Scott T. Tagawa, MD, FACP, shares his thoughts on remaining questions for imaging and PSMA-targeted therapy for mCRPC.
Scott T. Tagawa, MD, FACP: There are a number of different questions that remain for PSMA [prostate-specific membrane antigen]-targeted radionuclide therapy in general, but I’ll narrow it to lutetium-PSMA-617, which probably applies to the other lutetium-PSMA–targeted small molecules. One is patient selection. I may argue that in someone who’s received every known therapy, who doesn’t have a clinical trial available or other therapies available, and has good performance status, that maybe I don’t need a PSMA-PET [positron emission tomography] to treat them, in part because 95% of patients in the VISION study had a positive PET, at least defined by at least 1 lesion lit up brighter than liver. Even with discrepancies that are another small group, an overall patient population would probably still benefit. That’s one question in my mind.
There are a lot of other questions that are in the setting of choices. There are now 4 phase 3 trials that I know of looking at lutetium-PSMA–targeted beta in early lines of therapy: 3 in chemotherapy-naive metastatic CRPC [castration-resistant prostate cancer], and 1 in conjunction with AR [androgen receptor] pathway inhibitors and ADT [androgen deprivation therapy] for noncastrates, ie, castration-sensitive hormone-sensitive metastatic disease. So earlier lines of therapy make sense. There‘s less likely to be PSMA-negative disease. As I mentioned in one of the first segments of this, those who are more heavily pretreated with AR-targeted therapy are more likely to lose AR pathway and PSMA. It’s less likely in those earlier disease settings. Radiation resistance pathways or alterations such as TP53 are less likely in earlier lines of therapy. They’re more likely to benefit from an agent such as lutetium-PSMA-617. Does this work in earlier lines of therapy? We don’t know, but we’ll test those.
The other major part is combinations; we certainly are already testing these with-AR targeted therapy. In the VISION trial, a big proportion of the patients received AR-targeted therapy as standard of care and had lutetium-PSMA-617 added to that. But other types of therapy warrant additional study. We have some safety data and early efficacy data in combination with immune checkpoint inhibitors and PARP inhibitors. There’s at least 1 trial with concurrent lutetium-PSMA antibody and concurrent docetaxel. Those all make sense to me, besides assessing different lines of therapy. And then going back to one of the things I started with, in terms of patient selection, it’s not just imaging. Imaging is one thing. There’s the theragnostic paradigm: see what you treat. It makes sense; is the target there? But there are factors that are beyond that, including patient factors as well as likely tumor factors, such as genomics, that may play a role.
Transcript Edited for Clarity