<p>The radiopharmaceutical therapy landscape for advanced prostate cancer is evolving. In the presentation by Delphine L. Chen, MD, at the <strong>2025 Society of Nuclear Medicine & Molecular Imaging (SNMMI) Annual Meeting</strong> titled “Ongoing Large Phase 2 Radiopharmaceutical Therapy Trials,” many of the trials that were discussed focused on actinium (Ac)-based radiopharmaceuticals.</p> <p><br></p> <p><em>Following this presentation, 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>

Ac-based radiopharmaceuticals are coming through the pipeline. One of the agents I discussed during my talk at the 2025 SNMMI Annual Meeting, ²²⁵Ac rosopatamab tetraxetan (formerly known as ²²⁵Ac-J591), was previously evaluated in a smaller phase 1 clinical trial before being evaluated in the ongoing phase 2 CONVERGE-01 trial in patients with prostate-specific membrane antigen (PSMA)–positive, castration-resistant prostate cancer. The ligand is an antibody, and I think that we need to wait and see how well it performs in terms of toxicities because antibodies may circulate longer in the blood than small molecules and peptides, potentially leading to more bone marrow toxicities.

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The CONVERGE-01 trial is also evaluating dosimetry. We need to gather additional dosimetry data for ²²⁵Ac rosopatamab tetraxetan, as we do not yet have data to support exactly how to use it or what its benefits are. I think that the application of dosimetry generally comes down to our needing to improve the quantification. To address this, the SNMMI, working with the Clinical Trials Network, started the Therapy Clinical Trials Network to try to improve the standardization of quantification for dosimetry across different sites.

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Based on the physics of alpha and beta particles, if a drug has an extracellular target and is internalized by the cell, alpha particles from ²²⁵Ac may be more effective than beta particles from ¹⁷⁷Lu because alpha particles deposit their energy very close to the nucleus, which should induce a higher rate of DNA strand breakage. Because of their longer travel length, beta particles may not break the DNA in as many places. This may be why we have seen responses with ²²⁵Ac-PSMA-617 in clinical trials when treatment was given after patients had progressed after receiving ¹⁷⁷Lu-PSMA-617. The advantage of beta particles is that, if the targeting ligand stays at the cell surface, you need energy to travel further to induce DNA strand breakage. And that may be why ¹⁷⁷Lu therapies have been quite effective for a number of patients. I think that what complicates the decision of whether alpha or beta particles are the best first choice for an individual patient is that there may be variations in the degree of cellular uptake based on the targeting ligand in each patient. There may also be variability in the biodistribution of the ligand to consider.

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During my presentation at this year’s SNMMI meeting, I also discussed retrospective data on ²²⁵Ac-PSMA-I&T and an ongoing trial of ²²⁵Ac-PSMA-I&T and olaparib in patients with metastatic castration-resistant prostate cancer. I think that the advantage of PSMA I&T is being able to use positron emission tomography (PET) to determine the dosimetry up front.

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Moreover, data are emerging showing that the kinetics of ⁶⁸Ga-PSMA-11 and ¹⁷⁷Lu-PSMA-617 are very different, and we see this clinically. ⁶⁸Ga-PSMA-11 is designed to be a PET tracer with very high uptake within 1 hour of injection. In comparison, if you image 4 hours after administering ¹⁷⁷Lu-PSMA-617, you will not see the same number of sites that you saw in the baseline PSMA PET. However, if you wait 24 hours or longer to image, you will start seeing those same sites because the kinetics and tumor retention differ. The potential advantage of using the exact same compound before and after imaging is that you can model the dosimetry using PET quantification up front and tailor the first dose, as opposed to waiting to give the first dose, calculating the dosimetry, and then using that to optimize the second dose. The open question is: Will that make a difference?

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I think that, in some patients, it may make a difference. Patients whose tumors have very high uptake could potentially use a higher dose, or you could potentially tailor the dose in those whose tumors have very low uptake. Even patients whose tumors have low uptake may respond really well to treatment if you model the tumor kinetics up front. Some of those individuals may have cancers that just do not hold onto the tracer, and that would potentially help you determine which patients with lower-level uptake could be worth treating vs not treating. I anticipate that this would be the benefit of performing upfront dosimetry.