Andrew J. Armstrong, MD, MSc: Building on the VISION study’s success, there’s the great desire of patients to obtain a life-prolonging PSMA [prostate-specific membrane antigen]–targeted therapy for improved survival, a high quality of life, and having a chance at a durable remission but in earlier settings. For example, the PSMAfore study is nearly identical to the VISION study but in taxane-naïve patients, while the VISION study required prior docetaxel and cabazitaxel [Jevtana], moving the PSMA-617–lutetium-177 therapy in a randomized setting into this taxane-naïve setting.

The challenge with this trial is comparing it with a suitable control group. If a patient has mCRPC [metastatic castration-resistant prostate cancer] and they’ve progressed on either abiraterone [Zytiga] or enzalutamide [Xtandi] or another AR [androgen receptor] inhibitor, the standard of care for these patients isn’t another AR inhibitor. But in the community, many patients are still choosing to receive an AR inhibitor. It’s a community convention, but these aren’t life-prolonging therapies in the second-line setting.

The appropriate standard of care in this setting would be a taxane, such as docetaxel or cabazitaxel, if they’ve had docetaxel. In fact, PSMA-lutetium could be considered a standard of care for many of these patients themselves. The PSMAfore study is randomizing patients to PSMA-lutetium or a second AR inhibitor with crossover at progression. It offers patients an opportunity if that second AR inhibitor fails—it largely will fail—for PSMA-lutetium crossover. It’s a trial of early vs deferred PSMA-lutetium in all patients.

Likewise, there are trials moving PSMA-lutetium into the hormone-sensitive space where PSMA disease is less heterogeneous, there are fewer concerns about neuroendocrine differentiation, or there’s loss of PSMA expression. This is called the PSMAddition study. PSMAddition is moving this treatment into the metastatic hormone-sensitive setting where the standard of care is ADT [androgen deprivation therapy] plus an AR inhibitor, possibly triple therapy, and following that, patients would be randomized to 6 cycles of PSMA-lutetium for the control group.

There are other attempts to optimize therapy. Lutetium-177 is a beta emitter, which isn’t as strong of a radioligand therapy, as you could imagine. There are alpha emitters, such as radium itself, but there are many others, such as actinium, that are under study right now. The challenge is the toxicity; the decay of alpha particles to normal tissues; severe xerostomia, or dry mouth; and concerns over renal toxicity.

People are looking at combinations of beta and alpha emitters to take advantage of the fact that beta emitters can penetrate more deeply into tumor tissue. If you’re targeting bulky tumors, you may need a combination. People are also looking at other ligands and other tumor antigens where PSMA heterogeneity may be a limitation. There are attempts to study radioligand therapy against KLK2 or STEEP1 or neuroendocrine markers like CD46 or DLL3. As we learn some of the limitations of PSMA targeting and the emergence of PSMA-negative disease, we’ll need to rely on other radioligands that target other aspects of prostate cancer biology.

There are some other smaller phase 1 studies and other PSMA radioligand conjugates, with copper beta emitters or combining PSMA therapies with different combinations, such as PARP inhibitors, pembrolizumab [Keytruda], or SBRT [stereotactic body radiation therapy]. There are many innovative approaches trying to optimize therapy and improve durable remissions. For example, PSMA-lutetium is a beta emitter and is basically providing radiation and DNA damage. It makes sense to try to enhance and radio-sensitize tumors to that effect with a potent AR inhibitor, PARP, or chemotherapy, or try to take advantage of the inflammatory microenvironment that this creates with a PD-1 inhibitor. Some preliminary data suggest there may be some added benefits, but these are early phase 1/2 studies establishing dose toxicity and safety of this approach.

I’m looking forward to moving PSMA-targeted therapies earlier. We see in the VISION study that survival is notably improved, but it’s still incremental. We’re seeing only a few months of improvement in survival, and most patients are progressing within a year. That’s probably limited by the heterogeneity of PSMA expression on tumor cells. Just like with AR inhibitors and most of the approved agents, earlier use tends to result in greater improvements in survival.

I’m particularly excited about the hormone-sensitive disease setting, where PSMA itself is less heterogeneous. We have very effective therapies that can synergize with the radioligands, so I’m particularly excited about that. There are other approaches moving PSMA therapies into PET [positron emission tomography]–only positive disease settings where these approaches may not be standard of care.

I’m certainly excited about other ligands because you don’t want to put all your eggs in 1 basket. The PSMA basket is where most of the eggs are right now, but there are a lot of other ligands that emerge with this neuroendocrine disease variant. As we use AR inhibitors and PSMA-targeted therapies early, if we’re not curing the disease, even if we’re improving survival, the disease that emerges later will be more aggressive. There’s going to be clonal evolution and loss of PSMA, so it’s wise to invest in many of these other ligands. Even though these are early and it hasn’t moved into even phase 1 studies, there are a number of preclinical studies showing that a number of neuroendocrine markers may be amenable to radioligand therapies.

Transcript edited for clarity.