Andrew J. Armstrong, MD, MSc: When I think of prostate cancer in this metastatic setting, there are 2 flavors. There’s the AR [androgen receptor]-dependent version where PSMA [prostate-specific membrane antigen] is going to be highly expressed, PSA [prostate-specific antigen] is highly expressed, STEEP1, KLK2—these are lineage positive factors. Most prostate cancer, probably 70%, is going to be in that bucket.

But as treatment evolves and develops resistance over time, we see the loss of these lineage factors. Continuing to hammer at these lineage factors probably isn’t going to be very effective in many patients. We think that this is about 30% of men by the end of life. Making a difference for these men will largely involve targeting non–AR-dependent antigens. CD46 is a reasonable complement-dependent tumor factor. There have been other markers, such as DLL3. We see CEACAM5. There are other neuroendocrine markers, like CXCR2, and other neuropeptides that may be expressed that are involved in the signaling of these neuroendocrine cells that allow them to escape AR therapy.

You have to understand that some of these markers are expressed on normal tissues, such as neural tissues, or on immune cells. As you’re developing radioligand therapies or BiTEs [bispecific T-cell engagers] or CAR [chimeric antigen receptor] T-cell therapies, you have to understand that. That’s probably going to result in some of the dose-limiting toxicities and some of the off-target effects, or even on-target effects, but off-tumor effects. There’s going to be a careful drug development program using each of these radioligand therapies that are based on the overall net therapeutic index for these targets.

Oliver Sartor, MD: There are a wide variety of other targets and treatments. I mentioned the DNA repair enzymes. Those are involved with homologous recombination repair when mutated. We have the ability to use PARP inhibitors, where PARP inhibitors are potentially moving up in combination with the novel hormones. There are ongoing trials in that space. We have PSMA-targeted bispecific antibodies where we aren’t using a radioisotope. We’re using the immune system. These are CD3-PSMA bispecifics, in which we’ve seen some activity. We’ve seen activity in things like STEEP1-targeted agents and HK2-targeted agents. And then we have a whole variety of new targeted agents looking at things like mutated androgen receptors, very specific alterations, such as 875 and 878 mutations that may be associated with sensitivity to certain new drugs. There’s a lot going on in prostate cancer. I promise you, if you’re an investigator, you’re going to be busy for a long time to come.

Scott Tagawa, MD, MS, FACP: There are a lot of different therapies that look quite promising. I mentioned the AR pathway. This remains the dominant pathway, whether that’s with a PROTAC [proteolysis-targeting chimera] inhibitor or a drug that completely abrogates everything that’s downstream of cholesterol in terms of ligand formation, as well as inhibiting some bypass pathways, whether it’s PI3 kinase or AKT. You have to look at safety, but those are quite important. Or there’s glucocorticoid. I put them all in the AR pathway realm. Those are among the most important, because we’ve proven repeatedly that the AR pathway remains the dominant pathway.

That being said, there are a number of cell surface targets beyond PSMA that are quite important. Cell surface targets might be utilized for radionuclides that we have with PSMA, but also with drugs or new targeting, drugs such as antibody-drug conjugates or immune targeting moieties, such as bispecific [antibodies] or CAR T cells. Beyond PSMA, there’s STEEP1, PSCA, and DLL3 looks quite interesting, particularly for the neuroendocrine phenotype subset, which might be a nice match with PSMA. There’s KLK, which looks interesting. B7H3 looks quite interesting. There’s a long list of cell surface targets. As our technology has improved, the time is right for additional targeted radionuclides, antibody-drug conjugates, or small molecule toxins, as well as looking to utilize the immune system in bispecifics or CAR T cells.

Transcript edited for clarity.