Future Directions in mCRPC: Novel Therapies and the Role of Radium, Radioligand Treatments

A roundtable discussion, moderated by Pedro Barata, MD, of University Hospitals, highlighted the evolving treatment landscape of advanced prostate cancer, including hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC). The panelists analyze expanding treatment intensity, the utilization of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs), and integrating patient-reported outcomes (PROs) in care. Dr. Barata was joined by Andrew Armstrong, MD, MSc, of Duke University School of Medicine; Cora Sternberg, MD, of Weill Cornell Medicine; and Evan Yu, MD, of UW Medicine.

In the final segment of our roundtable series, the panelists continue their discussion on the treatment of CRPC with a focus on metastatic disease. Novel therapies presented at ESMO 2024 are discussed, along with the potential of radium and radioligand treatments.

View the first segment of this roundtable series: Exploring Post-Salvage Treatment: Risk Stratification, Therapeutic Options for Non-Metastatic HSPC

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Dr. Barata:
We have been talking a lot about radioligand therapy for the last few years. You guys have been involved in a lot of the data coming out on that. So there is at least one trial showing the safety of radium followed by lutetium PSMA, right?

Do you envision a world where you actually have both available prechemotherapy, like PSMAfore, if lutetium or other agents gets approves? What are your thoughts about RLTs available in the mCRPC setting, or if a patient is progressing on ARPI; what can you tell us about it?

Dr. Yu:
Yeah, I think it’s not crazy to think about using both of them. I think the reason why I really like the PEACE III study is not just because there’s overall survival benefit and the hazard ratio for rPFS and OS was the same – 0.69; that’s pretty impressive OS data, right?

As medical oncologists, we love OS, I mean that is the gold standard for us.

We learned from the ALSYMPCA trial years ago that there’s survival benefit with radium, but we weren’t using it that much because it was hard to find a place to put it. Patients had symptoms, yet they couldn’t have visceral metastasis; people don’t like the fact that their PSA is rising.

We knew that there was benefit, it’s just hard to find the right patient and keep them on for six cycles. So the thing I like about PEACE III is, is that it’s in combination with enzalutamide upfront. It should drop the PSA in the vast majority of patients.

If you were to do it after abiraterone – at around a 30% response rate, so it kind of takes PSA out of the equation – it takes the needing of symptoms out of the equation and so and it gets you the opportunity to add another life-prolonging therapy in there earlier.

With this, as long as there aren’t major myelosuppression issues as we gather more data using alpha and beta or beta and alpha in different sequences, I could easily see the opportunity for all that to occur even before chemotherapy.

Again, if you had a really rapidly progressive patient, they’re just going to need chemotherapy, but it depends.

Dr. Sternberg:
I think there’s less myelosuppression with radium than there is with lutetium and actinium. That’s my experience and I haven’t used it for a long time now.

Dr. Armstrong:
With PSMA lutetium, when patients progress, it’s commonly in the bone; that is a site of progression. The use of radium after PSMA lutetium is active and can be done sequentially even with docetaxel sandwiched in between. There is registry data and safety data around those sequences.

Dr. Barata:
Very good point. So before we wrap this up, I’ll start with you Cora; what do we expect in the future?

You can walk us through and I’ll ask the same question to the three of you or feel free to chime in.

Dr. Sternberg:
I’m working with many different agents, but I think what’s important is that patients with metastatic disease have genetic testing and have next-generation sequencing. We need to know who is BRCA-positive and we need to know who could benefit from a PARP inhibitor. I think that that’s very important.

We also have PROTACs that are very interesting, and the MacroGenics molecule that’s very interesting. There are many new interesting molecules that are around the corner. We haven’t cured prostate cancer yet. I think we’ve improved overall survival, but we still have a bit of a way to go until we can say we’ve cured it.

Dr. Yu:
I think other immunotherapies and bispecific antibodies certainly look very promising, maybe even CAR T cells. I’m a little biased coming from Fred Hutch, but we do a lot of that work there.

If I may just make one big comment, it’s the fact that there are a lot of good targets and there are a lot of good targets that we’ve abandoned in the past. The reason we abandoned them is that we didn’t have good drugs.

So beyond PSMA right now, there’s B7-H3, PD-L2, and TROP2 is another great target right now along with STEEP1. There’s a lot of great targets. But the key thing I want to emphasize are the drugs and there’s a lot of ways to target them, whether it’s a bispecific, whether it’s a CAR T, or whether it’s an antibody drug conjugate.

I think a big deal in all of oncology has been that we’ve gotten better at designing drugs. Antibody drug conjugate design is so much more complex and important now. There’s a linker that keeps some chemotherapy payload – it seems simple, but it’s actually much more complex. You have the antibody internalization, you need to know the stability of the linker and what the antibody ratio is; there are so many different components, but we’re getting good at it.

I’m going to say that in five to ten years, we’re going to be using traditional chemotherapy a lot less, and I think treatment is going to come in the form of antibody drug conjugates.

Dr. Armstrong:
I like these points. I guess I’m going to divide it into two – the first is that I do think we’ll be seeing more cures in three to five years because we’re already seeing that with STAMPEDE.

AR is the still the best target, and when you intensify treatment on AR in early localized, high-risk disease, we see higher cure rates. So abiraterone for two years with ADT is a very simple strategy that was very successful. But we’ll also see the ENZARAD, DAZZLE, HiCaP, and ATLAS studies in the next two years.

The cure rates are going to be higher; it’s almost guaranteed, so that’s exciting for our patients. They’ll never make it to our conversations of CRPC management because they’re not going to get it.

My second point is – how do you think of CRPC, and the unfortunate patients that present with metastatic disease who go on to get that? There’s still AR as a major target. We’re presenting some data tomorrow on an AR degrader and I think that’s going to go into phase three.

AR is still really important, but we can’t forget what happens when the tumor forgets about AR and then goes down a different path. Neuroendocrine prostate cancer is probably 20% of cases who are dying of prostate cancer. That’s a really different disease and different strategy; it’s different radioligands.

So I think stay tuned for some new targets for a totally different disease like tarlatamab that was just approved in small cell lung cancer. We’d love to see that get approved in small cell prostate cancer, for example.