ESMO 2023: Thoughts on ENZA-p Study

By Michael Morris, MD, Tanya Dorff, MD, Evan Yu, MD, Rana McKay, MD - Last Updated: November 16, 2023

A roundtable discussion, moderated by Michael Morris, MD, discussed the current landscape of radioligand therapy in prostate cancer, including recent trial highlights presented at ESMO 2023. Dr. Morris was joined by Tanya Dorff, MD; Evan Yu, MD; and Rana McKay, MD.

In the next segment of the roundtable series, the panel discussed the “innovative design” of the phase 2 ENZA-p study presented at ESMO 2023, which assessed different dosing schedules based on PSMA PET scans.

Watch the next segment in this series.

Dr. Morris: Let’s move on to ENZA-p. This was an interesting study. ENZA-p was a randomization, it was a phase 2 study, between enzalutamide or enzalutamide and lutetium. Evan, do you want to just give the audience a little bit of background on what the rationale for that combination would be?

Dr. Yu: Yeah, I mean you alluded a little bit to it earlier. There is some data that shows that, when you apply androgen deprivation or an AR [androgen receptor] pathway inhibitor, that you can get transient upregulation of PSMA expression. Now the exact timing of that, how sustainable that is, I think that some of that still has to be worked out. I think we know that it’s not permanently sustained because ultimately over time, if we give an ARPI [androgen receptor pathway inhibition] and it works, you’ll actually see a decrease of PSMA expression. But it does lend to some theory that if you time things correctly, which we’re still trying to figure out that timing, that if you give an ARPI like enzalutamide, that that might transiently increase PSMA expression, you might get more bang for your buck. This is always the question in oncology is that we give therapy and we usually keep giving therapy as long as we think it’s efficacious, as long as it’s not too toxic. But 1 question that I think is yet unanswered is for most therapies, are you getting most of your cell kill right upfront? Or do you really need to sustain the therapy?

Of course, there’s maintenance therapy in other cancers, etc., but that being said and done, the suspicion is that if you’re going to get cell kill apoptosis, that you’re probably getting your most right upfront. This that first dose, timed correctly with your ARPI, may actually have much more potent efficacy. I think that’s not just applicable to this study. It may be applicable to earlier-stage studies like PSMA in addition where you’re giving it for metastatic hormone-sensitive prostate cancer and giving it right upfront.

I do like this study and the fact that they had an adaptive design, they didn’t just blast ahead with tons of lutetium PSMA 617. They gave 2 doses and the rest was adaptive based on whether you still had PSMA PET expression or not. Because from my point of view, if someone’s PSMA PET is cold, I probably don’t want to keep blasting them with more.

Dr. Morris: Let’s just go into that a little bit for the audience’s benefit who weren’t at the presentation. As Evan alluded to, they got 2 doses, and then they got a repeat PSMA PET, and if their PSMA PET suggested that there is no further PSMA avid disease, then they stopped treatment. That was the stop of their on-study treatment. They could still get an additional 2 doses after protocol-dictated treatment. If they did have residual disease, then they continued on with another 2 doses of treatment. That’s a very innovative design, and I think that it’s something to really think about that’s different than how we usually dose treatment. Tanya, what are your thoughts on that?

Dr. Dorff: Yeah, I think that’s something that definitely needs to be explored. It makes a lot of sense. To Evan’s points about the optimal use of AR antagonism to upregulate PSMA, I think it would be really interesting since VISION had patients on ARSIs, and you do that in your practice, and in PSMAfore, they were not. Really giving the lutetium PSMA 617 with or without the AR pathway inhibitors seems like another area of exploration with some adaptive designing in terms of when and how long. I think this raises a lot of interesting questions, this study.

Dr. Morris: The tricky thing about those designs is that you lose your rPFS [radiographic progression-free survival] endpoint. Because you’re anticipating that when you stop therapy, that the patient will progress and then they’ll give more treatment. It doesn’t represent a traditional treatment failure. It simply indicates a need to retreat. Some of the endpoints of our trials, we’re going to need to really think about what we consider as well-qualified interim endpoints, because they no longer would indicate quite the same, “Okay, this is the end of this treatment; you’re done, you’re going to move on to the next thing,” but rather a planned, predictable expected event that’s going to trigger re-treatment, much as we would do intermittent hormonal therapy. Rana, you work in Alliance designing a lot of prostate cancer clinical trials. What do you think? How will this confound the landscape for you?

Dr. McKay: I think it’s a question that I think we desperately need to explore, because I think what we’ve seen across the board is that patients’ outcomes to lutetium PSMA are very heterogeneous, actually. There are some patients that have profound early PSA [prostate-specific antigen] responses, their PSAs drop dramatically. Then I think we’re really asking ourselves, what are we doing with continued therapy when their disease is actually being appropriately treated? The converse, there are individuals that are having a rapid rise in their PSA, they’re not experiencing that PSA 50 early on, and may actually be better served with switching over to chemotherapy.

Having trials where we adapt therapy based off of what an individual’s initial response are that are very pragmatic and take into account the changes that we’re seeing in the clinic, I think are really important. These are the types of trials that the Cooperative Groups are really poised to answer—treatment dosing, intermittent dosing, trials that may never happen otherwise. I think they’re critically important. The intermittent dosing question is even more relevant in the hormone-sensitive setting, where the majority of patients are having a dramatic response upfront, even from their ARSI and ADT [androgen deprivation therapy]. I think it’s something that we absolutely need to investigate.

Dr. Morris: We should be cautious in interpreting these data. If we recall TheraP, which was a randomized trial of lutetium versus cabazitaxel also looked like, in the interim endpoint realm in terms of PSA 50 and rPFS, looked like it was going to be in favor of lutetium, but then when the overall survival data came out, the 2 were looking pretty similar, at least based on a secondary endpoint of a phase 2 study. I think the same cautionary tale might be told of ENZA-p, that the primary endpoint was biochemical failure-free survival. We have to be careful not to over interpret that as indicating a meaningful clinical benefit, but it is a provocative design. The science seems to be really good because all of us have really looked at this question of how to upregulate PSMA in light of having now many families of PSMA-directed therapies under study, right? There’s bispecific antibodies, CAR [chimeric antigen receptor]-Ts, there’s ADCs [antibody-drug conjugates] that are PSMA-directed, and you think of the potential combinations that could boost treatment effects in clinical trials of all of these; it raises an exciting realm of possibilities.

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