<p>Theranostics is becoming more deeply integrated into the management of advanced prostate cancer, but there are still new opportunities available to improve its application. A study presented at the recent <strong>2025 Society of Nuclear Medicine & Molecular Imaging (SNMMI) Annual Meeting</strong> assessed the efficacy of retreatment with ¹⁷⁷Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer.</p> <p><br></p> <p><em>Following this presentation, featured expert Oliver Sartor, MD, was interviewed by </em>Conference Reporter<em> Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Sartor on these findings are presented here.</em></p>

The PSMA-DC trial is ongoing and is currently recruiting. It is enrolling patients who have prostate-specific antigen (PSA) recurrence after definitive therapy to the prostate with treatments such as radical prostatectomy and radiation. A number of these patients have prostate-specific membrane antigen positron emission tomography (PSMA PET)–positive oligometastatic disease. For these individuals, it has become standard to treat those lesions with stereotactic body radiotherapy, and many men would like to avoid receiving hormone therapy at that time. In this trial, everyone will receive stereotactic body radiotherapy to nodal and bone metastases, and half will be randomized to receive ¹⁷⁷Lu-PSMA-617 as well. We will observe subsequent progression.

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When I first entered this field, I thought that if you use PSMA-targeted treatment, patients who have tumor growth afterward must have PSMA PET–negative disease. It turns out that only a minority of patients who progress have PSMA PET–negative disease, and the vast majority still have PSMA expression. Radiation resistance is the number one problem we face. As discussed in a study by Gokce Belge Bilgin, MD, and colleagues presented at the 2025 SNMMI Annual Meeting, retreatment may be an option for some patients (abstract 251923), and, in my experience, the better a patient responds to the initial treatment, the more likely they are going to respond to retreatment.

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There is a lot of heterogeneity in how dosimetry is used among different cancer centers and clinicians. Some want to perform dosimetry after every dose, while others prefer PET scans. Moving forward, I think that we need to see a consistent demonstration of value. Why are you doing the dosimetry? What does it add to your practice? What are you doing as a consequence of what you see? Those are very important questions.

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Louise Emmett, MD, FRACP, MBChB, has been working to create consistency and perform the measurements in a similar way across centers, evaluate the data objectively, and then prognosticate based on the PET scan. Being able to quantitate images is a bit of a problem because they are immensely complex data with hundreds of thousands of pixels. I think that, one day, we will use artificial intelligence to analyze the volume, heterogeneity, location, and mean standardized update value (SUVmean), and we are broaching that with the “one button push” data that were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. So, we are getting closer to automation, but we are not there yet.

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I am already looking at PSMA expression heterogeneity today when evaluating overall PSMA expression. If you take it to the extreme, you can use the 2 PET system that has been popularized with fluorodeoxyglucose (FDG) PET and PSMA PET. Then you can see if a lesion is hot on PSMA PET and negative on FDG PET or hot on FDG PET and absent on PSMA PET. That heterogeneity is a bad thing, and we know that those patients do poorly. However, without performing 2 PETs, you can still look to see if there is consistent, strong uptake or if there are some lesions with high uptake and others without high uptake, although we cannot quantitate as well as we would like. Right now, we would need to compare all the individual lesions, look at the average SUVmean, and then get some idea about their variability, such as a standard deviation or a standard error of the mean. The more variation you have on a high-uptake tumor, the worse it is going to be. If every single lesion has a high SUVmean, that is a great patient to treat. However, if you have a high SUVmean but you find 15 or 20 lesions that are actually low producing and another 15 or 20 lesions that are high producing, that patient is going to do less well.

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I think that we will be looking more and more at combination therapies. We have already seen combinations with PD-1 inhibitors such as pembrolizumab and ¹⁷⁷Lu-PSMA-617 and combinations with PARP inhibitors and ¹⁷⁷Lu-PSMA-617. Going forward, people will be exploring the use of radiosensitizers, and we will also see attempts for the upregulation of PSMA, now being explored with an HDAC inhibitor.