New targeted therapies are the most promising option to improve the standard of care for advanced prostate cancer. At the 2024 Society of Nuclear Medicine & Molecular Imaging (SNMMI) Annual Meeting, experts presented data on targeted therapies.

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

One way to improve the standard of care for advanced castration-resistant prostate cancer is to identify newer targets and find newer ways of addressing these targets. Examples of newer targets include PROTACs that can target the ligand-binding domain of the AR gene. PROTACs are a novel group of compounds that basically aid in the degradation of proteins. Approximately 25% of patients with castration-resistant prostate cancer have AR ligand–binding mutations, and those mutations can drive prostate cancer growth. ARV-766 is an oral PROTAC AR degrader that targets at least 5 AR ligand–binding mutations and wild-type AR. It has a broader spectrum of activity than its parent compound ARV-110 and, in my opinion, is a better-tolerated drug.

At the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, we reported the safety data from all patients who were treated with ARV-766 and the subgroup of patients with AR ligand–binding domain mutations. We found that in those patients with AR ligand–binding mutations, 43% had at least a 50% prostate-specific antigen decline overall, and 30% had unconfirmed soft tissue responses. And it was a fairly well-tolerated drug. So, this is an interesting area to pursue. Other compounds are also looking at this approach. For example, MK-5684 (ODM-208) is an oral CYP11A1 inhibitor, and, according to recently presented phase 2 data, there may be more drug activity in patients with AR ligand–binding domain mutations. That looks very interesting.

PARP inhibitors are active in prostate cancer, and the real question is: How do you best use them? Should you be using them in the hormone-sensitive state? Should you be using them in the refractory space? The placement of therapy for PARP inhibitors will turn out to be important. The TALAPRO-3 trial is looking at that in hormone-sensitive disease. Combining a PARP inhibitor with an antiandrogen is a reasonable approach in patients who have not received previous antiandrogen therapy. However, many patients are getting an antiandrogen up front, which makes it a bit more difficult to determine where it should be used.

In terms of radioligand therapy (RLT), I go by the VISION criteria when identifying patients who may be candidates for therapy. I use these criteria because RLT is not yet approved by the US Food and Drug Administration (FDA) in another setting. ¹⁷⁷Lu-PSMA-617 is considered a targeted therapy, and, while it is not curative, it does help to improve survival and delay progression, which I think are important. As discussed in an abstract by Swiha and colleagues presented at the 2024 SNMMI Annual Meeting in a session titled “Prostate Cancer – Radiomics/Data Analysis,” some completely uncharted territory right now is using prostate-specific membrane antigen single-photon emission computed tomography (PSMA SPECT) or PSMA positron emission tomography to monitor responses after patients have been given RLT (abstract 242460). We are just starting to ask questions about their use. In my clinical practice, we do SPECT on the same day that we give PSMA.

During another session at the recent SNMMI meeting titled “Prostate Cancer: Focus on Imaging,” Zamanian et al provided insights from the 3TMPO study, presenting an abstract discussing the existence of the tumor sink effect in patients with metastatic castration-resistant prostate cancer (abstract 241300). Right now, we adjust the dose of RLT based on the patient’s creatinine clearance, but not on their specific tumor. In the future, the dose may be more individualized based on additional data.

An update of the PSMAfore trial was also presented in an abstract during the session titled “Prostate Cancer – Focus on Therapy” at the 2024 SNMMI Annual Meeting (abstract 241064). This trial is looking to show if there is an improvement in progression-free survival in favor of PSMA, and I think that is reasonable. However, the problem is that we are not seeing an overall survival benefit. That is, in part, due to the amount of patient crossover in the study, which may confound the results.