Targeted therapy is an important part of the treatment armamentarium for prostate cancer but could be improved by optimizing patient selection and treatment regimens. Researchers at the 2024 Society of Nuclear Medicine & Molecular Imaging (SNMMI) Annual Meeting discussed ways of optimizing these treatments, incorporating their learnings from recent clinical trials.

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.

As discussed in a prostate-specific membrane antigen (PSMA) radioligand therapy tumor board session at the 2024 SNMMI Annual Meeting, there are currently a lot of incompletely answered questions regarding optimizing radioligand therapy. We have study data looking at radiographic progression-free survival in the patients who were enrolled in the VISION trial, with PSMA mean standardized uptake value (SUV_mean) divided into quartiles. The advantages of being treated with ¹⁷⁷Lu-PSMA-617 were the best among patients who had the most PSMA positron emission tomography (PET) uptake, which was the highest SUV_mean quartile. The least amount of radiographic progression-free survival benefit was seen in those in the lowest SUV_mean quartile.

While this might be considered an optimization strategy, you have to realize that patients in the VISION trial had very few other options. If you decide not to give ¹⁷⁷Lu-PSMA-617 because your patient does not have the best PSMA expression, you may have already run out of other options. In the ¹⁷⁷Lu-PSMA-617–treated patients from VISION, even the lowest quartile was better than the control group. So, again, there are a lot of questions remaining with regard to the degree of optimization and potential benefits that I think need to be considered in the context of the alternative therapies that might or might not be offered.

In Australia, the SUV cutoff on PSMA PET scans is typically a bit higher than it is in the United States, excluding patients from the lower SUVs as a whole and enriching the results for those who respond a little better. Patients with this higher SUV cutoff selection criteria who are treated in Australia often have a higher prostate-specific antigen response rate. But, in addition to just looking at PSMA PET, they are also looking at fluorodeoxyglucose (FDG) PET. FDG PET has the ability to detect lesions that the PSMA PET may miss, as discussed at the 2024 SNMMI Annual Meeting (abstract 241044).

Using a double PET strategy improves the probability that those you treat will respond. In the United States, however, we sometimes have difficulty getting 1 PET scan, much less 2. The way that we do it is to look at PSMA PET positivity and cross-sectional imaging with a computed tomography (CT) scan. Seeing a 2.5-cm liver lesion that is PSMA PET negative, for example, is strange and indicates that this may not be a good patient to treat. So, there are ways to optimize the selection of patients using the PSMA PET and FDG PET that are potentially appropriate.

Patients with a lower hemoglobin, higher alkaline phosphatase, or higher lactate dehydrogenase typically do not do as well with ¹⁷⁷Lu-PSMA-617 therapy. Further, those with liver lesions also have a tendency to do very poorly. Thus, by looking at the distribution of lesions and at traditional laboratory parameters, we can try to come up with predictive biomarkers.

The single best predictive biomarker that I have seen so far, other than the PSMA PET scan, was presented in an analysis of the TheraP trial at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, which looked at circulating tumor DNA (ctDNA) as a percentage of the circulating cell-free DNA, so it was basically the quantitation of ctDNA. Patients who had less than 2% of ctDNA did very well with ¹⁷⁷Lu-PSMA-617, and patients who had greater than 30% of ctDNA did very poorly. Patients who were in between had an in-between response. Interestingly, for cabazitaxel, the TheraP control arm, the percentage of ctDNA did not make much of a difference. Some data on ctDNA biomarkers embedded in the PSMAfore trial were also presented at ASCO 2024. So, this is a rapidly evolving area.

In the broader context, I always think about the use of ¹⁷⁷Lu-PSMA-617 relative to the other therapies in my armamentarium. If I have a patient with a BRCA2 mutation, I might want to go with a PARP inhibitor. If I have a microsatellite instability–high patient, I might want to use pembrolizumab. Chemotherapy is, of course, not the friendliest class of agents, but it nevertheless might be a good choice for patients with relatively low PSMA PET uptake. We do not have a one-size-fits-all option, and we really are trying to continue our learning.

There are a lot of legitimate potential combinations with ¹⁷⁷Lu-PSMA-617, including alpha particles such as actinium-225 and radium-223. I think that there is a lot of interest in this type of combination. In addition, when combining ¹⁷⁷Lu-PSMA-617 with hormonal therapies, patients may even do better because of improved disease control.