PSMA-Targeted Radioligand Therapy in Advanced Prostate Cancer

Scott T. Tagawa, MD, MS, FACP: What is coming next, and what I am hoping for, is worldwide availability [of lutetium-177–PSMA-617] other than just in United States. I hope that [we see more FDA (US Food and Drug Administration) activity this year], now that this drug has breakthrough designation. Initially, I expect on-label use to involve prior use of at least 1 AR [androgen receptor] inhibitor and at least 1 taxane chemotherapy. I think that will be the initial period of time with ramp up. Even though I have been using this type of therapy since 2007, other people have never used it. This is a multidisciplinary type of an approach by nature, which is important to note.

The VISION trial was a combination study; there was not a specific combination [therapy], but most patients did get a combination with hormonal agents, which I think made the drug work better. A hormonal agent—especially one that is effective—may lead to an increase in PSMA [prostate-specific membrane antigen] expression, at least initially, and may lead to increased radiosensitization. The [lutetium-177–PSMA-617] may work a little bit better in that setting. It certainly was part of the VISION trial. I expect that to be allowed postapproval.

The next steps are to move this drug and similar drugs to earlier stages in the metastatic CRPC (castrate-resistant prostate cancer) setting. There are three phase 3 studies that have started or are about to start. There are probably more coming. Those are either head-to-head [comparisons] or [trials of] combinations with AR-pathway inhibitors. AFT-53, or the PSMA VISION study, is a phase 3 trial that is looking at the metastatic non-castrate (ie, castration- or hormone-sensitive) setting. Treatment is ADT (androgen deprivation therapy) plus an AR-pathway inhibitor with or without lutetium-177–PSMA-617, initially with crossover at progression for those who did not get it. The primary end point is progression-free survival. [It] has now launched worldwide, and it is coming to the United States soon.

I think moving earlier is interesting there. There has been a lutetium-177–PSMA-617 concurrent combination with chemotherapy; that was only 1 small safety study, but an overall regimen including docetaxel is also being looked at in a randomized phase 2 study in Australia. There is a similar patient population to the PSMA VISION study—that study with ADT, docetaxel, and then, in the control arm and sequentially in the investigational arm, lutetium-177–PSMA-617. Both included chemotherapy as well as pure hormonal therapy. We are looking at treating metastatic castration-sensitive or non-castrate disease in a randomized fashion as early as we can. Continuing to move forward, PSMA PET [positron emission tomography] clearly has a place in earlier lines of therapy. We can see micrometastatic disease not seen on prior types of imaging, although truly micrometastatic disease can evade a PSMA PET because of the volume issues. That might be a good group to undergo minimal PSMA-targeted radionuclide therapy.

Whether the small molecules are the right way to do it or whether betas are the way to do it, we do not know. I think that it is a natural place for alpha emitters, assuming that we can find an alpha emitter that we can administer safely. This is really where we need to move forward with this in a safe fashion, because these men potentially have an average of decades to live rather than just a few years. We really need to assess the safety.

I think there are other combinations that make sense. There are at least 3 trials that are looking at combinations with immune checkpoint inhibition. At least 1 of them is randomized. We have some safety studies in combination with PARP (poly [ADP-ribose] polymerase) inhibitors. So some DNA damage from the beta emission plus an inability to repair that with PARP inhibition makes sense. There are a number of other studies out there, mostly in earlier phases. We will see what pans out, but I think [that] because of the ubiquity of PSMA expression, that it is a good target. Even PSMA plus PSMA-targeted therapy may make sense when we use 2 different mechanisms. 

TRANSCRIPT EDITED FOR CLARITY