<p>Prostate-specific membrane antigen positron emission tomography (PSMA PET) has galvanized progress in the field, opening the door to new possibilities for the treatment of advanced prostate cancer. At the <strong>2025 Society of Nuclear Medicine & Molecular Imaging (SNMMI) Annual Meeting</strong>, a series of presentations provided an overview of the theranostic clinical trial landscape. Oliver Sartor, MD, discusses his presentation on highlighted trials during the session, “Overview of Theranostic Trial Landscape With Clinical Impact in the Near Future – Part 2.”</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>

Some of the clinical trials that we have been watching are now coming to fruition. At the 2025 SNMMI Annual Meeting, I was honored to give an overview of the key trials in prostate cancer theranostics, and I started my presentation with the phase 3 PSMAfore trial. This trial included patients with progressive metastatic castration-resistant prostate cancer (mCRPC). All of them had received ADT and an ARPI; however, these individuals were chemotherapy naive, as compared with the population in the previously published phase 3 VISION trial, upon which the 2022 US Food and Drug Administration (FDA) approval of ¹⁷⁷Lu-PSMA-617 (also known as lutetium Lu 177 vipivotide tetraxetan) for patients with mCRPC who were previously treated with taxane-based chemotherapy and ARPI therapy was based.

 

Patients in the PSMAfore trial were selected based on PSMA PET positivity, with metastatic lesion uptake greater than the liver, and the absence of exclusionary PSMA-negative lesions. Approximately 92% of the patients met the PSMA PET criteria. Patients were randomized to a hormonal therapy control group (ie, ARPI switch) or to the experimental arm (ie, ¹⁷⁷Lu-PSMA-617), and the primary end point was radiographic progression-free survival (rPFS). Individuals experiencing radiographic progression were eligible for crossover, and almost 80% of the patients did cross over, which must be considered when interpreting survival data. However, what was notable here was that the rPFS was roughly doubled. The median rPFS was 5.59 months in the ARPI switch group and 11.6 months in the ¹⁷⁷Lu-PSMA-617 group. So, clearly, it took longer to progress in the lutetium group. Other objective responses included prostate-specific antigen (PSA) response, with 51% of patients in the ¹⁷⁷Lu-PSMA-617 group having a confirmed PSA response vs 17% in the ARPI switch group. The safety with lutetium was good. As expected, there were reports of dry mouth and some gastrointestinal symptoms, but, overall, ¹⁷⁷Lu-PSMA-617 was tolerated quite well. Both groups of patients are living right around 2 years, but if you do a crossover-adjusted analysis, you see an improvement in survival in the lutetium arm, and I think that is a reasonable way to look at it.

 

The bottom line is that the findings from the PSMAfore trial led to the FDA approval of ¹⁷⁷Lu-PSMA-617 in March 2025 for patients with mCRPC in whom it is considered appropriate to delay taxane-based chemotherapy. So, people in the United States are now eligible to receive ¹⁷⁷Lu-PSMA-617 without having received prior chemotherapy, but they will have to progress on ADT and an ARPI, and they will need to have the right PSMA PET findings before treatment.

 

Another phase 3 trial, the PSMAddition study, was positive, according to a recent press release. We have not seen these data yet, but I thought that the press release was quite interesting. PSMAddition included people who have never received hormones before and are considered hormone sensitive. Some of these patients may have had de novo metastatic disease, while others could have been treated earlier in the development of metastatic disease, but they could not have had rapidly progressing tumors requiring chemotherapy. Typically, today, we give these patients an ARPI plus ADT (ie, standard treatment). In PSMAddition, patients were randomized to receive either ¹⁷⁷Lu-PSMA-617 plus standard treatment or the standard ARPI plus ADT, alone. According to the press release, investigators did find an improvement in rPFS and a trend in overall survival by adding lutetium. These are brand new data in metastatic hormone-sensitive prostate cancer, and we look forward to seeing those data at another future meeting.

 

Of course, there are many different approaches being considered in earlier-phase studies. For example, we can highlight that there are 2 basic ways to get more radiation into the tumor: you can inject more activity or you can cause the tumor to express more receptors. Both of these approaches are being worked on.

 

Higher doses will be explored in clinical trials of radiopharmaceuticals, and I think that those higher doses are likely to be more effective. The 23 Gray limit for a cumulative radiation dose to the kidneys that is seen in theranostic trials was initially derived from the external beam radiation therapy literature, and the applicability of this threshold to radiopharmaceuticals has been called into question. Adding to this is the observation that what most patients with mCRPC fear is not the toxicity to their kidneys 5 years later, but rather potentially fatal progression much sooner. For example, the median overall survival in the PSMAfore and VISION trials were only approximately 2 years and 15 months, respectively.

 

Another approach to get more radiation into the tumor is to increase the tumor’s target expression. There are some preclinical data suggesting that HDAC inhibitors may upregulate the PSMA, rendering the tumor susceptible to a higher absorbed dose with the same administered activity.

 

New targets are also an important part of the ongoing research. In particular, at the end of my presentation at this year’s SNMMI meeting, I noted an abstract presented by Capucine Baldini, MD, PhD, at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting showing promising early results with a bispecific antibody that targets KLK2 on tumor cells. This was potentially one of the most exciting findings at ASCO this year. It is a KLK2 x CD3 bispecific, so it binds the tumor cells that express the KLK2 and uses that binding to direct the T cells to become activated in that tumor microenvironment. That is an interesting concept.