Radioligand therapy is an important part of the treatment landscape for metastatic castration-resistant prostate cancer. At the 2024 Society of Nuclear Medicine & Molecular Imaging (SNMMI) Annual Meeting, clinical trial data on radioligand therapies and post-treatment imaging were presented.

Following these proceedings, featured expert Oliver Sartor, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Sartor’s clinical perspectives on these findings are presented here.

I presented data from the PSMAfore study at the 2024 SNMMI Annual Meeting, and we were awarded the SNMMI Henry N. Wagner, Jr., Abstract of the Year (abstract 241064). PSMAfore looked at the taxane-naive setting in metastatic castration-resistant prostate cancer, which is unlike the VISION trial, where you had to have a taxane. There is a whole series of prostate-specific membrane antigen (PSMA) lutetium (Lu) trials. The SPLASH and ECLIPSE studies are similar to PSMAfore, but neither has been presented in public, although a press release on the SPLASH trial was published last year.

The energy level of beta particles is important because you need a certain density of the particles to crisscross the tumor to cause crossfire. The high-energy particles go the furthest. Yttrium is a high-energy beta, Lu is a fairly low-energy beta, and copper-67 is a low-energy beta. An optimal size for something like Lu might be approximately 2 mm. You may have enough energy deposition within 1 mm to be able to damage those tumors, whereas, if something is 4 mm away, you do not get enough energy. Paradoxically, if it is 0.1 mm in size, you also may not get enough energy because most of the energy is extended beyond the tumor itself, and the distribution of energy is reasonably constant over the path length.

Alpha particles are very different and, from a theoretical perspective, do not need the same degree of crossfire. First of all, the distribution of energy is only over 40 to 80 µm, and it is not linear; rather, it is somewhat packed toward the end. Because of the very short path length, you might be able to get much smaller tumors. A 0.1-mm tumor may be fine to treat with an alpha particle because the energy is deposited within such a short range of the particle.

In abstract 242599 from the 2024 SNMMI Annual Meeting, Prasad et al showed that single-photon emission computed tomography (SPECT) scans can be performed after using ¹⁷⁷Lu isotopes. With SPECT, you can administer the therapy to the patient and then image later that same day (or the next day) and see the lesions, although not with the sensitivity of a positron emission tomography (PET) scan. After you have given the patient a few doses of therapy, you might be able to determine whether the lesions are getting bigger or smaller. You can see if there is a lot of uptake after the third dose vs after the first and second doses, or vice versa. So, you can get a substantial amount of information from the SPECT scan. I think that it will be possible to perform same-day SPECT, but you get a lot of background activity, as discussed in the abstract by Swiha and colleagues from the SNMMI meeting (abstract 242460). The best images will be captured after the agent has had a chance to wash out from nonspecific binding and vasculature. However, it is not clear if we really need optimal imaging or if we can get by with less optimal imaging, which is more convenient for the patient.

Post-treatment PET scanning is evolutionary. There are some proposals for what represents a response in progression, but they are not widely accepted. For example, the RECIP 1.0 framework looks at PET scans to measure response to progression. While these proposals provide some fairly good data, they do not provide the complete data that you would hope for before strongly adopting something in clinical practice.

My feeling at this point is that the adaptive dosing of radioligand therapy is appropriate for some patients. If a patient does not have a target, they would probably experience little benefit from treatment. So, if a PET scan is performed and nothing is seen on the scan, a reasonable assumption is that the targeted therapy is not going to go to what the PET scan cannot see. Right now, we use a total of 6 doses of radioligand therapy in the United States, and you probably want to use those doses when they are going to have the best effect. If a person has a great response, providing more treatment at that particular time may not add much benefit. You may want to pause and then treat again when there is evidence of progression.

Adaptive dosing is evolving, but we do not have as much solid data as we would prefer, and there are still some unanswered questions. For example, I am not certain of how insurance is going to manage long pauses. A doctor said to me, “I’m willing to pause, but I have an authorization to give 6 doses every 6 weeks. If I deviate from that, will my patient’s insurance withdraw its authorization?” I do not know the answer to this question, and I think that we will have to work through these issues one at a time.