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 discusses results of the phase 3 PSMAfore study presented at ESMO 2023, which showed a clinically meaningful and statistically significant benefit in radiographic progression-free survival in patients receiving lutetium PSMA 617.
Dr. Morris: Let’s move on to some of the newer data. There were 2 very important presentations at ESMO. One was done by Oliver Sartor, MD, and that was the PSMAfore study. The other was a randomized phase 2 study that Dr. Louise Emmett presented. Let’s start with PSMAfore, and then we’ll make our way to the ENZA-p study. PSMAfore was a randomized phase 3 trial for patients who had been on 1 ARSI [androgen receptor signaling inhibitor], and then for the trial, they were either randomized to the alternative ARSI that they had not been on. For example, abiraterone to enzalutamide, or enzalutamide to abiraterone, or apalutamide or darolutamide. The other arm was given a standard dose and 6 cycles of lutetium.
The trial showed that there was a hazard ratio in favor of lutetium of around 0.4. This was, excuse me, 0.41, 0.43 depending on when you looked at it. The primary endpoint was rPFS [radiographic progression-free survival] by standard Prostate Cancer Working Group 3 criteria. It was a study with a very aggressive crossover rate: 84% of the patients who progressed on the ARSI arm went on to receive Pluvicto, and overall survival had a hazard ratio of 1.16, and it’s pretty early. Only 45% of the anticipated survival events have now happened. That’s a summary of the trial. Rana, what were your takeaways from that?
Dr. McKay: I think this was a really important trial to have for the field because I think it provides data that lutetium 617, PSMA 617, works both prior to chemotherapy and after chemotherapy. We know from VISION this is a life-prolonging therapy, and I think this data provide rationale that yes, it can work prior to chemotherapy; yes, it can work post-chemotherapy. I don’t think it tells us what the right sequence is, but it gives us reassurance of its activity in the pre-chemotherapy setting. I think because of that, my hope is that it will actually improve access, hopefully in the future depending on what is determined by the FDA, because there may be some patients that we all see in the clinic that are not chemotherapy-eligible, they may never be chemotherapy-eligible, and then to restrict their ability to get life-prolonging radioligand therapy is also a limitation. I think the data hopefully will be practice-changing and provide lutetium earlier on for patients.
Dr. Morris: I think 1 of the striking things about the data was the difference in the treatment discontinuation rate, because the toxicity profile was much more favorable in favor of lutetium as opposed to an ARSI. Particularly in such domains such as fatigue, the ARSI really was more fatiguing, but other domains as well. What does that say to you, Evan, in terms of using… still about 40% of people are switching to another ARSI. How do the Pluvicto data, Evan, do you think speak to that ongoing practice presuming that Pluvicto is made available to this patient population from a regulatory standpoint?
Dr. Yu: Well, first I’m going to address the point that you’re saying that there were more grade 3/4 adverse events with ARSI than there were with lutetium 617 PSMA. I have some interesting thoughts about that, that when you look at the grade 3/4 adverse events, many of the grade 3/4 adverse events were more subjective grade 3/4 adverse events. We have a trial like this and you have the interesting patient demand out there that wants to crossover, I do wonder how significant those grade 3/4 adverse events really were, because it’s very easy to say, “I’m fatigued; let me crossover now.” That’s the first thing I’m going to throw out there in a trial.
Dr. Morris: Can I just address that?
Dr. Yu: Yeah.
Dr. Morris: The crossover was only permitted if you met Prostate Cancer Working Group 3 radiographic criteria, not for treatment discontinuation. If they were complaining of adverse events, and there was no radiographic, if they didn’t meet 2 plus 2 or have a RECIST-defined soft-tissue progression, they could not cross over.
Dr. Yu: That’s an excellent point. That said, I do think that there’s a reason why there’s blinding in studies. There still is a psychological component that I’m not getting what I wanted to get, and so I think it does affect adverse event reporting. Of course, there are ways for people to still get off-label treatment off of a trial, etc., and go to other countries, etc. It probably was a small effect, so thanks for pointing that out, but I still wonder whether there was an effect of that, because there is subjectivity to adverse event reporting.
That said, I do think that ARSIs can cause toxicities like fatigue. I don’t think it changes my stance on ARSI switch because I think it’s never been my preferred approach, but I do think we have to recognize that it is probably 1 of the most common approaches that’s done out there, and we also have to respect the fact that everything we do is doctor-patient shared decision-making. For a patient that’s been on an ARSI for a long time, to escalate care to something else, whether it’s chemotherapy, whether it’s radioligand therapy, that’s a potential life-changing event. To that patient, sometimes they prefer to just take another pill that’s another hormonal pathway inhibitor. Even though it’s not my preferred choice, it’s something that patients sometimes do prefer, and we have to be mindful and respectful of that. But very interesting points.
Dr. Morris: It’s really hard in the radiopharmaceutical world to do a trial with a blinded control. It’s pretty easy to figure out if you’re radioactive or not. In most cities, you just have to walk over to a bridge, and if you’re stopped, you know what arm you’re on. If you could walk right over the bridge, then you’re pretty much all set. Plus every iPhone you could just buy on the internet has a counter to plug into it. It’s hard. I think a lot of us in the field have thought about how to do a control arm that is a sham injection of a radiopharmaceutical. It’s tough. It’s not easy to do.
Tanya, what were your impressions of the PSMAfore data?
Dr. Dorff: These were long-awaited data. There are definitely patients, as Rana was saying, who are just not chemotherapy candidates, and it’s been heartbreaking to not really be able to offer them this life-prolonging therapy. But I do have some concerns as we used this earlier. I’ll be very interested in the longer-term follow-up. Are we going to see any late toxicities in terms of the marrow or the renal function? Does it compromise subsequent use of chemotherapy? Sort of the same questions we asked about radium-223 when we were trying to figure out whether it was better to use it before or after chemotherapy. But I think in terms of the question about ARSI, I think people have been waiting for another option because you often have a patient who’s progressing, sometimes even radiographically but totally asymptomatically, who’s just not ready to jump into chemotherapy, and having a different option for them might reduce the use of that second ARSI as the default option.
Dr. Morris: I think that finding those life-prolonging options other than the ARSI switch is a really important thing. The more things that we find that are more effective than that switch, I think the better it is for patients. If the agency does approve Pluvicto in this space, you would have then docetaxel as an option. You would have Pluvicto as an option. There’s another trial that was recently published called the ARTO trial for oligometastatic progression in CRPC [castration-resistant prostate cancer] that raises the possibility that SBRT [stereotactic body radiation therapy] for those patients is an option. You have now like 3 good studies to show that you have alternatives to the ARSI switch for the patient that Evan was describing who might prefer to just keep taking pills. Some of those might get some SBRT, and they can continue to take their pills, and others might want the radiopharmaceutical, and others still who may have transforming disease in a much more aggressive phenotype then chemotherapy.