Auger electrons do not quite get to the nucleus, it still emits beta particles that travel further and, potentially, can reach the nucleus. I think that the way we can take advantage of radiation physics for treatment is to improve how we target the delivery of isotopes. Beta emitters are targeted in a way that optimizes the higher energy emission. The additional Auger emissions are just an added benefit, as the drug is not specifically designed to target Auger electron delivery to the nucleus.

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During my presentation at the 2025 SNMMI Annual Meeting, I also discussed data on ⁶⁴Cu-SAR-bisPSMA and ⁶⁷Cu-SAR-bisPSMA. These therapies have 2 different PSMA-binding motifs, so they have the potential to bind different parts of PSMA and can lead to a higher level of uptake. ⁶⁴Cu-SAR-bisPSMA has a half-life of 12.7 hours, so it has the potential to be used with positron emission tomography (PET) imaging. If you perform imaging later, and if ⁶⁴Cu-SAR-bisPSMA binds with a very long retention time with PSMA, you have a better chance of seeing uptake in smaller lesions, lesions with slower kinetics, and, potentially, lesions with lower PSMA expression. The benefit of using a longer-lived PET isotope is that it may allow for longer imaging intervals, providing improved data to calculate tumor retention and dosimetry. Clinically, I am not sure whether that is practical because most PET centers want to image 1 hour after injection. However, if dosimetry becomes more established, you could adjust the clinical workflow to address this issue.

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In general, retreatment protocols have been used for many drugs. So, if a patient has a prolonged response to any prior drug and if they are running out of treatment options, oncologists will consider retreatment. In general, however, most patients typically will not have the same level of response with retreatment as they did with their initial treatment. A presentation by Gokce Belge Bilgin, MD, at this year’s SNMMI meeting discussed the outcomes of retreatment with ¹⁷⁷Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer and reported that patients still derived benefit from retreatment (abstract 251923).

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It is important to consider what the definition of retreatment is. Usually, ¹⁷⁷Lu-PSMA-617 is administered in 6 cycles. The definition of retreatment usually includes people whose therapy was paused during the initial treatment with ¹⁷⁷Lu-PSMA-617 but then their prostate-specific antigen levels rose, so they were dosed again. In some patients, this might take a few months, while, in others, it may take longer. And so, that could also be somewhat of an open question for which the approach is not yet defined.